deamino-arginine-vasopressin and von-Willebrand-Diseases

Intranasal, subcutaneous, or intravenous desmopressin can be utilized to release von Willebrand Factor and Factor VIII into circulation, enhance platelet adhesion and shorten bleeding time. Due to these properties, desmopressin can be effective in controlling bleeding in mild hemophilia A, certain subtypes of von Willebrand disease and in acute bleeding from uremia, end stage renal disease, and liver disease. Its use, however, can be complicated by hyponatremia and rarely arterial thrombotic events. While desmopressin has also been used as a prophylactic blood sparing agent in orthopedic, renal, and hepatic procedures, clinical studies have shown limited benefit in these settings. The purpose of this article is to review the evidence for desmopressin in primary hematologic disorders, discuss its mechanism of action and evaluate its utility as a hemostatic and blood sparing product in various bleeding conditions.

Topics: Deamino Arginine Vasopressin; Hemorrhage; Hemostasis; Hemostatics; Humans; von Willebrand Diseases; von Willebrand Factor

von Willebrand Disease (VWD) is associated with significant morbidity because of excessive bleeding. Early diagnosis and treatment are important to prevent and treat these symptoms. We systematically reviewed the accuracy of any von Willebrand factor (VWF) activity assay in the diagnosis and classification of patients for VWD. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies. The risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 and the certainty of evidence using the GRADE framework. We pooled estimates of sensitivity and specificity. The review included 77 studies that evaluated the use of newer tests of VWF platelet binding activity (VWF:GPIbR, VWF:GPIbM) and VWF:RCo for the diagnosis of VWD (13 studies), VWF propeptide to VWF:Ag ratio, and desmopressin trial for the diagnosis of type 1C VWD (5 studies), VWF multimer analysis and VWF:CB/VWF:Ag ratio for the classification of type 2 VWD (11 studies), genetic testing and ristocetin-induced platelet aggregation to diagnose type 2B VWD (14 studies), genetic testing and FVIII:VWF binding to diagnose type 2N VWD (17 studies). Based on available diagnostic test accuracy, there appear to be comparable test accuracy results between newer tests of platelet binding activity of VWF function and VWF:RCo. The findings of these reviews support VWF multimer analysis or VWF:CB/VWF:Ag to diagnose type 2 VWD. The desmopressin trial test with 1- and 4-hour postinfusion blood work is the test of choice to confirm increased VWF clearance in patients with suspected VWD type 1C. Additionally, genetic testing is most useful in diagnosing type 2B VWD and has a role in the diagnostic algorithm of suspected type 2N VWD.

Topics: Blood Coagulation Tests; Deamino Arginine Vasopressin; Humans; von Willebrand Disease, Type 2; von Willebrand Diseases; von Willebrand Factor

Desmopressin (DDAVP) is a proven therapy for bleeding disorders; however, the therapeutic efficacy of different parenteral formulations has never been systematically analyzed. This study investigated whether subcutaneous (SC) DDAVP provides equivalent hemostatic efficacy to intravenous (IV) desmopressin, particularly in patients with mild to moderate bleeding tendencies from hemophilia A (HA) or von Willebrand disease (vWD).. We searched PubMed, EMBASE, MEDLINE, Cochrane, and CINAHL databases for observational studies and randomized controlled trials which compared the hemostatic efficacy of parenteral formulations of DDAVP in healthy patients and those with bleeding disorders. Two reviewers independently performed screening and data extraction. Extracted data included Factor VIII (FVIII) levels, von Willebrand factor (vWF) antigen levels, and vWF activity.. The search strategy yielded a total of 5519 studies. Twelve studies met the inclusion criteria and were included in the review. Seven out of eight studies conducted in patients with bleeding disorders and all four studies conducted in healthy subjects found no difference in hemostatic efficacy between parenteral formulations. A meta-analysis was not performed due to disparities between study design and outcomes of interest.. Our study showed that IV and SC administration of DDAVP appeared to result in near equivalent hemostatic efficacy; however, the strength of these findings is limited by the small number and lack of comparability in the primary studies. A sizable contemporary study powered to detect differences in coagulation factor levels would be required to confirm our findings.

Topics: Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Hemostatics; Humans; von Willebrand Diseases; von Willebrand Factor

Recent studies have documented increased bleeding symptoms and related complications in patients with low von Willebrand factor (VWF), highlighting the clinical significance of this entity. Because children and adolescents with VWF deficiencies often present to primary care physicians with bleeding symptoms, physicians need to be aware of this condition for early detection.. Studies have found that children and adolescents with low VWF (VWF levels of 30-50 IU/dL) can present with clinically significant bleeding, including mucosal, menstrual, postsurgical, and posttraumatic bleeding, leading to complications such as anemia, iron deficiency, transfusion, hospitalization, and poor quality of life. Detecting and promptly managing low VWF in children and adolescents with bleeding are essential because failure to do so can lead to significant morbidity in adulthood, especially among female patients, including continued heavy menstrual bleeding; postpartum hemorrhage; related gynecologic complications, such as hemorrhagic ovarian cysts; and surgical interventions for heavy menstrual bleeding, including hysterectomy. This narrative review summarizes the observations of several studies that have shed light on the pathophysiologic mechanisms of low VWF and bleeding in these patients and the available diagnostic modalities and treatment options.. Studies in children and adolescents have provided important insights into the clinical phenotype, complications, pathophysiologic mechanisms, evaluation, and management of low VWF, now recognized as an important clinicopathologic entity, as presented in this review. As gatekeepers, primary care physicians play an important role in guiding patients with this recently recognized clinicopathologic entity toward appropriate specialty care and providing continued comanagement to prevent future complications as the patients enter adulthood.

Topics: Adolescent; Child; Deamino Arginine Vasopressin; Female; Humans; Male; Physician's Role; Physicians, Primary Care; von Willebrand Diseases

von Willebrand disease (VWD) is the most common inherited bleeding disorder characterised by a quantitative or qualitative deficiency in von Willebrand factor (VWF). During invasive surgical procedures, patients with VWD require additional treatment to maintain haemostasis; however, due to the complexity of VWD, there is a lack of consensus on the optimal management. In the perioperative period, patients are usually treated with VWF and factor FVIII (FVIII)-containing concentrates to provide an immediate haemostatic response to prevent excessive bleeding during both elective and emergency surgery. With the introduction of recombinant VWF (rVWF), there is a need for guidance on the use of the various VWF products in the perioperative period for all types of patients and surgeries. This review provides an overview of the current evidence for the surgical management of patients with VWD and, summarises the optimal treatment approach during the perioperative period, and highlights key unanswered questions and the research needed to address the evidence gaps.

Topics: Biomarkers; Blood Coagulation; Clinical Decision-Making; Deamino Arginine Vasopressin; Disease Management; Disease Susceptibility; Humans; Perioperative Care; Severity of Illness Index; Thromboembolism; von Willebrand Diseases; von Willebrand Factor

Gastrointestinal (GI) bleeding is distinctive of severe von Willebrand disease (VWD), generally arising in older patients; in most cases, blood transfusion and hospitalization are required. The presence of arteriovenous malformations is often described when endoscopic examinations are performed. Patients with congenital type 3, 2A, and 2B are those most frequently affected by this symptom, possibly due to the loss of high-molecular-weight multimers of von Willebrand factor (VWF). GI bleeding can also occur in patients affected by acquired von Willebrand syndrome. Endoscopic examination of the GI tract is necessary to exclude ulcers and polyps or cancer as possible causes of GI bleeding. In congenital VWD, prophylaxis with VWF/factor VIII concentrates is generally started after GI-bleeding events, but this therapy is not always successful. Iron supplementation must be prescribed to avoid chronic iron deficiency. Possible rescue therapies (high-dose statins, octreotide, thalidomide, lenalidomide, and tamoxifen) were described in a few case reports and series; however, surgery may be necessary in emergency situations or if medical treatment fails to stop bleeding. In this article, we present several clinical cases that highlight the clinical challenges of these patients and possible strategies for their long-term management.

Topics: Adult; Aged; Aged, 80 and over; Blood Transfusion; Deamino Arginine Vasopressin; Drug Combinations; Factor VIII; Female; Gastrointestinal Hemorrhage; Humans; Male; Middle Aged; Prognosis; von Willebrand Diseases; von Willebrand Factor

The deficiency or abnormal activity of von Willebrand factor, a multi-adhesive protein which binds platelets to exposed subendothelium and carries factor VIII in circulation, is responsible for von Willebrand disease, the most frequent inherited bleeding disorder. Clinical symptoms are characterized by mucous membrane and soft tissue bleeding, bleeding after surgery and rarely joint and gastrointestinal bleeding. Intriguingly, also factor VIII, the protein deficient in hemophilia A, may be variably reduced because VWF stabilizes it into circulation. Treatment strategies are well designed for patients with levels of VWF activity <30 U/dL, while the diagnosis and the magnitude of risk may be difficult to be assessed accurately for subjects with levels between 30 and 50 U/dL. Three types of the disorder have been identified according to partial (type 1) or severe VWF quantitative deficiency (type 3) while patients who present variable abnormality of VWF structure are categorized as type 2. The aim of treatment is to correct either the abnormal/reduced von Willebrand factor and the associated deficiency of factor VIII, when present. Desmopressin is able to transiently correct the deficiency of FVIII and VWF for up to 8-12 h in a significant proportion of patients with type 1 von Willebrand disease and factor VIII and von Willebrand factor levels ≥10 U/dL. When desmopressin is not usual (mainly in patients with type 2 and 3 VWD) or correction is required cannot be used for an extended time (e.g., major surgery), von Willebrand factor-containing concentrates, with or without FVIII, must be used.

Topics: Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Hemorrhage; Humans; von Willebrand Disease, Type 1; von Willebrand Diseases; von Willebrand Factor

The goal of treating Von Willebrand Disease (VWD) is to replace deficient or dysfunctional Von Willebrand Factor (VWF) protein. However, the choice of treatment has to be considered carefully in view of patient factors and the unique properties of replacement products. Tailoring a treatment plan to an individual patient's bleeding challenge is an intricate process. This review describes personalization of treatment selection for desmopressin (DDAVP), VWF replacement concentrates, including the newly available recombinant VWF (rVWF) and prophylaxis as a treatment approach in VWD.

Topics: Deamino Arginine Vasopressin; Hemorrhage; Humans; Precision Medicine; von Willebrand Diseases; von Willebrand Factor

The management of von Willebrand disease (VWD) is based upon the dual correction of the primary hemostasis defect, due to the inherited deficiency of von Willebrand factor (VWF), and of the secondary defect of factor VIII coagulant activity (FVIII:C), due to the loss of binding and stabilization by VWF of this intrinsic coagulation factor in flowing blood. The traditional therapeutic weapons (the synthetic derivative of the antidiuretic hormone desmopressin and plasma-derived VWF/FVIII concentrates) are able to transiently correct both the defects. With the goal of tackling the primary deficiency in the disease, that is, VWF, but at the same time exploiting the normal capacity of patients to produce FVIII, the novel approach of replacing only VWF was implemented in the last 10 years. Following the manufacturing of a concentrate fractionated from human plasma and of one obtained by recombinant DNA technology, clinical studies have shown that VWF-only products correct not only the primary VWF deficiency but also the secondary FVIII:C deficiency. The demonstrated efficacy of these products in various clinical situations and, ultimately, in such a hemostasis-challenging context as surgery testifies to the effectiveness and safety of this approach. It remains to be seen whether VWF-only products are efficacious and safe in still-unexplored situations, such as use in children; the long-term use for prophylaxis; and in recurrent gastrointestinal (GI) bleeding due to angiodysplasia, a major therapeutic problem in VWD.

Topics: Aged; Deamino Arginine Vasopressin; Factor VIII; Female; Gastrointestinal Hemorrhage; Humans; von Willebrand Diseases; von Willebrand Factor

von Willebrand disease (VWD) is one of the most common inherited bleeding disorders. Since its first description in 1926, the diagnosis and management of VWD has significantly improved due to increasing scientific knowledge of the genetics and biology of von Willebrand factor (VWF). This article reviews the molecular structure and function of VWF as well as the clinical symptoms, laboratory-based diagnostic workup, and classification schema for VWD. It highlights current treatment options and state-of-the art research in VWF and VWD.

Topics: Blood Coagulation Factors; Deamino Arginine Vasopressin; Hemostatics; Humans; von Willebrand Diseases

Topics: Deamino Arginine Vasopressin; Gastrointestinal Hemorrhage; Hemostatics; Humans; Reference Standards; von Willebrand Diseases; von Willebrand Factor

Inherited bleeding disorders increase the risk of bleeding in the obstetric patient. Randomized controlled trials to compare prophylactic or therapeutic interventions are rare, and guidance documents rely heavily on expert opinion. Here we report the results of a systematic review of the literature for the treatment and prevention of peripartum bleeding in women with an inherited bleeding disorder. The highest-quality evidence is for the use of tranexamic acid in postpartum hemorrhage, which has been shown to decrease bleeding-related mortality in women without bleeding disorders. There is limited evidence for prophylactic use of this agent in women with inherited bleeding disorders. Desmopressin has also been used in observational studies of patients with von Willebrand disease and carriers of hemophilia A with some success, although concerns about the risk of hyponatremia persist. In patients with deficiencies of specific factors, replacement is generally the preferred approach, and concentrates have been studied in deficiencies of VWF and factors VII, VIII, IX, XI, and XIII as well as in patients with fibrinogen deficiency. Because of the small size of these studies, neither safety nor efficacy is well established, although the literature suggests that bleeding history may be more predictive of outcomes than factor levels in many cases. Goal factor levels have not been studied or systematically established in any of these diseases, although observational data suggest that achieving normal levels may be inadequate, particularly for VWF and factor VIII, which are physiologically elevated in pregnancy. For factor deficiencies in which no specific concentrate is available, such as factors II (prothrombin) and V, prothrombin complex concentrate or fresh frozen plasma may be used, and for platelet defects or deficiencies, such as Glanzmann thrombasthenia or Bernard-Soulier syndrome, platelet transfusion is generally first line, although use of recombinant FVIIa has been reported in patients with Glanzmann thrombasthenia to avoid development of, or treat patients with, antibodies to platelet glycoprotein IIbIIIa. Ultimately, data are lacking to definitively support an evidence-based approach to management in any of these disorders, and prospective, controlled studies are desperately needed.

Topics: Blood Coagulation; Deamino Arginine Vasopressin; Female; Fibrinolytic Agents; Hematology; Hemophilia A; Heterozygote; Humans; Hyponatremia; Obstetrics; Postpartum Hemorrhage; Pregnancy; Pregnancy Complications, Hematologic; Tranexamic Acid; Treatment Outcome; von Willebrand Diseases

The mechanisms involved in regulating von Willebrand factor (VWF) clearance remain poorly understood. However recent studies have shown that macrophages play a critical role in regulating the half-life of VWF, and have identified specific lectin (including asialoglycoprotein, macrophage galactose-type lectin, Sigec-5 and C-type lectin domain family 4 member M) and scavenger receptors (including low-density lipoprotein receptor-related protein-1, scavenger receptor A1 and stabilin-2) that are involved in VWF clearance. Further studies will be required to determine the relative importance of these individual receptors with respect to physiological and pathological VWF clearance. Nevertheless, recent clinical data have highlighted the importance of enhanced VWF clearance in the pathogenesis of type 1 von Willebrand disease (VWD). Moreover, increased clearance also contributes to reduced VWF levels in many patients with type 2 and type 3 VWD. Improved understanding regarding VWF clearance is not only of direct biological relevance, but may also have important implications for the development of novel therapeutic agents with extended plasma half-lives for the treatment of both VWD and haemophilia A.

Topics: Deamino Arginine Vasopressin; Hemostatics; Humans; Mutation; Receptors, Mitogen; Receptors, Scavenger; Structure-Activity Relationship; von Willebrand Diseases; von Willebrand Factor

Von Willebrand disease (VWD) is the most common inherited bleeding disorder with an estimated prevalence of ~1% and clinically relevant bleeding symptoms in approximately 1:10,000 individuals. VWD is caused by a deficiency and/or defect of von Willebrand factor (VWF). The most common symptoms are mucocutaneous bleeding, hematomas, and bleeding after trauma or surgery. For decades, treatment to prevent or treat bleeding has consisted of desmopressin in milder cases and of replacement therapy with plasma-derived concentrates containing VWF and Factor VIII (FVIII) in more severe cases. Both are usually combined with supportive therapy, e.g. antifibrinolytic agents, and maximal hemostatic measures. Several developments such as the first recombinant VWF concentrate, which has been recently licensed for VWD, will make a more "personalized" approach to VWD management possible. As research on new treatment strategies for established therapies, such as population pharmacokinetic-guided dosing of clotting factor concentrates, and novel treatment modalities such as aptamers and gene therapy are ongoing, it is likely that the horizon to tailor therapy to the individual patients' needs will be extended, thus, further improving the already high standard of care in VWD in most high-resource countries.

Topics: Antifibrinolytic Agents; Aptamers, Nucleotide; Deamino Arginine Vasopressin; Factor VIII; Genetic Therapy; Hemorrhage; Hemostatic Techniques; Humans; Interleukin-11; von Willebrand Diseases; von Willebrand Factor

Von Willebrand Disease (VWD) is the most common human inherited bleeding disorder due to a defect of Von Willebrand Factor (VWF), which a glycoprotein crucial for platelet adhesion to the subendothelium after vascular injury. VWD include quantitative defects of VWF, either partial (type 1 with VWF levels < 50 IU/dL) or virtually total (type 3 with undetectable VWF levels) and also qualitative defects of VWF (type 2 variants with discrepant antigenic and functional VWF levels). The most bleeding forms of VWD usually do not concern type 1 patients with the mildest VWF defects (VWF levels between 30 and 50IU/dL). Von willebrand factor is a complex multimeric protein with two functions: it forms a bridge between the platelets and areas of vascular damage and it binds to and stabilizes factor VIII, which is necessary for the clotting cascade. By taking a clinical history of bleeding (mucocutaneous bleeding symptoms suggestive of a primary haemostatic disorder, a quantitative or qualitative abnormality of VWF is possible) it is important to think about VWD and to make the appropriate diagnosis. If the VWD is suspected diagnostic tests should include an activated partial thromboplastin time, bleeding time, factor VIII: C Ristocetin cofactor and vWF antigen. Additional testing of ristocetin induced plattlet adhesion (RIPA) the multimeric structure and collagen binding test and genanalysis allow diagnosing the different types of von. Willebrand Disease. The treatment of choice in mild forms is the synthetic agent desmopressin. In patients with severe type 1, type 2B, 2N and type 3 or in people who do not response to desmopressin, the appropriate treatment is a factor VIII concentrate that is rich of VWF. We report a case of infant in 27-month-old boy who had been referred due to haemorrhagic shock. His birth histories, his familie's social history and developmental milestones were unremarkable. He was born at full term with no antenatal or perinatal complications. Prior to the symptoms, the child was on a normal diet and was thriving appropriately. The child presented one days before his admission trauma to the inner face of the lower lip that caused an external acute bleeding loss. The laboratory data showed unfortunately, the most severe form of Von Willebrand's Disease; Type 3. The management was based on erythrocyte and fresh-frozen plasma (FFP) transfusions with administration of factor VII with good evolution.

Topics: Child, Preschool; Deamino Arginine Vasopressin; Erythrocyte Transfusion; Factor VIII; Hemorrhage; Humans; Male; Partial Thromboplastin Time; Plasma; Severity of Illness Index; von Willebrand Diseases; von Willebrand Factor

von Willebrand factor (VWF) is an adhesive plasma protein that primarily acts to bridge platelets to sites of vascular injury and thus prevent bleeding. von Willebrand disease (VWD) is the most common inherited bleeding disorder and is caused by deficiency and/or defects of VWF, leading to low levels of plasma VWF or dysfunctional VWF. Factor VIII (FVIII) is also reduced in many patients with VWD, since VWF stabilizes and protects FVIII from degradation. Treatment of VWD primarily entails replacement of VWF, and sometimes FVIII, to protect against bleeding. This may entail use of VWF/FVIII concentrates, and/or desmopressin (1-deamino-8-d-arginine vasopressin) to release endogenous VWF in some patients. Adjunct therapies include antifibrinolytics and hormonal therapies in women. Optimal treatment of VWD entails measuring the effects of treatment, either as a trial before surgery or during therapeutic management. This is usually accomplished by performance of the same tests that are used to help diagnose VWD, although additional monitoring (clinically and/or by laboratory testing) may also be performed. The current review provides an overview of the treatment of VWD but is primarily focused on the monitoring of such therapy.

Topics: Coagulants; Deamino Arginine Vasopressin; Drug Combinations; Drug Monitoring; Factor VIII; Female; Hemostatics; Humans; Menorrhagia; Treatment Outcome; von Willebrand Diseases; von Willebrand Factor

Von Willebrand disease (VWD) is the most common genetic bleeding disorder. VWD is caused by a deficiency or dysfunction of von Willebrand factor (VWF), a plasma protein that mediates the initial adhesion of platelets at sites of vascular injury and binds and stabilises coagulation factor VIII (FVIII) in the blood. Prophylaxis of surgical bleeding in patients with VWD requires consideration of the individual situation, including the type of procedure and the bleeding rate, before decisions about treatment type, dose, duration and adjunctive therapy with antifibrinolytics or antithrombotic prophylaxis can be made. Although desmopressin (DDAVP)-stimulated release of endogenous VWD is an effective treatment strategy in many patients, plasma concentrates containing VWF are the preferred option for most patients undergoing surgical procedures. Recommendations for the management of surgery in patients with VWD are summarised, including the severity of VWD and the type of the surgical procedure.

Topics: Clinical Decision-Making; Deamino Arginine Vasopressin; Disease Management; Factor VIII; Hemorrhage; Humans; Premedication; Surgical Procedures, Operative; Thrombosis; Treatment Outcome; von Willebrand Diseases; von Willebrand Factor

von Willebrand disease (VWD) is the most common congenital bleeding disorder. In women, menorrhagia is the most common bleeding symptom, and is disabling with iron deficiency anaemia, high health cost and poor quality of life. Current hormonal and non-hormonal therapies are limited by ineffectiveness and intolerance. Few data exist regarding von Willebrand factor (VWF), typically prescribed when other treatments fail. The lack of effective therapy for menorrhagia remains the greatest unmet healthcare need in women with VWD. Better therapies are needed to treat women with menorrhagia.. We conducted a survey of US haemophilia treatment centres (HTCs) and a literature review using medical subject heading (MeSH) search terms 'von Willebrand factor,' 'menorrhagia' and 'von Willebrand disease' to assess the use of VWF in menorrhagia. Analysis was by descriptive statistics.. Of 83 surveys distributed to HTC MDs, 20 (24.1%) provided sufficient data for analysis. Of 1321 women with VWD seen during 2011-2014, 816 (61.8%) had menorrhagia, for which combined oral contraceptives, tranexamic acid and desmopressin were the most common first-line therapies for menorrhagia, whereas VWF was third-line therapy reported in 13 women (1.6%). Together with data from 88 women from six published studies, VWF safely reduced menorrhagia in 101 women at a dose of 33-100 IU kg(-1) on day 1-6 of menstrual cycle.. This represents the largest VWD menorrhagia treatment experience to date. VWF safely and effectively reduces menorrhagia in women with VWD. A prospective clinical trial is planned to confirm these findings.

Topics: Antifibrinolytic Agents; Contraceptives, Oral; Databases, Factual; Deamino Arginine Vasopressin; Female; Humans; Menorrhagia; Tranexamic Acid; von Willebrand Diseases; von Willebrand Factor

Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPN) comprise a heterogeneous group of chronic hematologic malignancies. The quality of life, morbidity, and mortality of patients with MPN are primarily affected by disease-related symptoms, thromboembolic and hemorrhagic complications, and progression to myelofibrosis and acute leukemia. Major bleeding represents a common and important complication in MPN, and the incidence of such bleeding events will become even more relevant in the future due to the increasing disease prevalence and survival of MPN patients. This review discusses the causes, differential diagnoses, prevention, and management of bleeding episodes in patients with MPN, aiming at defining updated standards of care in these often challenging situations.

Topics: Anticoagulants; Antineoplastic Agents; Blood Coagulation Factors; Blood Loss, Surgical; Blood Transfusion; Blood Vessels; Clinical Trials as Topic; Contraindications; Deamino Arginine Vasopressin; Disease Management; Elective Surgical Procedures; Hemorrhage; Hemostatic Techniques; Humans; Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative; Liver; Multicenter Studies as Topic; Myeloproliferative Disorders; Platelet Aggregation Inhibitors; Platelet Function Tests; Platelet Transfusion; Postoperative Hemorrhage; Thrombophilia; Tranexamic Acid; von Willebrand Diseases; von Willebrand Factor

The State of the Art in von Willebrand disease (VWD) has been impacted not only by discoveries in the field of haemostasis, but also by changes in practice in other fields. The development of bleeding assessment tools has led to the clarification of bleeding symptoms and phenotype in VWD. New discoveries in the biology and genetics of von Willebrand factor (VWF) are challenging our existing diagnostics and classification(s). An improved understanding of reproductive physiology and the pathology of VWD along with changing obstetric, gynaecologic and haemostatic therapies necessitate an evolving response to the care of women with VWD. The survival of patients with autoimmune disease, malignancies and congenital heart disease along with increasing use of circulatory support devices and extracorporeal membrane oxygenation is increasing the prevalence of acquired von Willebrand syndrome. In each of these challenges, there are opportunities to improve the care of our patients with VWD.

Topics: Antibodies, Neutralizing; Deamino Arginine Vasopressin; Factor VIIa; Female; Humans; Male; Polymorphism, Genetic; Postpartum Hemorrhage; Pregnancy; Recombinant Proteins; von Willebrand Diseases; von Willebrand Factor

Von Willebrand disease (VWD) is the most common autosomally inherited bleeding disorder, characterized by a quantitative or qualitative defect of the multimeric adhesive glycoprotein von Willebrand factor (VWF). The mainstay of treatment of bleeding in VWD involves the use of desmopressin and plasma-derived factor VIII (FVIII)-VWF concentrates. In addition, a new recombinant VWF has been recently manufactured and licensed in the USA.. This narrative review, after a brief presentation of the current therapeutic strategies in VWD, will focus on recombinant VWF, analyzing its characteristics and the results of the completed phase I and III trials. Finally, the potential role of this recombinant drug in the therapeutic scenario of VWD is discussed. Expert commentary: Based on the evidence from literature analysis, we can conclude that recombinant VWF is a novel, interesting therapeutic option for VWD, which could help to further personalize the management of this complex inherited bleeding disorder.

Topics: Clinical Trials as Topic; Deamino Arginine Vasopressin; Factor VIII; Humans; Recombinant Proteins; Treatment Outcome; von Willebrand Diseases; von Willebrand Factor

von Willebrand disease (VWD) is a common, inherited bleeding disorder. There are three main types of VWD, which result in a quantitative or qualitative deficiency in von Willebrand factor (VWF) and in severe cases, also Factor VIII (FVIII). The severity of bleeding depends on the underlying pathophysiology. Type 1 VWD is usually mild, while types 2 or 3 VWD can be associated with moderate or significant bleeding. Managing pregnant women with VWD requires a multidisciplinary approach. Such patients are at increased risk of postpartum hemorrhage. Whether women with VWD are at increased risk of spontaneous abortion remains unclear. Because of increased risk of bleeding, there are special considerations for delivery and obstetrical analgesia. There is a lack of high-quality evidence supporting monitoring and treatment of VWD in pregnancy. Most experts recommend that FVIII and VWF levels be monitored prior to delivery and treatment initiated when levels remain below 0.50 IU/mL. Some experts consider desmopressin (DDAVP) to be the preferred initial treatment in type 1 and most type 2 VWD. DDAVP is relatively contraindicated in type 2B disease. Plasma-derived FVIII and VWF replacements are the treatment of choice in type 2B and 3 VWD and in type 1 or 2 VWD when patients do not respond to DDAVP.

Topics: Deamino Arginine Vasopressin; Factor VIII; Female; Humans; Postpartum Hemorrhage; Pregnancy; Pregnancy Complications, Hematologic; Risk Factors; von Willebrand Diseases; von Willebrand Factor

von Willebrand disease (VWD) is the commonest inherited bleeding disorder and results from either a quantitative or qualitative deficiency in the plasma glycoprotein von Willebrand factor (VWF). Recent large cohort studies have significantly enhanced our understanding of the molecular mechanisms involved in the pathogenesis of VWD. In contrast, however, there have been relatively few advances in the therapeutic options available for the treatment of bleeding in patients with VWD. Established treatment options include tranexamic acid, 1-deamino-8-d-arginine vasopressin (DDAVP), and plasma-derived VWF concentrates. In addition, a recombinant VWF has also recently been developed. In this review, we focus on how recent insights into the clinical and molecular aspects underpinning VWD are already beginning to influence treatment in the clinic. For example, a number of different bleeding assessment tools (BATs) have been developed to objectively assess bleeding symptoms in patients with VWD. Interestingly, however, these BAT scores may also have an important role to play in predicting bleeding risk in VWD. Furthermore, recent studies have demonstrated that enhanced VWF clearance plays a critical role in the etiology of both type 1 and type 2 VWD. These findings have direct translational relevance with respect to the use of DDAVP in patients with VWD. As understanding of the mechanisms involved in VWD pathogenesis continues to advance, novel treatment options are likely to emerge. Critically, however, large adequately powered and stratified clinical trials will be required to address the outstanding questions that remain regarding VWD treatment optimization.

Topics: Deamino Arginine Vasopressin; Hemorrhage; Humans; Tranexamic Acid; von Willebrand Diseases; von Willebrand Factor

Topics: Age Factors; Algorithms; Deamino Arginine Vasopressin; Female; Hemorrhage; Humans; Male; Menorrhagia; von Willebrand Diseases; von Willebrand Factor

von Willebrand disease (VWD) is caused by quantitative or qualitative defects in von Willebrand factor (VWF). The mainstay of therapy is desmopressin, which is, however, not useful in certain forms of VWD notwithstanding adverse events. For these patients, plasma-derived factor VIII (pdFVIII)/VWF concentrates have been available for close to three decades but have a theoretical risk of disease transmission, hypersensitivity/allergic reactions, inhibitors and thrombosis. A recombinant VWF (vonicog alfa, Vonvendi™; manufactured by Baxalta, now part of Shire) was approved by the U.S. Food and Drug Administration (FDA) in December 2015. This review will survey the literature based on a MEDLINE review on the safety, efficacy and pharmacokinetics of Vonvendi. It will also summarize the ongoing studies on Vonvendi available in the public domain. Vonvendi may have an important role in the management of VWD. However, more studies are needed, especially in special populations such as surgical patients, patients with major gastrointestinal bleeding from arteriovenous malformations and pregnant women and children, who are most likely to benefit from it.

Topics: Child; Deamino Arginine Vasopressin; Female; Humans; Pregnancy; Recombinant Proteins; von Willebrand Diseases; von Willebrand Factor

Treatment of mucosal bleeding (epistaxis, gastrointestinal bleeding, and menorrhagia) and joint bleeding remains problematic in clinically severe von Willebrand disease (VWD). Patients are often unresponsive to treatment (e.g. desmopressin or antifibrinolytic therapy) and may require von Willebrand factor (VWF) replacement therapy. There are little data on the use of prophylaxis in VWD, and none have been applied in a prospective, treatment escalation design.. Evaluate the effect of escalating dose prophylaxis in severe VWD.. Patients eligible for enrollment in this prospective study included those with type 1 VWD with VW factor activity-ristocetin cofactor ratio ≤ 20% and unresponsive to desmopressin, patients with type 2 VWD not responsive to desmopressin and all subjects with type 2B and type 3 VWD. Entry criteria were strictly defined, as were therapy escalation parameters and clinical data collection.. Eleven subjects completed the study. Six had type 2A, and five had type 3 VWD. Six patients presented with epistaxis, three with GI bleeding, and two with joint bleeding. Seven had dose escalation above the first level. Among the 10 subjects with evaluable bleeding log data, use of prophylaxis decreased the median annualized bleeding rate from 25 to 6.1 (95% confidence interval of the rate difference: -51.6 to -1.7), and the median annualized bleeding rate was even lower (4.0; 95% confidence interval: -57.5 to -5.3) when the subjects reached their final dosing level.. This is the first prospective study to demonstrate that prophylaxis with VW factor concentrates is highly effective in reducing mucosal and joint bleeding rates in clinically severe VWD.

Topics: Blood Loss, Surgical; Blood Transfusion; Clinical Trials as Topic; Deamino Arginine Vasopressin; Drug Administration Schedule; Factor VIII; Female; Hemarthrosis; Hemorrhage; Hospitalization; Humans; Male; Menorrhagia; Multicenter Studies as Topic; Postoperative Hemorrhage; Prospective Studies; Recombinant Proteins; Retrospective Studies; von Willebrand Diseases; von Willebrand Factor

Topics: Child; Deamino Arginine Vasopressin; Hemorrhage; Hemostatics; Humans; von Willebrand Diseases

The article represents a review of recent data about the therapy of von Willebrand disease in children and adolescents (hereditary as well as acquired forms of the disease). The treatment of bleeding events in these patients, the indications in different subtypes, and the future lines of research are mentioned.

Topics: Adolescent; Blood Loss, Surgical; Child; Deamino Arginine Vasopressin; Disease Progression; Factor VIII; Hemorrhage; Humans; Immunosuppressive Agents; Platelet Adhesiveness; Prognosis; von Willebrand Diseases; von Willebrand Factor

von Willebrand disease (VWD) is the most common autosomally inherited bleeding disorder. The disease represents a range of quantitative and qualitative pathologies of the adhesive glycoprotein von Willebrand factor (VWF). The pathogenic mechanisms responsible for the type 2 qualitative variants of VWF are now well characterized, with most mutations representing missense substitutions influencing VWF multimer structure and interactions with platelet GPIbα and collagen and with factor VIII. The molecular pathology of type 3 VWD has been similarly well characterized, with an array of different mutation types producing either a null phenotype or the production of VWF that is not secreted. In contrast, the pathogenetic mechanisms responsible for type 1 VWD remain only partially resolved. In the hemostasis laboratory, the measurement of VWF:Ag and VWF:RCo are key components in the diagnostic algorithm for VWD, although the introduction of direct GPIbα-binding assays may become the functional assay of choice. Molecular genetic testing can provide additional benefit, but its utility is currently limited to type 2 and 3 VWD. The treatment of bleeding in VWD involves the use of desmopressin and plasma-derived VWF concentrates and a variety of adjunctive agents. Finally, a new recombinant VWF concentrate has just completed clinical trial evaluation and has demonstrated excellent hemostatic efficacy and safety.

Topics: Blood Coagulation Tests; Deamino Arginine Vasopressin; Factor VIII; Genetic Testing; Humans; Mutation; Recombinant Proteins; von Willebrand Diseases; von Willebrand Factor

Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) has been used in children with von Willebrand disease (VWD) and Hemophilia A for almost 35 years. This treatment has substantially lowered the number of children exposed to human plasma derived products, with a good safety profile, and at very low cost. The response to DDAVP has been shown to be associated with age, baseline factor level, and genetic mutations. A DDAVP challenge test is recommended. DDAVP has also been used to prevent and treat bleeding episodes in children with platelet function defects and other disorders associated with bleeding tendency.

Topics: Blood Coagulation Disorders, Inherited; Blood Platelets; Child; Child, Preschool; Deamino Arginine Vasopressin; Hemophilia A; Hemostasis; Humans; Platelet Function Tests; von Willebrand Diseases

During the past 25 years, our knowledge concerning the pathogenesis, diagnostic strategies, and treatment of von Willebrand disease (VWD) has increased significantly. Following the immunological differentiation of factor VIII (FVIII) and von Willebrand factor (VWF) in the 1970s and the cloning of the FVIII and VWF genes in the mid-1980s, substantial progress has been made in our understanding of this, the most common inherited bleeding disorder. We now recognize that VWD represents a range of genetic diseases all with the clinical endpoint of increased mucocutaneous bleeding. The molecular pathology of Type 2 and 3 VWD is now comprehensively documented and involves rare sequence variants at the VWF locus. In contrast, the genetic causation of Type 1 disease remains incompletely defined and in many cases appears to involve genetic determinants in addition to or instead of VWF. The diagnostic triad of a personal history of excessive mucocutaneous bleeding, laboratory tests for VWF that are consistent with VWD, and a family history of the condition remain the keystone to VWD identification. In the laboratory, measurement of VWF antigen and function continue to be the most important diagnostic studies, and while our understanding of the molecular genetic pathology of VWD has advanced considerably in the past decade, genetic testing as a component of diagnosis is limited to certain distinct subtypes of the disorder. Treatment of VWD has been relatively unchanged for the past decade and continues to involve either stimulation of the release of intrinsic VWF with desmopressin or the infusion of VWF concentrates.

Topics: Cloning, Molecular; Deamino Arginine Vasopressin; Factor VIII; Genetic Testing; Hemorrhage; Hemostatics; Humans; von Willebrand Diseases; von Willebrand Factor

von Willebrand disease (VWD) is the most common inherited bleeding disorder and arises from deficiencies and/or defects in the plasma protein von Willebrand factor (VWF). VWD is classified into 6 different types, with type 1 identified as a (partial) quantitative deficiency of VWF, type 3 defined by a (virtual) total deficiency of VWF, and type 2 identifying four separate types (2A, 2B, 2M, 2N) characterised by qualitative defects. The classification is based on phenotypic assays including FVIII, VWF:Ag and VWF activity, typically by ristocetin cofactor (VWF:RCo), but also increasingly by collagen binding (VWF:CB). Phenotypic testing may be supplemented by multimer analysis, RIPA, and VWF:FVIII binding. Although genetic analysis is not required to diagnose VWD or to define a classification type, it may be useful in discrete situations. The current review briefly covers this diagnostic process, with a focus on newer approaches, including extended test panels and the use of data from desmopressin challenges as a diagnostic tool.

Topics: Blood Coagulation Tests; Deamino Arginine Vasopressin; Diagnostic Errors; Humans; Phenotype; von Willebrand Diseases; von Willebrand Factor

The population of elderly patients with von Willebrand Disease (VWD) is growing because of the improvement of medical care. The increase in comorbidities and their treatment as well as standard preventive measures like antiplatelet or anticoagulation therapy constitutes a challenge in the overall treatment of patients with coagulation disorders. Because of the lack of literature on older patients with VWD, we discuss different aspects related to ageing in those patients. Plasma levels of von Willebrand factor and factor VIII, bleeding symptoms, treatment requirements and comorbidities are possibly changing with age. Development of an evidence-based approach to the management of ageing VWD patients is therefore necessary.

Topics: Aged; Aging; Deamino Arginine Vasopressin; Factor VIII; Hemostasis; Humans; Thromboembolism; von Willebrand Diseases; von Willebrand Factor; Waterhouse-Friderichsen Syndrome

The acquired von Willebrand syndrome (AVWS) is a bleeding disorder that is frequently unrecognized or is misdiagnosed as von Willebrand disease. AVWS is characterized by structural or functional defects of von Willebrand factor (VWF) that are secondary to autoimmune, lymphoproliferative or myeloproliferative, malignant, cardiovascular, or other disorders. VWF abnormalities in these disorders can result from (1) antibody-mediated clearance or functional interference, (2) adsorption to surfaces of transformed cells or platelets, or (3) increased shear stress and subsequent proteolysis. Diagnosis can be challenging as no single test is usually sufficient to prove or exclude AVWS. Furthermore, there are no evidence-based guidelines for management. Treatments of the underlying medical condition, including chemo/radiotherapy, surgery, or immunosuppressants can result in remission of AVWS, but is not always feasible and successful. Because of the heterogeneous mechanisms of AVWS, more than one therapeutic approach is often required to treat acute bleeds and for prophylaxis during invasive procedures; the treatment options include, but are not limited to, desmopressin, VWF-containing concentrates, intravenous immunoglobulin, plasmapheresis or recombinant factor VIIa. Here, we review the management of AVWS with an overview on the currently available evidence and additional considerations for typical treatment situations.

Topics: Animals; Deamino Arginine Vasopressin; Factor VIIa; Hematologic Diseases; Hemostatics; Humans; Immunoglobulins, Intravenous; Plasmapheresis; Recombinant Proteins; Syndrome; von Willebrand Diseases; von Willebrand Factor

In the Netherlands, specialized care for patients with a bleeding disorder, including hemophilia, von Willebrand disease (VWD), and allied disorders, is concentrated in 13 Hemophilia Treatment Centers. The Dutch Hemophilia Treaters Society, the Dutch Hemophilia Nurses' Society, and the Netherlands Hemophilia Patients Society collaborate to optimize management of patients with a bleeding disorder. A recently updated consensus guideline of hemophilia and allied bleeding disorders provide guidance on the current optimal diagnostic strategy and treatment of VWD. Genetic testing is not routinely performed in the Netherlands. Desmopressin (DDAVP) is the choice of treatment in VWD patients responsive to DDAVP, as determined by a test infusion. Coagulation factor concentrates are used in nonresponsive individuals, in case of a contraindication for DDAVP, or in type 2B and type 3 VWD. These concentrates are available for all patients in the Netherlands; however, these may only be administered in a Hemophilia Treatment Center or under the care of a Hemophilia Treatment Center. Recently a study on moderate and severe VWD (the Willebrand in Netherlands study) was initiated to obtain more insight on VWD diagnosis, treatment, and the burden of the disease.

Topics: Blood Coagulation Disorders; Coagulants; Deamino Arginine Vasopressin; Genetic Testing; Geography; Hemostatics; Humans; Netherlands; von Willebrand Diseases; von Willebrand Factor

The UK treatment strategy for von Willebrand disease (VWD) is based on consensus guidelines produced by the United Kingdom Haemophilia Centre Doctors' Organization (UKHCDO) relating to the diagnosis and management of VWD. Selection of therapeutic products suitable for treatment of this complex inherited bleeding disorder is based on the observed response. Desmopressin (DDAVP), an analog of vasopressin, is the recommended treatment in individuals who respond to this drug on trial infusion. DDAVP clearly has no effect in type 3 VWD but may have variable clinical effect in individuals with other subtypes or may be contraindicated in some cases. In patients where DDAVP treatment is unsuitable, replacement factor concentrate containing von Willebrand factor (VWF) is the recommended alternative. Relevant concentrates are available for all patients in the United Kingdom, and treatment is administered by a network of 67 hemophilia treatment centers that also provide specialist care for individuals diagnosed with VWD. Patients diagnosed with the condition are registered on a national inherited bleeding disorder database administered by the UKHCDO on behalf of the Department of Health to aid in service planning and commissioning. Genetic testing is employed in the United Kingdom in certain situations, which is also performed in accordance with current UKHCDO guidelines.

Topics: Coagulants; Deamino Arginine Vasopressin; Guideline Adherence; Humans; Practice Guidelines as Topic; United Kingdom; von Willebrand Diseases; von Willebrand Factor

In Canada, care for individuals with inherited bleeding disorders, including Von Willebrand disease, is provided by 26 tertiary care multidisciplinary Inherited Bleeding Disorders clinics geographically spread across the country. The Association of Hemophilia Clinic Directors of Canada, the Canadian Association of Nurses in Hemophilia Care, the Canadian Physiotherapists in Hemophilia Care, the Canadian Social Workers in Hemophilia Care, and the Canadian Hemophilia Society all collaborate to provide optimal management for patients with inherited bleeding disorders. The standards of care for these patients were explicitly laid out in a 2007 document published by the Canadian Hemophilia Standards Group (with representation from all of the groups just mentioned) entitled Canadian Comprehensive Care Standards for Hemophilia and Other Inherited Bleeding Disorders. Separate Canadian guidelines for the management of patients with Hemophilia and Von Willebrand disease also exist, focused on diagnosis, comprehensive care, assessment, and treatment.

Topics: Canada; Comprehensive Health Care; Deamino Arginine Vasopressin; Factor VIII; Genetic Testing; Hemorrhagic Disorders; Hemostatics; Humans; Practice Guidelines as Topic; von Willebrand Diseases; von Willebrand Factor

Von Willebrand disease (VWD) is the most common inherited bleeding disorder and arises from deficiencies and/or defects in the plasma protein Von Willebrand factor (VWF). VWD is classified into six different types, with type 1 identifying a (partial) quantitative deficiency of VWF, type 3 defining a (virtual) total deficiency of VWF, and type 2 identifying four separate types (2A, 2B, 2M, and 2N) characterized by qualitative defects. The classification is based on phenotypic assays including factor VIII coagulant, VWF antigen, and VWF activity, primarily by ristocetin cofactor and collagen binding, as supplemented by additional testing. In Australia, >30 pathology-based laboratories perform VWD testing, and tests and test panels reflect a wide variety of practice. In our own referral laboratory, diagnosis is a staged process reflecting a combination of clinical and laboratory findings with a large panel of tests. We also use data from desmopressin trials to assist in VWD type assignment. The current report presents an overview of the VWD diagnostic process as applied within Australia, includes summary data from the Australian Bleeding Disorders Registry, and provides specific details of the diagnostic and management practice undertaken in our reference laboratory, which also maintains a local bleeding disorders database. This database currently contains 4070 entries, including 1832 suspected or confirmed cases of VWD. Excluding 311 as yet unclassified cases, 1254 cases (82.4%) would define (potential) quantitative deficiencies of VWF ("low VWF" or type 1 VWD), 241 (15.8%) qualitative defects (type 2 VWD), and 23 (1.5%) type 3 VWD. Most of the quantitative defects reflect only mild loss of VWF, and <15% of total cases would be identified to have VWF levels <35 U/dL. Most cases of type 2 remain unclassified (34.9%) because available data are limited. Type 2A and 2M VWD represent the most common qualitative defects, representing 22.8% and 22.2% of defined type 2 VWD cases. Type 2B and 2N reflect 8.3% and 12.9%, respectively, of type 2 VWD cases.

Topics: Australia; Clinical Laboratory Techniques; Deamino Arginine Vasopressin; Factor VIII; Genetic Testing; Humans; Mutation; von Willebrand Diseases; von Willebrand Factor

New Zealand is a small country of two islands and 4 million people, of which 1 million reside in the South Island. Canterbury Health Laboratories provides laboratory services to the whole of South Island and lower parts of North Island. There are 155 Von Willebrand disease (VWD) patients in our South Island database, of which 17 have type 2 and 3 have type 3 VWD. A brief overview of diagnostic services for VWD being followed in our region is detailed in this article. We strive continually to advance the repertoire of diagnostic tests. We also present an analysis of our experience with a flow-based functional Von Willebrand factor assay. The VWD patients are managed by hemostasis team members, who also provide screening and educational input to affected families. The Haemophilia Foundation of New Zealand is an active patient support group providing education and support both directed individually and in the group setting, through residential educational camps.

Topics: Clinical Laboratory Techniques; Deamino Arginine Vasopressin; Genetic Testing; Hemostatics; Humans; Mutation; New Zealand; von Willebrand Diseases; von Willebrand Factor

Special challenges exist in the management of patients with von Willebrand disease (VWD) because of limitations in diagnostic facilities and therapeutic options. However, even within these limitations, it is possible to establish comprehensive services for this condition. Our data show that among 202 patients with VWD, 107 were type 3, 62 were type 1, and the others different categories of type 2. Basic tests such as bleeding time and activated partial thromboplastin time with factor (F)VIII coagulant are able to diagnose most of those with severe disease. We have been able to adapt the specific tests such as von Willebrand factor (VWF) ristocetin cofactor and VWF antigen from the tedious batched manual methods to cost-effective automated methods on advanced coagulometers. Discriminatory tests such as VWF collagen binding, VWF:FVIIIB, ristocetin-induced platelet agglutination (RIPA) are done in batches. Therapeutic options and for the treatment of bleeding include desmopressin, cryoprecipitate, and intermediate purity VWF-containing clotting factor concentrates. Tranexamic acid is also widely used as well as hormonal therapy for menorrhagia. We have also shown that modest doses of intermediate purity FVIII (Koate DVI; Talecris Biotherapeutics, Raleigh, NC, USA) at 35 IU/kg preoperatively and 10 to 20 IU/kg after that are sufficient for surgical hemostasis in these patients.

Topics: Clinical Laboratory Techniques; Coagulants; Deamino Arginine Vasopressin; Developing Countries; Factor VIII; Humans; Tranexamic Acid; von Willebrand Diseases; von Willebrand Factor

Von Willebrand disease (VWD) is caused by a deficiency or dysfunction of Von Willebrand factor (VWF). The pathophysiology, classification, diagnosis, and management of VWD are relatively complex, but their understanding is important for proper diagnosis and management of patients with VWD. There are inherent difficulties in both the identification and classification of VWD because of clinical uncertainty and the limitations in the test processes and test panels typically used by laboratories. The most common test panel employed by laboratories, particularly in the geographic regions covered by the mutational studies, would comprise factor VIII coagulant (FVIII:C), VWF protein (antigen; VWF:Ag), and ristocetin cofactor (VWF:RCo). In our center, use of a desmopressin challenge with our core four-test panel (i.e., VWF:Ag, VWF:RCo, FVIII:C, and PFA-100) is expected to further assist laboratory diagnosis of VWD in Turkey. Molecular genetics is a rather new approach for Turkey, with gene analyses related to VWD being initiated in one center and the results used for confirmation of diagnosis in limited cases.

Topics: Clinical Laboratory Techniques; Coagulants; Deamino Arginine Vasopressin; Factor VIII; Humans; Turkey; von Willebrand Diseases; von Willebrand Factor

Little information is available on von Willebrand disease (VWD) in Iran. More than 900 patients with VWD are registered, but the real number of patients with VWD is likely to be larger. Fifteen hemophilia treatment centers in addition to 31 other academic centers are the main sites for the clinical management and treatment of VWD in Iran. All centers are staffed by specialists in the medical care of VWD. Epistaxis and menorrhagia are the most frequent clinical manifestations in Iranian patients with VWD. Von Willebrand factor/factor VIII concentrates, desmopressin, cryoprecipitates, and tranexamic acid are the main medications used routinely in Iranian patients, and they are administered based on the type of disease, the severity of bleeding, and sometimes for the prevention of bleeding during surgical procedures or delivery. It is hoped that the recent creation of a national registry for coagulation disorders and improvements in laboratory techniques will improve the diagnosis, national patients' registry, and management of VWD in Iranian patients and lead to gains in their quality of life in the near future.

Topics: Antifibrinolytic Agents; Deamino Arginine Vasopressin; Factor VIII; Hemostatics; Humans; Iran; von Willebrand Diseases; von Willebrand Factor

von Willebrand disease (VWD) is a bleeding disorder characterized by quantitative or qualitative defects in von Willebrand factor (VWF), a multimeric glycoprotein that is essential for platelet-dependent primary hemostasis. High molecular-weight multimers of VWF circulate and bind to collagen and platelets to induce primary hemostasis. The activity of VWF and its eventual proteolytic degradation are dependent on shear stress, ensuring that, under normal conditions, VWF is active in a high shear stress environment only. Deficiency in VWF results in mucocutaneous bleeding, including epistaxis, menorrhagia, and excessive bleeding after trauma or surgery. Classification of VWD is based on the combined results of multiple laboratory tests related to VWF amount and activity as well as the relative amounts of large VWF multimers as determined by gel electrophoresis. Recently, specific mutations in the gene encoding VWF have been linked to characteristic multimer profiles and may aid in subtyping patients with VWD and predicting response to therapy. These genotype-phenotype correlations are improving our understanding of the pathophysiology of VWD and helping to provide a more accurate diagnosis and classification with important treatment-related implications.

Topics: Deamino Arginine Vasopressin; Genetic Association Studies; Humans; von Willebrand Diseases; von Willebrand Factor

Von Willebrand's disease is an inherited bleeding disorder with a prevalence as high as 1% in the general population. The disease is caused by the quantitative deficiency or dysfunction of von Willebrand factor (VWF), a large multimeric glycoprotein. VWF has two main functions in hemostasis: it is essential for platelet-plug formation as an adhesion protein and it forms a non-covalent complex with coagulation factor VIII in plasma, thereby protecting it from inactivation and clearance. Inherited Von Willebrand's disease has been subdivided into 3 categories that reflect pathophysiology: partial quantitative deficiency of VWF (Type 1), qualitative deficiency (Type 2) and total deficiency (Type 3). The major clinical hallmark in Von Willebrand's disease is an increased tendency to mucocutaneous bleeding. Increased bleeding may also occur in sites such as muscles and joints when the level of factor VIII is particularly low. The mainstays of therapy are desmopressin, which induces secretion of autologous factor VIII and VWF into plasma, and plasma concentrates, which supply allogenic forms of these moieties. Other forms of treatment can be considered as adjunctive to these.

Topics: Bleeding Time; Cross-Sectional Studies; Deamino Arginine Vasopressin; Factor VIII; Female; Genetic Carrier Screening; Genotype; Germany; Hemostatics; Humans; Male; von Willebrand Diseases; von Willebrand Factor

Many patients with mild inherited bleeding disorders such as von Willebrand disease (VWD), mild haemophilia A (HA) and platelet function defects (PFD) undergo adenoidectomy and/or tonsillectomy (AT) procedures each year. Management of bleeding in these patients can be challenging, as little published data exist to guide haemostatic management during these relatively common procedures. Therefore, the literature was reviewed to identify AT procedures in patients with 1-deamino-8-D-argine vasopressin responsive mild bleeding disorders. The review revealed no randomized prospective trials of haemostatic management in this patient population. Case reports and small case series identified 144 patients who had AT procedures. Frequency of desmopressin and antifibrinolytic dosing varied widely. Fifteen percentage of patients experienced postoperative bleeding with nearly half being early (<24 h) bleeding and half being late (>24 h) bleeding. Hyponatraemia complicated the procedures in 47% of cases and six hyponatremic seizures were reported. Issues identified by this review that need to be addressed in future clinical trials include type and amount of fluid restriction when utilizing desmopressin, duration of antifibrinolytic therapy and duration and frequency of desmopressin dosing.

Topics: Adenoidectomy; Adolescent; Adult; Antifibrinolytic Agents; Child; Child, Preschool; Deamino Arginine Vasopressin; Hemophilia A; Hemostatics; Humans; Hyponatremia; Middle Aged; Postoperative Hemorrhage; Tonsillectomy; von Willebrand Diseases; Young Adult

von Willebrand disease is caused by either a quantitative or qualitative defect in von Willebrand factor (VWF). Patients may have extensive mucosal bleeding (because of platelet dysfunction) and prolonged bleeding after surgery (because of factor VIII deficiency). Up to 6 different subtypes of the disease have been described, and diagnosis is based on clinical suspicion and laboratory confirmation. Accurate diagnosis is of paramount importance because therapy will vary according to the subtype. Bleeding complications during pregnancy are more frequent when levels of the von Willebrand ristocetin cofactor assay and factor VIII levels are <50 IU/dL. In such cases, therapy before any invasive procedure or delivery must be instituted. The mainstays of therapy are desmopressin and plasma concentrates that contain von Willebrand factor. Delayed postpartum hemorrhage may occur, despite adequate prophylaxis. Frequent monitoring and continued prophylaxis and/or treatment are recommended for at least 2 weeks after delivery.

Topics: Blood Component Transfusion; Chromosomes, Human, Pair 12; Continuity of Patient Care; Deamino Arginine Vasopressin; Delivery, Obstetric; Factor VIII; Female; Hemostatics; Humans; Mutation; Postpartum Hemorrhage; Postpartum Period; Pregnancy; Pregnancy Complications, Hematologic; Ristocetin; Uterine Hemorrhage; von Willebrand Diseases; von Willebrand Factor

von Willebrand factor (VWF) is a large multimeric adhesive glycoprotein with complex roles in thrombosis and hemostasis. Abnormalities in VWF give rise to a variety of bleeding complications, known as von Willebrand disease (VWD), the most common inherited bleeding disorder in humans. Current treatment of VWD is based on the replacement of the deficient or dysfunctional protein either by endogenous release from endothelial Weibel-Palade bodies or by administration of plasma-derived VWF concentrates. During the last years, several efforts have been made to optimize existing therapies for VWD, but also to devise new approaches, such as inducing endogenous expression with interleukin-11, administering exogenous recombinant VWF, or introducing the protein via gene delivery. Clearly, the efficacy of any strategy will depend on several factors, including, for example, the quantity, activity, and stability of the delivered VWF. The inherent complexity of VWF biosynthesis, which involves extensive posttranslational processing, may be limiting in terms of producing active VWF outside of its native cellular sources. This review summarizes recent progress in the development of different treatment strategies for VWD, including those that are established and those that are at the experimental stage. Potential pitfalls and benefits of each strategy are discussed.

Topics: Deamino Arginine Vasopressin; Genetic Therapy; Humans; Interleukin-11; von Willebrand Diseases; von Willebrand Factor

Recent multicenter studies have clarified the molecular basis underlying the different von Willebrand disease (VWD) types, all of which are caused by the deficiency and/or abnormality of von Willebrand factor (VWF). These studies have suggested a unifying pathophysiologic concept. The diagnosis of VWD, remains difficult because its clinical and laboratory phenotype is very heterogeneous and may overlap with normal subjects. Stringent criteria are therefore required for a clinically useful diagnosis. In this paper, we delineate a practical approach to the diagnosis and treatment of VWD. Our approach is based on the critical importance of a standardized bleeding history that has been condensed into a final bleeding score and a few widely available laboratory tests, such as VWF ristocetin cofactor activity, VWF antigen and factor VIII. This approach would help identify those subjects who will probably benefit from a diagnosis of VWD. The next step involves performing a trial infusion with desmopressin in all patients who fail to exhibit an enhanced responsiveness to ristocetin. On the basis of these results and through a series of illustrative examples, the clinician will be able to select the best approach for the optimal management of VWD, according to the patient's characteristics and clinical circumstances.

Topics: Adolescent; Adult; Deamino Arginine Vasopressin; Female; Hemorrhage; Hemostatics; Humans; Male; Middle Aged; Multicenter Studies as Topic; Ristocetin; von Willebrand Diseases; von Willebrand Factor

A complete set of laboratory investigations, including bleeding time, PFA-100 closure times, factor VIII (FVIII) coagulant activity (FVIII:C), von Willebrand factor (VWF) ristocetin cofactor (VWF:RCo), collagen binding (VWF:CB), antigen (VWF:Ag) and propeptide (VWFpp), ristocetin-induced platelet aggregation (RIPA), multimeric analysis of VWF and the response of FVIII:C and VWF parameters to desmopressin (DDAVP), is necessary to fully diagnose all variants of von Willebrand disease (VWD) and to discriminate between type 1 and type 2 and between severe VWD type 1 and type 3. The response to DDAVP of VWF parameters is normal in pseudo VWD (mild VWF deficiency due to blood group O), in mild VWD type 1 and in carriers of recessive severe VWD type 1 and 3. The response to DDAVP is rather good but restricted followed by increased clearance in dominant type 1/2E, good but transient in mild type 2A group II, good for VWF:CB, with only poor response for VWF:RCo in 2M and 2U, poor in 2A group I, 2B, 2C and 2D, and very poor or non-responsive in severe recessive VWD type 1 and 3. Homozygosity or double heterozygosity for nonsense (null) mutations in the VWF gene result in recessive VWD type 3. The combination of a nonsense and missense mutation or of two missense mutations (homozygous or double heterozygous) may cause recessive severe VWD type 1. Recessive VWD type 2A subtype IIC (2C) is caused by homozygous or double heterozygous gene defects in the D1-D2 domain. Homozygosity or double heterozygosity for a FVIII binding defect of the VWF is the cause of recessive VWD type 2N (Normandy) characterized by low FVIII:C, mild or moderate VWF deficiency and normal VWF multimers. Dominant VWD type 1/2E is a mixed quantitative and qualitative multimerization defect caused by a heterozygous cysteine mutation in the D3 domain resulting in abnormal multimerization with a secretion and clearance defect of VWF not due to increased proteolysis. Dominant VWD type 1 Vicenza is a qualitative defect with normal secretion but rapid clearance with equally low levels of FVIII:C, VWF:Ag, VWF:RCo, VWF:CB and the presence of unusually large VWF multimers in plasma due to a specific mutation (R1205H) in the D3 domain. Dominant VWD type 2M and 2U are caused by loss-of-function mutations in the A1 domain resulting in quantitative/qualitative deficiencies with a selectively decreased platelet-dependent function with decreased VWF:RCo but normal VWF:CB, a relative decrease in large VWF multimer

Topics: Bleeding Time; Codon, Nonsense; Deamino Arginine Vasopressin; Genes, Dominant; Genes, Recessive; Genotype; Humans; Models, Molecular; Mutation, Missense; Platelet Aggregation; Protein Structure, Quaternary; Protein Structure, Tertiary; Ristocetin; von Willebrand Diseases; von Willebrand Factor

Mild type 1 von Willebrand disease (VWD) is characterized by low to variable penetrance of bleeding, a high (increased) prevalence of blood group O, von Willebrand factor (VWF) values around and above 30% with normal ratios of VWF:ristocetin cofactor activity (RCo)/VWF:antigen (Ag), VWF:collagen binding (CB)/VWF:Ag and factor VIII (FVIII):coagulant activity (C)/VWF:Ag. Within this group of patients, the combination of the C1584 mutation and blood group O is rather frequent. Patients with mild VWD type 1 present good/normal responses of FVIII:C and VWF parameters to desmopressin (DDAVP). With the exclusion of dominant VWD type Vicenza, type 1/2E, recessive 2N and dominant 2M, missense mutations in patients with mild VWD type 1 with normal multimers are mainly located in the regulatory sequence region, the D1/D2 propeptide region, the D' VWF-FVIII binding site region and the D4, B1-B3 and C1-C2 domains but rarely in the D3, A1 or A2 domain. A new category of either dominant or recessive mild VWD type 1 due to mutations in the D4, B1-B3 and C1-C2 domains of the VWF gene consists of two groups: one group with mild VWD with normal VWF multimers and a second group with mild/moderate VWD with smeary multimer pattern.

Topics: ABO Blood-Group System; Bleeding Time; Codon, Nonsense; Deamino Arginine Vasopressin; Dose-Response Relationship, Drug; Genes, Dominant; Genes, Recessive; Genotype; Humans; Models, Molecular; Mutation, Missense; Platelet Aggregation; Protein Structure, Quaternary; Protein Structure, Tertiary; Ristocetin; von Willebrand Diseases; von Willebrand Factor

This concise review is focused on genetic, molecular and clinical aspects of von Willebrand disease (VWD) type 2N and of mild hemophilia A due to mutations impairing FVIII-von Willebrand factor (VWF) interactions. Missense mutations in the VWF gene impairing the binding to FVIII do not impair the structure of VWF multimers nor the ability of VWF to aggregate platelets but causes an accelerated clearance of FVIII. Missense mutations in the FVIII gene impairing the binding to VWF are a common cause of mild/moderate hemophilia A. The implications of these observations for the treatment of patients with coagulation factor concentrates and desmopressin are discussed.

Topics: Binding Sites; Deamino Arginine Vasopressin; Endothelial Cells; Factor VIII; Genes, Recessive; Hemophilia A; Humans; Lung; Metabolic Clearance Rate; Mutation, Missense; Point Mutation; Protein Binding; Protein Interaction Mapping; Protein Structure, Tertiary; Protein Transport; von Willebrand Diseases; von Willebrand Factor

For a long time, autosomal recessive inheritance has been considered a unique feature of type 3 von Willebrand disease (VWD), which is characterized by the virtual absence of von Willebrand factor (VWF) in plasma and storage compartments. In recent years, it has been demonstrated that this type of inheritance is also present in some type 1 and 2 families, previously considered the epitome of true dominant transmission. In many patients of these families with recessive VWD, molecular basis studies have provided insights into the molecular mechanisms responsible for the heterogeneity of phenotypes. We report our experience with 12 families with clearly recessive inheritance, but definitely measurable factor VIII and VWF, which is not typical for severe type 3 VWD.

Topics: Blood Protein Electrophoresis; Child; Child, Preschool; Codon, Nonsense; Deamino Arginine Vasopressin; Factor VIII; Female; Gene Frequency; Genes, Recessive; Genetic Heterogeneity; Genotype; Humans; Infant; Introns; Male; Mutation, Missense; Phenotype; Point Mutation; Protein Structure, Quaternary; Protein Structure, Tertiary; Retrospective Studies; RNA Splice Sites; von Willebrand Diseases; von Willebrand Factor

The detection of even tiny amounts of von Willebrand factor (VWF):antigen after desmopressin treatment or in hidden sites like platelets allows the differentiation between patients with recessive von Willebrand disease (VWD) type 3, severe type 1, and 2C (2A subtype IIC). Recessive VWD 2C of various severity displays a characteristic multimeric pattern with pronounced dimer band, absence of triplet structure and lack of large multimers not due to increased proteolysis. Recessive VWD type 2C (2A subtype IIC) is caused by homozygosity or double heterozygosity of missense mutations in the D1 and D2 domains of the VWF propeptide (pp) that catalyzes the multimerization in the D3 domain at the N terminus of mature VWF. In expression studies of recombinant mutant VWF, secretion of VWF mainly consisted of dimers which failed to form intermediate- and high-molecular-weight multimers consistent with the clinical diagnosis of VWD 2C (2A subtype IIC). Carriers of a heterozygous missense mutation in the VWFpp region (D1-D2 domain) of the VWF gene may present mild VWD type 1 and show a typical multimeric pattern with a heavy predominance of VWF dimers.

Topics: Adult; Blood Protein Electrophoresis; Child; Deamino Arginine Vasopressin; Dimerization; Female; Genes, Recessive; Genotype; Humans; Male; Molecular Weight; Mutagenesis, Insertional; Mutation, Missense; Pedigree; Point Mutation; Protein Structure, Quaternary; Protein Structure, Tertiary; Recombinant Fusion Proteins; Sequence Deletion; von Willebrand Diseases; von Willebrand Factor

Missense mutations in the von Willebrand factor (VWF) gene impairing the binding to factor VIII (FVIII) do not impair the structure of VWF multimers nor the ability of VWF to aggregate platelets but causes an accelerated clearance of FVIII. Recessive VWD type Normandy (N) encompasses all patients with a deficiency in FVIII:coagulant activity (C) caused by a markedly decreased affinity of VWF for FVIII:C due to a FVIII binding defect in VWF but with normal or near normal VWF:antigen (Ag), VWF:ristocetin cofactor activity (RCo) and VWF:collagen binding (CB) levels, normal VWF:RCo/VWF:Ag ratio, normal VWF multimeric pattern and normal VWF-dependent platelet functions including ristocetin-induced platelet aggregation and bleeding time (BT) consistent with VWD type 1. The response to 1-deamino-8-D-arginine vasopressin (DDAVP) of VWF parameters is usually normal, but the degree of restricted response curves to DDAVP of FVIII:C depends on the severity of the FVIII binding defect to the mutated VWF. The homozygous mutations R816W and R854W are typically associated with severe and mild VWD 1/N, respectively. Homozygous or heterozygous/null mutations of C788, D879N or C1225G do not only dramatically decrease FVIII binding, but also induce a multimerization and secretion defect with a decrease in the large VWF multimers, lack of triplet structure and prolonged BT consistent with severe VWD 2E/N. The missense mutations Y795C and R763G either heterozygous or as a component of recessive VWD (double heterozygous) are responsible for the FVIII binding defect (VWD 1/N) and abnormal banding of VWF multimers leading to the presence of a smeary pattern with the presence of ultralarge VWF multimers.

Topics: Bleeding Time; Blood Protein Electrophoresis; Codon, Nonsense; Deamino Arginine Vasopressin; Exons; Factor VIII; Female; Genes, Recessive; Genotype; Hemophilia A; Humans; Male; Mutation, Missense; Pedigree; Platelet Aggregation; Point Mutation; Protein Binding; Protein Interaction Mapping; Protein Structure, Quaternary; Protein Structure, Tertiary; von Willebrand Diseases; von Willebrand Factor

Autosomal dominant von Willebrand disease (VWD) type 1/2E is a quantitative/qualitative defect in the von Willebrand factor (VWF) caused by heterozygous cysteine and non-cysteine mutations in the D3 domain of the VWF gene and results in a secretion-multimerization-clearance defect in mutant VWF with the loss of large VWF multimers not due to proteolysis. The multimers of patients with dominant VWD type 1/2E due to mutations in the D3 domain show an aberrant triplet structure with lack of outer bands but with pronounced inner bands of the triplet structure combined with a relative decrease in large multimers reflecting heterozygosity for multimerization defects. There is a good response to desmopressin (DDAVP) followed by rapid clearance of VWF:antigen (Ag), factor VIII coagulant activity (FVIII:C) and VWF:ristocetin cofactor activity (RCo) as the main cause of VWD type 1 or 2 with typical 2E multimeric pattern (VWD type 1/2E). Cysteine mutations in the D3 domains (C1130, C1149 and C1190) show pronounced features of VWD 1/2E with the relative loss of large and relative increase in small VWF multimers with abnormal triplet structure in heterozygotes. Such abnormalities are less pronounced in patients with a milder form of VWD type 1 due to non-cysteine mutations W1144G, T1156M and W1120S in the D3 domain. VWD type 1 Vicenza is caused by the R1205H mutation in the D3 domain and characterized by equally low levels of FVIII:C, VWF:Ag and VWF:RCo. The response to DDAVP in VWD Vicenza is good for FVIII:C, VWF:Ag and VWF:RCo, which is followed by a rapid clearance in less than a few hours of FVIII:C and VWF parameters. The ratios for FVIII:C/VWF:Ag, VWF:RCo/Ag and VWF:CB/Ag remain normal before and after DDAVP indicating that VWD Vicenza clearly differs from VWD type 1, 1/2E and 2M. A new set of missense mutations in D4, B1-B3 and C1-C2 domains has been discovered as the cause of a mild VWD type 1 secretion defect with normal VWF multimers or smeary VWF multimeric pattern. Cysteine mutations in exons 38, 40, 42 and 43 (D4, B1-B3 and C1 domain), show smeary patterns (either smf or sm), with the presence of large VWF multimers and a laboratory phenotype of mild VWD type 1 with variable penetrance of bleeding manifestations. Recent studies showed that the ratio of VWF propeptide (pp) to VWF:Ag can be used to predict a shorter than normal half-life for VWF:Ag. There is a strong inverse correlation between rapid clearance of VWF:Ag after DDAVP and increased VWFpp/Ag r

Topics: Bleeding Time; Deamino Arginine Vasopressin; Diagnosis, Differential; Female; Genes, Dominant; Genotype; Hemorrhage; Humans; Male; Models, Molecular; Mutation, Missense; Pedigree; Penetrance; Phenotype; Point Mutation; Protein Precursors; Protein Processing, Post-Translational; Protein Structure, Quaternary; Protein Structure, Tertiary; von Willebrand Diseases; von Willebrand Factor

A complete set of laboratory investigations, including bleeding time, PFA-100 closure time, factor VIII coagulant activity (FVIII:C), von Willebrand factor (VWF) ristocetin cofactor activity (RCo), collagen binding (CB) and antigen concentration (Ag), ristocetin-induced platelet aggregation (RIPA) and multimeric analysis of VWF in low and medium SDS-agarose resolution gels, is warranted to diagnose and classify all variants of von Willebrand disease (VWD). VWD type 2M and 2U are typically characterized by decreased RIPA and a poor response of VWF:RCo to desmopressin (DDAVP), but normal VWF:CB and good responses of VWF:CB, VWF:Ag and FVIII:C to DDAVP. VWF multimeric analysis in patients with VWD 2M and 2U show relative decreases in large VWF multimers with less resolved triplet structure of each of the multimeric bands in low-, medium- or high-resolution gels. VWD type 2M or 2U are caused by a loss-of-function mutation in the A1 domain. The laboratory manifestations and molecular defects in the A1 domain causing VWD type 2M and 2U are clearly distinct from all variants of type 1 VWD and also from all other variants [VWD type 2A, 2B, 2E (IIE) and 2C (IIC)].

Topics: Bleeding Time; Blood Protein Electrophoresis; Collagen; Deamino Arginine Vasopressin; Dose-Response Relationship, Drug; Exons; Genes, Dominant; Genotype; Humans; Models, Molecular; Molecular Weight; Mutation, Missense; Platelet Aggregation; Protein Structure, Quaternary; Protein Structure, Tertiary; Ristocetin; von Willebrand Diseases; von Willebrand Factor

Pertinent findings in patients with von Willebrand disease (VWD) type 2A include prolonged bleeding time (BT), consistently low von Willebrand factor (VWF):ristocetin cofactor activity (RCo)/antigen concentration (Ag) and VWF:collagen binding (CB)/Ag ratios, absence of high, and (depending on severity) intermediate and large VWF multimers, the presence of pronounced triplet structure of individual bands and increased VWF degradation products due to increased proteolysis caused by mutations in the A2 domain of VWF. Two categories of VWD type 2A can be distinguished: group I with severe and group II with mild VWD. A minority of VWD type 2A have mild VWD characterized by near normal to prolonged BT, normal factor VIII coagulant activity and VWF:Ag, low VWF:RCo and VWF:CB, a normal ristocetin-induced platelet aggregation and complete but transient correction of BT and functional VWF parameters to normal levels for only a few hours due to short half-lives for VWF:RCo and CWF:CB. Such transient complete responses to desmopressin (DDAVP) lasting only a few hours may facilitate treatment and prophylaxis of minor bleedings, but may not be able to prevent bleeding during minor and major surgery. Most VWD type 2A patients have pronounced VWD with very low VWF:RCo, prolonged BT, PFA-100 closure times >250 s, and response to DDAVP is only transient, minor, poor or absent, with no correction of the BT despite some increase in VWF:RCo, thus being candidates for factor VIII-VWF concentrate substitution for the acute and prophylactic treatment of bleeding symptoms.

Topics: ADAM Proteins; ADAMTS13 Protein; Adult; Aged; Bleeding Time; Blood Protein Electrophoresis; Collagen; Deamino Arginine Vasopressin; Exons; Female; Hemorrhage; Humans; Male; Middle Aged; Molecular Weight; Mutation, Missense; Platelet Aggregation; Pregnancy; Pregnancy Complications, Hematologic; Protein Structure, Quaternary; Protein Structure, Tertiary; von Willebrand Diseases; von Willebrand Factor

Guidelines and recommendations for the acute and prophylactic treatment of bleeding in von Willebrand disease (VWD) patients with von Willebrand factor (VWF)/factor VIII (FVIII) concentrates should be based on the analysis of the content of VWF/FVIII concentrates and on pharmacokinetic studies in patients with different severity of VWD (type 1, type 2 or type 3). The VW/FVIII concentrates should be assessed using the parameters FVIII:coagulant activity (C), VWF:ristocetin cofactor activity (RCo), VWF:collagen binding and VWF multimeric patterns for the presence of large multimers to determine their predicted efficacy and safety in prospective management studies. As the bleeding tendency is moderate in VWD type 2 and severe in type 3 and because the FVIII:C levels are subnormal in type 2 but very low in type 3 VWD patients, new guidelines using VWF:RCo unit dosing for the acute and prophylactic treatment of bleeding episodes are proposed. Such guidelines should be stratified for the severity of bleeding, the type of surgery (minor or major) and also for the bleeding score in either VWD type 1, 2 or 3.

Topics: Bleeding Time; Blood Loss, Surgical; Collagen; Deamino Arginine Vasopressin; Drug Combinations; Drug Therapy, Combination; Factor VIII; Genotype; Humans; Intraoperative Care; Platelet Aggregation; Postoperative Hemorrhage; Practice Guidelines as Topic; Preanesthetic Medication; Prospective Studies; Protein Structure, Quaternary; Ristocetin; von Willebrand Diseases; von Willebrand Factor

Acquired von Willebrand disease (aVWD) occurs in association with a variety of underlying disorders, most frequently in lymphoproliferative and myeloproliferative disorders, other malignancies, and cardiovascular disease. aVWD is a complex and heterogeneous defect with a multifactorial etiology and the pathophysiologic mechanisms remain unclear in many cases. Assays for anti-factor VIII (FVIII)/von Willebrand factor (VWF) activities often yield negative results although antibodies may be present in autoimmune disease and some lymphoproliferative disorders. Functional assays of VWF in patients' plasma and particularly in heart valve disease, VWF multimer analysis are important for aVWD diagnosis. In patients with normal partial thromboplastin times and normal VWF activity, the diagnosis of aVWD is based on clinical suspicion and a careful bleeding history, which should prompt the clinician to initiate further laboratory investigations. Management of bleeding in aVWD relies mainly on desmopressin, FVIII/VWF concentrates and high-dose intravenous immunoglobulin. The half-life of VWF may be very short, and in bleeding episodes high doses of FVIII/VWF concentrates at short intervals may be necessary even when high-dose intravenous immunoglobulin was applied before. Since the optimal treatment strategy has not yet been defined for aVWD of different etiology, controlled multicenter trials aiming at the development of standardized treatment protocols are urgently needed.

Topics: Antibody Specificity; Autoantibodies; Autoantigens; Autoimmune Diseases; Deamino Arginine Vasopressin; Heart Diseases; Hemorrhage; Humans; Immunoglobulin G; Immunoglobulin M; Immunoglobulins, Intravenous; Immunosuppressive Agents; Lymphoproliferative Disorders; Neoplasms; von Willebrand Diseases; von Willebrand Factor

Von Willebrand disease (VWD) is characterized by a wide heterogeneity of clinical and laboratory phenotypes. The complexity of the phenotype is further increased by a highly variable removal rate of von Willebrand factor (VWF) released by desmopressin, which is independent of post-infusion peak level. After the initial demonstration that a reduced VWF survival is present in patients with R1205H mutation (VWD Vicenza), several other mutations, mostly occurring in the VWF D3 domain, have been shown to be associated with accelerated removal of released VWF. Normal subjects with O blood group show reduced survival after desmopressin, underlining the role of different VWF glycosylation present in ABO blood group. Recent evidence suggests that liver and spleen macrophages are responsible for VWF clearance through uptake and endocellular degradation, but it is still not known why some VWF mutants are more prone to increased clearance.

Topics: ABO Blood-Group System; Deamino Arginine Vasopressin; Humans; Mutation; von Willebrand Diseases; von Willebrand Factor

Therapy for von Willebrand disease (VWD) aims to restore the hemostatic function conferred by von Willebrand factor (VWF), which facilitates platelet adhesion and aggregation, and serves to increase potentially low coagulation factor VIII (FVIII) in plasma. In patients unresponsive to desmopressin (DDAVP), the preferred treatment is with plasma-derived VWF-containing FVIII concentrates. Only a few of the available VWF/FVIII concentrates have been licensed for use in VWD based on prospective studies. The efficacy of VWF/FVIII concentrates depends on the content and quality of VWF and FVIII. Several studies have demonstrated the variability of the VWF contents, as well as the differences in the VWF multimer patterns (including the high molecular weight VWF multimers that are most effective in restoring hemostasis), among these concentrates. Treating physicians should be aware of these disparities and the potential clinical implications for patients with different VWD subtypes. Dosing has traditionally been calculated based on the FVIII content of the products, although dosing based on VWF functional activity [e.g., VWF ristocetin cofactor activity (VWF:RCo)] addresses the primary protein deficiency in VWD patients. Several clinical studies have demonstrated the efficacy of concentrates dosed according to VWF:RCo. Dosing is generally consistent across VWD subtypes, although patients with severe phenotypes or undergoing major procedures may require more infusions or longer treatment duration. Other considerations for the use of VWF-containing concentrates include laboratory monitoring of efficacy and safety issues such as thrombosis risk and thromboprophylaxis.

Topics: Clinical Trials as Topic; Deamino Arginine Vasopressin; Drug Combinations; Factor VIII; Hemostasis; Hemostatics; Humans; Platelet Adhesiveness; Platelet Aggregation; Thrombosis; Time Factors; von Willebrand Diseases; von Willebrand Factor

The wide clinical spectrum of von Willebrand disease (VWD), its complex pathophysiology and its classification into distinct quantitative (type 1 or type 3) and qualitative (type 2) types with further subtle distinctions have prevented most clinicians from establishing a straightforward approach to diagnosing and treating this inherited bleeding disorder. The results of studies involving large cohorts of patients with a wide range of bleeding manifestations and variable von Willebrand factor (VWF) reduction have recently become available. These data have allowed the proposal of minimal criteria for a clinically useful diagnosis and for differentiating patients with mild VWD from subjects with borderline or only slightly reduced VWF levels who will not benefit from a specific diagnosis. These criteria are based on measurement of VWF ristocetin cofactor (VWF:RCo), VWF antigen (VWF:Ag), factor VIII and a standardized bleeding score (BS). Demonstration of the inheritance of the disorder could help to classify patients for whom insufficient hemostatic challenges may produce a falsely reassuring BS (like in children). Using this approach, mild VWD appears to be mostly composed of type 1 cases. Complemented by the results of desmopressin trial infusion, these parameters form the basis for a clinically oriented classification of all forms of VWD and may be useful for selecting the best treatment according to the severity of the disease. Although few molecular data have revealed practical utility, there is no doubt that the clarification of the molecular pathophysiology of VWD has allowed the unification of this complex disorder into a simple conceptual framework. This framework underlies the proposed utilization of simple phenotypic markers for optimizing treatments in individual patients.

Topics: Adult; Child; Deamino Arginine Vasopressin; Disease Management; Factor VIII; Female; Hemorrhage; Humans; Male; Mutation; Patient Selection; Phenotype; Postpartum Hemorrhage; Pregnancy; Pregnancy Complications, Hematologic; Severity of Illness Index; von Willebrand Diseases; von Willebrand Factor

There has been much recent data published on type 1 von Willebrand disease (VWD) predominantly from three multi-centre cohort studies. These data have influenced a revision of the classification of type 1 VWD and have important implications for the management of this disorder. Patients with low von Willebrand factor (VWF) levels tend to have VWF mutations and VWD is transmitted predictably within families. In patients with VWF levels close to the lower end of the normal range, candidate mutations are found less often, ABO blood group is a more important factor and the disease has variable heritability within families. The importance of bleeding symptoms, in addition to VWF levels, in the diagnosis of type 1 VWD has been highlighted.

Topics: ABO Blood-Group System; Deamino Arginine Vasopressin; Genetic Linkage; Hemostatics; Humans; Mutation; Treatment Outcome; von Willebrand Diseases; von Willebrand Factor

Patients with severe forms of von Willebrand's disease (VWD) may have frequent haemarthroses, especially when factor VIII (FVIII) levels are below 10 U/dL, so that some of them develop target joints like patients with severe haemophilia A. Some patients have recurrent gastrointestinal bleeding, often without lesions in the gastrointestinal tract, and need treatment every day or every other day. Finally, there are children who have epistaxis frequently and severely enough to cause anaemia. In these frequent and severe bleeders, the optimal therapy may be secondary long-term prophylaxis with von Willebrand factor (VWF)/FVIII concentrates rather than on-demand treatment on the occasion of bleeding episodes. The largest experience on such prophylaxis in VWD has been in Sweden in 35 patients with severe forms of VWD. Long-term prophylaxis was also implemented in a cohort of Italian patients with VWD: prophylaxis was used in seven patients with types 3 (n = 1 ), 2A (n = 4), 2M (n = 1) and type 1 (n = 1) VWD because of recurrent gastrointestinal bleeds and in four patients with type 3 VWD because of joint bleeds. Prophylaxis prevented bleeding completely in eight patients and largely reduced hospitalisation for blood transfusions in the remaining three. The cost-effectiveness of these prophylaxis regimens versus on-demand therapy will now be investigated in one large international study

Topics: Clinical Trials as Topic; Deamino Arginine Vasopressin; Drug Administration Schedule; Drug Combinations; Epistaxis; Factor VIII; Female; Fibrinogen; Gastrointestinal Hemorrhage; Hemarthrosis; Hemorrhage; Humans; Male; Multicenter Studies as Topic; Prospective Studies; Retrospective Studies; Secondary Prevention; von Willebrand Diseases; von Willebrand Factor

Von Willebrand disease (VWD) is the most common genetic bleeding disorder with a prevalence of approximately 1-2 percent confirmed in different population studies. The severity of the bleeding tendency is usually proportional to the degree of the VWF defect, although the large majority of cases diagnosed appear to have a mild disease. Patients with VWD may require short- or long-term prophylaxis treatment. Short-term prophylaxis is usually performed to prevent excessive bleeding following surgery or invasive procedures, while long-term prophylaxis may be needed to control recurrent mucosal and joint bleeding complicating the more severe forms of VWD. This review is focused on the current knowledge on replacement treatment for patients with VWD disease undergoing surgical or invasive procedures. On the whole, the published studies document the safety and efficacy of VWF/FVIII concentrates as surgical prophylaxis in VWD patients, in particular of Haemate P, the most widely used VWF/FVIII concentrate due to its high VWF:FVIII ratio. The recent literature data also show that the best management of VWD patients undergoing surgery is that to perform a pharmacokinetic study in order to strictly tailor for each VWD patient loading and maintenance doses of VWF/FVIII concentrates. Furthermore, the same studies underscore that, along with VWF levels, FVIII levels should be monitored in the peri-operative period in order to prevent exposures to high FVII levels, associated with an increased risk of venous thrombosis.

Topics: Blood Loss, Surgical; Clinical Trials as Topic; Cross-Over Studies; Deamino Arginine Vasopressin; Dose-Response Relationship, Drug; Drug Combinations; Factor VIII; Half-Life; Humans; Infusions, Intravenous; Multicenter Studies as Topic; Postoperative Complications; Postoperative Hemorrhage; Retrospective Studies; Thromboembolism; Virus Inactivation; von Willebrand Diseases; von Willebrand Factor

Von Willebrand disease (VWD) is known for its marked heterogeneity which was already recognized by von Willebrand in 1926. The basis of phenotypic differentiation are quantitative and qualitative or functional differences between the different types and subtypes of VWD. Clinical relevant facts for the practioner on diagnosis and therapy of von Willebrand disease and von Willebrand syndrome are presented.

Topics: Deamino Arginine Vasopressin; Factor VIII; Hemostasis; Hemostatics; Humans; Phenotype; Platelet Aggregation; Ristocetin; von Willebrand Diseases; von Willebrand Factor

This review summarizes the steps that led to the development of desmopressin as a hemostatic agent. This drug has broadened the panel of pharmacological agents that can be used to treat or prevent bleeding in patients with mild hemophilia and von Willebrand disease.

Topics: Deamino Arginine Vasopressin; Hemophilia A; Hemostatics; Humans; von Willebrand Diseases

The aim of the treatment for von Willebrand disease (VWD) is to correct the dual defect of haemostasis, i.e. the abnormal platelet adhesion as a result of reduced and/or dysfunctional von Willebrand factor (VWF) and the abnormal coagulation expressed by low levels of factor VIII (FVIII). Correction of both deficiencies can be achieved by administering the synthetic peptide desmopressin (DDAVP) or, in cases unresponsive to this agent, the plasma concentrates containing VWF and FVIII (VWF/FVIII). DDAVP is the treatment of choice for type 1 VWD because it can induce release of normal VWF from cellular compartments, but the drug can be clinically useful also in other VWD types, including acquired von Willebrand syndrome (AVWS). A test dose of DDAVP at the time of diagnosis is recommended to establish the individual patterns of biological response and to predict clinical efficacy during bleeding and surgery. DDAVP is not effective in VWD type 3 and in severe forms of VWD 1 and 2. It can induce transient thrombocytopenia in patients with VWD type 2B. The results of several retrospective studies on the use of DDAVP in VWD management have been reported by many authors in different countries for the last 30 years. However, despite the widespread use of DDAVP in the treatment of VWD, there are only a few prospective clinical trials in a large number of cases on DDAVP efficacy and safety aimed at determining benefits and limits of this therapeutic approach. An investigator-driven observational prospective study on clinical efficacy of DDAVP in 200 patients with VWD types 1 and 2 has been recently organized: the effectiveness and safety of DDAVP will be evaluated prospectively for 24 months during bleeding episodes and minor or major surgeries in the VWD patients who were exposed to an infusion trial at enrollment.

Topics: Deamino Arginine Vasopressin; Hemorrhage; Hemostatics; History, 20th Century; History, 21st Century; Humans; von Willebrand Diseases

The haemostatic system has a central role in controlling the amount and the duration of menstrual bleeding, thus abnormally prolonged or profuse bleeding does occur in most women affected by inherited bleeding disorders. Whereas irregular, premenarchal or postmenopausal uterine bleeding is unusual in inherited or acquired heamorrhagic disorders, severe acute bleeding and menorrhagia at menarche and chronic menorrhagia during the entire reproductive life are common manifestations. Prevalence and morbidity of menorrhagia in inherited bleeding disorders have been poorly investigated. It can be estimated that 40% to 60% of currently menstruating women with type 1 or 2 and more than 60% of women with type 3 VWD complain of menorrhagia with a significant impact on their quality of life. Menorrhagia may be particularly distressing in adolescents because of their delicate emotional equilibrium. Similar epidermiology has been described in other inherited disorders like factor XI deficiency, platelet functional defects and in carriers of haemophilia A and B. Women presenting with ''isolated'' menorrhagia, that is without significant additional bleeding symptoms, a situation reported by up to 15% of healthy women, do not demand investigation to exclude an occult bleeding disorder. A multidisciplinary approach is required for diagnosis and treatment. Gynaecological supervision is always required to exclude organic causes unmasked by the bleeding disorder. Treatment options are similar to those for menorrhagia in general with the addition of desmopressin and replacement therapy and the exclusion of non-steroidal anti-inflammatory drugs. The therapeutic plan should take into consideration the patient's preferences, age and severity of bleeding. Iron supplementation is of paramount importance. Remedies used in clinical practice for menorrhagia in general (tranexamic acid, combined oral contraceptives [COC], levonorgestrel intrauterine system [LNG-IUS]) are first tried. In case of failure or contraindication (COC and LNG-IUS are best avoided in adolescents), before considering surgical options, treatment with desmopressin becomes the preferred choice in patients known to be responsive. The availability of desmopressin preparations for self-administration makes home treatment feasible in well selected cases. The treatment is efficacious and safe provided that patients are instructed to self-administer the agent only during the first two or three more heavy days of menstru

Topics: Deamino Arginine Vasopressin; Female; Hemostatics; Humans; Menorrhagia; von Willebrand Diseases

Acquired von Willebrand's syndrome type I is the supposed main underlying cause of bleeding tendency in hypothyroid patients. The purpose of this systematic review was to summarize the published evidence on the association between hypothyroidism and acquired von Willebrand's syndrome. All published clinical epidemiological and interventional studies, case reports and in vitro studies that investigated the association between hypothyroidism and acquired von Willebrand's syndrome were identified by a computer-assisted search of the MEDLINE and EMBASE electronic databases. A quality assessment was performed for clinical epidemiological studies. A total of 41 papers were included. A total of 22 epidemiological in vivo studies, two in vitro studies and 47 case reports were finally analyzed. No high quality in vivo study was identified. Almost all bleeding episodes described in the case reports were mucocutaneous. von Willebrand factor (VWF) antigen value was available for 23 patients: median value 28 U/dL (range: 4-45); VWF activity was available for 24 patients: median value 28.5 U/dL (range: <3-55); factor VIII activity was available for 16 patients: median value 47 U/dL (range: 9-74). Acquired von Willebrand's syndrome may be the main factor responsible for bleeding diathesis in overt hypothyroid patients. Even if bleeding episodes are mainly mild and mucocutaneous, blood transfusion, drug administration or surgical procedure may be required.

Topics: Adolescent; Adult; Aged; Bleeding Time; Child; Deamino Arginine Vasopressin; Disease Susceptibility; Female; Hemorrhage; Hemostatics; Humans; Hypothyroidism; Male; Middle Aged; Thyroxine; von Willebrand Diseases; von Willebrand Factor

Topics: Antigens; Autoimmune Diseases; Cardiovascular Diseases; Deamino Arginine Vasopressin; Disease Management; Hemorrhage; Humans; Immunosuppressive Agents; Incidence; Lupus Erythematosus, Systemic; Lymphoproliferative Disorders; Myeloproliferative Disorders; Neoplasms; Prospective Studies; Registries; von Willebrand Diseases; von Willebrand Factor

Topics: Deamino Arginine Vasopressin; Drug Combinations; Factor VIII; Hemostatics; Humans; von Willebrand Diseases; von Willebrand Factor

Acquired von Willebrand syndrome (aVWS) is a rare bleeding disorder with laboratory findings similar to those for congenital von Willebrand disease (VWD). However, unlike congenital VWD, it arises in individuals with no personal or family history of bleeding. aVWS occurs in association with a variety of underlying disorders, most frequently in lymphoproliferative disorders, myeloproliferative disorders, and cardiovascular diseases. Through an analysis of the more recent literature data, the pathophysiology and the clinical, laboratory, and therapeutic aspects of this syndrome are concisely reported in this review.

Topics: ADAM Proteins; ADAMTS13 Protein; Adsorption; Autoantibodies; Autoimmune Diseases; Blood Coagulation Tests; Cardiovascular Diseases; Deamino Arginine Vasopressin; Endocrine System Diseases; Factor VIII; Hematologic Diseases; Humans; Immunoglobulins, Intravenous; von Willebrand Diseases; von Willebrand Factor

The current standard set of von Willebrand factor (VWF) parameters used to differentiate type 1 from type 2 VWD include bleeding times (BTs), factor VIII coagulant activity (FVIII:C), VWF antigen (VWF:Ag), VWF ristocetine cofactor activity (VWF:RCo), VWF collagen binding activity (VWF:CB), ristocetine induced platelet aggregation (RIPA), and analysis of VWF multimers in low and high resolution agarose gels and the response to DDAVP. The BTs and RIPA are normal in asymptomatic carriers of a mutant VWF allele, in dominant type 1, and in recessive type 2N VWD, and this category has a normal response of VWF parameters to DDAVP. The response of FVIII:C is compromised in type 2N VWD. The BTs and RIPA are usually normal in type Vicenza and mild type 2A VWD, and these two VWD variants show a transiently good response of BT and VWF parameters followed by short in vivo half life times of VWF parameters. The BTS are strongly prolonged and RIPA typically absent in recessive severe type 1 and 3 VWD, in dominant type 2A and in recessive type 2C (very likely also 2D) VWD and consequently associated with low or absent platelet VWF, and no or poor response of VWF parameters to DDAVP. The BTs are prolonged and RIPA increased in dominant type 2B VWD, that is featured by normal platelet VWF and a poor response of BT and functional VWF to DDAVP. The BTs are prolonged and RIPA decreased in dominant type 2A and 2U, that all have low VWF platelet, very low VWF:RCo values as compared to VWF:Ag, and a poor response of functional VWF to DDAVP. VWD type 2M is featured by the presence of all VWF multimers in a low resolution agarose gel, normal or slightly prolonged BT, decreased RIPA, a poor response of VWF:RCo and a good response of FVIII and VWF:CB to DDAVP and therefore clearly in between dominant type 1 and 2U. The existing recommendations for prophylaxis and treatment of bleedings in type 2 VWD patients with FVIII/VWF concentrates are mainly derived from pharmocokinetic studies in type 3 VWD patients. FVIII/VWF concentrates should be characterised by labelling with FVIII:C, VWF:RCo, VWF:CB and VWF multimeric pattern to determine their safety and efficacy in prospective management studies. As the bleeding tendency is moderate in type 2 and severe in type 3 VWD and the FVIII:C levels are near normal in type 2 and very low in type 3 VWD patients. Proper recommendations of FVIII/VWF concentrates using VWF:RCo unit dosing for the prophylaxis and treatment of bleeding episodes are pr

Topics: Deamino Arginine Vasopressin; Drug Combinations; Factor VIII; Hemorrhage; Humans; Premedication; von Willebrand Diseases; von Willebrand Factor

Desmopressin, a synthetic derivative of the antidiuretic hormone vasopressin, is the treatment of choice for most patients with von Willebrand disease and mild hemophilia A. Moreover, the compound has been shown to be useful in a variety of inherited and acquired hemorrhagic conditions, including some congenital platelet function defects, chronic liver disease, uremia, and hemostatic defects induced by the therapeutic use of antithrombotic drugs such as aspirin and ticlopidine. Finally, desmopressin has been used as a blood saving agent in patients undergoing operations characterized by large blood loss and transfusion requirements, but studies suggest that this is not as effective as other methods. This review briefly summarizes the current clinical indications on the use of desmopressin as a hemostatic agent.

Topics: Deamino Arginine Vasopressin; Drug-Related Side Effects and Adverse Reactions; Hemophilia A; Hemorrhage; Hemostatics; Humans; von Willebrand Diseases

Von Willebrand disease (VWD), the most common hereditary bleeding disorder, is divided into three types depending on the quantitative (type 1 and 3) or qualitative (type 2) abnormality of von Willebrand factor (VWF). About 70-80% of VWD patients can be treated with the synthetic product desmopressin, while the others necessitate factor VIII/VWF concentrates. In addition to the treatment of bleeding episodes, therapeutic regimens include short- or long-term prophylaxis. While the literature data on short-term prophylaxis in VWD are consistent and clearly show the safety and efficacy of such a therapeutic approach, little evidence is available regarding long-term prophylaxis, and although the preliminary results are encouraging, they need to be validated by large prospective studies.

Topics: Deamino Arginine Vasopressin; Factor VIII; Hemostatics; Humans; Male; Prospective Studies; Time Factors; von Willebrand Diseases; von Willebrand Factor

Von Willebrand disease (VWD) is the most frequent inherited bleeding disorder and is due to quantitative (types 1 and 3) or qualitative (type 2) defects of von Willebrand factor (VWF). VWD is inherited by autosomal dominant or recessive patterns, but women with mild forms are more symptomatic. VWD is classified in six VWD types (1, 2A, 2B, 2M, 2N, 3) with peculiar phenotype and genotype. The ristocetin cofactor activity (VWF:RCo) is the most useful test for VWD diagnosis, because it can mimic the interactions of VWF with its platelet receptor. Knowledge of the segments of VWF involved in the binding to its receptor and to factor VIII prompted the search for mutations in specific exons of the VWF gene, with mutations causing VWD types 2A, 2B, 2M, 2N localized in exons 18-28. In case of VWD types 1 and 3 the mutations are spread within the entire gene. Desmopressin (DDAVP) is the treatment of choice for type 1 VWD because it can induce release of normal VWF from cellular compartments. In type 3 and in severe forms of types 1 and 2 VWD, DDAVP is not effective and plasma virally inactivated VWF concentrates should be used in bleedings, surgery, and secondary long-term prophylaxis.

Topics: Blood Component Transfusion; Deamino Arginine Vasopressin; Diagnosis, Differential; Female; Hemorrhage; Hemostatics; Humans; Inheritance Patterns; Male; Mutation; von Willebrand Diseases; von Willebrand Factor

Topics: Deamino Arginine Vasopressin; Hemostatics; Humans; Molecular Diagnostic Techniques; Prognosis; von Willebrand Diseases; von Willebrand Factor

Willebrand's disease is the most frequent inborn coagulopathy and type 3 is its most severe form. Pregnancy and delivery are critical events in women with Willebrand's disease of type 3. Prophylactic treatment for delivery and early postpartum period is recommended. We report the management of pregnancy and successful delivery of a 32-year-old woman with type 3. Prophylactic treatment with 2000 IU of Willebrand's disease factor (WdF) was given twice a day during the delivery day and the day after, and 1000 IU per day during the next three days. The patient did not show any spontaneous metrorrhagia but anemia. No bleeding was observed in the newborn.

Topics: Adult; Blood Loss, Surgical; Cesarean Section; Consanguinity; Deamino Arginine Vasopressin; Female; Humans; Infant, Newborn; Placenta Previa; Platelet Aggregation; Postpartum Hemorrhage; Pregnancy; Pregnancy Complications, Hematologic; Uterine Hemorrhage; von Willebrand Diseases; von Willebrand Factor

von Willebrand factor (VWF) performs a critical function in platelet binding at the site of vascular injury and also serves as the carrier protein for coagulation factor FVIII (FVIII), protecting it from proteolytic degradation in plasma. Both proteins undergo rapid, regulated release in response to DDAVP administration in patients with mild hemophilia A or von Wille-brand disease. Here, we attempt to summarize our current understanding of the establishment of the regulated storage pool of VWF and FVIII. The data presented indicate that regulated secretion of both proteins occurs only if there is endogenous synthesis of FVIII together with VWF.

Topics: Coagulants; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Humans; von Willebrand Diseases; von Willebrand Factor

Topics: Antifibrinolytic Agents; Blood Coagulation Tests; Contraceptives, Oral; Deamino Arginine Vasopressin; Diagnosis, Differential; Female; Hemostatics; Humans; Incidence; Menorrhagia; Platelet Function Tests; Prevalence; von Willebrand Diseases

Considerable progress has been made in the past decade in describing the obstetrical and gynaecological aspects of von Willebrand's disease (VWD). In addition, epidemiological studies have established an approximately 11-16% prevalence of the laboratory diagnosis of VWD in women presenting with menorrhagia. However, it is not established presently whether an upfront VWD screening should be a part of the standard evaluation of menorrhagia. This is because it is presently not known whether therapy in the VWD patient tailored specifically for VWD will appreciably alter the natural history of menorrhagia compared with the non-VWD menorrhagia patient. There are also subtleties involved in securing the diagnosis of VWD in women presenting with menorrhagia in terms of fluctuation of von Willebrand factor (VWF) levels vis-à-vis the menstrual cycle and the potential impact of oral contraceptive on VWF levels. Regarding management of VWD-related menorrhagia, pending ongoing comparative trials of intranasal desmopressin (DDAVP), tranexamic acid, oral contraceptive and the levonorgestrel intrauterine device, specific recommendations cannot be made presently regarding the superiority of one intervention compared with the other. The management of VWD-related postpartum haemorrhage is also an area of active debate in terms of 'best practice' in type 1 (? prophylactic DDAVP), type 2 [? expectant management if factor VIII:C (FVIII:C) level normalizes] and type 3 patients (? intensity and duration of infusional therapy with a VWF-containing plasma-derived FVIII concentrate). This review summarizes the present state of knowledge and highlights numerous questions for future study based on our present understanding of VWD in women.

Topics: Deamino Arginine Vasopressin; Female; Hemostatics; Humans; Mass Screening; Menorrhagia; Postpartum Hemorrhage; von Willebrand Diseases

The aim of treatment of von Willebrand's disease (VWD) is to correct the dual defect of haemostasis, i.e. the abnormal platelet adhesion due to reduced and/or dysfunctional von Willebrand factor (VWF) and the abnormal coagulation expressed by low levels of factor VIII (FVIII). Desmopressin (DDAVP) is the treatment of choice for type 1 VWD because it can induce release of normal VWF from cellular compartments. Prospective studies on biological response versus clinical efficacy of DDAVP in VWD type 1 and 2 are in progress to further explore its benefits and limits as therapeutic option. In type 3 and in severe forms of type 1 and 2 VWD, DDAVP is not effective and for these patients plasma virally inactivated concentrates containing VWF and FVIII are the mainstay of treatment. Several intermediate- and high-purity VWF/FVIII concentrates are available and have been shown to be effective in clinical practice (bleeding and surgery). New VWF products almost devoid of FVIII are now under evaluation in clinical practice. Although thrombotic events are rare in VWD patients receiving repeated infusions of concentrates, there is some concern that sustained high FVIII levels may increase risk of postoperative venous thromboembolism. Dosage and timing of VWF/FVIII administrations should be planned to keep FVIII level between 50 and 150 U/dL. Appropriate dosage and timing in repeated infusions are also very important in patients exposed to secondary long term prophylaxis for recurrent bleedings.

Topics: Deamino Arginine Vasopressin; Hemorrhage; Hemostatics; Humans; Treatment Outcome; von Willebrand Diseases; von Willebrand Factor

Acquired von Willebrand syndrome (AvWS) is not a well-known bleeding disorder among clinicians and is associated with various underlying diseases. The clinical manifestations are similar to congenital von Willebrand disease. Diagnosis is confirmed mainly by a decrease of ristocetin cofactor activity (vWF:RCo) and/or collagen binding activity (vWF:CBA) and by vWF multimeric analysis, usually with a selective loss of large multimers. Plasma von Willebrand factor propeptide (vWF:AgII) is a good marker of vWF synthesis. Various pathogenic mechanisms have been proposed, including development of autoantibodies to the von Willebrand factor (vWF), adsorption of vWF onto tumor cells or activated platelets, increase of vWF proteolysis, and mechanical destruction of vWF under high shear stress. Treatment of the underlying disorder may resolve AvWS. Desmopressin (DDAVP) is a first-line therapeutic option. Factor VIII/vWF concentrates and high-dose immunoglobulin infusions are reserved for patients unresponsive to DDAVP.

Topics: Deamino Arginine Vasopressin; Factor VIII; Humans; Immunoglobulins, Intravenous; von Willebrand Diseases

The correct diagnosis and classification of von Willebrand disease (von Willebrand disorder; vWD) is crucial because the presenting biological activity of von Willebrand factor (vWF) determines both the hemorrhagic risk and subsequent clinical management. Many laboratory assays are employed, given that assay limitations and vWD heterogeneity results in no single test being able detect all forms of vWD. Minimal laboratory identification requires assessments of vWF:antigen, factor (F) VIII:coagulant activity, and functional vWF (using vWF:ristocetin cofactor activity and vWF:collagen-binding activity). Tests to help subclassify vWD include ristocetin-induced platelet aggregation, vWF:multimers, and vWF:FVIII binding assays. New diagnostic developments are now influencing vWD diagnosis, including advancements in methodologies, automation, new platelet function analyzers, genetic mutational analysis, and a better understanding of therapeutic pharmacokinetics. This review focuses on the current recommended laboratory process for investigation of vWD from a practical scientific technical laboratory perspective. Selection of appropriate combination test panels and testing sequence is crucial for the proper diagnosis and classification of congenital vWD.

Topics: Bleeding Time; Clinical Laboratory Techniques; Deamino Arginine Vasopressin; Family; Hemostatics; Humans; Platelet Count; Reproducibility of Results; Sensitivity and Specificity; Skin; von Willebrand Diseases

Clinical management of von Willebrand disease (or von Willebrand disorder [vWD]) often involves factor replacement or desmopressin acetate (DDAVP) therapy to control (potential) bleeding. Laboratory monitoring involves testing patient samples prior to therapy and at discreet time points after therapy. Classical testing generally comprises assays for factor VIII:coagulant activity, von Willebrand factor (vWF):antigen and vWF:ristocetin cofactor activity. The PFA-100 (platelet function analyser) is a relatively new tool for the investigation of primary hemostasis, and studies have shown its potential utility in identifying both vWD and platelet disorders, and in monitoring DDAVP therapy in these patients. However, the PFA-100 has limited utility in monitoring factor replacement therapy. The collagen-binding activity (vWF:CB) assay is a relatively new functional vWF assay and studies have also shown its utility in identifying vWD, and in monitoring both DDAVP and factor replacement therapy in these patients. This review assesses the laboratory monitoring of therapy for vWD with a special focus on the combined potential utility of the PFA-100 and a vWF:CB assay sensitive for the presence or absence of large vWF multimers. This review should be of value to both hemostasis scientists and clinical specialists.

Topics: Chemistry, Clinical; Clinical Laboratory Techniques; Collagen; Deamino Arginine Vasopressin; Hemostasis; Humans; Laboratories; Platelet Function Tests; Protein Binding; Time Factors; von Willebrand Diseases; von Willebrand Factor

von Willebrand disease (vWD) is the commonest bleeding disorder in women. More than 70% of women with vWD suffer from menorrhagia and half of them suffer from dysmenorrhea. There is also the risk of hemorrhage with ovulation and mid-cycle pain. These have a significant effect on all aspects of quality of life. vWD also can be the underlying cause of menorrhagia in a small but significant proportion of women. There are still several unanswered issues in the diagnosis and management of menorrhagia in these women. There is no consensus whether testing for vWD should be part of the routine investigations in menorrhagia. Diagnosis of vWD is difficult. There are intraindividual variations in von Willebrand factor and factor VIII levels influenced by age, race, and blood group. This is further complicated in women because of the fluctuation of these factor levels during the menstrual cycle and possibly with hormonal therapy. The diagnosis of menorrhagia is also difficult due to the lack of a simple objective tool for the assessment of menstrual blood loss. In vWD, the treatment of menorrhagia is usually medical, but there is lack of prospective data on the efficacy of commonly used medical therapies in these women. The levonorgestrel intrauterine system, Mirena, is effective and should be considered prior to surgical management. Surgical interventions may be required in patients unresponsive to medical treatments. These procedures can be complicated by hemorrhage in these women. A multidisciplinary approach in the management of these women is essential in ensuring an optimal outcome. Multicenter clinical trials are required to answer the controversial issues in the management of women with vWD.

Topics: Adolescent; Adult; Antifibrinolytic Agents; Contraceptives, Oral, Synthetic; Deamino Arginine Vasopressin; Endometrium; Female; Genital Diseases, Female; Humans; Levonorgestrel; Menorrhagia; Middle Aged; Quality of Life; Tranexamic Acid; von Willebrand Diseases

The aim of treatment of von Willebrand disease (VWD) is to correct the dual defect of hemostasis (i.e., the abnormal platelet adhesion due to reduced and/or dysfunctional von Willebrand factor [VWF] and the abnormal coagulation expressed by low levels of factor [F] VIII). Desmopressin acetate (DDAVP) is the treatment of choice for type 1 VWD because it can induce release of normal VWF from cellular compartments. Prospective studies on biological response versus clinical efficacy of DDAVP in VWD types 1 and 2 are in progress to explore its benefits and limits as a therapeutic option. In type 3 and in severe forms of type 1 and 2 VWD, DDAVP is not effective, and for these patients plasma virally inactivated concentrates containing VWF and FVIII are the mainstay of treatment. Several intermediate- and high-purity VWF/FVIII concentrates are available and have been shown to be effective in clinical practice (bleeding and surgery). New VWF products almost devoid of FVIII are now under evaluation in clinical practice. Although thrombotic events are rare in VWD patients receiving repeated infusions of concentrates, there is some concern that sustained high FVIII levels may increase risk of postoperative venous thromboembolism. Dosage and timing of VWF/FVIII administrations should be planned to keep the FVIII level between 50 and 150 IU/dL. Appropriate dosage and timing in repeated infusions are also very important in patients exposed to secondary long-term prophylaxis for recurrent bleedings.

Topics: Clinical Trials as Topic; Deamino Arginine Vasopressin; Factor VIII; Hematology; Humans; Isoantibodies; Risk; Time Factors; Venous Thrombosis; von Willebrand Diseases; von Willebrand Factor

Treatment of type 3 von Willebrand disease (vWD) relies on infusion with plasma-derived factor concentrates containing von Willebrand factor (vWF). Patients with types 1 and 2 vWD who do not respond satisfactorily after receiving desmopressin need treatment with concentrates. The rationale for long-term prophylaxis in vWD is obvious: prophylaxis has been successfully used in hemophilia, and joint hemorrhages with development of hemophilic arthropathy can occur, especially in type 3 vWD. In Sweden, prophylaxis for vWD began during the 1960s, and we now have experience from a cohort of 37 patients treated for a median of 11 years (range, 2 to 45 years). The majority of subjects (n = 28) have type 3 vWD. The mean dose used for treatment is 24 units factor VIII/kg body weight given one to three times weekly. Indications for prophylaxis have included joint bleeds, bleeds from nose and mouth, menorrhagia and gastrointestinal bleeds. The annual number of bleeds has decreased dramatically following onset of prophylaxis. We conclude that long-term prophylactic treatment of vWD is warranted in the majority of cases with type 3 and in some cases, depending on the clinical phenotype, for patients with other subtypes. Additional studies are ongoing in an international effort, the von Willebrand Disease Prophylaxis Network.

Topics: Adolescent; Adult; Blood Transfusion; Child; Child, Preschool; Deamino Arginine Vasopressin; Factor VIII; Female; Hemophilia A; Hemorrhage; Humans; Infant; Male; Middle Aged; von Willebrand Diseases

The current standard for the diagnosis and management of patients with congenital von Willebrand disease (vWD) includes bleeding times (BTs), PFA-100 closure time (PFA-CT), factor (F) VIII:coagulant activity (C), vWF:antigen (Ag), vWF:ristocetin cofactor activity (RCo), a sensitive vWF:collagen-binding activity (CB), ristocetin-induced platelet aggregation (RIPA), analysis of vWF multimers in low- and high-resolution agarose gels, and the response to desmopressin. Guidelines and recommendations for prophylaxis and treatment of bleedings in vWD patients with vWF/FVIII concentrates should be derived from analysis of the content of these concentrates and from pharmacokinetic studies in different types of vWD patients with severe type 1, 2, or 3 vWD. The vWF/FVIII concentrates should be characterized by labeling with FVIII:C, vWF:RCo, vWF:CB, and vWF multimeric pattern, which will determine their predicted efficacy and safety in prospective management studies. Because the bleeding tendency is moderate in type 2 and severe in type 3 vWD, and because the FVIII:C levels are subnormal in type 2 and very low in type 3 vWD patients, new guidelines using vWF:RCo unit dosing for the prophylaxis and treatment of bleeding episodes are proposed. Such guidelines should be stratified for the severity of bleeding, the type of surgery (either minor or major), and also for the severity and type of vWD (i.e., either type 2 or 3 vWD).

Topics: Coagulants; Deamino Arginine Vasopressin; Factor VIII; Guidelines as Topic; Hemorrhage; Humans; Infusions, Intravenous; von Willebrand Diseases; von Willebrand Factor

von Willebrand disease (VWD), the most common inherited bleeding disorder, is caused by a quantitative (type 1 and 3) or qualitative (type 2) defect of von Willebrand factor (VWF). In this review, the present knowledge regarding the diagnosis and the management of VWD is briefly analyzed.

Topics: Antigens; Biopolymers; Case Management; Deamino Arginine Vasopressin; Disease Management; Factor VIII; Genes, Dominant; Genes, Recessive; Hemorrhage; Hemostatic Techniques; Humans; Phenotype; Platelet Count; Protein Subunits; Retrospective Studies; von Willebrand Diseases; von Willebrand Factor

The bleeding tendency in von Willebrand disease (VWD) is heterogeneous and some patients with the mildest form of the disease have no significant bleeding symptoms throughout their lives. In some cases, the most difficult task for a clinician is to decide whether any treatment is actually required. However, cases with moderate to severe factor VIII (FVIII) and von Willebrand factor (VWF) deficiency usually require treatment to stop or prevent bleeding. Increasing autologous FVIII/VWF by desmopressin administration or providing normal allogeneic VWF through the infusion of plasma-derived concentrates can correct FVIII and VWF deficiencies and normalize or shorten bleeding time (BT). FVIII levels are the best predictors of soft tissue or surgical bleeding, while BT normalization, reflecting the correction of platelet-dependent functions of VWF, is considered a reliable indicator of an effective treatment of mucosal bleeding. Recombinant concentrates of FVIII are not indicated (apart from cases with alloantibodies against exogenous VWF), since they are devoid of VWF and lack its stabilizing effect on circulating FVIII. A very-high-purity concentrate of VWF has recently been made available, but its advantages over conventional concentrates containing both FVIII and VWF moieties are not obvious. The best way to select the appropriate treatment is to perform a test infusion with desmopressin in any patient with clinically significant VWD, provided that he/she has no contraindication to the compound or belongs to subtype with an anticipated lack of response (for example, type 3 VWD with FVIII/VWF lower than 5%).

Topics: Bleeding Time; Deamino Arginine Vasopressin; Factor VIII; Female; Hemorrhage; Hemostatics; Humans; Male; Postoperative Hemorrhage; von Willebrand Diseases; von Willebrand Factor

von Willebrand disease (VWD) is considered to be the most common inherited bleeding disorder. Data on its epidemiology and impact in developing countries are limited. The biologic heterogeneity and variable presentation of VWD make diagnosis difficult. Although there is no accurate estimate of the prevalence of VWD in developing countries, available data suggest that the proportion of diagnosed cases is lower than the expected number, often accounting for only 6% to 13% of patients with hereditary bleeding disorders. Although accurate subtyping is often not possible, the number with severe disease tends to be much higher, particularly in those parts of the world where consanguinity is common. Agents used to treat patients with VWD range from plasma to purified factor concentrates. Desmopressin (DDAVP) is commonly used. Preliminary data on molecular genetics suggests that there are significant population differences. There is inadequate awareness of this condition and lack of support for these patients from the health care system in many developing countries. Concerted efforts are needed at the scientific and social levels to improve this situation.

Topics: Africa; Asia; Deamino Arginine Vasopressin; Delivery of Health Care; Developing Countries; Female; Hemostatics; Humans; Male; Prevalence; South America; von Willebrand Diseases

Topics: Deamino Arginine Vasopressin; Female; Hemorrhage; Humans; Infant, Newborn; Infant, Newborn, Diseases; Pregnancy; Pregnancy Complications, Hematologic; von Willebrand Diseases

Recessive type 3 von Willebrand disease (vWD) is a severe hemophilia-like bleeding disorder caused by homozygosity or double heterozygosity for two nonsense mutations (null alleles) and characterized by a strongly prolonged bleeding time (BT), absence of ristocetin-induced platelet aggregation (RIPA), absence of von Willebrand factor (vWF) protein, and prolonged activated partial thromboplastin time (APTT) due to factor VIII (FVIIIC): deficiency. Recessive severe type 1 vWD is caused by homozygosity or double heterozygosity for a missense mutation and differs from type 3 vWD by the detectable presence vWF:antigen (Ag) and FVIII:C levels between 0.09 and 0.40 U/mL. Carriers of one null allele or missense mutations are usually asymptomatic at vWF levels of 50% of normal. Mild recessive type 1 vWD may be due to a missense mutations, or one missense mutation plus blood group O. The so-called dominant type 1 vWD secretion defect and type 1 Vicenza are caused by a heterozygous missense mutation in the vWF gene that produces a mutant vWF protein having a dominant effect on the normal vWF protein produced by the normal vWF allele with regard to the defective processing, storage secretion, and/or proteolysis of vWF in endothelial cells and clearing from plasma consistent with a type 2 phenotype of vWD. Typical type 2 vWD patients, except 2N, show a defective vWF protein, decreased ratios for vWF:ristocetin cofactor [vWF:RCo]/vWF:Ag and vWF:collagen binding factor [vWF:CB]/vWF:Ag and prolonged BT. The BT is normal and FVIII:C levels clearly are lower than vWF:Ag in type 2N vWD. Multimeric analysis of vWF in plasma demonstrates that proteolysis of vWF is increased in type 2A and 2B vWD, with increased triplet structure of each band (not present in types 2M and 2U). Proteolysis of vWF is minimal in type 2C, 2D, and 2E variants that show aberrant multimeric structure of individual oligomers. vWD 2B differs from 2A by normal vWF in platelets, and increased RIPA. RIPA is normal in mild, decreased in moderate, and absent in severe type 2A vWD. RIPA is decreased or absent in 2M, 2U, 2C, and 2D; variable in 2E; and normal in 2N and dominant type 1. vWD 2M is usually mild and features decreased vWF:RCo and RIPA, and a normal or near-normal vWF multimeric pattern in a low-resolution agarose gel. vWD 2A-like or unclassifiable (2U) is distinct from 2A and 2B and typically features low vWF:RCo and RIPA with the relative lack of large vWF multimers. vWD type 2C is recessive; the

Topics: Blood Coagulation Factors; Blood Group Antigens; Deamino Arginine Vasopressin; Hemorrhage; Humans; Mutation; von Willebrand Diseases

A variety of treatment options are available at present for patients with von Willebrand disease (vWD), some of which are affordable for patients in developing countries. For most patients who have type 1 vWD, desmopressin acetate (DDAVP) is the treatment of first choice, at least for minor bleedings and for prophylaxis. It is advisable, however, to use a test dose first to note the patient's response. DDAVP is safe to use, affordable, and easy to administer. However, most patients with type 2 vWD and all patients with type 3 fail to respond to DDAVP. For these patients, other options are used. Almost all patients with vWD will benefit from fresh frozen plasma and from cryoprecipitate, and these are viable options for developing countries. Both have certain disadvantages, but they can, depending upon the circumstances and facilities, be produced in developing countries. In developed countries, factor VIII/von Willebrand factor concentrates are widely used, especially for major bleedings and for surgeries on these patients. These concentrates are safe and virus inactivated, but costly. Ancillary treatment modalities such as antifibrinolytic agents and certain hormones are usually given in conjunction with other modalities. The treatment of patients with antibodies to vWF is also described, and monitoring needs during therapy are reviewed.

Topics: Blood Coagulation Factors; Chemotherapy, Adjuvant; Deamino Arginine Vasopressin; Developing Countries; Disease Management; Hemorrhage; Humans; Practice Guidelines as Topic; Treatment Outcome; von Willebrand Diseases

Von Willebrand disease (VWD) is known for its marked heterogeneity which was already recognized by von Willebrand in 1926. The basis of phenotypic differentiation are quantitative and qualitative or functional differences between the different types and subtypes of VWD. Clinical relevant facts for the practitioner on diagnosis and therapy of von Willebrand disease and von Willebrand syndrome are presented.

Topics: Deamino Arginine Vasopressin; Hemostatics; Humans; Phenotype; von Willebrand Diseases; von Willebrand Factor

Topics: Blood Platelets; Deamino Arginine Vasopressin; Hemophilia A; Hemostatics; Humans; von Willebrand Diseases

Von Willebrand disease is the most frequent bleeding disorder caused by inherited defects in the concentration, structure, or function of von Willebrand factor (VWF). The genetic defects are essentially located in the VWF gene, but can potentially be located within other genes, and induce an heterogeneous clinical pattern inherited as an autosomal trait, mostly dominant. Three main categories are distinguished; type 1 includes partial quantitative deficiency of VWF, type 3 (recessive form) includes virtually complete deficiency of VWF, and type 2 includes variants with either a defective VWF-dependent platelet function or a defective binding of VWF to factor VIII. These categories correlate with important clinical features and therapeutic requirements. In type 1, the mildest form, desmopressin, which induces secretion of VWF from endothelial cells, is most effective with a variable-lasting response. In type 2, responsiveness to desmopressin is variable (contraindicated in type 2B) with the persistence of the qualitative abnormality, and replacement therapy with blood products containing VWF is often necessary. Patients with type 3, the severe form, are unresponsive to desmopressin since they lack VWF in storage compartments, and the treatment or the prophylaxis of bleeding require replacement therapy.

Topics: Deamino Arginine Vasopressin; Hemostatics; Humans; von Willebrand Diseases; von Willebrand Factor

During the last couple of decades improved pathophysiological insight, use of improved diagnostic tools, and improved understanding of treatment requirements, have converged on an improved safety of treatment and quality of life for the patient suffering VWD. The scientific development in this area has elucidated a vast heterogeneity in VWD now appreciated as a vastly heterogeneous group of bleeding disorders. In some subtypes, dysfunctional VWF protein characteristics are clarified and logically linked with the distinct site of the VWF gene mutation abolishing specific functions of VWF, while in other subtypes such relationships have not yet been established. With the most frequently occurring variant, designated type 1, the quantitative loss in VWF seems to correlate with its reduced function. However, we are only at the beginning of the era of molecular genetics of this specific variant. Medical evidence based guidelines by ordinary standards for treatment of VWD do not exist. Therefore, treatment is based on a mechanistic approach and empirical knowledge. The review presented here focuses on the management of bleeding in VWD. Its basis is a mixture of data reported to literature and the authors' personal clinical observations. Our intention is the presentation and discussion of current issues related to VWD as well as the various pharmaceutical treatment options available for patients afflicted with von Willebrand's disease, together with some theoretical thoughts on possible future modalities.

Topics: Blood Platelets; Deamino Arginine Vasopressin; Hemorrhage; Hemostatics; Humans; Mutation; Receptors, Collagen; von Willebrand Diseases; von Willebrand Factor

Topics: Aminocaproates; Blood Component Transfusion; Deamino Arginine Vasopressin; Factor VIII; Female; Hemophilia A; Hemostasis; Humans; Isoantibodies; Menorrhagia; Phenotype; Plasma; Pregnancy; Pregnancy Complications, Hematologic; Tranexamic Acid; von Willebrand Diseases; von Willebrand Factor

Topics: Adult; Deamino Arginine Vasopressin; Diagnosis, Differential; Drug Monitoring; Female; Hemostatics; Humans; Medical History Taking; Menorrhagia; Nurse Practitioners; Nurse's Role; Patient Education as Topic; Physical Examination; Primary Health Care; von Willebrand Diseases

Von Willebrand's disease (VWD) is an autosomally inherited bleeding disorder caused by a deficiency or abnormality of von Willebrand factor (VWF). VWF is a multimeric adhesive protein which plays an important role in primary hemostasis by promoting platelet adhesion to the subendothelium at sites of vascular injury and platelet-platelet interactions in high shear-rate conditions. It is also the carrier of factor VIII (FVIII), thus indirectly contributing to the coagulation process. VWD has a prevalence of about 1% in the general population, but the figure for clinically relevant cases is lower (about 100/million inhabitants). Bleeding manifestations are heterogeneous: mucosal bleeding is typical of all VWD cases but hemarthrosis and hematomas may also be present when FVIII levels are low.. Most cases appear to have a partial quantitative deficiency of VWF (type 1 VWD) with variable bleeding tendency, whereas qualitative variants (type 2 VWD), due to a dysfunctional VWF, are clinically more homogeneous. Type 3 VWD is rare and the patients have a moderate to severe bleeding diathesis because of the virtual absence of VWF, and a recessive pattern of inheritance. The diagnosis of VWD, especially type I, may be difficult, because the laboratory phenotype is highly heterogeneous and is confounded by the fact that factors outside the VWF gene (e.g., blood group) influence VWF levels. An array of tests is usually required to characterize the VWD types of the disorder and establish the best treatment modality.. The aim of treatment is to correct the dual defect of hemostasis, i.e. abnormal coagulation expressed by low levels of FVIII and abnormal platelet adhesion expressed by the prolonged bleeding time (BT). Desmopressin (DDAVP) is the treatment of choice for type 1 VWD because it corrects the FVIII/VWF levels and the prolonged BT in the majority of cases. In type 3 and in severe forms of type 1 and 2 VWD, DDAVP is not effective and for these patients plasma virally-inactivated concentrates containing FVIII and VWF are the mainstay of treatment. These concentrates are clinically effective and safe, although they do not always correct the BT.

Topics: Deamino Arginine Vasopressin; Factor VIII; Hemostasis; Humans; von Willebrand Diseases; von Willebrand Factor

Acquired von Willebrand's disease or syndrome (AVWS) is a rare bleeding disorder distinguished from congenital von Willebrand's disease by age at presentation and absence of personal and family history of bleeding disorders. We report on 22 patients with AVWS seen over 25 years. Mean age at diagnosis was 61.3 years (range 38-86 years); most patients had a spontaneous or a post-operative hemorrhage at presentation. Gastrointestinal bleeding and epistaxis were the most common spontaneous symptoms. Bleeding time was prolonged in most patients, associated with marked reductions in plasma von Willebrand factor antigen and ristocetin cofactor activity. Plasma VWF multimer distribution was normal (type 1 pattern) in 5 patients, indeterminate (no multimers detectable) in 6 patients (type 3 pattern), and abnormal (decreased higher-molecular-weight multimers, type 2 pattern) in 11 patients. None of 17 patients tested had an inhibitor of ristocetin cofactor activity. An underlying malignant or benign hematologic disease was found in 18 patients, and 1 patient had Crohn's disease. Desmopressin was effective in only half the patients so treated, but all patients responded to treatment with VWF-containing concentrates. Resolution of AVWS occurred with therapy of lymphoma (1 patient) and chronic lymphocytic leukemia (1 patient). Sixteen patients were alive at last follow-up; no deaths were related to bleeding. AVWS may be more prevalent than has been appreciated; we estimate up to 0.04%. Awareness of the existence of AVWS is essential for diagnosis and appropriate management. Therapy of associated diseases may improve the bleeding disorder.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibody Specificity; Autoantibodies; Autoimmune Diseases; Bleeding Time; Crohn Disease; Deamino Arginine Vasopressin; Female; Hematologic Diseases; Hematologic Neoplasms; Humans; Male; Middle Aged; Minnesota; Paraproteins; Postoperative Hemorrhage; Retrospective Studies; von Willebrand Diseases; von Willebrand Factor

The presence of coagulation pathology in children who are candidates for adenotonsillectomy (AT) is a challenge to the otolaryngologist. von Willebrand's disease (vWD) is the most common hereditary coagulopathy and is due to a quantitative and/or qualitative deficiency of von Willebrand's factor (vWF). In recent years, the administration of 1-deamino-8-D-arginine vasopressin (DDAVP) has been recommended as coadjuvant therapy for surgical procedure. This synthetic hormone promotes the release of vWF and factor VIII from endothelial cells. In this report, the authors describe the history of a child with vWD undergoing successful AT after administration of DDAVP. Furthermore, a review of the literature with particular emphasis on the use of DDAVP is made.

Topics: Adenoidectomy; Blood Loss, Surgical; Chemotherapy, Adjuvant; Child, Preschool; Deamino Arginine Vasopressin; Hemostatics; Humans; Male; Postoperative Hemorrhage; Time Factors; Tonsillectomy; von Willebrand Diseases

Von Willebrand disease (vWD) is the most widespread inherited bleeding disorder caused by quantitative or qualitative abnormalities of von Willebrand factor (vWF), an adhesive glycoprotein found in blood plasma and platelets and participating in primary and secondary/endothelium haemostasis as well. Although bleeding symptoms are often mild or moderate, patients with vWD represent a very heterogenous group with different phenotypes and a wide variability of the clinical pattern. In accordance with different defects of vWF, vWD is classified into various types and subtypes. This is illustrated by two case reports of patients with different types of vWD. Two main therapeutic options are available for the prevention and treatment of bleeding: desmopressin (DDAVP) and replacement therapy with plasma concentrates containing both factor VIII and vWF. DDAVP is the treatment of choice for most patients with type 1, representing about 80% of all patients with vWD. In patients with most types of type 2 and in all patients of type 3, DDAVP alone is ineffective or even contraindicated, and it is usually necessary to switch to plasma concentrates. Although treatment of vWD seems to be relatively simple in most cases, the exact diagnosis and phenotype characterization requires specialized or expert laboratory facilities. Furthermore, no reliable screening method for the diagnosis of vWD exists. Acquired vWD has similar clinical features and laboratory findings to the congenital forms and is mostly associated with lymphoproliferative or autoimmune disorders or neoplasia.

Topics: Adolescent; Deamino Arginine Vasopressin; Humans; Male; Phenotype; von Willebrand Diseases; von Willebrand Factor

Acquired von Willebrand disease (AvWD) is a relatively rare acquired bleeding disorder that usually occurs in elderly patients, in whom its recognition may be delayed. Patients usually present predominantly with mucocutaneous bleeding, with no previous history of bleeding abnormalities and no clinically meaningful family history. Various underlying diseases have been associated with AvWD, most commonly hematoproliferative disorders, including monoclonal gammopathies, lymphoproliferative disorders, and myeloproliferative disorders. The pathogenesis of AvWD remains incompletely understood but includes autoantibodies directed against the von Willebrand factor (vWF), leading to a more rapid clearance from the circulation or interference with its function, adsorption of vWF by tumor cells, and nonimmunologic mechanisms of destruction. Laboratory evaluation usually reveals a pattern of prolonged bleeding time and decreased levels of vWF antigen, ristocetin cofactor activity, and factor VIII coagulant activity consistent with a diagnosis of vWD. Acquired vWD is distinguished from the congenital form by age at presentation, absence of a personal and family history of bleeding disorders, and, often, presence of a hematoproliferative or autoimmune disorder. The severity of the bleeding varies considerably among patients. Therapeutic options include desmopressin and certain factor VIII concentrates that also contain vWF. Successful treatment of the associated illness can reverse the clinical and laboratory manifestations. Intravenous immunoglobulins have also shown some efficacy in the management of AvWD, especially cases associated with monoclonal gammopathies. Awareness of AvWD is essential for diagnosis and appropriate management.

Topics: Age Distribution; Age of Onset; Aged; Autoimmune Diseases; Comorbidity; Deamino Arginine Vasopressin; Diagnosis, Differential; Factor VIII; Hemorrhage; Hemostatics; Humans; Lymphoproliferative Disorders; Myeloproliferative Disorders; Paraproteinemias; Prevalence; Risk Factors; Severity of Illness Index; Treatment Outcome; von Willebrand Diseases

von Willebrand disease (VWD) is a bleeding disorder caused by quantitative (type 1 and 3) or qualitative (type 2) defects of von Willebrand factor (VWF). The mechanisms of most inherited VWD types have been recently elucidated by genetic and molecular diagnosis, but the phenotypic tests based on measurements of plasma and platelet VWF, the ability of VWF to interact with its platelet receptor, and the analysis of the multimeric composition of VWF are always essential to identify patients with different VWD subtypes. The aim of treatment is to correct the dual defects of hemostasis, ie, abnormal coagulation expressed by low levels of factor VIII (FVIII) and abnormal platelet adhesion expressed by prolonged bleeding time (BT). Desmopressin is the treatment of choice in most patients with type 1 and type 2 VWD, who account for 60 to 70% of cases. In type 3 and in some severe forms of type 1 and type 2 VWD, desmopressin is not effective, and it is necessary to resort to plasma concentrates containing FVIII and VWF. Treated with virucidal methods, these concentrates are effective and currently safe, but they do not always correct the BT defect. Platelet concentrates or desmopressin can be used as adjunctive treatments when poor correction of the BT after concentrates is associated with continued bleeding.

Topics: Child; Deamino Arginine Vasopressin; Delivery, Obstetric; Factor VIII; Female; Hemostatics; Humans; Phenotype; Pregnancy; Prenatal Diagnosis; Prevalence; von Willebrand Diseases; von Willebrand Factor

von Willebrand disease (vWD) is a very common autosomal inherited bleeding disorder, caused by a quantitative deficiency or a qualitative structural defect of von Willebrand factor (vWF). Two main therapeutic options are available for the treatment of spontaneous bleeding episodes and for prevention of bleeding: desmopressin (DDAVP) and replacement therapy with plasma products. DDAVP is the treatment of choice for most patients with type 1 vWD. In patients with the type 3 disease and in most subjects with type 2 disease, DDAVP alone is ineffective or contraindicated, and it is usually necessary to switch to plasma concentrates containing both factor VIII (FVIII) and vWF. Concentrates subjected to virucidal treatment (e.g. solvent/detergent treatment) during manufacture should always be used in preference to cryoprecipitate. A recombinant vWF concentrate is now undergoing preclinical development and preliminary data suggest it possesses good haemostatic function and may correct the bleeding in vWD after its administration in several animal models. Although treatment of vWD is relatively simple (assuming access to even basic laboratory facilities), actual diagnosis is often far from straightforward, and the patients should be well characterized phenotypically to tailor the treatment to the different types and subtypes of the disease. It is probably wise to refer samples for the characterization to expert laboratories.

Topics: Chemotherapy, Adjuvant; Deamino Arginine Vasopressin; Factor VIII; Female; Hemorrhage; Humans; Male; Pregnancy; von Willebrand Diseases; von Willebrand Factor

Von Willebrand disease (vWD) is a frequent inherited disorder of hemostasis that affects both sexes. Two abnormalities are characteristic of the disease, which is caused by a deficiency or a defect in the multimeric glycoprotein called von Willebrand factor: low platelet adhesion to injured blood vessels and defective intrinsic coagulation owing to low plasma levels of factor VIII. There are 2 main options available for the treatment of spontaneous bleeding episodes and for bleeding prophylaxis: desmopressin and transfusional therapy with plasma products. Desmopressin is the treatment of choice for most patients with type 1 vWD, who account for approximately 70% to 80% of cases. This nontransfusional hemostatic agent raises endogenous factor VIII and von Willebrand factor 3 to 5 times and thereby corrects both the intrinsic coagulation and the primary hemostasis defects. In patients with the more severe type 3 and in most patients with type 2 disease, desmopressin is ineffective or is contraindicated and it is usually necessary to resort to plasma concentrates containing both factor VIII and von Willebrand factor. Concentrates treated with virucidal methods should be preferred to cryoprecipitate because they are equally effective and are perceived as safer. (Blood. 2001;97:1915-1919)

Topics: Blood Loss, Surgical; Combined Modality Therapy; Contraindications; Deamino Arginine Vasopressin; Endothelium, Vascular; Factor VIII; Female; Hemorrhage; Humans; Isoantibodies; Male; Myocardial Infarction; Postoperative Hemorrhage; Postpartum Hemorrhage; Pregnancy; Pregnancy Complications, Hematologic; Receptors, Vasopressin; Safety; Stroke; Thrombocytopenia; Transfusion Reaction; Virus Diseases; von Willebrand Diseases; von Willebrand Factor

Limited data are available regarding optimal treatment with desmopressin (DDAVP) or intermediate-purity FVIII concentrates rich in VWF (CFCs) in patients with von Willebrand disease (VWD) who undergo planned surgery. We undertook a retrospective review over 10 years (1988-1997) and identified 27 patients treated with DDAVP for 35 surgical events and 38 patients who received CFCs for 68 elective surgical events. Tranexamic acid was usually added for mucosal surgery. The FVIII:C levels and the severity of surgery were used to determine the frequency and the doses of postoperative treatment. For major surgery the median pre- and post-operative doses of CFCs were 54 and 43 IU/kg, respectively, and for minor surgery the median doses varied between 34 and 52 IU/kg preoperatively and between 23 and 37 IU/kg postoperatively. The effectiveness of haemostasis was excellent in 32 events (91%) treated with DDAVP and in 56 events (82%) treated with CFCs. It is concluded that patients with VWD do not carry an increased operative risk if appropriate therapy is given.

Topics: Anesthesia, Obstetrical; Antifibrinolytic Agents; Blood Loss, Surgical; Cesarean Section; Deamino Arginine Vasopressin; Elective Surgical Procedures; Factor VIII; Female; Humans; Male; Postoperative Hemorrhage; Preanesthetic Medication; Pregnancy; Retrospective Studies; Surgery, Oral; Surgical Procedures, Operative; Tranexamic Acid; Treatment Outcome; von Willebrand Diseases; von Willebrand Factor

Disorders of thrombosis and hemostasis represent both diagnostic and therapeutic challenges for the clinician, in part because of sex-based differences in incidence and presentation. The hemophilias are characterized by specific sex-linked patterns of inheritance, and there are sex differences in the presentation of the autosomally inherited disorders, particularly von Willebrand's disease. The diagnosis of these disorders can be affected by variations in either endogenous or exogenous estrogens, and the hemostatic stresses presented by menstruation and childbirth render any coagulopathy more severe in females than in males. Women are also at increased risk for developing thrombotic and embolic problems while on exogenous estrogens and during pregnancy. This article presents recommendations about the most appropriate and cost-effective ways to screen for the inherited disorders of both thrombosis and hemostasis in men and women. Recommendations are also developed for the treatment of women with these disorders, particularly in the context of pregnancy, contraception, uterine bleeding, and postmenopausal management.

Topics: Contraceptives, Oral, Hormonal; Deamino Arginine Vasopressin; Estrogen Replacement Therapy; Female; Hemophilia A; Hemostasis; Humans; Infusions, Parenteral; Male; Risk Factors; Sex Factors; Thrombosis; Venous Thrombosis; von Willebrand Diseases; X Chromosome

In von Willebrand disease, there are two main options for the treatment of spontaneous bleeding episodes and for bleeding prophylaxis: desmopressin and transfusional therapy with plasma products. Desmopressin is the treatment of choice for most patients with type 1, who account for approximately 70 to 80 per cent of all cases with the disease. This non-transfusional hemostatic agent raises endogenous factor VIII and von Willebrand factor three- to fivefold and thereby transiently corrects both the intrinsic coagulation and primary hemostasis defects. In patients with the more severe type 3 and in the majority of those with type 2 desmopressin is not effective or is contraindicated, so that it is usually necessary to resort to plasma concentrates containing factor VIII and von Willebrand factor. Concentrates treated with virus inactivation methods should be preferred to cryoprecipitate because they are equally effective and perceived as safer.

Topics: Blood Component Transfusion; Contraindications; Deamino Arginine Vasopressin; Female; Hemostatics; Humans; Isoantibodies; Male; Practice Guidelines as Topic; Pregnancy; von Willebrand Diseases; von Willebrand Factor

Topics: Autoantibodies; Cardiovascular Diseases; Deamino Arginine Vasopressin; Diagnosis, Differential; Drug Combinations; Factor VIII; Humans; Lymphoproliferative Disorders; Myeloproliferative Disorders; Platelet Membrane Glycoproteins; Receptors, Cell Surface; von Willebrand Diseases; von Willebrand Factor

Von Willebrand disease (VWD) is the most commonly inherited bleeding disorder, caused by inheritance of a quantitative or qualitative abnormality of von Willebrand factor (VWF). While the majority of patients with VWD are successfully treated with adjunctive therapies or with the synthetic vasopressin analog desmopressin acetate (DDAVP), a subset of patients requires replacement therapy. In the past, cryoprecipitate was the mainstay of therapy; however, it was associated with seroconversion to hepatitis B (HBV), hepatitis C (HCV), and the human immunodeficiency virus (HIV) in treated individuals. With the advent of virucidal methodology and, more recently, nucleic acid testing (NAT) of plasma fractions, the plasma-derived concentrates containing VWF are now considered the therapeutic standard of care.

Topics: Blood Component Transfusion; Deamino Arginine Vasopressin; Humans; von Willebrand Diseases; von Willebrand Factor

The indications, pharmacokinetics, and therapeutic guidelines for available coagulation products are reviewed. Patients with hemophilia, von Willebrand's disease (VWD), or acquired inhibitors to antihemophilic factor (AHF) cannot spontaneously stop an acute hemorrhage. Coagulation products used to manage bleeding in patients with these disorders include AHF concentrates, factor IX concentrates, factor VIIa concentrate, factor IX complexes, anti-inhibitor coagulant complexes, and desmopressin acetate. Typically, these commercially available products are used to manage acute bleeding or to prevent excessive bleeding during surgery. The dosage of the coagulation products and the duration of therapy depend on many variables, including the severity of the hemorrhage, the pharmacokinetics of the coagulation products, and patient-specific factors. Product purity and viral attenuation are also important considerations in determining an appropriate dosage regimen. Recombinant versions of some coagulant factors are available and can eliminate the risk of viral transmission. A thorough understanding of each coagulation product can guide product selection, dosing, and treatment duration and can reduce the risk of viral transmission.

Topics: Animals; Deamino Arginine Vasopressin; Factor IX; Factor VIII; Hemophilia A; Hemostasis; Humans; Swine; von Willebrand Diseases

Acquired von Willebrand syndrome (AVWS) is a rare acquired bleeding disorder similar to the congenital von Willebrand disease (VWD) in terms of laboratory findings. Diagnosis of AVWS can be very difficult, with treatment normally taking an empirical form. Although more than 200 cases have been reported since 1968, no retrospective or prospective studies are available on AVWS. Recently, an International Registry on AVWS, gathering data directly from worldwide Departments of Haematology-Oncology and Haemophilia Centres, has been organised by a group working on behalf of the Subcommittee on VWF in the Scientific Standardisation Committee (SSC) of International Society on Thrombosis and Haemostasis (ISTH). Information about an additional 211 AVWS patients is now available, with more detailed data on demography, type of haemorrhage, diagnostic tests for AVWS and management of bleeding episodes. The additional 211 AVWS cases are associated with lymphoproliferative (47%) or myeloproliferative (19%) disorders, cardiovascular diseases, neoplasia (7%) and other miscellaneous diseases (14%). Bleeding episodes of AVWS patients were managed by different compounds including desmopressin (22%), FVIII/VWF concentrates (26%) and high-dose immunoglobulin (10%), plasmapheresis (2%), steroids (5%) and immunosuppressive drugs (20%). Based on complied data, we can conclude that none of the therapeutic approaches proposed are 100% effective in all AVWS cases. Therefore, treatment must be customized for each patient according to the underlying disorder, as well as to the type and the severity of bleeding episode and must be targeted to each specific case.

Topics: Coagulants; Deamino Arginine Vasopressin; Glucocorticoids; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Plasmapheresis; Syndrome; von Willebrand Diseases; von Willebrand Factor

Topics: Bernard-Soulier Syndrome; Blood Platelet Disorders; Deamino Arginine Vasopressin; Female; Fetal Diseases; Hemostatics; Humans; Platelet Aggregation; Platelet Storage Pool Deficiency; Pregnancy; Pregnancy Complications, Hematologic; Prenatal Diagnosis; von Willebrand Diseases

von Willebrand disease (vWD) is the most common of the hereditary disorders of coagulation. We describe the pathophysiology, diagnosis and the new simplified classification of the disorder and discuss the management of patients about to undergo dental procedures and maxillofacial surgery. Close collaboration between oral and maxillofacial surgeons and haematologists in the management of patients with vWD is essential.

Topics: Blood Loss, Surgical; Deamino Arginine Vasopressin; Dental Care for Chronically Ill; Factor VIII; Humans; Oral Surgical Procedures; von Willebrand Diseases

This review focuses on new developments in the pathophysiology and treatment of von Willebrand disease (vWd). New aspects of the cell biology, gene control, and structure-function correlates of von Willebrand factor (vWf) are reviewed. vWd is more prevalent than previously recognized, affecting up to 1% of the population; this is particularly evident in women's health. Blood group is an important determinant of von Willebrand factor levels; individuals of blood group O tend to have lower plasma levels of vWf than those in other blood groups. Currently available blood tests of vWf quantity and function are discussed, in addition to newer tests undergoing validation. Treatment of classical vWd with desmopressin acetate and plasma derivatives is discussed, as is the potential for intravenous immunoglobulin and corticosteroids in acquired vWd. Special situations, such as the management of vWd in pregnancy, are also discussed.

Topics: ABO Blood-Group System; Antigens; Deamino Arginine Vasopressin; Female; Humans; Pregnancy; Pregnancy Complications; Structure-Activity Relationship; von Willebrand Diseases; von Willebrand Factor

Topics: Deamino Arginine Vasopressin; Diagnosis, Differential; Factor VIII; Hemostatics; Humans; Platelet Membrane Glycoproteins; Prognosis; Receptors, Cell Surface; von Willebrand Diseases; von Willebrand Factor

von Willebrand disease is the most frequent of inherited bleeding disorders (1:100 affected individuals in the general population). The aim of treatment is to correct the dual defects of haemostasis, i.e., abnormal coagulation expressed by low levels of factor VIII and abnormal platelet adhesion expressed by a prolonged bleeding time. There are two main options available for the management of von Willebrand disease: desmopressin and transfusion therapy with blood products. Desmopressin is the treatment of choice in patients with type 1 von Willebrand disease, who account for approximately 80% of cases. This pharmacological compound raises endogenous factor VIII and von Willebrand factors and thereby corrects the intrinsic coagulation defect and the prolonged bleeding time in most type 1 patients. In type 3 and in the majority of type 2 patients desmopressin is not effective, and it is necessary to resort to plasma concentrates containing factor VIII and von Willebrand factor. Treated with virucidal methods, these concentrates are effective and currently safe, but the bleeding time defect is not always corrected by them. Platelet concentrates or desmopressin can be used as adjunctive treatments when poor correction of the bleeding time after concentrates is associated with continued bleeding.

Topics: Blood Transfusion; Deamino Arginine Vasopressin; Factor VIII; Hemostatics; Humans; von Willebrand Diseases; von Willebrand Factor

Topics: Antifibrinolytic Agents; Deamino Arginine Vasopressin; Factor VIII; Hemostatics; Humans; von Willebrand Diseases; von Willebrand Factor

von Willebrand's disease (vWD) arises from abnormalities in von Willebrand factor (vWF), an adhesive glycoprotein uniquely involved in key aspects of both primary and secondary hemostasis. The current classification distinguishes disorders arising from partial (type 1) or complete (type 3) deficiencies and from qualitative defects (type 2). Type 2 vWD is further divided into four subtypes (A, B, N, and M), reflecting distinct classes of functional abnormalities. Mis-sense mutations account for most of type 2 vWD, whereas major disruptions in the vWF gene produce type 3 variants. The molecular basis of type 1 vWD is largely undefined. The laboratory diagnosis of vWD and its several variants is made on the basis of immunologic and functional studies of vWF, factor VIII levels, and specialized electrophoretic analysis (multimer gels). The mainstay of therapy for most patients with vWD in desmopressin, a pharmacologic agent that stimulates the release of endogenous pools of vWF. Cryoprecipitate and selected factor VIII concentrates are useful sources of exogenous vWF for the treatment of patients unresponsive to this desmopressin.

Topics: Combined Modality Therapy; Deamino Arginine Vasopressin; Diagnosis, Differential; Factor VIII; Humans; Mutation; von Willebrand Diseases; von Willebrand Factor

This paper discusses clinical experience of the use of desmopressin in patients with either congenital or acquired bleeding disorders. The bleeding disorders reviewed herein are haemophilia A, von Willebrand's disease and platelet function disorders (congenital bleeding disorders); uraemia, liver cirrhosis and drug-induced bleeding (acquired bleeding disorders).

Topics: Deamino Arginine Vasopressin; Hemorrhage; Hemostatics; Humans; Thrombosis; von Willebrand Diseases

Von Willebrand's disease was recognized by a careful observant clinician. Research advances in blood banking technology and molecular biology, in addition to astute clinical observation, have led to unraveling the factor VIII molecule, classification of a heterogenous disease, and rational therapy.

Topics: Deamino Arginine Vasopressin; Factor VIII; Humans; Structure-Activity Relationship; von Willebrand Diseases; von Willebrand Factor

Topics: Animals; Deamino Arginine Vasopressin; Dogs; Drug Therapy, Combination; Factor VIII; Humans; Mice; Recombinant Proteins; Swine; von Willebrand Diseases; von Willebrand Factor

Topics: Animals; Blood Loss, Surgical; Deamino Arginine Vasopressin; Factor VIII; Female; Hemophilia A; Hemorrhage; Hemorrhagic Disorders; History, 18th Century; History, 20th Century; Humans; Italy; Kidney Diseases; Liver Diseases; Male; Platelet Adhesiveness; Rabbits; von Willebrand Diseases; von Willebrand Factor

von Willebrand's disease is the most frequent of inherited bleeding disorders (1:100 affected individuals in the general population). The aim of therapy is to correct the dual defects of haemostasis, i.e. abnormal coagulation expressed by low levels of factor VIII and abnormal platelet adhesion expressed by a prolonged bleeding time. There are two main options available for the management of von Willebrand's disease: desmopressin and transfusion therapy with blood products. Desmopressin is the treatment of choice in patients with Type 1 von Willebrand's disease, who account for approximately 80% of cases. The pharmacological compound raises endogenous factor VIII and von Willebrand factor and corrects the prolonged bleeding time in most patients. In Type 3 and in the majority of Type 2 patients, desmopressin is not effective and it is necessary to resort to plasma concentrates containing factor VIII and von Willebrand factor. Treated with virucidal methods, these concentrates are currently effective and quite safe, even though the bleeding time defect is not always corrected by them. Platelet concentrates or desmopressin can be used as adjunctive treatments when poor correction of the bleeding time is associated with continued bleeding.

Topics: Autoantibodies; Blood Coagulation; Blood Component Transfusion; Deamino Arginine Vasopressin; Factor VIII; Female; Humans; Isoantibodies; Pregnancy; Pregnancy Complications, Hematologic; von Willebrand Diseases; von Willebrand Factor

The term von Willebrand disease includes many bleeding disorders caused by abnormalities of vWF. Frequent or severe bleeding may be indicative of vWD or other bleeding conditions. Primary care practitioners need to be familiar with vWD and evaluate possibly affected individuals with appropriate laboratory studies. Patients with vWD should be educated about their disorder and preventive measures to limit its effect. Medications are available that can treat or prevent bleeding complications for most patients with vWD. Intervention with blood products is occasionally necessary.

Topics: Adolescent; Child; Child, Preschool; Chromosomes, Human, Pair 12; Deamino Arginine Vasopressin; Gene Deletion; Heart Defects, Congenital; Humans; Hypothyroidism; Incidence; Platelet Count; von Willebrand Diseases; von Willebrand Factor

Topics: Deamino Arginine Vasopressin; DNA, Complementary; Genetic Linkage; Hemostasis; Humans; Mutation; Polymorphism, Genetic; Prevalence; Pseudogenes; von Willebrand Diseases; von Willebrand Factor

Von Willebrand's disease is probably the most common congenital bleeding disorder, with a prevalence close to 1% in some epidemiological studies. The disease is caused by a quantitative deficiency or a qualitative defect of the von Willebrand factor, which is a multimeric glycoprotein consisting of subunits of 2050 amino acids. The size of multimers ranges from approximately 500 kDa to 20 MDa. Each subunit consist of repeated domain structures. Several functional domains have been identified which can bind such structures as platelet receptors glycoprotein Ib or IIb/IIIA, heparin, collagen or factor VIII. The von Willebrand factor has two main functions in haemostasis, to promote normal platelet adhesion and to be a carrier protein for factor VIII. Von Willebrand's disease is divided into three major types and several subtypes depending on the quantity and quality of the von Willebrand factor in plasma and platelets. A new classification has recently been proposed. Typical symptoms are mucosal bleeding, easy bruising and increased bleeding tendency in connection with tooth extractions and other invasive procedures. Severe cases may have joint bleeding and other haemophilia-like bleeding. Desmopressin is the treatment of choice in mild cases, whereas more severe cases need treatment with factor VIII concentrates.

Topics: Deamino Arginine Vasopressin; Factor VIII; Female; Hemostasis; Humans; Male; Renal Agents; von Willebrand Diseases; von Willebrand Factor

Topics: Animals; Blood Coagulation Disorders; Cat Diseases; Cats; Deamino Arginine Vasopressin; Diabetes Insipidus; Dog Diseases; Dogs; Humans; Polyuria; von Willebrand Diseases

Extensive bleeding is an important complication of dental extractions in haemophiliacs. Based on 26 case reports, the different therapeutic possibilities are discussed. When general or regional anaesthesia is required, protocols can be proposed for coagulation factor supplementation or even treatment with Minirin. In cases with local anaesthesia, substitution is not required. The importance of mandatory local haemostatic measures combined with antifibrinolytic treatment is emphasized.

Topics: Adolescent; Adult; Antifibrinolytic Agents; Child; Clinical Protocols; Deamino Arginine Vasopressin; Female; Hemophilia A; Hemostasis, Surgical; Humans; Length of Stay; Male; Middle Aged; Oral Hemorrhage; Retrospective Studies; Tooth Extraction; von Willebrand Diseases

von Willebrand's disease is the most common of the inherited bleeding disorders. It is caused by quantitative and/or qualitative abnormalities of von Willebrand factor, and it usually presents with bleeding from mucosal surfaces. The diagnosis is confirmed by measuring von Willebrand factor activity and antigen levels, factor VIII activity, and performing a multimer analysis of von Willebrand factor. Treatment may require plasma-derived concentrates, but can often be accomplished with DDAVP, a vasopressin analogue that causes transient release of von Willebrand factor from body storage sites.

Topics: Deamino Arginine Vasopressin; Factor VIII; Humans; von Willebrand Diseases; von Willebrand Factor

Topics: Blood Platelets; Deamino Arginine Vasopressin; Endothelium, Vascular; Factor VIII; Genes, Dominant; Genes, Recessive; Humans; von Willebrand Diseases; von Willebrand Factor

Topics: Deamino Arginine Vasopressin; Factor VIII; Fibrinogen; Hemophilia A; Humans; von Willebrand Diseases

Topics: Adult; Deamino Arginine Vasopressin; Humans; Male; von Willebrand Diseases

Impressive progress has been made in the treatment of von Willebrand disease. Desmopressin is the drug of choice for mild to moderate type I von Willebrand disease patients in whom adequate hemostatic levels of vWF activity can be achieved. Cryoprecipitate from random donors is no longer an optimal choice because of the risk of transfusion-associated viral infections. In special circumstances, cryoprecipitate from a very small donor pool, particularly if obtained following desmopressin stimulation, remains an attractive alternative because these donors can be intensively screened. This therapy may also be somewhat less expensive than commercial concentrates. Virally attenuated commercial concentrates containing intact vWF multimers are currently the treatment of choice to achieve high levels of vWF for moderate to severe von Willebrand disease and for patients with variants of von Willebrand disease that cannot be adequately treated with desmopressin or for whom desmopressin is contraindicated. It is hoped that concentrates of vWF specifically designed for treatment of von Willebrand disease will prove to be safe and efficacious. Standardized assays of vWF in concentrates need to be established. Although, the optimal treatment product has not been produced, several of the more recently developed products have structures that more closely resemble intact normal plasma vWF and appear promising.

Topics: Blood Transfusion; Deamino Arginine Vasopressin; Factor VIII; Humans; von Willebrand Diseases; von Willebrand Factor

Recent unraveling of the molecular and cellular biology of vWF and clearer knowledge of the pathophysiology of vWD have dramatically advanced our understanding of this group of disorders. Nonetheless, safe, effective, therapeutic management remains a formidable challenge for the clinician caring for these patients.

Topics: Blood Component Transfusion; Deamino Arginine Vasopressin; Factor VIII; Female; Growth Hormone; Hemorrhage; Humans; Male; Surgical Procedures, Operative; von Willebrand Diseases; von Willebrand Factor

Topics: Administration, Intranasal; Blood Coagulation Disorders; Deamino Arginine Vasopressin; Hemophilia A; Humans; Injections, Intravenous; Injections, Subcutaneous; von Willebrand Diseases

Desmopressin (1-deamino-8-D-arginine vasopressin) is a synthetic analogue of the antidiuretic hormone L-arginine vasopressin. Because it can raise circulating levels of factor VIII and von Willebrand factor, desmopressin is used for nontransfusional treatment of mild and moderate hemophilia and von Willebrand disease. Desmopressin also shortens the prolonged skin bleeding time in patients suffering from von Willebrand disease and is given to prevent or stop excessive bleeding in such conditions.

Topics: Animals; Bleeding Time; Deamino Arginine Vasopressin; Drug Evaluation; Endothelium, Vascular; Factor VIII; Hemodynamics; Hemophilia A; Hemorrhage; Humans; Liver; Stimulation, Chemical; von Willebrand Diseases

Topics: Amino Acid Sequence; Deamino Arginine Vasopressin; Genetic Counseling; Humans; Molecular Sequence Data; Prognosis; von Willebrand Diseases

In von Willebrand disease, the goal of treatment is to correct the two laboratory hallmarks of abnormal hemostasis, i.e. the deficiency of factor VIII (FVIII) and the prolonged bleeding time (BT). Since desmopressin (DDAVP) is able to achieve both these goals in the majority of patients, it is the treatment of choice. Some patients, however, are not responsive or become refractory to DDAVP. In these, blood products maintain an important therapeutic role, and there is a need to assess the efficacy of the recently available virus-inactivated plasma concentrates, which contain both FVIII and von Willebrand factor and carry a low risk of transmitting blood-borne viruses. Our survey of the data reported in the literature indicates that all available concentrates are similarly effective in attaining high and sustained levels of FVIII after infusion. Although they often shorten or normalize the prolonged BT, that effect is less uniform. Since concentrates appear efficacious in the majority of clinical situations that require the use of blood products, they should be preferred, because of their greater safety, to cryoprecipitate produced by blood banks, which cannot be virus inactivated.

Topics: Bleeding Time; Blood Component Transfusion; Combined Modality Therapy; Deamino Arginine Vasopressin; Detergents; Freeze Drying; Hot Temperature; Humans; Plasma; Prevalence; Safety; Solvents; Virus Diseases; Viruses; von Willebrand Diseases; von Willebrand Factor

In the majority of patients with congenital and acquired von Willebrand disease (vWD), desmopressin (DDAVP) is able to increase circulating factor VIII coagulant (VIII: C) to levels sufficient to secure satisfactory hemostasis. The bleeding time (BT) is also often normalized. In this review, all cases of vWD treated with DDAVP for the prevention or control of hemorrhage and reported in the literature for whom at least basal and peak values of VIII:C were available have been analysed. When reported, the effect on the BT was also considered. It appears that, in keeping with clinical experience gained with blood products, the correction of VIII:C defect is often sufficient to secure normal hemostasis. The only significant exception is mucosal bleeding, for which the correction of BT also appears to be necessary. Several patients (mainly with type I vWD) with basal VIII:C levels of 5-10% have been successfully treated to prevent bleeding after tooth extractions and minor surgery and to control spontaneous and post-traumatic bleeding. Experience with DDAVP in major surgery is still limited, so that the compound cannot be recommended for routine use. In acquired vWD, a trial with DDAVP is advised before resorting to substitutive therapy with blood derivatives. Since side effects to DDAVP treatment are limited and no major complications have been consistently demonstrated, DDAVP can be proposed as the treatment of first choice for most patients with vWD. The recent availability of concentrated preparations of DDAVP for intranasal administration and the demonstration that the subcutaneous route is an effective and simpler alternative to the intravenous route should further facilitate its use and make home-therapy feasible.

Topics: Deamino Arginine Vasopressin; Humans; von Willebrand Diseases

Activation and inhibition of the haemostatic system was reviewed including the interaction between the four biological systems involved in haemostasis: the vessel wall, the platelets, the coagulation system and the fibrinolytic system. The haemostatic mechanism is initiated at the site of injury through local activation of surfaces and release of tissue thromboplastin, resulting in formation and deposition of fibrin. The coagulation process is regulated by physiological anticoagulants. Activation of fibrinolysis is triggered by the presence of fibrin, and the role of tissue-type plasminogen activators (t-PA) at the site of fibrin formation in particular is emphasized. The process is regulated by physiological inhibitors, of which alpha 2-antiplasmin, histidine-rich glycoprotein and plasminogen activator inhibitor are reported to be of major physiological significance. The role of fibrinolysis in the regulation of the dynamic haemostatic balance is discussed, elucidated through examples of congenital deficiencies of the coagulation and the fibrinoytic system. Pharmacological inhibitors of fibrinolysis (i.e. epsilon-aminocaproic acid and tranexamic acid) and their possible effect on the haemostatic system are described. The systemic effects on the fibrinolytic system of surgery and oral surgery is reviewed, and it is concluded, that oral surgery has insignificant effects on blood fibrinolysis. In contrast, oral surgery induces changes of fibrinolysis in the oral environment; initially the fibrinolytic activity of saliva is reduced, due to the presence of inhibitors of fibrinolysis originating from the blood and the wound exudate. When bleeding and exudation cease, the fibrinolytic activity of the saliva will increase. Plasminogen and plasminogen activator, identified as t-PA are present in the oral environment under physiological conditions. Plasminogen is secreted in the saliva and the sources of t-PA include oral epithelial cells and gingival crevicular fluid. The presence of plasminogen and t-PA in the oral environment implies that when fibrin is present (i.e. after surgery), fibrinolysis is triggered. Haemorrhagic complications to oral surgery in patients without known defects of the coagulation system is reviewed. It is concluded that the investigations conducted to the present day do not permit final conclusions with respect to the pathophysiological role of defects in the coagulation and the fibrinolytic systems for the development of bleeding after

Topics: Anticoagulants; Blood Coagulation; Blood Platelets; Deamino Arginine Vasopressin; Fibrin; Fibrinolysis; Gingiva; Hemophilia A; Hemorrhage; Hemostasis; Hemostasis, Surgical; Humans; Mouth Mucosa; Saliva; Surgery, Oral; Tissue Plasminogen Activator; von Willebrand Diseases

Topics: Blood Coagulation Disorders; Blood Coagulation Factors; Blood Loss, Surgical; Blood Platelets; Deamino Arginine Vasopressin; Fibrinolysis; Hemophilia A; Hemostasis; Humans; von Willebrand Diseases

This review summarizes the current knowledge of the structure and function of von Willebrand factor and of the pathophysiologic features, diagnosis, classification, and treatment of von Willebrand's disease, the most common congenital bleeding disorder in humans. Specific regions of the von Willebrand factor subunit that are of functional importance have been identified. The structure of these functional domains of von Willebrand factor, as known to date, is described. A classification of von Willebrand's disease, based on the definition of structural and functional abnormalities of the molecule and initial characterization of genetic mutations, is discussed. With more precise characterization of molecular abnormalities, more selective therapeutic intervention for specific subtypes of von Willebrand's disease should eventuate.

Topics: Binding Sites; Blood Transfusion; Collagen; Deamino Arginine Vasopressin; Factor VIII; Glycoproteins; Heparin; Humans; Platelet Aggregation; Platelet Membrane Glycoproteins; Ristocetin; von Willebrand Diseases; von Willebrand Factor

This review focuses on the pathophysiology of the Factor VIII molecule as it relates to Von Willebrand's disease. Three major categories of Von Willebrand's disease are identified. The perioperative diagnosis and management of all categories are reviewed. 1-Deamino-8-D-arginine vasopressin (DDAVP) is presented as an alternative to the transfusion of blood and blood products for the management of a bleeding diathesis.

Topics: Blood Transfusion; Deamino Arginine Vasopressin; Humans; Surgical Procedures, Operative; von Willebrand Diseases

Abnormalities of platelet and plasma Willebrand's factor produce noticeable effects on the clinico-laboratory manifestations of Willebrand's disease. This is confirmed by more pronounced gravity of the hemorrhagic syndrome, the lack of the correcting effect in response to physiological conditions (pregnancy) and administration of DDAVP in contrast to beneficial effect seen in patients with normal content of Willebrand's factor in platelets.

Topics: Blood Platelets; Deamino Arginine Vasopressin; Female; Genetic Variation; Humans; Plasma; Pregnancy; von Willebrand Diseases; von Willebrand Factor

Patients with a history of epistaxis, menorrhagia or excessive bleeding after dental or surgical procedures may have von Willebrand's disease. Although screening coagulation tests may be normal, many patients with this disease will have excessive bleeding after surgical procedures if the disorder has not been recognized and appropriately treated. Patients with von Willebrand's disease may be treated with a medication that stimulates an increase in von Willebrand's factor, allowing them to avoid the need for blood product support.

Topics: Adolescent; Antifibrinolytic Agents; Deamino Arginine Vasopressin; Female; Humans; von Willebrand Diseases

Since the pressor and antidiuretic properties of the native hormone were characterized, chemists have been working to synthesize vasopressin analogues selective for particular biologic activities. Desmopressin has had the longest clinical track record. Subsequently, three more analogues have been formulated and have found specific clinical application. Their actions and uses are reviewed.

Topics: Blood Platelet Disorders; Cardiac Surgical Procedures; Deamino Arginine Vasopressin; Diabetes Insipidus; Hemophilia A; Humans; Liver Cirrhosis; Uremia; von Willebrand Diseases

von Willebrand factor (vWF) is a plasma protein with multiple functions in haemostasis. The vWF gene, located on chromosome 12p2.1, encodes a primary gene product of 2813 amino acids. Post-translational modification, assembly and secretion of vWF are highly complex. The pro vWF promoter is covalently linked by intermolecular disulphide bonds to form a dimer of MW approximately 440 kDa. This then polymerises to form multimers ranging in MW from 1-20 x 10(6). Simultaneously the pro piece of vWF is cleaved, releasing a 741 amino acid peptide known as vW Ag II from the polymerised protomers. Two distinct secretion pathways are found in the endothelial cell, a regulated pathway with storage in Weibl-Palade bodies and a constitutive pathway. Platelets store vWF in their alpha-granules. Mature vWF participates in platelet adhesion, spreading and aggregation and is a carrier of factor VIII, protecting the latter from degradation. Disorders of vWF are highly diverse. At least 20 subtypes of von Willebrand's disease have been described to date, based on features of the vWF present in or absent from patients plasma and platelets. Some patients have reduced amounts of apparently normal vWF whilst others have clearly abnormal vWF with aberrant structure and function. Rare patients virtually or completely lack vWF. The genetic and structural basis of some of these abnormalities is just beginning to emerge. This article outlines the molecular biology and physiology of vWF, and reviews some recent progress on the molecular pathology and genetics of von Willebrand's disease.

Topics: Animals; Chromosomes, Human, Pair 12; Deamino Arginine Vasopressin; DNA; Factor VIII; Gene Expression Regulation; Genes; Hemostasis; Humans; Platelet Adhesiveness; Protein Processing, Post-Translational; Swine; Swine Diseases; von Willebrand Diseases; von Willebrand Factor

Topics: Deamino Arginine Vasopressin; Dental Care for Disabled; Hemostatic Techniques; Humans; von Willebrand Diseases

Desmopressin (1-deamino-8-D-arginine vasopressin, abbreviated DDAVP) is a synthetic analogue of the antidiuretic hormone L-arginine vasopressin. Because it can raise circulating levels of factor VIII coagulant activity (FVIII) and von Willebrand factor and shorten the prolonged bleeding time, DDAVP is established as a nontransfusional form of treatment for mild and moderate hemophilia and von Willebrand disease. Recently, DDAVP has also been purported to be useful for shortening the prolonged skin bleeding times that occur with uremia, cirrhosis, and platelet dysfunctions of various etiologies. Finally, there is evidence from controlled clinical trials that DDAVP can reduce blood loss and transfusion requirements for hemostatically normal individuals undergoing spinal fusion surgery and for patients undergoing cardiopulmonary bypass surgery. The purpose of this report is to review the therapeutic applications of DDAVP in congenital and acquired bleeding disorders and to discuss areas in which further basic and clinical research is needed.

Topics: Blood Coagulation Disorders; Deamino Arginine Vasopressin; Hemophilia A; Humans; Tachyphylaxis; Uremia; von Willebrand Diseases

von Willebrand disease (vWD) is a bleeding disorder characterized by a complex hemostatic defect. Abnormal platelet function, usually reflected by a prolonged bleeding time, is the result of a quantitative or qualitative defect of von Willebrand factor (vWF). A secondary deficiency of factor VIII procoagulant protein (factor VIII) may occur leading to a coagulation defect as well. These two glycoprotein macromolecules circulate as a complex in plasma. This article will review current understanding of structures and functions of vWF factor and factor VIII as they relate to the pathogenesis, diagnosis, classification and therapy of vWD.

Topics: Carbohydrates; Carrier State; Chemical Precipitation; Cold Temperature; Deamino Arginine Vasopressin; Factor VIII; Humans; Immunologic Tests; Plasma Exchange; von Willebrand Diseases; von Willebrand Factor

Von Willebrand's disease (vWD), one of the most frequent hereditary bleeding disorders, is associated with a deficiency or a defective structure of von Willebrand factor (vWF). The defect is transmitted by autosomal inheritance. vWF is a plasma glycoprotein which mediates platelet adherence to the subendothelium of the injured blood vessel and is thus indispensable for primary hemostasis. vWF is composed of identical subunits linked together by disulfide bridges. Each subunit contains binding site(s) for factor VIII, collagen and platelets. The highly polymeric vWF factor is the largest known plasma protein. Functional activity is preferentially associated with the largest multimeric forms of vWF. Binding of vWF onto collagen fibrils activates its platelet binding sites, which are apparently not accessible in circulating vWF. Aggregation of washed fixed platelets in the presence of ristocetin or collagen is used for assessment of vWF's biological activity. Important additional information for the diagnosis of vWD is provided by the antigen assay and by electrophoretic analysis of the multimeric pattern of vWF. In type I vWD, all polymeric forms of vWF are reduced in the same proportion, while only the largest, i.e. the most active, multimers are deficient in type II vWD. The most severe type III vWD is characterized by an undetectable concentration of vWF. DDAVP corrects the prolonged bleeding time in patients with mild forms of vWD. Cryoprecipitate or "virus inactivated" factor VIII concentrates are employed for substitution therapy. Our results suggest that the newly introduced "virus inactivated" factor VIII concentrate from SRK is likewise suitable for this purpose.

Topics: Deamino Arginine Vasopressin; Factor VIII; Female; Humans; Male; von Willebrand Diseases; von Willebrand Factor

At this time, when the acquired immunodeficiency syndrome, hepatitis, and other blood-borne diseases threaten patients, with bleeding disorders, who need treatment with blood products, it is rewarding to realize that a number of them can be safely and effectively treated through the stimulation of their own VIII:C and vWF production with desmopressin. Desmopressin is clinically useful for treatment of patients with moderate and mild hemophilia. The limits of the clinical indications are the nature of the bleeding episode, the resting factor level, the level that must be achieved, and the length of time the level must be maintained to manage any given bleeding episode. Desmopressin can be used more extensively to raise VIII:C in von Willebrand's disease, than in classic hemophilia, because fewer of the patients have the severe form of the disease that is unresponsive to desmopressin. VIII:C increases to about four times the resting values that can be expected in both hemophilia and von Willebrand's disease, but it must be kept in mind that the range of individual responses is large. Even though it is not easy to correct the prolonged bleeding time, particularly in patients with dysfunctional vWF, this drawback is of clinical importance for only a minority of cases. Use of desmopressin in acquired diseases of primary hemostasis has been proposed more recently, and our experience is more limited than for congenital bleeding disorders. Uremia is probably the most firmly established indication, because the bleeding time is often dramatically shortened by desmopressin, and hemorrhages can be stopped or prevented. The indications for the compound in liver cirrhosis and congenital and acquired platelet dysfunctions are promising but much less well-established. The mechanism of action of desmopressin is not well-known, and more work must be done to fill this important gap. This problem is not only of theoretical importance, because understanding of the mechanism of action of the compound should open up new perspectives into understanding the physiological mechanisms that regulate hemostasis. Many unclarified aspects of the mechanism of desmopressin action might be elucidated by using specific antagonists and also by using appropriate animal models. (Dogs and primates respond partially to desmopressin, but rats and rabbits do not respond at all).(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Hemorrhagic Disorders; Humans; Uremia; von Willebrand Diseases

The complex interactions of platelets, von Willebrand factor (VWF), and vascular endothelium have been explored by many investigators during the last decade. With the development of better methods to assess these components has come an increased recognition of diseases associated with defects in the platelet-VWF interaction. Moreover, alternative therapeutic approaches have become available for the clinician who treats patients with disorders of VWF function.

Topics: Aminocaproic Acid; Antibodies, Monoclonal; Blood Platelets; Blood Vessels; Collagen; Deamino Arginine Vasopressin; Diagnosis, Differential; Electrophoresis, Agar Gel; Factor VIII; Genes; Glycoproteins; Hemostasis; Humans; Membrane Proteins; Platelet Adhesiveness; Platelet Membrane Glycoproteins; Protein Binding; von Willebrand Diseases; von Willebrand Factor

At a time when the acquired immunodeficiency syndrome as well as hepatitis and other blood-borne diseases are a threat to patients with bleeding disorders who need treatment with blood products, it is rewarding to realize that a number of these patients can be safely and effectively treated with their own desmopressin-stimulated F.VIII:C and vWF. Desmopressin is clinically useful for treatment of patients with moderate and mild hemophilia. The limits of the clinical indications are established by the nature of the bleeding episode, the resting factor level, the level that must be achieved, and the length of time the level must be maintained to manage any given bleeding episode. In von Willebrand disease, desmopressin can be used more extensively to raise F.VIII:C levels than in classic hemophilia, because fewer of the patients have the severe form of the disease that is unresponsive to desmopressin. Increases in the level of F.VIII:C of about four times the resting value can be expected both in hemophilia and von Willebrand disease, but it must be borne in mind that the range of individual responses is large. Even though it is not easy to correct the prolonged bleeding time, particularly in patients with dysfunctional vWF, this drawback is of clinical relevance only in a minority of cases. A role for the use of desmopressin in acquired diseases of primary hemostasis has been proposed more recently, and experience is more limited than in congenital bleeding disorders. Uremia is probably the most firmly established indication because it has been shown that the bleeding time is often dramatically shortened by desmopressin, and hemorrhages can be stopped or prevented before surgical procedures. The indications for use of the compound in liver cirrhosis and congenital and acquired platelet dysfunctions are promising but much less established from a clinical standpoint. The bulk of available clinical experience is based on intravenous administration. Intranasal and subcutaneous administration have been successfully attempted and might be more convenient in selected circumstances, such as home treatment and the stimulation of blood donors to provide more abundant supplies of F.VIII:C and vWF. However, the responses after intranasal administration are less predictable and consistent than after intravenous administration. Desmopressin has few troublesome side-effects. Mild facial flushing, a small increase in heart rate, and, more rarely, mild headache can occur t

Topics: Administration, Cutaneous; Administration, Intranasal; Amino Acid Sequence; Blood Coagulation Disorders; Deamino Arginine Vasopressin; Endothelium; Factor VIII; Fibrinolysis; Hemophilia A; Hemostasis; Humans; Injections, Intravenous; Tachyphylaxis; Uremia; von Willebrand Diseases; von Willebrand Factor

Topics: Blood Platelet Disorders; Blood Transfusion; Deamino Arginine Vasopressin; Hemorrhage; Hepatitis, Viral, Human; Humans; Infant, Newborn; Plasma Exchange; Platelet Transfusion; Purpura; Purpura, Thrombocytopenic; Purpura, Thrombotic Thrombocytopenic; Thrombocytopenia; Transfusion Reaction; von Willebrand Diseases

Desmopressin (dDAVP), a synthetic analog of the neurohypophyseal nonapeptide arginine vasopressin, has enhanced antidiuretic potency, markedly diminished pressor activity, and a prolonged half-life and duration of action compared to the natural hormone. Desmopressin is the treatment of choice for central diabetes insipidus and can be administered either intranasally or parenterally. A newly approved indication is treatment of mild classical hemophilia and von Willebrand's disease, in which deficient concentrations of factor VIII and von Willebrand's factor are transiently increased to levels that allow minor surgery.

Topics: Anemia, Sickle Cell; Animals; Arginine Vasopressin; Deamino Arginine Vasopressin; Diabetes Insipidus; Drug Synergism; Enuresis; Hemophilia A; Humans; Kidney Concentrating Ability; Learning; Memory Disorders; Structure-Activity Relationship; Urinary Incontinence; von Willebrand Diseases

Topics: Blood Platelets; Blood Vessels; Chemical Phenomena; Chemistry; Deamino Arginine Vasopressin; Diagnosis, Differential; Female; Genes, Dominant; Genes, Recessive; Genetic Counseling; Humans; Syndrome; von Willebrand Diseases; von Willebrand Factor

Topics: Acquired Immunodeficiency Syndrome; Analgesics; Anti-Inflammatory Agents; Antifibrinolytic Agents; Blood Transfusion; Child; Child, Preschool; Danazol; Deamino Arginine Vasopressin; Factor IX; Factor VIII; Fibrinogen; Hemarthrosis; Hemophilia A; Hemorrhage; Humans; Infant; Infant, Newborn; Male; Plasma; von Willebrand Diseases

Treatment of hemophilia and von Willebrand's disease has become easier in recent years because of the development of more effective factor replacement products. The median age and the life expectancy of patients with hemophilia have risen markedly, as has the median age at death.

Topics: Acquired Immunodeficiency Syndrome; Antigens; Blood Coagulation Factors; Cerebral Hemorrhage; Danazol; Deamino Arginine Vasopressin; Factor VIII; Female; Gastrointestinal Hemorrhage; Hemophilia A; Hemorrhage; Hepatitis B; Hepatitis C; Humans; Pregnancy; Surgical Procedures, Operative; Thrombosis; Tooth Extraction; von Willebrand Diseases

Topics: Blood Coagulation Factors; Blood Coagulation Tests; Deamino Arginine Vasopressin; Factor VIII; Female; Fibrinogen; Genes, Dominant; Genetic Variation; Humans; Male; Pedigree; von Willebrand Diseases; von Willebrand Factor

Topics: Animals; Antigens; Bleeding Time; Blood Platelets; Blood Transfusion; Cattle; Chemical Phenomena; Chemistry, Physical; Deamino Arginine Vasopressin; Disease Models, Animal; Endothelium; Factor VIII; Fibrinogen; Glycoproteins; Humans; Megakaryocytes; Platelet Adhesiveness; Rabbits; Swine; von Willebrand Diseases; von Willebrand Factor

Von Willebrand factor (VWF) and factor VIII (FVIII) circulate in a noncovalent complex in blood and promote primary hemostasis and clotting, respectively. A new VWF A1-domain binding aptamer, BT200, demonstrated good subcutaneous bioavailability and a long half-life in non-human primates. This first-in-human, randomized, placebo-controlled, doubleblind trial tested the hypothesis that BT200 is well tolerated and has favorable pharmacokinetic and pharmacodynamic effects in 112 volunteers. Participants received one of the following: a single ascending dose of BT200 (0.18-48 mg) subcutaneously, an intravenous dose, BT200 with concomitant desmopressin or multiple doses. Pharmacokinetics were characterized, and the pharmacodynamic effects were measured by VWF levels, FVIII clotting activity, ristocetin-induced aggregation, platelet function under high shear rates, and thrombin generation. The mean half-lives ranged from 7-12 days and subcutaneous bioavailability increased dose-dependently exceeding 55% for doses of 6-48 mg. By blocking free A1 domains, BT200 dose-dependently decreased ristocetin-induced aggregation, and prolonged collagen-adenosine diphosphate and shear-induced platelet plug formation times. However, BT200 also increased VWF antigen and FVIII levels 4-fold (P<0.001), without increasing VWF propeptide levels, indicating decreased VWF/FVIII clearance. This, in turn, increased thrombin generation and accelerated clotting. Desmopressin-induced VWF/FVIII release had additive effects on a background of BT200. Tolerability and safety were generally good, but exaggerated pharmacology was seen at saturating doses. This trial identified a novel mechanism of action for BT200: BT200 dose-dependently increases VWF/FVIII by prolonging half-life at doses well below those which inhibit VWF-mediated platelet function. This novel property can be exploited therapeutically to enhance hemostasis in congenital bleeding disorders.

Topics: Deamino Arginine Vasopressin; Factor VIII; Humans; Ristocetin; Thrombin; von Willebrand Diseases; von Willebrand Factor

Von Willebrand disease (VWD) is a bleeding disorder, caused by a deficiency or defect of von Willebrand factor (VWF). In case of medical procedures or bleeding, patients are treated with desmopressin and/or VWF-containing concentrates to increase plasma VWF and factor VIII (FVIII). However, in many cases these factor levels are outside the targeted range. Therefore, population pharmacokinetic (PK) models have been developed, which aim to quantify and explain intraindividual and interindividual differences in treatment response. These models enable calculation of individual PK parameters by Bayesian analysis, based on an individual desmopressin test or PK profile with a VWF-containing concentrate. Subsequently, the dose necessary for an individual to achieve coagulation factor target levels can be calculated.. Primary aim of this study is to assess the predictive performance (the difference between predicted and measured von VWF activity and FVIII levels) of Bayesian forecasting using the developed population PK models in four different situations: (A) desmopressin testing (n≥30); (B) medical procedures (n=70; 30 receiving desmopressin, 30 receiving VWF-containing concentrate and 10 receiving a combination of both); (C) bleeding episodes (n=20; 10 receiving desmopressin and 10 receiving VWF-containing concentrate) and (D) prophylaxis with a VWF-containing concentrate (n=3 to 5). Individuals with all types of VWD and individuals with low VWF (VWF 0.30-0.60 IU/mL) will be included. Reliability and feasibility of PK-guided dosing will be tested by assessing predictive performance, treatment duration, haemostasis, patient satisfaction and physician satisfaction.. The OPTI-CLOT:to WiN study was approved by the medical ethics committee of the Erasmus MC, University Medical Centre Rotterdam, the Netherlands. Results of the study will be communicated through publication in international scientific journals and presentation at (inter)national conferences.. NL7212 (NTR7411); Pre-results, EudraCT 2018-001631-46.

Topics: Bayes Theorem; Deamino Arginine Vasopressin; Humans; Multicenter Studies as Topic; Reproducibility of Results; von Willebrand Diseases; von Willebrand Factor

Von Willebrand disease (VWD) is the most prevalent inherited bleeding disorder. Diagnosis requires measurement of VWF-platelet binding function, for which VWF ristocetin cofactor activity (VWF:RCo) is the reference method. Recently, an automated latex particle-enhanced immunoturbidimetric von Willebrand factor activity assay (VWF:Ab) has been validated showing superior characteristics. We further validate VWF:Ab in a prospective study including post-treatment patient samples.. A total of 1151 samples were collected from patients tested for VWD, including 119 samples from patients treated with desmopressin or VWF replacement product. All samples were tested for VWF:Ab and VWF:RCo, and the methods were compared using linear regression. Imprecision, linearity and lower detection limit were determined for both assays.. VWF:Ab showed improved precision compared to VWF:RCo. Linear regression of VWF:Ab and VWF:RCo across all samples exhibited good agreement (R. Our analysis validates the VWF:Ab assay in a prospective study of a large cohort of patient samples and extends these results to post-treatment patient samples.

Topics: Deamino Arginine Vasopressin; Female; Humans; Latex; Male; Prospective Studies; von Willebrand Diseases; von Willebrand Factor

Analyses of the bleeding tendency by means of the bleeding score (BS) have been proposed until now to confirm diagnosis but not to predict clinical outcomes in patients with inherited von Willebrand disease (VWD). We prospectively followed up, for 1 year, 796 Italian patients with different types of VWD to determine whether the previous BS of European VWD1 is useful to predict the occurrence of spontaneous bleeds severe enough to require replacement therapy with desmopressin (DDAVP) and/or von Willebrand factor (VWF)/factor VIII concentrates. Among the 796 patients included, 75 (9.4%) needed treatment of 232 spontaneous bleeding events. BS >10 and VWF:ristocetin cofactor activity <10 U/dL were associated with the risk of bleeding, but only a BS >10 remained highly associated in a multivariable Cox proportional hazard model (adjusted hazard ratio: 7.27 [95% confidence interval, 3.83-13.83]). Although the bleeding event-free survival was different in VWD types, only a BS >10 could predict for each type which patient had bleeding events severe enough to require treatment with DDAVP and/or concentrates. Therefore, BS can be considered a simple predictor of clinical outcomes of VWD and may identify patients needing intensive therapeutic regimens.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Deamino Arginine Vasopressin; Disease-Free Survival; Factor VIII; Female; Follow-Up Studies; Hemorrhage; Hemostatics; Humans; Male; Middle Aged; Prospective Studies; Risk Factors; Severity of Illness Index; Survival Rate; von Willebrand Diseases; von Willebrand Factor

Desmopressin (DDAVP) is the treatment of choice in those with mild von Willebrand disease (VWD), yet 20% are unresponsive to DDAVP, and among the 80% who respond, the response is transient, as endothelial stores are depleted after three days. We, therefore, conducted a single-center Phase II clinical trial to determine safety and biologic efficacy of recombinant interleukin-11 (rhIL-11, Neumega®) in patients with VWD unresponsive or allergic to DDAVP, or mild or moderate haemophilia A (HA). Increases in VWF:RCo wer e observed by 48 hours after rhIL-11, with a 1.54-fold increase by Day 4, 1.30-fold in VWD and 1.73-fold in HA. Similarly, by 48 hours, increases in VIII:C were observed, with a 1.65-fold increase by Day 4, 1.86-fold in VWD and 1.48-fold in HA. Platelet VWFmRNA expression by qPCR increased 0.81-fold but did not correlate with plasma VWF:Ag responses. rhIL-11 was well tolerated, with grade 1 or less fluid retention, flushing, conjunctival erythema, except for transient grade 3 hyponatraemia in one subject after excess fluid intake for diabetic hyperglycaemia, which resolved with fluid restriction. In summary, rhIL-11 increases VWF levels in two of four DDAVP-unresponsive or allergic VWD and F.VIII levels in four of five mild or moderate haemophilia A subjects, suggesting its potential use in treatment of these disorders.

Topics: Adult; Biomarkers; Deamino Arginine Vasopressin; Drug Resistance; Factor VIII; Female; Hemophilia A; Hemostatics; Humans; Interleukin-11; Male; Middle Aged; Pennsylvania; Prospective Studies; Protein Multimerization; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Severity of Illness Index; Time Factors; Treatment Outcome; von Willebrand Diseases; von Willebrand Factor; Young Adult

Accelerated clearance of von Willebrand factor (VWF) has been recently identified as a major pathophysiologic mechanism inducing low VWF in some patients with von Willebrand disease (VWD). The frequency of bleeding and the best treatment of these patients have never been evaluated prospectively in large series of patients. It was the aim of the present study to prospectively evaluate clinical events of 60 heterozygous patients with VWD Vicenza (VWD-VI) carrying R1205H VWF mutation and 23 with C1130F mutation, both characterised by markedly increased VWF clearance. During 71 months of follow-up, 65% of patients with VWD-VI and 61% with C1130F required treatment. The rate of spontaneous bleeding requiring consultation/treatment was 7.5/100 patients-year in patients with C1130F mutation vs. 1.9/100 patients-year in those with R1205H (p=0.004). This difference persisted also by multivariate analysis adjusted for sex, age and blood group (hazard ratio [HR]=3.3 for C1130F, 95% confidence interval [CI] 1.16-9.27) and females were at greater risk of bleeding (HR=3, 95%CI 1.01-9.93) because of menorrhagia. Only 3/15 (20 %) women in fertile age with VWD-VI compared to 8/9 (89 %) with C1130F mutation required consultation/treatment for menorrhagia (iron supplementation, combined oral contraceptives, tranexamic acid). Almost all dental extractions, minor surgeries and deliveries occurring during follow-up were successfully managed with desmopressin. Major surgery required factor VIII/VWF concentrates, but a few cases benefited from desmopressin. In conclusion, similar to patients with type 1 VWD, also in patients with increased VWF clearance desmopressin maintains a major therapeutic role.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Deamino Arginine Vasopressin; Female; Follow-Up Studies; Hemorrhage; Hemostatics; Humans; Infant; Italy; Male; Menorrhagia; Middle Aged; Mutation; Prospective Studies; Risk; Sex Factors; von Willebrand Disease, Type 1; von Willebrand Diseases; von Willebrand Factor

von Willebrand factor (VWF) is a multimeric glycoprotein that mediates platelet adhesion and is decreased in von Willebrand disease (VWD). 1-8 deamino-d-arginine vasopressin (DDAVP), the most common treatment for VWD, is limited by tachyphylaxis and inconvenience, and in 20% of the patients, unresponsiveness. Recombinant human interleukin-11 (rhIL-11), a gp-130 signalling cytokine with haematopoietic and anti-inflammatory activity, increases VWF antigen and its activity in heterozygous VWF(+/-) mice and dogs. To determine the biological efficacy and safety of rhIL-11 in non-bleeding human subjects with mild VWD, we conducted a phase II prospective open-label trial of rhIL-11 at 10, 25 and 50 mug kg(-1) subcutaneously (s.c.), given daily for 7 days in nine subjects with mild VWD. VWF and factor VIII (FVIII) levels increased gradually and progressively after s.c. rhIL-11, which was sustained through 7 days of dosing to 1.5- to 3-fold over baseline. Following intravenous DDAVP, 0.3 mug kg(-1), on day 7 there was a further boost in VWF and FVIII levels, suggesting that the mechanism of rhIL-11 differs from that of DDAVP. Platelet VWF mRNA expression measured by quantitative PCR increased from two- to eightfold over baseline, suggesting that the mechanism of rhIL-11 effect may be upregulation of VWF mRNA. VWF and FVIII levels returned to baseline by day 14. rhIL-11 was well tolerated with less than grade-1 hypertension, hypokalaemia and fluid retention. Recombinant IL-11 increases VWF levels in humans with mild VWD, justifying future clinical trials to determine its potential in preventing or reducing bleeding in this patient population.

Topics: Adult; Deamino Arginine Vasopressin; Dose-Response Relationship, Drug; Drug Administration Schedule; Factor VIII; Female; Hemostatics; Humans; Injections, Subcutaneous; Interleukin-11; Male; Platelet Count; Polymerase Chain Reaction; Prospective Studies; Recombinant Proteins; RNA, Messenger; von Willebrand Diseases; von Willebrand Factor; Young Adult

We have prospectively evaluated the biologic response to desmopressin in 77 patients with type 1 von Willebrand disease (VWD) enrolled within the Molecular and Clinical Markers for the Diagnosis and Management of type 1 VWD project. Complete response to desmopressin was defined as an increase of both ristocetin cofactor activity (VWF:RCo) and factor VIII coagulant activity (FVIII:C) to 50 IU/dL or higher and partial response as VWF:RCo or FVIII:C lower than 50 IU/dL after infusion, but at least 3-fold the basal level. Complete response was observed in 83% of patients; partial in 13%; and no response in 4%. Patients with some abnormality of VWF multimeric pattern had significantly lower basal FVIII:C and VWF, lower VWF:RCo/Ag ratio, and less complete responses to desmopressin than patients with a normal multimeric pattern (P=.002). Patients with mutations at codons 1130 and 1205 in the D'-D3 domain had the greatest relative increase, but shortest FVIII and VWF half-lives after infusion. Most partial and nonresponsive patients had mutations in the A1-A3 domains. Response to desmopressin in these VWD patients seemed to be associated with the location of the causative mutation. The presence of subtle multimeric abnormalities did not hamper potential clinically useful responses, as in typical type 1 VWD.

Topics: Adolescent; Adult; Aged; Blood Coagulation Tests; Child; Deamino Arginine Vasopressin; Factor VIII; Female; Genotype; Hemostatics; Humans; Male; Middle Aged; Mutation; Prospective Studies; Protein C; Protein Structure, Tertiary; Ristocetin; von Willebrand Diseases

Reduced plasma survival of von Willebrand factor (VWF) may contribute towards the pathogenesis of type 1 von Willebrand disease (VWD). However, little is known about mechanism(s) of VWF clearance and factors that may affect it. The half-life of VWF-related parameters following the administration of DDAVP was measured in 26 patients with type 1 VWD and 10 haemophilia A controls. Binding of lectins Ricinus communis (RCA-I) and Erythina crystagalli (ECA) agglutinins to VWF and VWF susceptibility to ADAMTS-13-mediated proteolysis were investigated. Sequence analysis of targeted regions of the VWF gene was performed to inspect for mutations that have been associated with increased clearance. Post-DDAVP clearance of VWF was increased approximately three-fold in the type 1 VWD cohort overall. However this was not shown to consistently associate with steady-state VWF antigen (VWF:Ag) levels. Furthermore, increased VWF clearance was not consistently associated with increased ratios of VWF propeptide (VWFpp) to VWF:Ag indicating that a normal ratio does not necessarily reflect normal post-DDAVP survival in type 1 VWD patients. RCA-I and ECA binding to VWF were increased in type 1 VWD patients and, although inversely correlated with VWF levels, this was independent of VWF clearance. There was no association between VWF clearance and ADAMTS-13-mediated proteolysis. Three novel candidate mutations with an increased clearance phenotype were identified. The data are consistent with heterogeneity in pathogenic mechanisms in type 1 VWD and are consistent with type 1 VWD representing a complex genetic trait.

Topics: ADAM Proteins; ADAMTS13 Protein; Cohort Studies; Deamino Arginine Vasopressin; DNA Mutational Analysis; Female; Genetic Predisposition to Disease; Genotype; Glycosylation; Half-Life; Hemostatics; Humans; Infusions, Intravenous; Male; Mutation; Phenotype; Plant Lectins; Protein Binding; Protein Precursors; Protein Processing, Post-Translational; Treatment Outcome; von Willebrand Diseases; von Willebrand Factor

Type 2M von Willebrand disease (VWD) Vicenza is characterized by the presence of ultra-large von Willebrand factor (VWF) multimers in plasma and very low factor VIII (FVIII)/VWF measurements. So far, R1205H mutation, alone or associated with M740I defect, has been constantly detected in these patients. No data on FVIII/VWF changes after desmopressin and during pregnancy in patients with phenotypic VWD Vicenza has been reported.. To evaluate biological responsiveness to desmopressin, the FVIII/VWF changes during pregnancy and the clinical outcome in pregnancies and deliveries of six primipara with type 2M VWD Vicenza prospectively followed.. Three women with single (R1205H) and three with double (R1205H and M740I) mutation in the VWF gene were enrolled in the study. Prior to pregnancy, all patients had undergone desmopressin test-infusion to assess biological responsiveness and its possible clinical usefulness.. The results of test-infusion with desmopressin showed the full normalization of FVIII/VWF measurements, with rapid clearance of all moieties postinfusion. However, FVIII/VWF measurements in patients with double defect remained greater after 4 h than those of patients with single defect. The severely reduced basal FVIII/VWF measurements did not change during pregnancy, although somewhat higher VWF levels were observed in patients with double defect. Five out of six women underwent successful delivery under desmopressin prophylaxis, without immediate or delayed bleeding and only one was given a FVIII/VWF concentrate because of a cesarean section.. Delivery in women with VWD type 2M Vicenza is safely managed by using desmopressin, despite the fact that basal low FVIII/VWF is not significantly increased during the pregnancy.

Topics: Adult; Deamino Arginine Vasopressin; Factor VIII; Female; Genotype; Hemostatics; Humans; Phenotype; Point Mutation; Pregnancy; Pregnancy Complications, Hematologic; Prospective Studies; von Willebrand Diseases; von Willebrand Factor

This study prospectively evaluated the rate of biologic response to desmopressin (DDAVP) in 66 patients with type 1 or 2 von Willebrand disease (VWD), each of whom had, on the basis of available records, a clinically significant bleeding history and at least one of the following laboratory abnormalities: bleeding time (BT) longer than 15 minutes, ristocetin cofactor activity (VWF:RCo) less than 10 IU/dL, factor VIII coagulant activity (FVIII:C) less than 20 IU/dL (severe VWD). Before the study, responsive patients were defined as those who, 2 hours after infusion of 0.3 microg/kg DDAVP, had increased baseline values of VWF:RCo and FVIII:C by at least 3-fold and achieved levels of at least 30 IU/dL for both and a BT of 12 minutes or less. The rate of biologic response varied according to VWD types and was higher in type 1 (7 of 26, 27%) than in type 2 (7 of 40, 18%) (type 2A [1 of 15, 7%], type 2M [3 of 21, 14%], type 2N [3 of 4, 75%]). Mutations in the VWF gene were previously known or newly identified in most patients with types 2A (n = 15 of 15), 2M (n = 15 of 21), and 2N (n = 4 of 4), but in none of those with type 1 VWD. Genotype provided more information than phenotype in predicting individual responses to DDAVP only in patients with 2A and 2N VWD. This prospective study showed that the rate of biologic response to DDAVP is relatively low not only in type 2 but also in type 1 VWD when uniform and stringent criteria for patient selection and responsiveness are applied.

Topics: Adolescent; Adult; Aged; Child; Deamino Arginine Vasopressin; Europe; Genotype; Hemostatics; Humans; Middle Aged; Phenotype; Point Mutation; Prospective Studies; Severity of Illness Index; Treatment Outcome; von Willebrand Diseases

In a prospective study, 254 of 5649 unselected patients scheduled for surgery at our hospital were identified preoperatively as having either acquired (n=182) or inherited (n=72) impaired primary hemostasis (platelet dysfunction including von Willebrand disease). All patients were initially pretreated with desmopressin (DDAVP). Response to DDAVP or subsequent treatment(s) was defined as correction of any one of the abnormal PFA-100 platelet function tests. The non-responders were additionally treated with tranexamic acid or aprotinin; those with von Willebrand disease (vWD) received factor VIII concentrates with von Willebrand factor (vWF). Those still unresponsive to therapy received conjugated estrogens and, as a last attempt, a platelet transfusion. The administration of DDAVP led to a correction of platelet dysfunction in 229 of the 254 patients treated (90.2%). Tranexamic acid was effective in 12 of 16, aprotinin in 3 of 5, and factor VIII concentrates with vWF in all 4 patients with unresponsive to DDAVP. The remaining 6 patients were pretreated with conjugated estrogens, and 2 of these patients were additionally treated with platelet transfusion. The frequency of blood transfusion was lower, but not statistically significant (9.4% vs. 12.2%: p = 0.202) in preoperatively treated patients with impaired hemostasis than in patients without impaired hemostasis. In a retrospective group, the frequency of blood transfusion was statistically significant higher (89.3% vs. 11.3%: p < 0.001) in patients without preoperative correction of impaired hemostasis than in patients without impaired hemostasis. Preoperative correction of impaired primary hemostasis is possible in nearly all patients affected, and results in a reduction of homologous blood transfusions.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bleeding Time; Blood Platelet Disorders; Blood Platelets; Blood Transfusion; Deamino Arginine Vasopressin; Female; Hemostasis; Humans; Male; Middle Aged; Preoperative Care; von Willebrand Diseases

Topics: Deamino Arginine Vasopressin; Female; Hemostatics; Humans; Infant, Newborn; Postpartum Hemorrhage; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Outcome; Time Factors; Treatment Outcome; von Willebrand Diseases

To assess DDAVP (1-deamino-8-d-arginine vasopressin; desmopressin) nasal spray in the management of menorrhagia in patients with inherited bleeding disorders, 39 women (aged 18-50 years) with menorrhagia were recruited and were randomized to start 2 months' therapy with placebo or DDAVP (300 micro g) spray in a double-blind crossover study. Twenty-eight and 24 completed first and second period of treatment, respectively. Menstrual loss was assessed using the pictorial blood assessment chart (PBAC) during each treatment period. The main outcome measure was comparison of PBAC scores following DDAVP and placebo treatments. The safety of DDAVP spray was also assessed by monitoring side-effects. Overall, PBAC scores were significantly lower in the second treatment period than the first (P = 0.01). After adjusting for this differences, mean PBAC scores were slightly lower (mean difference 8; 95% confidence interval of - 15.5 to 31.6) in women receiving DDAVP than when receiving placebo, although this difference was not statistically significant (P = 0.51). In conclusion, although there was an indication that menstrual bleeding was less heavy when women received DDAVP than when receiving placebo, the small sample size meant that this difference was not significant.

Topics: Administration, Intranasal; Adolescent; Adult; Blood Coagulation Disorders, Inherited; Cross-Over Studies; Deamino Arginine Vasopressin; Double-Blind Method; Female; Hemostatics; Humans; Menorrhagia; Middle Aged; Treatment Outcome; von Willebrand Diseases

In the present study, we prospectively evaluated the contribution of the von Willebrand factor collagen-binding activity (vWF:CBA) assay, vWF multimeric analysis, and the response to intravenous desmopressin (DDAVP) to correctly diagnose and classify congenital von Willebrand disease (CvWD) in 24 probands with mild to moderate type 1 vWD, 6 probands with severe CvWD type 1, and 12 probands with type 2 CvWD. CvWD type 1 of mild to moderate severity is featured by proportionally decreased levels of vWF antigen (vWF:Ag), vWF ristocetin cofactor activity (vWF:RCof), and vWF:CBA between 0.20 and 0.60 u/mL and a normal response to DDAVP of factor (F) VIIIc and all vWF parameters. Severe type 1 CvWD with vWF parameters below 0.10 or 0.20 u/mL is associated with a decreased response to DDAVP of all vWF parameters, indicating a defective synthesis or secretion vWF by endothelial cells, or both. CvWD 2M may present as severe type 1 CvWD, as type 1 "platelet-discordant" CvWD, or with the combination of a discrepant vWF:RCof/Ag ratio and the presence of all vWF multimers. Ristocetin-induced platelet aggregation (RIPA) is normal in type 1 CvWD. CvWD 2M is typically featured by decreased RIPA, normal or near normal vWF multimers, and no or only a poor response to DDAVP of vWF:RCof as compared with a fairly good response to DDAVP of vWF:Ag and vWF:CBA. CvWD Vicenza is characterized by unusually large vWF multimers and very low levels of FVIIIc, vWF:Ag, and vWF:RCof. CvWD Vicenza differs from CvWD 2M because the vWF:RCof/Ag ratios are completely normal before and after DDAVP; the response to DDAVP is equally good for FVIIIc, vWF:Ag, vWF:RCof, and vWF:CBA and is followed by very short half-life times for FVIIIc and all vWF parameters. Pertinent findings in type 2A and 2B CvWD included prolonged Ivy bleeding time (BT), low vWF:RCof/Ag and vWF:CBA ratios, absence of the high vWF multimers, and, depending on the severity of the absence of intermediate vWF multimers, pronounced increase of low vWF multimers and vWF degradation products because of increased proteolysis of the high and intermediate vWF multimers. RIPA is normal in CvWD 2A and increased in CvWD 2B. The response to DDAVP in CvWD 2A is normal for FVIIIc and vWF:Ag but is transient with partial correction and short half-life times of vWF:CBA and vWF:RCof. DDAVP does not correct BT and multimeric patterns in CvWD type 2B, despite significant increase of vWF parameters. CvWD types 2C, 2D, and 2E are featured by very

Topics: Adult; Bleeding Time; Cohort Studies; Collagen; Deamino Arginine Vasopressin; Dimerization; Factor VIII; Family Health; Female; Humans; Male; Middle Aged; Prospective Studies; Protein Binding; Severity of Illness Index; von Willebrand Diseases; von Willebrand Factor

The objective of the study was to evaluate the safety and efficacy of high-concentration intranasal desmopressin (HCIN-DDAVP) 1.5 mg/mL, in patients weighing < or = 50 kg with mild hemophilia A or mild type 1 von Willebrand disease (VWD).. This was a single-center, nonrandomized, open-label, single-dose trial of HCIN-DDAVP. Nine boys with hemophilia A, 8 girls with mild VWD, and 8 boys with mild VWD were evaluated. HCIN-DDAVP responses were compared with historic IV-DDAVP responses in 13 of the patients.. HCIN-DDAVP administration resulted in statistically significant mean increases in factor VIII procoagulant activity, ristocetin cofactor, and von Willebrand factor antigen levels in each of the 3 study groups. Mean (+/- 1 SD) increase in factor VIII procoagulant activity was 25.7 +/- 11.9 U/dL in mild hemophilia A. Ristocetin cofactor increased 108.5 +/- 53.8 U/dL in girls and 95.8 +/- 36.0 U/dL in boys with mild VWD. Intravenous desmopressin acetate responses were comparable to HCIN-DDAVP responses in patients who received both preparations. Adverse events were mild and resolved without intervention.. We conclude that administration of 150 microg of high concentration intranasal desmopressin is safe and effective in patients weighing < or = 50 kg with mild hemophilia A or mild type 1 VWD.

Topics: Administration, Intranasal; Adolescent; Analysis of Variance; Child; Child, Preschool; Deamino Arginine Vasopressin; Female; Hemophilia A; Hemostatics; Humans; Infant; Infusions, Intravenous; Male; von Willebrand Diseases

An open-label multicentre trial was conducted to evaluate high-dose DDAVP (desmopressin acetate) intranasal spray (Stimate; 1.5 mg mL(-1)), for the control of bleeding in 333 patients with mild haemophilia A, mild or moderate type 1 von Willebrand disease, or symptomatic carriers of haemophilia A. Overall, 278 patients received 2170 doses of high-dose DDAVP intranasal spray (1.5 mg mL(-1)). Using study-defined guidelines, patients evaluated the efficacy of high-dose DDAVP intranasal spray (1.5 mg mL(-1)) as 'excellent' or 'good' in 743 (95%) of 784 bleeding episodes. It demonstrated 'excellent' results in 384 (93%) of 413 administrations for prophylaxis and in eight of eight uses prior to acute surgical or dental procedures. When used for the treatment of menorrhagia, the efficacy of high-dose DDAVP intranasal spray (1.5 mg mL(-1)) was rated as 'excellent' after 655 (92%) of 721 daily uses. Of 2170 doses of high-dose DDAVP intranasal spray (1.5 mg mL(-1)), 172 (8%) were associated with adverse events. A total of 272 adverse events were reported among 80 patients. Of these, 239 (88%) were mild or moderate in intensity and only one patient was removed from the study due to an adverse event. These results demonstrate the safety and efficacy of high-dose DDAVP intranasal spray (1.5 mg mL(-1)) for control of bleeding episodes in patients with mildly decreased levels of factor VIII, von Willebrand factor, or both.

Topics: Administration, Intranasal; Adolescent; Adult; Blood Loss, Surgical; Child; Child, Preschool; Cohort Studies; Consumer Product Safety; Deamino Arginine Vasopressin; Female; Follow-Up Studies; Hemophilia A; Hemorrhage; Heterozygote; Humans; Male; Menorrhagia; Middle Aged; Therapeutic Equivalency; von Willebrand Diseases

We report our experience with the incidence of adverse events during the use of Stimate brand intranasal desmopressin acetate (IN DDAVP) for patients with haemophilia A (HA) or von Willebrand disease (vWD) after noting two severe adverse events in one adult patient. All patients with documented vWD (type 1 or 2 A) or haemophilia A (mild, moderate or symptomatic carrier) from the Emory Comprehensive Hemophilia Center who had IN DDAVP challenge testing or were using Stimate for treatment of bleeding were evaluated for adverse events by patient report or nursing observation of clinical signs and symptoms. Forty patients were studied. Sixty-eight per cent (27/40) experienced clinical signs and/or symptoms. The majority of these symptoms were mild, however several patients reported moderate to severe side-effects and one adult patient required medical intervention for symptomatic hyponatraemia. In our experience, two-thirds of patients tested experienced adverse signs and/or symptoms with the use of Stimate; considerably higher than that reported from preliminary results in the literature. Young age did not correlate positively with adverse reactions. Severe adverse events requiring medical intervention were rare, however symptoms such as moderate to severe headache, nausea, vomiting and weakness may necessitate evaluation for hyponatraemia. This is the first report of symptomatic hyponatraemia in an adult patient with recommended dosing of Stimate. Side-effects may be minimized if patients adhere to instructions regarding fluid intake and composition while using IN DDAVP.

Topics: Administration, Intranasal; Adolescent; Adult; Age Factors; Child; Child, Preschool; Deamino Arginine Vasopressin; Fatigue; Female; Headache; Hemophilia A; Hemostatics; Heterozygote; Humans; Hyponatremia; Male; Menorrhagia; Middle Aged; Nausea; Potassium; Sex Factors; Sodium; von Willebrand Diseases; Weight Gain

Bleeding after dental extractions is very frequent in patients with von Willebrand disease (vWD) and in the past often necessitated transfusions with factor VIII/von Willebrand factor concentrates (vWFc). To evaluate the benefits of a standard local therapy on bleeding complications during oral surgery, 63 consecutive patients with vWD were analysed retrospectively. All types of vWD were included: type 1 (n=31), type 2 (n=22) and type 3 (n=10). All the patients had dental extractions or periodontal surgery at the same hospital by the same oral surgeons. All cases had been given tranexamic acid (TA) before and for 7 days after surgery. As additional local therapy fibrin glue (FG) was used during surgery in several patients. Additional systemic therapies were: desmopressin (DDAVP, 0.3 microg kg-1) and fVIII/vWF concentrates (vWFc, 40 U kg-1) given as a single dose before surgery. The 29 subjects (46%) treated locally did not bleed. Among the remaining cases, 24 (38%) were given DDAVP as additional systemic therapy and 6 (9.5%) received vWFc. There was bleeding after surgery in only two cases who had been given local FG (type 2 B) or systemic vWFc (type 3), but bleeding was stopped with an additional local application of FG. Our data suggest that a standard local therapy with TA and FG with DDAVP can prevent bleeding complications during oral surgery in the majority of patients (84%) with vWD and reduce the need for concentrates, with all their possible complications and high costs.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Deamino Arginine Vasopressin; Diagnosis, Differential; Disease Management; Factor VIII; Female; Fibrin Tissue Adhesive; Hemorrhage; Hemostasis; Hospitalization; Humans; Male; Middle Aged; Oral Hemorrhage; Oral Surgical Procedures; Periodontal Diseases; Postoperative Hemorrhage; Retrospective Studies; Tooth Extraction; Tranexamic Acid; von Willebrand Diseases; von Willebrand Factor

In von Willebrand disease (vWD) type 1 and mild haemophilia A patients we studied the effect of an infusion of DDAVP (0.3 microg/kg body weight) on thrombin generation in platelet-rich plasma (PRP) and platelet-poor plasma (PPP). Baseline thrombin generation in PRP was diminished both in the haemophilia A and vWD patients. It was normal in vWD plasma when sufficient procoagulant phospholipids were present, either via adding phospholipid vesicles to PPP or via scrambling of the platelet membrane with ionomycin in PRP. In haemophilia A plasma, thrombin generation did not normalize by providing procoagulant phospholipids. Treatment with DDAVP temporarily restored thrombin generation in PRP to normal in both diseases. To investigate the individual roles of von Willebrand factor (vWF) and factor VIII, we also studied the effect of factor VIII infusion on thrombin generation in a severe haemophilia patient. It appears that at a fixed normal vWF concentration, <25% factor VIII is sufficient for normal thrombin generation in PRP. At a sufficient factor VIII concentration, however, thrombin generation is still lower than normal in vWD patients; approximately 40% of vWF is required for half-normal thrombin generation in PRP. It thus appears that vWF is also a clotting factor, in the sense that it is required for normal thrombin generation. This underlines the importance of the interaction between coagulation and the platelets in normal haemostasis. Thrombin generation in PRP appears to be a suitable test to reflect the combined function.

Topics: Deamino Arginine Vasopressin; Hemophilia A; Hemostatics; Humans; Infusions, Intravenous; Platelet Count; Thrombin; von Willebrand Diseases

A new in vitro von Willebrand factor-collagen binding activity (vWF:CBA) assay was used to assess qualitative changes in vWF in normal dogs and dogs with Type I von Willebrand's disease (vWD) following treatment with desmopressin acetate (DDAVP). Although DDAVP induced increases in vWF antigen concentrations at 1 hour postinfusion in both normal and vWD dogs (57% and 60% increases, respectively), there were disproportionately greater increases in vWF:CBA (96% and 103% increases). These results support the hypothesis that the enhanced hemostatic activity induced by DDAVP is, at least in part, due to the selective release of more functionally active vWF multimers. The assay, as described, provides a convenient means of simultaneously assessing vWF quantity and function before and after DDAVP administration.

Topics: Animals; Antigens; Collagen; Deamino Arginine Vasopressin; Dog Diseases; Dogs; Enzyme-Linked Immunosorbent Assay; Infusions, Intravenous; Renal Agents; von Willebrand Diseases; von Willebrand Factor

Patients with monoclonal gammopathies of uncertain significance (MGUS) may develop an acquired bleeding disorder similar to congenital von Willebrand disease, called acquired von Willebrand syndrome (AvWS). In these patients, measures to improve hemostasis are required to prevent or treat bleeding episodes. We diagnosed 10 patients with MGUS and AvWS: 8 had IgGkappa (3) or lambda (5) MGUS and 2 IgM-kappa MGUS. Three therapeutic approaches were compared in them: (1) desmopressin (DDAVP), (2) factor VIII/von Willebrand factor (FVIII/vWF) concentrate, and (3) high-dose (1 g/kg/d for 2 days) intravenous Ig (IVIg). In patients with IgG-MGUS, DDAVP and FVIII/vWF concentrate increased factor VIII and von Willebrand factor in plasma, but only transiently. IVIg determined a more sustained improvement of the laboratory abnormalities and prevented bleeding during surgery (short-term therapy). In addition to the standard 2-day infusion protocol, a long-term IVIg therapy was performed in 2 patients with IgG-MGUS: repeated (every 21 days) single infusions of IVIg did improve laboratory abnormalities and stopped chronic gastrointestinal bleeding. On the other hand, IVIg failed to correct laboratories abnormalities in patients with IgM-MGUS. These comparative data obtained in a relative large and homogeneous group of patients with AvWS and MGUS confirm that DDAVP and FVIII/vWF concentrates improve the bleeding time (BT) and FVIII/vWF measurements only transiently, whereas IVIg provides a sustained treatment of AvWS associated with IgG-MGUS, but not with IgM-MGUS.

Topics: Adult; Aged; Autoimmune Diseases; Bleeding Time; Cross-Over Studies; Deamino Arginine Vasopressin; Factor VIII; Female; Hemorrhage; Humans; Immunoglobulins, Intravenous; Male; Middle Aged; Paraproteinemias; Paraproteins; Treatment Outcome; von Willebrand Diseases; von Willebrand Factor

To describe the main characteristics and response to desmopressin infusion in 103 patients suffering from von Willebrand disease (vWD).. The criteria for diagnosis were (except for type 2N) the coexistence of von Willebrand factor ristocetin cofactor (vWF:RCo) activity < 50 U/dl with bleeding disease or one of the following data: von Willebrand factor antigen (vWF:Ag) activity < 50 U/dl, factor VIII (FVIII) activity < 50 U/dl or the existence of a increased bleeding time (BT). Multimeric studies of vWF were performed in 51 cases and ristocetin induced platelet aggregation (RIPA) was also performed.. Spontaneous bleeding was found in 36 patients, while in 18 cases the diagnosis was done after surgical bleeding. Thirteen patients (6 presenting with mild bleeding) were studied for abnormalities in the routine preanestesic tests. Other 22 patients were diagnosed with vWD by familial studies. There were 3 patients with type 2B, 1 case with type 2N and other patient with type 3. BT was found increased in 26 out of 58 patients. The activities of vWF:CoR and vWF:Ag were 38.4 (9.4) U/dl and 45.8 (23.2) U/dl, respectively, while the activity of FVIII was 49.9 (20.8) U/dl. Prophylactic DDAVP (desmopressin) was infused in 32 patients. After 1 h, basal activities of vWF:CoR and vWF:Ag were increased by 3.1 (3.2) and 3.4 (3.1) times, respectively, and maintained for 3 h. FVIII activity increased 3.6 (2.3) times the basal levels decreasing after 3 h (2.9 [2.1]; p < 0.01). The BT was corrected in 8 out of ten patients.. vWD is a major cause of surgical bleeding. Preanestesic anamnesis and coagulation tests can be useful to identify vWD. Many patients with vWD have normal BT. A failure in the response to desmopressin infusion is unusual.

Topics: Deamino Arginine Vasopressin; Female; Hemostatics; Humans; Male; von Willebrand Diseases

Desmopressin is the treatment of choice in most patients with von Willebrand disease (vWD) and mild hemophilia A (HA). Several studies have demonstrated that the intravenous and subcutaneous route of administration are equivalent in terms of pharmacokinetics and clinical efficacy. Home therapy of vWD and mild HA is desirable but so far there have been only a few case reports and no prospective studies. We report the results of a prospective study of home therapy in patients with vWD and mild-moderate HA using concentrated desmopressin self-administered subcutaneously. Clinical efficacy and safety were assessed by the patient using a questionnaire and direct interview. The patients were instructed on self-administration and dosage, reasons for treatment, recognition of side effects and recording clinical efficacy. The study lasted 12 months (range 6-17). During this time, 43/100 (43%) of the enrolled vWD patients (median basal VIII:C 24%, range 9-49) and 36/69 (52%) of HA patients (median basal VIII:C 10%, range 5-34) self-administered the drug. A total of 127 bleeding episodes requiring treatment occurred in patients with vWD and 92 in HA patients. There were 10 treatment failures of which 7 required in-hospital treatment. Overall, in 94% of treatments (excluding menorrhagia) the response was scored as excellent or good. In 86% of treated episodes of menorrhagia the response was scored as excellent or good. According to the patients, 81% of clinical situations would have required in-hospital treatment. Mild flushing, with or without headache, was the only consistent side-effect, reported in about 30% of treatments. In conclusion, home therapy with subcutaneous desmopressin for von Willebrand disease and hemophilia A was well accepted by the patients and proved feasible, efficacious and safe for the prevention or prompt treatment of bleeding.

Topics: Adolescent; Adult; Aged; Child; Deamino Arginine Vasopressin; Hemophilia A; Hemorrhage; Humans; Infusions, Intravenous; Injections, Subcutaneous; Male; Middle Aged; Prospective Studies; Self Administration; Treatment Outcome; von Willebrand Diseases

Patients with severe von Willebrand disease (vWD) usually show no increase of factor VIII/von Willebrand factor (VIII/vWF) after desmopressin (DDAVP) infusion and the bleeding time (BT) remains markedly prolonged. We have tested the biological responsiveness to DDAVP in six patients, belonging to six different families, with phenotypic evidence for severe vWD. Baseline VIII:C ranged from 12 to 32IU/dl, ristocetin cofactor activity (RiCof) was unmeasurable in all the patients, vWF antigen (vWF:Ag) ranged from 0.5 to 3.5 IU/dl, and in all patients the BT was longer than 30 min. No measurable vWF was present in patient's platelets, and plasma and platelet vWF multimers were virtually absent. An autosomal recessive pattern of inheritance was evident in all the propositi. After DDAVP infusion, there was no BT shortening. In four patients, VIII:C increased post-infusion and in three patients levels greater than 50 IU/dl were attained. RiCof reached a maximum of 11 IU/dl and vWF:Ag 9 IU/dl. In one of these four patients, DDAVP allowed a safe dental extraction, without resorting to blood products. In the remaining two patients no VIII/vWF changes were observed after DDAVP. In conclusion, a subgroup of patients with severe vWD shows an increase of VIII:C after DDAVP. A test infusion with this agent is advisable in patients with severe vWD before considering treatment with VIII/vWF concentrates.

Topics: Adolescent; Adult; Bleeding Time; Deamino Arginine Vasopressin; Factor VIII; Female; Genes, Recessive; Humans; Male; Phenotype; Tissue Plasminogen Activator; Tooth Extraction; von Willebrand Diseases; von Willebrand Factor

DDAVP has been shown to provide hemostasis in patients with bleeding disorder. Thirty-one episodes of intravenous DDAVP administration (0.3-0.4 microgram/kg) in 22 patients with bleeding disorder were studied. There were 13 patients with hemophilia A, 1 with type I vWD and 8 with inherited and acquired platelet dysfunction. The age ranged from 2.3-26 yrs (mean +/- SD = 10 +/- 4.8). None of the 3 severe hemophilia A patients responded to the treatment. Two out of five episodes in 4 moderate hemophilia A patients responded clinically and had minute increments of F VIII:C. Ten out of eleven episodes (91%) in 6 mild hemophilia A patients had good responses. The dental procedures for these patients were successfully performed without blood component transfusion. The increments of F VIII:C ranged from 1.5-6.8 folds over the baseline levels (mean +/- SD = 2.5 +/- 1.4). In addition, two episodes of epistaxis in a vWD patient responded excellently and one dental procedure was successfully performed by giving DDAVP. The increments of F VIII:C and vWF:Ag ranged from 2.8-12.5 and 2.9-8 fold over the baseline levels respectively. The prolonged bleeding times were shorten to 6.5-7 minutes. Only three out of eight episodes in 8 inherited and acquired platelet dysfunction patients showed temporary responses. The bleeding time responses did not correlate with in vitro platelet aggregation.

Topics: Adolescent; Adult; Blood Coagulation Tests; Blood Platelet Disorders; Child; Child, Preschool; Deamino Arginine Vasopressin; Drug Costs; Hemophilia A; Humans; Infusions, Intravenous; Treatment Outcome; von Willebrand Diseases

In healthy volunteer donors, intranasal instillation of adiuretin-SD in doses of 0.0002-0.001 mg/kg a day provoked an increase of the activity VIII:WF in the plasma and acceleration of euglobulin lysis. Out of 15 patients suffering from Willebrand's disease, the activity of Willebrand's factor rose in 9 patients. Activated partial thromboplastic time became shorter in all the patients. In addition, acceleration of euglobulin lysis was noted. In view of that fact adiuretin was used later in combination with aminocaproic acid (0.2 g/kg a day). All the patients suffering from menorrhagias demonstrated the lowering of hemorrhagic diathesis. The data obtained allow recommending the use of adiuretin combined with aminocaproic acid in patients suffering from Willebrand's disease.

Topics: Adult; Aminocaproates; Deamino Arginine Vasopressin; Drug Therapy, Combination; Factor VIII; Female; Hemostasis; Humans; Male; Time Factors; von Willebrand Diseases; von Willebrand Factor

After infusion of cryoprecipitate, the very prolonged bleeding time of patients with severe von Willebrand disease (vWD) is shortened but not always normalized in spite of normalization of plasma von Willebrand factor (vWF) levels. Therefore treatments that further improve primary hemostasis in severe vWD patients are needed. Since DDAVP shortens the bleeding time in a variety of bleeding disorders, we investigated in a double-blind, placebo-controlled crossover study the effects of the intravenous (IV) infusion of DDAVP (0.3 microgram/kg) on the bleeding times of 10 patients with severe vWD treated with cryoprecipitate. Their very prolonged bleeding times (greater than 30 minutes), partially corrected by the infusion of cryoprecipitate (14 +/- 2 minutes, mean +/- SEM), were further shortened by the administration of DDAVP (9 +/- 2 minutes, P less than .01) but not of saline (15 +/- 3 minutes, ns). Plasma vWF levels, raised from unmeasurable to normal values by cryoprecipitate, were not changed after DDAVP or saline. The defective deposition of platelets from eight patients onto human umbilical artery subendothelium was increased but not normalized by cryoprecipitate and was not significantly affected by DDAVP or saline. Therefore the infusion of DDAVP after cryoprecipitate may be of clinical benefit for management of bleeding episodes in severe vWD patients. Since severe vWD patients do not have releasable tissue stores of vWF, DDAVP must shorten their prolonged bleeding times independently of released vWF.

Topics: Bleeding Time; Blood Platelets; Deamino Arginine Vasopressin; Double-Blind Method; Factor VIII; Fibrinogen; Humans; von Willebrand Diseases; von Willebrand Factor

Topics: Clinical Trials as Topic; Deamino Arginine Vasopressin; Female; Hemophilia A; Humans; Male; von Willebrand Diseases

Studies on the effect of DDAVP both in vitro and in vivo are reported. In order to define the extent of the DDAVP induced rise of circulating endothelial cell proteins in normal individuals and the endothelial cell defect in von Willebrand's disease (vWd) we have measured the effect of intravenous DDAVP on a range of possible endothelial cell markers in normal subjects and in patients with mild haemophilia and vWd. In a series of double blind cross over studies on normal volunteers we have tested the effect of naloxone, DDAVP or saline on circulating levels of factor VIII related activities (VIIIR) and plasminogen activator (PA). The results confirmed the effect of DDAVP on circulating levels of VIIIR and PA but showed that it did not induce release of these activities from cultured endothelial cells in vitro nor did it influence circulating levels of other endothelial cell markers including fibronectin, antithrombin III and platelet factor 4. Infusion of nalaxone did not significantly alter circulating levels of VIIIR or PA nor the response of these to DDAVP suggesting that normally these activities are not subjected to a vasopressin drive.

Topics: Adolescent; Adult; Aged; Antigens; Antithrombin III; Arginine Vasopressin; Cells, Cultured; Child; Deamino Arginine Vasopressin; Endothelium; Factor VIII; Female; Hemophilia A; Humans; Male; Middle Aged; Naloxone; Plasminogen Activators; Umbilical Veins; von Willebrand Diseases; von Willebrand Factor

Three experimental models have been employed to investigate the mechanism of the prolonged bleeding time in patients with von Willebrand's disease (vWd). 1-deamino-8-D-arginine vasopressin (DDAVP), a synthetic analogue of the antidiuretic hormone, was administered to normal volunteers and patients with vWd in order to induce a short-term, endogenous increase of factor VIII procoagulant activity (VIIIAHF), factor VIII-related antigen (VIIIAGN), and Willebrand factor (VIIIVWF); and to investigate the relationship between bleeding time and plasma variations of factor VIII-associated properties. In normal subjects DDAVP administration was followed by a marked increase of VIIIAHF, VIIIAGN, and VIIIVWF; yet the bleeding time remained unchanged. The same parameters were also raised in two groups of patients with vWd. In a third group of patients with severe recessive vWd, factor VIII-associated properties, which were not measurable before the infusion, were unmodified. The bleeding time remained unchanged in all vWd patients. To investigate the effect of the exogenous increase of factor VIII-associated properties, cryoprecipitate was given to ten vWd patients before dental surgery. Despite the marked increase of VIIAHF, VIIAGN, and VIIVWF observed after the infusion, bleeding time was not shortened. Finally, in order to evaluate the hypothesis that factor VIII may exert its effect on primary hemostasis locally in the vessel wall, VIIIAGN and its relationship with the bleeding time were studied by direct immunofluorescence in gum-biopsy specimens obtained in vWd patients before cryoprecipitate infusion. No reaction could be elicited in five patients with severe, recessive vWd, whereas venules and arterioles stained positively in five patients with a moderate form of the disease. Immunofluorescence microscopy was also carried out in specimens obtained after cryoprecipitate at a time when the plasma defects were corrected but the long bleeding time was not modified; no reaction was detectable on the vessel wall of the three patients who were negative before the infusion.

Topics: Adult; Clinical Trials as Topic; Deamino Arginine Vasopressin; Factor VIII; Female; Fluorescent Antibody Technique; Hemostasis; Humans; Male; von Willebrand Diseases

Increased von Willebrand factor (VWF) clearance plays a key role in the pathogenesis of type 1 and type 2 von Willebrand disease (VWD). However, the pathological mechanisms involved in patients with mild to moderate reductions in plasma VWF:Ag (range, 30-50 IU/dL; low VWF) remain poorly understood. In this study, we investigated the hypothesis that enhanced VWF clearance may contribute to the pathobiology of low VWF. Patients with low VWF were recruited to the LoVIC study after ethics approval and receipt of informed consent. Desmopressin was administered IV in 75 patients, and blood samples were drawn at baseline and at the 1-hour and 4-hour time points. As defined by recent ASH/ISTH/NHF/WFH guidelines, 20% of our low-VWF cohort demonstrated significantly enhanced VWF clearance. Importantly, from a clinical perspective, this enhanced VWF clearance was seen after desmopressin infusion, but did not affect the steady-state VWF propeptide (VWFpp)-to-VWF antigen (VWF:Ag) ratio (VWFpp/VWF:Ag) in most cases. The discrepancy between the VWFpp/VWF:Ag ratio and desmopressin fall-off rates in patients with mild quantitative VWD may have reflected alteration in VWFpp clearance kinetics. Finally, bleeding scores were significantly lower in patients with low VWF with enhanced VWF clearance, compared with those in whom reduced VWF biosynthesis represented the principle pathogenic mechanism. This trial was registered at http://www.clinicaltrials.gov as #NCT03167320.

Topics: Clinical Relevance; Deamino Arginine Vasopressin; Humans; Protein Precursors; von Willebrand Diseases; von Willebrand Factor

Topics: Blood Platelet Disorders; Deamino Arginine Vasopressin; Hemostatics; Humans; von Willebrand Diseases; von Willebrand Factor

Peri-procedural management of von Willebrand disease (VWD) utilizes von Willebrand factor (VWF) concentrates or desmopressin (DDAVP) to increase VWF levels. DDAVP is safe, easily administered, and inexpensive. Currently, a consensus definition for adequate DDAVP response is lacking, and outcomes of peri-procedural DDAVP use in VWD patients are seldom reported.. This single-centre retrospective review aims to characterize DDAVP-responsiveness and assess clinical outcomes of peri-procedural DDAVP use in VWD.. We reviewed records for all our adult VWD patients (age ≥18 years) who underwent DDAVP challenge testing between January 2007 and January 2022. DDAVP-responsiveness was assessed using six definitions. Bleeding outcomes following procedures covered by DDAVP were classified as excessive or expected bleeding.. Eighty-four of 94 (89.4%) patients were DDAVP-responsive by our definition (1-h VWF Activity/Factor VIII ≥0.50 IU/mL). However, the proportion of DDAVP-responders varied from 53.2% to 91.5%, depending on the literature definition used. Ninety-nine procedures pre-treated with DDAVP were performed during the study period. Eighty-six (86.7%) procedures (31 major; 55 minor) were covered with only DDAVP ± tranexamic acid (TXA). Excessive bleeding occurred following 4/31 major procedures and 2/55 minor procedures (both performed in a single patient with a bleeding score of 16). When covered with DDAVP+Factor ± TXA, one each of 10 major and 3 minor procedures (performed in 2 patients with bleeding scores 15-16) resulted in post-procedural bleeding.. Peri-procedural DDAVP prophylaxis appears to be effective among individuals with VWD. Beyond DDAVP-responsiveness, patient bleeding history and procedure invasiveness should be considered in determining suitability for DDAVP prophylaxis.

Topics: Adolescent; Adult; Deamino Arginine Vasopressin; Factor VIII; Hemorrhage; Humans; Retrospective Studies; Tranexamic Acid; von Willebrand Diseases; von Willebrand Factor

Topics: Deamino Arginine Vasopressin; Factor VIII; Hemostatics; Humans; von Willebrand Disease, Type 1; von Willebrand Diseases; von Willebrand Factor

Topics: Administration, Intranasal; Deamino Arginine Vasopressin; Drug Recalls; Hemophilia A; Humans; von Willebrand Diseases

Although COVID-19 is associated with high von Willebrand factor (vWF) parameters promoting thrombosis, venovenous extracorporeal membrane oxygenation (vvECMO) is associated with the development of acquired von Willebrand syndrome (AVWS) promoting bleeding. This study was designed to assess both the incidence and severity of AVWS in COVID-19 patients undergoing vvECMO, and the benefit of comprehensive vWF analyses.. Prospective observational study.. ICU at a tertiary-care center.. Twenty-seven consecutive COVID-19 patients with acute respiratory distress syndrome (ARDS) requiring vvECMO.. Comprehensive vWF analyses (including sodium dodecyl-sulfate polyacrylamide gel electrophoresis) were performed before, during, and after vvECMO. In a subgroup of 12 patients with AVWS, effectiveness of treatment with desmopressin was assessed. The patients' mean age was 53 years (range, 23-73), 70% were male, and all had various comorbidities. Following markedly elevated vwf antigen (vWF: Ag; mean, 546% ( sd , 282]), vWF collagen binding capacity (mean, 469% [ sd , 271]), vWF activity (vWF:A; mean, 383% [ sd , 132]), and factor VIII activity (mean, 302% [ sd , 106]), and only borderline decreases in high-molecular-weight (HMW) vWF multimers before vvECMO, all of these variables decreased and HMW vWF multimers became undetectable within hours following initiation of vvECMO. All variables fully recovered within 3-38 hours after discontinuation of vvECMO. During vvECMO, decreases in the vWF:A/vWF:Ag ratio correlated with absent HMW vWF multimers. Desmopressin did not affect vWF parameters.. In patients with COVID-19-associated ARDS, AVWS developed soon after initiation of vvECMO. The vWF:A/vWF:Ag ratio was a suitable screening test for AVWS. As desmopressin was ineffective, bleeding during vvECMO-associated AVWS should preferably be treated with concentrates containing vWF.

Topics: Adult; Aged; COVID-19; Deamino Arginine Vasopressin; Extracorporeal Membrane Oxygenation; Female; Hemorrhage; Humans; Male; Middle Aged; Respiratory Distress Syndrome; von Willebrand Diseases; von Willebrand Factor; Young Adult

Patients with type 1 and type 2 von Willebrand disease (VWD) can be treated with desmopressin. Although a previous study has shown that the location of the causative VWF gene variant is associated with desmopressin response in type 1 VWD, the association between variants in the VWF gene and desmopressin response is not yet fully understood. Our primary aim was to compare desmopressin response in type 1 VWD patients with and without a VWF gene variant. Secondly, we investigated whether desmopressin response depends on specific VWF gene variants in type 1 and type 2 VWD. We included 250 patients from the Willebrand in the Netherlands study: 72 type 1 without a VWF gene variant, 108 type 1 with a variant, 45 type 2A, 16 type 2M, and 9 type 2N patients. VWF gene was analyzed with ion semiconductor sequencing and Multiplex Ligation-dependent Probe Amplification. Complete response to desmopressin was observed in all type 1 VWD patients without a variant, 64.3% of type 1 patients with a variant, and 31.3% of type 2 patients (P < .001). Despite a large interindividual variability in desmopressin response, patients with the same variant had comparable desmopressin responses. For instance, in 6 type 1 patients with exon 4 to 5 deletion, mean VWF activity at 1 hour after desmopressin was 0.81 IU/mL, with a coefficient of variation of 22.9%. In conclusion, all type 1 VWD patients without a VWF gene variant respond to desmopressin. In type 1 and type 2 VWD patients with a VWF variant, desmopressin response highly depends on the VWF gene variants.

Topics: Deamino Arginine Vasopressin; Exons; Humans; von Willebrand Disease, Type 2; von Willebrand Diseases; von Willebrand Factor

Deficiency or dysfunction of von Willebrand factor (VWF) is associated with a bleeding disorder known as von Willebrand disease (VWD). The clinical manifestations of VWD are heterogeneous, and are in part dictated by the structural or functional defects of VWF. The tools to control bleeding in VWD are dominated by VWF concentrates, desmopressin and antifibrinolytic therapy. In view of these treatments being considered as effective, it is surprising that quality-of-life studies consistently demonstrate a significant mental and physical burden in VWD patients, particularly in women. Apparently, the current weaponry to support the management of VWD is insufficient to fully address the needs of the patients. It is important therefore to continue to search for innovative treatment options which could better serve the VWD patients. In this short review, two of such options are discussed in more detail: emicizumab to correct for the deficiency of factor VIII (FVIII), and the pegylated aptamer BT200 to increase endogenous levels of the VWF/FVIII complex.

Topics: Antifibrinolytic Agents; Deamino Arginine Vasopressin; Factor VIII; Female; Hemorrhage; Hemostatics; Humans; von Willebrand Diseases; von Willebrand Factor

Desmopressin can be used to prevent bleeding in von Willebrand disease (VWD), but the relationship between desmopressin and von Willebrand factor activity (VWF:Act) has yet to be quantified.. To quantify the relationship between desmopressin dose, its plasma concentration and the VWF:Act response in type 1 VWD patients.. Forty-seven VWD patients (median age 25 years, IQR: 19-37; median body weight 71 kg, IQR: 59-86) received an IV desmopressin dose of .3 mcg/kg. In total, 177 blood samples were available for analysis. We developed an integrated population pharmacokinetic-pharmacodynamic (PK-PD) model using nonlinear mixed effect modelling. Subsequently, we performed Monte Carlo simulations to investigate the efficacy of the current dosing regimen.. A one-compartment PK model best described the time profile of the desmopressin concentrations. In the PD turnover model, the relationship between desmopressin plasma concentration and release of VWF:Act from the vascular endothelium was best described with an Emax model. Typically, VWF:Act increased 452% with an EC50 of .174 ng/ml. Simulations demonstrated that after .3 mcg/kg desmopressin intravenously, >90% patients with a VWF:Act baseline of ≥.20 IU/mL attain a VWF:Act >.5 IU/ml up to ≥4 h after administration. A capped dose of 30 mcg was sufficient in patients weighing over 100 kg.. The relationship between desmopressin and VWF:Act was quantified in a PK-PD model. The simulations provide evidence that recently published international guidelines advising an intravenous desmopressin dose of .3 mcg/kg with a capped dose of 30 mcg > 100 kg gives a sufficient desmopressin response.

Topics: Adult; Deamino Arginine Vasopressin; Factor VIII; Humans; von Willebrand Disease, Type 1; von Willebrand Diseases; von Willebrand Factor

In children with congenital heart disease (CHD), excessive perioperative bleeding is associated with increased morbidity and mortality, thus making adequate perioperative hemostasis crucial. We investigate the prevalence of acquired von Willebrand syndrome type 2A (aVWS) in CHD and develop a treatment algorithm for patients with aVWS and CHD (TAPAC) to reduce perioperative blood loss.. Retrospective cohort study.. Single-center study.. A total of 627 patients with CHD, undergoing corrective cardiac surgery between January 2008 and May 2017.. The evaluation of perioperative bleeding risk was based on the laboratory parameters von Willebrand factor (VWF) antigen, ristocetin cofactor activity, platelet function analyzer (PFA) closure time adenosine diphosphate, and PFA epinephrine. According to the bleeding risk, treatment was performed with desmopressin or VWF.. aVWS was confirmed in 63.3 %, with a prevalence of 45.5% in the moderate and 66.3 % in the high-risk group. In addition, prevalence increased with ascending peak velocity above the stenosis (v max ) from 40.0% at less than or equal to 3 m/s to 83.3% at greater than 5 m/s. TAPAC reduced mean blood loss by 36.3% in comparison with a historical control cohort ( p < 0.001), without increasing the number of thrombotic or thromboembolic events during the hospital stay. With ascending v max , there was an increase in perioperative blood loss in the historical cohort ( p < 0.001), which was not evident in the TAPAC cohort ( p = 0.230).. The prevalence of aVWS in CHD seems to be higher than assumed and leads to significantly higher perioperative blood loss, especially at high v max . Identifying these patients through appropriate laboratory analytics and adequate treatment could reduce blood loss effectively.

Topics: Adenosine Diphosphate; Algorithms; Blood Loss, Surgical; Child; Deamino Arginine Vasopressin; Epinephrine; Heart Defects, Congenital; Humans; Retrospective Studies; Syndrome; von Willebrand Diseases; von Willebrand Factor

BACKGROUND von Willebrand disease (VWD) is characterized by a bleeding tendency due to abnormalities in von Willebrand factor (VWF). Severe traumatic brain injury (TBI) can induce secondary coagulopathy and hemostatic disorders. We herein present a rare case of multiple trauma, including severe TBI, in a patient with VWD who was successfully treated with repeated factor VIII/VWF transfusion in addition to standard critical care. CASE REPORT A 22-year-old man with type 2A VWD sustained head and lower limb injuries in a traffic accident and was comatose. Computed tomography indicated multiple trauma, including severe TBI (left-sided traumatic epidural hematoma, left-sided traumatic subdural hematoma, traumatic subarachnoid hemorrhage, skull fracture, and skull base fracture). The patient underwent emergency craniotomy for hematoma removal, external decompression, and intracranial pressure monitoring along with massive transfusion and repeated perioperative transfusion of factor VIII/VWF concentrates according to the level of bleeding. He recovered consciousness and eventually survived without neurological deficits. CONCLUSIONS Multiple trauma including TBI in patients with VWD is a critical condition. The active transfusion of factor VIII/VWF is essential for controlling hemorrhage early and in the perioperative period.

Topics: Adult; Brain Injuries, Traumatic; Deamino Arginine Vasopressin; Factor VIII; Hematoma; Hemorrhage; Humans; Male; Multiple Trauma; von Willebrand Diseases; von Willebrand Factor; Young Adult

Topics: Adolescent; Deamino Arginine Vasopressin; Exercise; Factor VIII; Hemophilia A; Humans; Male; von Willebrand Diseases

 The way by which 1-deamino-8-D-arginine vasopressin (DDAVP) acts on platelets remains unclear. Data from the literature tend to show that there is no definite effect on platelet activation, but recent work has suggested that a subtype of platelets, activated by the combined action of collagen and thrombin, was triggered by DDAVP. Moreover, platelet microparticles (PMPs), which have been shown to be procoagulant, have rarely been studied in this context. The goal of this study was to analyze the effects of DDAVP on PMPs' release through platelet activation..  Fifteen out of 18 consecutive patients undergoing a therapeutic test with DDAVP were included. They were suffering from factor VIII deficiency or from von Willebrand disease. The expression of P-selectin and PAC-1 binding on platelets and the numbers of circulating PMPs were evaluated ex vivo before and after DDAVP infusion. Peripheral blood was collected on CTAD to limit artifactual platelet activation..  DDAVP induced a significant decrease of platelet counts and volume. Only small changes of P-selectin expression and PAC-1 binding were observed. Considering PMPs, two populations of patients could be defined, respectively, with (120%,.  This study shows that DDAVP induces the generation/release of PMPs in some patients with factor VIII deficiency and von Willebrand disease 1 hour after DDAVP infusion.

Topics: Arginine Vasopressin; Blood Platelets; Deamino Arginine Vasopressin; Hemophilia A; Humans; P-Selectin; Platelet Activation; von Willebrand Diseases; von Willebrand Factor

von Willebrand disease (VWD) is the most common inherited bleeding disorder and caused by an absence, deficiency or defect in von Willebrand factor (VWF). VWD is currently classified into six different types: 1, 2A, 2B, 2N, 2M, 3. Notably, 2M VWD is more often misdiagnosed as 2A or type 1 VWD than properly identified as 2M VWD.. To describe an algorithmic approach to better ensure appropriate identification of 2M VWD, and reduce its misdiagnosis, as supported by sequential laboratory testing.. Comparative assessment of types 1, 2A, 2B and 2M VWD using various laboratory tests, including VWF antigen and several VWF activity assays, plus DDAVP challenge data, ristocetin-induced platelet agglutination (RIPA) data, multimer analysis and genetic testing.. Types 1, 2A, 2B and 2M VWD give characteristic test patterns that can provisionally classify patients into particular VWD types. Notably, type 1 VWD shows low levels of VWF, but VWF functional concordance (VWF activity/Ag ratios >0.6), with both baseline assessment and post-DDAVP. Types 2A, 2B and 2M VWD show VWF functional discordance (low VWF activity/Ag ratio(s)) dependent on the defect, but type 2M separates from 2A/2B VWD based on specific test patterns, especially with collagen binding vs glycoprotein Ib binding assays. RIPA identifies 2B VWD. Multimers separate 2M from 2A/2B.. We provide strategies to improve correct diagnosis of VWD, especially focussed on 2M VWD, and which can be used by most diagnostic haemostasis laboratories, reserving genetic analysis (if required) for confirmation.

Topics: Blood Coagulation Tests; Deamino Arginine Vasopressin; Humans; Ristocetin; von Willebrand Diseases; von Willebrand Factor

Topics: Biological Products; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Humans; von Willebrand Diseases

Topics: Aged; Angiodysplasia; Deamino Arginine Vasopressin; Factor VIII; Female; Hemostasis; Hemostatics; Humans; Infusions, Intravenous; Middle Aged; Platelet Function Tests; Treatment Outcome; von Willebrand Diseases; von Willebrand Factor

von Willebrand disease (VWD) is a quantitative or qualitative defect in von Willebrand factor (VWF) resulting in mucocutaneous bleeding symptoms and hemorrhage following hemostatic challenges, such as trauma or surgery. VWD-specific therapy, DDAVP (1-desamino-8-D-arginine vasopressin) and VWF concentrates, is necessary periprocedurally to ensure adequate hemostasis. The aging VWD patient may complicate this matter. The plasma concentration of many coagulation proteins, including VWF, increases with age. While it has been established that VWF levels increase with age in a healthy population, emerging research demonstrates this occurs in certain subtypes of VWD, too. Thus, the management of periprocedural VWD-specific therapy in the aging VWD patient is problematic when VWF levels increase over time to normal, and hematologists are left with uncertainty regarding whether or not periprocedural VWD-specific therapy is still necessary. In this article, we will review the current state of the literature regarding the effect of age on VWF levels in the healthy population and VWD while exploring possible etiologies for this phenomenon. Further, we will detail how this affects bleeding symptoms and highlight what research remains to be done to optimize care in this patient population.

Topics: Aged; Aging; Blood Coagulation Factors; Deamino Arginine Vasopressin; Diverticulitis; Female; Hemorrhage; Humans; Preoperative Care; von Willebrand Diseases; von Willebrand Factor

 Most von Willebrand disease (VWD) patients can be treated with desmopressin during bleeding or surgery. Large interpatient variability is observed in von Willebrand factor (VWF) activity levels after desmopressin administration. The aim of this study was to develop a pharmacokinetic (PK) model to describe, quantify, and explain this variability..  Patients with either VWD or low VWF, receiving an intravenous desmopressin test dose of 0.3 µg kg.  The PK model was developed using 951 VWF activity level measurements from 207 patients diagnosed with a VWD type. Median age was 28 years (range: 5-76), median predose VWF activity was 0.37 IU/mL (range: 0.06-1.13), and median VWF activity response at peak level was 0.64 IU/mL (range: 0.04-4.04). The observed PK profiles were best described using a one-compartment model with allometric scaling. While.  A PK model was developed, describing VWF activity versus time profile after desmopressin administration in patients with VWD or low VWF. Interpatient variability in response was quantified and partially explained. This model is a starting point toward more accurate prediction of desmopressin dosing effects in VWD.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Deamino Arginine Vasopressin; Female; Hemostatics; Humans; Male; Middle Aged; Models, Biological; von Willebrand Diseases; von Willebrand Factor; Young Adult

Topics: Clinical Decision Rules; Deamino Arginine Vasopressin; Drug Therapy, Combination; Female; Hemorrhage; Hemostatics; Humans; Male; Middle Aged; Prevalence; Research Design; Retrospective Studies; Risk Assessment; von Willebrand Diseases; von Willebrand Factor

Von Willebrand disease (VWD) is one of the most severe inherited bleeding disorder in humans, and it is associated with a qualitative and/or quantitative deficiency of von Willebrand factor, a multimeric glycoprotein fundamental in the coagulation process. At present, the diagnosis of VWD is extremely challenging and mostly based on clinical experience. Kinetic models have been recently proposed and applied to help in the diagnosis and characterization of VWD, but the complexity of these models is such that they requires long and stressful clinical tests, such as the desmopressin response test (DDAVP), to achieve a satisfactory estimation of the individual haemostatic parameters. The goal of this paper is to design a minimal set of clinical tests for the identification of akinetic model to decrease the required time and effort for the characterization and diagnosis of VWD.. A model proposed in the literature is used as a building block to develop a new model, where response surface methodologies have been applied to determine a set of explicit correlations linkingkinetic model parameters to basal clinical trials data. Model-based design of experiments techniques are then used to devise optimally informative tests for model validation which are shorter and easier to implement.. Results show an excellent agreement between the original model for VWD and the new proposed model on representing healthy and VWD subjects. The application of experimental design techniques for model validation shows the possibility to drastically reduce the duration of DDAVP tests from 24 h-3 h by exploiting complementary information from basal clinical tests.. Basal clinical tests can be used alongside a time-reduced DDAVP test to validate pharmacokinetic models for a quantitative characterisation of subjects affected by VWD and for a quicker and easier diagnosis of the disease.

Topics: Case-Control Studies; Clinical Protocols; Clinical Trials as Topic; Computer Simulation; Deamino Arginine Vasopressin; Diagnosis, Computer-Assisted; Humans; Likelihood Functions; Models, Biological; Time Factors; von Willebrand Diseases; von Willebrand Factor

Accurate diagnosis of von Willebrand disease (VWD) enables effective patient management. von Willebrand factor (VWF) multimer analysis provides useful information regarding VWF multimer structure, thereby aiding VWD subtyping and management; however, historically technically challenging assays have had limited utility. This study evaluates the Sebia Hydrasys Hydragel-11 semi-automated VWF multimer assay and further validates the Hydragel-5 gel system, as primarily pertaining to VWD diagnostics and monitoring of therapy.. Provisionally diagnosed (via a reference assay test panel) archived patient samples and prospective test patient samples, including those undergoing desmopressin trial or therapy monitoring, along with commercial and in-house control material and various external quality assessment (EQA) samples, were analysed. VWF multimers were evaluated for presence, loss or partial loss of high molecular weight (HMWM) and intermediate molecular weight (IMWM) multimers by both visual inspection and densitometric scanning, and comparison with reference assay results.. All anticipated multimer patterns were reproduced, with patients generally showing multimer profiles matching expected patterns according to VWD type based on reference test panel 'diagnosis'. Occasional discrepancies were resolved by retesting. The increase in plasma VWF following desmopressin therapy was also clearly demonstrated. Multimer profiles of EQA samples complemented reference test panel results and matched EQA targets. There were some 'technical' limitations noted.. This easy to use, standardised, semi-automated multimer analysis system can demonstrate the multimer profile of VWD patients, thus representing an additional laboratory tool for improved diagnosis, thereby facilitating appropriate patient management.

Topics: Deamino Arginine Vasopressin; Humans; Molecular Weight; Protein Multimerization; Reference Standards; von Willebrand Diseases; von Willebrand Factor

Topics: Accidents, Traffic; Arm Injuries; Deamino Arginine Vasopressin; Electroencephalography; Hematoma; Hemorrhage; Hemostatics; Humans; Hyponatremia; Male; Middle Aged; Multiple Trauma; Nasal Bone; Saline Solution, Hypertonic; Seizures; Skull Fractures; von Willebrand Diseases

Topics: Adolescent; Adult; Child; Deamino Arginine Vasopressin; Female; Hemostatics; Humans; Male; Middle Aged; von Willebrand Diseases; von Willebrand Factor; Young Adult

Topics: Adult; Aged; Deamino Arginine Vasopressin; Female; Humans; Male; Middle Aged; Treatment Outcome; von Willebrand Diseases; von Willebrand Factor

A reduced von Willebrand factor (VWF) synthesis or survival, or its increased proteolysis, alone or in combination, contributes to the development of von Willebrand disease (VWD).We describe a new, simple mechanistic model for exploring how VWF behaves in well-defined forms of VWD after its 1-desamino-8-D-arginine vasopressin (DDAVP)-induced release from endothelial cells. We aimed to ascertain whether the model can consistently predict VWF kinetic changes. The study involved 9 patients with VWD types Vicenza (a paradigmatic form with a reduced VWF survival), 8 type 2B, 2 type 2A-I, 1 type 2A-II (associated with an increased VWF proteolysis), and 42 normal controls, whose VWF levels were measured after a 24-hour-long DDAVP test. The rate constants considered were:

Topics: Adult; Bleeding Time; Deamino Arginine Vasopressin; Factor VIII; Hemostasis; Humans; Kinetics; Middle Aged; Models, Theoretical; Proteolysis; Treatment Outcome; von Willebrand Diseases; von Willebrand Factor; Young Adult

Topics: Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Humans; von Willebrand Diseases

Desmopressin is commonly used to reduce bleeding in patients with mucocutaneous bleeding disorders and is available in both intravenous and intranasal forms. Given the variability in response to desmopressin at an individual level, its effectiveness should be assessed with a test dose prior to being advised for use. At this time, no trial has extensively compared the use of intranasal desmopressin to intravenous desmopressin.. To determine whether both forms of desmopressin are equally effective in yielding a positive response in laboratory assays in paediatric patients with von Willebrand disease or probable von Willebrand disease.. We evaluated medical record data for 58 patients who underwent desmopressin stimulation testing in our haematology clinic during a 1-year period. Data were collected on demographic information and haematologic laboratory assays prior to desmopressin administration and one hour following desmopressin.. There was an absolute increase in von Willebrand antigen to levels appropriate for haemostasis following both forms of desmopressin, although this increase was significantly greater in the intravenous group compared to the intranasal group. There was also a significant absolute increase in Ristocetin Cofactor and Factor VIII levels following desmopressin in both groups.. Both intravenous and intranasal forms of desmopressin produce a positive response during desmopressin stimulation testing and can be used to identify patients for whom this medication would be effective.

Topics: Administration, Intranasal; Administration, Intravenous; Child; Deamino Arginine Vasopressin; Female; Humans; Male; Treatment Outcome; von Willebrand Diseases

Bleeding contributes to the high mortality of venovenous extracorporeal membrane oxygenation (vvECMO). The development of acquired von Willebrand syndrome (AVWS) has been identified as relevant pathology during ECMO. This study was performed to determine the onset of AVWS after implantation and the recovery of von Willebrand factor (VWF) parameters after explantation of ECMO in a large cohort of patients.. VWF parameters of 59 patients treated with vvECMO at a university ECMO center were obtained before ECMO implantation, during therapy, and after explantation. In a subgroup of patients, light transmission aggregometry of platelets and flow-cytometric quantification of platelet granule secretion were performed.. All patients developed severe AVWS hours after implantation of vvECMO. After explantation, AVWS recovered within 3 hours in 60%, within 6 hours in 86%, and in all patients within 1 day. Aggregometry showed hypoaggregability of platelets after stimulation with ADP, ristocetin, collagen, and epinephrine. Flow-cytometric platelet analyses revealed severely reduced expression of CD62 and CD63.. All patients during vvECMO support rapidly develop AVWS and platelet dysfunction, resulting in severe impairment of coagulation. After explantation, AVWS overwhelmingly recovers within hours, resulting in a hypercoagulative state. These findings augment the need for novel extracorporeal technologies with reduced shear stress, and shift the emphasis for intense anti-coagulation during ECMO instead to a time-point after explantation.

Topics: Adult; Aged; Anticoagulants; Blood Platelet Disorders; Deamino Arginine Vasopressin; Drug Combinations; Erythrocyte Transfusion; Extracorporeal Membrane Oxygenation; Factor VIII; Female; Follow-Up Studies; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Transfusion; Remission, Spontaneous; Thrombocytopenia; von Willebrand Diseases; von Willebrand Factor

The diagnosis of von Willebrand disease is complex due to the heterogeneity of the disease. About eighty percent of von Willebrand disease patients are diagnosed with a quantitative defect of von Willebrand factor (VWF) where fifty percent is due to an increased clearance of von Willebrand factor. These patients do not respond well to the treatment of choice, Desmopressin (DDAVP) due to decreased efficacy. The ratio between the VWF propeptide and the mature VWF antigen is used to diagnose these patients. Commercial VWF propeptide assays are too expensive for use in developing countries. In this study, we developed a cost-effective ELISA assay.. We first displayed VWF propeptide on yeast. Antibody fragments were selected against the displayed VWF propeptide by using phage display technology. The antibodies were used to develop a cost-effective VWF propeptide assay and compared to a commercial VWF propeptide assay.. Two of these antibody fragments bound specific to the VWF propeptide and not to the yeast used for the expression of the propeptides. These purified antibody fragments were able to detect VWF propeptide in normal plasma.. Our assay performed well when compared to a commercial kit. It also showed a higher binding affinity for VWF propeptide in plasma at especially lower plasma concentrations.

Topics: Bacteriophages; Blood Coagulation Tests; Deamino Arginine Vasopressin; Humans; von Willebrand Diseases; von Willebrand Factor; Yeasts

Topics: Adolescent; Adult; Deamino Arginine Vasopressin; Equipment Design; Female; Hematocrit; Humans; Lab-On-A-Chip Devices; Male; Microfluidic Analytical Techniques; Middle Aged; Platelet Aggregation; Platelet Function Tests; von Willebrand Diseases; von Willebrand Factor; Young Adult

Despite the increased worldwide awareness, over the last decade, of the platelet-type von Willebrand Disease (PT-VWD), many uncertainties remain around this rare platelet bleeding disorder. This report aims to correctly identify and study the phenotype of new patients and highlights the diagnostic and therapeutic challenges this disease remains to pose. We describe four PT-VWD cases confirmed by genetic analysis in which either the diagnosis and/or the treatment posed challenge. We provide the details of the clinical presentation, laboratory analysis, and the treatment and the responses in each case. We show that in addition to type 2B VWD, PT-VWD can be misdiagnosed as idiopathic thrombocytopenic purpura, neonatal alloimmune thrombocytopenia, and unexplained gestational thrombocytopenia. The disease can be diagnosed as early as 1 year of age and with phenotypically normal parents. Bleeding in some patients can be managed successfully using Humate P and DDAVP combined with tranexamic acid with no significant thrombocytopenia. We provide for the first time an evidence of an efficient response to rFVIIa in PT-VWD. Anaphylactic reaction to VWF preparations may be related to PT-VWD and the development of HLA antibodies is not uncommon. Progressive thrombocytopenia with normal VWF levels can be seen with PT-VWD and the platelet count was normalized at 2.5 weeks postpartum in one case. We conclude that these studies represent a record of clinical observations/interventions that help improve diagnoses/management of PT-VWD, highlight the variations in age and clinical presentations, laboratory diagnostic approaches, the importance of genetic testing for accurate diagnosis and consideration of therapeutic alternatives.

Topics: Adolescent; Child, Preschool; Deamino Arginine Vasopressin; Drug Therapy, Combination; Factor VIIa; Factor VIII; Female; Hemorrhage; Humans; Infant, Newborn; Male; Recombinant Proteins; Tranexamic Acid; von Willebrand Diseases

Desamino D-arginine vasopressin (DDAVP or desmopressin) is a useful and effective haemostatic treatment for patients with von Willebrand Disease (VWD). However, there are still issues regarding in which subtypes of VWD DDAVP is appropriate and little consensus on its use in different surgical settings. We also lack information concerning the appropriate laboratory parameters that should be monitored.. The European Haemophilia Therapy Strategy Board (EHTSB) wished to investigate published information and clinical use of DDAVP in VWD patients.. We conducted a literature survey on management of VWD during surgical interventions and undertook a survey of specialist haematologist centres across Europe to assess current management of VWD patients.. DDAVP is ineffective in type 3 VWD and its use in type 2B remains controversial due to the possibility of thrombocytopenia. It can, however, be used effectively to cover minor surgery and dental procedures in most other VWD patients. For major surgery there is wider use of factor concentrate in preference to DDAVP depending on the subtype of VWD. We give consensus recommendations on the use of DDAVP for surgical interventions in VWD including laboratory parameters that denote an adequate response and contraindications to its use.. DDAVP can be recommended to cover invasive procedure in selected patients with VWD, however, we need more information and systematic recording of adverse events associated with DDAVP use in VWD. A companion paper will be published covering the use of factor concentrates in VWD patients.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Deamino Arginine Vasopressin; Europe; Female; Humans; Infant; Male; Middle Aged; Practice Guidelines as Topic; Surveys and Questionnaires; von Willebrand Diseases; Young Adult

Despite the availability of subcutaneous desmopressin (1-deamino-8-d-arginine vasopressin, SC-DDAVP) as a haemostatic agent for children with mild bleeding disorders, few publications specifically address the safety or efficacy of this mode of administration.. Our aim was to assess whether a defined fluid restriction protocol was effective in preventing hyponatremia in children receiving perioperative SC-DDAVP, and to document adequate biological and clinical response in this setting.. We retrospectively analysed a cohort of children with mild bleeding disorders prescribed SC-DDAVP over a 5-year period following institution of a 'two-thirds maintenance' fluid restriction protocol.. Sixty-nine patients received SC-DDAVP following this protocol, including 15 with mild haemophilia A, 49 with von Willebrand disease (VWD) and five with platelet storage pool disorder. In patients who underwent formal preoperative assessment a complete or partial response was observed in 28/29 with type 1 VWD and 14/15 with mild haemophilia A. Perioperative SC-DDAVP provided excellent haemostasis in all patients, with no requirement for factor concentrate or blood products. Mild asymptomatic hyponatremia was detected in seven children who received multiple doses of DDAVP (lowest sodium 129 mmol L(-1) ); however, adherence to the prescribed fluid restriction protocol was questionable in six of these cases. Symptomatic hyponatremia was not observed.. Subcutaneous desmopressin was well-tolerated, with no serious side-effects observed, and good biological responses in preoperative trials. A two-thirds maintenance fluid regimen was effective at preventing symptomatic hyponatremia in our cohort, and is now the standard protocol for fluid restriction post-DDAVP administration in our centre.

Topics: Adolescent; Blood Coagulation Disorders, Inherited; Child; Child, Preschool; Deamino Arginine Vasopressin; Hemophilia A; Hemostatics; Humans; Hyponatremia; Injections, Subcutaneous; Platelet Storage Pool Deficiency; Retrospective Studies; Severity of Illness Index; von Willebrand Diseases

The diagnosis of von Willebrand disease (VWD) is difficult due to the wide spectrum of clinical phenotypes associated with this disorder. We have analysed and characterized haemostatic function in VWD patients using a microchip-based flow chamber system. Microchips coated with either collagen [platelet (PL)-chip] or collagen/thromboplastin [atherome (AR)-chip] were used to evaluate platelet thrombus formation at 1000 s(-1) and fibrin-rich platelet thrombus formation at 240 s(-1) respectively. Blood samples from an asymptomatic patient with VWD type 1 [von Willebrand factor (VWF): RCo 3.2%; bleeding score (BS 2] displayed normal thrombus formation in both PL- and AR-chips, whereas blood from a symptomatic type 1 patient (VWF: RCo 14%, BS 9) had significantly delayed capillary occlusion. Nearly complete suppression of the flow pressure increase was observed in symptomatic patients with VWD type 2A (BS 13) and 2N (BS 27), whereas no flow pressure was found for the type 3 patient (BS 6). Fibrin-rich platelet thrombus formation was only weakly increased by the in vitro addition of factor VIII (FVIII) to blood samples from the type 3 patient, but was normalized by the addition of VWF/FVIII. The in vivo effects of treatment with desmopressin or VWF/FVIII for the symptomatic patients were analysed using two types of microchips. The PL-chip was highly sensitive for patients' VWF-mediated platelet functions, whereas the AR-chip allowed assessment of overall haemostatic ability, including sensitivity to both VWF and FVIII. The combined analysis with PL- and AR-chips may be potentially useful for the diagnosis of VWD based on clinical phenotypes, and for monitoring drug effects.

Topics: Deamino Arginine Vasopressin; Drug Combinations; Factor VIII; Female; Hemostasis; Hemostatics; Humans; von Willebrand Diseases; von Willebrand Factor

Topics: Adolescent; Child; Child, Preschool; Deamino Arginine Vasopressin; Female; Humans; Male; Treatment Outcome; von Willebrand Diseases; von Willebrand Factor

Most circulating von Willebrand factor (VWF) is normally inactive and incapable of binding platelets, but numerous disorders may modify the proportion of active VWF. We explored active VWF levels in patients with von Willebrand disease (VWD) whose VWF had a higher affinity for platelet glycoprotein (GP)Ib, but different susceptibilities to ADAMTS13 and multimer patterns (9 patients lacking large multimers, 10 with a normal pattern); 12 patients with VWF C2362F and R1819_C1948delinsS mutations, which make VWF resistant to ADAMTS13 were also studied. Type 2B patients with abnormal or normal multimers had significantly more active VWF (3·33 ± 1·6 and 3·74 ± 0·74, respectively; normal 0·99 ± 0·23). The type of VWF mutation influenced VWF activation: V1316M was associated with the highest levels in patients with abnormal multimers, and R1341W in those with normal multimers. Pregnancy induced gradually rising active VWF levels and declining platelet counts in one type 2B VWD patient without large multimers. Active VWF levels dropped significantly in patients homozygous for the C2362F mutation or heterozygous for R1819_C1948delinsS mutations (0·2 ± 0·03 and 0·23 ± 0·1, respectively), and less in cases heterozygous for the VWF C2362F mutation (0·55 ± 0·17). We demonstrate that VWF may be more or less activated, with or without any direct involvement of the A1 domain, and regardless of ADAMTS13.

Topics: ADAM Proteins; ADAMTS13 Protein; Deamino Arginine Vasopressin; Female; Hemostatics; Heterozygote; Homozygote; Humans; Mutation; Platelet Aggregation; Platelet Count; Platelet Glycoprotein GPIb-IX Complex; Pregnancy; Pregnancy Complications, Hematologic; Thrombocytopenia; von Willebrand Diseases; von Willebrand Factor

Haemostatic management of surgery in patients with von Willebrand disease (VWD) includes DDAVP or von Willebrand factor (VWF)-containing concentrates. Although the recommendations are for monitoring by VWF activity assays, it is quite common for clinicians to use factor VIII due usually to longer turnaround times required for VWF ristocetin cofactor assay (VWF:RCo) measurements. The aim of this study was to evaluate use of the rapid HaemosIL VWF activity (VWF:Act) latex immuno assay (LIA) on an automated coagulometer (ACL TOP(™) 700; Instrumentation Laboratory, Bedford, MA, USA) compared to platelet-based VWF:RCo assays in this setting. One hundred and sixty-seven plasma samples from 42 patients [Type 1 (n = 22), Type 2A (n = 2), Type 2B (n = 3), Type 2M (n = 10), Type 3 (n = 3)] and acquired von Willebrand syndrome (n = 2) with VWD treated with DDAVP or VWF-containing concentrates were included in the study. Method comparison and method bias were evaluated by Bland-Altman analysis (BA) and Passing and Bablok regression modelling respectively. BA of baseline samples (n = 39) showed a mean difference of -3.0 (±1.96 SD -25.2 to +19.4). Post (treatment) samples (n = 120) were separated into two groups. Group 1 contained samples with VWF:RCo levels 10 to ≤175 IU dL(-1) (n = 97) and group 2, samples with VWF:RCo levels >175 IU dL(-1) (n = 23). BA of group 1 postsamples showed a mean difference of +3.4 (±1.96 SD -44.6 to +51.5), and the BA of Group 2 samples was -23.9 (±1.96 SD -136.1 to +88.3). In conclusion, use of HaemosIL VWF:Act LIA test on an automated coagulometer is a reproducible and rapid assay that can be used as an alternative test for monitoring VWF replacement therapy, facilitating dose adjustments on a real-time basis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Platelets; Child; Child, Preschool; Deamino Arginine Vasopressin; Female; Freeze Drying; Humans; Immunoassay; Latex; Male; Middle Aged; Retrospective Studies; Time Factors; Treatment Outcome; von Willebrand Diseases; von Willebrand Factor; Young Adult

Topics: Aged; Deamino Arginine Vasopressin; Diuresis; Dose-Response Relationship, Drug; Drinking; Elective Surgical Procedures; Female; Health Personnel; Humans; Hyperparathyroidism, Primary; Hyponatremia; Parathyroidectomy; Postoperative Complications; Seizures; von Willebrand Diseases

Desmopressin (DDAVP) 1-deamino-8-D-arginine vasopressin is used in patients with bleeding disorders, including mild factor VIII deficiency, types 1 and 2 von Willebrand disease, and platelet function defects, undergoing surgeries to help control bleeding. We conducted a retrospective chart review of bleeding disorder patients undergoing inpatient surgery at Toledo Children's Hospital, OH, from 2005 to 2009. Our study population included 107 patients aged 2 to 19 years with platelet function defects and von Willebrand disease. Our study aimed to evaluate the extent of hyponatremia caused by DDAVP and to propose a safe and effective treatment regimen for these patients. The mean change in sodium level before and after DDAVP was statistically significant within each age group. Thirteen patients had second dose of DDAVP withheld, and 11 patients had postoperative sodium levels ≤ 130 mEq/L. There were 2 patients with significant complications: a 6-year-old with postoperative bleeding and a 2-year-old with post-DDAVP tonic-clonic seizures. We conclude that DDAVP causes significant hyponatremia, despite appropriate fluid restrictions. On the basis of our analysis, we recommend monitoring sodium levels before each dose of DDAVP and fluid restriction. These patients should be observed in the hospital setting after DDAVP administration for complications such as seizures and postoperative bleeding.

Topics: Adolescent; Blood Coagulation Disorders; Blood Loss, Surgical; Blood Platelet Disorders; Child; Child, Preschool; Deamino Arginine Vasopressin; Hemophilia A; Hemostatics; Humans; Hyponatremia; Intraoperative Period; Postoperative Complications; Postoperative Period; Retrospective Studies; Sodium; von Willebrand Diseases; Water-Electrolyte Imbalance; Young Adult

In this issue of Blood, Federici et al present compelling evidence that bleeding score (BS) predicts the risk of future bleeding in von Willebrand disease (VWD) patients.

Topics: Deamino Arginine Vasopressin; Female; Hemorrhage; Hemostatics; Humans; Male; Severity of Illness Index; von Willebrand Diseases; von Willebrand Factor

Topics: Deamino Arginine Vasopressin; Hemorrhage; Hemostatics; Humans; von Willebrand Diseases; von Willebrand Factor

Recent studies have suggested a unifying pathophysiological concept to explain the underlying defects of von Willebrand factor (VWF) causing von Willebrand disease (VWD) and have highlighted the relevance of simple VWF related activities in producing a useful diagnosis. A standardized bleeding history condensed into a final bleeding score and few widely available laboratory tests, such as VWF ristocetin cofactor activity, VWF antigen and factor VIII (FVIII), in the index case and in his/her relatives are of critical importance. Ristocetin-induced platelet aggregation (RIPA) should also be tested. Trial with desmopressin should be carried out in patients, except those with virtual absence of VWF or with increased RIPA. Desmopressin should be used in all responsive patients as first choice. Substitutive treatment with VWF/FVIII containing products should be used in unresponsive patients, in those with heightened response to desmopressin or in those undergoing interventions requiring good hemostasis for more than 3-5 days. Special consideration should be deserved to the treatment of menorrhagia and parturition.

Topics: Deamino Arginine Vasopressin; Factor VIII; Female; Hemorrhage; Hemostasis; Hemostatics; Humans; Male; Menorrhagia; Menstruation; Pregnancy; Pregnancy Complications, Hematologic; von Willebrand Diseases; von Willebrand Factor

The anesthetic management of patients undergoing cardiac surgery on cardiopulmonary bypass can be challenging. Contact of blood with extracorporeal surfaces results in altered coagulational integrity and increased risk of bleeding. Patients with preexisting bleeding disorders are particularly vulnerable. In this article we discuss the anesthetic management of a patient with von Willebrand disease (vWD) undergoing mitral valve replacement on cardiopulmonary bypass. vWD describes a number of different von Willebrand factor disorders, associated with variable degrees of bleeding, which require an individualized approach. The extent of the surgery, the patient-specific vWD coagulopathy, and clinical indicators guided our therapy, which included desmopressin, cryoprecipitate, and vWF/Factor VIII concentrate.

Topics: Anesthesia; Cardiopulmonary Bypass; Deamino Arginine Vasopressin; Heart Valve Prosthesis Implantation; Hemostasis, Surgical; Hemostatics; Humans; Male; Middle Aged; Mitral Valve Insufficiency; Perioperative Care; von Willebrand Diseases; von Willebrand Factor

Topics: Contraceptives, Oral, Hormonal; Deamino Arginine Vasopressin; Factor VIII; Hemostatics; Humans; von Willebrand Diseases

Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder that is characterized by structural or functional alterations in von Willebrand factor (VWF) caused by a range of lymphoproliferative, myeloproliferative, cardiovascular, autoimmune, and other disorders. The pathogenic mechanisms responsible for the VWF abnormalities depend on the underlying condition, but include clearance due to binding of paraproteins, inhibition of VWF, adsorption to the surface of platelets, increased fluid shear stress, and resultant proteolysis or, more rarely, decreased synthesis. The diagnosis and treatment of AVWS are complicated by the need for multiple laboratory tests and the management of bleeding risk in a typically elderly population with serious underlying conditions that predispose towards thrombosis. Recently developed diagnostic algorithms, based on standard laboratory assays, may assist clinicians with the diagnostic workup and help differentiate between AVWS and von Willebrand disease (VWD) types 1 and 2. AVWS should be considered in all patients with new-onset bleeding whenever laboratory findings suggest VWD, particularly in the presence of an AVWS-associated disorder. AVWS testing is also recommended prior to surgery or an intervention with a high risk of bleeding in any individual with an AVWS-associated disorder. Treatment of the underlying condition using immunosuppressants, surgery, or chemotherapy, can lead to remission of AVWS in some individuals and should always be considered. Strategies to prevent and/or treat bleeding episodes should also be in place, including the use of VWF-containing factor VIII concentrates, desmopressin and tranexamic acid. Treatment success will depend largely on the underlying pathogenesis of the disorder.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Child; Child, Preschool; Deamino Arginine Vasopressin; Humans; Middle Aged; Risk Factors; Tranexamic Acid; von Willebrand Diseases; von Willebrand Factor; Young Adult

In women, von Willebrand disease (VWD) is the most common inherited bleeding disorder. Since VWD and other inherited bleeding disorders are autosomal disorders, they affect women and men. Menorrhagia, or heavy menstrual bleeding (HMB), is the most common symptom of women with bleeding disorder experience. Objectively, it is defined as bleeding that lasts for more than seven days or results in the loss of more than 80 ml of blood per menstrual cycle. The prevalence of menorrhagia in a woman with a bleeding disorder ranges from 32 to 100% in patients with VWD, from 5 to 98% in patients with a platelet dysfunction and from 35 to 70% in women with a rare factor deficiency. A detailed history and a careful physical exam are the first steps towards a diagnosis in adolescents, adding a PBAC>100 increased the sensitivity of the screening tool further to 95%. Laboratory testing should be made at the time of menstrual bleeding in an effort to capture the lowest level of VWF:Ag and FVIII:C. Treatment options for menorrhagia in VWD: (1) antifibrinolytic therapy with tranexamic acid, (2) the non-transfusional agent desmopressin (DDAVP), (3) purified blood products that contain factor VIII and VWF concentrated from plasma and (4) hormonal preparations.

Topics: Adolescent; Antifibrinolytic Agents; Deamino Arginine Vasopressin; Female; Hemostatics; Humans; Menorrhagia; von Willebrand Diseases

Recently, the INNOVANCE® PFA P2Y (P2Y) cartridge of the PFA-100® system (Siemens Healthcare Diagnostics, Marburg, Germany) has been developed for the monitoring of adenosine diphosphate (ADP) P2Y(12) receptor inhibition in patients under dual antiplatelet therapy. The aim of this study was to evaluate the influence of pre-existing defects in primary haemostasis on the P2Y cartridge independent from specific antiplatelet medication. Therefore, the closure time (CT) of the P2Y cartridge was measured in a cohort of 176 patients with assumed bleeding disorders and compared with the results of established methods for the assessment of primary haemostasis. Von Willebrand disease (VWD) was found in 25 patients (14%). The detection rate of the P2Y cartridge regarding VWD was 64% and lower compared to the two conventional cartridges (collagen/epinephrine cartridge, CEPI, 80%; collagen/ADP cartridge, CADP, 76%). In the subgroup of VWD patients with VWF:RCo < 60 IU/dL (n = 22), the correlation analysis and the inter-rater agreement revealed only limited accordance with the two established cartridges. The correlation with the CADP cartridge (C(r) = 0.767, R(2) = 0.461; Kappa = 0.41) was higher than the correlation with the CEPI cartridge. Except for severe forms, platelet function disorders (9 patients, 5%) did not prolong the CT of the P2Y cartridge. Interestingly, the P2Y cartridge was less interference-prone to unspecific medications (23 patients, 13%). As the main conclusion, it must be taken into account that low von Willebrand factor activity can significantly influence the CTs of the P2Y cartridge when using it for the monitoring of antiplatelet therapy.

Topics: Adenosine Diphosphate; Adolescent; Adult; Aged; Aged, 80 and over; Blood Coagulation Tests; Deamino Arginine Vasopressin; Female; Hemostasis; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y; Reproducibility of Results; Sensitivity and Specificity; von Willebrand Diseases; von Willebrand Factor

The effective diagnosis and monitoring of Von Willebrand Disease (VWD) requires an accurate assessment of ristocetin co-factor activity (VWF:RCo). Current methodologies include automated platelet aggregometry and manual visual agglutination both of which are laborious to perform and notoriously subject to a high degree of inter and intra assay variation.. We have evaluated an automated VWF:RCo assay (BC Von Willebrand Reagent, Siemens, Marberg, Germany) for use on the Sysmex CS2100i analyser (Milton Keynes, UK) and retrospectively compared the results with an in-house manual visual agglutination assay and VWF antigen (Siemens) in normal subjects and in 53 patients with various types of VWD and 23 patients following VWF therapeutic treatment.. The intra and interassay CV was improved with the automated assay (2.3% and 3.8% respectively) compared to 7% with the manual VWF:RCo assay. Good correlation was found between the two assays (r=0.91) in 53 patients with VWD. The mean manual VWF:RCo was 0.25IU/ml and mean automated VWF:RCo was 0.27IU/ml. A comparable increase in VWF:RCo following treatment, mostly with Desmopressin, was found in 13 patients with type 1 VWD (mean 3.9 fold increase with manual VWF:RCo and 3.1 fold with the automated VWF:RCo). In 13 patients with type 2 or 3 VWD following treatment mostly with concentrate , a higher increase was found with the automated VWF:RCo assay than the manual assay (mean 11.9 fold manually and mean 20.3 automated).. The automated VWF:RCo assay shows enhanced precision and analysis time in this difficult and time consuming laboratory test and its introduction should greatly improve the reliability of VWF testing.

Topics: Blood Coagulation Tests; Blood Platelets; Deamino Arginine Vasopressin; Hemostatics; Humans; Platelet Aggregation; Platelet Function Tests; Ristocetin; Time Factors; von Willebrand Diseases; von Willebrand Factor

Topics: Administration, Intranasal; Deamino Arginine Vasopressin; Drug Administration Schedule; Facial Asymmetry; Free Tissue Flaps; Hemostatics; Humans; Injections, Intravenous; Male; Microsurgery; Plastic Surgery Procedures; Treatment Outcome; von Willebrand Diseases; Young Adult

To analyze the incidence and severity of hyponatremia in patients receiving synthetic desmopressin (DDAVP) in the perioperative setting of oropharyngeal surgery in the treatment of von Willebrand disease and to propose a standardized protocol for perioperative fluid resuscitation and postoperative sodium monitoring after DDAVP administration.. Retrospective medical record review.. A retrospective medical record review in an academic pediatric medical center was conducted. From October 1, 2002, to February 1, 2009, all patients undergoing adenotonsillectomy and receiving DDAVP preoperatively for the treatment of von Willebrand disease were identified. A total of 76 patients were identified by initial database review; 63 patients were included in the study, and 13 patients were excluded secondary to incomplete data. DDAVP dose and timing, perioperative fluid volume and composition, and postoperative sodium levels were collected. Extreme adverse events related to hyponatremia were recorded.. Forty-seven of 63 (74.6%) patients developed some degree of hyponatremia after DDAVP administration, and six of 63 (9.5%) patients developed extreme hyponatremia, with the degree of hyponatremia related to the volume of perioperative fluid resuscitation. The sodium nadir occurred within 9 to 20 hours after DDAVP administration. No serious adverse events related to hyponatremia were recorded during the study period.. The incidence of hyponatremia in children receiving DDAVP for prophylaxis of intraoperative bleeding following oropharyngeal surgery is high. The degree of hyponatremia is related to the perioperative fluid volume administered. A protocol for DDAVP administration, perioperative fluid resuscitation, and postoperative sodium monitoring that aims to reduce the incidence of hyponatremia in this population is proposed.

Topics: Academic Medical Centers; Adenoidectomy; Adolescent; Blood Loss, Surgical; Child; Child, Preschool; Cohort Studies; Deamino Arginine Vasopressin; Female; Follow-Up Studies; Humans; Hyponatremia; Incidence; Male; Perioperative Care; Postoperative Complications; Postoperative Hemorrhage; Preoperative Care; Retrospective Studies; Risk Assessment; Severity of Illness Index; Tonsillectomy; Treatment Outcome; von Willebrand Diseases

In this single-center retrospective study, we evaluated the accuracy of laboratory tests in diagnosing acquired von Willebrand syndrome associated with lymphoproliferative disorders in 36 consecutive patients diagnosed at the University Hospital of Nantes, France. We also compared hemostatic treatments in the following groups: 21 patients with Waldenström macroglobulinemia (WM), 14 with monoclonal gammopathy of undetermined significance (MGUS) (10 with IgG-MGUS and 4 with IgM-MGUS), and 1 with IgA multiple myeloma (IgA-MM). The diagnosis was made in 18 (50%) patients during systematic screening, in 6 (17%) during active mild hemorrhage, and in 12 (33%) during an active, severe bleed. Of the laboratory tests studied, only closure times measured on the Platelet Function Analyzer (PFA)-100 device reliably diagnosed the hemostatic problem. There was no relationship between the factor VIII activity (FVIII:C) or von Willebrand factor activity (VWF:RCo) levels and the previous history of hemorrhage described by patients.We studied hemostatic treatment in most patients: IgG-MGUS patients responded well to high-dose intravenous immunoglobulin (IVIg) infusions (1 g/kg per d), although patients with IgM-MGUS did not. Desmopressin infusions were effective in 3 patients with IgG-MGUS and 2 patients with IgM-MGUS when the baseline values were above 10 IU/dL, but levels soon returned to the baseline. The 7 WM patients had a good response to desmopressin. These results confirm the efficacy of IVIg in IgG-MGUS patients and the prominent role of closure time in the diagnosis of acquired von Willebrand syndrome.

Topics: Adult; Aged; Aged, 80 and over; Deamino Arginine Vasopressin; Female; Hemostatics; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Male; Middle Aged; Paraproteinemias; Retrospective Studies; von Willebrand Diseases; von Willebrand Factor

Cauterization, nasal packing, and topical and/or injection of intranasal vasoconstrictors have been the mainstay of treatment for epistaxis following outpatient nasal surgery. In this study, the authors report the clinical outcomes in a cohort of patients with postoperative epistaxis managed with a single dose of intravenous desmopressin.. A retrospective chart review of 268 consecutive nasal operations (rhinoplasty, septoplasty, and/or turbinectomy for cosmetic and/or functional purposes) was conducted. Information on demographics, perioperative blood pressure, postoperative management, and effectiveness of the measures used was assessed. The primary outcome variable was cessation of bleeding.. Nine patients were identified who experienced excessive postoperative bleeding following discharge from the surgical facility. Each patient received 0.3 μg/kg of intravenous desmopressin over 30 minutes under the supervision of the local emergency room physician with verbal instructions from the treating plastic surgeon. After administration of desmopressin, bleeding either stopped completely (eight patients) or slowed down significantly to allow discharge (one patient). No significant adverse side effects of desmopressin were observed. No patient was known to be taking medication negatively affecting coagulation perioperatively. Preoperatively, two patients were documented to have von Willebrand disease and thus received desmopressin preoperatively. Average blood pressure was 116/71 mmHg intraoperatively (range, 109 to 126/66 to 83 mmHg) and 118/74 mmHg postoperatively (range, 105 to 129/65 to 85 mmHg).. Unremitting postoperative epistaxis following outpatient nasal surgery can be successfully controlled by a protocol using intravenous desmopressin without the need for alternative maneuvers.

Topics: Adolescent; Adult; Cohort Studies; Deamino Arginine Vasopressin; Epistaxis; Female; Follow-Up Studies; Hemostatics; Humans; Infusions, Intravenous; Intraoperative Complications; Male; Middle Aged; Nasal Septum; Postoperative Complications; Postoperative Hemorrhage; Rhinoplasty; Treatment Outcome; Turbinates; von Willebrand Diseases; Young Adult

von Willebrand disease (VWD) is the most common inherited bleeding disorder and arises from deficiencies and/or defects in the plasma protein von Willebrand factor (VWF). The current report overviews the diagnosis and management of VWD as reflected by differential processes applied within centers around the world. The prevalence of VWD, as well as the frequency of different VWD types, is also reported. VWD prevalence data varies according to methodology used, with epidemiological/population screening estimates approximating 1% of the population (or 10,000 cases per million population), several orders of magnitude higher than estimates from bleeding disorders registry data or regional/center analysis (which instead range from <1 to ~450 cases per million population). Frequency of different VWD types also varies according to source and analysis, with type 1 VWD identified as the clear dominant type in most developed countries (ranging from 40% to 90% of all VWD cases), whereas type 3 VWD predominates in developing countries such as India and Iran. The frequency of qualitative (i.e., type 2) VWD also varies considerably among different reports, ranging from 3% to >50% of all VWD cases, as does the frequency of specific qualitative VWD types (i.e., 2A, 2B, 2M, and 2N). Although type 2A VWD is considered the most common form of type 2 VWD, in some reports workers consider type 2M VWD to be as, or more, common. Although not considered to be a "true" VWD, given its platelet origin, platelet-type VWD is only rarely identified. Finally, management of VWD also differs according to geographic region. Most developed countries use standard therapy, employing desmopressin (DDAVP) wherever possible, factor concentrate in other situations, and antifibrinolytic therapy as required. In contrast, the relative high cost and unavailability of factor concentrates in developing countries, and sometimes the unavailability of DDAVP, requires different management strategies to be applied.

Topics: Antifibrinolytic Agents; Deamino Arginine Vasopressin; Developing Countries; Global Health; Hemostatics; Humans; von Willebrand Diseases; von Willebrand Factor

The correct diagnosis and classification of Von Willebrand disease (VWD) is important for therapy and genetic counseling but is made difficult due to the variability of its clinical expression and limitations of laboratory methods. A national registry of VWD patients has been initiated in Spain. The results of a concise survey on the diagnosis of VWD show the frequency of VWD is fivefold greater in Spain than that expected from epidemiological studies in other European countries; this may result from overdiagnosis and/or a higher prevalence of VWD. These results clearly reinforce the need for the Spanish VWD registry. A consensus guideline for optimal treatment of VWD is being elaborated in Spain. Desmopressin (DDAVP) is the choice of treatment in responsive VWD patients. Von Willebrand factor concentrates (VWF/factor VIII) are used in individuals nonresponsive to DDAVP, when DDAVP is contraindicated, or in VWD types 2B and 3.

Topics: Deamino Arginine Vasopressin; Factor VIII; Hemostatics; Humans; Practice Guidelines as Topic; Prevalence; Spain; Surveys and Questionnaires; von Willebrand Diseases; von Willebrand Factor

Von Willebrand disease (VWD) is the most common inherited bleeding disorder and is due to quantitative and/or qualitative defects of von Willebrand factor (VWF). Despite the improved knowledge of the disease, detailed data on VWD types requiring specific treatments have not been reported thus far. To determine the number and types of VWD requiring therapy with desmopressin (DDAVP) and/or VWF/FVIII concentrates in Italy, a national registry on VWD (RENAWI) was organized. Only 16 of 48 centers included VWD in the RENAWI with diagnoses performed locally. Patients with uncertain results were retested by two expert laboratories using multimeric analysis and mutations of the VWF gene. A total of 1234 of 1529 (81%) cases satisfied the inclusion criteria and could be classified as VWD1 (63%), VWD2A (7%), VWD2B (6%), VWD2M (18%), VWD2N (1%), and VWD3 (5%). VWD types were also confirmed by DNA analyses and occur in young adults (83%), mainly in women (58%). Mucosal bleedings (32 to 57%) are more frequent than hematomas (13%) or hemarthrosis (6%). Most patients were exposed to an infusion trial with desmopressin (DDAVP) and found responsive with the following rates: VWD1 (69%), VWD2A (26%), VWD2M (29%), and VWD2N (71%). However, DDAVP was not always used to manage bleeding in all responsive patients and VWF/FVIII concentrates were given instead of or together with DDAVP in VWD1 (30%), VWD2A (84%), VWD2B (62%), VWD2M (63%), VWD2N (30%), and VWD3 (91%). Data of the RENAWI showed that correct VWD identification and classification might be difficult in many Italian centers. Therefore, evidence-based studies should be organized only in well-characterized patients tested by laboratories that are expert in the clinical, laboratory, and molecular markers of VWD.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Deamino Arginine Vasopressin; Factor VIII; Female; Gene Frequency; Hemostatics; Humans; Infant; Italy; Male; Middle Aged; Mutation; Retrospective Studies; von Willebrand Diseases; von Willebrand Factor; Young Adult

We have analyzed the databases for von Willebrand disease (VWD) from the hemophilia center for adult patients with bleeding disorders in South Australia. We define the prevalence of types of VWD to determine the proportion of who would be treated with factor (F) VIII/von Willebrand factor (VWF) concentrate to prevent or control hemorrhage. In severe or moderately severe patients, we use plasma-derived FVIII/VWF concentrate, and for mild to severe cases, we use desmopressin plus tranexamic acid. There are 103 patients with VWF ristocetin (RCo) ≤50 IU/dL: 38 (37%) severe (VWF:RCo <10 IU/dL), 28 (27%) moderate (VWF:RCo 10 to 29 IU/dL), and 37 (36%) mild (VWF:RCo 30 to 50 IU/dL). Hence in 66 (64%), FVIII/VWF concentrate is the mainstay of treatment. The prevalence of VWD in our region according to data from our center is ~1 per 12,000. A total of 52% of patients are type 1, 44% type 2, and 5% type 3. In our experience, type 2M (45% of type 2) is much more common than types 2A and 2B (each 9% of type 2). Mutation detection is useful for identifying some subtypes of VWD.

Topics: Adult; Aged; Aged, 80 and over; Antifibrinolytic Agents; Databases, Factual; Deamino Arginine Vasopressin; Female; Genetic Testing; Hemostatics; Humans; Male; Middle Aged; Mutation; South Australia; Tranexamic Acid; von Willebrand Diseases; von Willebrand Factor; Young Adult

Clinical and laboratory data of children with von Willebrand disease (VWD) types have been derived from retrospective studies and small case series. This article reports on the clinical and laboratory data of a large pediatric cohort in one single Argentinian center. The biological and clinical responses to desmopressin and replacement therapies are also described. Over a 15-year period, 194 of 1150 children (16.9%) were diagnosed as having type 1 VWD (80%), type 2 VWD (19%), and type 3 VWD (1%). The distribution of the different type 2 VWD subtypes was type 2A VWD, 43%; type 2B VWD, 32%; type 2M VWD, 19%; and type 2N VWD, 6%. Eighty patients with type 1 VWD and 12 patients with type 2 VWD were prospectively evaluated to desmopressin (DDAVP) response. A complete response was observed in all children with type 1 VWD, whereas 40% of the children with severe type 1 VWD and with type 2 VWD achieved a complete response. All the children who received DDAVP as prophylaxis or treatment for bleeding had good clinical evolution. Considering the restricted availability of specialized hemostasis centers, we believe our clinical and laboratory approach appropriate for the detection of patients with different types of VWD. Further studies are necessary to determine epidemiological aspects of VWD in Argentina to estimate the necessary facilities and trained personnel for the diagnosis and management of patients with VWD.

Topics: Adolescent; Argentina; Child; Child, Preschool; Coagulants; Cohort Studies; Deamino Arginine Vasopressin; Factor VIII; Female; Follow-Up Studies; Humans; Infant; Male; Mutation; Treatment Outcome; von Willebrand Diseases; von Willebrand Factor

Von Willebrand disease (VWD) is a bleeding disorder with variable clinical expression. In this article we describe types, clinical features, genetic testing when needed, genotype/phenotype relationships, and the response to desmopressin (DDAVP) testing, according to our experience. Our findings are possible type 1, 69.6%; type 1, 13.5%; severe type 1, 0 .35%; type 3, 0.55%; type 2A, 9.5%; probable 2B, 0.6%; type 2M, 2.5%; and probable type 2N, 3.4%. The most frequent symptoms are ecchymoses-hematomas and epistaxis, and, in females >over 13 years also menorrhagia. In pregnant patients, assessment of laboratory parameters in months 7 and 8 is recommended to plan the need for prophylaxis at term. DDAVP merits to be considered as the first-choice therapy, including pregnant women and children, and no patient showed significant unwanted effects. Because this is a safe, effective, and affordable therapy, we hope to encourage clinicians, mainly pediatricians and obstetricians, to a wider use of DDAVP, especially in developing countries. We also report two patients with prophylactic treatment.

Topics: Adolescent; Adult; Argentina; Child; Child, Preschool; Deamino Arginine Vasopressin; Female; Genetic Association Studies; Hemostatics; Humans; Male; Middle Aged; Mutation; Pregnancy; Treatment Outcome; von Willebrand Diseases; von Willebrand Factor; Young Adult

Patients with Von Willebrand disease (VWD) in South Africa are cared for in 17 Hemophilia Treatment Centers. The exact prevalence of the disease is uncertain, but 539 patients are annotated in registries. VWD patients are mostly diagnosed in the five largest academic centers, and the classification of the subtypes is performed by one of these, the VWD testing facility. An algorithm is used for the diagnosis of VWD. The distribution of subtypes diagnosed by the VWD reference center is 38%, 58%, and 4% for type 1, 2, and 3, respectively, and ~15% of plasma samples received are rejected due to poor storage and transport conditions. A novel single nucleotide polymorphism has been found in an African patient with type 2B VWD. From the type 1 VWD patients who were diagnosed by the VWD testing facility, 45% seem to have an increased VWF clearance phenotype with a propeptide-to-antigen ratio of 1.9 ± 0.3. VWD patients are treated with desmopressin, factor (F)VIII/VWF concentrate (Haemosolvate FVIII; National Bioproducts Institute, Durban, South Africa), and tranexamic acid. Haemosolvate FVIII contains a VWF antigen concentration of 167 ± 27 IU/mL, a ristocetin cofactor activity of 100 ± 29 IU/mL, a collagen binding activity of 99 ± 29 IU/mL, normal VWF multimers, and a FVIII concentration of 50 IU/mL. Not all patients with VWD are currently classified, and many VWD patients in South Africa are probably undiagnosed.

Topics: Algorithms; Clinical Laboratory Techniques; Coagulants; Deamino Arginine Vasopressin; Factor VIII; Genetic Testing; Humans; Mutation; von Willebrand Diseases; von Willebrand Factor

Von Willebrand disease (VWD) in all developing countries including India is considered a rare coagulation disorder, contrary to many reports from Western countries. Prevalence data based on hospital referrals identifies type 3 VWD as the most common subtype followed by type 1 and type 2. Approximately 60 to 70% cases of type 3 VWD are reportedly born of consanguineous marriages. The discriminatory diagnostic tests mainly include assays for factor (F)VIII:C and ristocetin-induced platelet agglutination and Von Willebrand factor (VWF) antigen either by immunoelectrophoresis or by enzyme-linked immunosorbent assay. VWD-type assisting tests like VWF collagen binding, VWF ristocetin cofactor assay, VWF-FVIII binding assay, and multimer analysis are occasionally used but not routinely applied in many laboratories. Among women, menorrhagia is an important presenting manifestation. Except for a handful of centers mainly in metropolitan cities, most laboratories in the remote parts of the country have no facilities for VWD-related investigations, resulting in occasional misdiagnoses of VWD as hemophilia A. Genetic diagnosis is being offered in two or three centers using the indirect linkage method in type 3 VWD, and efforts are continuing to implementing a direct mutation detection technique for routine practice in a few laboratories. Depending on the subtype or the severity of VWD, desmopressin, cryoprecipitate, fresh-frozen plasma, and factor VIII/VWF concentrates are used for management. Antifibrinolytic agents like epsilon-aminocaproic acid and tranexamic acid are widely used as an adjuvant therapy. In women with menorrhagia, oral contraceptives as a supplementary treatment are also being widely advocated to reduce bleeding. Products like danazol, ethenyl estradiol, thalidomide, and atorvastatin have been used in individual patients; acquired VWD associated with hypothyroidism has been managed successfully with thyroid hormone treatment. Both minor and major surgical procedures are performed in a few centers with judicious use of cryoprecipitate or FVIII concentrate containing VWF along with other supplementary therapeutic products to achieve adequate hemostasis. Awareness about the disease, establishment of the comprehensive coagulation laboratory, and treatment centers will be successful in increasing diagnosis of VWD and consequently better management of affected patients. This is likely to tilt the ratios of different VWD types, and VWD is likely to emerg

Topics: Deamino Arginine Vasopressin; Factor VIII; Genetic Testing; Hemostatics; Humans; India; Mutation; von Willebrand Diseases; von Willebrand Factor

Topics: Adult; Child, Preschool; Deamino Arginine Vasopressin; Factor VIII; Female; Humans; Male; Middle Aged; Retrospective Studies; von Willebrand Diseases

Pregnancy in von Willebrand's disease may carry a significant risk of bleeding. Information on changes in factor VIII and von Willebrand factor and pregnancy outcome in relation to von Willebrand factor gene mutations are very scanty.. We examined biological response to desmopressin, changes in factor VIII and von Willebrand factor and pregnancy outcome in a cohort of 23 women with von Willebrand's disease characterized at molecular level and prospectively followed during 2000-2007.. Thirty-one pregnancies occurred during the study period. Remarkably, similar changes of factor VIII and von Willebrand factor were observed after desmopressin and during pregnancy in nine women with R854Q, R1374H, V1665E, V1822G and C2362F mutations. Women with von Willebrand's disease and R1205H and C1130F mutations (17 pregnancies in 12 women) had only a slight increase of factor VIII and von Willebrand factor during pregnancy while their response to desmopressin was marked but short-lived. For these women, two to three desmopressin administrations within the first 48 hours were sufficient to successfully manage vaginal delivery. Two women with recessive von Willebrand's disease due to compound heterozygosity for different gene mutations had a spontaneous, major increase in factor VIII while von Willebrand factor remained severely reduced. Desmopressin increased factor VIII and was clinically useful in the first case, while a factor VIII/von Willebrand factor concentrate was required in the second patient not responsive to the compound. Factor VIII/von Willebrand factor concentrate was also required for two women with type 2 A von Willebrand's disease with V1665E mutations who had no von Willebrand factor activity change during pregnancy. In one of them, delayed bleeding occurred 15 days later requiring treatment with Factor VIII/von Willebrand factor concentrate. No miscarriages or stillbirths occurred.. Close follow-up and detailed guidelines for the management of parturition have produced a very low rate of immediate and late bleeding complications in this setting. Desmopressin was effective and safe in preventing significant bleeding at delivery in most of these patients.

Topics: Adult; Cohort Studies; Deamino Arginine Vasopressin; Delivery, Obstetric; Female; Follow-Up Studies; Humans; Infant, Newborn; Mutation; Pregnancy; Pregnancy Complications, Hematologic; Prospective Studies; von Willebrand Diseases; von Willebrand Factor; Young Adult

1) Compare rates of post-tonsillectomy bleeding in pediatric patients with and without von Willebrand disease (vWD). 2) Identify factors that may increase the risk for post-tonsillectomy bleeding in children with and without vWD.. Historical cohort study.. Tertiary care, university-based pediatric hospital.. Medical records were examined for 99 patients with vWD and 99 patients without vWD younger than 18 years who underwent tonsillectomy with or without adenoidectomy from August 1997 to October 2005. Subjects were matched for age, year of surgery, type of surgery, and indication for surgery.. Post-tonsillectomy hemorrhage occurred in eight of 99 (8%) vWD patients and in six of 99 (6%) non-vWD patients (P = 0.58, odds ratio 1.36, 95% CI 0.45-4.08). A two-sample test of proportions demonstrated lower and upper limits of -0.051 and 0.092. Four of eight children with vWD and two of six non-vWD patients required surgical intervention for control of bleeding. Ninety-three of 99 vWD patients received desmopressin acetate (DDAVP) preoperatively. In patients with vWD who responded to DDAVP challenge, there was no increased likelihood of post-tonsillectomy bleeding compared with non-vWD patients. No significant difference in the number of bleeding events was noted on the basis of demographics, preoperative laboratories, or use of aminocaproic acid.. Children with vWD undergoing tonsillectomy have a postoperative bleeding rate similar to that of a matched group. However, the sample size was not sufficient to eliminate the possibility of a clinically important difference between the two groups.

Topics: Adolescent; Child; Child, Preschool; Cohort Studies; Deamino Arginine Vasopressin; Female; Hemorrhage; Humans; Male; Postoperative Complications; Tonsillectomy; von Willebrand Diseases

Inherited disorders of platelets constitute a group of rare diseases that give rise to bleeding syndromes of variety severity, with more severe cases being first diagnosed during infancy and childhood. To appropriate diagnose a platelet function disorder during early childhood the knowledge of the physiological characteristics of platelets in the paediatric population is mandatory. Apart from thrombocytopenia which is quite common in neonates and children the present overview is aimed to focus on inherited platelet function disorders. Furthermore, knowledge on platelet maturation and reference values according to age are given, and a diagnostic strategy specifically adapted to a pediatric population is presented on the bases of plasmatic and molecular laboratory methodologies. Finally, therapeutic approaches are briefly summarized (antifibrinolytic agents, Desmopressin, HLA-matched platelets, recombinant factor VIIa).

Topics: Antifibrinolytic Agents; Blood Platelet Disorders; Child; Deamino Arginine Vasopressin; Diagnosis, Differential; DNA Mutational Analysis; Factor VIIa; Hemorrhagic Disorders; Humans; Infant; Infant, Newborn; Molecular Motor Proteins; Myosin Heavy Chains; Partial Thromboplastin Time; Platelet Count; Platelet Function Tests; Platelet Transfusion; Recombinant Proteins; Syndrome; Thrombocytopenia; von Willebrand Diseases; von Willebrand Factor

Topics: ABO Blood-Group System; Adult; Animals; Area Under Curve; Deamino Arginine Vasopressin; Female; Humans; Male; Middle Aged; Mutation; Recombinant Proteins; von Willebrand Diseases; von Willebrand Factor

Hemophilia A and B and von Willebrand disease (VWD) belong to the most frequent congenital coagulation disorders and are a significant problem in patients who require periodontal therapy or tooth extraction. These patients need specialist management because even minor invasive procedures can precipitate a prolonged bleeding episode. However, although dental care presents major challenges in these patients, only a few studies are available.. In this case series, the comprehensive periodontal treatment of four patients with hemorrhagic disorders (VWD type I and mild hemophilia B) is described. There was a close collaboration between the periodontist and the hematologist: all patients were scheduled for premedication with desmopressin and other pharmaceuticals at the hematologist's office. After one session of scaling and root planing was performed in all patients, local agents such as tranexamic acid were used. In the course of periodontal therapy, access-flap surgery was performed in one of the four patients.. Before treatment, the rates of probing depths (PDs) of 4 to 6 mm (20% to 57%) or ≥ 7 mm (2% to 20%) were high. Three months after treatment, the rates of PDs of 4 to 6 mm (5% to 42%) or ≥ 7 mm (0% to 2%) decreased significantly in all patients. Attachment gains were also observed. A secondary hemorrhage did not occur in any of the patients, and wound healing proceeded without any complications.. Effective periodontal treatment can be provided to patients with hemorrhagic disorders with the combined efforts of the periodontist and hematologist.

Topics: Adult; Aggregatibacter actinomycetemcomitans; Aggressive Periodontitis; Anti-Bacterial Agents; Chronic Periodontitis; Deamino Arginine Vasopressin; Dental Care for Chronically Ill; Dental Scaling; Factor IX; Factor VIII; Female; Hemostatics; Humans; Male; Middle Aged; Premedication; Tranexamic Acid; von Willebrand Diseases

The diagnosis and management of von Willebrand disease (VWD) in paediatrics is challenging. Our aim was to review patient's characteristics related to biological and clinical response to DDAVP in children with low von Willebrand factor (VWF) levels and bleeding history from a single institution. We included a retrospective cohort of 221 children (median age 11 years; 137 females): 27 type 1 (VWF levels within 15-30 IU dL-1) and 194 possible type 1 (VWF levels within 31-49 IU dL-1). The DDAVP infusion-test was performed in 214/221 children, 93.4% of whom showed good response. Patients with type 1 were at higher risk of DDAVP-test failure: 9/26 (34.6%) vs. 18/188 (9.6%) with possible type 1 (RR 3.44, 1.75-6.79; p= 0.002, Fisher's exact test). In 68 children, the clinical response to DDAVP was evaluated 87 times: i) to stop bleeding: menorrhagia (13), mucocutaneous (12), haemarthrosis (1); and ii) to prevent surgical bleeding: adenotonsillectomy (17), major (15) and minor surgery (10); and dental procedures (19). No major adverse events or bleeding were observed. The treatment was effective with one single dose of DDAVP in almost all patients, without antifibrinolytic or local therapy, except in a girl with severe haemorrhage during menarche who required replacement therapy. In conclusion, patients with VWD type 1 were at higher risk of no response to DDAVP infusion-test. In this series, one dose of DDAVP proved effective and safe for children with VWD. Since this is a safe, effective and affordable therapy, we consider that a wider use should be promoted, especially in developing countries.

Topics: Adolescent; Argentina; Biomarkers; Child; Deamino Arginine Vasopressin; Female; Hemorrhage; Hemostatics; Humans; Infusions, Intravenous; Male; Treatment Outcome; von Willebrand Diseases; von Willebrand Factor

Recent studies indicate that bleeding disorders, particularly von Willebrand disease (VWD) is more prevalent than previously thought in adolescents with menorrhagia. Menorrhagia management in undiagnosed disorders of hemostasis may be associated with unwanted risks and complications. The prevalence of symptomatic VWD in the pediatric primary care setting appears to be 0.11% (95% CI, 0.04-0.25%). Studies evaluating the prevalence of VWD in adolescents with menorrhagia have included over 500 patients with a prevalence range from 3 to 36% depending on the clinical setting studied, with the highest prevalence seen in adolescents referred to an outpatient Hemophilia Center, while the lowest prevalence is seen in the acute hospital setting. Recently, the diagnosis of VWD has been facilitated by the use of pediatric bleeding questionnaires that have proved useful in quantifying the severity of bleeding symptoms. Treatment of VWD is often complex because a combination of therapies is often required. Potential treatment options include estrogen-progesterone preparations, desmopressin, antifibrinolytic agents and von Willebrand factor concentrates. More research is needed to evaluate the effectiveness of the various treatment modalities in the adolescent population.

Topics: Adolescent; Aminocaproic Acid; Antifibrinolytic Agents; Child; Contusions; Deamino Arginine Vasopressin; Epistaxis; Female; Hemostatics; Humans; Medical History Taking; Menorrhagia; Platelet Transfusion; Prevalence; Surveys and Questionnaires; Tranexamic Acid; von Willebrand Diseases; von Willebrand Factor

It is very difficult to determine if patients with a moderate low level of VWF parameters have mild disease or if they are just low normal (so called grey area of VWD). This applies particularly to pediatrics, because it is difficult to evaluate the bleeding history of children. Al our centres every child diagnosed with vWD gets DDAVP to test the response for it. This study was done to evaluate the DDAVP- test as a diagnostic tool.. A retrospective analysis of data obtained with routine DDAVP administration for test purposes in 52 patients with borderline von Willebrand disease at the haemophilia centre Graz was done. The increase of VWF:Ag, VWF:RiCof and FVIII:C has been document and compared.. All of our patients had a very good response after application of DDAVP. The increase of VWF:Ag, VWF:RiCof and FVIII:C was compared in patients with positive and negative bleeding anamneses. The patients with positive anamneses had significantly lower parameters at the beginning. The increase of VWF parameters did not differ significantly between the groups at the different time-points. These results demonstrate that a positive anamnesis is not significantly associated with a lower increase. On the other side a high increase is not associated with a negative anamnesis.. It is not possible to use the DDAVP test as a diagnostic tool for patients within the diagnostic grey area of VWD.

Topics: Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Humans; Reference Values; Reproducibility of Results; Retrospective Studies; von Willebrand Diseases; von Willebrand Factor

We performed a retrospective audit of desmopressin (DDAVP) usage to assist in the functional characterisation of von Willebrand disease (VWD). Data was evaluated for 208 patients, comprising those with VWD (Type 1 [n=160], Type 2A [n=19], Type 2M [n=10]), plus 19 individuals with haemophilia or carriers of haemophilia. Laboratory testing comprised pre- and post-DDAVP evaluation of factor VIII (FVIII:C), von Willebrand factor (VWF) antigen (VWF:Ag), VWF ristocetin cofactor (VWF:RCo) activity, VWF collagen binding (VWF:CB) activity, and in one laboratory an alternate VWF activity assay. In brief, combined usage of VWF:RCo and VWF:CB appears to provide improved functional characterisation and/or 'classification' of VWD types, in particular better differentiation of Type 2A and 2M VWD, and clearer validation of a Type 1 VWD diagnosis. Thus, (i) Type 1 VWD displayed generally good absolute and relative rises in all test parameters, although relative rises were greatest for FVIII:C and VWF:CB, and CB/Ag ratio increases overshadowed those for RCo/Ag; (ii) Type 2A VWD patients showed good absolute and relative rises in both FVIII:C and VWF:Ag, but poor absolute rises in both VWF:CB and VWF:RCo; although small rises in both CB/Ag and RCo/Ag were also observed, both ratios tended to remain below 0.7; (iii) finally, Type 2 M VWD patients generally showed good absolute and relative rises in FVIII:C, VWF:Ag and VWF:CB, but a poor absolute and relative rise in VWF:RCo; thus, there were good rises in CB/Ag ratios but little change in RCo/Ag, which tended to remain below 0.7. Future multi-centre prospective investigations are warranted to validate these findings and to investigate their therapeutic implications.

Topics: Collagen; Deamino Arginine Vasopressin; Hemostatics; Humans; In Vitro Techniques; Retrospective Studies; von Willebrand Diseases; von Willebrand Factor

Topics: Deamino Arginine Vasopressin; Hemostatics; Humans; Platelet Function Tests; Retrospective Studies; von Willebrand Diseases

Mutation C1149R in the von Willebrand factor (VWF) gene has been thought to cause autosomal dominant severe type 1 von Willebrand disease (VWD).. Eight patients from three unrelated families with this mutation were included in the present study who had distinct VWF abnormalities, not described in earlier studies.. The patients showed notably low levels of VWF antigen (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo), VWF collagen binding (VWF:CB), and a reduced ristocetin-induced platelet aggregation (RIPA). VWF:RCo/VWF:Ag and VWF:CB/VWF:Ag ratios were lower than 0.7. At basal conditions, all the VWF multimers were decreased in plasma, with a clearly lower relative proportion of the high molecular weight VWF multimers (HMWM). In high-resolution agarose gels, a large decrease in the relative proportions of the satellite bands was seen. The patients had a brief good response to desmopressin (DDAVP) administration, but the released VWF half-life was shorter than normal, indicating an accelerated clearance of their VWF. Platelet VWF was abnormal.. We conclude from the results obtained in these patients for plasma phenotypic data that this mutation should be classified as a VWD type 2A (IIE). DDAVP therapy may be somewhat helpful for this mutation, at least for mild to moderate bleeding. These data provide evidence that for VWD classification factors other than basal VWF, such as DDAVP response and platelet VWF, should be considered.

Topics: Blood Platelets; Deamino Arginine Vasopressin; Electrophoresis, Agar Gel; Female; Genes, Dominant; Humans; Male; Molecular Weight; Mutation; Phenotype; Protein Multimerization; Time Factors; von Willebrand Diseases; von Willebrand Factor

The diagnosis and functional characterization of von Willebrand disease (VWD) is challenging. There are inherent difficulties in both its identification and classification because of clinical uncertainty, the limitations in the test processes and test panels typically used by laboratories, and because the classification scheme does not always allow unequivocal assignment of any subtype. This article reviews current thoughts and alternatives to the classic approach of the classification and functional characterization of VWD. Of particular interest to this author is the utility of an extended core test panel that includes additional functional VWF assays, such as the collagen binding assay, and the potential for desmopressin (DDAVP) challenge to not only provide therapeutic information but also assist in the better characterization of individuals with defects or deficiencies in von Willebrand factor (VWF). The potential use of supplementary assays such as the PFA-100 and the VWF propeptide assay after DDAVP challenge is also worth noting.

Topics: Biomarkers; Clinical Laboratory Techniques; Collagen; Deamino Arginine Vasopressin; Diagnostic Errors; Factor VIII; Humans; Platelet Aggregation; von Willebrand Diseases; von Willebrand Factor

To review the incidence of postoperative bleeding in children with type 1 von Willebrand disease (VWD) who were treated with a single institution protocol.. We performed a retrospective study to determine the postoperative hemorrhage rate in pediatric patients with type 1 VWD who were treated via the Children's Hospital of Philadelphia institutional protocol. This protocol utilizes intravenous desmopressin (DDAVP), oral aminocaproic acid, and overnight observation.. Between the years of 2000 to 2006, 41 children with type 1 VWD underwent an adenotonsillar procedure and were treated with this protocol. Seven patients (17%) experienced delayed (>24 hours after surgery) postoperative hemorrhage requiring intervention. Five of the 7 patients required cautery to control the bleeding, and the remaining 2 patients responded to DDAVP and aminocaproic acid alone. Older age and lower VW antigen levels were associated with postoperative hemorrhage (P = .05).. Despite therapeutic intervention to decrease the risk of postoperative hemorrhage, the incidence of hemorrhage was higher in pretreated patients with type 1 VWD than in children without bleeding disorders. Further prospective studies are necessary to determine the optimal treatment to reduce bleeding complications in these patients.

Topics: Adenoidectomy; Administration, Oral; Adolescent; Age Factors; Aminocaproates; Cautery; Child; Child, Preschool; Deamino Arginine Vasopressin; Female; Hemostatics; Humans; Infusions, Intravenous; Male; Postoperative Hemorrhage; Postoperative Nausea and Vomiting; Retrospective Studies; Tonsillectomy; von Willebrand Diseases; von Willebrand Factor

We have prospectively evaluated the biologic response to desmopressin (DDAVP) in 28 children with type 2 von Willebrand disease (VWD) in correlation with the phenotype and the molecular defect of VWF. The diagnosis of VWD type 2 was mainly based on VWF functional parameters and/or an aberrant VWF multimer pattern. Seventeen different mutations were identified (6 of them novel). No response with respect to the functional parameters VWF:RCo and/or VWF:CB was seen in patients with severe abnormality of the VWF multimer pattern. One patient with VWD type 2A phenotype IIC Miami did not respond with respect to VWF:CB, but showed a good response of VWF:Ag and FVIII:C as expected. Interestingly he showed a persistently high level of VWF:Ag and FVIII:C up to 4 hours after DDAVP infusion. Patients with minor alterations of multimer structure and particular mutations responded well to DDAVP, whereas patients with normal multimer structure but a defect in platelet dependent functional parameters did not respond with VWF:RCo.. Children with VWD type 2 show a variable response to desmopressin depending on the mutation that correlates with the functional defect and the presence or absence as well as the half-life of large VWF multimers. Our data emphasize the usefulness of DDAVP testing even in patients with VWD type 2, possibly with the exception of VWD type 2B.

Topics: Child; Deamino Arginine Vasopressin; Hemostatics; Humans; Mutation; Phenotype; von Willebrand Diseases; von Willebrand Factor

Topics: Adult; Deamino Arginine Vasopressin; Female; Hemostatics; Humans; Hyponatremia; Seizures; von Willebrand Diseases

Topics: Child; Deamino Arginine Vasopressin; Epistaxis; Factor V Deficiency; Female; Hemophilia A; Humans; von Willebrand Diseases

Fearing the devastating neurological complications in a parturient with the von Willebrand disease secondary to paucity of studies defining the guidelines to assess the risk of bleeding complications, anesthesiologists are often reluctant to administer neuroaxial anesthesia. We present a case report of a parturient with type I von Willebrand disease who presented for induction of labor at 39 weeks of gestation. After consultation with the hematologist well ahead of the conception, appropriate laboratory workup including clotting factor levels including FVIII, vWF:RcoF, vWF:Ag on different occasions peripartum, and provision of adequate prophylactic medical treatment, she underwent Cesarean section under epidural anesthesia without neurological or bleeding complications. von Willebrand disease is the most common inherited bleeding disorder that may result in various bleeding complications in a parturient as a result of hemostatic challenges during pregnancy. Yet the recommendations are based on anecdotal observations of the authors of small case series and surveys. Our case report emphasizes the importance of advanced planning, careful patient assessment, and multi-disciplinary team approach for the successful regional anesthesia as suggested by the guidelines based on clinical experiences.

Topics: Adult; Anesthesia, Epidural; Anesthesia, Obstetrical; Cesarean Section; Deamino Arginine Vasopressin; Factor VIII; Female; Hemorrhage; Hemostatics; Humans; Pregnancy; Pregnancy Complications, Hematologic; von Willebrand Diseases

Reproductive tract bleeding in women is a naturally occurring event during menstruation and childbirth. In women with menorrhagia, however, congenital bleeding disorders historically have been underdiagnosed. This consensus is intended to allow physicians to better recognize bleeding disorders as a cause of menorrhagia and consequently offer effective disease-specific therapies.

Topics: Adult; Blood Coagulation Disorders; Deamino Arginine Vasopressin; Decision Trees; Factor VIII; Female; Hemostatics; Humans; Menorrhagia; Postpartum Hemorrhage; Pregnancy; Pregnancy Complications, Hematologic; Quality of Life; von Willebrand Diseases; von Willebrand Factor

von Willebrand disease (VWD) is the most common hereditary bleeding disorder affecting both males and females. It arises from quantitative or qualitative defects of von Willebrand factor (VWF) and causes bleeding of mucous membranes and soft tissues. The aim of treatment is to correct the dual defect of haemostasis caused by the abnormal/reduced VWF and the concomitant deficiency of factor VIII (FVIII).. This document contains evidence-based recommendations for the management of VWD compiled by AICE (the Italian Association of Haemophilia Centres). All the evidence supporting these recommendations are based on non-randomised comparative studies or case series, because randomised controlled clinical trials or meta-analyses are not available for this disease.. Desmopressin (DDAVP) is the treatment of choice for patients with type 1 VWD with FVIII and VWF levels of 10 U/dL or more, while VWF/FVIII concentrates are indicated for those who are unresponsive or insufficiently responsive to DDAVP (severe type 1, type 2 and 3 VWD). VWF concentrates devoid of FVIII, not yet licensed in Italy, may be considered for short-term prophylaxis in elective surgery or for long-term secondary prophylaxis.

Topics: Deamino Arginine Vasopressin; Drug Therapy, Combination; Evidence-Based Medicine; Factor VIII; Female; Hemostatics; Humans; Italy; Male; Treatment Outcome; von Willebrand Diseases; von Willebrand Factor

We performed a retrospective audit of cross-laboratory testing of desmopressin and factor concentrate therapy to assess the potential utility of supplementary testing using the PFA-100 with functional von Willebrand factor (VWF) activity testing. Data were evaluated for a large number of patients with von Willebrand disease of type 1, type 2A or type 2M, as well as a comparative subset of individuals with haemophilia or carriers of haemophilia. Laboratory testing comprised pre and postdesmopressin, or pre and postconcentrate, evaluation of factor VIII, VWF antigen (VWF:Ag) and VWF ristocetin cofactor activity as traditionally performed, supplemented with collagen-binding (VWF:CB) testing and PFA-100 closure times. In brief, both therapies tended to normalize VWF test parameters and closure times in individuals with type 1 von Willebrand disease, with the level of correction in closure times related to the level of normalization of VWF, particularly the VWF:CB. However, although occasional correction of closure times was observed in patients with type 2A or type 2M von Willebrand disease, these did not in general normalize PFA-100 closure times either with desmopressin or factor concentrate therapy. In these patients, improvement in closure times was more likely in those in whom VWF:CB values normalized or when VWF:CB/VWF:Ag ratios normalized. This study confirms that there is a strong relationship between the presenting levels of plasma VWF and PFA-100 closure times, and that the supplementary combination of PFA-100 and VWF:CB testing might provide added clinical utility to current broadly applied testing strategies limited primarily to VWF:Ag, VWF ristocetin cofactor and factor VIII:coagulant. Future prospective investigations are warranted to validate these relationships and to investigate their therapeutic implications.

Topics: Blood Coagulation Factors; Deamino Arginine Vasopressin; Drug Monitoring; Factor VIII; Hemophilia A; Heterozygote; Humans; Platelet Function Tests; Retrospective Studies; Time Factors; von Willebrand Disease, Type 1; von Willebrand Disease, Type 2; von Willebrand Diseases; von Willebrand Factor

The influence of desmopressin on hemostasis is mediated by the release of von Willebrand factor and of coagulation factor VIII from vascular endothelium. The necessity of testing desmopressin effectiveness on hemostasis is a matter of controversy and the performance of the test is not yet standardized. For this reason the desmopressin tests in 114 children with von Willebrand syndrome (type 1, n=98; type 2A, n=12; type 2M, n=2; type 2N, n=2) carried out in 7 paediatric haemostaseologic centers were retrospectively analyzed. The effectiveness of desmopressin was assessed using defined response criteria. As expected, the test performance showed a wide variation among the centers. In 99 children desmopressin was given intravenously as a short infusion at a dosage ranging from 0.25 to 0.41 microg/kg and in 15 intranasally at an absolute dose of 40 to 300 microg. The points of time for blood taking after desmopressin application ranged from 0.5 to 12 h. The absent desmopressin response in 7 patients (6%) and the partial response in 15 indicate the necessity of testing desmopressin effectiveness before the first therapeutic use. The application of desmopressin was well tolerated by the patients.

Topics: Administration, Intranasal; Adolescent; Child; Child, Preschool; Deamino Arginine Vasopressin; Female; Germany; Hemostasis; Hemostatics; Humans; Infant; Infusion Pumps; Male; Retrospective Studies; Time Factors; von Willebrand Diseases

Epidural anesthesia, combined with general anesthesia, was performed in a patient with type 1 von Willebrand disease (VWD). VWD is a common inherited bleeding disorder, and an anesthetic concern in patients with VWD is susceptibility to postoperative bleeding and epidural or spinal hematoma associated with neuraxial block. After confirming the patient's responsiveness to 1-desamino-8-D-arginine vasopressin (DDAVP) and obtaining informed consent, epidural anesthesia was performed to avoid the use of analgesics that inhibit platelet function. The patient's postoperative course was uneventful. Epidural anesthesia could be one of the choices of treatment for postoperative pain in those patients with type 1 VWD for whom the conditions discussed are fulfilled, to ensure safe usage of this technique.

Topics: Adolescent; Anesthesia, Epidural; Anesthesia, General; Anterior Cruciate Ligament; Deamino Arginine Vasopressin; Female; Humans; Nerve Block; Orthopedic Procedures; Postoperative Hemorrhage; Renal Agents; von Willebrand Diseases

Although von Willebrand disease (VWD) is now well-described, many facets of diagnosis and management continue to be debated. The diagnosis of type 1 disease can be difficult but recent genetic analyses help to distinguish many factors which can influence von Willebrand factor (VWF) levels and bleeding phenotype. Type 2 disease (functional abnormalities) includes a particularly interesting group of disorders with faulty binding between VWF and FVIIIC (Normandy) where treatment methods need careful consideration. Type 3 VWD is the most severe form of VWD and a new international study is underway to examine the use of prophylaxis.

Topics: Coagulants; Deamino Arginine Vasopressin; DNA Mutational Analysis; Drug Administration Schedule; Female; Hemostatics; Humans; Male; Molecular Sequence Data; Phenotype; Quality of Life; Treatment Outcome; von Willebrand Diseases; von Willebrand Factor

Topics: Deamino Arginine Vasopressin; Female; Hemostatics; Humans; Ischemic Attack, Transient; Middle Aged; Pulmonary Embolism; von Willebrand Diseases

Reduced von Willebrand factor (VWF) half-life has been suggested as a new pathogenic mechanism in von Willebrand disease (VWD). The usefulness of VWF propeptide (VWFpp) in exploring VWF half-life was assessed in 22 type 1 and 14 type Vicenza VWD patients, and in 30 normal subjects, by comparing the findings on post-Desmopressin (DDAVP) VWF t(1/2) elimination (t(1/2el)). The VWFpp/VWF antigen ratio (VWFpp ratio) was dramatically increased in type Vicenza VWD (13.02 +/- 0.49) when compared to normal subjects (1.45 +/- 0.06), whereas it appeared to be normal in all type 1 VWD patients (1.56 +/- 0.7), except for the four carrying the C1130F mutation (4.69 +/- 0.67). A very short VWF t(1/2el) was found in type Vicenza VWD (1.3 +/- 0.2 h), while all type 1 VWD patients had a t(1/2el) similar to that of the controls (11.6 +/- 1.4 and 15.4 +/- 2.5 h respectively), except for the four patients carrying the C1130F mutation, who had a significantly shorter VWF survival (4.1 +/- 0.2 h). A significant inverse correlation emerged between VWFpp ratio and VWF t(1/2el) in both VWD patients and normal subjects. The VWFpp ratio thus seemed very useful for distinguishing between type 1 VWD cases with a normal and a reduced VWF survival, as well as for identifying type Vicenza VWD.

Topics: Case-Control Studies; Deamino Arginine Vasopressin; DNA Mutational Analysis; Half-Life; Hemostatics; Humans; Mutation; Protein Precursors; von Willebrand Diseases; von Willebrand Factor

Topics: Blood Chemical Analysis; Chemistry, Clinical; Clinical Laboratory Techniques; Collagen; Deamino Arginine Vasopressin; Factor VIII; Hemostasis; Humans; Monitoring, Physiologic; Platelet Count; Platelet Function Tests; Protein Binding; von Willebrand Diseases

Dose-response relationship was studied between PFA-100 closure times (PFA CTs) and factor (F)VIII-von Willebrand factor (VWF) parameters in patients with von Willebrand disease (VWD) type 1 and type 2 before and after treatment with DDAVP (n=84) or FVIII/VWF concentrate (n=38). DDAVP treatment of patients with VWD type 1 normalised the PFA CTs by increasing VWF levels to normal. Of the 14 patients with VWD type 2, PFA CTs did not normalize in eight. Haemate-P substitution in patients with VWD type 1 induced a less favourable response as compared to DDAVP, because PFA CTs did not correct in all patients. Of 12 patients with VWD type 2 treated with Haemate-P, six showed a correction of PFA CTs (<250 sec), which correlated with the normalisation of the VWF CB/Ag ratio. In-vitro studies were performed by using whole blood of patients with VWD and adding various amounts of FVIII/VWF concentrate. Addition of Haemate-P induced an increase of the VWF CB/Ag ratio from 0.30 to 0.70 in blood of patients with VWD type 2 with correction of the PFA CTs. Immunate did not result in an increase of VWF CB/Ag ratio in blood of VWD type 2 patients, and the PFA CTs remained prolonged. We conclude that PFA-100 might be an adequate instrument not only for diagnosis but also for monitoring of DDAVP responses and FVIII/VWF substitution of patients with VWD type 1 and 2, but this is dependent upon the type of VWD and the concentrate used.

Topics: Blood Platelets; Coagulants; Collagen; Deamino Arginine Vasopressin; Factor VIII; Hemostatics; Humans; Platelet Adhesiveness; Platelet Function Tests; Protein Binding; Reference Values; Retrospective Studies; Time Factors; von Willebrand Diseases; von Willebrand Factor

Topics: ADAM Proteins; ADAMTS13 Protein; Amino Acid Substitution; Biopolymers; Deamino Arginine Vasopressin; Humans; Mutation, Missense; Platelet Adhesiveness; Point Mutation; Protein Structure, Tertiary; von Willebrand Diseases; von Willebrand Factor

Desmopressin (DDAVP) affects haemostasis by the release of von Willebrand factor and coagulation factor VIII from endothelium. The aim of the study was to evaluate the results of DDAVP testing in paediatric patients with congenital bleeding disorders. Forty-one patients consisting of children with von Willebrand's disease (VWD, n = 26) and platelet function defects (PFD, n = 15) received DDAVP intravenously at a dosage of 0.3 mug/kg over 30 min. FVIII activity (FVIII), von Willebrand factor antigen (VWF:Ag), collagen-binding activity (VWF:CB) and PFA 100((R)) closure times (CT) were measured before, 60, 120 and 240 min after DDAVP. In VWD, the VWF:Ag increased threefold until 60 min and then it decreased continuously. Compared with baseline, VWF:Ag was significantly higher at 60 and 120 min but not at 240 min. In contrast, in PFD, the peak of VWF:Ag was reached after 120 min. Two hundred and forty minutes after DDAVP, the mean was still significantly elevated compared with baseline values. The course of VWF:CB corresponded to that of VWF:Ag. In patients with VWD and PFD, FVIII rose two- to threefold within 2 h after DDAVP. CT in patients with VWD shortened markedly within 120 min and then rose again. In all children with PFD, except one non-responder, the CT shortened within 240 min after DDAVP. Two non-responders with VWD were identified by the failed increase of VWF:Ag, VWF:CB and by prolonged CT. Haemostatic effects of DDAVP differ interindividually and dependent on the coagulation disorder. DDAVP was effective in most, but not in all patients. DDAVP testing is recommended to determine the individual haemostatic response.

Topics: Adolescent; Bleeding Time; Blood Coagulation Factors; Child; Child, Preschool; Coagulation Protein Disorders; Deamino Arginine Vasopressin; Drug Evaluation; Female; Hemostasis; Hemostatics; Humans; Infusions, Intravenous; Male; Retrospective Studies; Time Factors; von Willebrand Diseases

The aim of this study was to characterize the adequacy and longevity of biological response to desmopressin (DDAVP) in a large Amish kindred of Type 2M von Willebrand disease (VWD) possessing C-to-T transition at nucleotide 4120 in exon 28 of A1 domain of von Willebrand factor (VWF) gene. Response to both intranasal (Stimate) and subcutaneous DDAVP administration was assessed. Rise in ristocetin cofactor activity (VWF:RCo) > or = 40% at 90-min post-Stimate and 1-2 h after subcutaneous DDAVP was defined as initial response; response longevity was assessed only after subcutaneous dosing by measuring VWF:RCo levels at time-points 1, 2, 4 and 6 h. Eleven patients (five males, six females; age range: 20-56 years) participated in intranasal and 9/11 (four males, five females) in subcutaneous testing. Baseline haemostatic profiles included: VWF:RCo < 15%, VWF:Ag < 40% and normal VWF multimers. Initial response was comparable by both intranasal (6/11; 54.5%) and subcutaneous (4/9; 44%) routes; sustained response (VWF:RCo > 40% for 2 h) was observed in only one in nine (11%) patients tested. Median VWF:RCo peak levels after intranasal (40%) and subcutaneous (39%) routes were equivalent. Peak VWF:Ag levels were significantly higher after subcutaneous than intranasal DDAVP (94% vs. 54%; P = 0.03). Area under the curve for VWF:RCo was significantly decreased (170 microg h mL(-1)) compared with VWF:Ag (471 microg h mL(-1)) and FVIII:C (624.60 microg h mL(-1)). This study suggests that in this population: (i) intra-individual DDAVP response is consistent with subcutaneous and intranasal administration; and (ii) extending DDAVP challenge test up to at least 6 h is required to characterize adequacy and longevity of biologic response prior to using DDAVP as a sole haemostatic intervention.

Topics: Administration, Intranasal; Adult; Bleeding Time; Deamino Arginine Vasopressin; Female; Founder Effect; Hemostasis; Hemostatics; Humans; Injections, Subcutaneous; Male; Middle Aged; Mutation, Missense; Time Factors; Treatment Outcome; von Willebrand Diseases; von Willebrand Factor

Topics: Adult; Deamino Arginine Vasopressin; Female; Hemostatics; Humans; Menorrhagia; von Willebrand Diseases

von Willebrand disease (VWD) is a commonly encountered inherited bleeding disorder affecting both males and females, causing mucous membrane and skin bleeding symptoms, and bleeding with surgical or other haemostatic challenges. VWD may be disproportionately symptomatic in women of child-bearing age. It may also occur less frequently as an acquired disorder (acquired von Willebrand syndrome). VWD is caused by deficiency or dysfunction of von Willebrand factor (VWF), a plasma protein that mediates platelet haemostatic function and stabilizes blood coagulation factor VIII. The pathophysiology, classification, diagnosis and management of VWD are relatively complex, but understanding them is important for proper diagnosis and management of patients with VWD. These evidence-based guidelines for diagnosis and management of VWD from the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel (USA) review relevant publications, summarize current understanding of VWD pathophysiology and classification, and present consensus diagnostic and management recommendations based on analysis of the literature and expert opinion. They also suggest an approach for clinical and laboratory evaluation of individuals with bleeding symptoms, history of bleeding or conditions associated with increased bleeding risk. This document summarizes needs for further research in VWF, VWD and bleeding disorders, including clinical research to obtain more objective information about bleeding symptoms, advancements in diagnostic and therapeutic tools, and enhancement in the education and training of clinicians and scientists in bleeding and thrombotic disorders. The NHLBI Web site (http://www.nhlbi.nih.gov/guidelines/vwd) has a more detailed document, a synopsis of these recommendations, and patient education information.

Topics: Antifibrinolytic Agents; Deamino Arginine Vasopressin; Factor VIII; Female; Genetic Therapy; Hemostatics; Humans; Male; Pregnancy; von Willebrand Diseases; von Willebrand Factor

The decreased survival of von Willebrand factor (VWF) in plasma has been implicated as a mechanism in a subset of type 1 von Willebrand disease (VWD) patients. We have previously reported that the ratio of plasma levels of VWF and its propeptide (VWFpp) can be used to identify patients with reduced VWF survival. In this study, we report the assay of VWFpp and VWF:Ag in 19 individuals recruited from 6 European centers within the MCMDM-1VWD study. Eight individuals had a VWF:Ag level less than 30 IU/dL. Seven of these patients had a robust desmopressin response and significantly reduced VWF half-life that was predicted by a markedly increased steady-state plasma VWFpp/VWF:Ag ratio. VWF mutations previously associated with reduced VWF survival were identified in each of the 7 individuals. Thus, a substantially increased ratio of steady-state VWFpp/VWF:Ag predicted a reduced VWF half-life in patients with markedly decreased VWF:Ag levels. These data indicate that a reduced VWF survival is found in a subpopulation of patients with type 1 VWD. The systematic assay of both plasma VWF and the VWF propeptide in moderately severe type 1 VWD patients may identify patients with a reduced VWF survival phenotype.

Topics: Biomarkers; Deamino Arginine Vasopressin; Europe; Half-Life; Humans; Mutation; Predictive Value of Tests; Protein Precursors; Survival Analysis; Treatment Outcome; von Willebrand Diseases; von Willebrand Factor

Type 2A von Willebrand disease (VWD) is characterized by decreased platelet-dependent function of von Willebrand factor (VWF); this in turn is associated with an absence of high-molecular-weight multimers. Sequence analysis of the VWF gene from two unrelated type 2A VWD patients showed an identical, novel, heterozygous T-->G transversion at nucleotide 4508, resulting in the substitution of L1503R in the VWF A2 domain. This substitution, which was not found in 60 unrelated normal individuals, was introduced into a full-length VWF cDNA and subsequently expressed in 293T cells. Only trace amount of the mutant VWF protein was secreted but most of the same was retained in 293T cells. Co-transfection experiment of both wild-type and mutant plasmids indicated the dominant-negative mechanism of disease development; as more of mutant DNA was transfected, VWF secretion was impaired in the media, whereas more of VWF was stored in the cell lysates. Molecular dynamic simulations of structural changes induced by L1503R indicated that the mean value of all-atom root-mean-squared-deviation was shifted from those with wild type or another mutation L1503Q that has been reported to be a group II mutation, which is susceptible to ADAMTS13 proteolysis. Protein instability of L1503R may be responsible for its intracellular retention and perhaps the larger VWF multimers, containing more mutant VWF subunits, are likely to be mal-processed and retained within the cell.

Topics: Adolescent; Amino Acid Substitution; Deamino Arginine Vasopressin; DNA Mutational Analysis; Epistaxis; Exons; Female; Gene Expression; Hemostasis; Humans; Male; Middle Aged; Models, Molecular; Molecular Biology; Mutation; Platelet Adhesiveness; Polymerase Chain Reaction; Recombinant Proteins; Structure-Activity Relationship; Transfection; von Willebrand Diseases; von Willebrand Factor

Topics: Adult; Cerebral Hemorrhage; Deamino Arginine Vasopressin; Fatal Outcome; Glasgow Coma Scale; Hemostatics; Humans; Male; von Willebrand Diseases

This case report describes a 9-year-old Caucasian girl who required comprehensive dental treatment under general anaesthesia but gave a history of Noonan's syndrome. The patient was extremely needle phobic. Because of the association between Noonan's syndrome and underlying coagulopathies, for which no previous investigations were evident, dental treatment had to be postponed pending further investigation. The patient was referred to a haematologist and underwent coagulation screening, which revealed the presence of von Willebrand's disease. The patient was prescribed Desmopressin to raise plasma levels of factor VIII: C and von Willebrand's factor (VWF) in order that dental treatment, including extractions, could be carried out under an in-patient general anaesthetic.. Congenital heart defects and bleeding diatheses are regarded as a common association of Noonan's syndrome. Witt et al estimated that around one-third of the patients have an associated bleeding disorder, although a later report suggested that as many as 74% of the coagulation profiles could be abnormal. Most of the bleeding problems are reported to be mild, and resolve with age in some patients, but, clearly, they may cause problems during dental treatment, necessitating haematological investigations and a multidisciplinary approach.

Topics: Anesthesia, General; Child; Comprehensive Dental Care; Deamino Arginine Vasopressin; Dental Care for Chronically Ill; Female; Hemostatics; Humans; Noonan Syndrome; von Willebrand Diseases

Topics: Deamino Arginine Vasopressin; Factor VIII; Humans; Thrombosis; von Willebrand Diseases; von Willebrand Factor

This case report describes anesthetic considerations for a 6-year-old boy, admitted for adenoidectomy under general anesthesia, who had a complicated medical history, including mastocytosis, Noonan syndrome, and von Willebrand disease. Each affected the anesthetic plan and was addressed preoperatively among all surgical and anesthesia providers. Mastocytosis created a major concern, with its increased numbers of histamine-filled mast cells. Each drug that was added or eliminated from the anesthetic plan, to prevent histamine release by the activation of triggers, was considered. Patient handling and temperature control were also concerns. One of Noonan syndrome's characteristics is heart anomalies. This patient had a history of a patent foramen ovale and pulmonary stenosis; therefore, air was carefully removed from all intravenous lines and syringes. The main concern for bleeding difficulties was attributed to the history of von Willebrand disease, which results in prolonged bleeding time and can lead to delayed bleeding or serious postsurgical hemorrhage. Desmopressin was administered preoperatively to increase platelet aggregation and the von Willebrand factor level. The use of aspirin and other nonsteroidal anti-inflammatory drugs was avoided. We discuss the clinical and anesthetic management of this case with a review of pertinent literature.

Topics: Adenoidectomy; Anesthesia, General; Child; Deamino Arginine Vasopressin; Hemostatics; Histamine Antagonists; Humans; Intraoperative Care; Male; Mastocytosis; Nasal Obstruction; Noonan Syndrome; Nurse Anesthetists; Patient Care Planning; Premedication; Preoperative Care; von Willebrand Diseases

von Willebrand's disease (VWD) is a heterogeneous bleeding disorder caused by quantitative or qualitative defects in von Willebrand factor (VWF). The diagnosis of VWD requires several laboratory tests. The aim of our study was to validate a flow cytometric test for the diagnosis of VWD and for monitoring the effects of desmopressin therapy.. Flow cytometric analysis of ristocetin-induced VWF binding to platelets was performed in platelet-rich plasma (PRP) samples from patients with VWD and from control subjects and in samples of formalin-fixed platelets in the presence of plasma from patients or controls. In 12 VWD patients the test was conducted before and 1 hour after desmopressin infusion. Results were compared with VWF:Ag, VWF:RCo, VWF:CB, RIPA, PFA-100 and the skin bleeding time.. Ristocetin-induced VWF binding to platelets, evaluated by both flow cytometry-based assays, was significantly reduced in patients with type1, 2A and 2M VWD as compared with that in healthy subjects. Patients with type 2B VWD showed reduced binding of VWF to formalin-fixed platelets, but increased binding to autologous platelets in PRP, similar to RIPA. VWF binding to platelets assessed by both flow cytometric assays correlated significantly with VWF:Ag, VWF:RCo, VWF:CB, RIPA, PFA100 and bleeding time. VWF binding to platelets increased after desmopressin infusion.. The measurement of ristocetin-induced binding of VWF to platelets by flow cytometry is a sensitive, simple and rapid test for the diagnosis of VWD and for the monitoring of the effects of desmopressin therapy. The flow cytometric assay performed with autologous platelets is useful in the identification of type 2B VWD patients.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Bleeding Time; Blood Platelets; Child; Child, Preschool; Deamino Arginine Vasopressin; Female; Flow Cytometry; Hemostatics; Humans; Male; Middle Aged; Monitoring, Physiologic; Platelet Function Tests; Ristocetin; Time Factors; von Willebrand Diseases; von Willebrand Factor

Two therapeutic approaches are available to manage patients with von Willebrand disease (VWD): (i) the release of endogenous von Willebrand factor (VWF) from endothelial compartments induced by desmopressin (DDAVP); (ii) the transfusion of exogenous VWF contained in VWF/FVIII plasma-derived concentrates. Only a few high-purity VWF/FVIII concentrates have been extensively evaluated in pharmacokinetic (PK) trials as well as in retrospective or prospective efficacy studies in VWD. The Alphanate Study Group published results of PK and clinical efficacy studies in 2002. Efficacy results showed that 75% of bleeding episodes were controlled with one or two infusions, and 71% of patients who received prophylactic treatment for surgeries or invasive procedures had good clinical responses. In another retrospective study, 22 VWD patients in Italy received Fanhdi, a VWF concentrate similar to Alphanate. Excellent-good clinical responses were seen in 92% of bleeding episodes and in 93% of surgical procedures. More recently, the efficacy and safety of Fanhdi have been evaluated retrospectively in a larger cohort of Italian patients (n = 103) with 97% (bleedings) and 99% (surgeries) of excellent/good clinical responses. The largest experience on secondary prophylaxis in VWD has been collected in Sweden in 35 patients with severe forms of VWD. Secondary prophylaxis was also implemented in a cohort of Italian patients with VWD. Prophylaxis was started because of GI bleeds in seven patients with types 3 (n = 1), 2A (n = 4), 2M (n = 1) and type 1 (n = 1) and for joint bleeds in four patients with type 3 VWD (n = 4). Prophylaxis prevented bleeding completely in eight patients and largely reduced hospitalization for blood transfusions in the remaining three. The cost-effectiveness of these prophylaxis regimens versus on demand therapy will be now investigated in one large prospective study (PRO.WILL) organized in Italy.

Topics: Deamino Arginine Vasopressin; Female; Hemostatics; Humans; Italy; Male; Multicenter Studies as Topic; Patient Selection; Randomized Controlled Trials as Topic; Research Design; von Willebrand Diseases; von Willebrand Factor

Recently, three multicentre prospective international studies have been carried out to evaluate the clinical efficacy and safety of Fanhdi [high-purity, double-inactivated plasma-derived factor VIII/von Willebrand factor (VWF) concentrate] in patients with von Willebrand's disease (VWD). Pharmacokinetic parameters, clinical efficacy and safety of Fanhdi in acute bleedings episodes or invasive procedures were determined in this population.. Pharmacokinetic parameters observed were similar to previous reported for other highly purified plasma-derived FVIII/VWF concentrate. The mean in vivo recovery (IU dL(-1) per IU kg(-1)) was 1.9 +/- 0.6 for VWF:RCof; 2.1 +/- 0.6 for VWF:Ag and 2.6 +/- 0.6 for FVIII:C. The mean half-life (h) was 14.4 +/- 10.5 for VWF:RCof; 27.5 +/- 11.0 for VWF:Ag and 33.4 +/- 16.4 for FVIII:C. Therapeutic benefit of Fanhdi in VWD patients treated during bleeding episodes was clearly demonstrated. The achievement of haemostasis was excellent or good in 100% of the cases (major or minor bleeding episodes). Also, the clinical efficacy of Fanhdi in preventing excessive bleeding during surgery showed a very good profile. Efficacy was rated as excellent in six cases (three major/three minor surgical procedures) and good in three cases (two major/one minor surgical procedures). In addition, the product was well tolerated and no adverse events potentially related to the study drug were reported.. Fanhdi is an effective and safe plasma-derived FVIII/VWF concentrate that can be used as an alternative to the current replacement therapy in patients with VWD to provide an adequate haemostasis during surgical procedures and treatment of bleeding episodes.

Topics: Acute Disease; Coagulants; Deamino Arginine Vasopressin; Factor VIII; Half-Life; Hemorrhage; Hemostasis, Surgical; Humans; Prospective Studies; von Willebrand Diseases; von Willebrand Factor

Topics: Blood Coagulation Tests; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Humans; Risk Factors; von Willebrand Diseases

The missense mutation of cysteine 2362 to a phenylalanine in von Willebrand factor (VWF) has been detected in several Italian families with autosomal recessive, severe von Willebrand disease. We investigated how this amino acid change in VWF may lead to a predominantly quantitative defect. This mutation was studied in vitro by transient expression of the full-length mutant VWF-C2362F protein and in vivo by analysis of plasma VWF after infusion of 1-deamino-8-d-arginine vasopressin (DDAVP) in a patient homozygous for this mutation. Single transfections of pSVHVWF-C2362F and co-transfections of mutant and wild-type constructs resulted in 8% and 50% VWF antigen, respectively, in conditioned medium. These reduced levels are in accordance with observations in homozygous and heterozygous carriers of the mutation. In addition, VWF-C2362F was retained intracellularly. Similar results were obtained for C2362F and C2362A. After infusion of DDAVP in a homozygous patient, a twofold decrease in half-life of plasma VWF-C2362F was observed. This was not explained by increased susceptibility of recombinant VWF-C2362F to ADAMTS13. It was concluded that VWF-C2362F causes reduced VWF plasma levels due to impaired secretion and intracellular retention. Furthermore, it is the loss of cysteine 2362 rather than the introduction of the bulky amino acid side chain that causes these effects.

Topics: ADAM Proteins; ADAMTS13 Protein; Deamino Arginine Vasopressin; Factor VIII; Genes, Recessive; Half-Life; Hemostatics; Heterozygote; Homozygote; Humans; Mutation, Missense; von Willebrand Diseases; von Willebrand Factor

von Willebrand disease (VWD) caused by the R1205H mutation has distinct and reproducible clinical and laboratory features. This report describes the phenotypic and molecular investigation of seven kindreds with VWD Vicenza R1205H. All affected individuals have historically been diagnosed with moderate to severe type 1 VWD. Amongst all families with highly penetrant type 1 VWD investigated at our centre, heterozygosity for the R1205H mutation was found to be the most common underlying molecular defect. A severe laboratory phenotype associated with a bleeding history that was milder than expected was commonly observed, consistent with previous published case reports; however, abnormal ultralarge high molecular weight multimers were not detected in resting plasma samples. We also provide evidence that the R1205H mutation may arise de novo--evidence that a common genetic origin for this mutation is unlikely.

Topics: Deamino Arginine Vasopressin; DNA Mutational Analysis; Female; Haplotypes; Hemostatics; Humans; Male; Mutation; Pedigree; von Willebrand Diseases; von Willebrand Factor

We undertook an international, multicenter study to describe the clinical picture and to estimate the bleeding risk in a group of obligatory carriers of type 3 von Willebrand disease (VWD).. Obligatory carriers (OC) of type 3 VWD were identified by the presence of offspring with type 3 VWD or by being an offspring of a type 3 patient. Normal controls were age- and sex-matched with the obligatory carriers. A physician-administered standardized questionnaire was used to evaluate hemorrhagic symptoms at presentation. A score system ranging from 0 (no symptom) to 3 (hospitalization, replacement therapy, blood transfusion) was used to quantitate bleeding manifestations. Odds ratios were computed for each symptom.. Ten centers participated to the study, enrolling a total of 35 type 3 VWD families, with 70 OC. A total of 215 normal controls and 42 OC for type 1 VWD were also included. About 40% of type 3 OC had at least one bleeding symptom compared to 23% of normal controls and 81.8% of type 1 OC (P < 0.0001 by chi-squared test), showing that type 3 OC clearly represent a distinct population from type 1 OC. The clinical situations associated with an increase of bleeding risk in type 3 OC were epistaxis [odds ratio 3.6; 90% confidence intervals (CI) 1.84-21.5], cutaneous bleeding (odds ratio 5.5; 90% CI 2.5-14.1) and postsurgical bleeding (odds ratio 16.3; 90% CI 4.5-59). The severity of bleeding score correlated with the degree of factor (F) VIII reduction in plasma.. OC for type 3 VWD represent a distinctive population from type 1 OC. These patients, however, present with more frequent bleeding symptoms in comparison to normal controls, especially in case of significantly low FVIII. Desmopressin and/or tranexamic acid might be useful to prevent or treat bleeding in these cases.

Topics: Adolescent; Adult; Aged; Case-Control Studies; Child; Child, Preschool; Deamino Arginine Vasopressin; Factor VIII; Female; Hemorrhage; Heterozygote; Humans; Infant; Male; Middle Aged; Odds Ratio; Risk; Surveys and Questionnaires; Tranexamic Acid; von Willebrand Diseases; von Willebrand Factor

Topics: Administration, Intranasal; Adult; Bleeding Time; Deamino Arginine Vasopressin; Drug Evaluation; Factor VIII; Humans; Retrospective Studies; Treatment Outcome; von Willebrand Diseases; von Willebrand Factor

When patients with von Willebrand's disease were given a single injection of desmopressin (0.4 microg/kg body weight), there was a considerable increase in platelet reactivity (from 0.95 +/- 0.19 to 1.44 +/- 0.42; p = 0.0033). On flow cytometry, increased glycoprotein Ib/IX expression in the platelets was found after the desmopressin injection; when phycoerythrin-marked anti-CD62 antibodies were used, the mean fluorescence rose from 428.9 +/- 56.6 to 440.7 +/- 51.4 (p = 0.0056), and from 425.9 +/- 55.0 to 437.4 +/- 53.9 (p = 0.0018) when phycoerythrin-marked anti-thrombospondin antibodies were used. Apart from the rise in the von Willebrand factor, this could explain the increased platelet reactivity. However, the surface expression of CD62, CD63 and thrombospondin on platelets did not change following the desmopressin injection.

Topics: Adolescent; Adult; Antigens, CD; Blood Platelets; Deamino Arginine Vasopressin; Female; Hemostatics; Humans; Male; Middle Aged; Platelet Membrane Glycoproteins; von Willebrand Diseases

Topics: Adult; Deamino Arginine Vasopressin; Female; Hemostasis, Surgical; Hemostatics; Humans; Mammaplasty; Risk Factors; Ristocetin; von Willebrand Diseases

Young patients with vitreous, retinal and subvitreal haemorrhages without neovascularisation or prior trauma are a diagnostic challenge for the physician. In this case report, a patient is presented who developed unilateral, spontaneous, subvitreal, retinal and subretinal haemorrhages and was diagnosed with von Willebrand's disease.. A 33-year-old Caucasian woman presented at our clinic with unilateral subvitreal, retinal and subretinal haemorrhages. The haemorrhages occurred spontaneously without prior trauma, and the patient had no history of prior bleeding complications. Analysis of the coagulation-fibrinolysis system and von Willebrand multimer analysis led to the diagnosis von Willebrand's disease type I.. Spontaneous subvitreal, retinal and subretinal haemorrhages may be associated with coagulation disorders. Especially in young patients, von Willebrand's disease should be considered as a possible cause.

Topics: Adult; Deamino Arginine Vasopressin; Female; Fluorescein Angiography; Hemostatics; Humans; Retinal Hemorrhage; Vitreous Hemorrhage; von Willebrand Diseases

To assess the effect of desmopressin (DDAVP) administration in Doberman Pinschers with type 1 von Willebrand disease (vWD) on plasma von Willebrand factor (vWF) multimers through determination of vWF collagen binding activity (vWF:CBA; a functional vWF assay dependent on the presence of high-molecular-weight [HMWI multimers), comparison of vWF antigen concentration (vWF:Ag) to vWF:CBA, and vWF multimer size distribution.. 16 Doberman Pinschers with type 1 vWD and 5 clinically normal control dogs.. Plasma vWF:Ag and vWF:CBA assays and vWF multimer analysis were performed before and 1 hour after administration of DDAVP (1 microg/kg, SC).. Following DDAVP administration, dogs with type 1 vWD had an increase in mean baseline values of plasma vWF:Ag and vWF:CBA from 10% to 17% for both variables. The mean vWF Ag:CBA ratio at baseline (0.95) was similar after DDAVP administration (0.97), indicating concordant increases in plasma vWF concentration and activity. In control dogs, mean plasma vWF:Ag and vWF:CBA increased from baseline values of 64% to 113% and 58% to 114%, respectively, and the vWF Ag:CBA ratios were unchanged (1.1 vs 1.0) after DDAVP administration. Plasma vWF multimer analysis revealed proportional increases in band intensity for all multimer sizes following DDAVP administration, in comparison to baseline for the control dogs and Doberman Pinschers with vWD, consistent with vWF Ag:CBA ratios of approximately 1.. Beneficial effects of DDAVP on primary hemostasis in Doberman Pinschers with type 1 vWD cannot be explained by preferential increases in HMW vWF multimers.

Topics: Animals; Deamino Arginine Vasopressin; Dog Diseases; Dogs; Female; Hemostatics; Male; Multiprotein Complexes; von Willebrand Diseases; von Willebrand Factor

Topics: Cerebral Arterial Diseases; Contraceptives, Oral, Combined; Deamino Arginine Vasopressin; Female; Hemostatics; Humans; Intracranial Thrombosis; Patient Selection; Risk Factors; Smoking; von Willebrand Diseases

To develop plans for the haemostatic management of intraoral bleeding in patients with von Willebrand disease (VWD).. Thirty-seven episodes of haemostatic management of intraoral bleeding in 19 VWD patients were analysed retrospectively based on the medical records.. When performing tooth extractions in patients with type 1 or 2A VWD [responsive to 1-deamino-8-D-arginine-vasopressin (DDAVP)], 0.35-0.4 microg kg(-1) of DDAVP should be administered intravenously at three times. In patients with type 2A VWD (unresponsive to DDAVP) or patients with type 2B or 2N VWD, 50-90 U [as ristocetin cofactor (VWF:RCof)] kg(-1) of a factor VIII concentrate containing von Willebrand factor (FVIII/VWF concentrate) should be administered twice in routine extractions, and four to six times in surgical extractions. Gingival bleeding related to primary teeth can be mostly managed by pressure haemostasis alone. However, when treating gingival bleeding caused by marginal periodontitis, it is often necessary to administer 0.4 microg kg(-1) of DDAVP or 40-70 U (as VWF:RCof) kg(-1) of a FVIII/VWF concentrate. As local haemostasis is difficult to achieve in bleeding from the tongue or labial or mandibular haematoma, it is necessary to administer 0.4 microg kg(-1) of DDAVP or 60-80 U (as VWF:RCof) kg(-1) of a FVIII/VWF concentrate. In addition, oral administration of 20 mg kg(-1) day(-1) of tranexamic acid should be combined with the regimens described above.

Topics: Adolescent; Adult; Child; Deamino Arginine Vasopressin; Dental Care for Chronically Ill; Factor VIII; Female; Hemostatics; Humans; Male; Middle Aged; Oral Hemorrhage; Postoperative Hemorrhage; Pressure; Retrospective Studies; Tooth Extraction; Tranexamic Acid; von Willebrand Diseases; von Willebrand Factor

The purpose of this study was to examine patterns of use for oral contraceptive and desmopressin acetate nasal spray, both used in managing menorrhagia in adolescents with von Willebrand disease (vWD). Hospital records of adolescents with documented vWD and menorrhagia were reviewed retrospectively. Subjects with vWD type 1 (n = 36) administered either oral contraceptives (OC) or intranasal desmopressin acetate (DDAVP) and followed from 6 months to 4 years were selected for inclusion. Treatment outcomes were examined with respect to effectiveness and safety. Assessing menstrual blood loss using PBAC scores from pretreatment and treatment periods determined effectiveness. Safety was evaluated by monitoring reported adverse events. No significant differences were identified in treatment effectiveness for controlling menorrhagia in vWD adolescents in the OC and intranasal DDAVP group comparisons: 86% versus 77% (P > 0.05), respectively. When combining both treatment groups, the majority of vWD adolescents, 81% (P > 0.05), experienced alleviation of menorrhagia symptoms. Treatment failures were attributed to either the inability of a regimen to control bleeding or to adverse events, including severe headaches and flushing with DDAVP. Safety outcomes were not significantly greater in vWD patients with menorrhagia when OC were compared with intranasal DDAVP. Both medical approaches, OC and DDAVP nasal spray, used in managing menorrhagia in adolescents with documented type I vWD were well tolerated and showed equivalent effectiveness, and no serious adverse events were reported.

Topics: Administration, Intranasal; Adolescent; Child; Contraceptives, Oral; Deamino Arginine Vasopressin; Female; Hematocrit; Hemostatics; Humans; Menorrhagia; Retrospective Studies; Treatment Outcome; von Willebrand Diseases

To diagnose von Willebrand disease (vWD) and to monitor drug efficacy, several tests have been established that are not, however, focused on the platelet adhesion properties of von Willebrand factor (vWF). The new platelet retention test Homburg (RTH) is characterized by a nonthrombogenic filter that retains platelets from blood when it is pressed through this filter. It was the aim of this study to examine the capability of this test to monitor the adhesive properties of vWF after its substitution in vWD or its release by desmopressin infusion. The RTH demonstrated a striking sensitivity for vWF after its release from endogenous storage sites or its supplementation in vivo as well as in vitro, whereas it did not detect an inhibition of platelet aggregability due to aspirin. Desmopressin infusions led to an immediate and highly significant increase of RTH platelet retention, followed by a gradual decline to initial values during the next 4 hours. The transfusion of a vWF concentrate also resulted in RTH data that demonstrated different kinetics than established parameters such as vWF:antigen, vWF:RiCoF, or the PFA-100 in vitro bleeding analysis. Additional in vitro experiments confirmed the correlation of RTH values with vWF concentrations. In conclusion, the RTH may be efficient to complement presently used measures to monitor vWD therapy with desmopressin or vWF concentrates.

Topics: Aspirin; Blood Platelets; Cell Adhesion; Deamino Arginine Vasopressin; Drug Monitoring; Factor VIII; Hemostatics; Humans; Kinetics; Platelet Adhesiveness; Platelet Function Tests; Polyurethanes; Sensitivity and Specificity; Time Factors; von Willebrand Diseases; von Willebrand Factor

The aim of the study was to analyze the effectiveness of the application of DDAVP (desmopressin) and Hemate P with cryoprecipitate pre- and postpartum in patients with von Willebrand disease.. We monitored 32 patients with von Willebrand disease during the study period 1993-2003. DDAVP was applied in the 36th/37th week of gestation and cryoprecipitate and fresh frozen plasma were applied 1 day before and 3 days after delivery. DDAVP treatment continued for 4 weeks. Factor VIII (Hemate P) at the day of delivery. No complications occurred in the studied population.. Precipitation of DDAVP, Hemate P, and cryoprecipitate may help in the treatment of pregnant women with von Willebrand disease.

Topics: Deamino Arginine Vasopressin; Delivery, Obstetric; Factor VIII; Female; Fibrinogen; Gestational Age; Hemostatics; Humans; Partial Thromboplastin Time; Postpartum Period; Pregnancy; Pregnancy Complications, Hematologic; Prothrombin Time; von Willebrand Diseases

von Willebrand disease (VWD) is a bleeding disorder caused by the decrease of functional von Willebrand factor (VWF). Low levels of VWF can result from decreased synthesis, impaired secretion, increased clearance or combinations thereof. Several mutations lead to impaired synthesis or secretion of VWF, however, little is known about the survival of VWF in the circulation.. To evaluate the effect of several VWF mutations on VWF clearance.. The effect of three cysteine-mutations (C1130F, C1149R or C2671Y) on the in vivo survival of VWF was studied in patients carrying these mutations and in a VWF-deficient mice model.. In patients carrying these mutations, we observed increased propeptide/mature VWF ratios and rapid disappearance of VWF from the circulation after desmopressin treatment. Detailed analysis of in vivo clearance of recombinant VWF in a VWF-deficient mice model revealed a fourfold increased clearance rate of the mutants. The mutations C1130F, C1149R and C2671Y are each associated with reduced survival of VWF in the circulation. Detailed analysis of the recombinant mutant VWF demonstrated that increased clearance was not due to increased proteolysis by ADAMTS-13. We did not identify functional or structural characteristics that the mutant proteins have in common and could be associated with the phenomenon of increased clearance.. Cysteine-mutations in VWF may result in reduced in vivo survival. The observation that various mutations are associated with increased in vivo clearance may have major implications for the therapeutic strategies that rely on the rise of endogenous VWF after desmopressin administration.

Topics: ADAMTS13 Protein; Animals; Cysteine; Deamino Arginine Vasopressin; Humans; Metabolism; Metalloendopeptidases; Mice; Mice, Knockout; Mutation, Missense; Recombinant Proteins; von Willebrand Diseases; von Willebrand Factor

Topics: 3' Untranslated Regions; Activated Protein C Resistance; Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Contraindications; Coronary Disease; Deamino Arginine Vasopressin; Factor V; Factor VIII; Female; Genetic Predisposition to Disease; Genotype; Heparin; Humans; Hypertension; Postoperative Complications; Prothrombin; Pulmonary Embolism; Thrombophilia; von Willebrand Diseases; von Willebrand Factor

von Willebrand disease (VWD) is the commonest inherited bleeding disorder. The aim of therapy for VWD is to correct the two defects of haemostasis in this disorder, impaired primary haemostasis because of defective platelet adhesion and aggregation and impaired coagulation as a result of low levels of factor VIII. The objective of this guideline is to inform individuals making choices about the treatment and management of VWD including the use of therapeutic products. This is the second edition of this UK Haemophilia Centre Doctors' Organization (UKHCDO) guideline and supersedes the previous edition which was published in 1994.

Topics: Antifibrinolytic Agents; Blood Component Transfusion; Deamino Arginine Vasopressin; Hemostatics; Humans; von Willebrand Diseases

Desmopressin [1-deamino-8-d-arginine vasopressin (DDAVP)] has been successfully used in the treatment of type 1 von Willebrand disease (VWD) and mild haemophilia A (MHA). Data suggest that DDAVP can increase factor XI (FXI) plasma levels and may represent an effective treatment for mild FXI deficiency. We assessed the DDAVP response of FXI coagulant activity (FXI:C), FXI antigen (FXI:Ag), factor V coagulant activity (FV:C), and factor X coagulant activity (FX:C) in 33 individuals with VWD or MHA. DDAVP did not produce a clinically significant increase in FXI:C, FXI:Ag, FX:C or FV:C in any patient. The mean +/- SD FXI:C pre-DDAVP (time 0) and at 1 h post-DDAVP was 90.7 (+/-22.9) U/dl and 92.1 (+/-20.9) U/dl, respectively. The mean (+/-SD) FXI:Ag at time 0 and 1 h was 92.2 (+/-20.1) U/dl and 89.9 (+/-21.3) U/dl, respectively. There was a small reduction at 1 h post-DDAVP in both FV:C, from 101.8 (+/-20.9) U/dl to 97.2 (+/-21.4) U/dl (P < 0.001), and FX:C from 103 (+/-19.5) U/dl to 98.8 (+/-18.7) U/dl (P < 0.001). No significant increase in FXI:C, FXI:Ag, FV:C or FX:C levels was seen at 4 h post-DDAVP. This study failed to demonstrate a clinically significant increase in the levels of FXI, FX or FV following administration of DDAVP.

Topics: Adolescent; Adult; Blood Coagulation Factors; Child; Deamino Arginine Vasopressin; Factor V; Factor X; Factor XI; Female; Hemophilia A; Hemostatics; Humans; Male; Middle Aged; Statistics, Nonparametric; Treatment Failure; von Willebrand Diseases

A patient was referred to the intensive care unit with sudden delirium and a serum sodium level of 111 mEq/L (mmol/L). A computerized tomographic scan revealed marked cerebral edema. Laboratory values were highly consistent with the action of the antidiuretic hormone. She had received desmopressin acetate (DDAVP) for 4 days preoperatively and postoperatively for putative van Willebrand's disease. Hyponatremia as a sequel to DDAVP treatment is an unusual complication and the medication is generally safe. However, our patient nevertheless teaches that vigilance equals avoidance.

Topics: Brain Edema; Deamino Arginine Vasopressin; Delirium; Drug Administration Schedule; Female; Humans; Hyponatremia; Middle Aged; Ovarian Cysts; Premedication; Sodium; Tomography, X-Ray Computed; von Willebrand Diseases

ADAMTS-13, the metalloprotease that disposes physiologically of the most thrombogenic multimers of von Willebrand factor (VWF), tends to be low in plasma when VWF is high. We evaluated the behaviour of these two proteins in naturally occurring, experimental and clinical situations associated with VWF levels spanning from undetectable to supranormal. ADAMTS-13 was approximately 10% higher (and VWF 35% lower) in 65 healthy individuals of blood group O than in 65 individuals of groups A, B and AB. Thirty-three patients with type 3 von Willebrand disease (VWD) with undetectable plasma VWF had approximately 35% higher levels of ADAMTS-13 than a comparable group of healthy individuals with normal VWF. When VWF was raised to supranormal levels by desmopressin (DDAVP) in 10 healthy volunteers, ADAMTS-13 decreased by approximately 20%, with no change of the protease in three patients with severe VWD who had no post-DDAVP VWF rise. When VWF was raised from very low to normal levels by the infusion of VWF-containing plasma concentrates in four patients with type 3 VWD and one with type 1 VWD plasma, ADAMTS-13 decreased in parallel. These data show that throughout a large spectrum of plasma VWF levels there is a negative association between this protein and the activity of its major cleaving protease.

Topics: ADAM Proteins; ADAMTS13 Protein; Adult; Blood Group Antigens; Case-Control Studies; Deamino Arginine Vasopressin; Factor VIII; Female; Hemostatics; Humans; Male; Metalloendopeptidases; Middle Aged; Statistics, Nonparametric; von Willebrand Diseases; von Willebrand Factor

Topics: Deamino Arginine Vasopressin; Factor VIII; Humans; Mutation; von Willebrand Diseases; von Willebrand Factor

Type 2A von Willebrand's disease (VWD) refers to disease variants with decreased platelet-dependent function of von Willebrand factor (VWF) associated with the absence of high molecular weight (HMW) multimers. The candidate G1629R mutation, identified in an Italian patient with type 2A VWD, was expressed to confirm the relationship between phenotype and genotype.. Plasma samples from the patient were studied after DDAVP or FVIII/VWF concentrate injections. Furthermore, an expression vector carrying the G1629R mutation was constructed by site-directed mutagenesis and transiently expressed in Cos-7 cells. The characteristics of the corresponding recombinant protein were analyzed.. After 1-deamino-8-D-argine vasopressin (DDAVP) infusion, factor VIII and VWF activities increased and HMW VWF multimers were transiently observed in the patient's plasma. VWF activity increased only after administration of a dual FVIII/VWF concentrate. ADAMTS-13 activity did not change significantly before or after the therapies. Secretion, in culture medium, of the corresponding mutated protein (R1629-rVWF) was slightly decreased and this rVWF contained intermediate and HMW multimers. Furthermore, binding of R1629-rVWF to platelet GPIb was moderately reduced compared to that of the wild-type rVWF.. Based on the DDAVP and in vitro expression results, we classified the G1629R mutation in group 2 type 2A mutations. Our findings could explain why DDAVP may only be partially effective and suggest that FVIII/VWF concentrates should be used in cases of prolonged mucosal bleeding and major surgery when functional VWF is required.

Topics: ADAM Proteins; ADAMTS13 Protein; Amino Acid Substitution; Animals; Biopolymers; Blood Coagulation Tests; Blood Platelets; Chlorocebus aethiops; COS Cells; Deamino Arginine Vasopressin; Drug Combinations; Drug Resistance; Factor VIII; Genotype; Gingival Hemorrhage; Humans; Molecular Weight; Mutation, Missense; Phenotype; Point Mutation; Protein Binding; Protein Structure, Tertiary; Recombinant Fusion Proteins; Tooth Extraction; von Willebrand Diseases; von Willebrand Factor

We report on a new mutation (4337T-->C) in exon 28 of the von Willebrand factor (VWF) gene, resulting in a substitution of L with P at residue 1446 (L1446P) of pre-pro-VWF. The defect is transmitted as a dominant trait and induces a reduced VWF synthesis, an abnormal VWF multimer pattern and a deficient VWF-platelet glycoprotein Ib interaction. The proband had low plasma and platelet VWF antigen levels, a reduced VWF collagen-binding capacity, and a disproportionately low VWF ristocetin cofactor activity, associated with the absence of ristocetin-induced platelet aggregation. Multimer analysis showed that the smaller multimers were slightly low, whereas the larger ones were significantly reduced or absent, with a clear cutoff between the two patterns. Similar hemostatic findings were observed in the proband's sister and nephew. Desmopressin administration restored VWF levels to near normal, but this was not so for VWF ristocetin cofactor activity or ristocetin-induced platelet aggregation. VWF multimers improved after desmopressin, moreover, with the larger forms restored and the smaller ones still relatively more represented. Recombinant P1446 VWF synthesis was reduced at heterozygous level, and its multimer pattern was similar to that observed in plasma VWF. These findings confirm the role of L1446P mutation in determining the von Willebrand disease (VWD) phenotype observed in our patients. Given the lack of large and intermediate VWF multimers, and the fact that the VWF-platelet interaction defect appears to be partially independent of multimer pattern, the VWD associated with L1446P mutation may belong to the type 2A/2M VWD variant.

Topics: Adult; Blood Platelets; Collagen; Deamino Arginine Vasopressin; Hemostasis; Hemostatics; Heterozygote; Humans; Male; Mutation; Phenotype; Platelet Aggregation; Platelet Glycoprotein GPIb-IX Complex; Recombinant Proteins; Ristocetin; von Willebrand Diseases; von Willebrand Factor

Von Willebrand factor (VWF) is synthesized in endothelial cells, where it is stored in Weibel-Palade bodies. Administration of 1-desamino-8-D-arginine-vasopressin (DDAVP) to patients with type 1 von Willebrand disease and to healthy individuals causes a rapid increase in plasma VWF levels. This increase is the result of stimulated release of VWF from Weibel-Palade bodies in certain beds of endothelial cells. The VWF propeptide (VWFpp) targets VWF to storage granules through a noncovalent association. The nature of the VWFpp/VWF interaction was investigated by using cross-species differences in VWF storage. While canine VWFpp traffics to storage granules and facilitates the multimerization of human VWF, it does not direct human VWF to storage granules. Since storage takes place after furin cleavage, this defect appears to be due to the defective interaction of canine VWFpp and human VWF. To determine the regions within VWFpp and VWF important for this VWFpp/VWF association and costorage, a series of human-canine chimeric VWFpp and propeptide-deleted VWF (Deltapro) constructs were produced and expressed in AtT-20 cells. The intracellular localization of coexpressed proteins was examined by confocal microscopy. Two amino acids, 416 in VWFpp and 869 in the mature VWF molecule, were identified as being critical for the association and granular storage of VWF.

Topics: Adrenocorticotropic Hormone; Amino Acid Sequence; Animals; Cell Line; Deamino Arginine Vasopressin; Dogs; Embryo, Mammalian; Endothelium; Humans; Kidney; Mice; Microscopy, Confocal; Molecular Sequence Data; Pituitary Neoplasms; Point Mutation; Protein Precursors; Recombinant Fusion Proteins; Species Specificity; Structure-Activity Relationship; Transfection; Tumor Cells, Cultured; von Willebrand Diseases; von Willebrand Factor; Weibel-Palade Bodies

von Willebrand factor-cleaving protease (ADAMTS13) cleaves von Willebrand factor (VWF) and regulates its physiologic function. To investigate the relation between ADAMTS13 activity and VWF, we compared ADAMTS13 activity with the VWF-related parameters VWF antigen (VWF:Ag), VWF collagen-binding activity (VWF:CBA), VWF-propeptide, proVWF, and VWF multimeric composition in 10 healthy volunteers and 3 patients with type 1 von Willebrand disease before and after infusing 0.3 microg/kg desmopressin. The VWF-related parameters in the volunteers increased 60 minutes after start of infusion by 3.7-fold for VWF:Ag, 7.2-fold for propeptide, and 2.2-fold for VWF:CBA. Unusually large VWF multimers and traces of proVWF appeared. The ADAMTS13 activity decreased to about half the initial value. After 24 hours values returned to baseline. Patients with type 1 von Willebrand disease showed similar results. We conclude that the inverse correlation between ADAMTS13 and VWF-related parameters suggests a consumption of ADAMTS13 after the desmopressin-induced release of higher multimers of VWF.

Topics: ADAM Proteins; ADAMTS13 Protein; Adult; Case-Control Studies; Collagen; Deamino Arginine Vasopressin; Dimerization; Female; Humans; Infusions, Parenteral; Male; Metalloendopeptidases; Middle Aged; von Willebrand Diseases; von Willebrand Factor

A middle-aged woman was admitted to the hospital after being found unconscious at home. A brain CT scan excluded an intracranial bleed or other focal abnormality. Laboratory analysis showed hyponatraemia (sodium: 121 mmol L(-1)) and a low plasma osmolality, with normal sodium excretion and urine osmolality. A diagnosis of hyponatraemic coma was made. The patient was treated with water restriction; 24 h later the sodium was 135 mmol L(-1) and the patient was neurologically fully recovered. The patient, who suffered from von Willebrand's disease, had received desmopressin and ibuprofen for analgesia 2 days before after a dental intervention. She had received desmopressin several times in the past without any complications. A few patients treated with desmopressin for coagulation abnormalities have been reported to develop water intoxication and severe hyponatraemia resulting in seizures and coma. By inhibiting prostaglandin synthesis, non-steroid anti-inflammatory agents (NSAIDs) potentiate the effect of water reabsorption in the renal tubules of vasopressin, therefore enhancing water retention. Desmopressin and NSAIDs should not be used in combination in patients with bleeding disorders, but it is often followed in clinical practice. In addition, this is probably not an unusual situation in patients treated with desmopressin for other 'non-haemorrhagic' indications. This report emphasizes the need for practitioners to be aware of this rare but severe complication.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Coma; Deamino Arginine Vasopressin; Drug Therapy, Combination; Female; Humans; Hyponatremia; Ibuprofen; Middle Aged; Renal Agents; von Willebrand Diseases

Recombinant human interleukin-11 (rhIL-11), a glycoprotein 130 (gp130)-signaling cytokine approved for treatment of thrombocytopenia, also raises von Willebrand factor (VWF) and factor VIII (FVIII) by an unknown mechanism. Desmopressin (1-deamino-8-d-arginine vasopressin [DDAVP]) releases stored VWF and FVIII and is used for treatment of VWF and FVIII deficiencies. To compare the effect of these 2 agents, heterozygous von Willebrand disease (VWD) and normal dogs were treated with either rhIL-11 (50 microg/kg/d subcutaneously x 7 days) or DDAVP (5 microg/kg/d intravenously x 7 days). The rhIL-11 produced a gradual and sustained elevation of VWF and FVIII levels in both heterozygous VWD and normal dogs while DDAVP produced a rapid and unsustained increase. Importantly, rhIL-11 treatment produced a 2.5- to 11-fold increase in VWF mRNA in normal canine heart, aorta, and spleen but not in homozygous VWD dogs, thus identifying a mechanism for elevation of plasma VWF in vivo. Moreover, dogs pretreated with rhIL-11 retain a DDAVP-releasable pool of VWF and FVIII, suggesting that rhIL-11 does not significantly alter trafficking of these proteins to or from storage pools. The half-life of infused VWF is unchanged by rhIL-11 in homozygous VWD dogs. These results show that rhIL-11 and DDAVP raise plasma VWF by different mechanisms. Treatment with rhIL-11 with or without DDAVP may provide an alternative to plasma-derived products for some VWD and hemophilia A patients if it is shown safe in clinical trials.

Topics: Animals; Aorta; Deamino Arginine Vasopressin; Dogs; Drug Evaluation, Preclinical; Factor VIII; Half-Life; Heart; Heterozygote; Interleukin-11; Myocardium; Recombinant Proteins; RNA, Messenger; Spleen; von Willebrand Diseases; von Willebrand Factor; Weibel-Palade Bodies

The bleeding time test is difficult to perform, standardize, and interpret in children. In this study the authors evaluated the sensitivity, specificity, and efficiency of the bleeding time test and the PFA-100 in a series of children referred for possible bleeding problems.. Between February 2000 and August 2001 patients aged more than 6 months and less than 18 years of age who were referred to the authors' institution for a hemostatic evaluation were included in the study if residual blood was available for testing on the PFA-100 instrument. Fifty-two children had platelet count, prothrombin time, partial thromboplastin time, bleeding time, and PFA-100 testing performed as well as an evaluation by a hematologist. For PFA-100 testing, 52 patients had Col/Epi measurements; adequate sample remained for Col/ADP testing on 32. Additional testing for diagnostic purposes was at the discretion of the treating physician.. Use of the Col/Epi cartridge in the PFA-100 instrument offered 100% sensitivity and 97% specificity for detection of qualitative platelet abnormalities, compared with 37% and 88%, respectively, for bleeding time testing. For pediatric patients with von Willebrand disease, the sensitivity was 100% using the Col/Epi cartridge, compared with 17% for the bleeding time test. The sensitivities for combined qualitative platelet defects and von Willebrand disease using the Col/Epi or Col/ADP cartridges were 100% and 87%, respectively, compared with 37% for the bleeding time test.. The PFA-100 is a more efficient test; it can replace the bleeding time test as a component of the laboratory evaluation of children with a potential bleeding problem.

Topics: Adolescent; Bleeding Time; Blood Platelets; Case-Control Studies; Child; Child, Preschool; Deamino Arginine Vasopressin; Female; Hematocrit; Humans; Infant; Male; Partial Thromboplastin Time; Platelet Count; Platelet Function Tests; Predictive Value of Tests; Prothrombin Time; Sensitivity and Specificity; von Willebrand Diseases

Topics: Adaptation, Psychological; Anti-Inflammatory Agents, Non-Steroidal; Antifibrinolytic Agents; Blood Coagulation Tests; Deamino Arginine Vasopressin; Estrogens; Hemostatics; Humans; Nurse's Role; Patient Care Planning; Patient Education as Topic; Progesterone; von Willebrand Diseases

The mechanism of von Willebrand factor (VWF) clearance is not fully understood. The factors that affect VWF clearance, and the normal in vivo mechanism of clearance, may be relevant to the pathogenesis of Type 1 von Willebrand disease (VWD), in which there is a partial deficiency of VWF. In order to investigate the clearance of VWF in Type 1 VWD, the current study assessed the half-life of VWF antigen (t(1/2) VWF:Ag) in Type 1 VWD patients and individuals with mild hemophilia A following the administration of 1-deamino-8-d-arginine vasopressin (DDAVP; desmopressin). To date 20 individuals have been assessed, 13 with Type 1 VWD and seven with mild hemophilia A. The median t(1/2) VWF:Ag in the Type 1 VWD and mild hemophilia A groups were 4.6 h and 9.5 h, respectively. The difference between the t(1/2) VWF:Ag for the two groups was significant, P < 0.02. Analysis of the data showed a correlation between the t(1/2) VWF:Ag and the baseline VWF:Ag level prior to administration of DDAVP: lower baseline VWF:Ag levels were associated with a shorter t(1/2) VWF:Ag. These data suggest that increased clearance of VWF may be the pathogenic mechanism in some cases of Type 1 VWD.

Topics: Adult; Deamino Arginine Vasopressin; Female; Hemophilia A; Hemostatics; Humans; Kinetics; Male; Middle Aged; Time Factors; von Willebrand Diseases; von Willebrand Factor

Diagnosis of mild forms of type 1 and 2 von Willebrand disease (VWD) may be difficult, especially when the levels of von Willebrand factor (VWF) activities measured as ristocetin cofactor are close to normal (30-60 U/dL) because the laboratory phenotype is highly heterogeneous and confounded by factors outside the VWF gene (eg, blood group) that may influence VWF levels. An array of tests is often required to characterize the VWD types of the disorder and establish the best treatment modality, but laboratory data should always be interpreted in the presence of personal and family bleeding history. The aim of treatment is to correct the dual defect of hemostasis (ie, abnormal coagulation expressed by low levels of factor VIII:C and abnormal platelet adhesion expressed by the prolonged bleeding time). Desmopressin (1-deamino-8-D-arginine vasopressin; DDAVP) is the treatment of choice for the mild forms of type 1 and 2 VWD because it often corrects the factor VIII/VWF levels and the prolonged bleeding time in most patients, but no prospective studies on clinical effects of DDAVP are available. In type 1 and type 2 VWD unresponsive to DDAVP, plasma virally inactivated concentrates containing VWF and factor VIII are the mainstay of treatment.

Topics: Deamino Arginine Vasopressin; Humans; von Willebrand Diseases; von Willebrand Factor

Two patients, a man aged 69 and a woman aged 64, were diagnosed with Von-Willebrand syndrome caused by monoclonal gammopathy. The man, who was admitted for hip surgery, had a history of long episodes of epistaxis. The patient was treated with immunoglobulin and the hip operation was carried out with no complications. The woman suffered from haemorrhagic diathesis. She was advised that should she undergo an invasive procedure then treatment with a prophylactic with intravenous immunoglobulin or Von-Willebrand factor (VWF)/factor-VIII-concentrates must be administered. Acquired Von-Willebrand syndrome is a rare condition with an estimated prevalence of 0.04-0.13%. It is linked to a large number of underlying diseases such as paraproteinaemia, multiple myeloma (Kahler's disease), myeloproliferative disease, lymphoproliferative disease, auto-immune disease, solid tumours and hypothyroidism. Recognition depends on a careful case-history and identification of the underlying disease. For its diagnosis VWF antigen. VWF propeptide, activated partial thromboplastin time and factor VIII are of importance. Technically, it is difficult to show the presence of VWF antibodies as it concerns a heterogeneous group of antibodies. There are two pillars of treatment: symptomatic treatment of the bleeding tendencies using desmopressin, VWF-concentrate or intravenous gammaglobulin, and treatment of the underlying disease. The latter form of treatment can lead to acquired Von-Willebrand-syndrome disappearing altogether.

Topics: Aged; Deamino Arginine Vasopressin; Female; Hemorrhage; Hemostatics; Humans; Immunoglobulins, Intravenous; Male; Middle Aged; Paraproteinemias; von Willebrand Diseases; von Willebrand Factor

To determine the pattern and predictors of response to desmopressin (DDAVP) in children with von Willebrand disease (VWD).. The authors reviewed the hospital records of all children with type 1 (n = 70) and type 2A (n = 5) VWD who were followed in the institution's Bleeding Disorders Clinic from January 1989 to June 2001 and who had a DDAVP challenge test after diagnosis. The major outcome evaluated was response to DDAVP, defined as an increase of greater than twofold over baseline of von Willebrand factor, ristocetin cofactor (VWF:RCo), and factor VIII coagulant (FVIII:C) and levels above 0.3 IU/mL.. Response to DDAVP was observed in 56 (80%) of the 70 children with type 1 VWD. Age and baseline VWF:RCo and FVIII:C levels were positively associated with DDAVP response. A total of 36 children (28 responders, 8 nonresponders) with type 1 VWD were treated for bleeding episodes or for prophylaxis; of these 75% (6/8) of the nonresponders compared with 7% (2/28) of the responders to a DDAVP challenge test received blood component therapy (P < 0.01). One of the five children with type 2A VWD responded to DDAVP.. DDAVP challenge tests are recommended in children with newly diagnosed VWD to identify responders in whom DDAVP may be used for the prevention or treatment of bleeding, thus avoiding exposure to blood products. The association of DDAVP response with age merits further investigation.

Topics: Adolescent; Child; Child, Preschool; Deamino Arginine Vasopressin; Factor VIII; Female; Humans; Male; Retrospective Studies; von Willebrand Diseases

A 33-year-old primipara with von Willebrand disease type I was admitted in labor at 37 weeks, requesting epidural analgesia. The consultant hematologist advised treating with desmopressin acetate (DDAVP) before inserting an epidural catheter. Desmopressin at a dose of 0.3 microgram/Kg was administered intravenously and the catheter was inserted to L3-L4 to infuse 0.1% bupivacaine with 2 micrograms/mL of fentanyl at a rate of 12 mL/h. Four hours later the patient was brought to the operating room for forceps delivery of a healthy boy. One hour later, she had recovered normal motor tone followed by normal sensitivity in the lower extremities. The catheter was then withdrawn with no signs of bleeding. A woman with von Willebrand's disease can receive an epidural block for analgesia during childbirth. The decision to perform the block should be individualized, based on coagulation tests. DDAVP may play a role in improving hemostasis.

Topics: Adult; Analgesia, Epidural; Analgesia, Obstetrical; Deamino Arginine Vasopressin; Female; Hemostatics; Humans; Pregnancy; Pregnancy Complications, Cardiovascular; von Willebrand Diseases

Topics: Deamino Arginine Vasopressin; History, 20th Century; Humans; Japan; von Willebrand Diseases; von Willebrand Factor

von Willebrand disease (vWD) is a bleeding disorder caused by quantitative (type 1 and 3) or qualitative (type 2) defects of von Willebrand factor (vWF). The molecular basis of type 2 and 3 vWD are now known and those of type 1 vWD are being understood. Phenotypic diagnosis is based on the measurements of plasma and platelet vWF, of the ability of vWF to interact with platelet receptors and the analysis of the multimeric structure of vWF. Due to the heterogeneity of vWF defects and the variables that interfere with vWF levels, a correct diagnosis of types and subtypes may sometimes be difficult but is very important for therapy. The aim of treatment is to correct the dual defects of haemostasis, i.e. abnormal intrinsic coagulation expressed by low levels of factor VIII (FVIII) and abnormal platelet adhesion. Desmopressin is the treatment of choice in patients with type 1 vWD, who account for approximately 70% of cases, because it corrects FVIII-vWF levels and the prolonged bleeding time (BT) in the majority of these patients. In type 3 and in severe forms of type 1 and 2 vWD patients, desmopressin is not effective and it is necessary to resort to plasma concentrates containing FVIII and vWF. Treated with virucidal methods, these concentrates are effective and safe, but they cannot always correct BT defect. Platelet concentrates or desmopressin can be used as adjunctive treatments when poor correction of BT after plasma concentrate treatment is associated with continued bleeding.

Topics: Deamino Arginine Vasopressin; Factor VIII; Female; Genes, Dominant; Hemostatics; Humans; Isoantibodies; Italy; Pedigree; Postoperative Hemorrhage; Pregnancy; Pregnancy Complications, Hematologic; Prenatal Diagnosis; Risk Factors; von Willebrand Diseases; von Willebrand Factor

Topics: Animals; Animals, Genetically Modified; Autoantibodies; Deamino Arginine Vasopressin; Factor IX; Factor VIII; Female; Genetic Therapy; Hemophilia A; Hemostatics; Humans; Male; Menorrhagia; Mutation; Recombinant Proteins; Sex Factors; Swine; Synovitis; von Willebrand Diseases

To assess the efficacy, safety, and complications of otolaryngologic surgery in children with von Willebrand disease (vWD) undergoing surgery.. A prospective, controlled study of 41 children with vWD who underwent surgery between June 1, 1999, and January 31, 2001.. A tertiary care, university-based children's hospital.. All children had a preoperative diagnosis of vWD. The patients were treated with either a protocol that includes the use of desmopressin acetate and tranexamic acid (37 children) or factor VIII concentrate in children with a positive history of seizures (4 children).. Immediate and delayed postoperative bleeding, hyponatremia, seizures, and urine output.. Two adenotonsillectomy patients (5%) had an immediate postoperative hemorrhage. Delayed postoperative bleeding was not detected in our patients. Severe hyponatremia occurred in 2 patients (1 of them with clinical manifestations).. Our management of children with vWD was efficacious in otolaryngologic surgery. One child had important adverse effects with the use of desmopressin (seizure). Thus, the use of desmopressin should be weighed and closely monitored.

Topics: Adenoidectomy; Adolescent; Antifibrinolytic Agents; Child; Child, Preschool; Deamino Arginine Vasopressin; Hemostatics; Humans; Infant; Myringoplasty; Otorhinolaryngologic Diseases; Otorhinolaryngologic Surgical Procedures; Postoperative Hemorrhage; Prospective Studies; Tonsillectomy; Tranexamic Acid; Tympanic Membrane; von Willebrand Diseases

To evaluate primary hemostasis following administration of desmopressin acetate (DDAVP) to Doberman Pinschers with type-1 von Willebrand disease (vWD).. 16 nonanemic Doberman Pinschers with type-1 vWD.. Closure time (CT), defined as time required for occlusion of an aperture by a platelet plug assessed within the point-of-care instrument, plasma von Willebrand factor (vWF) concentration, and buccal mucosal bleeding time (BMBT) were determined before and 1 hour after administration of DDAVP (1 microg/kg, SC).. Baseline closure times measured with adenosine diphosphate ([ADP-CT], 108 to > 300 seconds; reference range, 52 to 86 seconds) and epinephrine ([EPI-CT], 285 to > 300 seconds; 97 to 225 seconds) as platelet agonists were prolonged in all dogs. Following DDAVP administration, ADP-CT (59 to 186 seconds) was significantly shortened from baseline, but there was no decrease in EPI-CT. Although mean plasma vWF concentration increased significantly after DDAVP administration, only 1 dog had an increase of > 35 U/dL. There was no correlation between increase in plasma vWF concentration and shortening of the ADP-CT. Baseline BMBT was prolonged in 12 of 14 dogs, with significant shortening of BMBT after DDAVP administration in 6 of 7 dogs. In vitro replacement of vWF-deficient plasma with plasma from an unaffected dog shortened the ADP-CT whereas in vitro addition of DDAVP had no effect.. Administration of DDAVP to Doberman Pinschers with type-1 vWD resulted in improved hemostatic function, as assessed by the point-of-care instrument and shortening of BMBT, despite minimal increase in plasma vWF concentration.

Topics: Adenosine Diphosphate; Animals; Bleeding Time; Deamino Arginine Vasopressin; Dog Diseases; Dogs; Epinephrine; Female; Hemostasis; Hemostatics; Male; Platelet Aggregation; Platelet Count; von Willebrand Diseases

In this article the possibility of using the Minirin (desmopressin) in maxillofacial surgery in person with hemostatic disorders has been described. The our case of patient with von Willebrand's disease type I indicates that this drug is very effective in bleeding after teeth extractions.

Topics: Adult; Deamino Arginine Vasopressin; Drug Administration Schedule; Hemostasis, Surgical; Hemostatics; Humans; Infusions, Intravenous; Male; Premedication; Tooth Extraction; Tooth, Impacted; von Willebrand Diseases

Type Vicenza variant of von Willebrand disease (VWD) is characterized by a low plasma von Willebrand factor (VWF) level and supranormal VWF multimers. Two candidate mutations, G2470A and G3864A at exons 17 and 27, respectively, of the VWF gene were recently reported to be present in this disorder. Four additional families, originating from northeast Italy, with both mutations of type Vicenza VWD are now described. Like the original type Vicenza subjects, they showed a mild bleeding tendency and a significant decrease in plasma VWF antigen level and ristocetin cofactor activity but normal platelet VWF content. Unlike the original patients, ristocetin-induced platelet aggregation was found to be normal. Larger than normal VWF multimers were also demonstrated in the plasma. Desmopressin (DDAVP) administration increased factor VIII (FVIII) and VWF plasma levels, with the appearance of even larger multimers. However, these forms, and all VWF oligomers, disappeared rapidly from the circulation. The half-life of VWF antigen release and of elimination was significantly shorter than that in healthy counterparts, so that at 4 hours after DDAVP administration, VWF antigen levels were close to baseline. Similar behavior was demonstrated by VWF ristocetin cofactor activity and FVIII. According to these findings, it is presumed that the low plasma VWF levels of type Vicenza VWD are mainly attributed to reduced survival of the VWF molecule, which, on the other hand, is normally synthesized. In addition, because normal VWF-platelet GPIb interaction was observed before or after DDAVP administration, it is proposed that type Vicenza VWD not be considered a 2M subtype.

Topics: Blood Platelets; Deamino Arginine Vasopressin; DNA Mutational Analysis; Drug Stability; Factor VIII; Half-Life; Humans; Italy; Kinetics; Macromolecular Substances; Mutation; Platelet Aggregation; Ristocetin; von Willebrand Diseases; von Willebrand Factor

Topics: Blood Coagulation Tests; Deamino Arginine Vasopressin; Diagnosis, Differential; Hemostatics; Humans; Male; Time Factors; von Willebrand Diseases

This study evaluated the effectiveness of a protocol to prevent bleeding after dental extraction in patients with hemophilia, von Willebrand's disease (VWD), or platelet disorders.. Replacement therapy was used in cases involving general anesthesia, and nerve trunk infiltration was used in patients with severe bleeding disorders (severe-to-moderate hemophilia or type 2-3 VWD). Desmopressin was used in good responders with mild hemophilia A, type 1 VWD, and platelet disorders. Local hemostatic measures and antifibrinolytic treatment were used systematically.. Ninety-three patients underwent 103 dental extractions; 2 of these patients had secondary bleeding requiring surgical hemostasis.. The indication for replacement therapy depended on the type of anesthesia that was used. Coagulation factor concentrates or desmopressin were necessary to avoid upper airway hematoma with general anesthesia or nerve trunk infiltration. With local anesthesia, substitutive treatment was indicated in patients with severe-to-moderate hemophilia and type 2-3 VWD. Inexpensive desmopressin was effective in those who responded well. Local hemostatic measures and antifibrinolytic treatment were performed systematically.

Topics: Adolescent; Adult; Aged; Antifibrinolytic Agents; Blood Platelet Disorders; Blood Transfusion; Child; Clinical Protocols; Deamino Arginine Vasopressin; Dental Care for Chronically Ill; Female; Hemophilia A; Hemorrhagic Disorders; Hemostatics; Humans; Male; Middle Aged; Oral Hemorrhage; Retrospective Studies; Tooth Extraction; von Willebrand Diseases

Two women aged 39 and 30 years were investigated for possible coagulation disorders because of menorrhagia, anaemia and postoperative haemorrhages. These investigations revealed that they had type 1 Von Willebrand's disease. During the treatment with desmopressin, factor VIII and Von Willebrand factor (VWF) activity normalised. About one third of the patients referred to a gynaecologist for menorrhagia have an inherited bleeding disorder, of which type 1 Von Willebrand's disease is the most prevalent. Once a gynaecological cause of the menorrhagia has been excluded, or in the case of an increased risk on the basis of the medical history, a limited haemostatic investigation can establish or exclude an inherited coagulation disorder. For women with a coagulation disorder the menorrhagia can be treated. Surgical interventions can be carried out safely following treatment with desmopressin or factor VIII/VWF concentrates.

Topics: Adult; Anemia; Deamino Arginine Vasopressin; Factor VIII; Female; Hemostatics; Humans; Menorrhagia; Postoperative Hemorrhage; von Willebrand Diseases; von Willebrand Factor

Coagulation abnormalities may occur in patients with thyroid diseases. We report on 14 patients undergoing thyroid surgery for a thyroid disease with an alteration of coagulation parameters resembling von Willebrand disease. Subcutaneous desmopressin was first tested and then used successfully in these patients as surgical prophylaxis, with no side-effects or bleeding complications during or after surgery. This study highlights the need for coagulation studies in patients with thyroid diseases undergoing thyroid surgery. Subcutaneous desmopressin may be used in these patients in order to prevent a surgically related bleeding risk.

Topics: Adult; Blood Coagulation Tests; Blood Loss, Surgical; Deamino Arginine Vasopressin; Female; Hemostasis, Surgical; Hemostatics; Humans; Male; Thyroid Diseases; von Willebrand Diseases

Acquired von Willebrand disease (aVWD) is a rare bleeding disorder that mimics congenital VWD in previously healthy individuals; it is most frequently associated with monoclonal gammopathy. Hemostatic therapy of aVWD is challenging due to the extremely shortened half-life of endogenous and exogenous VWF. High-dose intravenous immunoglobulin (ivIG) is recommended as the treatment of choice, usually rapidly normalizing coagulation; but in case of failure, alternative treatment options are not well explored. We report successful major orthopedic surgery in a 61-year-old woman with multiple myeloma IgG lambda and aVWD. IvIG alone failed to correct hemostasis. However, ivIG pretreatment improved the VWF ristocetin cofactor (VWF:RCo) half-life from only 1.5 hr to more than 4 hr, allowing desmopressin infusions twice daily to maintain sufficient VWF:RCo levels. Because of diminishing desmopressin effect, we attempted for the first time in aVWD a continuous VWF/FVIII infusion (Haemate HS), 2.1-2.7 FVIII U/kg/hr or 51-64 U/kg/day, respectively 4.6-6.0 VWF:RCo U/kg/hr or 110-145 U/kg/day) to reach constant factor levels. The steady-state clearance was 2.4 mL/kg/hr for FVIII:C and 13.5 mL/kg/hr for VWF:RCo. During surgery, VWF:RCo, FVIII:C, and PFA-100 closure time were normalized. Until day 5, VWF:RCo was kept above 50%, from day 6 to 10 at least 30% activity were attained. FVIII:C levels were always >70%. The clinical course was uneventful without bleeding. Two weeks after hip surgery the patient was discharged from the hospital without complaints. The therapy described can be recommended as safe and feasible for further evaluation in aVWD patients who are hyporesponsive to ivIG treatment alone. Continuous VWF/FVIII infusion can improve substitution therapy in aVWD.

Topics: Arthroplasty, Replacement, Hip; Deamino Arginine Vasopressin; Dose-Response Relationship, Drug; Drug Combinations; Factor VIII; Female; Hemostasis; Hemostatics; Humans; Immunoglobulins, Intravenous; Infusions, Intravenous; Middle Aged; Treatment Outcome; von Willebrand Diseases; von Willebrand Factor

Topics: Adult; Deamino Arginine Vasopressin; Drug Monitoring; Female; Hemostasis; Humans; Male; Platelet Function Tests; von Willebrand Diseases

We report a quite rare case of acquired type 3-like von Willebrand syndrome (vWS) that preceded full-blown systemic lupus erythematosus (SLE). A 16-year-old woman with no previous disease history and no family history of hemorrhagic diathesis was referred to our hospital because of recurrent epistaxis and gingival bleeding. She was diagnosed as having atypical type 3 von Willebrand disease because of prolonged bleeding time with normal platelet count and prolonged activated partial thromboplastin time (aPTT), and an almost complete absence of von Willebrand factor (vWF) antigen, ristocetin cofactor activity (vWF:RCo) and ristocetin-induced platelet agglutination (RIPA). Furthermore, electrophoretic analysis of plasma vWF revealed a trace amount of vWF and an absence of the multimeric form of vWF. Infusions of either vasopressin or factor VIII/vWF concentrates improved bleeding symptoms and corrected the aPTT and RIPA. However, she complained of low-grade fever, general fatigue and polyarthralgia 5 months later, and leukocytepenia and hypo-complementemia developed. Anti-double-stranded DNA antibodies and lupus erythematosus cells became positive. These findings were compatible with SLE. Mixing the patient's platelet-poor plasma (PPP) with normal platelet-rich plasma (PRP) (PPP/PRP = 2/1) resulted in a complete inhibition of RIPA, suggesting the presence of vWF inhibitor in her plasma. Treatment with prednisolone (40 mg/day) started and the bleeding tendency gradually improved. One month later, all of the laboratory data including aPTT, bleeding time, RIPA and vWF:RCo became normal. These findings indicate that she has an acquired type 3-like vWS associated with SLE.

Topics: Adolescent; Deamino Arginine Vasopressin; Female; Hemorrhage; Humans; Lupus Erythematosus, Systemic; Prednisolone; von Willebrand Diseases

Topics: Carcinoma, Papillary; Carcinoma, Renal Cell; Deamino Arginine Vasopressin; Female; Hemorrhagic Disorders; Humans; Hyponatremia; Kidney Neoplasms; Laparoscopy; Middle Aged; Neoplasms, Multiple Primary; Nephrectomy; Postoperative Complications; Seizures; Thyroid Neoplasms; Thyroidectomy; von Willebrand Diseases

The exact function of the carbohydrate component of von Willebrand factor (VWF) is unknown. ABO blood group antigens are present as integral structures on the oligosaccharide side chains and it has long been recognised that ABO blood group is a determinant of VWF levels. The mechanism for this is not known. Using a monoclonal antibody against the A-antigen, we investigated the presence of this antigen on VWF from plasma, platelets, human umbilical vein endothelial cells (HUVEC) and saphenous vein endothelial cells. Initial studies on plasma VWF revealed that 23.5% of samples appeared to be negative for the A-antigen. This was shown to correlate with the A2 subtype of the A-antigen (p < 0.01). Analysis of intracellular VWF from saphenous vein endothelial cells revealed low levels of A-antigen to be present in comparison to the corresponding plasma VWF. In contrast, VWF from platelets and HUVEC gave no detectable A-antigen. However, within 1 h of administration of DDAVP to type 1 VWD patients, there was a > 2-fold increase in the A-antigen/VWF: Ag ratio for VWF in the plasma. In vitro experiments with serum N-acetlygalactosaminyltransferase failed to demonstrate any addition of A-antigen to platelet or HUVEC VWF. These data are consistent with heterogeneity in the content of A-antigen on VWF from different physiological compartments. Also, they are consistent with either a change in the A-antigen content of VWF after release from the intracellular compartment or a difference in the intracellular addition of A-antigen to VWF by endo thelium from different vascular beds.

Topics: ABO Blood-Group System; Antibodies, Monoclonal; Blood Platelets; Deamino Arginine Vasopressin; Endothelium, Vascular; Humans; Plasma; Saphenous Vein; Umbilical Veins; von Willebrand Diseases; von Willebrand Factor

We describe a von Willebrand disease (VWD) variant characterized by low plasma and platelet von Willebrand factor (VWF), impaired ristocetin-induced VWF binding to platelet glycoprotein Ib (GPIb), and abnormal VWF multimer pattern not associated with the absence of large forms. A C-to-T transition at nucleotide 4120 in exon 28 of the VWF gene was found; this mutation introduces a cysteine at the codon for Arg 611 of mature VWF. In addition to the decreased factor VIII (FVIII) and VWF levels, ristocetin-induced platelet aggregation (RIPA) was almost absent, and VWF ristocetin cofactor activity (VWF:RCo) was significantly more decreased than VWF antigen. The patients (mother and son) also showed a defect in VWF collagen-binding activity. Plasma VWF multimers were decreased, with no limit in the size of large forms, and the normal discontinuous multimer organization was replaced by a diffuse smear, especially detectable in the large forms. This picture was emphasized by 1-deamino-8-D -arginine vasopressin (DDAVP) infusion, so that the abnormal VWF multimers appeared to have a molecular weight higher than those present in, or released by, human umbilical vein endothelial cells. DDAVP also increased FVIII and VWF levels but did not normalize the GPIb-dependent VWF functions expressed as RIPA and VWF:RCo. We include this variant in type 2M VWD, focusing on the abnormality in GPIb-dependent VWF function. We advance that this defect depends on the mutation in the GPIb binding domain of VWF rather than the abnormal VWF multimer pattern.

Topics: Adult; Anti-Bacterial Agents; Cells, Cultured; Collagen; Deamino Arginine Vasopressin; Endothelium, Vascular; Factor VIII; Family Health; Female; Hemostatics; Humans; Male; Middle Aged; Molecular Weight; Platelet Aggregation; Point Mutation; Polymers; Ristocetin; Umbilical Veins; von Willebrand Diseases; von Willebrand Factor

The capability of von Willebrand factor (VWF) to bind platelet glycoprotein Ib (GPIb) and promote platelet plug formation is currently evaluated in vitro using the ristocetin co-factor activity (VWF:RCo) assay. The replacement of this cumbersome and not always reproducible test with the collagen binding activity of VWF (VWF:CBA) has been attempted with controversial results. To evaluate the capacity of VWF:CBA to identify classic and variant von Willebrand disease (VWD) compared with VWF:RCo, we studied 10 type 2A and 12 type 2B VWD patients, together with 30 type 1 VWD patients with reduced platelet VWF content. In both 2A and 2B VWD, VWF:CBA and VWF:RCo were decreased, but that of VWF:CBA was more consistent. The difference was more evident when values were expressed as a ratio, obtained by normalizing VWF:CBA and VWF:RCo with the VWF antigen value; the ratio for VWF:CBA was always below 0.2, while that for VWF:RCo was greater than 0.4, and in no patient was the VWF:CBA value higher than VWF:RCo. In contrast, in type 1 VWD, the decrease in VWF:CBA was similar to that seen in VWF:RCo with the ratios always within the normal range. To better investigate the relationship between VWF:CBA and VWF:RCo, and the representation of large/intermediate VWF multimers, to which both tests are sensitive, 1-deamino-cys-8-D-arginine-vasopressin (DDAVP) was infused in type 2A and 2B VWD patients. The differences between the two tests were even more evident after DDAVP, and in type 2A, even though large multimers were persistently decreased, VWF:RCo was normalized, while VWF:CBA remained defective. These findings clearly indicate that VWF:CBA detects the absence of large and intermediate VWF multimers better than VWF:RCo. Hence, we suggest adding VWF:CBA to the panel of tests employed in the diagnosis of VWD. Moreover, owing to the difficulty in performing VWF:RCo and its low reproducibility, we suggest that, when necessary, VWF:CBA may be substituted for VWF:RCo.

Topics: Blood Coagulation Tests; Collagen; Deamino Arginine Vasopressin; Humans; Mutation; Predictive Value of Tests; Protein Binding; Ristocetin; von Willebrand Diseases; von Willebrand Factor

We have coevaluated a combination of test processes for diagnosing von Willebrand disease (vWD) and monitoring deamino-delta-D-arginine vasopressin (DDAVP) therapy. Using normal controls (n = 23), closure time (CT) ranges measured by PFA-100(R) were (mean +/- 2SD): (i) collagen/ADP cartridge (C/ADP): 67-127 s (ii) collagen/epinephrine (C/Epi): 94-162 s. From a panel of 125 patients undergoing evaluation for clinical haemostatic defects, 29/30 samples from patients with vWD [17/18 type 1, 1/1 type 3, 3/3 type 2A, 7/7 type 2B and 1/1 pseudo-vWD] gave prolonged CTs using C/Epi. The C/ADP was less sensitive, being normal in 7/18 of the type 1 vWD individuals, with higher sensitivity to more severe vWD. Individuals with haemophilia (six factor VIII-deficient, one factor XI-deficient) gave normal CTs, while those with clinical thrombocytopenia (n=13) gave normal or prolonged CTs, somewhat dependent on platelet count. The PFA-100 was also evaluated as a part of the laboratory monitoring procedure in patients with either vWD or haemophilia undergoing a DDAVP trial as a therapeutic management process. For vWD, correction of an initially prolonged CT by DDAVP, accompanied by normalization of von Willebrand factor (vWF) measurable by von Willebrand factor antigen, vWF collagen binding activity and vWF ristocetin cofactor assays (vWF:Ag, vWF:CBA and vWF:RCof), was achieved in type 1 vWD (n=5). In an individual with type 2A vWD, DDAVP normalized vWF:Ag and vWF:RCof, but had no apparent effect on the baseline maximally prolonged CT. In an individual with type 2B vWD, factor VIII/vWF concentrate also normalized vWF:Ag and vWF:RCof, but similarly had no apparent effect on the baseline maximally prolonged CT. vWF:CBA did not normalize for either of these individuals, potentially suggesting that normalization of vWF:CBA might be required for normalization of CT. This concept is supported by correlation analysis undertaken between CT and various vWF parameters. Among these, vWF:CBA held the strongest relationship in our data set, which showed an inverse progressive rise in CT for falling vWF:CBA. Based on these results, we would conclude that the PFA-100 is highly sensitive to the presence of vWD, and may thus provide a valuable screening test for vWD. Furthermore, the combined utility of the PFA-100 and vWF:CBA as markers of DDAVP responsiveness may prove to be simple, quick but powerful, predictors for its clinical efficacy.

Topics: Blood Protein Disorders; Case-Control Studies; Clinical Laboratory Techniques; Deamino Arginine Vasopressin; Drug Monitoring; Factor VIII; Hemostatics; Humans; Platelet Function Tests; Reference Values; Sensitivity and Specificity; von Willebrand Diseases

Topics: Adult; Blood Coagulation; Colonic Polyps; Deamino Arginine Vasopressin; Gastrointestinal Hemorrhage; Humans; Sigmoid Neoplasms; Sigmoidoscopy; von Willebrand Diseases

Von Willebrand Factor (vWF) is essential for normal haemostasis involving platelet aggregation induced by high shear forces. In vitro a functional test of platelet aggregation using the filterometer is abnormal in von Willebrand's disease. However in normal people there is no significant correlation between the antigenic assay of vWF and the filter results. To study this discrepancy normal blood before and during venous occlusion, and blood before and after infusion of 1 deamino-(8-D-arginine) vasopressin was studied. During venous occlusion (VO) the increase in vWF due to the release of large multimers correlated precisely with the increase in the filterometer results. That this was due to the plasma vWF and not to any change induced in the platelets was shown as follows: The methodology was altered so that a small amount of the donor's platelet-poor plasma (PPP) was added to homologous normal substrate blood. The effect of the added donor's PPP was then shown to be closely correlated to the increase in the antigenic assay. Analysis of vWF multimer size showed during VO an increase in large multimers. We conclude that the effect of vWF on normal blood may be obscured by variation in platelet aggregability. In the filterometer system as elsewhere the large active multimers probably play a major part in causing platelet adhesion, aggregation and filter blocking. The filterometer test is influenced by the amount of vWF antigen, by the molecular size and activity of the vWF and by platelet sensitivity. Clinically this is a useful global test.

Topics: Adult; Aged; Aged, 80 and over; Antigens; Case-Control Studies; Constriction, Pathologic; Deamino Arginine Vasopressin; Dimerization; Female; Filtration; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Function Tests; Stress, Mechanical; Veins; von Willebrand Diseases; von Willebrand Factor

Acquired von Willebrand syndrome (AvWS) has been reported in eight children with Wilms tumor (nephroblastoma in four boys and four girls) at a mean age of 3.3 years (range, 0.33-9 years). Only three of eight patients with AvWS in Wilms tumor presented with mild mucocutaneous bleeding symptoms. The AvWS in seven children with Wilms tumor featured either undetectable or very low von Willebrand factor antigen (vWF.Ag) levels (mean, 3%) and decreased values for vWF ristocetin cofactor (RCF) activity (mean, 20%) and factor VIII coagulant (VIIIc) activity (mean, 16%). The response to 1-desamino-8-arginine vasopressin (DDAVP) was good in two and poor in one patient. Multimeric analysis of the vWF showed a normal pattern of type I von Willebrand disease (vWD) in three patients and an absence of multimers consistent with type III vWD in two patients. The higher functional levels, as compared with antigen levels, with increased ratios for factor VIIIc/vWFAg (mean, 5.3) and vWF.RCF/vWF.Ag (mean, 6.6) in seven patients with Wilms tumor are unexplained physiologically and are not consistent with type I vWF deficiency. The absence of vWD in the patient's family, and the return of factor VIII-vWF parameters to normal after chemotherapy or surgical removal of the Wilms tumor, support the diagnosis of AvWS causally related to the Wilms tumor. The causative agent is thought to be hyaluronic acid secreted by nephroblastoma cells of the Wilms tumor. Prospective studies to determine the nature of AvWS in children with Wilms tumor are warranted.

Topics: Child; Child, Preschool; Deamino Arginine Vasopressin; Factor VIII; Female; Genetic Variation; Hemorrhage; Humans; Hyaluronic Acid; Infant; Male; Neuroblastoma; Treatment Outcome; von Willebrand Diseases; von Willebrand Factor; Wilms Tumor

Acquired von Willebrand syndrome (AvWS) in systemic lupus erythematodes (SLE) is caused by autoantibodies directed against the circulating von Willebrand factor (vWF)/factor VIII (FVIII) complex. The autoantibody-vWF/FVIII antigen complex is cleared rapidly from the circulation, leading to a moderate to severe quantitative and qualitative deficiency of both vWF and FVIIIc. Consequently, AvWS in SLE is featured by a prolonged bleeding time and normal platelet count, a prolonged activated partial thromboplastin time (APTT) and normal prothrombin time (PT), decreased or absent ristocetin-induced platelet aggregation (RIPA), and type II vWF deficiency on multimeric analysis of the vWF protein. Acquired von Willebrand syndrome type II in SLE responds poorly to 1-desamino-8-D-arginine vasopressin (DDAVP) and FVIII concentrate, but responds transiently well to high-dose gammaglobulin given intravenously. All reported cases of AvWS in SLE were cured by appropriate treatment of the underlying autoimmune disease with prednisone or immunosuppression.

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents; Deamino Arginine Vasopressin; Factor VIII; Female; Hemorrhage; Hemostatics; Humans; Lupus Erythematosus, Systemic; Male; Middle Aged; Prednisone; Severity of Illness Index; Treatment Outcome; von Willebrand Diseases

A guide for the dental management of the three inherited bleeding disorders, von Willebrand's disease, haemophilia A and haemophilia B, was established jointly by the Institute of Medical and Veterinary Science Transfusion and Haemostasis Unit in conjunction with the Medically Compromised Dental Unit at the Adelaide Dental Hospital. This protocol was subjected to a successful trial for 24 months.

Topics: Adolescent; Adult; Aged; Antifibrinolytic Agents; Clinical Protocols; Deamino Arginine Vasopressin; Dental Care for Chronically Ill; Factor IX; Factor VIII; Hemophilia A; Hemophilia B; Hemostatics; Humans; Middle Aged; Oral Hemorrhage; Postoperative Care; Tranexamic Acid; von Willebrand Diseases

The optimal treatment of patients with von Willebrand's disease (vWD) remains to be defined. Moreover, it has not been firmly established which, if any, commonly measured parameters of von Willebrand factor (vWF) protein in the plasma are useful in guiding treatment. To better understand what guidelines physicians follow in the management of vWD, we surveyed 194 North American physicians who are members of the Hemophilia Research Society. Ninety-nine per cent of responding physicians depend on factor VIII (FVIII):C, vWF:RCo activity and vWF:AG to diagnose vWD, while only 49% use the bleeding time. The minimal goals of treatment for patients undergoing major surgery/trauma or central nervous system haemorrhage were FVIII:C and vWF:RCo activity greater than 80% while levels of more than 50% for minor surgery and dental extractions were considered adequate. Treatment of vWD was based on the type of vWD with type 1 patients being treated most often with desmopressin acetate (DDAVP) alone, types 2A and 2B patients with a combination of DDAVP and a vWF-containing FVIII product, type 3 patients with vWF-containing concentrate. Viral infections, including human immunodeficiency virus, hepatitis A, B and C viruses, and parvovirus have been seen in vWD and the efficacy of viral attenuation processes is a major criterion for the selection of treatment by physicians. Based on this survey, prospective studies need to be designed to address the clinical efficacy, safety and predictive value of laboratory monitoring of patients with vWD.

Topics: Ambulatory Care Facilities; Data Collection; Deamino Arginine Vasopressin; Disease Management; Factor VIII; Hemorrhage; Humans; Infections; North America; Partial Thromboplastin Time; Societies, Scientific; von Willebrand Diseases; von Willebrand Factor

A patient with von Willebrand's disease had recurrent gastrointestinal bleeding from angiodysplasia, with inadequate response to von Willebrand factor substitution, medical and endoscopic treatment, and resection of affected bowel. Frequent blood transfusions were required. She started home treatment with recombinant activated factor VII (rFVIIa) at the onset of bleeding, in addition to her standard therapy. From then on, bleeds could be controlled rapidly and no more blood transfusions were needed. We conclude that rFVIIa is effective in this case of angiodysplasia and might be a therapeutic option in similar patients.

Topics: Angiodysplasia; Blood Transfusion; Combined Modality Therapy; Deamino Arginine Vasopressin; Estrogens; Factor VIIa; Factor VIII; Female; Gastrointestinal Hemorrhage; Gastroscopy; Humans; Iron; Jejunal Diseases; Melena; Middle Aged; Omeprazole; Recombinant Proteins; Recurrence; Tranexamic Acid; Treatment Outcome; von Willebrand Diseases; von Willebrand Factor

Topics: Antifibrinolytic Agents; Contusions; Deamino Arginine Vasopressin; Diagnosis, Differential; Female; Hemorrhage; Hemostatics; Humans; Male; Societies, Medical; von Willebrand Diseases

An analysis was conducted in four members of the same family, two of whom had a history of severe bleeding associated with type 2B von Willebrand's disease (VWD) which, although found to be due to the same mutation, nevertheless exhibited different phenotype patterns in the two subjects involved. Von Willebrand's factor (VWF) multimers were assayed with high- and low-resolution sodium dodecyl sulfate (SDS) agarose gels. The patients were studied before and after intravenous administration of desmopressin (DDAVP) at doses of 0.4 microg/kg body weight. Automatic sequencing techniques were used to analyze VWF gene exon 28. The propositus presented with mild basal thrombocytopenia with ristocetin-induced platelet aggregation (RIPA) at low concentrations of ristocetin. He had a very prolonged bleeding time (BT), and his plasma VWF was found to be lacking in large and intermediate multimers. Thrombocytopenia was observed to intensify transiently after the administration of DDAVP. The propositus' mother, in contrast, presented reduced RIPA while in a basal state, with only partial loss of the high molecular weight VWF multimers. Although she had a very prolonged BT, her platelet count was borderline. Transient correction of BT and a decrease in the platelet count were observed after administration of DDAVP and RIPA was observed at low concentrations of ristocetin. Exon 28 sequencing revealed a G4196A-->Val1316Met mutation in both patients. No other abnormality was detected within this exon. Val1316Met has been reported in type 2B VWD. In conclusion, in the family presented here, the phenotype pattern in one patient was typical of type 2B VWD, whereas the pattern in his mother was closer to type 2A VWD. After administration of DDAVP, however, a type 2B phenotype could be clearly attributed to both, indicating that this drug can be a useful tool for elucidating ambiguous phenotypes.

Topics: Adult; Amino Acid Substitution; Case-Control Studies; Deamino Arginine Vasopressin; DNA Mutational Analysis; Family Health; Genetic Heterogeneity; Humans; Male; Mutation; Pedigree; Phenotype; Platelet Function Tests; Thrombocytopenia; von Willebrand Diseases

Despite the intensive clinical use of 1-deamino-8-D-arginine vasopressin (desmopressin; DDAVP) for 20 years, its mechanism of action is still not completely explained. It has been proposed that DDAVP stimulates release of a 'second messenger' which in turn stimulates release of von Willebrand factor (vWF) from endothelial cells. Platelet-activating factor (PAF) and interleukin (IL)-6 were individually proposed to be mediators for haemostatic action. The aim of this study was to investigate cellular-based PAF levels in patients with haemophilia A (HA) and von Willebrand disease (vWD) before and after DDAVP treatment and also to look for any probable relationship between the haemostatic response of DDAVP and cellular PAF activities. In total, 20 patients (11 HA and nine vWD) were enrolled in the study. DDAVP was given subcutaneously as a single dose (0.3 microg kg(-1)). Ten patients responded to DDAVP and were defined as the 'able group' (four mild HA, six type 1 vWD). The remaining 10 patients did not respond to DDAVP and were defined as the 'unable group' (seven severe HA, three type 3 vWD). Released (extracellular) and intracellular (intraleucocyte) PAF levels under the stimulation of specific agents (A23187 and Zymosan) were measured by high-performance liquid chromatography and radioimmunoassay. Extracellular and intracellular PAF activities were not detected without stimulation in healthy children whereas significantly higher PAF levels were found in the patients (extracellular: 37.5 +/- 34.4 ng per 10(7) cells; intracellular: 24.8 +/- 23.5 ng per 10(7) cells; P=0.0001). Intracellular PAF levels obtained from in vitro unstimulated cells were significantly higher in DDAVP-responsive (able) patients in comparison to DDAVP-unresponsive (unable) patients (52.1 +/- 18.5 vs. 28.9 +/- 8.0 ng per 10(7)cells). After in vitro stimulation by A23187, intracellular PAF activities were significantly higher in patients than in controls (209.3 +/- 26.1 vs. 172 +/- 18.1 ng per 10(7) cells). Intracellular PAF levels obtained from in vitro stimulated cells by A23187 were also significantly higher in the 'able' patients in comparison to the 'unable' patients (277 +/- 43.5 vs. 225 +/- 30 ng per 10(7)cells). In conclusion, cellular PAF activities are significantly higher in patients with HA and vWD. We also suggest that PAF, especially intracellular PAF mediates intracellular signalling and may be one of the important mediators for the haemostatic response of DDAVP.

Topics: Adolescent; Adult; Calcimycin; Child; Child, Preschool; Deamino Arginine Vasopressin; Female; Hemophilia A; Hemostatics; Humans; Ionophores; Leukocytes; Male; Platelet Activating Factor; Treatment Outcome; von Willebrand Diseases

A collagen type III based collagen-binding assay was developed for measuring the functional activity of the von Willebrand factor. The assay had a low coefficient of variance (4.8%) for normal values under optimized conditions. The results of the collagen-binding activity (CBA) assay correlated with ristocetin cofactor activity tested in normal plasma samples (n=29). We found that the CBA of blood group O is lower than that of other blood groups. The test was used for the diagnosis of von Willebrand's disease (VWD) and for estimating the response to treatment with DDAVP (1-deamino-D-arginine-8 vasopressin) and factor VIII concentrate. A mean ratio of VWF antigen (VWF:Ag) to CBA of 1.5 indicated type 1 and of 2.7 indicated type 2 VWD. The increase in the collagen-binding activity of VWF released in type 1 VWD patients (n=7) after treatment with DDAVP was higher than the increase in the VWF antigen; this is characteristic of very high multimers with greater functional activity. Factor VIII concentrate Koate-HP (Bayer) administered to a patient with VWD type 3 had a mean residence time of 12.6 h for VWF:Ag and 11.2 h for CBA. These findings suggest that the collagen-binding assay is a useful test for measuring the functional activity of VWF in plasma samples, factor VIII concentrates, as well as for estimating the outcome of treatment.

Topics: Collagen; Deamino Arginine Vasopressin; Enzyme-Linked Immunosorbent Assay; Factor VII; Humans; Reference Values; von Willebrand Diseases; von Willebrand Factor

A 67-year-old man with von Willebrand's disease, was referred to our hospital for operation of the lung cancer. He underwent right upper lobectomy of the lung and mediastinal lymph node dissection under general anesthesia. Three days before surgery, 1-desamino-8-D-arginine-vasopressin (DDAVP) was infused with good response of bleeding time shortening from 6 minutes to 3 minutes. Therefore, immediately before operation, DDAVP was infused. During the operation bleeding tendency was observed. Heat-treated factor VIII concentration and fresh frozen plasma were administered. Bleeding tendency was controlled. Total blood loss was 613 ml. During intraoperative and postoperative period, factor VIII activity and von Willebrand factor (vWF) activity were kept at adequate levels (factor VIII: 105-150%; vWF: 65-225%). The postoperative course was uneventful and he was discharged 18 days after the operation.

Topics: Aged; Anesthesia, General; Deamino Arginine Vasopressin; Factor VIII; Humans; Lung Neoplasms; Lymph Node Excision; Male; Perioperative Care; Pneumonectomy; von Willebrand Diseases

Topics: Carcinoma, Hepatocellular; Combined Modality Therapy; Deamino Arginine Vasopressin; Endothelium, Vascular; Fatal Outcome; Female; Humans; Immunosuppression Therapy; Liver; Liver Neoplasms; Liver Transplantation; Middle Aged; Recurrence; Remission Induction; von Willebrand Diseases; von Willebrand Factor

A 42-year-old female with von Willebrand's disease was managed with desmopressin and tranexamic acid to aid haemostasis following a vaginal hysterectomy. Severe acute hyponatraemia (134 to 108 mmol/l) developed over two days, culminating in a generalized tonic-clonic seizure and cerebral oedema. Fluid restriction, cessation of desmopressin and hypertonic saline administration led to a full recovery. Desmopressin is known to reduce free water elimination and produce hyponatraemia, but its extent and rate of development in this patient was surprising. Close monitoring of serum sodium and fluid balance is recommended in these patients.

Topics: Acute Disease; Adult; Deamino Arginine Vasopressin; Female; Hemostatics; Humans; Hyponatremia; Hysterectomy; Postoperative Hemorrhage; Tranexamic Acid; von Willebrand Diseases

Twenty-four apparently unrelated Italian patients with autosomal dominant type 1 von Willebrand disease (VWD) and a clear autosomal pattern of inheritance of bleeding symptoms were screened for the C1149R and C1130F mutations. None of the patients had the C1149R mutation; three patients and four affected relatives were heterozygous for the C1130F mutation. The mutation appeared to be linked to a single haplotype, defined by five genetic markers [variable number tandem repeat (VNTR) I and II in intron 40, RsaI in exons 13 and 18 and HphI in exon 28], suggesting a founder effect. The patients responded well to desmopressin infusion. The C1130F mutation might have a dominant negative effect on the secretion of the normal protein that desmopressin would appear to overcome.

Topics: Deamino Arginine Vasopressin; Female; Founder Effect; Genes, Dominant; Genotype; Haplotypes; Hemostatics; Humans; Italy; Male; Phenotype; Point Mutation; von Willebrand Diseases; von Willebrand Factor

Von Willebrand's disease (vWD) is one of the most common inherited hemorrhagic disorders, and there have been few reports on major thoracic surgery performed in a patient with the disease. We report a vWD patient who underwent of surgical resection of lung cancer. A 67-year-old gentleman, was diagnosed to have vWD when he was an infant, but he needed no medical treatment. Abnormal shadow in the lung was detected on a mass screening chest X-ray. We performed open biopsy, which proved the shadow to be large cell cancer, and performed right upper lobectomy and lymph node dissection. We used Contact-F, monitoring factor VIII, vWD factor and factor VIII-related antigen, during and after the operation, with a successful result.

Topics: Aged; Carcinoma, Large Cell; Deamino Arginine Vasopressin; Hemostatics; Humans; Intraoperative Care; Lung Neoplasms; Lymph Node Excision; Male; Pneumonectomy; von Willebrand Diseases

Desmopressin (DDAVP), a synthetic analogue of vasopressin has been successfully used in the treatment of type I von Willebrand's disease (VWD), mild factor VIII (FVIII) deficiency and intrinsic platelet function defects (PFDs) for almost three decades. However, there is limited published data documenting its efficacy and the reliability of circulating plasma FVIII:C as a surrogate marker of response to therapy in VWD. We report the haemostatic response to DDAVP in 133 consecutive patients (91 type I VWD, 20 mild FVIII deficiency and 22 PFDs). Minimal therapeutic response to DDAVP (0.3 microg/kg) was defined by normalization 30 min post- infusion of bleeding time for PFDs, factor VIII:C (FVIII:C) for mild haemophilia A, and von Willebrand factor antigen (VWF:Ag), von Willebrand factor functional activity (VWF:Ac) and FVIII:C for VWD. Nine out of 91 (10%) VWD patients failed to achieve minimal therapeutic response to DDAVP; plasma FVIII:C levels were an unreliable surrogate marker of DDAVP response as 6 out of 9 (67%) of these patients had normal post-infusion FVIII:C levels. Five out of the 20 (25%) patients with mild FVIII deficiency and 5 out of 22 (23%) patients with PFDs failed to achieve a minimal therapeutic response to DDAVP. DDAVP is an effective therapy in the majority of patients with type I VWD, PFDs and mild FVIII deficiency. The significant failure rate associated with this therapy supports the recent recommendations that response should be assessed in all patients at the time of diagnosis. FVIII:C is an unreliable guide of response to DDAVP in patients with VWD and therefore VWF:Ag and VWF:Ac should also be assessed. Failure to demonstrate the response of VWF:Ag, VWF:Ac and FVIII:C to DDAVP in patients with VWD is likely to increase the risk of haemorrhagic complications in patients with bleeding episodes or who are undergoing surgery.

Topics: ABO Blood-Group System; Adolescent; Adult; Blood Coagulation Disorders; Child; Child, Preschool; Deamino Arginine Vasopressin; Dose-Response Relationship, Drug; Female; Hemophilia A; Hemostatics; Humans; Male; von Willebrand Diseases

Intra-arterial desmopressin caused dose and time dependent increases (p <0.001 for all) in forearm blood flow (all doses) and plasma tissue plasminogen activator (t-PA) concentrations (desmopressin > or = 70 ng/min). Although plasma t-PA concentrations rose in both forearms, there was a modest local release of t-PA in the infused forearm (14 ng/100 mL of tissue/min, p <0.05). At desmopressin doses > or = 300 ng/min, plasma von Willebrand factor (vWf) and Factor VIII:C concentrations rose in both forearms (p <0.001) and correlated with the rise in interleukin-6 concentrations (r = 0.92, p <0.001: r = 0.85, p = 0.002 respectively). Neither desmopressin nor substance P caused t-PA, vWf or Factor VIII:C release in the patients, although desmopressin increased plasma interleukin-6 concentrations as in healthy volunteers. We conclude that desmopressin releases t-PA, vWf and Factor VIII:C predominantly via systemic mechanisms, possibly mediated by cytokine release. Patients with type 3 vWD appear to have a generalised failure to release t-PA acutely despite a normal interleukin-6 response to desmopressin infusion.

Topics: Adult; Deamino Arginine Vasopressin; Dose-Response Relationship, Drug; Factor VIII; Forearm; Hemodynamics; Humans; Infusions, Intra-Arterial; Interleukin-6; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Substance P; Time Factors; Tissue Plasminogen Activator; von Willebrand Diseases; von Willebrand Factor

Topics: Deamino Arginine Vasopressin; Factor VIII; Female; Hemorrhage; Heterozygote; Humans; Mutation, Missense; Phenotype; Point Mutation; Postpartum Hemorrhage; Pregnancy; Pregnancy Complications, Hematologic; von Willebrand Diseases; von Willebrand Factor

Topics: Adult; Anesthesia, Epidural; Anesthesia, Obstetrical; Anti-Bacterial Agents; Contraindications; Deamino Arginine Vasopressin; Female; Hemostatics; Humans; Pregnancy; Pregnancy Complications, Hematologic; Ristocetin; von Willebrand Diseases; von Willebrand Factor

A variety of haemostatic agents can be helpful for patients with von Willebrand disease in case of bleeding. There are orally administered substances, such as tranexamic acid, oestrogens and prednisone; agents for topical or local use; and medicines for injection or infusion, including desmopressin, blood plasma products and recombinant activated factor VII. The choice depends on the type of haemorrhage, the severity of the disease, presence of inhibitors, availability and cost. Some of these aspects are reviewed here.

Topics: Blood Transfusion; Deamino Arginine Vasopressin; DNA, Recombinant; Factor VII; Hemostasis; Hemostatics; Recombinant Proteins; von Willebrand Diseases

Haemostatic treatment in patients with von Willebrand disease (vWD) in connection with surgery aims at normalizing the haemostatic defect in order to avoid bleeding complications. Factor VIII (FVIII) levels in plasma must be normalized in connection with major surgery, whereas the bleeding time is more important for mucous membrane bleedings. Most patients respond well to treatment with desmopressin which stimulates the endogenous release of FVIII and von Willebrand factor (vWF) and shortens the bleeding time. Non-responders to desmopressin are substituted with a plasma-derived factor concentrate which contains vWF and FVIII. This paper includes a summary of retrospective data from the last 10 years on haemostatic treatment in connection with surgery from four haemophilia centres in Sweden and Denmark on 40 invasive procedures in 27 vWD patients and on one normal delivery. If a FVIII-containing concentrate is given prior to surgery a dose of 30-40 IU VIII:C kg(-1) will normalize FVIII levels in most severe cases. If a pure vWF concentrate is used, a dose of 40-50 IU RCoF kg(-1) will normalize RCoF in most cases, but FVIII levels will not be normalized until after about 12 h or later. Repeated doses of FVIII-vWF concentrate may lead to very high levels of FVIII in plasma because of the combined effect of the exogenous FVIII-substitution and the endogenous FVIII-release induces by the infused vWF. Dosage should be adjusted according to FVIII levels in plasma.

Topics: Blood Loss, Surgical; Deamino Arginine Vasopressin; Factor VIII; Hemostatics; Humans; von Willebrand Diseases; von Willebrand Factor

A case of idiopathic immune-mediated von Willebrand's disease (AvWD) associated angiodysplasia and recurrent lower gastrointestinal bleeding is reported. Coagulation parameters at presentation were activated partial thromboplastin time of 41 sec, bleeding time >15 min, factor VIII procoagulant activity, 5%; von Willebrand factor antigen (WF:Ag) 5%, and vWF:ristocetirn cofactor activity 11% sodium dodecyl sulfate-agarose gel electrophoresis pattern of plasma vWF showed a pattern similar to type II vWD. An in vitro inhibitor against vWF in the immunoglobulin (Ig)G fraction of the patient's plasma was demonstrated vWF parameters showed a short-lived increase after 1-deamino-8-D-arginine vasopressin (DDAVP) administration. The patient's bleeding episodes were initially managed adequately with cryoprecipitate replacement therapy and DDAVP, to which she became refractory. No significant improvement was achieved following the institution of immunosuppressive therapy in the form of high-dose steroids and cyclophosphamide. She was then treated with intravenous immunoglobulin (IvIg) to which she showed an adequate response in terms of her clinical situation and her hemostatic parameters. The patient is on maintenance treatment with repeated courses of IvIg based on vWF parameter monitoring. To our knowledge, this is the third reported association between idiopathic immune-mediated AvWD and angiodysplasia.

Topics: Aged; Angiodysplasia; Autoantibodies; Bleeding Time; Deamino Arginine Vasopressin; Electrophoresis, Polyacrylamide Gel; Factor VIII; Female; Gastrointestinal Hemorrhage; Humans; Immunoglobulin G; Immunoglobulins, Intravenous; Metabolic Clearance Rate; Partial Thromboplastin Time; von Willebrand Diseases; von Willebrand Factor

Thrombocytopenia is frequently reported in type 2B von Willebrand disease (vWD), and thought to be related to the abnormally high affinity of 2B von Willebrand factor (vWF) for platelet GPIb-IX. To gain an insight into the nature of this thrombocytopenia, we measured plasma glycocalicin (GC) levels (as a marker of platelet turnover), and platelet surface expression of the alpha granule protein P-selectin (as a marker of platelet activation) in 9 patients with type 2B vWD before, and in 4 patients also following the infusion of 1-desamino-8-d-arginine vasopressin (DDAVP). Three patients presented a persistent decrease of platelet counts in the resting condition. GC levels were within the normal range, regardless of the platelet counts, in all but one patient who presented, on the other hand, a normal platelet count. Moreover, platelets expressed normal amounts of P-selectin on their surface, regardless of platelet counts. These findings suggest that the thrombocytopenia observed in type 2B vWD is not due to platelet activation and subsequent consumption in circulation. Despite a significant, albeit transient, decrease in platelet count, DDAVP did not induce an increase in plasma GC levels, nor enhance P-selectin expression. These observations indicate that the acute post-DDAVP thrombocytopenia in type 2B vWD is not related to platelet activation and consumption. We advance that the post-DDAVP 2B vWF is hemostatically more active, and able to induce agglutination but not aggregation of circulating platelets. This would explain both the prompt recovery of basal platelet counts after the post-DDAVP decrease, and the lack of reported thrombotic complications in this disorder. Therefore, even though 2B vWF is characterized by an enhanced affinity for the platelet surface, its binding to platelet GPIb-IX in the soluble phase is not able to induce true platelet aggregation: vWF thus appears to be mainly an adhesive protein, rather than an aggregating agent.

Topics: Adult; Aged; Contraindications; Deamino Arginine Vasopressin; Female; Hemostatics; Humans; Male; Middle Aged; P-Selectin; Platelet Activation; Platelet Count; Platelet Glycoprotein GPIb-IX Complex; Platelet Membrane Glycoproteins; Receptors, Cell Surface; Thrombocytopenia; von Willebrand Diseases; von Willebrand Factor

We developed a new method for the detection of large von Willebrand factor (vWf) multimers binding to collagen and for the determination of vWf antigen (vWf:Ag) using flow cytometry. Collagen is coated on to polystyrene beads, allowing detection of found large vWf multimers. In addition, rabbit antibody against vWf is coated on to the beads allowing detection of all vWf:Ag. In plasma samples from healthy persons and patients (with type 1, 2A, 2N, or severe von Willebrand disease or hemophilia), 4 different assays were performed: vWf:Ag by immunoelectrophoresis; vWf ristocetin cofactor (vWf:RCof); CBA; and vWf:Ag based on an enzyme-linked immunosorbent assay using polystyrene beads. We assayed the flow cytometric method using 2 bead sizes. The optimal bead size was 3.136 microns. The results of CBA and vWf:Ag closely correlated with those of vWf:RCof and vWf:Ag (immunoelectrophoresis), respectively, and showed a low limit of detection. Interassay variance of cytometric methods was lower than interassay variance of traditional assays. In addition, we used the new assays to monitor desmopressin therapy.

Topics: Animals; Collagen; Deamino Arginine Vasopressin; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Hemophilia A; Humans; Immunoelectrophoresis; Microspheres; Molecular Weight; Polystyrenes; Protein Binding; Rabbits; Reference Values; Sensitivity and Specificity; von Willebrand Diseases; von Willebrand Factor

Topics: Adolescent; Deamino Arginine Vasopressin; Female; Humans; Nursing Assessment; von Willebrand Diseases

A 26 year old woman presented to the accident and emergency department with a painful right elbow. There had been no history of trauma. Clinical examination suggested an effusion, which was confirmed on radiological examination. Her elbow was aspirated and revealed a haemarthrosis. Subsequent investigations revealed a diagnosis of von Willebrand's disease (vWD). A spontaneously occurring effusion of the elbow may be due to a haemarthrosis. Aspiration of blood in the absence of trauma may lead to a diagnosis of an occult coagulopathy in addition to relieving pain. The diagnosis and treatment of vWD is discussed.

Topics: Acute Disease; Adult; Arthralgia; Deamino Arginine Vasopressin; Diagnosis, Differential; Elbow Joint; Female; Hemarthrosis; Hemostatics; Humans; von Willebrand Diseases

Topics: Adolescent; Adult; Child; Child, Preschool; Deamino Arginine Vasopressin; Hemophilia A; Hemostatics; Humans; Platelet Activating Factor; von Willebrand Diseases

To review the effectiveness of a perioperative management protocol and our experience with a large population of patients with von Willebrand disease (vWD) who require adenotonsillar surgery (T&A).. A retrospective review of the medical records of all patients having the diagnosis of vWD who underwent T&A between January 1, 1992, and July 31, 1996.. A tertiary care, university-based children's hospital.. Patients having a preoperative diagnosis of vWD received a single intravenous dose of desmopressin acetate, 0.3 pg/kg, approximately 20 minutes before the induction of anesthesia. Beginning January 15, 1994, a standard management protocol involving the postoperative administration of fluids and electrolytes was followed.. Operative blood loss and the incidence of postoperative bleeding and of hyponatremia.. Of approximately 4800 patients who underwent T&A during the study period, 69 patients had a diagnosis of vWD. All 67 patients identified preoperatively received desmopressin; 2 were identified by postoperative workup as a result of excessive surgical bleeding. Minimal immediate postoperative bleeding was noted in 7 patients (10%), but none required intervention. Delayed bleeding occurred in 9 patients (13%); all were readmitted to the hospital for observation, 4 (6%) requiring operative cauterization. Substantial postoperative hyponatremia occurred in 3 patients, and 1 patient had seizure activity. Symptomatic hyponatremia has been avoided since a protocol of fluid and electrolyte administration was instituted.. Although T&A can be performed safely in patients with vWD, it is not without an increased risk of postoperative hemorrhage. The administration of desmopressin has been reported to reduce the risk of bleeding, but it is not without risk. A protocol for fluid and electrolyte management is recommended.

Topics: Adenoidectomy; Adenoids; Adolescent; Age Distribution; Child; Child, Preschool; Deamino Arginine Vasopressin; Female; Hemostatics; Humans; Infant; Lymphatic Diseases; Male; Postoperative Hemorrhage; Retrospective Studies; Tonsillectomy; Tonsillitis; von Willebrand Diseases

We have evaluated platelet function at high shear with the PFA-100 system in different subtypes of von Willebrand disease (vWD), before and after the intravenous infusions of desmopressin or a factor-VIII/von Willebrand factor (vWF) concentrate. Closure times with the PFA-100 system were determined for both the collagen/ADP and the collagen/epinephrine cartridges in 52 patients with vWD (9 type 1 "platelet normal", 5 type 1 "platelet-discordant", 8 type 1 "platelet-low", 6 type 2A, 9 type 2B, 6 type 2M Vicenza. 6 type 3 and 3 acquired vWD) and 40 controls. Measurements were repeated 1 and 4 h after the i.v. infusion of desmopressin (0.3 microg/Kg) in 26 patients with types 1, type 2M Vicenza or type 2A vWD, or of a factorVIII/vWF concentrate (Alphanate HT, 60 U/Kg) in 4 patients with type 3 vWD. At all time points, vWF plasma levels and the bleeding time (Symplate II) were also determined. Baseline closure times were longer in vWD patients than in controls with both the collagen/ADP and the collagen/ epinephrine cartridges. The sensitivity of the PFA-100 system (88% and 87% with the two cartridges) was higher than that of the bleeding time (65%). Treatment with desmopressin normalized the closure times in patients with type 1 "platelet-normal" or type 2M Vicenza vWD, had no significant effects in patients with type 1 "platelet-low", type 1 "platelet-discordant" or type 2A vWD. Infusion of a factorVIII/vWF concentrate in patients with type 3 vWD slightly shortened their prolonged closure times. In general, changes in PFA-100 were paralleled by shortenings of the bleeding times and increases in plasma vWF levels. The PFA-100 test reflects vWF-dependent platelet function under high shear stress and could be useful in the diagnosis and therapeutic monitoring of patients with vWD.

Topics: Blood Platelets; Deamino Arginine Vasopressin; Equipment and Supplies; Hemostatics; Humans; Infusions, Intravenous; Platelet Activation; von Willebrand Diseases; von Willebrand Factor

We have evaluated the position of the Platelet Function Analyzer PFA-100TM in the management of 41 patients with von Willebrand disease (VWD) receiving either desmopressin (23 patients with type 1, five with type 2M, three with type 2A and three with type 2B) or von Willebrand factor (VWF) concentrates (four patients with type 3, two with type 2M 'type B', two with type 2A and one type 1 'platelet low'). In all patients the following were studied before and 30 min after infusion of desmopressin and/or VWF concentrates: VWF ristocetin cofactor activity (VWFRCo), bleeding time (BT) and closure time with the PFA-100 using ADP (CT-ADP) as well as epinephrine (CT-Epi) cartridges. After the infusion of desmopressin, the CT was modified in the same way as the VWFRCo levels, being always normalized in patients with type 1 and not constantly corrected in those with type 2. Thus, our results indicated that the measurement of the CT enabled a quick and accurate evaluation of the response to desmopressin which, in fact, measured the releasable VWF cellular compartment containing the highly multimerized forms of VWF. For patients with type 2 or 3 VWD who were non-responsive to desmopressin, VWF concentrates corrected the VWFRCo defect but not the CT as none of these patients had a normal platelet VWF content and the VWF concentrates did not contain the ultralarge VWF multimers. In conclusion, the very high shear conditions in the PFA-100 make it very sensitive to the contribution of platelet VWF and to the ultralarge VWF multimers, indicating that the evaluation of the CT is a very simple and rapid tool to discriminate between good and non-responders to desmopressin.

Topics: Adolescent; Adult; Bleeding Time; Child; Child, Preschool; Deamino Arginine Vasopressin; Female; Hemostatics; Humans; Male; Middle Aged; Platelet Function Tests; Sensitivity and Specificity; von Willebrand Diseases; von Willebrand Factor

In 1997 the UK Haemophilia Centre Directors Organization published the guidelines for diagnosis and management of von Willebrand disease (vWD). The guidelines stated that desmopressin (DDAVP) should be used in type 1 and type 2N vWD, that it might be useful in other types 2 vWD and that it is ineffective in type 3 vWD. If patients are unresponsive to DDAVP or if it is contraindicated, the treatment of choice is clotting factor concentrates (CFC). In the light of these guidelines, we audited our practice for 1997. Furthermore, we undertook a retrospective review of the changing patterns of treatment of vWD between 1980 and 1997. During 1997, 10 patients with vWD received DDAVP and another 30 patients were treated with CFC (a total of 1.2 million IU): Haemate P (Centeon, Germany) and/or 8Y (BPL, Elstree, UK). Few patients had clear contraindications to DDAVP, but several patients with type 1 and 2 vWD received CFC on the basis of age or reduced levels of von Willebrand factor - where DDAVP was considered suboptimal for adequate haemostasis. However, this assumption was made without a preliminary test dose to assess the response to DDAVP. The analysis of treatment of vWD for the past 17 years showed that cryoprecipitate was discontinued from use in the early 1990s and that both DDAVP and CFC usage has been on the increase. In conclusion, the audit illustrated a general good adherence to guidelines but it highlighted the need for a DDAVP test before using CFC.

Topics: Blood Coagulation Factors; Deamino Arginine Vasopressin; Humans; Medical Audit; Practice Guidelines as Topic; United Kingdom; von Willebrand Diseases; von Willebrand Factor

Topics: Child, Preschool; Deamino Arginine Vasopressin; Diagnosis, Differential; Genetic Markers; Hemostatics; Humans; Male; Purpura, Thrombocytopenic, Idiopathic; von Willebrand Diseases

von Willebrand disease (vWD) type 2M is characterized by the decreased platelet-dependent function of the von Willebrand factor (vWF) that is not caused by the absence of HMW vWF multimers. We report here on a 4-year-old boy with vWD type 2M, who underwent adenotomy and paracentesis after correction of his hemostatic defect by stimulation with DDAVP. The decreased basal levels of vWF Antigen (Ag), ristocetin cofactor activity (RiCoF) and collagen binding activity (CBA) (32%, 14% and 9% respectively) could be stimulated to maximum levels of 69%, 70% and 95% 2 h post DDAVP administration. DDAVP was administered in a dosage of 0.4 microg/kg BW intravenously 30 min prior to surgery. No bleeding occurred intra- and perioperatively. vWF multimer analysis revealed supranormal multimers with an abnormal satellite banding pattern. The typical separation by gel electrophoresis into oligomers with a triplet structure was missing even after stimulation with DDAVP. Thus, the functional hemostatic defect was corrected in this patient after DDAVP administration, although the structural abnormalities of the vWF multimers were still persisting.. In conclusion, type 2M vWD might be effectively treated with DDAVP administration in cases of elective surgery, dispensing with vWF replacement by pooled blood products.

Topics: Blood Loss, Surgical; Child, Preschool; Deamino Arginine Vasopressin; Elective Surgical Procedures; Hemostatics; Humans; Male; Premedication; von Willebrand Diseases

Of 260 patients enrolled, 25 patients (9.6%) were associated with acquired von Willebrand syndrome (AvWS). We studied 25 patients with AvWS, retrospectively. AvWS was diagnosed by reduced levels of von Willebrand factor (vWF) (decrease of von Willebrand factor antigen [vWF:Ag] and von Willebrand ristocetin cofactor [vWF:RCoF]), a decrease of ristocetin-induced platelet agglutination (RIPA), sometimes decreased high-molecular-weight multimers, and prolonged bleeding time with neither prior nor family histories of bleeding problems and the evidence of normal vWF:RCoF in their families. The inhibitor of vWF was determined by mixing patient plasma with pooled normal plasma. Eight patients in this study had the inhibitors to vWF that were of the IgG class; the subclasses were IgG1 (7 cases) and IgG2 (1 case). Multimeric analysis of vWF showed selective loss of large multimers in most patients with AvWS similar to that of congenital type-2 von Willebrand disease (vWD). All inhibitors blocked ristocetin-mediated vWF binding to platelets. Five out of 6 IgGs evaluated here recognized the 39/34-kD fragment (residues 480/481-718) and Fragment III (residues 1-1365) that implied binding domain of glycoprotein Ib (GPIb), whereas 1 recognized Fragment I (residues 911-1365). A close relationship was found between the presence of the inhibitor and bleeding tendency. Of the 7 patients with inhibitors, 6 patients (86%) had a bleeding tendency, as well as 1 of the 15 patients without inhibitors (6%). The efficacy of treatment of underlying diseases and/or therapy with deamino D-arginine vasopressin (DDAVP) for the treatment of AvWS also depends on the presence of an inhibitor. Four of 8 patients with inhibitors (50%) had poor response to treatment of the underlying disease and/or therapy with DDAVP, as well as 1 of the 16 patients without inhibitors (6%). These results indicate that patients with AvWS developing inhibitors to vWF are likely to have bleeding problems and might be resistant to treatment of underlying diseases and/or therapy with DDAVP for bleeding to AvWS. We also showed evidence that intravenous immunoglobulin therapy (0.3 g/kg, 3 days) was effective to correct a hemostatic defect and manage severe bleeding in a patient with AvWS developing inhibitors. We might consider an additional treatment including expensive high-dose immunoglobulin therapy when uncontrollable bleeding is continued after the treatment of the underlying diseases and/or therapy with DDAVP.

Topics: Adult; Aged; Aged, 80 and over; Autoimmune Diseases; Deamino Arginine Vasopressin; Epitopes; Female; Hematologic Diseases; Hemorrhage; Humans; Immunoglobulin G; Immunoglobulins, Intravenous; Male; Middle Aged; Molecular Weight; Peptide Fragments; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIb-IX Complex; Retrospective Studies; von Willebrand Diseases; von Willebrand Factor

Topics: Adult; Canada; Deamino Arginine Vasopressin; Female; Hemophilia A; Humans; Male; Sex Distribution; Societies; von Willebrand Diseases

Desmopressin was administered intranasally to seven patients with von Willebrand disease (type 1: 4 patients, type 2A: 3 patients) to assess the response and safety. von Willebrand factor antigen ranged from 8% to 60% before treatment and increased significantly after intranasal DDAVP administration (the median relative increase: two- to threefold). Factor VIII levels also increased substantially over baseline levels after intranasal administration. Before treatment ristocetin cofactor activity was 32 +/- 12% in patients with type 1 vWD and 9 +/- 5% in patients with type 2A vWD. After intranasal administration, the levels of ristocetin cofactor activity increased to 56 +/- 21% and 29 +/- 9%, respectively. The bleeding time was normalized in 86% of the patients. The abnormality of vWF multimers in type 1 vWD returned more or less to normal after intranasal DDAVP administration whereas that in type 2A vWD did not. The intranasal administration of DDAVP is safe and effective for minor bleeding episodes and is adaptable for home use in patients with type 1 and type 2A vWD.

Topics: Administration, Intranasal; Bleeding Time; Coagulants; Crotalid Venoms; Deamino Arginine Vasopressin; Female; Humans; Male; Ristocetin; von Willebrand Diseases; von Willebrand Factor

Two patients with a long history of unexplained thrombocytopenia, eventually diagnosed with von Willebrand's disease (vWD) type 2B are reported. In one patient with platelet counts of 80 x 10(9)/l 1-desamino-8-D-arginine vasopressin (DDAVP) had a favourable effect during bleeding episodes. The second patient received intermediate purity von Willebrand's factor (vWF)/factor VIII concentrate (Haemate HS), which helped haemostasis during tooth extraction. It increased platelet counts from 15 to 30 x 10(9)/l, whereas platelet transfusions produced no increase, nor prevented severe bleeding during abdominal surgery. Thus the treatment of vWD type 2B might depend on the degree of thrombocytopenia. It is recommended that in patients with mild to moderately decreased platelet counts, DDAVP treatment can be tried, whereas in patients with severely decreased platelet counts intermediate purity vWF/factor VIII concentrate substitution is preferred. In addition, vWD type 2B should be considered in the differential diagnosis of any child with chronic thrombocytopenia as the treatment strategy is different.

Topics: Adolescent; Child; Chronic Disease; Deamino Arginine Vasopressin; Factor VIII; Humans; Male; Thrombocytopenia; von Willebrand Diseases; von Willebrand Factor

Topics: Deamino Arginine Vasopressin; Humans; von Willebrand Diseases

Topics: Deamino Arginine Vasopressin; Factor IX; Factor VIII; Hemophilia A; Humans; Italy; Practice Guidelines as Topic; Recombinant Proteins; von Willebrand Diseases

To determine the effect of 1-Deamino-8-D-arginine vasopressin on plasma concentrations of von Willebrand factor and factor VIII in Greyhound blood donors, and to compare the response of 1-Deamino-8-D-arginine vasopressin injection on plasma concentrations of von Willebrand factor between groups with different resting plasma concentrations of von Willebrand factor.. Fifteen Greyhound blood donors were used. Dogs were grouped into three categories depending on their von Willebrand factor concentrations.. Desmopressin was administered subcutaneously at 1 microgram/kg [corrected] to all dogs. Plasma von Willebrand factor and factor VIII concentrations were measured before and 10, 20, 30, 45, 60, 90 and 120 min after desmopressin injection.. The von Willebrand factor and factor VIII concentrations in all dogs increased significantly and remained higher than base-line throughout the 2 h period.. Desmopressin is useful in increasing von Willebrand factor concentrations in Greyhound blood donors, including those with low resting concentrations.

Topics: Animals; Blood Donors; Deamino Arginine Vasopressin; Dogs; Enzyme-Linked Immunosorbent Assay; Factor VIII; Hemostatics; Partial Thromboplastin Time; von Willebrand Diseases; von Willebrand Factor

While certain plasma-derived factor VIII/von Willebrand factor (FVIII/vWF) concentrates have proven to be quite useful in preventing or controlling bleeding in persons with von Willebrand disease who are not candidates for DDAVP, most of the information concerning dosage and effectiveness has been anecdotal. Additionally, the laboratory tests used to quantify vWF (the vWF:RCoF assay and collagen binding assay) are not well standardized. Thus, the US Food and Drug Administration (FDA) has been reluctant to grant licensed indication for use of these products in von Willebrand disease. This brief report describes a survey of non-US physicians (from major centres) who are recognized experts in haemophilia and von Willebrand disease. Twenty-four of 27 questionnaires were completed, returned and analysed. Products thought to be effective in von Willebrand disease included Haemate P, Facteur von Willebrand, Alphanate, and the UK's BPL '8Y'. In calculating dosage to stop or prevent bleeding, most aim for a certain level of both FVII and vWF:RCoF. Postoperatively, 16/24 respondents follow both of these laboratory tests once daily. Twenty-two of 24 would follow FVIII levels once daily. It is noteworthy that FVIII assay results are generally the only test results readily available to guide the respondents' clinical decisions. For treatment of significant mucous membrane bleeding, respondents often individualize dosage and monitoring, depending on the type, location and extent of bleeding. Gastrointestinal bleeding is generally treated more aggressively. Patient monitoring varies between merely looking for cessation of bleeding, to a battery of laboratory tests, including haemoglobin and haematocrit. Seven out of 24 would monitor BT as well. In addition to FVIII content, 22/24 respondents noted that they would find it helpful to have vWF:RCoF listed on the label, while 15/24 would like to know the vWF multimeric composition.

Topics: Deamino Arginine Vasopressin; Factor VIII; Health Care Surveys; Humans; Practice Guidelines as Topic; Surveys and Questionnaires; von Willebrand Diseases; von Willebrand Factor

A document entitled Guidelines for the Diagnosis and Management of von Willebrand's Disease was produced by the von Willebrand Working Party of the United Kingdom Haemophilia Centre Directors' Organization. Under the chairmanship of Dr Beverley Hunt, an independent board of haematologists and anaesthesiologists reviewed the use of a synthetic vasopressin analogue, desmopressin (DDAVP), in the management of patients with von Willebrand's disease. The Advisory Board considered that production of the guidelines was to be applauded, but that the contraindications for DDAVP were imprecisely defined and may thus be misleading. This paper summarizes the Advisory Board's discussion of the suggestions.

Topics: Deamino Arginine Vasopressin; Hemostatics; Humans; United Kingdom; von Willebrand Diseases

Topics: Deamino Arginine Vasopressin; Guidelines as Topic; Hemostatics; Humans; United Kingdom; von Willebrand Diseases

Topics: Administration, Inhalation; Deamino Arginine Vasopressin; Hemophilia A; Humans; von Willebrand Diseases

DDAVP is effective treatment in most types of von Willebrand's disease; however, in type 2B von Willebrand's disease the use of DDAVP has been contraindicated due to DDAVP-induced thrombocytopenia. Several reports have confirmed the thrombocytopenic effects of DDAVP and the presence of circulating platelet aggregates in type 2B von Willebrand's disease. We have infused three type 2B patients with DDAVP. The three patients had different mutations of their vWf. All three patients had a missense mutation which resulted in a single amino acid substitution in the disulfide loop of the A1 domain. Administration of 20 micrograms of DDAVP resulted in significant elevations of factor VIII, vWf antigen, and ristocetin cofactor levels. In contrast to other studies, DDAVP did not induce or enhance thrombocytopenia in these three patients. When blood was obtained by fingerstick and diluted into sodium oxalate (Unopette) or EDTA (Microvette), the platelet counts did not change over 4 hr. In contrast, blood collected directly into evacuated tubes containing sodium citrate, lithium heparin, or EDTA consistently demonstrated varying degrees of thrombocytopenia and platelet clumping. We also observed a shortening of the pre-infusion bleeding time over the 4 hr period. All three patients have been studied twice and each has shown consistent results. DDAVP appears to be a useful form of treatment in type 2B vWd.

Topics: Adult; Deamino Arginine Vasopressin; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Renal Agents; Thrombocytopenia; von Willebrand Diseases

A patient with type 2N ("Normandy" variant) von Willebrand's disease is described. Her von Willebrand factor level was borderline low, while her factor VIII was markedly decreased to 7%. Her plasma von Willebrand factor demonstrated a decreased ability to complex with factor VIII in vitro, binding less than 10% when compared to normal plasma von Willebrand factor. The factor VIII released into the circulation after the patient received DDAVP had a shortened survival in vivo. Nucleotide sequence analysis revealed a T-to-A transition at nucleotide 2451 on both alleles. This transition results in a substitution of Gln for His at amino acid 54 in the mature subunit of von Willebrand factor.

Topics: Adult; Alleles; Base Sequence; Deamino Arginine Vasopressin; Factor VIII; Female; Humans; Male; Molecular Sequence Data; Point Mutation; Protein Binding; von Willebrand Diseases; von Willebrand Factor

Topics: Deamino Arginine Vasopressin; Humans; Mutation; Thrombocytopenia; von Willebrand Diseases; von Willebrand Factor

Platelets of anticoagulated whole blood forced at 40 mmHg through a fine filter are activated, aggregated and retained, so block the filter (platelet filter test, O'Brien JR, Salmon GP. Blood 1987; 1354-1361). Our clinical experiences with this simple and quick haemostasis test are summarized. Patients were investigated with different types of vWD (type-1 = 35, type-2A = 7, type-2B = 7, type-3 = 1), Glanzmann's thrombasthenia, congenital deficiency of cyclo-oxygenase, acquired Bernard-Soulier syndrome, FXII-, FXIII-deficiency and a control group. The cumulative drop count and the platelet retention were carefully measured during two phases of the filter test. Platelet count, bleeding time, vWF:Ag and vWF:Rcof activity were measured along with the platelet filter test. The filter was not blocked and the platelet retention was abnormally low in all patients with thrombasthenia, type-2a, type-2B, type-3 vWD. Treatment with 1-desamino-8-D-arginine-vasopressin (DDAVP) caused enhanced platelet retention in 16 patients with type-1 vWD. The test is simple, quick and cheap, has good reproducibility, and may be useful in clinical haemostasis laboratories for examination of high shear induced platelet functions.

Topics: Adolescent; Adult; Aged; Deamino Arginine Vasopressin; Factor XII Deficiency; Factor XIII Deficiency; Female; Hemorrhagic Disorders; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Function Tests; Thrombasthenia; von Willebrand Diseases

The changes of the FVIII binding capacity of vWF after the infusion of FVIII/vWF concentrate was studied in two patients with type 2N vWD, and also during pregnancy in one of them. After infusion of FVIII or DDAVP to the patients, FVIII:C in plasma increased as expected, but it then decreased, with a markedly short half-life, of about 2 h, due to the defect in the FVIII binding capacity of vWF in plasma. However, after infusion of FVIII/vWF concentrate (40 U of FVIII:C/kg), FVIII:C increased, from 4-6 to 100-160 U/dl, more than the expected values, and decreased with the half-life expected. The FVIII binding capacity of vWF in plasma changed in parallel with the concentration of exogenous normal vWF, with a half-life of more than 24 h. During pregnancy, no increase of FVIII:C was observed, although vWF:Ag increased from 40 (before pregnancy) to 90 U/dl in plasma at 35th week of gestation. The FVIII binding capacity of vWF in plasma showed no increase during pregnancy. Accordingly, the administration of FVIII/vWF concentrate to the patient at delivery resulted in adequate hemostasis.

Topics: Deamino Arginine Vasopressin; Factor VIII; Female; Half-Life; Humans; Pregnancy; Pregnancy Complications, Hematologic; Protein Binding; von Willebrand Diseases; von Willebrand Factor

1-desamino-8-D-arginine vasopressin (DDAVP) increases factor VIII (FVIII) and von Willebrand factor (vWF) levels in patients with haemophilia A and in some patients with von Willebrand disease. It is generally held that the increase of FVIII is a consequence of the increase of vWF. Carriers of haemophilia A generally, but not always, show plasma FVIII levels lower than vWF due to an abnormality in one of the two alleles of the FVIII gene. We investigated the time-course of plasma FVIII:C and vWF:Ag levels in 25 obligate carriers of haemophilia A after DDAVP infusion. In carriers with a normal FVIII to vWF ratio (> 0.8), DDAVP induced a progressive ratio decrease that reached levels significantly lower than that taken as cut-off to discriminate between low and normal values (0.68 +/- 0.1 vs before 0.912 +/- 0.18). In carriers with a borderline (0.7-0.8) or reduced (< 0.7) ratio DDAVP induced a further decrease in the FVIII/vWF ratio, albeit with a different kinetic; after an initial increase, values were lower than pre-DDAVP figures. In all subjects, following the post-DDAVP peak, plasma FVIII progressively decreased while vWF contemporaneously continued to increase. In contrast, DDAVP did not induce significant changes in the FVIII/vWF ratio in normal females, and the two molecules appeared to increase similarly throughout the observation period. These findings indicate that after DDAVP, FVIII increases less or for a shorter time than vWF, also in haemophilia A carriers who have a normal FVIII/vWF ratio. Hence, DDAVP may help identify haemophilia A carriers, especially subjects with normal or borderline ratios. Even though molecular biology procedures at present are the best and more reliable tools to identify the carrier state, DDAVP seems to improve the accuracy of haemostatic parameters.

Topics: Adult; Deamino Arginine Vasopressin; Factor VIII; Female; Genetic Carrier Screening; Hemophilia A; Humans; Male; Middle Aged; Predictive Value of Tests; von Willebrand Diseases; von Willebrand Factor

Plasma von Willebrand factor (vWf) displays a complex pattern of repeating multimers, whose heterogeneous size distribution seems to depend on the proteolytic cleavage of the constituent vWf subunit. Smaller vWf multimers are thought to derive by proteolytic cleavage of the larger forms. To clarify the relationship between large multimer representation and the structure of small vWf oligomers, DDAVP was infused in patients with type-2A and -2B von Willebrand disease (vWd) variants which lack circulating high vWf forms. Before infusion, high-resolution multimer analysis demonstrated a more pronounced representation of the satellite bands of each oligomer, mainly concerning fast-moving components, especially in type 2B vWd. After DDAVP, in type-2A vWd each oligomer displayed a different organization depending on whether restoration of large vWf multimers occurred. The lack of large vWf multimer restoration, as shown in citrated samples, was associated with the fast band being significantly more represented than the slower, and almost similar to the central component. In contrast, when the high-molecular-weight vWf forms were restored, as occurred in the samples collected in the presence of protease inhibitors, the relative representation of the fast- and slow-moving bands was similar to that of normal samples. In type-2B vWd, regardless of the anticoagulant used, DDAVP infusion did not restore large vWf multimers, and each oligomer displayed a significant increase in both the central band and fast-moving satellite, the fast being even more highly represented. These findings suggest that, regardless of the origin, the disappearance of large circulating multimers in type-2A and -2B vWd induces an increased representation of the fast-moving satellite of the low-molecular-weight multimers. Moreover, the time course of large and low/intermediate multimer decrease and increase provides a further demonstration that low vWf multimers derive from the larger ones, and that mainly the fast-moving band of the oligomer is involved.

Topics: Deamino Arginine Vasopressin; Densitometry; Electrophoresis, Agar Gel; Female; Humans; Male; Protease Inhibitors; von Willebrand Diseases; von Willebrand Factor

To present current strategies for the treatment of hemophilia and von Willebrand's disease.. Prophylactic and corrective therapy with hemostatic and adjunctive agents: DDAVP (1-desamino-8-D-arginine vasopressin [desmopressin acetate]), recombinant coagulation products (human Factor VIII and human Factor VIIa) or virally inactivated plasma-derived products (high- or ultra-high-purity human Factor VIII or human Factor VIII concentrate containing von Willebrand factor activity, porcine Factor VIII, high-purity human Factor IX, human prothrombin-complex concentrate, human activated prothrombin-complex concentrate), adjunctive antifibrinolytic agents, topical thrombin and fibrin sealant. The induction of immune tolerance in patients in whom inhibitors develop should also be considered.. Morbidity and quality of life associated with bleeding and treatment.. Relevant clinical studies and reports published from 1974 to 1994 were examined. A search was conducted of our reprint files, MEDLINE, citations in the articles reviewed and references provided by colleagues. In the MEDLINE search the following terms were used singly or in combination: "hemophilia," "von Willebrand's disease," "Factor VIII," "Factor IX," "von Willebrand factor," "diagnosis," "management," "home care," "comprehensive care," "inhibitor," "AIDS," "hepatitis," "life expectancy," "complications," "practice guidelines," "consensus statement" and "controlled trial." The in-depth review included only articles written in English from North America and Europe that were relevant to human disease and pertinent to a predetermined outline. The availability of treatment products in Canada was also considered.. Minimizing morbidity and maximizing functional status and quality of life were given a high value.. Proper prophylactic or early treatment with appropriate hemostatic agents minimizes morbidity and functional disability and improves quality of life. Economic gains are realized through the reduction of mortality and morbidity and their associated costs. The patient has a better opportunity to contribute to society through gainful employment and the fulfillment of social roles. Potential harms include HIV infection, hepatitis B, hepatitis C and the development of inhibitor antibodies to clotting-factor concentrates. The risk of viral transmission has been minimized through the development of procedures for the viral inactivation of plasma-derived clotting-factor concentrates and through the use of recombinant coagulation-factor concentrates and other non-plasma-derived hemostatic agents.. DDAVP is the drug of choice for patients with mild hemophilia or type 1 or 2 (except 2B) von Willebrand's disease whose response to DDAVP in previous testing has been found to be adequate. Therapeutic blood components of choice include recombinant products and virally inactivated plasma-derived products. In Canada the recommended products are recombinant Factor VIII for hemophilia A, high-purity plasma-derived Factor IX for hemophilia B and plasma-derived Factor VIII concentrates containing adequate von Willebrand factor (e.g., Haemate P) for von Willebrand's disease. Dosages vary according to specific indications. Adjunctive antifibrinolytic agents, topical thrombin and fibrin sealant are useful for the treatment of oral or dental bleeds and localized bleeds in accessible sites. In patients with inhibitor antibodies, high-dose human or porcine Factor VIII is usually effective when the inhibitor titre is less than 5 Bethesda units/mL. In nonresponsive patients, or in those whose inhibitor titre is higher, "bypassing" agents (e.g., activated prothrombin-complex concentrate and recombinant Factor VIIa) are useful. Long-term management may include immune-tolerance induction.. These recommendations were reviewed and approved by the Association of Hemophilia Clinic Directors of Canada (AHCDC) and the Medical and Scientific Advisory Committee of the Canadian Hemophilia Society. No similar consensus statements or practice guidelines are available for comparison.. These recommendations were developed at the request of the Canadian Blood Agency, which funds the provision of all coagulation-factor concentrates for people with congenital bleeding disorders, and were developed and endorsed by the AHCDC and the Medical and Scientific Advisory Committee of the Canadian Hemophilia Society.

Topics: Antifibrinolytic Agents; Canada; Deamino Arginine Vasopressin; Factor IX; Factor VIII; Fibrin; Health Care Costs; Hemophilia A; Humans; Recombinant Proteins; Thrombin; von Willebrand Diseases

This patient required reconstructive surgery for a productive life, free of pain. The use of desmopressin provided effective hemostasis and avoided the transfusion of potentially hazardous blood products.

Topics: Blood Coagulation Tests; Child; Deamino Arginine Vasopressin; Female; Flatfoot; Humans; Risk Factors; von Willebrand Diseases

Topics: ABO Blood-Group System; Adolescent; Adult; Deamino Arginine Vasopressin; Drug Resistance; Factor VIII; Female; Humans; Male; Middle Aged; von Willebrand Diseases; von Willebrand Factor

Topics: Deamino Arginine Vasopressin; Humans; Platelet Aggregation; Ristocetin; von Willebrand Diseases

In three affected members of a family with type I 'platelet discordant' von Willebrand's disease displaying desmopressin-induced thrombocytopenia, we have detected in exon 28 of the von Willebrand factor gene a heterozygous G(4121)-->A transition, which predicts an Arg611-->His substitution. The mutated allele was absent in 50 normal individuals. An unrelated patient with a similar phenotype was also found to be heterozygous for this mutation. The mutation is located in the A1 domain of von Willebrand factor, where most type 2B von Willebrand's disease mutations are found. Mutations in this domain result in von Willebrand factor multimers with enhanced affinity for platelet glycoprotein Ib, and this may explain the association of Arg611-->His with the moderate thrombocytopenia observed after desmopressin infusion.

Topics: Base Sequence; Deamino Arginine Vasopressin; Humans; Molecular Sequence Data; Platelet Membrane Glycoproteins; Point Mutation; Thrombocytopenia; von Willebrand Diseases; von Willebrand Factor

Topics: Adolescent; Adult; Deamino Arginine Vasopressin; Female; Humans; Infusions, Intravenous; Male; Middle Aged; von Willebrand Diseases; von Willebrand Factor

Topics: Deamino Arginine Vasopressin; Factor VIII; Humans; von Willebrand Diseases; von Willebrand Factor

An international registry was established on the reproductive health of women with types of von Willebrand disease (vWd) unresponsive to DDAVP. Data was collected on 44 women from 16 treatment centers in nine countries. Severe menorrhagia requiring blood product therapy occurred at least once in 80% of the women for whom data was reported. Most of the reported episodes occurred prior to the diagnosis of vWd and/or the use of oral contraceptive (OC) therapy. OC therapy was clinically effective in the treatment of chronic menorrhagia in 22 of 25 (88%) women treated. Two of the women, however, were unable to tolerate chronic OC use and a third became refractory to treatment. Hysterectomy was performed in 10 of the 44 women (23%). The reported indication for six of the procedures was menorrhagia. Seventy percent were performed at two treatment centers, suggesting different thresholds for the performance of the procedure. There were 69 pregnancies reported in 31 of the 44 women. Fifteen of the pregnancies resulted in spontaneous abortions. The incidence of miscarriage was 22% and appeared clustered, with 10 of 15 of the miscarriages occurring in just four of the women.

Topics: Abortion, Spontaneous; Adult; Blood Coagulation Factors; Blood Transfusion; Contraceptives, Oral, Hormonal; Deamino Arginine Vasopressin; Europe; Female; Humans; Hysterectomy; Menorrhagia; Postpartum Hemorrhage; Pregnancy; Pregnancy Outcome; Registries; Treatment Failure; United States; von Willebrand Diseases

An international registry was established by the Subcommittee on von Willebrand Factor of the SSC/ISTH on the treatment of patients with types of von Willebrand disease (vWD) unresponsive to DDAVP infusion. Data was collected on 76 surgical events in 64 patients from 19 treatment centers. Thirty-three non-mucosal, 12 mucosal, 10 orthopedic and 21 dental procedures were reported. In the 76 surgical events, 14 cases prophylactically received cryoprecipitate while 62 received factor VIII (FVIII) concentrate. Surgical hemostasis was reported as satisfactory, good, or excellent in 75 of the 76 cases. Post-infusion bleeding times were measured in only three of 14 surgical events treated with cryoprecipitate. All three cases had a reduction but not correction of the bleeding time. The post-infusion bleeding time was measured in 27 of 62 cases in which FVIII concentrates were used. The bleeding time time was normalized in 15, reduced but not normalized in eight, and not changed from baseline in four. Data was also collected from 16 treatment centers on 50 serious bleeding events in 35 patients. These included 19 gastrointestinal, 15 other mucosal, four central nervous system, seven orthopedic, and five other mucosal, four central nervous system, seven orthopedic, and five other bleeds. Eleven cases received cryoprecipitate and 39 received FVIII concentrate as primary therapy. The efficacy of treatment was considered good or excellent in 49 of 50 cases. Post-infusion bleeding times were measured in only 15 of the 50 reported bleeding events. The post-infusion bleeding time was normalized in six, decreased but not normalized in eight, and not changed from baseline in one. In this retrospective survey, FVIII concentrates were subjectively as efficacious as cryoprecipitate in both the surgical setting and for the treatment of severe bleeds in patients with types of vWd unresponsive to DDAVP. Since the bleeding time was monitored during therapy in only a minority of these cases, a definitive relationship between the efficacy of therapy and normalization or reduction of the bleeding time in these two clinical settings cannot be established from this study. A prospective study on the use of FVIII and/or vWf concentrates in these clinical settings is necessary to address this issue.

Topics: Cryoglobulins; Deamino Arginine Vasopressin; Drug Resistance; Factor VIII; Health Surveys; Hemorrhage; Humans; Registries; von Willebrand Diseases

It is generally thought that the plasma increase in factor VIII (FVIII) after desmopressin (dDAVP) infusion is related to the plasma increase in von Willebrand factor (vWF), which is the plasma carrier for FVIII. The aim of this study was to evaluate the FVIII and vWF responses in patients with type 2N vWD, characterized by the mild FVIII deficiency related to markedly decreased affinity of vWF for FVIII. At different times after one intravenous dose of dDAVP (0.3 or 0.4 microgram/kg) we measured the FVIII coagulant activity, FVIII antigen, vWF antigen and ristocetin cofactor activity, in eight patients with either Arg91Gln or Arg53Trp amino acid substitution in mature vWF. In all the patients, whatever their mutation, the dDAVP infusion resulted in a 2.3 +/- 0.7-fold increase of vWF and a variable rise (9.5 +/- 7.7 times) of FVIII, whereas the vWF capacity to bind FVIII was not improved. The FVIII response was more transient than vWF response, and FVIII half disappearance time was evaluated to be approximately 3 h. The data indicate that the stabilizing effect of vWF on FVIII is not responsible for the FVIII increase induced by dDAVP. The clinical implication of this study is that, in the 2N vWD patients, dDAVP may be a useful prophylactic or curative treatment when the test dose has been shown to be effective to reach a haemostatic FVIII level.

Topics: Adult; Child; Child, Preschool; Deamino Arginine Vasopressin; Factor VIII; Female; Genotype; Half-Life; Humans; Male; Middle Aged; Mutation; von Willebrand Diseases

Type I von Willebrand's disease (vWd) is characterized by a concomitant decrease in plasma of von Willebrand factor antigen (vWf:Ag) and vWf ristocetin cofactor activity (vWf:RCoF), associated with the presence of all-size multimers. As a rule, there is no evidence of intrinsic abnormality in vWf. We describe a family with type I vWd with an abnormal plasma vWf multimer pattern. Analysis of plasma vWf multimeric structure by short-SDS-agarose gel electrophoresis showed an abnormal banding pattern for each vWf oligomer, which was organized as a doublet instead of the normal triplet. The electrophoretic mobility of each component appeared to be normal. Multimeric analysis on a long gel showed all the bands that were detectable in normal subjects, but unlike normals the fast moving satellite stained as the major component. The platelet vWf multimer pattern was normal. The infusion of DDAVP normalized vWf:Ag, vWf:RCoF and VIII:C, but not the abnormal multimer pattern observed on both short- and long-gel electrophoresis. The return of factor VIII/vWf complex to the baseline condition was more rapid than that observed in normal subjects or classic type I vWd patients. Analysis of the subunit fragments in the patients' plasma vWf demonstrated a relatively greater proportion, compared to the normal counterpart, of a 115(140)-kD fragment, which derives from the aminoterminal region of the mature molecule; in contrast, no intact subunit was detectable. These findings indicate a new, previously unreported, variant of type I vWd, which is characterized by plasma vWf oligomers organized as doublets, instead of triplets. The reduced post-DDAVP half-life, and the abnormal subunit fragments of vWf, suggest a molecule characterized by an increased susceptibility to proteolytic degradation. As a result, the decrease in circulating vWf levels may be due to an instability of the abnormal vWf, rather than, or in addition to, a decrease in its synthesis.

Topics: Adult; Child, Preschool; Deamino Arginine Vasopressin; Electrophoresis, Polyacrylamide Gel; Factor VIII; Family Health; Female; Genetic Variation; Hemostasis; Humans; Male; Middle Aged; Pedigree; Peptide Fragments; von Willebrand Diseases; von Willebrand Factor

With few exceptions, 1-desamino-8-D-arginine vassopressin (DDAVP) has been shown to be useful in securing haemostasis in patients with von Willebrand's disease (vWd). In type IIB vWd, DDAVP has been reported to have no beneficial effects and to be contraindicated because it causes or worsens thrombocytopenia, due to in vivo platelet aggregation. Nevertheless, it was previously demonstrated that DDAVP may have clinical utility in some patients with type IIB vWd. Additional findings obtained in seven type IIB vWd patients of different kindreds undergoing minor surgical procedures are now reported. It was observed that DDAVP corrected the bleeding time in every case, with effects lasting for 2 h. Mean platelet counts decreased 30 min after DDAVP to variable degrees, depending on the anticoagulant used for blood collection, but were normal 2 h later. Furthermore DDAVP normalized FVIII, von Willebrand factor (vWf) antigen (vWf:Ag), and to a lesser extent, vWf ristocetin cofactor activity (vWf:RCoF). Intermediate and large vWf multimers appeared after 30 min. There were no bleeding complications during or after surgery, nor evidence of thrombosis. It was thus confirmed that DDAVP has clinical utility in the prevention of bleeding symptoms in different type IIB vWd patients. Therefore, despite the transitory thrombocytopenia and the incomplete restoration of larger vWf multimers, the use of this drug should be reconsidered for patients with type IIB vWd.

Topics: Deamino Arginine Vasopressin; Factor VIII; Hemorrhage; Humans; Intraoperative Complications; Kinetics; Platelet Count; Thrombocytopenia; von Willebrand Diseases; von Willebrand Factor

An 82-year-old patient with acquired von Willebrand's disease in association with a non-Hodgkin's lymphoma and a benign IgG-lambda monoclonal paraproteinemia is described with severe recurring nasopharyngeal bleedings, who responded poorly to desmopressin (DDAVP) and factor VIII/von Willebrand factor concentrates but was successfully treated with high-dose e intravenous gamma-globulin therapy.

Topics: Aged; Aged, 80 and over; Autoantibodies; Autoimmune Diseases; Deamino Arginine Vasopressin; Factor VIII; Hemorrhage; Humans; Immunoglobulin lambda-Chains; Immunoglobulin M; Immunoglobulins, Intravenous; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Male; Monoclonal Gammopathy of Undetermined Significance; von Willebrand Diseases; von Willebrand Factor

Topics: Animals; Blood Loss, Surgical; Breeding; Castration; Deamino Arginine Vasopressin; Dog Diseases; Dogs; Female; Male; von Willebrand Diseases; von Willebrand Factor

The aim of this study was to compare the secretory response of the vascular wall in vivo to DDAVP (i.v. 0.3 microgram/kg, 30 min) and to venous occlusion (VO, 20 min) in control healthy subjects, patients with von Willebrand's disease type I (vWd I) and patients with von Willebrand's disease type III (vWd III). In controls (n = 10) and vWd I (n = 12), DDAVP induced a 2 to 3-fold rise in plasma von Willebrand factor antigen (vWf: Ag), factor VIII coagulant activity (VIII: C) and tissue--type plasminogen activator antigen (t-PA:Ag). VO was less effective in increasing vWf: Ag and VIII:C but produced a greater rise in t-PA:Ag. Large increments (over 10-fold) were observed in plasmin-alpha 2-antiplasmin complexes following both stimuli. In vWd III (n = 10), DDAVP and VO failed to increase vWf:Ag, VIII:C and t-PA:Ag. No significant changes in plasmin-alpha 2-antiplasmin complexes were observed in this group. Moreover, the baseline t-PA:Ag values were significantly lower in vWd III (2.17 +/- 1.13 ng/ml) than in controls (4.84 +/- 1.97 ng/ml, p < 0.001). A significant increase in urokinase--type plasminogen activator antigen (u-PA:Ag) was found only in controls after VO. Neither controls nor patients with vWd showed any changes in plasma fibronectin levels following DDAVP. The low t-PA:Ag results and the abnormal fibrinolytic response to DDAVP and VO in patients with severe (type III) vWd indicate that their endothelial cell abnormality is more extensive than the defect in the synthesis or release of vWf.

Topics: Adult; Constriction; Deamino Arginine Vasopressin; Endothelium, Vascular; Female; Humans; Male; Middle Aged; Plasminogen Activators; Receptors, Cell Surface; Receptors, Urokinase Plasminogen Activator; Veins; von Willebrand Diseases

Because of menorrhagia, a 13-year-old girl was found to have type I von Willebrand disease and then chronic autoimmune thyroiditis with hypothyroidism. All clinical and laboratory evidence of von Willebrand disease resolved transiently after infusion of desmopressin, and permanently with L-thyroxine therapy. We recommend investigation for hypothyroidism in patients with newly diagnosed acquired von Willebrand disease.

Topics: Adolescent; Deamino Arginine Vasopressin; Diseases in Twins; Drug Therapy, Combination; Female; Humans; Hypothyroidism; Infusions, Intravenous; Thyroiditis, Autoimmune; Thyroxine; von Willebrand Diseases

A simplified phenotypic classification of von Willebrand disease is proposed that is based on differences in pathophysiology. Quantitative defects are divided into partial deficiency (type 1) and severe deficiency (type 3). Qualitative defects (type 2) are divided into four subcategories. Type 2A refers to variants with decreased platelet-dependent function associated with the loss of high-molecular weight VWF multimers. Type 2B refers to variants with increased affinity for platelet glycoprotein Ib. Type 2M refers to qualitatively abnormal variants with decreased platelet-dependent function not associated with the loss of high-molecular weight multimers. Type 2N refers to variants with decreased affinity for factor VIII. When recognized, mixed phenotypes caused by compound heterozygosity are indicated by separate classification of each allele. Standard amino acid and nucleotide numbering schemes are recommended for the description of mutations.

Topics: Blood Coagulation Factors; Deamino Arginine Vasopressin; Humans; von Willebrand Diseases

Von Willebrand's disease (vWD) is the most common inherited bleeding disorder. Typical clinical features such as bleeding after surgery or trauma might suggest the disease. We present a series of 24 patients with vWD treated between 1989 and 1992. Diagnosis was confirmed by a reduction in plasma factor VIII antigen concentration, reduction of ristocetin cofactor activity and reduced factor VIII activity. Seventeen of the patients underwent surgery (7 adenoidectomies, 8 tonsillectomies, 2 paranasal sinus operations) and received preoperative stimulation of von Willebrand factor (vWF) using DDAVP. This resulted in a rapid increase in plasma vWF concentration from an average of 56% before stimulation to 190% of the normal value after stimulation. A reduction of partial thromboplastin time from an average of 44.4 seconds to 34.4 seconds was observed following DDAVP. No bleeding complications or other side-effects occurred. Preoperative stimulation of vWF using DDAVP proved to be a safe method to reduce the risk of bleeding in patients with vWD undergoing surgery.

Topics: Adolescent; Adult; Blood Coagulation Tests; Blood Loss, Surgical; Child; Child, Preschool; Deamino Arginine Vasopressin; Female; Humans; Male; Otorhinolaryngologic Diseases; Premedication; von Willebrand Diseases

Some well-described similarities exist between tissue plasminogen activator (t-PA) and von Willebrand factor (vWf) which may suggest a link in either the synthesis or release of both proteins from endothelial cells. To investigate this relationship further immunocytochemical localization of t-PA and vWf was performed in normal tissues and in skin obtained from patients with type I and type III von Willebrand's disease (vWd). Components of the fibrinolytic system were measured at baseline and after venous occlusion in healthy controls and patients with vWd. Patients with severe vWd received intravenous vWf concentrate, followed by desmopressin (DDAVP), to study the plasma response of vWf and t-PA. By immunocytochemical staining, t-PA was demonstrated in endothelial cells of normal skin, kidney and liver and also in the skin of patients with type I and type III vWd. vWf was localized in endothelial cells of all tissues except the specimens from an individual with severe vWd. Basal plasma levels of fibrinolytic components were normal in patients with vWd. Venous occlusion resulted in a rise of fibrinolytic activity in controls and patients with type I, but not type III, vWd. No rise in plasma t-PA was observed following DDAVP in severe vWd, even though near-normalization of plasma vWf levels had been obtained by prior infusion of vWf concentrate. It is concluded that the synthesis of t-PA and vWf is probably regulated by independent processes. Constitutive and regulated release of both proteins occur through different mechanisms and the basal secretion of t-PA is intact in severe vWd.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Deamino Arginine Vasopressin; Endothelium, Vascular; Fibrinolysis; Humans; Immunoenzyme Techniques; Immunohistochemistry; Kidney; Kinetics; Middle Aged; Skin; Tissue Plasminogen Activator; von Willebrand Diseases; von Willebrand Factor

We evaluated the effectiveness of desmopressin to control bleeding of patients with coagulation defects during dental surgery. Thirty-five patients, mainly with moderate and mild hemophilia and Willebrand disease, were undergoing dental extractions (over 80 extractions in total). Bleeding was successfully prevented in 28 patients with the use of a combined treatment incorporating IV desmopressin, an antifibrinolytic agent (tranexamic acid), and local methods (surgical glue and compression techniques). Seven patients had a bleeding episode after dental extraction, which was controlled in two cases by repeated injection of desmopressin and in another two by local methods; Factor VIII substitutive treatment was needed in only three patients. Desmopressin offers an alternative to blood products to control bleeding risk in patients with moderate and mild coagulation defects. Our experience tends to specify the mode of administration of both desmopressin and the associated treatments. Our findings suggest that desmopressin can be used in conjunction with other treatments to prevent bleeding in patients with coagulation defects who undergo dental surgery. This work highlights the concept of multifactorial medical care of these patients in which desmopressin plays a major role.

Topics: Adolescent; Adult; Blood Loss, Surgical; Deamino Arginine Vasopressin; Dental Care for Chronically Ill; Female; Hemophilia A; Humans; Infusions, Intravenous; Male; Middle Aged; Premedication; Retrospective Studies; Tooth Extraction; von Willebrand Diseases

We determined whether administration of cryoprecipitate or fresh-frozen plasma (FFP) would enhance glass bead platelet retention and shorten the bleeding time in von Willebrand factor (vWf)-deficient Doberman Pinschers. Plasma concentration of vWf was < 15% of the reference value in these dogs and, on the basis of multimeric analysis of vWf, these dogs had type-I von Willebrand's disease (vWd). Concentration of vWf in cryoprecipitate (prepared from FFP of clinically normal dogs) was enriched almost 20 times, and the preparation was a concentrate of the largest and most physiologically active multimers. Administration of a dose of cryoprecipitate calculated to increase plasma vWf concentration of recipient dogs to 50 U/dl increased plasma vWf concentration in recipient dogs to about 40 U/dl. Mean buccal mucosal bleeding time (BMBT) shortened from 6.7 minutes before treatment to 3.8 minutes at 2 hours after treatment. Cryoprecipitate from donor dogs treated with deamino-8-D-arginine vasopressin (1 micrograms/kg of body weight) effectively shortened mean BMBT from 6.4 minutes to 3.1 minutes. Administration of cryoprecipitate from vWf-deficient dogs prolonged, rather than shortened, the BMBT. After FFP (450 ml) infusion, plasma vWf concentration increased in recipient dogs, but the BMBT did not shorten. Glass bead platelet retention did not change after administration of cryoprecipitate or FFP.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Bleeding Time; Blood Component Transfusion; Deamino Arginine Vasopressin; Dog Diseases; Dogs; Electrophoresis, Polyacrylamide Gel; Female; Male; Plasma; Reference Values; von Willebrand Diseases; von Willebrand Factor

Type IIA von Willebrand disease (vWD) is a heterogeneous disorder for which two different pathogenetic mechanisms have been proposed: increased proteolytic susceptibility of von Willebrand factor (vWF), and/or interference of its post-translational processing. Subunit analysis of vWF in type-IIA vWD has revealed an increased relative proportion of the 176- and 140-kDa subunit-derived fragments, suggesting an augmented fragmentation of vWF, even in the resting state. We analyzed the subunit pattern of vWF in plasma from five previously described patients with type-IIA vWD. All of them showed the above-mentioned pattern. In addition, the presence of a new band with an apparent molecular mass of 200 kDa, not described in normal individuals or in patients with vWD, was repeatedly observed in one of these patients. This patient also exhibited an abnormal vWF multimeric structure in platelets and in plasma, before and after desmopressin administration, when the blood was collected either in the presence or in the absence of proteinase inhibitors. We believe that an abnormal primary structure of vWF could be responsible for this abnormal proteolytic fragmentation pattern, as well as for the abnormal multimerization of vWF. Moreover, an abnormal susceptibility to proteolysis appears to be present, as suggested by the increase in the relative proportion of the 176-kDa fragment observed in the same patient. Future sequencing studies and genetic analysis may clarify whether there are one or two different defects related to the vWF of that patient. Our results indicate that the subunit analysis of vWF may reveal additional defects present in type-IIA vWD that may help our understanding of the pathogenesis of such disease.

Topics: Blood Platelets; Deamino Arginine Vasopressin; Endopeptidases; Female; Humans; Macromolecular Substances; Molecular Weight; Peptide Fragments; von Willebrand Diseases; von Willebrand Factor

1-deamino-8-D-Arginine vasopressin (DDAVP) shortens the bleeding time in some patients with platelet dysfunction and decreases blood loss in some cardiopulmonary bypass patients. We studied platelet membrane glycoproteins in patients with von Willebrand disease (vWD), disorders of platelet function, and in cardiopulmonary bypass patients after infusion of 0.3 microgram/kg of DDAVP. Platelets from 8 cardiopulmonary bypass patients, receiving DDAVP immediately after surgery, were compared to those of 14 patients not receiving DDAVP. We also studied 12 patients with vWD, and 8 patients with platelet dysfunction receiving DDAVP. Fixed platelets, stained with monoclonal fluorescein (FITC)-labeled antibodies directed against GPIb (CD42b antigen), GPIb/IX, GPIIb/IIIa (CD41a antigen), CD63 antigen (a platelet activation protein), and P-selectin (CD62 antigen) were studied by flow cytometry. Binding of CD42b monoclonal antibody (MoAb) and anti-GPIb/IX to platelets from both groups of bypass patients increased during the 18-20 hr after surgery, but the group receiving DDAVP showed the greater increase (P = 0.032). Platelets from patients receiving DDAVP for vWD or for platelet dysfunction, had increases in CD42b MoAb and anti-GPIb/IX binding (P < 0.01) that coincided with shortening of their bleeding time. No changes were seen in binding of other antibodies. When platelets from normal donors were incubated with DDAVP for 20 hr, there were increases in platelet surface CD42b MoAb binding, while immunogold-stained transmission electron micrographs of permeabilized platelets demonstrated decreases in cytoplasmic CD42b MoAb binding. DDAVP increases platelet membrane GPIb expression in a variety of patients and may account for improvement in hemostasis seen in some studies. Redistribution of GPIb from the cytoplasm to the membrane may account for this increased expression.

Topics: Adult; Aged; Aged, 80 and over; Blood Platelet Disorders; Blood Platelets; Cardiopulmonary Bypass; Deamino Arginine Vasopressin; Female; Humans; Male; Middle Aged; Platelet Membrane Glycoproteins; von Willebrand Diseases

It is generally held that factor VIII (FVIII) does not increase in the plasma of severe von Willebrand disease (vWD) patients treated with DDAVP because they lack von Willebrand factor (vWF), which is the plasma carrier for FVIII. To test this hypothesis, FVIII plasma levels were monitored in severe vWD patients treated with DDAVP after normalization of vWF plasma levels with infusions of cryoprecipitate. Each of four severe vWD patients underwent four different treatments at intervals of at least 15 d: (1) cryoprecipitate plus DDAVP; (2) cryoprecipitate plus saline; (3) cryoprecipitate plus recombinant FVIII (rFVIII); (4) saline plus rFVIII. Cryoprecipitate increased the plasma levels of FVIII and vWF. The infusions of saline or DDAVP after cryoprecipitate did not further increase FVIII and vWF plasma levels and had no effect on the plasma levels of tissue plasminogen activator (tPA), which are raised by DDAVP in normal subjects and in patients with vWD of other types. The infusion of rFVIII further increased by 182 +/- 32 U/dl (mean +/- SEM) the plasma levels attained after cryoprecipitate, which disappeared from the circulation with a half-life of 11.95 +/- 0.86 h. In contrast, the infusion of rFVIII after saline increased by only 107 +/- 18 U/dl the plasma levels of FVIII, which disappeared from the circulation with a half-life of 2.68 +/- 0.14 h, indicating that the vWF infused with cryoprecipitate is able to bind additional FVIII. These studies indicate that DDAVP does not increase the plasma levels of FVIII in patients with severe vWD even after normalization of plasma vWF. The possibility is discussed that severe vWD patients may be insensitive to the releasing effect of DDAVP.

Topics: Deamino Arginine Vasopressin; Drug Resistance; Factor VIII; Half-Life; Humans; Recombinant Proteins; Tissue Plasminogen Activator; von Willebrand Diseases; von Willebrand Factor

This report describes studies investigating the use of a collagen binding assay to improve the laboratory monitoring of desmopressin (DDAVP) therapy in patients with von Willebrand's disease (vWD). We evaluated the response of seven patients with vWD (four type I, three type IIA) to DDAVP, administered using a standard protocol, by assessing levels of von Willebrand factor (vWF) and factor VIII, as well as performing skin bleeding times (SBT) prior to, and at sequential time points following, DDAVP administration. The study employed the following assays: von Willebrand factor antigen assay (vWF:Ag; determined by ELISA); a novel functionally based collagen binding assay (CBA; determined by ELISA); ristocetin cofactor assay (RCof; determined by platelet aggregometry); von Willebrand factor multimer analysis (using SDS-agarose gels); factor VIII coagulant (FVIIIC; determined by clotting assay); and factor VIII antigen (FVIIICAG; determined by ELISA). All patients showed an initial incremental increase in vWF/FVIII levels using all assays above, and some showed some correction in SBT. Although the absolute levels of vWF/FVIII antigen or activity varied between patients, the CBA was found to provide consistently the greatest proportional incremental increases (i.e., -fold) compared to baseline (pre-DDAVP) levels. Accordingly, we consistently observed an increase in the CBA to vWF:Ag ratio for all patients evaluated. This supplements previous findings that have suggested a unique ability of our CBA procedure to bind preferentially to higher molecular weight (i.e., more functionally active) forms of vWF. We therefore propose that the use of the above test combination (e.g., vWF:Ag plus CBA) may provide the basis for more accurate estimation of a patient's functional responsiveness to DDAVP therapy in future studies.

Topics: Biopolymers; Blood Coagulation Tests; Collagen; Deamino Arginine Vasopressin; Enzyme-Linked Immunosorbent Assay; Factor VIII; Humans; Protein Binding; von Willebrand Diseases; von Willebrand Factor

Thrombocytopenia after desmopressin (DDAVP) infusion is usually observed in patients with type IIB von Willebrand disease (vWD). No other subtypes of vWD with thrombocytopenia after DDAVP have been reported so far. We describe here the occurrence of thrombocytopenia after DDAVP in a 39 year old male and his son with phenotypic characteristics of type I vWD, "platelet discordant subtype." After DDAVP, the abnormal ristocetin cofactor/von Willebrand factor antigen ratio in plasma was not corrected and the bleeding time remained markedly prolonged. Platelet count dropped 30 min after DDAVP (from 279 to 96 x 10(3)/microL in the propositus and from 298 to 116 x 10(3)/microL in his affected son) and returned to normal at 60 min. Platelet clumping was evident on peripheral blood smears obtained after infusion. These cases indicate that after DDAVP thrombocytopenia can occur in vWD other than type IIB.

Topics: Adult; Blood Platelets; Child; Deamino Arginine Vasopressin; Electrophoresis, Polyacrylamide Gel; Female; Humans; In Vitro Techniques; Infusions, Intravenous; Kinetics; Male; Ristocetin; Thrombocytopenia; von Willebrand Diseases; von Willebrand Factor

A family with concurrent haemophilia A and type I von Willebrand's disease (vWd) is described. The propositus was affected by both disorders. The propositus' mother was an obligate carrier of haemophilia A being the daughter of a haemophilic. The father and sister were affected by vWd. The sister was also a possible carrier of haemophilia A. This is the first report of both disorders occurring simultaneously. The infusion of 1-desamino-8-d-arginine vasopressin (DDAVP) induced, in the propositus, a normalization of circulating levels of vWf, with a less pronounced enhancement of factor VIII:C. In the father, the response to DDAVP infusion of factor VIII/vWf complex was normal. In the mother, the time-course of factor VIII:C was characterized, after a peak at 30 min, by a progressive decrease until 2 hours after infusion, in contrast to vWf which appeared further increased at the same times. Therefore, the low factor VII:C/vWf:Ag ratio, already present before infusion, became significantly more pronounced 2 hours after DDAVP. Similar findings were observed in another obligate carrier of the family, in the propositus' sister and in 10 other haemophilia A carriers, belonging to different kindreds. In all patients, even when the basal factor VIII:C/vWf:Ag ratio was normal, two hours after DDAVP it decreased in agreement with the haemophilia A carrier state.

Topics: Adult; Deamino Arginine Vasopressin; Factor VIII; Female; Hemophilia A; Humans; Infusions, Intravenous; Male; Middle Aged; Pedigree; von Willebrand Diseases; von Willebrand Factor

We report the development of significant hyponatremia (121 mEq/L) following three daily intravenous doses of desmopressin acetate (DDAVP; 18 micrograms; 0.3 micrograms/kg) in a healthy adult with moderate von Willebrand's disease. Previous reports suggest that clinically important hyponatremia due to DDAVP administration only occurs in the very young, those receiving hypotonic intravenous fluids or those given multiple frequent (e.g., every 8-12 hours) doses of DDAVP. None of these conditions was present in this case. Consideration should be given to monitoring serum sodium levels and fluid balance in patients receiving more than a single dose of DDAVP, even in the absence of previously reported risk factors for the development of hyponatremia.

Topics: Adult; Age Factors; Deamino Arginine Vasopressin; Dose-Response Relationship, Drug; Female; Humans; Hyponatremia; Injections, Intravenous; Risk Factors; Sodium; von Willebrand Diseases; Water-Electrolyte Balance

We describe the management of tonsil or tonsil and adenoid surgery in our hospital in 10 patients with inherited bleeding disorders, over a 10-year-period. The approach to the management of the haemostatic defect is outlined in detail. All underwent successful surgery, two patients had limited secondary haemorrhage. This report demonstrates that patients with inherited bleeding disorders can safely undergo adenotonsillectomy, providing there is close liaison between surgeons and haematologists throughout the peri-operative period.

Topics: Adenoidectomy; Blood Coagulation Disorders; Child; Child, Preschool; Deamino Arginine Vasopressin; Factor VII Deficiency; Female; Hemophilia A; Hemostasis, Surgical; Humans; Male; Tonsillectomy; Tranexamic Acid; von Willebrand Diseases

We report a family with a combined factor VII Padua defect and von Willebrand's disease (vWd). The propositus is a 9-year-old child with a moderate bleeding tendency who appeared to be heterozygous for both factor VII Padua and type I vWd. The diagnosis of factor VII Padua was based on a normal factor VII antigen and factor VII activity which was low with rabbit brain thromboplastin but normal with ox brain thromboplastin. Type I vWd was diagnosed because of a concomitant decrease of von Willebrand factor antigen (vWf:Ag) and vWf ristocetin-cofactor activity (vWf:RCoF), associated with the presence of vWf multimers of all sizes in plasma and platelets. The parents were not consanguineous but came from the same isolated river Piave valley in North Eastern Italy where the factor VII Padua defect was first described. The father had the factor VII Padua defect but was clinically asymptomatic in accordance with the heterozygous state. The propositus's mother had type I vWd and was mildly symptomatic. The propositus' sisters, who were clinically asymptomatic, were both heterozygotes for factor VII Padua. The infusion of DDAVP normalized the factor VIII/vWf pattern in all patients. In the propositus, in contrast to the mother and normal subjects, showed a more rapid clearance both of vWf and factor VIII. The same pattern, albeit to a lesser degree, was also observed in the father.

Topics: Child; Deamino Arginine Vasopressin; Factor VII; Factor VII Deficiency; Female; Humans; Italy; Male; Pedigree; Thromboplastin; von Willebrand Diseases

Desmopressin (1-desamino-8-D-arginine vasopressin), an established hemostatic agent for the treatment of bleeding in mild hemophilia A, von Willebrand's disease, or platelet disorders, has mostly been given parenterally as intravenous or subcutaneous injections. Intranasal administration by spray has been shown to yield significant and highly reproducible increases in the plasma concentrations of factor VIII and von Willebrand factor and platelet adhesiveness, and to be suitable for self-administration at home, as it is easy to handle and does not involve the use of needles. This paper presents data from a questionnaire answered by 78 patients with mild hemophilia A, von Willebrand's disease, or platelet disorders, who had used the spray at home to treat bleeding symptoms. The patients experienced decreased blood loss and shortened duration of epistaxis, menorrhagia, tissue bleeding, and bleeding in connection with minor surgery or tooth extraction. The use of factor VIII concentrates was diminished, as were the number of visits to outpatient care and absence from school or work.

Topics: Adult; Blood Coagulation Disorders; Blood Platelet Disorders; Child; Deamino Arginine Vasopressin; Female; Hemophilia A; Hemorrhage; Humans; Male; Self Administration; Socioeconomic Factors; Surveys and Questionnaires; von Willebrand Diseases

A patient with von Willebrand's disease presenting for dental treatment requires thorough evaluation prior to the determination of a proper course of treatment. In this case report, a patient with von Willebrand's disease presented to the emergency room with dental trauma. A modified treatment plan, taking into account the severity of the patient's systemic illness and the need for medical management, yielded successful results.

Topics: Aminocaproic Acid; Child; Deamino Arginine Vasopressin; Dental Care for Disabled; Hemostatic Techniques; Humans; Male; Plasma; Tooth Avulsion; von Willebrand Diseases

Topics: Adolescent; Adult; Antibodies, Monoclonal; Binding Sites; Child; Deamino Arginine Vasopressin; Factor VIII; Female; Hemophilia A; Humans; Immunosorbent Techniques; Male; Pedigree; Polymorphism, Restriction Fragment Length; Protein Binding; von Willebrand Diseases; von Willebrand Factor

Topics: Adult; Child, Preschool; Deamino Arginine Vasopressin; Electrophoresis, Agar Gel; Female; Humans; Male; von Willebrand Diseases; von Willebrand Factor

Topics: Blood Platelets; Deamino Arginine Vasopressin; Female; Heterozygote; Humans; Male; von Willebrand Diseases; von Willebrand Factor

A patient with benign monoclonal IgG lambda paraproteinemia, acquired von Willebrand syndrome (AVWS), and chronic melena successfully responding to high-dose intravenous immunoglobulin (lvlg) is reported. Coagulation parameters at admission were APTT (ratio) 1.68; VIII:C 11 IU/dL; vWF:Ag 7 IU/dL:Ricof less than 3 IU/dl. RIPA was greater than 1.8 mg/ml, and bleeding time (BT) was prolonged (18 min). No evidence for an in vitro inhibitor against the VIII/vWF complex was observed. VIII/vWF measurements showed a short-lived increase after both DDAVP and Hemate P, and BT was transiently normalized. After intravenous Ig (1 g/kg for 2 days), VIII/vWF measurements, hemostatic parameters and multimeric pattern were completely corrected (VIII/C 106 IU/dl, vWF:Ag 168 IU/dl, RiCof 147 IU/dl, APTT ratio 0.89, BT 5'), with a return to pre-infusion values after 15 days. Hemoccult test became negative and packed red cell transfusions, of which 130 units were administered during the last year, were no longer required. After 18 months the patient is on maintenance treatment with repeated courses of Ig, at 3 to 4-week intervals based on VIII/vWF and BT monitoring.

Topics: Bleeding Time; Chronic Disease; Deamino Arginine Vasopressin; Dose-Response Relationship, Drug; Factor VIII; Humans; Immunoelectrophoresis; Immunoglobulins, Intravenous; Male; Melena; Middle Aged; Paraproteinemias; von Willebrand Diseases; von Willebrand Factor

When patients with mild haemophilia or von Willebrand disease (vWD) are repeatedly treated with desmopressin (DDAVP) at relatively short time intervals, some of them may become less responsive or unresponsive. The development of tachyphylaxis would limit the usefulness of DDAVP in clinical management of these patients. On the other hand, tachyphylaxis is not consistent, and its patterns of development are unknown. The aim of this study was to evaluate in controlled conditions the occurrence of tachyphylaxis by giving intravenous DDAVP (0.3 microgram/kg) on four consecutive days to a selected group of patients with mild haemophilia A (n = 22) and type I vWD (n = 15). After each dose, we measured parameters known to change after DDAVP, i.e. factor VIII coagulant activity, bleeding time, von Willebrand factor antigen, ristocetin cofactor and tissue-type plasminogen activator antigen. We found that on average the responses obtained after the second dose of DDAVP were approximately 30% less than those obtained after the first, but were not further reduced after the third and fourth dose. At all time intervals after DDAVP, patients with vWD responded relatively better than patients with haemophilia, and there were fewer vWD patients who responded poorly or became unresponsive. In vWD patients there were no significant changes in the bleeding time responses and in blood pressure and heart rate. The clinical implications of these findings are that repeated doses of DDAVP can be given efficaciously to many patients (particularly to those with vWD), even though responses lower than those seen after the first dose should be expected.

Topics: Adult; Antigens; Bleeding Time; Deamino Arginine Vasopressin; Factor VIII; Female; Hemophilia A; Humans; Male; Middle Aged; Tachyphylaxis; Tissue Plasminogen Activator; von Willebrand Diseases; von Willebrand Factor

Haemophilia is a rare and complex disorder and its successful management will depend upon the establishment of a network of 'comprehensive care' including the services of haematologists, orthopaedic surgeons, rheumatologists, dental surgeons, physiotherapists, specialised nurses and counsellors. One of the major lessons to be learned from the HIV epidemic in haemophilia is that it is critical to strive to obtain the safest and purest forms of blood products for these patients. The advent of clinically available recombinant factor VIII is expected soon; in the meantime there is a move towards treating all patients with high purity products.

Topics: Cerebral Hemorrhage; Deamino Arginine Vasopressin; Factor IX; Factor VIII; Genetic Counseling; Hemarthrosis; Hemophilia A; Hemophilia B; Humans; Male; Patient Care Team; Prevalence; Transfusion Reaction; Virus Diseases; von Willebrand Diseases

We describe a patient with moderate von Willebrand's disease who developed severe hyponatremia during prophylaxis with 1-deamino-8D-arginine vasopressin (desmopressin) to prevent bleeding in connection with surgery. This is a rare complication to desmopressin treatment in adults. Our present policy is to restrict administration of desmopressin to three 12-hourly infusions, to measure serum sodium before and during the treatment period, to determine body weight daily and to restrict administration of fluids.

Topics: Adult; Deamino Arginine Vasopressin; Female; Humans; Hyponatremia; Infusions, Intravenous; Premedication; von Willebrand Diseases

Platelet count, prothrombin time, and activated partial thromboplastin time provide a baseline to evaluate patients with known coagulopathy, as well as present an opportunity to diagnose disease in previously symptom free patients. Current hematologic management of patients with Von Willebrand's disease uses heated Factor VIII that allows patients to undergo orthognathic surgery without significant risk of disease transmission from banked blood products.

Topics: Adult; Deamino Arginine Vasopressin; Factor VIII; Hemostasis; Humans; Male; Orthognathic Surgical Procedures; Osteotomy; Partial Thromboplastin Time; Platelet Count; Preoperative Care; Prothrombin Time; von Willebrand Diseases

Although DDAVP has been shown to be haemostatically efficacious in patients with various congenital or acquired platelet disorders, no reasonable explanation has been found for this effect. We have previously shown DDAVP to increase platelet adhesiveness as measured with a platelet retention test. The aim of the present study was to investigate the mechanism of action responsible for the increased platelet retention in response to DDAVP. Patients with vWD type III and type Ia, severe haemophilia and severe thrombasthenia, as well as healthy controls, were included in the study. The effect of different concentrations of vWF in plasma and platelets was explored, as was the effect on platelet function of apyrase and monoclonal antibodies against GP IIb/IIIa and GP Ib. We found the effect of DDAVP on platelet retention to be unaffected by changes in the plasma concentration of vWF. The enhanced platelet retention after DDAVP is apparently dependent on the presence of platelet-vWF and on a normal function of the GP IIb/IIIa. The effect is not mediated via ADP or thrombin. The platelet-stimulating effect of DDAVP may be one explanation for the positive haemostatic effect in patients with certain platelet disorders.

Topics: Adolescent; Adult; Antibodies, Monoclonal; Apyrase; Blood Platelets; Child; Deamino Arginine Vasopressin; Female; Hemophilia A; Heparin; Humans; Male; Platelet Membrane Glycoproteins; Pregnancy; Thrombasthenia; von Willebrand Diseases; von Willebrand Factor

The fibrinolytic response after infusion of 1-deamino-8-d-arginine vasopressin (DDAVP) was examined in 4 patients with the severe form and 17 patients with the moderate form of Von Willebrand's disease (VWd) and compared to that of 9 normal subjects. Tissue plasminogen activator (t-PA) antigen (Ag) and activity and tissue plasminogen activator inhibitor (PAI) were measured before and after DDAVP. t-PA Ag was found to be significantly higher before DDAVP in patients than in controls. No release of t-PA Ag was observed in the 4 patients with the severe form of VWd but increased release was observed in patients with moderate forms. However, t-PA released into the circulation in these 17 patients had a lower functional activity as compared to that of normal subjects. PAI was significantly lower in patients before DDAVP than in normal subjects and the decrease in PAI after DDAVP was significantly less in patients than in controls. It is concluded from this study that patients with VWd have an abnormal fibrinolytic response after stimulation regardless of the severity of the disease. Furthermore, the results suggest either that patients with VWd have a double defect in VWF and tissue plasminogen activator or that the primary deficiency of VWF influences the synthesis and/or release of t-PA by endothelial cells.

Topics: Adolescent; Adult; Deamino Arginine Vasopressin; Endothelium, Vascular; Female; Fibrinolysis; Humans; Male; Middle Aged; Plasminogen Inactivators; Tissue Plasminogen Activator; von Willebrand Diseases; von Willebrand Factor

Nine healthy volunteers and 23 patients with various types of von Willebrand disease were studied before and after DDAVP infusion. We investigated the behaviour of factor VIII/von Willebrand factor measurements, and of tissue plasminogen activator and urokinase-type plasminogen activator. In mild von Willebrand disease the increase of both plasminogen activators was similar to that seen in normal controls. A different fibrinolytic behaviour was found in the type I platelet low and in the type III von Willebrand disease patients. An impaired and absent fibrinolytic response to DDAVP was seen in the former and in the latter von Willebrand disease, respectively. A close relation between either u-PA and t-PA or von Willebrand factor was observed. The possibility of a linkage among these three proteins was discussed.

Topics: Adolescent; Adult; Child; Deamino Arginine Vasopressin; Endothelium, Vascular; Factor VIII; Fibrinolysis; Humans; Middle Aged; Plasminogen Activators; Stimulation, Chemical; Urokinase-Type Plasminogen Activator; von Willebrand Diseases; von Willebrand Factor

A new family with a bleeding diathesis and FVIII deficiency secondary to abnormal binding of von Willebrand factor (vWF) to factor VIII (FVIII) is described. Two propositi of this family, an 18-year-old male and a 33-year-old female, both with a history of epistaxis, bruising, bleeding from the gums, epistaxis, hemarthrosis, and hematoma, were analyzed. Also additional members of the same family with no bleeding history were also studied. The propositi showed normal vWF activities, low FVIII activity; one of them had been diagnosed as having hemophilia A and the other was a hemophilia A carrier. Both showed a very poor response to treatment with FVIII concentrates and desmopressin (DDAVP) but a good clinical response to cryoprecipitate. APTT was prolonged and no inhibitory activity was noticeable in their plasmas. Thirty-five units per kilogram body weight of Hemofil M was infused to both propositi and FVIII reached basal level within 60 minutes of the infusion. No FVIII response at all was observed in the female after intravenous DDAVP administration. However, the male who received the infusion of 35 U/kg body weight of Humate-P achieved a normal FVIII level that was maintained for 12 hours. Multimeric analysis of vWF was normal in all the members studied. Von Willebrand factor domain for FVIII binding was assayed in the two propositi and in six other members of the same family by using a non-isotopic and sensitive method, a modification of the one previously described, using the Hemofil M concentrate as exogenous FVIII. The data obtained showed that both propositi had similar binding to that observed by using plasma of a patient with severe von Willebrand disease. Furthermore, five siblings had a decreased binding of vWF to FVIII, when compared with plasma from normal individuals or patients with hemophilia A. We also observed that, for screening purpose, the ratio of bound FVIII/immobilized vWF (at saturation of the anti-vWF and offering of 1 U/ml of exogenous FVIII) distinguished two levels of abnormality (normal range 0.70-1.15, propositi 0.004-0.007, and remaining members affected 0.25-0.42). The most probable explanation is that the propositi are homozygous or double heterozygous, the other five siblings affected being heterozygous for a recessive vWF defect. This more accessible assay presented here may be of help in routine analysis for diagnosing this type of von Willebrand disease, which has important implications for therapy and genetic counse

Topics: Deamino Arginine Vasopressin; Factor VIII; Genes, Recessive; Heterozygote; Humans; Pedigree; Protein Binding; von Willebrand Diseases; von Willebrand Factor

Tissue plasminogen activator (t-PA) and von Willebrand factor (vWF) are both released by vascular endothelial cells after the infusion of DDAVP. Such release has not been observed in patients with severe von Willebrand's disease (vWD). In the present work we demonstrate that the degree of simultaneous DDAVP-induced release of t-PA and vWF, in patients with vWD, is strictly related to the platelet vWF content. Twelve patients with type I, and three patients with type III vWD were studied. The type I vWD group included three patients with reduced platelet vWF content (platelet-low) and nine patients with normal levels (platelet-normal). In all patients studied the plasma t-PA levels were within the normal range. No significant change in either t-PA or vWF was observed after DDAVP in the patients with undetectable levels of platelet vWF (type III vWD). A mild increase was found in those patients with type I platelet-low, while in type I platelet-normal vWD the response was similar to that observed in normal subjects. The release of the two molecules appeared, therefore, to be linked to platelet vWF content and the rates of increase in both t-PA and vWF were similar in each group of patients studied. Since platelets are regarded as a tissue compartment of vWF our findings seem to suggest that the presence of vWF and its release from endothelial cells is required for a normal concomitant release of t-PA. In contrast, post-DDAVP release of vWF seems to be independent from that of t-PA since it was normal in a patient with congenital deficiency of t-PA release.

Topics: Adolescent; Adult; Antigens; Blood Platelets; Deamino Arginine Vasopressin; Factor VIII; Female; Genetic Diseases, Inborn; Humans; Male; Middle Aged; Tissue Plasminogen Activator; von Willebrand Diseases; von Willebrand Factor

We have identified a patient with von Willebrand's disease (vWD) resembling type IIB vWD, with increased ristocetin induced platelet aggregation (RIPA), the absence of the large multimers of von Willebrand factor (vWF) in plasma, and the presence of the large multimers in platelets in whom a family study indicated a probable double heterozygous inheritance pattern. The propositus was a 12-year-old boy with frequent epistaxis and bruising. Abnormal hemostatic findings included a prolonged bleeding time (BT), decreased levels of factor VIII coagulant activity (VIIIC), von Willebrand factor antigen (vWF:Ag), ristocetin cofactor (RCof), and an increased RIPA. In the presence of ristocetin, binding of the patient's plasma vWF to normal platelets was increased but binding of normal vWF to his platelets was normal. SDS-agarose gel (1.5%) electrophoresis revealed that plasma vWF lacked the large multimers, and 3.0% gel electrophoresis revealed that the multimers had a 5-band pattern similar to normal. The above findings were consistent with type IIB vWD, but 1-deamino[8-D-arginine]-vasopressin (DDAVP) infusion resulted in a shortened BT and the transient appearance of large multimers without a decrease in the platelet count. Family studies revealed that his mother has mild bleeding symptoms, decreased VIIIC, vWF:Ag, and RCof levels and normal to slightly reduced RIPA with a multimer pattern consistent with type I vWD. In contrast, the father, sister, and paternal grandfather were asymptomatic, with a slightly decreased VIIIC level but a normal BT and vWF:Ag and RCof levels. Their RIPA and vWF binding to normal platelets were increased, but unlike the propositus their plasma contained large multimers. We concluded that the propositus is a type IIB-like variant differing from previously reported IIB variants in two ways: 1) his response to DDAVP and 2) a possible double heterozygous mode of inheritance rather than the usual dominant route.

Topics: Blood Platelets; Child; Deamino Arginine Vasopressin; Electrophoresis, Agar Gel; Heterozygote; Humans; Infusions, Intravenous; Male; Pedigree; Platelet Aggregation; Ristocetin; Sodium Dodecyl Sulfate; von Willebrand Diseases; von Willebrand Factor

The authors describe two cases of wisdom tooth germ removal in female adolescents presenting with von Willebrand's disease. The effect of the Minirin injection was studied during a preoperative test and allowed carrying out the operation with normalized hemostasis, without using substitution factors and with no postoperative complications. The authors specify the indications and limitations of the use of desmopressin before surgery.

Topics: Adolescent; Contraindications; Deamino Arginine Vasopressin; Factor VIII; Female; Hemostasis; Humans; Molar, Third; Tooth Extraction; Tooth Germ; von Willebrand Diseases

We have studied a patient with von Willebrand's disease (vWd) whose von Willebrand factor (vWf) multimer patterns showed significant decreases of all but the major fast moving vWf multimer (promoter). Bleeding time (BT) was very prolonged, there was almost no ristocetin-induced platelet aggregation (RIPA) and vWf levels were very low. The factor VIII: C/vWf: Ag ratio appeared to be higher than normal because of the relatively increased concentration of factor VIII: C. The infusion of DDAVP normalized BT, improved RIPA and restored normal factor VIII: C levels, these effects lasted for 5 h even though only a slight increase of vWf: Ag and vWf: RCoF was observed. RIPA was completely inhibited by an anti-glycoprotein (GP) Ib monoclonal antibody that recognizes the ristocetin-induced vWf binding site. Plasma vWf multimer analysis revealed only slight increases of all components and an additional, more pronounced representation of vWf protomer. These data suggest that the patient has an abnormal vWf molecule characterized by a greater ability to carry factor VIII than would be expected from the vWf levels. Furthermore, since the vWf protomer was the only significant vWf component present both before and after DDAVP infusion we hypothesize that some of the haemostatic functions of the patient's vWf may depend on it.

Topics: Bleeding Time; Deamino Arginine Vasopressin; Factor VIII; Female; Humans; Middle Aged; von Willebrand Diseases; von Willebrand Factor

To evaluate the effect of a nasal spray preparation of desmopressin (DDAVP) on levels of factor VIII activity, ristocetin cofactor activity, and von Willebrand antigen as well as the length of bleeding time in patients with mild hemophilia A and von Willebrand disease; to determine whether effective hemostatic levels can be attained; and to compare the effect of this spray with that of standard intravenous desmopressin treatment.. Before-and-after trial in patients known to respond to intravenous desmopressin.. Regional, comprehensive, hemophilia diagnosis and treatment center.. A total of 22 patients, including 11 patients with von Willebrand disease, 8 patients with mild hemophilia A, and 3 symptomatic hemophilia carriers.. Patients were infused with desmopressin, 0.3 micrograms/kg body weight. At least 1 week later, they were taught to self-administer desmopressin nasal spray, 150 micrograms to each nostril.. In patients with hemophilia, the level of factor VIII activity was measured; in patients with von Willebrand disease, levels of factor VIII activity, ristocetin cofactor activity, and von Willebrand antigen as well as bleeding time were measured before and after each administration of desmopressin.. Desmopressin, when administered intravenously or intranasally, elevated levels of factor VIII, ristocetin cofactor, and von Willebrand antigen in both mildly hemophiliac patients and patients with von Willebrand disease when compared with baseline measures (P less than 0.05). Factor VIII levels adequate for hemostasis were achieved by 82% of the hemophiliac patients. An abnormal bleeding time was corrected in the majority (62%) of patients with von Willebrand disease.. A nasal spray preparation of desmopressin apparently was effective both in treating bleeding episodes and when used prophylactically for minor surgical procedures in several patients.

Topics: Administration, Intranasal; Antigens; Bleeding Time; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Heterozygote; Humans; Immunoelectrophoresis; Infusions, Intravenous; von Willebrand Diseases; von Willebrand Factor

The treatment with desmopressin prior to surgery of patients with mild haemophilia A (HA) and Von Willebrand's disease (VWD) was retrospectively evaluated in a general hospital, from 1978 until 1987. From a group of 87 treated patients, 40 patients are reported (21 VWD, 19 HA) of which plasma factor VIII (FVIII) and Von Willebrand factor (VWF) concentrations were determined before, and twice after desmopressin treatment. Desmopressin was administered intravenously at a dose of 0.4 micrograms/kg body weight. Tranexamic acid was used only when surgery in the mouth cavity was performed, at a dose of 1 gram three times a day. Side effects were seen only in 5 patients (3 VWD, 2 HA). No significant difference between both groups was seen in bleeding tendency, transfusion necessity and side effects (chi 2 test). In both groups, FVIII and VWF concentrations increased significantly after 20 and 60 minutes following DDAVP administration (paired t-test). After 360 minutes, the FVIII concentration increased significantly in both groups, however, only in the VWD patients did VWF increase significantly. In neither group did initial FVIII concentrations correlate with the increase in FVIII (linear regression analysis). One female patient reacted differently to DDAVP, with a decrease in FVIII and VWF values. Desmopressin is a safe and effective agent in the management and prophylaxis of bleeding tendency in patients with mild HA and mild VWD.

Topics: Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Hemorrhage; Humans; Premedication; Retrospective Studies; Surgical Procedures, Operative; von Willebrand Diseases; von Willebrand Factor

Early recognition that plasma infusions could correct the prolonged bleeding time and factor VIII deficiency in von Willebrand's disease (vWD) prompted major research efforts. Identification of the factor VIII molecule, its components, and its functions has provided critical information about replacement requirements to prevent or control bleeding. Plasma and cryoprecipitate have been the mainstay of therapy. Until recently, lyophilized coagulation factor concentrates had little usefulness in treating vWD. Current factor VIII concentrates prepared by monoclonal or recombinant technology (or both) are devoid of von Willebrand factor. Desmopressin has been a revolutionary synthetic agent useful in numerous patients with mild or moderately severe vWD. In many patients, however, desmopressin is ineffective. Only a few currently available factor VIII concentrates contain biologically active von Willebrand factor and can be used to prepare patients for surgical procedures or to stop hemorrhage. Inhibitors of von Willebrand factor arise de novo or in patients with vWD. Management with activated prothrombin complex concentrates or removal of antibody with protein A columns has been successful. Despite current technologic advances, not all patients with vWD can be successfully treated. Many problems with vWD continue to be unresolved.

Topics: Blood Transfusion; Deamino Arginine Vasopressin; Factor VIII; Female; Humans; Male; Pregnancy; Tachyphylaxis; von Willebrand Diseases; von Willebrand Factor

Topics: Deamino Arginine Vasopressin; Factor IX; Factor VIII; Hemophilia A; Hemophilia B; Humans; Mutation; von Willebrand Diseases; von Willebrand Factor

We describe two members of a single family, father and son, with mild factor XII deficiency associated to von Willebrand disease (vWD) with aberrant structure in whom distinct multimeric abnormalities and an abnormal proteolytic processing of von Willebrand factor (vWF) after desmopressin (DDAVP) administration were present. They had a mild bleeding history, low levels of vWF-related activities, and a prolonged bleeding time. Low-resolution agarose gel electrophoresis showed a vWF with all size multimers in plasma and platelets. Higher-resolution agarose gels demonstrated that the main band was present, but the relative proportion of the satellite bands was markedly reduced. The smallest oligomer was not increased. After the infusion of DDAVP to the father, a transient increase in the relative proportion of the satellite bands was seen, as described in normal individuals. No difference in the structure of vWF was observed when blood was collected with proteinase inhibitors. The analysis of native subunits of vWF and their proteolytic derived fragments, after DDAVP administration, showed a temporary augmentation of the 176 kDa fragment, as seen in normal subjects, as well as an increase of the 189 kDa fragment. This finding had not been reported previously either in normal individuals or in patients with vWD.

Topics: Adult; Child, Preschool; Deamino Arginine Vasopressin; Electrophoresis, Agar Gel; Factor XII Deficiency; Humans; Infusions, Intravenous; Male; Peptide Fragments; von Willebrand Diseases; von Willebrand Factor

Topics: Adolescent; Cerebral Hemorrhage; Cerebral Ventricles; Combined Modality Therapy; Deamino Arginine Vasopressin; Female; Humans; Intracranial Arteriovenous Malformations; Subarachnoid Hemorrhage; von Willebrand Diseases

A 73-year old patient suffering from IgM-paraproteinemia, plasma hyperviscosity, and acquired v. Willebrand's disease developed two consecutive bleeding episodes. He was treated by double-bag plasmapheresis and double-bag plasmapheresis combined with DDAVP. This combined therapy was superior to plasmapheresis alone, since bleeding ultimately stopped and did not reoccur. Thus, labour and expense of large volume plasma exchange and the costs of F VIII therapy could be prevented.

Topics: Aged; Blood Viscosity; Combined Modality Therapy; Deamino Arginine Vasopressin; Hemorrhagic Disorders; Humans; Male; Plasmapheresis; von Willebrand Diseases; Waldenstrom Macroglobulinemia

Endothelial cells in biopsied blood vessels from von Willebrand factor (vWf)-deficient Doberman pinscher dogs contain immunologically detectable vWf. These dogs and normal dogs were treated with DDAVP (0.6 microgram/kg) and epinephrine (0.5 microgram/kg/min for 30 minutes) and were exercised, using 5 different exercise protocols, (3-4 m/s for 5-40 minutes at 0-5% grade) to determine if treatments reported to increase plasma factor VIII:C/vWf complex in humans would elevate canine plasma vWf. Following the two most strenuous exercise conditions--30 and 40 minutes--plasma von Willebrand factor antigen (vWf:Ag) increased in normal dogs by 30% and 70%, respectively. Factor VIII:C was increased 47% by the most strenuous exercise conditions. The vWf-deficient dogs would not exercise beyond 30 minutes and neither vWf:Ag nor factor VIII:C activity increased. Following DDAVP, plasma vWf:Ag increased in the normal dogs by 47% and factor VIII:C activity was increased by 48%. Factor VIII:C activity increased by 30% in the vWf-deficient dogs, but there was only a slight change in vWf:Ag. Bleeding time decreased in 5 of 6 vWf-deficient dogs. In the normal dogs vWf:Ag increased by 14% after epinephrine infusion, but factor VIII:C activity did not change; neither parameter was altered in the vWf-deficient dogs. While the factor VIII:C/vWf:Ag complex was increased in the normal dog by exercise and DDAVP, the increase is not as pronounced as has been reported for humans. It is not known whether the poor response of the vWf-deficient dog is due to low levels of vWf in their endothelium or to a release defect.

Topics: Animals; Deamino Arginine Vasopressin; Dog Diseases; Dogs; Endothelium, Vascular; Epinephrine; Factor VIII; Immunohistochemistry; Physical Exertion; von Willebrand Diseases; von Willebrand Factor

DDAVP has a major therapeutic role to play in the management of moderate to mild haemophilia and vWD, particularly type I. In addition it helps to classify vWD patients and to procure more and better blood products for treatment. The addition of suitable, reliable preparations for subcutaneous and intranasal use will enable early and follow-up treatment to be self-administered. The limiting features are that FVIII:C levels are not high enough or sustained long enough for some bleeding episodes and lytic activity may occasionally be clinically significant warranting simultaneous use of antifibrinolytic agents. Side effects are minimal but caution is needed in the very young and those with vascular disease. Cryoprecipitate remains the commonest source of normal multimeric VIII:vWF. The evaluation of procedures to decrease viral transmission is incomplete as is effectiveness of different preparations in correcting the BT in vWD. Wet cryo continues to be the product most likely to correct BT in severe vWD but laboratory tests better able to predict clinical haemostasis need to be developed.

Topics: Child; Child, Preschool; Deamino Arginine Vasopressin; Drug Therapy, Combination; Factor VIII; Female; Fibrinogen; Hemophilia A; Humans; Male; New Zealand; von Willebrand Diseases

Desmopressin acetate (1-desamino-8-D-arginine vasopressin, DDAVP) has mostly been given by the parenteral route for the treatment of mild hemophilia A and von Willebrand's disease type I. In the present study the hemostatic effects of desmopressin acetate administered intranasally by spray in a dose of 300 micrograms and intravenously 0.3-0.4 micrograms/kg were assessed and compared in 8 patients with hemophilia A and 22 patients with von Willebrand's disease type I. A bioequivalent response to intravenous and intranasal desmopressin acetate was found in Factor VIII coagulant activity (VIII:C) in the hemophilia patients. In the von Willebrand patients, an equivalent shortening of the bleeding time was seen after the two modes of administration, even though intravenous injection gave a higher increase in plasma levels of VIII:C and vWF:Ag. In five patients with von Willebrand's disease the duration of the spray effect on VIII:C and vWF:Ag was followed for 24 h. After 12 h the mean level of VIII:C was 1.4, and of vWF:Ag 1.5, times the basal level. The findings suggest that the spray can be recommended for home or prophylactic treatment of patients with mild hemophilia A and von Willebrand's disease.

Topics: Administration, Intranasal; Antigens; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Hemostasis; Humans; Injections, Intravenous; von Willebrand Diseases; von Willebrand Factor

Factor VIII (FVIII) response to desmopressin (deamino-8-D-arginine vasopressin, abbreviated DDAVP) was studied in patients with mild Hemophilia A and von Willebrand Disease (vWD) who attend our Hemophilia Clinic. Thirty eight children and 9 adults had their F VIII components assayed 60 minutes after intravenous (IV) administration of DDAVP, 0.35 microgram/kg. Among 27 hemophiliacs, F VIII coagulant activity (F VIII: C) increased from a mean of 16.8 to 59.2 u/dL; with an average 3.2-fold increase. In 20 vWD patients, the mean F VIII:C and von Willebrand Factor increased from a mean of 50.1 to 136%; and from 22.6 to 75.6%; with an average 3.0 and 5.7-fold increase, respectively. The overall F VIII:C response was good or excellent in 81.5% of the hemophiliacs, and in 89.5% of the vWD patients tested. No significant side effects were observed. This study has demonstrated that IV DDAVP can cause an increase of F VIII:C and vWF to hemostatic levels, and thus it may be useful for the control of bleeding episodes in most of the patients tested in our clinic.

Topics: Adult; Child; Deamino Arginine Vasopressin; Drug Evaluation; Factor VIII; Hemophilia A; Humans; von Willebrand Diseases; von Willebrand Factor

Our study shows that the thrombocytopenia described in type IIB von Willebrand's disease (vWd) after 1-desamino-8-D-arginine vasopressin (DDAVP) infusion is, at least partially, a pseudothrombocytopenia. There was a discrepancy in platelet counts in blood anticoagulated with EDTA (less than 10 x 10(3)/microliters) or citrate (55 x 10(3)/microliters) in one patient with type IIB vWd and chronic thrombocytopenia (80 x 10(3)/microliters) after DDAVP infusion. Furthermore, DDAVP induced a normalization of patient's prolonged bleeding time. Spontaneous platelet aggregation (SPA) observed in platelet-rich plasma before DDAVP infusion was inhibited completely by monoclonal antibodies which block binding of fibrinogen, vWf and fibronectin to GPIIb-IIIa. SPA was partially inhibited by a monoclonal antibody which blocks the binding of vWf to GPIb. After DDAVP, in contrast, SPA partially persisted in the presence of anti-GPIIb-IIIa monoclonal antibodies but was completely inhibited by anti-GPIb monoclonal antibody. Therefore GPIb and GPIIb-IIIa complex seem to play a different role in SPA before and after DDAVP infusion into type IIB vWd.

Topics: Adult; Antibodies, Monoclonal; Anticoagulants; Bleeding Time; Blood Platelets; Citrates; Citric Acid; Deamino Arginine Vasopressin; Edetic Acid; Humans; Macromolecular Substances; Male; Platelet Aggregation; Thrombocytopenia; von Willebrand Diseases; von Willebrand Factor

Mice of the RIIIS/J inbred strain have prolonged bleeding times (greater than 15 minutes) after experimental injury when compared with normal C57BL/6J mice (1.8 minutes) and other strains of mice. The prolonged bleeding time was accompanied by normal platelet counts. Platelet aggregation with collagen and agglutination with ristocetin were not significantly altered in RIIIS/J mice. Also, platelets from RIIIS/J mice had normal serotonin content and normal numbers of dense granules by electron microscopy. Thus, the bleeding abnormality is not due to platelet storage pool deficiency as has been found in several other mouse mutants. The activated partial thromboplastin time (APTT) which plasma from RIIIS/J mice was prolonged compared with normal mice, and factor VIII:C activity and von Willebrand antigen levels were one half to one third that of normal mouse plasma. Factor XI activity was also significantly deficient (levels at 42% to 64% of normal). Plasma of RIIIS/J mice contained the full complement of multimers of von Willebrand factor, although each multimer was lower in concentration compared with that in normal mice. Platelet alpha-granule von Willebrand antigen levels were similar to those of normal mice. The prolonged bleeding time of RIIIS/J mice was corrected by treatment with desmopressin. Heterozygous C57BL/6J x RIIIS/J F1 animals had low plasma von Willebrand antigen levels like the RIIIS/J parent and had variable bleeding times. Inheritance of the bleeding tendency was as an incomplete dominant, autosomal trait. These data indicate the RIIIS/J strain is a suitable animal model for type IA von Willebrand disease.

Topics: Animals; Antigens; Bleeding Time; Blood Platelets; Cytoplasmic Granules; Deamino Arginine Vasopressin; Disease Models, Animal; Factor VIII; Factor XI; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Microscopy, Electron; Partial Thromboplastin Time; Platelet Aggregation; Platelet Count; Serotonin; von Willebrand Diseases; von Willebrand Factor

A case of acquired von Willebrand disease (AvWD) associated with an IgA lambda multiple myeloma is reported. No form of inhibitor could be detected. SDS-agarose gel electrophoresis patterns of von Willebrand factor (vWF) both in plasma and platelet lysates were normal but a decrease in all-sized multimers with a type IA pattern was seen. After 1-deamino-8-D arginine vasopressin (DDAVP) infusion, vWF multimers larger than those seen in the resting state appeared in patient plasma, which were progressively cleared. Indirect immunofluorescence studies with a monoclonal antibody to vWF showed that vWF was selectively absorbed into myelomatous cells. This is the first case of AvWD associated with multiple myeloma resulting from the selective absorption of vWF into abnormal plasma cells. This feature established a new pathophysiological mechanism of AvWD in multiple myeloma and probably in other lymphoproliferative diseases.

Topics: Absorption; Aged; Deamino Arginine Vasopressin; Electrophoresis, Agar Gel; Female; Fluorescent Antibody Technique; Humans; Multiple Myeloma; Plasma Cells; von Willebrand Diseases; von Willebrand Factor

Topics: Blood Coagulation Tests; Deamino Arginine Vasopressin; Humans; Postoperative Period; Preoperative Care; von Willebrand Diseases

We have investigated the effects of 1-desamino-8-D-arginine vasopressin (DDAVP) infusion on platelet count and bleeding time in 4 patients with type IIB von Willebrand's disease (vWd). Three of four patients showed a normalization of the bleeding time within 1 h after the infusion, while bleeding time was not modified in the fourth. In accordance with the literature, thrombocytopenia was observed after DDAVP infusion, but this thrombocytopenia was due to the anticoagulants used for blood collection. In two patients (F.I., G.F.) no thrombocytopenia was observed when platelets were counted by fingerstick method but there was a 20% platelet decrease in blood samples collected in sodium citrate and a 50% decrease in samples collected in EDTA. Dramatic falls in platelet counts (70-95%) were observed in the additional two patients (C.A., D.Z.) after DDAVP infusion, when both sodium citrate or EDTA were used as anticoagulants. In the latter two patients there was also a 50% decrease in platelet count when the fingerstick method was used. The decrease in the patient's platelet count in EDTA samples after DDAVP infusion could be prevented, in part, by the previous additions of an anti GPIb monoclonal antibody and an anti GPIIb-IIIa monoclonal antibody. Thus, the thrombocytopenia observed in the four IIB vWd patients studied after DDAVP infusion seems to be, at least partially, a pseudothrombocytopenia depending on the calcium concentration in the blood samples and the availability of GPIb and GPIIb-IIIa receptors. These findings and the normalization of the bleeding time observed in three of the four patients has led us to reconsider the possible use of DDAVP in the treatment of our IIB vwd patients.

Topics: Anticoagulants; Bleeding Time; Blood Coagulation; Deamino Arginine Vasopressin; Humans; Infusions, Intravenous; Platelet Count; Platelet Membrane Glycoproteins; Thrombocytopenia; von Willebrand Diseases

Von Willebrand's disease is categorized into types and subtypes based on multimeric analysis of plasma von Willebrand's factor. Such categorization is of value because both the mode of inheritance and the choice of therapeutic material differ between subtypes. The Type IIB variant is characterized by hypersensitivity in vitro to ristocetin and thrombocytopenia after administration of desmopressin (DDAVP). Hypersensitivity to ristocetin has also been described in Type I variants but without thrombocytopenia after DDAVP. This report describes a new Type II variant characterized by the converse situation, absence of hypersensitivity to ristocetin in vitro but transient thrombocytopenia after intravenous administration of DDAVP.

Topics: Deamino Arginine Vasopressin; Drug Hypersensitivity; Female; Humans; Infusions, Intravenous; Male; Pedigree; Platelet Aggregation; Platelet Count; Ristocetin; Thrombocytopenia; von Willebrand Diseases; von Willebrand Factor

Von Willebrand's disease is a genetic bleeding disorder characterized by either a reduced plasma concentration of von Willebrand's factor (vWF) or a qualitative deficiency in that vWF which is produced. Previous therapy consisted of injecting concentrates of vWF manufactured from the pooled plasma of multiple donors. With the increased incidence and risk of serum borne transmission of such diseases as hepatitis and AIDS, the advantages of an alternative mode of therapy was obvious. In the course of using 1-desamino-8-D-arginine (desmopressin or DDAVP, a synthetic analogue of 8-arginine vasopressin, a hormone secreted in the posterior pituitary gland) in the treatment of diabetes insipidus, it was discovered that this drug causes the release of bound vWF into the plasma. The elevation lasts for several hours and is effective in producing hemostasis in some types of mild to moderate von Willebrand's disease. In 1984, desmopressin was approved for this usage in the United States. This paper discusses the use of DDAVP in the management of von Willebrand's disease and present two case reports of patients with von Willebrand's disease and in need of periodontal surgery.

Topics: Adult; Bone Resorption; Deamino Arginine Vasopressin; Hemostasis, Surgical; Humans; Male; Middle Aged; Periodontal Diseases; Periodontal Pocket; Surgical Flaps; von Willebrand Diseases

A Case of delivery in a 23-year-old woman after a prophylactic infusion of DDAVP is described. She had a life-long history of easy bruising and frequent epistaxis, with the diagnosis of vWD being made when she was 14 years old. A hemostatic examination showed a prolonged bleeding time, a moderate reduction in the factor VIII level (VIII: C) and von Willebrand Factor Antigen (vWF: Ag), decreased platelet aggregation by ristocetin, and depletion of platelet retention. In April, 1988, in the 34th week of pregnancy, she was admitted to our clinic in order to avoid abnormal bleeding during labor. On admission, the level of factor VIII, ristocetin aggregation, and platelet retention were normal, but the bleeding time remained prolonged. The diagnosis of vWD type I was made on the normal multimeric structure. The DDAVP infusion test revealed a shortening of the bleeding time and an increase in the vWF: Ag. In the 41st week of pregnancy, labor was induced, accompanied by infusion of DDAVP, she gave birth to an infant without any abnormal bleeding. Since conventional treatments with human plasma derivatives may cause complicating viral infections, we propose the infusion of DDAVP is one of the treatments to prevent the abnormal bleeding of the patient with vWD during labor.

Topics: Adult; Deamino Arginine Vasopressin; Female; Hemorrhage; Humans; Labor, Obstetric; Obstetric Labor Complications; Pregnancy; Pregnancy Complications, Hematologic; von Willebrand Diseases

Persistent gross hematuria associated with sickle hemoglobinopathy that fails to respond to conventional supportive therapy represents a difficult management dilemma. Two such patients with protracted, often painful, sickle trait macrohematuria are described. Both patients had normal renal anatomy and vasculature and had failed to respond to bed rest, intravenous hydration, and a trial of oral epsilon-aminocaproic acid. Patient 1 had normal coagulation function. Patient 2 had von Willebrand disease (decreased factor VIII antigen and quantitative ristocetin cofactor activity). Patient 1 responded to intravenous desmopressin acetate at a dose of 0.3 microgram/kg with a 155% increase in factor VIII clotting activity and a 135% increase in ristocetin cofactor and cessation of her macrohematuria within 18 hours after completion of the desmopressin infusion. She remained free of gross hematuria for 5 months with the exception of short-lived trauma-induced hematuria (in three voids) 6 weeks after desmopressin therapy. Patient 2 did not respond to intravenous desmopressin infusion despite a 234% and a 360% increase in factor VIII clotting activity and ristocetin cofactor, respectively. Intravenous desmopressin acetate may be helpful in halting protracted significant macrohematuria associated with sickle trait hemoglobinopathy in some patients when conventional management fails.

Topics: Adolescent; Anemia, Sickle Cell; Blood Coagulation Factors; Deamino Arginine Vasopressin; Female; Hematuria; Humans; Infusions, Intravenous; Male; Sickle Cell Trait; von Willebrand Diseases

Topics: Administration, Intranasal; Administration, Topical; Antifibrinolytic Agents; Deamino Arginine Vasopressin; Hemophilia A; Hemorrhage; Hemorrhagic Disorders; Hemostatics; Humans; Injections, Subcutaneous; Liver Cirrhosis; Surgical Procedures, Operative; Uremia; von Willebrand Diseases

A new variant of von Willebrand disease (vWD) was identified by a new analytic method which characterizes the ability of plasma von Willebrand Factor (vWF) to bind to purified factor VIII (F.VIII). vWF was isolated from small amounts of plasma by immunoadsorption with a selected monoclonal antibody to vWF previously coated onto wells of microtitration plates. Plasma F.VIII was removed from immobilized vWF by washing with 0.4 mol/L CaCl2; purified F.VIII was then added to the well. The amount of bound F.VIII was estimated directly in the wells by a chromogenic assay and immobilized vWF was estimated by an immunologic a pool of normal plasma, ten control individuals, 13 with hemophilia A and five with type I vWD. In all cases, the dose-response curves were linear and the slopes of the regression lines were essentially the same. The method was then applied to investigate the binding of vWF to F.VIII in two vWD patients (sister and brother) who demonstrated significantly lower activity of F.VIII than of vWF. The first patient, with a long history of epistaxis, bruising, and hematomas, showed a slightly prolonged bleeding time (10 minutes); 15% VIII:C and 39% of vWF:Ag and vWFRCo. Her brother, who has a bleeding syndrome but no hematomas, showed similar data (bleeding time 9 minutes, 20% VIII:C, 53% vWF:Ag and vWFRCo). Similar levels of F.VIII were observed in the two propositi by four different methods (one- and two-stage clotting and chromogenic and immunologic assays). Sodium dodecyl sulfate (SDS) 1.4% agarose gel electrophoresis showed that all multimers of vWF were present in both patients. vWF binding to F.VIII was markedly decreased in the two propositi. The abnormal binding of vWF to F.VIII was not corrected during pregnancy or after infusion of 1-deamino (8-D-arginine) vasopressin despite an increase in vWF levels. The qualitative abnormality of vWF in both patients was associated with a subtle alteration of the multimeric structure by SDS 3% agarose gel electrophoresis in which the two central subbands of the quintuplet of individual oligomers were undetectable or poorly visible. SDS-polyacrylamide gel electrophoresis under reducing conditions demonstrated a single band of 275 Kd in the plasma of both patients, and there was no evidence of a second band corresponding to pro-vWF, the precursor of the mature vWF subunit, suggesting that proteolytic processing of vWF was normal.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Blood Coagulation Tests; Deamino Arginine Vasopressin; Enzymes, Immobilized; Factor VIII; Female; Genetic Variation; Humans; Kinetics; Male; Protein Binding; von Willebrand Diseases; von Willebrand Factor

In this study a new variant of type II von Willebrand disease is identified by multimeric analyses of increasing resolving power. Prior to multimeric analysis, the patient was misdiagnosed as carrying an undefined abnormality in platelet function because of his normal von Willebrand factor antigen (vWF:Ag) and low borderline ristocetin cofactor (Ricof) levels. Absence of the largest multimers from the patient's plasma and platelets was shown in a low-resolution system, but all the multimers were present in his relatives. An abnormality in the complex multimeric structure was demonstrated in both plasma and platelets with high-resolution agarose gels. The plasma of the proband and of several family members shows a broader central band with a minor, faster moving satellite band differing from the typical "triplet pattern" observed with normal plasma. Platelets show a "doublet" that runs with a mobility different from the "doublet" in normals. Therefore the proband may be either a homozygote or double heterozygote for this new abnormality. Treatment with desmopressin (DDAVP) on several occasions corrected the prolonged bleeding time of the patient only transiently. Factor VIII increased significantly, but vWF:Ag and Ricof responded poorly. We conclude that this vWF abnormality is different from those observed in the other variants (II A-G) previously described. Therefore the proposed designation for this new variant is type II H.

Topics: Adult; Antigens; Bleeding Time; Blood Platelets; Deamino Arginine Vasopressin; Factor VIII; Genetic Variation; Humans; Macromolecular Substances; Male; Platelet Aggregation; Ristocetin; von Willebrand Diseases; von Willebrand Factor

Dominant transmission of a variant of von Willebrand's disease (vWD) with aberrant polymerization of von Willebrand factor (vWF) has been identified in a Scottish family. Multimer analysis of plasma vWF from the propositus and her father revealed an identical pattern to that previously reported in families designated as type IID vWD. There is loss of the larger multimers and presence of an intermediate subsidiary band not seen in normal subjects or other vWD variants. Platelet/vWF interaction induced by ristocetin is not enhanced in these cases and the platelet vWF shows the same aberrant multimer pattern as plasma vWF. DDAVP infusion in two affected members of the Scottish family and in one of the index cases produced a rise in plasma vWF antigen and factor VIII. Higher molecular weight vWF multimers appeared transiently after infusion of desmopressin (1-deamino-8-D-arginine vasopressin, abbreviated DDAVP) coincident with shortening of the bleeding time. The platelet counts did not change after the DDAVP infusions. DDAVP should be considered for management of bleeding in this variant of von Willebrand's disease.

Topics: Adult; Blood Platelets; Deamino Arginine Vasopressin; Female; Humans; Macromolecular Substances; Male; von Willebrand Diseases; von Willebrand Factor

A case of acquired von Willebrand's syndrome (avWs) secondary to benign monoclonal gammopathy, is described, in which desmopressin (DDAVP) has proven effective repeatedly in preventing bleeding after tooth extraction. The laboratory pattern was similar to that of congenital type IA von Willebrand's disease. After DDAVP, prolonged bleeding time and factor VIII/von Willebrand factor activities were normalized. The disappearance rate of the elicited activities was similar to that observed in patients with congenital disease. This report adds to the scarce data concerning the haemostatic effectiveness of DDAVP in avWs and suggests that this agent might also be used in controlling or preventing bleeding in patients with the acquired disease, selected on the basis of their biological responsiveness to a test-infusion.

Topics: Deamino Arginine Vasopressin; Humans; Male; Middle Aged; Oral Hemorrhage; Paraproteinemias; Tooth Extraction; von Willebrand Diseases; von Willebrand Factor

Topics: Bleeding Time; Deamino Arginine Vasopressin; Female; Humans; Infusions, Intravenous; Middle Aged; Platelet Count; von Willebrand Diseases

The consistency in time of responses to separate desmopressin (DDAVP) infusions in patients with von Willebrand's disease (vWD) and mild or moderate hemophilia A has been the subject of limited investigation. We report here the results of a clinical study undertaken to test the consistency of responses to repeated DDAVP administrations in 22 patients with vWD and 10 with mild or moderate hemophilia A (time interval between first and last infusion ranging from 1 to 77 months; median, 13 months). In patients with vWD, 80% of cases showed a departure of less than 20% from the average VIII:C peak level calculated after the two infusions. A similarly consistent pattern was observed for bleeding times recorded 30 minutes after each infusion. In patients with hemophilia A, some infused on more than two instances, the departure from the average VIII:C peak level was less than 20% in nearly 70% of cases. A good within-family consistency was also demonstrated by analyzing data obtained from seven kindreds with vWD and two with hemophilia A. In conclusion, our study suggests that the pattern of responsiveness observed after a DDAVP test-infusion can be reliably used to decide the future clinical management of the individual patient and that a similar pattern of response is usually observed within the same kindred.

Topics: Deamino Arginine Vasopressin; Drug Administration Schedule; Hemophilia A; Humans; Time Factors; von Willebrand Diseases

Desmopressin (DDAVP) has recently been found to improve hemostasis in patients with congenital or acquired disorders of coagulation and to reduce operative blood loss in patients with normal hemostasis undergoing certain surgical procedures. Despite its potent antidiuretic effect, severe hyponatremia after the intravenous administration of DDAVP is felt to be rare. We report four cases of severe hyponatremia with serious clinical sequelae occurring in patients with underlying coagulopathies who were treated prophylactically with DDAVP to improve hemostasis prior to surgical procedures. Each patient received multiple (3-22) doses of DDAVP and was given intravenous hydration with hypotonic solutions before developing clinical signs and laboratory evidence of hyponatremia. We believe that the risk of significant hyponatremia after treatment with intravenous DDAVP may be higher than is generally appreciated and that patients undergoing surgical procedures, who often receive multiple doses of DDAVP and intravenous hydration, are at particular risk for this complication. Hypotonic intravenous solutions should be avoided and serum sodium levels should be monitored frequently in those patients receiving multiple doses of DDAVP.

Topics: Adenoidectomy; Adolescent; Adult; Cesarean Section; Child, Preschool; Deamino Arginine Vasopressin; Drainage; Female; Hemophilia A; Hemostasis, Surgical; Humans; Hyponatremia; Male; Thrombocytopenia; Tonsillectomy; von Willebrand Diseases

Out of 113 patients with vWD 15 were of type II. The basic test programme included F VIII:C, vWF-Ag, RCF and BT (Ivy). All type II patients had relatively high vWF-Ag and low RCF values. CIEP proved increased anodal migration velocity. IRMA testing of vWF:Ag was showing narrow correlation with RCF. Thrombocyte count was unchanged after DDAVP infusion and RIPA was always diminished. Finally multimeric sizing was done in 6 patients. From the completely diagnosed patients 5 are of type IIA and one seems to have type IIC. Nobody of the 15 had the characteristics of type IIB.

Topics: Antigens; Bleeding Time; Deamino Arginine Vasopressin; Humans; von Willebrand Diseases; von Willebrand Factor

In our study, we wanted to evaluate the clinical effect of s.c. DDAVP on haemostasis in different kinds of bleeding disorders. A total of 109 patients was treated with DDAVP s.c. at a dose of 0.4 microgram/Kg body weight. An effect of DDAVP on F VIII modalities was found after s.c. injection in all patients, but in comparison to i.v. DDAVP, the effect seems to be somewhat less. From our data, the patients blood groups do not influence the amount of F VIII modalities. Furthermore, the s.c. injection of DDAVP was found to be effective in patients with disorders of primary haemostasis. A number of operations was performed under the use of s.c. DDAVP in 24 patients with different kinds of bleeding disorders, in none of them, bleeding complications occurred.

Topics: Administration, Intranasal; Adolescent; Adult; Aged; Bleeding Time; Child; Child, Preschool; Deamino Arginine Vasopressin; Hemophilia A; Hemorrhage; Humans; Infusions, Intravenous; Injections, Subcutaneous; Middle Aged; von Willebrand Diseases

Topics: Deamino Arginine Vasopressin; Filtration; Humans; Male; Platelet Aggregation; Platelet Function Tests; von Willebrand Diseases

Topics: Adult; Deamino Arginine Vasopressin; Dental Care for Disabled; Female; Humans; Male; Oral Hemorrhage; Tooth Extraction; von Willebrand Diseases

Topics: Aminocaproates; Aminocaproic Acid; Deamino Arginine Vasopressin; Dental Care for Disabled; Humans; Molar, Third; Oral Hemorrhage; Tooth Extraction; Tooth, Impacted; Tooth, Unerupted; von Willebrand Diseases

Topics: Adolescent; Adult; Child; Deamino Arginine Vasopressin; Dental Care for Disabled; Hemophilia A; Hemostasis, Surgical; Humans; Middle Aged; Oral Hemorrhage; Tooth Extraction; Tranexamic Acid; von Willebrand Diseases

Desmopressin (DDAVP) has gained wide acceptance as the drug of first choice in the treatment or prevention of haemorrhages in the majority of patients with von Willebrand's disease (vWd). However, data concerning the clinical effectiveness of DDAVP refer generally to mild vWd, with factor VIII and vW factor levels usually above 20% of normal. In 14 patients with type I vWd characterized by very low plasma levels of factor VIII coagulant activity (VIII:C) and vWf, measured as ristocetin cofactor activity (lower than 20% and 3% of normal respectively), but with a normal intraplatelet content of vWf, a test infusion of DDAVP (0.4 microgram/kg) elicited a very marked increase of VIII:C and vWf and normalized the bleeding time. All these patients subsequently underwent tooth extraction after DDAVP infusion. The incidence of bleeding was remarkably low, with only two minor late bleeding episodes easily stopped by repeating DDAVP infusion. Compared to the cases of type I vWd with unknown intraplatelet vWf content reported in the literature, this subgroup of patients had a more marked, albeit short-lived, increment of VIII:C and vWf.

Topics: Adolescent; Adult; Antigens; Blood Platelets; Deamino Arginine Vasopressin; Factor VIII; Female; Hemorrhage; Humans; Male; Middle Aged; Tooth Extraction; von Willebrand Diseases; von Willebrand Factor

An acquired von Willebrand's disease developed in two patients in association with a monoclonal gammopathy plus a Sjögren's syndrome and a chronic lymphocytic leukaemia (CLL). In both cases a plasma inhibitor to von Willebrand factor (vWf) was suspected and characterized after plasma gel filtration. The inhibitor was shown to be entirely complexed with vWf and was only demonstrated after complex dissociation by heating. The inhibitor was able to inhibit the binding of 125I-vWf to platelets in the presence of ristocetin in both cases and to thrombin-stimulated platelets in one case. In the two patients, the highest molecular weight multimers (HMWM) of vWf were absent when assessed by sodium dodecyl-sulphate agarose plasma electrophoresis. Intravenous infusion of 1-deamino-(8-D-arginine) vasopressin (DDAVP) resulted in the appearance of the HMWM in both cases and of the satellite bands of each multimer subunit which were lacking prior to the infusion in one patient. After transfusion of a VIII/vWf concentrate containing a significant amount of HMWM, there was a rapid plasma clearance of the vWf-related activities and of the HMWM when compared to that seen in a patient with type III constitutional vWD. We conclude that in the two patients studied the coagulation defect was related to the presence of a circulating inhibitor to vWf which could be responsible for the disappearance of the HMWM from plasma.

Topics: Aged; Blood Platelets; Deamino Arginine Vasopressin; Factor VIII; Female; Humans; von Willebrand Diseases; von Willebrand Factor

Infusion of 1-deamino-(8-D-arginine)-vasopressin (DDAVP) into patients with IIB von Willebrand's disease (vWD) has been reported to induce thrombocytopenia. In some families with this disorder thrombocytopenia is present even in the resting state. We have investigated the basis of this chronic thrombocytopenia in one such patient by performing platelet recovery and survival studies. Increased platelet consumption was suggested by a decrease in platelet recovery (40.5%, normal 45%) and mean platelet survival (112 h, normal range 144-224 h). In addition, we have administered test infusions of DDAVP and observed the effect on bleeding time and platelet count. DDAVP caused a decrease in the median platelet count from 86 x 10(9)/l (range 30-221) to 60 x 10(9)/l (range 5-144), the individual decline in the nine subjects ranging from 12% to 84% compared to the pretreatment values. Formation of platelet aggregates was observed in all patients following DDAVP. The bleeding time was prolonged before DDAVP in all patients and lengthened further in two after the infusion. However, partial correction of the bleeding time was seen in three and normalization in one patient following DDAVP infusion. Two IIB vWD patients were treated with virus-inactivated cryoprecipitate (Ristofact). Infusion of cryoprecipitate was followed by rapid appearance of all but the largest vWF multimers in plasma and did not affect the platelet count. The bleeding time was normalized in one patient but remained prolonged in the other. In conclusion, in IIB vWD patients virus-inactivated cryoprecipitate is the treatment of choice in the case of bleeding. Infusion of DDAVP might be effective in a subset of IIB vWD patients that has yet to be characterized.

Topics: Bleeding Time; Blood Platelets; Cell Survival; Deamino Arginine Vasopressin; Factor VIII; Fibrinogen; Humans; Platelet Count; von Willebrand Diseases; von Willebrand Factor

When normal volunteers or patients with type I von Willebrand disease (VWD) are given desmopressin (DDAVP), a set of larger-than-normal (supranormal) von Willebrand factor (VWF) multimers, similar to those present in VWF-containing cells such as platelets megakaryocytes and endothelial cells, appear transiently in postinfusion plasma. In two kindreds with mild lifelong bleeding symptoms transmitted as an autosomal dominant trait, all ten symptomatic members (but none of the five asymptomatic members) had a supranormal multimeric structure for plasma VWF, apparently identical to that seen for postdesmopressin normal plasma. Plasma factor VIII coagulant activity (VIII:C), VWF antigen (VWF:Ag), ristocetin-induced platelet agglutination, and ristocetin cofactor (RiCof) activity were low. Platelet VWF:Ag and RiCof levels (tested for three patients only) were normal. Bleeding times were normal or slightly prolonged. The patients' platelet multimeric structure was the same as that for normal platelets. After desmopressin infusion the plasma VWF multimeric structure remained supranormal as for preinfusion plasma, with VIII:C VWF:Ag and RiCof increasing markedly over baseline values and disappearing at a normal rate. Examination of the VWF subunit composition from three of these patients indicated that proteolytic processing of their VWF did not differ from normal. This study describes the first variant of VWD with a supranormal multimeric structure.

Topics: Blood Platelets; Deamino Arginine Vasopressin; Humans; Pedigree; Polymers; von Willebrand Diseases; von Willebrand Factor

Topics: Animals; Blood Transfusion; Deamino Arginine Vasopressin; Dog Diseases; Dogs; Female; Plasma; von Willebrand Diseases

Topics: Animals; Deamino Arginine Vasopressin; Dog Diseases; Dogs; Female; Hemorrhage; Intraoperative Complications; Spinal Cord Compression; von Willebrand Diseases

1-deamino-8D-arginine vasopressin was given subcutaneously at the dosage of 0.3 micrograms/Kg. b.w. to 24 mild factor VIII deficient patients (16 mild, 2 moderate hemophiliacs and 6 patients with von Willebrand's Disease), to treat bleedings (10 episodes) or to prevent bleeding during and after dental extractions (6 extractions) and surgery (11 interventions). None of the patients who underwent surgery bled. The vasopressin analogue was effective in the early treatment of muscle hematomas and promptly stopped all mucosal hemorrhages. Most of the patients treated for "spontaneous" bleedings performed self-injections at home. The drug was administered in two pharmaceutical forms (4 and 40 micrograms/ml): no differences in the clinical outcome were found. No significant side effects were recorded. The subcutaneous route of DDAVP administration thus seems to be particularly useful (mainly in the concentrated pharmaceutical form) in treating mild factor VIII deficiencies even on self- and home-treatment basis.

Topics: Deamino Arginine Vasopressin; Hemophilia A; Hemorrhage; Humans; Injections, Subcutaneous; Surgical Procedures, Operative; Tooth Extraction; von Willebrand Diseases

Topics: Anesthesia, General; Child, Preschool; Deamino Arginine Vasopressin; Hernia, Inguinal; Humans; Male; Premedication; von Willebrand Diseases

Topics: Deamino Arginine Vasopressin; Dental Care for Disabled; Hemophilia A; Humans; Oral Hemorrhage; Oral Hygiene; Tooth Extraction; von Willebrand Diseases

Desmopressin acetate (DDAVP) is efficacious in patients with von Willebrand's disease. It additionally appears to have value in patients with uremic or aspirin-induced platelet dysfunction. We report here three patients with primary platelet defects who had previously experienced grossly inadequate hemostasis to whom we administered DDAVP. Each successfully underwent surgical procedures with DDAVP as the only hemostatic agent. Although the mechanism of these salutary effects is unclear, DDAVP may exert an influence directly on the endothelium independent of correcting abnormalities of the factor VIII:von Willebrand complex associated with von Willebrand's disease.

Topics: Adolescent; Deamino Arginine Vasopressin; Factor VIII; Female; Hemophilia A; Hemorrhagic Disorders; Hemostasis, Surgical; Humans; Male; Middle Aged; Platelet Aggregation; Preoperative Care; von Willebrand Diseases; von Willebrand Factor

We have studied the factor VIII multimeric structure in four patients with acquired von Willebrand's disease associated with a circulating inhibitor to the factor VIII complex. In three of the four patients tested, the high and medium molecular weights bands were absent when assessed by sodium dodecyl sulphate-agarose electrophoresis. Plasma from the fourth patient contained all the factor VIII multimeric forms, although the high molecular weight bands were markedly decreased in concentration. Intravenous infusion of 1-deamino-(8-D-arginine)-vasopressin (DDAVP) resulted in the appearance of a full complement of multimers in the plasma of the two patients tested. This response was, however, transient and a return to pre-infusion multimeric composition occurred within 2-4 h. In the patients studied, an inhibitor to the factor VIII complex has induced an acquired variant von Willebrand's disease which transiently corrects after the infusion of DDAVP.

Topics: Deamino Arginine Vasopressin; Factor VIII; Genetic Variation; Humans; Immunoelectrophoresis, Two-Dimensional; Molecular Weight; von Willebrand Diseases

Type IIA von Willebrand's Disease (vWD) is the most common type II variant, and all reported cases (56 individuals in 26 families) have had autosomal dominant inheritance. An eight-year-old female with an increased bleeding tendency since infancy was found to have laboratory values typical of type IIA vWD, but her parents and siblings were asymptomatic. With the exception of uniformly decreased levels of ristocetin cofactor in relation to von Willebrand factor antigen, the results of family studies were normal including the presence of large multimeric forms of von Willebrand factor antigen. These findings are consistent with the propositus having the homozygous state of an autosomal recessive trait. Desmopressin infusion in the propositus was followed by a significant increase of factor VIII coagulant and von Willebrand factor antigen but a limited change in ristocetin cofactor with no development of large multimers.

Topics: Antigens; Child; Deamino Arginine Vasopressin; Electrophoresis, Polyacrylamide Gel; Factor VIII; Female; Genes, Recessive; Genetic Variation; Humans; Pedigree; Protein Conformation; von Willebrand Diseases; von Willebrand Factor

Eight unanesthetized normal dogs and seven dogs with von Willebrand's disease (vWD) were given desmopressin (0.6 micrograms/kg, IV) in order to determine the effects of this drug on plasma Factor VIII/vWF activity. Seven of the normal dogs and four of the vWD dogs were administered an equal volume of saline (control infusion) on another occasion. The other three vWD dogs underwent major surgery after treatment with desmopressin. Plasma FVIII coagulant activity (FVIII:C), von Willebrand factor antigen (vWF:Ag), and FVIII-ristocetin co-factor activity (FVIII:RC) were quantitated before infusion and at 60 minutes postinfusion. Activities were expressed as a percentage of the activity of a pooled canine plasma (12 dogs) arbitrarily designated as having 100% FVIII:C, vWF:Ag, and FVIII:RC activity. Plasma FVIII:C activity increased by 28% in the normal dogs and by 37% in the dogs with vWD. Plasma vWF:Ag increased more than twofold in normal dogs after desmopressin treatment. In the vWD dogs the average increase was also twofold, however there was much greater variability between dogs with increases ranging from 1.2 fold to 2.4 fold. Plasma FVIII:RC activity almost doubled in normal dogs, however like vWF:Ag, the increases in vWD dogs were more variable. One vWD dog had no increase in FVIII:RC while in the remaining six dogs FVIII:RC increases ranged from 1.8 to 2.9 fold. The results of this study indicate that a single intravenous dose of desmopressin (0.6 micrograms/kg) causes a significant elevation in plasma vWF:Ag and FVIII:RC activity and a much lesser increase in FVIII:C activity in normal unanesthetized dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Deamino Arginine Vasopressin; Dog Diseases; Dogs; Factor VIII; von Willebrand Diseases; von Willebrand Factor

Platelet function and factor VIII complex were evaluated in ten patients with polycythemia rubra vera. Seven patients showed abnormal epinephrine-induced aggregation. The intracellular concentrations of adenosine diphosphate (ADP) were below normal, and the ratio of adenosine triphosphate (ATP)/ADP was greater than normal. In four of eight cases, there was a decrease in ristocetin cofactor activity and a reduction in the slowly migrating forms of vWF:Ag on crossed immunoelectrophoresis. Defect of large multimers of vWF:Ag was also observed. The ratio of vWF:Ag to ristocetin cofactor was elevated in these patients. Plasma from the patients had no effect on normal plasma except in one case, in which isolated IgG appeared to cause inactivation of ristocetin cofactor. Treatment with 1-deamino-8-arginine vasopressin caused correction of the vWF abnormalities with rapid return of ristocetin cofactor to baseline in some patients. The present study shows that the alterations of multimeric structure of vWF occur in more than 50% of patients with polycythemia rubra vera and are in some part due to the inhibitor specific for vWF.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Aged; Antigens; Deamino Arginine Vasopressin; Factor VIII; Humans; Middle Aged; Platelet Aggregation; Polycythemia Vera; von Willebrand Diseases; von Willebrand Factor

A patient with acquired von Willebrand's syndrome associated with polycythemia rubra vera is described. Ristocetin cofactor activity was decreased, while the levels of vWF:Ag and VIII:C were normal. Crossed immunoelectrophoretic analysis showed that vWF:Ag was composed of much more anodic component. The mixture study using pooled normal plasma and the patient IgG fractions showed the inhibition of ristocetin cofactor and the decrease of less anodic parts of vWF:Ag in normal plasma. After 1-deamino-8-arginine vasopressin (DDAVP) infusion the marked increases of vWF:Ag, VIII:C and ristocetin cofactor and a rapid return of ristocetin cofactor to the baseline were observed. Transient increase of vWF:Ag after DDAVP infusion showed less anodic forms and in the relative proportion as normal plasma. The present study showed that the patient IgG fractions had the specific inhibitory activity against the antigenic sites on the active subfractions of von Willebrand's factor.

Topics: Aged; Antigens; Autoantibodies; Autoimmune Diseases; Bleeding Time; Deamino Arginine Vasopressin; Factor VIII; Female; Humans; Immunoglobulin G; Platelet Aggregation; Polycythemia Vera; von Willebrand Diseases; von Willebrand Factor

Topics: Administration, Intranasal; Deamino Arginine Vasopressin; Hemophilia A; Humans; Injections, Intravenous; von Willebrand Diseases

The infusion of 1-deamino-8-D-arginine vasopressin (DDAVP) in normal individuals is followed by an increase in factor VIII/von Willebrand factor (vWF) in plasma, by an increase in intensity of all sizes of multimers, and by the appearance of larger multimers of vWF than those seen in the resting state. Since the larger multimers are rapidly cleared and proteolysis is known to cause disaggregation of large multimers, we evaluated the degree of vWF proteolysis after DDAVP administration. DDAVP was infused into eight normal adult volunteers, and the relative proportions of the intact 225 kilodalton (kDa) subunit and the 189, 176, and 140 kDa vWF fragments were compared before and at different times after DDAVP infusion. The relative proportion of the 176 kDa fragment was increased, whereas that of the other species was decreased, thereby indicating that proteolytic fragmentation had occurred. However, plasmin did not appear to be responsible because the vWF fragments characteristically produced by this enzyme could not be detected. Concomitant analysis of vWF multimeric structure showed that these changes were accompanied by an increase in the relative proportion of the satellite bands, which suggests that they were proteolytically generated. Proteolysis may explain, at least in part, rapid clearance of larger vWF multimers released by DDAVP.

Topics: Adolescent; Adult; Antibodies, Monoclonal; Autoradiography; Collodion; Deamino Arginine Vasopressin; Electrophoresis, Agar Gel; Female; Humans; Infusions, Intravenous; Male; Molecular Weight; Protein Processing, Post-Translational; Reference Values; von Willebrand Diseases; von Willebrand Factor

Topics: Adult; Blood Coagulation; Deamino Arginine Vasopressin; Female; Humans; Oral Hemorrhage; Tooth Extraction; von Willebrand Diseases

1-D-Amino(8-D-arginine)-vasopressin (DDAVP) infusion in three patients with type IIa von Willebrand's disease (vWD) resulted in a normalization of the factor VIII coagulant, factor VIII-related antigen, and von Willebrand factor (vWF) (ristocetin cofactor) activities and the bleeding time. The normalization of these hemostatic parameters persisted for four hours. Over the same time period there was a marked increase in the quantity of the vWF multimers when blood was collected in the presence of protease inhibitors. The vWF multimers present were even larger than the normal. When blood was collected in the absence of protease inhibitors, a smaller increase in the plasma vWF multimers was observed and fewer of the intermediate and larger vWF multimers were seen; multimers larger than those present in normal plasma were not visualized. The platelet vWF multimers and activities did not change with or without inhibitors. These studies suggest that there is a subgroup of patients with type IIa vWD who respond to DDAVP with complete normalization of their hemostatic abnormalities and whose vWF is sensitive to proteolysis.

Topics: Antigens; Deamino Arginine Vasopressin; Factor VIII; Humans; Macromolecular Substances; Peptide Hydrolases; von Willebrand Diseases; von Willebrand Factor

Desamino-D-arginine vasopressin (DDAVP) is known to stimulate factor VIII (FVIII) and plasminogen activator release from endothelial cells, and has been shown to stimulate prostacyclin (PGI2) production in normal and haemophilic subjects. In von Willebrand's disease (vWd) some patients have a dissociate response with regard to FVIII and plasminogen activator. The aim of our study was to compare the PGI2, FVIII and plasminogen activator response to DDAVP infusion in vWd with the response to DDAVP in normal and haemophilic subjects. PGI2 metabolites thromboxane B2 (TxB2), factor VIII coagulant activity, factor VIII-related antigen and plasminogen activator were measured before and after DDAVP infusion. There was a significant increase in PGI2 metabolites, factor VIII-related antigen and plasminogen activator in all groups following DDAVP, but no effect on TxB2 was found, and there was no evidence of any dissociate response to DDAVP in any of the groups. Basal levels of PGI2 metabolites, however, were significantly lower in vWd as compared to normal and haemophilic subjects. Post-DDAVP levels of PGI2 metabolites were also significantly lower in vWd as compared with normal subjects. This may be due to a reduced stimulus to PGI2 production in vWd secondary to defective platelet adhesion.

Topics: Antigens; Deamino Arginine Vasopressin; Endothelium; Epoprostenol; Factor VIII; Female; Hemophilia A; Humans; Male; Plasminogen Activators; Thromboxane B2; von Willebrand Diseases; von Willebrand Factor

A variant of von Willebrand disease (vWD) has been identified in a 19-year-old woman with a severe bleeding syndrome. She had a very prolonged bleeding time (over 20 min), 24 U/dl factor VIII coagulant activity (F.VIII:C), 16 U/dl von Willebrand factor antigen (vWF:Ag), no ristocetin cofactor activity, and an anodal mobility of vWF:Ag on crossed immunoelectrophoresis (CIE). vWF:Ag was markedly reduced in her platelet lysate. In plasma and platelets, SDS-agarose electrophoresis consistently demonstrated the absence of large multimers, a relatively increased concentration of the fastest-moving multimer, and gross abnormalities of the internal structure of each vWF multimeric unit. Five members from the maternal side of the family had a double vWF:Ag peak by CIE and a relative increase of the fastest-moving vWF multimer by SDS-agarose electrophoresis; no quantitative or qualitative vWF defects were found in the paternal side of the family. The pattern of the findings in the propositus and her family is similar to those of type IIC vWD. However, there are some unique characteristics suggesting phenotypic variability in this subtype, such as low level of platelet vWF:Ag and the absence of increase of vWF after DDAVP administration.

Topics: Adult; Antigens; Bleeding Time; Deamino Arginine Vasopressin; Electrophoresis; Factor VIII; Female; Humans; Immunoelectrophoresis, Two-Dimensional; Macromolecular Substances; Platelet Aggregation; Ristocetin; von Willebrand Diseases; von Willebrand Factor

Bone marrow from a normal male pig was transplanted into a related female pig with severe homozygous von Willebrand's disease (vWd). After engraftment the circulating leukocytes were of the male karyotype, and the platelets were strongly positive for von Willebrand factor (vWF) by indirect immunofluorescence. The average level of vWF was 1.96 U/dl and of ristocetin cofactor was 2.8 U/dl. The ear immersion bleeding time before transplantation was consistently more than 15 min and afterwards varied between 5 min and more than 15 min. Transfused vWF corrected the bleeding time at a level of 10 U/dl, which is lower than that required for a von Willebrand pig. We concluded that: the plasmatic compartment is only minimally replenished by the vWF from platelets and megakaryocytes; and the platelet vWF alone only partially corrects the abnormal tests of the hemostatic mechanism in severe vWd.

Topics: Animals; Antigens; Bleeding Time; Blood Platelets; Blood Transfusion; Bone Marrow Transplantation; Deamino Arginine Vasopressin; Electrophoresis, Polyacrylamide Gel; Factor VIII; Female; Fluorescent Antibody Technique; Hemostasis; Homozygote; Karyotyping; Leukocytes; Male; Swine; Transplantation, Homologous; von Willebrand Diseases; von Willebrand Factor

The response to a single intravenous infusion of 1-deamino-8-D-arginine vasopressin (DDAVP, desmopressin) was studied in two patients with acquired von Willebrand syndrome associated with IgG-kappa myeloma. Following infusion of DDAVP (0.3-0.4 micrograms/kg), prolonged bleeding time was normalized; plasma ristocetin cofactor activity, von Willebrand factor antigen, and factor VIII activity were remarkably increased; and high-molecular-weight forms of von Willebrand factor were demonstrated by crossed immunoelectrophoresis in both patients. Excellent hemostasis was achieved following administration of DDAVP in one patient when it was used for the treatment of gum bleeding and for the prophylaxis of bleeding during and after dental extractions. These observations suggest that DDAVP is an effective alternative to blood products for at least some patients with acquired von Willebrand syndrome in addition to patients with inherited von Willebrand disease, hemophilia A, and uremia.

Topics: Blood Coagulation Tests; Deamino Arginine Vasopressin; Female; Hemostasis, Surgical; Humans; Immunoglobulin G; Immunoglobulin kappa-Chains; Infusions, Parenteral; Middle Aged; Multiple Myeloma; von Willebrand Diseases

Six patients having different subtypes of von Willebrand's disease were followed up during eight complete pregnancies. Two additional pregnancies terminated in spontaneous abortions. Five pregnancies ended in cesarean section either because of obstetric problems (three) or electively (two) to avoid infant bleeding. Three deliveries were complicated by vaginal bleeding attributed to von Willebrand's disease, while bleeding during two deliveries had clear obstetric causes. Only two deliveries were associated with no bleeding complications. Five newborn babies were found to have von Willebrand's disease. One of them was born with a head hematoma. Management, which included cryoprecipitate and desmopressin (Stimate), is discussed. It is important to manage each case individually since obstetric parameters and severity of bleeding disorder must be known before treatment is planned.

Topics: Adolescent; Adult; Antigens; Blood Coagulation Tests; Deamino Arginine Vasopressin; Delivery, Obstetric; Factor VIII; Female; Fetal Blood; Fibrinogen; Genetic Counseling; Humans; Infant, Newborn; Perinatology; Pregnancy; Pregnancy Complications, Hematologic; Puerperal Disorders; Uterine Hemorrhage; von Willebrand Diseases; von Willebrand Factor

A chromogenic substrate kit for determination of factor VIII activity (COATEST Factor VIII) was compared to a one-stage clotting assay and the correlation was evaluated in different genetic variants of mild and moderate haemophilia A, in severe haemophilia A and in all known variants of von Willebrand's disease. In all these cases a high correlation between the two methods was obtained. A good correlation was also obtained after intranasal administration of DDAVP (1-desamino-8-D-arginine vasopressin) to patients with von Willebrand's disease. The chromogenic substrate method was performed using a microtray technique.

Topics: Chromogenic Compounds; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Humans; von Willebrand Diseases

A 60-yr-old woman had had a bleeding disorder for the last 13 yr, with laboratory features of monoclonal gammopathy and von Willebrand's disease (vWD). There was no evidence of family vWD. She had a prolonged bleeding time, low levels of factor VIII/von Willebrand factor activities and decreased ristocetin-induced platelet agglutination. Platelet von Willebrand factor (vWF) was normal. Plasma vWF showed a unique multimeric pattern with absence of larger and intermediate multimers and a disproportionate increase of the fastest moving multimer with normal satellite bands, thus differing from previously described types of vWF. No evidence for inhibitor, non neutralizing antibody or proteolytic activity against vWF was found in her plasma or IgG fraction. DDAVP response was very poor. We suggest that this patient had a unique, probably acquired, vWD. Nevertheless the possibility of its being a new subtype of congenital vWD associated with an unrelated monoclonal gammopathy cannot be ruled out.

Topics: Deamino Arginine Vasopressin; Female; Humans; Macromolecular Substances; Middle Aged; Paraproteinemias; von Willebrand Diseases; von Willebrand Factor

Platelet function was evaluated in 20 patients with chronic myelocytic leukemia (CML), all Ph positive. Seven showed abnormal epinephrine-induced aggregation, while four had impaired both ADP- and collagen-induced aggregation. The platelets of all patients aggregated with arachidonic acid, thus ruling out cyclooxygenase or lipoxygenase deficiency. The intracellular concentrations of ATP and ADP were significantly below normal, and the ratio of ATP/ADP was greater than normal in all 12 patients. ATP released from platelets by Lumi-aggregometer was reduced. In four patients with abnormal ristocetin-induced aggregation, vWF:Ag, RCoF, and FVIII:C were all reduced. No significant inactivation of factor VIII was induced in normal plasma by incubation with patient's plasma. The crossed immunoelectrophoretic analysis revealed that vWF:Ag in these patients was mainly composed of more anodic component as compared with that of normal plasma. The ratio of vWF:Ag/RCoF was significantly greater than normal. A marked increase of factor VIII and a rapid return of vWF:Ag and RCoF to the baseline after the 1-deamino-8-arginine vasopressin (DDAVP) infusion were observed. Transient increase in vWF:Ag after the infusion of DDAVP appeared with less anodic forms and in the same relative proportion as that in normal plasma. The present study shows that in some patients with CML storage pool disease occurs with acquired von Willebrand disease.

Topics: Adenosine Triphosphate; Adult; Blood Coagulation Tests; Blood Platelet Disorders; Blood Platelets; Deamino Arginine Vasopressin; Humans; Leukemia, Myeloid; Middle Aged; Platelet Aggregation; Platelet Storage Pool Deficiency; von Willebrand Diseases

In eight members of one family, platelets in platelet-rich plasma aggregated at much lower ristocetin concentrations than normal. Ivy bleeding time was variously prolonged, and von Willebrand factor antigen (vWF:Ag), ristocetin cofactor activity, and factor VIII coagulant activity were decreased. Most of the affected members had had slight to rather severe bleeding symptoms. Platelet-type von Willebrand's disease (vWD) could be ruled out. All multimers of vWF:Ag were found in plasma as well as platelets. Administration of 1-desamino-8-D-arginine vasopressin (DDAVP) to the propositus did not cause thrombocytopenia, and platelet-poor plasma obtained immediately after did not aggregate normal platelets. The molecular defect in this family, inherited as an autosomal dominant, resembles the one in type IIB because of the response to ristocetin but differs from IIB because all vWF:Ag multimers are present in plasma and the response to DDAVP is atypical. We conclude that this family has a new subtype of vWD and propose that structural as well as functional criteria should be used for a proper classification of vWD.

Topics: Blood Platelets; Deamino Arginine Vasopressin; Humans; Immunoelectrophoresis, Two-Dimensional; Macromolecular Substances; Pedigree; Platelet Aggregation; Ristocetin; von Willebrand Diseases; von Willebrand Factor

The absence of large von Willebrand factor (vWF) multimers from plasma is a characteristic of Type IIA von Willebrand's disease (vWD) and is thought to contribute to the clinical expression of this disorder. Recently, three IIA patients have been reported in whom intermediate and large multimers could be restored if blood were collected in 5 mm EDTA, 6 mmol/L N-ethylmaleimide, and 1 mmol/L leupeptin. This suggested that absence of large multimers resulted from in vitro proteolysis. We have now collected blood from ten Type IIA vWD patients in these inhibitors but were not able to detect large multimers in the plasma of any of them. In addition, intermediate-sized multimers were reduced or completely absent in all. The inclusion of inhibitors in the citrate anticoagulant, as compared to citrate alone, was found to increase the relative proportion of intermediate multimers in some patients but had no effect in others, and in none did it restore large multimers to plasma. The results with platelet vWF were more varied. Four patients showed an absence or decrease of large multimers, whereas in seven patients large multimers were present. When compared with citrate anticoagulant alone, the inclusion of inhibitors in the anticoagulant had little or no effect on the platelet multimeric pattern. 1-Deamino-8-D-Arginine Vasopressin (DDAVP) was administered to six patients from five families. Two patients from one family showed complete correction and a third patient showed almost complete correction of her bleeding time. Two patients showed minimal correction and one showed no detectable correction. An increase in multimer size after DDAVP tended to be associated with correction of the bleeding time. However, in no case did the largest multimers appear in plasma even in patients with complete bleeding time correction. The presence or absence of inhibitors in the anticoagulant had little or no effect on the multimeric pattern after DDAVP. These results indicate that Type IIA vWD is a heterogeneous disorder in which absence of largest and intermediate multimers is an in vivo phenomenon.

Topics: Bleeding Time; Deamino Arginine Vasopressin; Female; Humans; Macromolecular Substances; Male; Protease Inhibitors; von Willebrand Diseases; von Willebrand Factor

Topics: Adult; Aged; Blood Platelets; Deamino Arginine Vasopressin; Female; Humans; Male; Middle Aged; Platelet Aggregation; Thrombocythemia, Essential; von Willebrand Diseases

Topics: Adolescent; Adult; Blood Coagulation; Child; Deamino Arginine Vasopressin; Dental Care for Disabled; Factor VIII; Hemophilia A; Humans; Middle Aged; von Willebrand Diseases

Topics: Deamino Arginine Vasopressin; Dental Care for Disabled; Hemophilia A; Humans; Tooth Extraction; von Willebrand Diseases

Type I von Willebrand disease (vWD) is characterized by equally low plasma concentrations of von Willebrand factor antigen (vWF:Ag) and ristocetin cofactor (RiCof) and by the presence of all vWF multimers in sodium dodecyl sulfate (SDS)-agarose gel electrophoresis. For 17 patients (13 kindreds) diagnosed with these criteria, we have studied the platelet contents of vWF:Ag and RiCof and the changes of these in plasma after DDAVP infusion. Platelet vWF:Ag and RiCof were normal in four kindreds (called "platelet normal" subgroup); following 1-deamino-8-D-arginine vasopressin; plasma vWF:Ag, RiCof and the bleeding time (BT) became normal. In six kindreds, platelet vWF:Ag and RiCof were equally low (platelet low); after DDAVP, plasma vWF:Ag and RiCof remained low, and the BT was prolonged. In three additional kindreds, platelets contained normal concentrations of vWF:Ag, but RiCof was very low (platelet discordant); even though a complete set of multimers was found in plasma and platelets, there was a relatively small amount of large multimers. After DDAVP, plasma vWF:Ag became normal, but RiCof remained low and the BT was very prolonged. These findings demonstrated that there can be an abnormal vWF (RiCof less than vWF:Ag) even in type I vWD, coexisting with a complete set of vWF multimers (platelet discordant); that the abnormal vWF can be shown more clearly in platelets than in plasma or else in plasma after DDAVP infusion; and that DDAVP normalizes the BT only in those patients with normal platelet levels of both vWF:Ag and RiCof (platelet normal).

Topics: Autoradiography; Blood Platelets; Deamino Arginine Vasopressin; Densitometry; Humans; Phenotype; Radioimmunoassay; von Willebrand Diseases; von Willebrand Factor

Type IIB von Willebrand's disease (vWD) is a distinct form of this disorder in which the largest multimers of the von Willebrand factor (vWF) are lacking in plasma but present in platelets. When the vasopressin analogue, 1-deamino-8-D-arginine vasopressin (DDAVP), is given to patients with type IIB vWD, an abnormal vWF is released to plasma. This vWF causes thrombocytopenia in vivo and platelet aggregation in vitro. Aggregation occurs in the plasma milieu and thus at physiological fibrinogen concentration. In this study we demonstrate that IIB post-DDAVP vWF aggregated only metabolically active platelets. The platelet aggregation was completely inhibited by EDTA and PGE1, and either inhibited or greatly weakened by ASA, demonstrating the role of divalent cations and thromboxane A2 formation. In spite of inhibiting platelet aggregation, EDTA, PGE1 and ASA did not prevent platelet binding of IIB post-DDAVP vWF. An antiserum against GP Ib made normal platelets less responsive to the IIB vWF although neither platelet aggregation nor vWF binding were completely prevented. The aggregation was fibrinogen-dependent and platelets from patients with Glanzmann's thrombasthenia were unresponsive. The studies provide evidence that IIB post-DDAVP vWF is bound to unstimulated platelets and that the interaction between vWF and platelets in type IIB vWD is different from ristocetin-induced as well as thrombin- and epinephrine-induced binding to platelets of normal vWF.

Topics: Blood Platelets; Deamino Arginine Vasopressin; Fibrinogen; Humans; Platelet Aggregation; Ristocetin; Thrombasthenia; Thrombocytopenia; von Willebrand Diseases; von Willebrand Factor

Desmopressin was administered intravenously to 68 patients with hemophilia and von Willebrand's disease of mild or moderate severity to assess the safety, reproducibility, and range of response to this new therapeutic alternative. A rise in factor VIII-von Willebrand factor levels was seen in 64 patients, and the magnitude was sufficient to provide normal hemostasis in 55 to 68 spontaneous or traumatic bleeding episodes, dental procedures, or operations. Thus, our experience shows that most patients with mild or moderate hemophilia and von Willebrand's disease can be treated effectively without plasma derivatives. Patients who had two or more infusions of desmopressin at different times had similar responses each time, and members of the same family also had similar responses after desmopressin infusions. Because this drug can be administered without significant side effects, it should have an important role in the management of patients with mild or moderate hemophilia and von Willebrand's disease.

Topics: Adolescent; Adult; Aged; Arginine Vasopressin; Autoantibodies; Child; Child, Preschool; Deamino Arginine Vasopressin; Dental Care; Factor VIII; Female; Hemophilia A; Hemorrhage; Heterozygote; Humans; Male; Middle Aged; Premedication; Preoperative Care; von Willebrand Diseases

Topics: Antigens; Arginine Vasopressin; Deamino Arginine Vasopressin; Drug Evaluation; Factor VIII; Humans; von Willebrand Diseases; von Willebrand Factor; Whole Blood Coagulation Time

The effect of infusing DDAVP and cryoprecipitate either singly or in combination was studied in a patient with variant von Willebrand disease. Both DDAVP and cryoprecipitate caused only partial correction in the hemostatic defect when used as a single agent. A combination of DDAVP and cryoprecipitate induced a complete correction of the hemostatic defect as well as factor VIII related properties.

Topics: Deamino Arginine Vasopressin; Drug Therapy, Combination; Factor VIII; Fibrinogen; Genetic Variation; Humans; Infusions, Parenteral; Male; Middle Aged; von Willebrand Diseases

Topics: Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Humans; Male; von Willebrand Diseases; von Willebrand Factor

A chromogenic substrate kit for the determination of factor VIII activity (COATEST Factor VIII) has been evaluated in five different laboratories, one of them using a semi-automated procedure. This chromogenic method was compared to one-stage clotting assays for factor VIII determination in plasmas from healthy subjects, carriers of hemophilia A, severe, mild and moderate hemophilia A as well as von Willebrand's patients. In all these cases, a high correlation between these two methods was obtained (r = 0.96-0.99, n = 385) with a good agreement of the assigned potencies at all levels of factor VIII. A good correlation (r = 0.94) was also obtained for the levels of factor VIII after infusion of concentrates in six severe hemophiliacs or after administration of DDAVP to von Willebrand's patients. The chromogenic method is insensitive to preactivation of factor VIII by thrombin, thus yielding valid potency assignments also in these situations. The precision was higher with the chromogenic method than with the one-stage clotting assays (C.V. = 2-5% vs 4-15%). Altogether, the new chromogenic substrate method has proven itself suitable for determination of factor VIII in plasma and concentrates.

Topics: Blood Coagulation Tests; Chromogenic Compounds; Deamino Arginine Vasopressin; Evaluation Studies as Topic; Factor VIII; Genetic Carrier Screening; Hemophilia A; Humans; Reference Standards; Thrombin; von Willebrand Diseases

Topics: Adult; Antigens; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Humans; Male; von Willebrand Diseases; von Willebrand Factor

To evaluate the effect of 1-deamino-8-D-arginine vasopressin (DDAVP) in various bleeding disorders, 10 micrograms/m2 DDAVP was administered to subjects with von Willebrand disease (13), platelet function defects (12), von Willebrand disease and platelet defects together (8), or isolated prolongation of the bleeding time (5). DDAVP shortened the bleeding time similarly in all patient groups. Shortening of the bleeding time was also observed in 2 patients with aspirin-induced platelet defects and in 2 normal subjects. DDAVP administration was associated with falls in the platelet count, mean platelet volume, and partial thromboplastin time, and rises in platelet adhesion, factor VIII coagulant activity, factor VIII related antigen, and von Willebrand factor activity. The basal bleeding time was the only predictor of the magnitude of the bleeding-time correction. Normal haemostatis was achieved with DDAVP plus epsilon-aminocaproic acid and no blood product support during operations in 18 patients with bleeding disorders.

Topics: Adolescent; Adult; Aminocaproic Acid; Arginine Vasopressin; Aspirin; Bleeding Time; Blood Platelet Disorders; Blood Platelets; Child; Child, Preschool; Deamino Arginine Vasopressin; Drug Evaluation; Hemostasis; Hemostasis, Surgical; Humans; Partial Thromboplastin Time; Platelet Adhesiveness; Platelet Count; Platelet Function Tests; von Willebrand Diseases

Topics: Arginine Vasopressin; Deamino Arginine Vasopressin; Hemophilia A; Humans; von Willebrand Diseases

Topics: Adolescent; Adult; Blood Coagulation; Child; Deamino Arginine Vasopressin; Female; Fibrinolysis; Hemophilia A; Hemophilia B; Humans; Male; Middle Aged; Oral Hemorrhage; Tooth Extraction; von Willebrand Diseases; Wound Healing

An acquired hemorrhagic disorder developed in two patients in association with postsplenectomy thrombocytosis and leukocytosis during the course of the myeloproliferative syndrome. The presence of acquired von Willebrand's disease in these individuals was demonstrated by a decrease or absence of the larger von Willebrand factor (vWF) multimers, alteration of the repeating vWF multimeric "triplet," decreased ristocetin cofactor activity (vWF:RCo), and prolonged bleeding time. The bleeding stopped in both patients after treatment with either 1-deamino-[8-D-arginine]-vasopressin (DDAVP) or Cohn fraction I. Treatment with thrombocytapheresis and azathioprine or busulfan resulted in reduction of the elevated platelet and white cell counts and was associated with partial correction of the vWF abnormalities and remission of the hemostatic abnormalities. In five additional patients with the myeloproliferative syndrome, but without bleeding symptoms, large multimers of plasma vWF were diminished also. These findings suggest that acquired von Willebrand's disease should be considered when a bleeding diathesis develops during the course of the myeloproliferative syndrome.

Topics: Adult; Bleeding Time; Blood Proteins; Deamino Arginine Vasopressin; Female; Humans; Male; Myeloproliferative Disorders; Postoperative Complications; Splenectomy; von Willebrand Diseases; von Willebrand Factor

To permit home treatment in our patients we investigated the response to intranasal administration of 260 micrograms DDAVP in 28 patients with either mild hemophilia A or von Willebrand's disease. 6 patients with mild hemophilia A responded, and 6 did not. In the group with von Willebrand's disease 6 responded well, 4 responded partially and 6 did not respond. Knowledge of the severity of the disease did not allow us to predict the response, and therefore every patient should be tested individually. Intranasal DDAVP in our patients was used with success for bleeding into the knee joint, muscle hematoma and hematuria.

Topics: Arginine Vasopressin; Deamino Arginine Vasopressin; Hemophilia A; Humans; Solutions; von Willebrand Diseases

We studied four patients who showed aggregation of platelets in platelet-rich plasma at lower concentrations of ristocetin than those required for normal platelet-rich plasma and who demonstrated an increased capacity of the platelets to bind normal von Willebrand factor. The four patients were from two Japanese families. Platelets from one family aggregated spontaneously in vitro, and platelets from both families aggregated upon the addition of normal plasma and cryoprecipitate, in the absence of ristocetin or other agonists. Analysis of the multimeric composition of von Willebrand factor by sodium dodecyl sulfate-agarose gel electrophoresis revealed a decrease in large multimers or a decrease in both large and intermediate multimers in plasma, but normal multimers in platelets. 1-Deamino-[8-D-arginine]-vasopressin caused by an immediate appearance of larger multimers in plasma, followed by the rapid disappearance of these multimers from circulating plasma. Analysis of platelet membrane glycoproteins from the patients showed that there were two distinct bands in the glycoprotein I region; one migrated in a slower region and the other in a faster region than normal glycoprotein Ib. We suggest that the platelet receptor abnormality in these patients is related to this abnormality of glycoprotein Ib.

Topics: Deamino Arginine Vasopressin; Electrophoresis, Agar Gel; Glycoproteins; Humans; Membrane Proteins; Platelet Aggregation; Ristocetin; Sodium Dodecyl Sulfate; von Willebrand Diseases; von Willebrand Factor

Of 120 patients presenting with mild bleeding disorders, 63 were found to have a definite coagulopathy. The commonest disorders were haemophilia, Christmas disease and von Willebrand's disease (vWd), the latter being predominant. Diagnosis led to prophylactic treatment prior to surgery in 18 patients with prevention of excessive haemorrhage. Three patients who had received blood products developed hepatitis. DDAVP (desamino-cys-1-8-D-arginine vasopressin) is the treatment of choice in suitable mildly affected patients with haemophilia A and vWd. Examination of blood group distribution suggests an excess of group O among patients with bleeding disorders, especially those with vWd.

Topics: Adult; Arginine Vasopressin; Deamino Arginine Vasopressin; Female; Hemophilia A; Hemophilia B; Hemorrhage; Humans; Male; Middle Aged; Postoperative Complications; Tooth Extraction; von Willebrand Diseases

The effect of intravenous 1-deamino (8-D-arginine)vasopressin (DDAVP) administration on platelet interaction with human artery subendothelium was investigated with flowing blood from five normal individuals and 12 patients with von Willebrand's disease (vWD). Three of the patients were diagnosed as vWD subtype I, four as subtype IIa, and five as subtype IIb. DDAVP administration to normals enhanced platelet adherence, in parallel with increasing plasma levels of factor VIII-related antigen ( FVIIIR :Ag) and ristocetin cofactor activity ( FVIIIR :RCF). Platelet aggregate formation was transiently increased within 90 minutes. Platelet adherence in patient blood before DDAVP infusion was subnormal. In patients with subtype I, administration of DDAVP normalized the bleeding time, enhanced the platelet adherence, and transiently improved the platelet aggregate formation. The platelet adherence was more corrected than would have been expected on the basis of the FVIIIR :Ag and FVIIIR :RCF levels. In patients with subtype IIa, infusion of DDAVP increased the FVIIIR :Ag levels approximately threefold, without affecting the FVIIIR :RCF levels, and in only two of four patients was a transiently enhanced platelet adherence with a corresponding shortening of the bleeding time observed. In patients with subtype IIb, administration of DDAVP increased the FVIIIR :Ag levels about threefold and the FVIIIR :RCF levels five to tenfold, but decreased the platelet adherence significantly. The bleeding time values were not normalized. A close association between the bleeding time values and corresponding platelet adherence values before and after DDAVP infusion was observed. Normalization of the bleeding time was paralleled with normalization of platelet adherence. We conclude that DDAVP improves the primary hemostasis by causing enhanced FVIII-vWF-mediated platelet adherence. DDAVP has little or no effect on the bleeding time in patients with subtype IIa and subtype IIb, because the platelet adherence is not normalized.

Topics: Arginine Vasopressin; Bleeding Time; Deamino Arginine Vasopressin; Factor VIII; Humans; Platelet Adhesiveness; Platelet Aggregation; Ristocetin; von Willebrand Diseases

In seven patients with acquired von Willebrand's disease (AvWD) associated with lymphoproliferative disorders or benign monoclonal gammopathies, the platelet contents of von Willebrand factor antigen and ristocetin cofactor (vWF:Ag and vWF:RiCof, respectively) were normal. All the multimers of vWF:Ag could be seen in the 1.6% SDS-agarose gel electrophoresis patterns of plasma and platelet lysates. Infusion of 1-deamino-8-D-arginine vasopressin (DDAVP) augmented plasma levels of vWF:Ag and vWF:RiCof of all patients and corrected prolonged bleeding times (BT). However, compared with patients with congenital vWD type I and comparable degrees of baseline abnormalities treated in the same way, vWF:Ag and vWF:RiCof were increased less and cleared more rapidly from plasma and the BT remained normal for a shorter period of time. These studies provide evidence that these AvWD patients have qualitatively normal vWF in plasma, but at lower concentrations, that vWF in platelets is normal both qualitatively and quantitatively, and that cellular vWF can be rapidly released into plasma by DDAVP to correct the hemostatic abnormalities. However, vWF is removed rapidly from plasma, making the correction more transient than in congenital vWD type I.

Topics: Adult; Aged; Antibodies; Blood Platelets; Deamino Arginine Vasopressin; Factor VIII; Female; Humans; Hypergammaglobulinemia; Lymphoproliferative Disorders; Macromolecular Substances; Male; Middle Aged; von Willebrand Diseases; von Willebrand Factor

Topics: Adult; Arginine Vasopressin; Blood Coagulation; Deamino Arginine Vasopressin; Factor VIII; Humans; Male; von Willebrand Diseases

Topics: Acquired Immunodeficiency Syndrome; Antigens; Blood Coagulation Tests; Blood Transfusion; Child; Deamino Arginine Vasopressin; Factor IX; Factor VIII; Female; Genetic Carrier Screening; Hemophilia A; Hepatitis B; Humans; Pregnancy; Prenatal Diagnosis; von Willebrand Diseases; von Willebrand Factor

1-deamino-8-D-arginine-vasopressin (DDAVP), was used in a wide spectrum of clinical situations employing two different dosages (0.3 and 0.4 microgram/kg b.w.) for the management of 43 patients with factor VIII deficiencies--mild and moderate haemophilia A and von Willebrand's disease (vWD). In most instances, the drug was given in association with antifibrinolytics. Twenty-five dental extractions were carried out with two different protocols: one based upon a single infusion and the other based upon three infusions. Bleeding occurred in three patients regardless of the protocol used. The vasopressin analogue promptly stopped bleeding in 12 'spontaneous' open bleeds (haematuria, epistaxis, menometrorrhagia, gum bleeding) and it appears to be also effective in closed bleeds. DDAVP was used to minimize blood loss during surgical interventions and to avoid haemorrhage in the postoperative period. Nine surgical procedures were carried out in six vWD patients and three haemophiliacs. Bleeding occurred late in the postoperative period on one occasion only. No difference was demonstrated between the two doses of the drug either in terms of clinical benefit or rise of factor VIII coagulant activity. The efficacy of DDAVP and the absence of side-effects make this vasopressin analogue worthy of consideration as a reliable alternative to factor VIII concentrates in a wide variety of clinical situations.

Topics: Antigens; Arginine Vasopressin; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Hemorrhage; Humans; Intraoperative Care; Postoperative Care; Tooth Extraction; von Willebrand Diseases; von Willebrand Factor

The infusion of 1-deamino-(8-D-arginine)-vasopressin (DDAVP) causes not only an elevation in factor VIII-related antigen (FVIIIR:Ag), but also a marked elevation of plasma von Willebrand antigen II (vWAgII). vWAgII reaches a peak concentration at 60 min and is elevated 3-8-fold over basal levels in normal individuals and individuals with type I, IIA, and IIB von Willebrand's disease. As the mechanism of hemostatic alteration brought about by DDAVP might be due to release of endothelial cell proteins, endothelial cell cultures were performed. The cultures demonstrated synthesis and secretion of vWAgII, as evidenced by the incorporation of 35S-methionine into the vWAgII molecule. Thus, vWAgII, like FVIIIR:Ag, is an endothelial cell protein.

Topics: Antigens; Arginine Vasopressin; Blood Coagulation Factors; Deamino Arginine Vasopressin; Endothelium; Humans; Immunoelectrophoresis; Infant, Newborn; Male; Umbilical Veins; von Willebrand Diseases; von Willebrand Factor

Topics: Arginine Vasopressin; Deamino Arginine Vasopressin; Humans; In Vitro Techniques; Platelet Aggregation; von Willebrand Diseases

Topics: Adolescent; Adult; Arginine Vasopressin; Deamino Arginine Vasopressin; Hemophilia A; Hemorrhage; Humans; von Willebrand Diseases

Topics: Arginine Vasopressin; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Humans; von Willebrand Diseases

The effect of the vasopressin analog 1-deamino-8-d-arginine vasopressin (DDAVP) was studied in three normal individuals, 31 subjects with von Willebrand disease, and seven subjects with mild or moderate hemophilia A. None of those with von Willebrand disease had qualitative abnormalities of factor VIII-related antigen (F VIII:RAg). Both intranasal (2 to 4 micrograms/kg) and intravenous (0.2 micrograms/kg) DDAVP were used. All normal subjects, 27 of 31 with von Willebrand disease, and six of seven with hemophilia had a more than 200% increase in F VIII coagulant activity, with lesser but definite increases in F VIII:RAg and ristocetin cofactor activity. Two subjects with severe von Willebrand disease had no increase in F VIII-related activities. In six subjects with von Willebrand disease who had prolonged bleeding times, there was transient correction after DDAVP therapy. None of eight subjects who received DDAVP prior to surgical procedures had any unusual bleeding during or after surgery. None received any blood products. No untoward side effects were noted in any of the 41 subjects. We conclude that DDAVP is a safe and effective alternative to the use of blood products in certain individuals with von Willebrand disease and hemophilia A.

Topics: Administration, Intranasal; Adolescent; Adult; Antigens; Arginine Vasopressin; Bleeding Time; Child; Child, Preschool; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Hemostasis, Surgical; Humans; Injections, Intravenous; Middle Aged; von Willebrand Diseases; von Willebrand Factor

Topics: Arginine Vasopressin; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Humans; Male; Stimulation, Chemical; von Willebrand Diseases

Topics: Arteriosclerosis; Blood Coagulation Tests; Blood Transfusion; Deamino Arginine Vasopressin; Factor VIII; Humans; Platelet Aggregation; Prenatal Diagnosis; Ristocetin; von Willebrand Diseases; von Willebrand Factor

Type IIB von Willebrand's disease is a distinct form of this disorder, in which there are abnormal factor VIII/von Willebrand factor multimers in plasma (but normal multimers in platelets) and heightened interaction between the von Willebrand factor and platelets in the presence of ristocetin. We have found that infusion of desmopressin acetate (1-desamino-8-D-arginine vasopressin [DDAVP]), an agent used in the treatment of von Willebrand's disease, causes platelet aggregation and thrombocytopenia in patients with Type IIB disease. In vitro, platelets in normal plasma and those obtained from patients with Type IIB disease before DDAVP infusion aggregated upon the addition of platelet-poor plasma from Type IIB patients treated with DDAVP. Platelet aggregation was associated with adsorption of multimers of factor VIII/von Willebrand factor onto the platelets and was inhibited by EDTA. We conclude that in Type IIB von Willebrand's disease, DDAVP releases an abnormal factor with platelet-aggregating properties. DDAVP should not be used to treat patients with Type IIB disease, since the presence of platelet aggregates in the circulation may be harmful.

Topics: Adult; Arginine Vasopressin; Child; Child, Preschool; Deamino Arginine Vasopressin; Edetic Acid; Female; Humans; In Vitro Techniques; Male; Middle Aged; Platelet Aggregation; Thrombocytopenia; von Willebrand Diseases; von Willebrand Factor

Intravenous administration of 0.4 micrograms DDAVP/kg body weight in 16 normal controls, 34 patients with haemophilia A and 30 patients with von Willebrand's disease (vWd) was followed by an increase in FVIII: C from 230 to 410%, in FVIIIR:Ag from 160 to 260% and FVIIIR:RC of from 160 to 320%. Additionally, in the patients with vWd, a shortening of the bleeding time and improvement in platelet retention was observed. In 7 haemophiliacs with pretreatment levels of FVIII: C ranging from between 11 and 43% dental extractions were performed successfully after DDAVP whereas in 2 patients with FVIII: C levels of 5 and 6%, respectively, severe bleeding necessitated administration of factor VIII concentrates. In 8 haemophiliacs (FVIII: C between 6.5 and 50%) and 2 patients with vWd (FVIII: C 18 and 36%, respectively) DDAVP enabled minor surgery and successful therapy of spontaneous or traumatic bleeding complications. However, severe postoperative bleeding after stomach surgery in 2 haemophiliacs (FVIII: C 23 and 40%, respectively) and severe menstrual bleeding in one patient with vWd (FVIII: C 15%) required administration of factor VIII concentrates. At present DDAVP therapy should be restricted to minor surgery and non-life-threatening, spontaneous or traumatic bleeding complications in patients with pretreatment FVIII: C levels higher than 10%.

Topics: Arginine Vasopressin; Deamino Arginine Vasopressin; Factor VIII; Fatigue; Flushing; Hemophilia A; Hemorrhage; Humans; Hypertension; Surgical Procedures, Operative; Tooth Extraction; von Willebrand Diseases

Topics: Arginine Vasopressin; Deamino Arginine Vasopressin; Hemophilia A; Humans; von Willebrand Diseases

Topics: Adult; Arginine Vasopressin; Deamino Arginine Vasopressin; Female; Hemorrhage; Humans; Ovarian Diseases; Ovarian Neoplasms; Postoperative Complications; von Willebrand Diseases

Topics: Adolescent; Adult; Aged; Deamino Arginine Vasopressin; Factor VIII; Female; Humans; Male; Middle Aged; Preoperative Care; Surgery, Oral; von Willebrand Diseases

Topics: Adolescent; Adult; Aged; Antigens; Child; Child, Preschool; Deamino Arginine Vasopressin; Factor VIII; Female; Hemophilia A; Humans; Male; Middle Aged; Plasminogen Activators; von Willebrand Diseases

We have studied the modifications in the multimeric composition of plasma factor VIII/von Willebrand factor and the bleeding time response following administration of 1-Deamino-[8-D-arginine]-Vasopressin (DDAVP) to patients with different subtypes of von Willebrand's disease. In type I, all multimers were present in plasma in the resting state, though they were decreased in concentration. Administration of DDAVP resulted in an increased concentration of these forms as well as the appearance of larger forms than were previously present. There was concomitant correction of the bleeding time. In type IIA, large multimers were absent in the resting state, and although DDAVP induced an average threefold increase in the plasma concentration of factor VIII/von Willebrand factor, the larger multimers did not appear and the bleeding time, although shortened, was not corrected. In contrast, the larger multimers that were also absent from type IIB plasma in the resting state rapidly appeared following DDAVP administration. However, their appearance was transitory and the bleeding time, as in IIA patients, was shortened but not corrected. The characteristic multimeric composition of platelet factor VIII/von Willebrand factor in given subtypes predicted the alteration in plasma factor VIII/von Willebrand factor induced by DDAVP. These studies provide evidence that the different subtypes of von Willebrand's disease represent distinct abnormalities of factor VIII/von Willebrand factor. They also suggest that complete hemostatic correction following DDAVP can be routinely expected only in type I von Willebrand's disease, and only if factor VIII/von Willebrand factor can be raised to normal levels.

Topics: Arginine Vasopressin; Autoradiography; Bleeding Time; Blood Coagulation Factors; Deamino Arginine Vasopressin; Electrophoresis, Agar Gel; Factor VIII; Humans; von Willebrand Diseases; von Willebrand Factor

Topics: Administration, Intranasal; Adolescent; Adult; Arginine Vasopressin; Blood Donors; Child; Deamino Arginine Vasopressin; Factor VIII; Female; Hemophilia A; Hemophilia B; Humans; Injections, Intravenous; Male; Middle Aged; von Willebrand Diseases

Topics: Adolescent; Adult; Arginine Vasopressin; Deamino Arginine Vasopressin; Female; Fibrinolysis; Humans; Male; Plasminogen Activators; Urokinase-Type Plasminogen Activator; von Willebrand Diseases

Topics: Deamino Arginine Vasopressin; Fibrinolysis; Humans; von Willebrand Diseases

The abnormal multimeric composition of plasma von Willebrand factor in type IIB von Willebrand's disease is transiently corrected after infusion of 1-deamino-[8-D-arginine]-vasopressin. However, the larger multimers released into the circulation disappear more rapidly in these patients than in type I von Willebrand's disease or normals. We demonstrate that the larger multimers of normal von Willebrand factor transfused into a type IIB patient are cleared from the circulation more slowly than multimers of similar size endogenously released from tissue stores. The rate of disappearance of large von Willebrand factor multimers after infusion of cryoprecipitate is similar in IIB, IIA, and severe homozygous-like von Willebrand's disease. Platelets from the IIB patient exhibited normal ristocetin-induced binding of normal von Willebrand factor. However, like normal platelets, they bound IIB von Willebrand factor at lower ristocetin concentrations than required for normal von Willebrand factor. These findings provide evidence that absence of the larger multimers from IIB plasma is related to a molecular abnormality of von Willebrand factor rather than to enhanced affinity of abnormal tissue or cellular binding sites, as is the case in the recently described "pseudo" von Willebrand's disease and "platelet-type" von Willebrand's disease.

Topics: Blood Coagulation Factors; Blood Platelets; Blood Transfusion; Deamino Arginine Vasopressin; Female; Humans; Macromolecular Substances; von Willebrand Diseases; von Willebrand Factor

These studies were designed with the purpose of providing clinico-pharmacological information relevant to the use of DDAVP in the management of mild haemophilia and von Willebrand's disease (VWD). In healthy subjects, intravenous DDAVP produced its maximal response at a dose of 0.3 micrograms/kg. The extent of the increase in factor VIII coagulant activity (VIII:C) and factor VIII related antigen (VIIIR:Ag) induced by this dose was not significantly different from that observed with the same dose in haemophiliacs and VWD patients. In these, the bleeding time was not shortened. DDAVP given intranasally was followed by a two-fold increase of VIII:C. This route of administration might be adopted to provide an emergency aid in bleeding patients and to yield higher VIII:C levels in blood donors. In healthy subjects, the half-disappearance time of autologous VIII:C after increase induced by i.v. DDAVP is similar to that observed in patients with VWD treated in the same conditions, whereas the response appears to be more prolonged in haemophiliacs. This study shows that the consistency of the VIII:C response tends to decrease when repeated doses are given to healthy subjects. Repeatedly-treated haemophiliacs and VWD patients showed varied patterns, ranging from no change of the response to its early abolishment.

Topics: Adult; Arginine Vasopressin; Bleeding Time; Blood Coagulation Factors; Deamino Arginine Vasopressin; Dose-Response Relationship, Drug; Factor VIII; Female; Hemophilia A; Humans; Male; von Willebrand Diseases; von Willebrand Factor

Topics: Arginine Vasopressin; Deamino Arginine Vasopressin; Hemophilia A; Humans; von Willebrand Diseases

Topics: Arginine Vasopressin; Deamino Arginine Vasopressin; Hemophilia A; Humans; von Willebrand Diseases

Topics: Blood Coagulation Factors; Cells, Cultured; Deamino Arginine Vasopressin; Dexamethasone; Endothelium; Epinephrine; Humans; Hydrocortisone; Ristocetin; Umbilical Veins; Vasopressins; von Willebrand Diseases; von Willebrand Factor

5 patients suffering from von Willebrand's syndrome were treated with DDAVP administered intravenously or intransally. The concentration of F. VIII-related activities (F. VIII:C, F. VIII R:AG, F. VIII R:WF), as well as the mobility of F. VIII R:AG in crossed immunoelectrophoresis and the alterations of bleeding time were continuously monitored. DDAVP induced both quantitative and qualitative changes of F. VIII-related properties. The bledding time was markedly reduced for some hours. The therapy was well tolerated and should be submitted to further clinical trials as a possible way to avoid the disadvantages connected with the transfusion of blood components.

Topics: Adolescent; Arginine Vasopressin; Bleeding Time; Child; Deamino Arginine Vasopressin; Factor VIII; Female; Humans; Immunoelectrophoresis; Male; Middle Aged; von Willebrand Diseases

Topics: Administration, Intranasal; Adolescent; Adult; Arginine Vasopressin; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Humans; Osmolar Concentration; Urine; von Willebrand Diseases

Deamino-8-D-argenine vasopressin (DDAVP) was given by intravenous infusion to normal subjects, haemophiliacs and patients with von Willebrand's disease (vWd) and the factor VIII and plasminogen activator response was studied. In normal subjects and most patients with mild haemophilia and mild (intermediate) von Willebrand's disease there was an increase in plasminogen activator and all factor VIII related activities. In patients with mild vWd the prolonged bleeding time was shortened by DDAVP despite only a modest rise in factor VIII related Ristocetin cofactor activity (VIIIR:RiCoF). Sub-groups of patients have been characterized in whom atypical responses was observed. In two brothers with clinically severe haemophilia, but with 5--6 u/dl procoagulant factor VIII (VIIIC), there was an increase in VIIIC but no rise of the corresponding antigen, suggesting increased release of an antigenically abnormal poorly functioning molecule. A patient with intermediate vWd was studied in whom neither DDAVP, adrenaline infusion, nor venous occlusion resulted in an increase in either plasminogen activator or factor VIII related antigen (VIIRAg), although there was a significant increase in VIIIC. In a further patient with severe vWd, DDAVP failed to elicit any plasminogen activator or VIII response. The results obtained from these two patients suggested that in some individuals the presumed endothelial cell abnormality in vWd may be more extensive than a defect in VIIIRAg synthesis. Sub-groups of patients have been identified for whom treatment with factor VIII concentrates would be more appropriate than DDAVP prior to minor surgery.

Topics: Adolescent; Adult; Aged; Antigens; Arginine Vasopressin; Deamino Arginine Vasopressin; Factor VIII; Female; Fibrinolysis; Hemophilia A; Humans; Male; Middle Aged; Plasminogen Activators; Time Factors; von Willebrand Diseases

Topics: Adolescent; Adult; Arginine Vasopressin; Deamino Arginine Vasopressin; Factor XIII; Female; Hemostasis; Humans; Male; Middle Aged; Time Factors; von Willebrand Diseases

Topics: Adolescent; Aged; Arginine Vasopressin; Blood Coagulation; Blood Donors; Child; Deamino Arginine Vasopressin; Factor VIII; Female; Hemophilia A; Humans; Male; Ristocetin; Tranexamic Acid; von Willebrand Diseases

Topics: Administration, Intranasal; Arginine Vasopressin; Blood Coagulation; Child; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Humans; Partial Thromboplastin Time; von Willebrand Diseases; von Willebrand Factor

Topics: Arginine Vasopressin; Blood Coagulation; Deamino Arginine Vasopressin; Female; Hemorrhage; Humans; Preoperative Care; Time Factors; Tooth Extraction; von Willebrand Diseases

Topics: Adult; Arginine Vasopressin; Blood Coagulation Tests; Child; Deamino Arginine Vasopressin; Factor VIII; Female; Humans; Male; Time Factors; von Willebrand Diseases

1-Deamino-8-d-arginine vasopressin (D.D.A.V.P.) infusion causes a marked increase in factor-VIII (antihaemophilic-factor)-related properties in patients with moderate and mild haemophilia and von Willebrand's disease (vWd). The possibility was therefore evaluated that such an autologous factor-VII response might be haemostatically effective, allowing patients to undergo surgery without plasma concentrates. 0.3 microng/kg of D.D.A.V.P. given before dental surgery and repeated in the early postoperative period was followed by a two to three fold rise in factor-VIII coagulant activity (VII C.A.) in four patients with moderate and mild haemophilia. In two, there was no abnormal bleeding after dental extraction, whereas plasma concentrates were necessary to control oozing from the sockets in the remaining two patients. A higher D.D.A.V.P. dosage (0.4-0.5 microng/kg) in patients with higherstarting VII C.A. (9% or more) was followed by a more marked response (four to six fold). VII C.A. levels up to 100% of average normal were achieved and dental extraction and major surgery (such as cholecystectomy, thoracotomy, and two tonsillectomies) were carried out successfullly in six patients with mild haemophilis and in two with vWd. The mean half-life of autologous VII C.A. was 9.4 h (range 7.5-11.6). Plasma and urine osmolality showed no consistent variation after drug administration. Thus D.D.A.V.P. appears a promision pharmacological alternative to plasma concentrates in the management of some patients with haemophilis and vWd.

Topics: Adolescent; Adult; Biopsy; Blood Coagulation Tests; Cholecystectomy; Deamino Arginine Vasopressin; Drug Evaluation; Factor VIII; Female; Hemophilia A; Hemorrhage; Hemostasis, Surgical; Humans; Infusions, Parenteral; Male; Middle Aged; Postoperative Care; Postoperative Complications; Preoperative Care; Thoracic Surgery; Thorax; Tonsillectomy; Tooth Extraction; Vasopressins; von Willebrand Diseases

Topics: Blood Coagulation; Deamino Arginine Vasopressin; Hemophilia A; Hemorrhage; Humans; Vasopressins; von Willebrand Diseases