deamino-arginine-vasopressin and Hemophilia-A

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

Hemophilia A and B are bleeding disorders caused by a deficiency of clotting factor VIII and IX, respectively. Patients with severe hemophilia (< 0.01 IU mL

Topics: Blood Coagulation Factors; Child; Deamino Arginine Vasopressin; Hemophilia A; Humans

It is important to discard those practices that do not add value. As a result, several initiatives have emerged. All of them try to improve patient safety and the use of health resources.. To present a compendium of "do not do recommendations" in the context of hemophilia.. A review of the literature and current clinical guidelines has been made, based on the best evidence available to date.. The following 13 recommendations stand out: 1) Do not delay the administration of factor after trauma; 2) do not use fresh frozen plasma or cryoprecipitate; 3) do not use desmopressin in case of hematuria; 4) do not change the product in the first 50 prophylaxis exposures; 5) do not interrupt immunotolerance; 6) do not administer aspirin or NSAIDs; 7) do not administer intramuscular injections; 8) do not do routine radiographs of the joint in case of acute hemarthrosis; 9) Do not apply closed casts for fractures; 10) do not discourage the performance of physical activities; 11) do not deny surgery to a patient with an inhibitor; 12) do not perform instrumental deliveries in fetuses with hemophilia; 13) do not use factor IX (FIX) in patients with hemophilia B with inhibitor and a history of anaphylaxis after administration of FIX.. The information mentioned previously can be useful in the management of hemophilia, from different levels of care. As far as we know, this is the first initiative of this type regarding hemophilia.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Blood Coagulation Factors; Deamino Arginine Vasopressin; Disease Management; Exercise; Factor VIII; Fibrinogen; Hemarthrosis; Hemophilia A; Hemostatics; Humans; Practice Guidelines as Topic

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

Hemophilia A and hemophilia B are hereditary bleeding disorders, caused by a deficiency of clotting factor VIII or clotting factor IX, respectively. To treat and prevent bleedings, patients can administer clotting factor concentrates (hemophilia A and B) or desmopressin (hemophilia A). Both clotting factor concentrates and desmopressin are currently dosed according to the patients' body weight. However, clotting factor concentrates exhibit considerable pharmacokinetic (PK) variability. Therefore, several alternative dosing strategies to individualize dosing of clotting factor concentrates and desmopressin in hemophilia A and B have been proposed. In this study, a review of the existing literature on the individualization of dosing based on PK guidance was performed. In total, 79 articles were included. The methods to individualize dosing were divided into 3 categories: (1) methods using clinical parameters, (2) empirical individual PK-guided methods, and (3) maximum a posteriori (MAP) Bayesian estimation methods. The clinical parameter mainly used to individualize dosing is bleeding phenotype. Dosing based on bleeding phenotype may decrease clotting factor consumption. However, with this method, it is not possible to individualize on-demand dosing during bleeding events or in the perioperative setting. Empirical individual PK-guided methods can be used both for prevention and treatment of bleedings. These methods include dose individualization using a nomogram and individualized in vivo recovery. In the perioperative setting, adjustment of the rate of continuous infusion can be applied to obtain a specific target level. The final category, MAP Bayesian estimation methods, relies on the availability of a population PK model. In total, 22 population PK models describing clotting factor concentrate or desmopressin dosing are currently available in literature. MAP Bayesian estimates can be used to calculate the individualized doses required to achieve or maintain a target level in every setting. The application of PK-guided and pharmacodynamic-guided dosing of clotting factor concentrates and desmopressin seems promising, although further investigation is warranted. Prospective studies analyzing its potential benefit are on the way.

Topics: Blood Coagulation Factors; Deamino Arginine Vasopressin; Hemophilia A; Hemophilia B; Humans; Precision Medicine

Desmopressin is an effective haemostatic agent for patients with non-severe haemophilia A; however, response may differ between patients of similar severity. Responsiveness is classified based on various cut-off values for plasma levels of FVIII post-desmopressin administration. Patients may be classified differently depending on the values chosen.. To classify desmopressin response in non-severe haemophilia A patients with respect to current test-response definitions. Also, to characterize relationships between test response and clinical outcome of desmopressin use.. Current desmopressin test-response definitions were obtained from the literature. We adopted peak FVIII level (at 1 hour post-administration) ≥50 IU/dL and <20 IU/dL as complete and no response, respectively, thereby satisfying most reported definitions. Test-responses and clinical outcomes of use between 2007 and 2017 for adult mild/moderate haemophilia A patients were reviewed and correlated.. All patients classified as complete responders (n = 31; peak FVIII ≥50 IU/dL) and the majority of partial responders (n = 11; peak FVIII ≥20 to <50 IU/dL) had good clinical outcomes after desmopressin use for a variety of bleeding episodes and procedures. Two non-responders (peak FVIII <20 IU/dL) given desmopressin for minor bleeding/procedures also had good clinical outcomes. One patient with a partial test-response (peak FVIII 23 IU/dL) required additional factor concentrate to achieve haemostasis.. Based on our review, we suggest that the determination of desmopressin responsiveness should consider both the change in plasma FVIII levels as well as clinical outcomes associated with prior therapeutic use.

Topics: Canada; Deamino Arginine Vasopressin; Female; Hemophilia A; Humans; Male; Treatment Outcome

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

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

Management of acquired hemophilia A is challenging and should be undertaken in close collaboration with a hemophilia center with expertise in the field. Treatment involves controlling and preventing bleeds and using immunosuppression to eradicate the inhibitor. Prompt diagnosis is important to allow early hemostatic treatment and to prevent nonessential invasive procedures. First-line hemostatic treatment should be with a bypassing agent. Recombinant activated factor VII and the activated prothrombin complex concentrate anti-inhibitor coagulant complex (Factor Eight Inhibitor Bypassing Activity, or FEIBA) but equally efficacious but both associated with thrombotic events when used in acquired hemophilia. Immunosuppression should be started as soon as a diagnosis has been confirmed. The combination of steroids and cyclophosphamide may induce more patients into remission than steroids alone. Current data do not suggest that rituximab results in better outcomes. Relapse is common (10%-20%) in the first 6 months after immunosuppression is stopped, and patients need to be followed up regularly to allow early diagnosis and treatment of relapse.

Topics: Cyclosporine; Deamino Arginine Vasopressin; Factor VII; Factor VIII; Hemophilia A; Hemostasis; Humans; Immunoglobulins, Intravenous; Immunosuppression Therapy; Immunosuppressive Agents; Recombinant Proteins; Recurrence; Remission Induction; Steroids; Treatment Outcome

Topics: Deamino Arginine Vasopressin; Hemophilia A; Hemostatics; Humans

Acquired haemophilia A is an auto-immune disease caused by an inhibitory antibody to factor VIII. Patients with an acquired factor VIII inhibitor are at risk of life- and limb-threatening bleeding until the inhibitor has been eradicated. Management relies on rapid and accurate diagnosis, control of bleeding episodes, investigation for a precipitating cause and eradication of the inhibitor by immunosuppression. Patients should always be managed jointly with a specialist centre even if they present without overt bleeding. Despite an extensive literature, few controlled data are available and management guidelines are predominantly based on case reports, retrospective cohorts and expert opinion. This paper reviews the current literature on incidence, pathogenesis, diagnosis, haemostatic therapy and inhibitor eradication strategies. Potential future developments are discussed.

Topics: Adult; Child; Deamino Arginine Vasopressin; Factor VIII; Female; Hemophilia A; Humans; Immunoglobulins; Immunologic Factors; Immunosuppressive Agents; Male; Pregnancy; Pregnancy Complications; Recurrence

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

Owing to its ability to raise plasma levels of factor VIII and von Willebrand factor levels, the synthetic vasopressin analogue desmopressin has become the mainstay of treatment for type 1 von Willebrand disease and mild hemophilia A. A long clinical experience with this drug for prevention or treatment of bleedings in these patients has been accumulated over the past 30 years, supporting its hemostatic effectiveness and safety. In this paper, we summarize the current knowledge on the mechanisms of action as well as its biological effects in patients with mild hemophilia A. The results of the most important clinical trials in this setting are also reviewed.

Topics: Deamino Arginine Vasopressin; Hemophilia A; Humans; Treatment Outcome; von Willebrand Disease, Type 1

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

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

In mild/moderate haemophilia A (MHA) patients, many factor VIII (FVIII) gene defects, mainly missense mutations, have been identified and greatly improved the understanding of the structure and function of FVIII molecule. Characterization of the molecular mechanisms involved in MHA has helped to identify regions critical for proper FVIII biosynthesis, thrombin activation, intramolecular stability as well as binding regions for important intermolecular interactions with von Willebrand factor, factor IXa and the phospholipid surface. Some missense mutations were also recognized as contributing factors to inhibitor development in MHA, in parallel to acquired factors such as inflammatory state or intensity of treatment. Treatment of MHA with inhibitor patients raises questions on how best to stop or prevent bleeding episodes and eradicate the inhibitor. Longitudinal data collection is currently being conducted in France and Belgium to enhance our knowledge in this field and to further help make treatment decision. The description of mutations in MHA finally contributed to the identification of epitopes involved in the immune response to FVIII. In some patients, the epitope specificity of inhibitor antibodies recognizing normal exogenous FVIII alone and not patient ('self') FVIII was described. This distinguished epitope specificity could also be demonstrated at the T-cell clonal level. One might expect that these molecular studies will have a major impact on development of new FVIII products in the future.

Topics: Antibodies; Deamino Arginine Vasopressin; Epitopes; Factor IXa; Factor VIII; Genotype; Hemophilia A; Hemorrhage; Hemostatics; Humans; Immune Tolerance; Mutation, Missense; Thrombin

Inherited deficiencies of plasma proteins involved in blood coagulation generally lead to lifelong bleeding disorders. The severity of these disorders is generally inversely proportional to the degree of factor deficiency. Among all the autosomal recessive rare bleeding disorders, which include afibrinogenaemia, factor (F) II, FV, FV + VIII, FVII, FX, FXI, FXIII, the combined deficiency of coagulation FV and FVIII (F5F8D or FV + FVIII) is exceptional because it is due to mutations in genes encoding proteins involved in the FV and FVIII intracellular transport (LMAN1 and MCFD2) rather than DNA defects in the genes that encode the corresponding coagulation factors. F5F8D is estimated to be extremely rare (1:1.000.000) in the general population, but an increased frequency is observed in regions where consanguineous marriages is practiced. F5F8D is characterized by concomitantly low levels (usually between 5% and 20%) of both FV and FVIII, and is associated with a mild to moderate bleeding tendency. Treatment of bleeding episodes requires a source of both FV and FVIII; replacement of FV is achieved through the use of fresh frozen plasma, and that of FVIII by desmopressin or specific FVIII concentrates, plasma-derived or recombinant FVIII products. We focus here on the clinical, molecular, treatment-related and diagnostic features of F5F8D.

Topics: Blood Coagulation; Coagulants; Deamino Arginine Vasopressin; DNA Mutational Analysis; Factor V Deficiency; Factor VIII; Female; Hemophilia A; Hemorrhage; Hemostatics; Humans; Male; Mannose-Binding Lectins; Membrane Proteins; Mutation; Plasma; Pregnancy; Pregnancy Complications, Hematologic; Rare Diseases; Vesicular Transport Proteins

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 synthetic vasopressin analogue (1-deamino-8-D-arginine-vasopressin) increases plasma concentration of factor VIII and von Willebrand factor in normal subjects and patients with mild haemophilia A and von Willebrand disease. Since its first clinical use in 1977, desmopressin has become the treatment of choice for patients with haemophilia A and factor VIII coagulant activity (FVIII:C) > 5% and has spared several patients the risk of acquiring blood-borne viral infections due to the use of non-virally inactivated plasma-derived FVIII concentrates. An average two to sixfolds FVIII:C increase is typically observed in most patients and return to baseline occurs usually within 8 hours. Several clinical studies have demonstrated the clinical efficacy and safety of desmopressin and the availability of concentrated formulation for subcutaneous injection and of a nasal spray has paved the way to home-treatment. However, overall it appears that haemophilic children may have a lower rate of biologic response compared to adults and a minority of adult patients are not able to attain clinically useful FVIII:C levels post-desmopressin administration. Thus, in every patient with haemophilia A likely to be treated or candidate to an elective invasive procedure, a test-infusion/injection should be carried out to assess the future usefulness of the compound.

Topics: Administration, Intranasal; Adult; Child; Deamino Arginine Vasopressin; Hemophilia A; Hemostatics; Humans; Injections, Intravenous

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 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

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

Inhibitor patients do not always respond satisfactorily to treatment with bypassing agents, and options to the standard practice are sometimes needed. Temporary inhibitor removal may be achieved using extracorporeal immunoadsorption. This technique uses a column system including either protein A or antihuman IgG. Immunoadsorption may be used as part of an immune tolerance protocol, or in the case of acute bleeds or prior to surgery, thus rendering the patient more responsive to ordinary replacement therapy with factor VIII or factor IX. Desmopressin is a valuable haemostatic agent in many situations and can be especially recommended in mild haemophilia complicated by an inhibitor. Antifibrinolytics are often administered as an adjunct therapy to the treatment protocol and have also been reported to have a direct anti-inhibitor effect.

Topics: Antifibrinolytic Agents; Coagulants; Deamino Arginine Vasopressin; Extracorporeal Circulation; Factor IX; Factor VIII; Hemophilia A; Hemorrhage; Humans; Immunosorbent Techniques; Staphylococcal Protein A

Topics: Autoantibodies; Blood Coagulation Factor Inhibitors; Blood Coagulation Factors; Blood Coagulation Tests; Deamino Arginine Vasopressin; Epitopes; Factor VII; Factor VIII; Hemophilia A; Humans; Japan; Plasma Exchange; Recombinant Proteins

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

Haemophilia A and B are the most common of the inherited bleeding disorders. Haemophilia in the newborn presents a number of challenges in terms of both diagnosis and management which reflect features unique to this age group. In the presence of a family history of haemophilia optimal management requires close co-operation between three individual specialist groups - obstetricians, haematologists and neonatologists, who each have an important role to play in ensuring a safe outcome for these infants. More problematic is where a family history is absent or has not been adequately elucidated in which case the diagnosis of haemophilia in the neonate will be unsuspected. Diagnostic difficulties may then arise due to failure to recognise the presence of abnormal bleeding, which is often different from that typically observed in older children with haemophilia. In addition, diagnostic investigations are complicated by physiological differences in the neonatal haemostatic system. Although major bleeding is relatively uncommon, the incidence of intracranial haemorrhage is higher during the first few days of life than at any other stage in childhood, which relates to the trauma of delivery. Controversy, however, remains on optimal strategies for both prevention and management of this potentially devastating complication.

Topics: Deamino Arginine Vasopressin; Factor IX; Factor VIII; Hemophilia A; Hemophilia B; Hemorrhage; Hemostatics; Humans; Infant, Newborn; Male; Pedigree; Vitamin K; Vitamin K Deficiency Bleeding

Topics: Combined Modality Therapy; Deamino Arginine Vasopressin; Female; Hemophilia A; Hemophilia B; Humans; Male; Perioperative Nursing; Preoperative Care; Prognosis; Quality of Life; Risk Assessment; Severity of Illness Index; United Kingdom

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

Replacement therapy with blood products has long been the only available therapeutic option for patients with bleeding disorders. Plasma-derived cryoprecipitate and factor (F) VIII concentrates, which have been used for hemophilia A patients, involve the risk of transmitting blood-borne diseases. Both plasma-derived and recombinant FVIII concentrates are expensive, and there is a global shortage. The synthetic vasopressin analogue desmopressin acetate (1-deamino-[8-D-arginine]-vasopressin, DDAVP) increases plasma concentrations of coagulation FVIII and von Willebrand factor (vWF) two fold to six fold through endogenous release. The drug is an attractive therapeutic alternative because it carries no risk of transmission of infectious diseases. Desmopressin is today a widely used hemostatic agent not only in patients with mild hemophilia A or von Willebrand disease (vWD) but also in those with congenital or acquired platelet dysfunction. There is a long clinical experience with the drug because it has been used for prevention of bleedings in connection with invasive procedures and for treatment of bleedings since the mid-1970s. Not all hemophilia A patients can be treated. The clinical usefulness depends on the postdesmopressin plasma concentration of FVIII, which in turn depends on the patient's basal FVIII level. Therefore, a test dose is recommended in candidate patients. In general, only the mildest hemophilia A patients respond sufficiently. Optimal hemostatic effect is achieved with a dosage of 0.3 microg/kg given intravenously. An intranasal desmopressin spray is suitable for the home treatment.

Topics: Coagulants; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Hemostatics; Humans; Models, Chemical; Recombinant Proteins; Tachyphylaxis; Time Factors; von Willebrand Factor

This paper discusses selected reports on the management of acquired haemophilia A, a rare bleeding disorder characterized by the development of an autoantibody directed against plasma coagulation factor VIII (FVIII) (Morrison et al., Blood 81:1513-1520, 1993). The current literature consists of reports of cohorts of patients from referral centres and retrospective surveys of referral centres (Green and Lechner, Thromb Haemost 45:200-203, 1981). This suggests that the current literature may be biased both by referral practice to tertiary centres and reporting bias of these centres and may not be representative of the full spectrum of the disease. The published studies describe various immunosuppressive regimens to eradicate factor VIII inhibitors but usually lack control patients. Only one report describes a randomized, controlled study. Studies that address treatment of bleeding episodes give data on safety and efficacy for individual products but no comparative studies are available.

Topics: Adrenal Cortex Hormones; Adult; Animals; Autoantibodies; Autoimmune Diseases; Bias; Blood Coagulation Factors; Deamino Arginine Vasopressin; Factor VIII; Female; Hemophilia A; Humans; Immunoglobulins, Intravenous; Immunosorbent Techniques; Immunosuppressive Agents; Postpartum Hemorrhage; Pregnancy; Retrospective Studies; Swine

Over the last 4 decades, there have been very significant advances in the treatment of haemophilia. Plasma products first became available in the 1960s, beginning with cryoprecipitate and then intermediate-purity plasma concentrates, for the treatment of haemophilia A and B. The disasters of viral infections amongst people with haemophilia in the 1980s served to stimulate both the development of techniques of viral inactivation of concentrates and the manufacture of purer products. We therefore now have safe plasma products that are also pure in that they are concentrates of only the deficient protein responsible for the congenital coagulopathy. Preparations of specific coagulation proteins obtained using recombinant biotechnology techniques have been available since 1995. By contrast, pharmacological options for the treatment of the haemophilia remain very limited. The only therapeutic alternatives of real practical value which have been available in the last 30 years for the treatment of haemophilic patients are desmopressin, antifibrinolytic agents, aprotinin, concentrated oestrogens, and local haemostatic agents such as topical thrombin or fibrin glue. This article aims to assess the pharmacological basis and accumulated experience relating to these drugs when used for the prevention and treatment of bleeding in patients with haemorrhagic disorders.

Topics: Antifibrinolytic Agents; Contraindications; Deamino Arginine Vasopressin; Hemophilia A; Hemophilia B; Hemorrhage; Humans

Hemophilia is an inherited bleeding disorder caused by quantitative or qualitative defects in the synthesis of factor VIII (FVIII) or factor IX (FIX). Clinically, it is divided into severe, moderate and mild disease depending on the levels of FVIII or FIX in the blood. The bleeding tendency is most pronounced and can start at a very young age in severe hemophilia, which is characterized by repeated hemorrhage into the joints and muscles. Without treatment, these episodes lead to severe arthropathy, and there is also a high risk of lethal cerebral hemorrhage. The treatment of bleeding symptoms requires the correction of the coagulation defect. Factor concentrates have been available for 30 years, initially with the development of cryoprecipitate, subsequently with increasingly purified plasma-derived forms, and ultimately with recombinant clotting factor concentrates. The advantage of this highly effective therapy has been subdued by the outbreak of HIV and Hepatitis C infections in patients with hemophilia treated with factor concentrates which did not have adequate viral inactivation steps in the purification process. Plasma-derived and recombinant factor concentrates are today considered to have a good safety profile, but are only available for a small group of hemophilia patients worldwide. A multidisciplinary team approach is important for early diagnosis, communication with the patient and parents, and to tailor the best treatment possible with the amount of clotting factor concentrates available. The main goal of hemophilia treatment is to prevent bleeding symptoms and allow normal integration in social life. In patients with severe hemophilia, this can best be achieved by early home treatment and primary prophylaxis. Future developments in gene therapy may transform severe hemophilia to a mild form, with no need for regular injections of clotting factor concentrates.

Topics: Antifibrinolytic Agents; Child; Child, Preschool; Deamino Arginine Vasopressin; Hemophilia A; Humans

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

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

Although the nature of haemophilia has been understood for thousands of years, knowledge of its molecular genetics is recent. These X-linked bleeding disorders have diverse underlying DNA defects and, in 1992, DNA inversion within the X chromosome was found to explain half of the most serious cases of haemophilia A. The life-span and quality-of-life for patients with haemophilia had improved steadily throughout the early 1980s but the principal cause of death remained intracranial haemorrhage until the epidemic of HIV infection due to contaminated factor concentrates. Infection with hepatitis C virus is almost universal for patients treated with clotting factors before 1985. No curative treatment is available for hepatitis C at present. Knowledge of the transmission of viruses in concentrates has led to important developments in processing techniques to eliminate them. Recombinant technology has produced factor VIII and, more recently, factor IX concentrate which is likely to be very safe. Development of inhibitors to factor concentrates (especially factor VIII) remains one of the most serious complications of haemophilia. The variety of treatments available testifies to the lack of a single universally efficacious one. The use of prophylactic treatment has been conclusively demonstrated to result in a preservation of joint function in severely affected patients who might otherwise develop significant joint problems. The many facets of the care of patients with severe haemophilia, ranging from dental care to genetic counselling, can be advantageously co-ordinated in a haemophilia comprehensive care centre.

Topics: Acquired Immunodeficiency Syndrome; Cause of Death; Cerebral Hemorrhage; Contraindications; Deamino Arginine Vasopressin; Drug Contamination; Factor IX; Factor VIII; Female; Hemophilia A; Hepatitis C; Humans; Hypoglycemic Agents; Male; Recombinant Proteins; United Kingdom

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

The development of auto-antibodies against clotting factor VIII is a rare disease that occurs predominantly in adults: in pregnant women or people with various immunologic disorders or with no apparent underlying disease. As a consequence of an immune system dysregulation, the evolution of this condition is unpredictable. The aim of treatment is to restore normal factor VIII levels in circulation using desmopressin (DDAVP), massive doses of factor VIII (human or porcine), plasmapheresis and factor VIII infusions. In patients with high-titer inhibitors, products with 'bypasing' activity can be used. The most difficult task is to treat the immune disorder. High-dose infusions of immunoglobulins might be useful, due to the presence of anti-idiotypes to factor VIII inhibitors in the commercial preparations. Corticosteroids and cyclophosphamide are currently the most widely used treatments for the immune disease.

Topics: Adult; Autoantibodies; Autoimmune Diseases; Deamino Arginine Vasopressin; Factor VIII; Female; Hemophilia A; Humans; Immunoglobulins, Intravenous; Pregnancy

Splenic laceration, the most common visceral lesion following blunt abdominal trauma, can be treated in a nonoperative fashion in only a select group of stable patients with minimal injury. We report a unique case of life-threatening splenic trauma in a Jehovah's Witness with hemophilia that was successfully managed without surgery.

Topics: Adolescent; Christianity; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Humans; Male; Spleen; Tomography, X-Ray Computed; Wounds, Nonpenetrating

Recent years have witnessed advances in the treatment of haemophilia such as the introduction of prophylaxis, continuous infusion and pharmacological treatment with desmopressin (DDAVP). Prophylactic treatment on a long-term basis appears to be effective in preventing the development of arthropathy in severe haemophilia. The largest body of experience is that from Sweden, where prophylaxis is started at the age of 1-2 years. The dosage used is 25-40 U factor VIII/IX per kilogram bodyweight given three times or twice weekly, respectively. In some cases an intravenous access device has to be used during the first years of treatment. The patients grow up like normal boys and can live virtually normal lives. The beneficial psychological impact of prophylaxis on the family cannot be overestimated. Side-effects are not more frequent with prophylaxis than with on-demand treatment. The feasibility of continuous infusion of factor VIII/IX concentrates during bleeding episodes, or as cover for surgery, has been documented. This mode of delivery increases convenience and the cost-benefit ratio of the treatment, with savings in postoperative replacement of factor concentrate of about 50-75%. Many modern concentrates are stable enough for the purpose, and several pump systems, including portable ones, are available. The haemostatic drug DDAVP can be effectively used in most cases of mild haemophilia A. Intravenous administration is to be preferred as cover for surgery or in the case of severe bleeds. There is an effective nasal spray which can also be used for home therapy in mild or moderate bleedings.

Topics: Adolescent; Catheterization, Central Venous; Catheterization, Peripheral; Child; Child, Preschool; Deamino Arginine Vasopressin; Factor IX; Factor VIII; Female; Hemarthrosis; Hemophilia A; Hemophilia B; Hemorrhage; Hemostatics; Humans; Infant; Infusions, Intravenous; Injections, Intravenous; Male; Practice Guidelines as Topic; Treatment Outcome; World Health Organization

Factor VIII auto-antibody inhibitors, though rare, may present significant and often life-threatening haemorrhage. These auto-antibodies, arising predominantly in older individuals, occur in association with autoimmune disorders, lymphoproliferative disorders, solid tumours, medications and the postpartum state. Almost half of the patients develop auto-antibodies spontaneously without an underlying medical condition. Factor VIII auto-antibody inhibitors are characterized as polyclonal IgG immunoglobulins directed against the FVIII procoagulant activity. Laboratory diagnosis is made by performing the aPTT clotting time in conjunction with a mixing study, and subsequently with specific factor assays. Auto-antibodies are quantified most commonly utilizing the Bethesda assay. Acquired inhibitors to other coagulation factors, including factors IX, XI, XIII, vWF protein, and the vitamin K-dependent proteins are extremely rare. The principles of therapy are similar to those which apply to the management of factor VIII auto-antibodies. Treatment of patients with acquired factor VIII auto-antibody inhibitors varies depending upon the underlying medical condition, the titre of the inhibitor, and the clinical presentation. Acutely bleeding patients with high-titre auto-antibodies generally respond well with infusions of porcine factor VIII concentrate, PCCs or rFVIIa. Extracorporeal plasmapheresis with exchange will acutely reduce circulating antibodies and can be used in conjunction with factor infusions and/or IgIV. Haemorrhage in a patient with a low titre auto-antibody will usually respond to high doses of human factor VIII concentrate. DDAVP may also increase factor VIII levels in patients with low-titre inhibitors. Long-term reduction of auto-antibodies can be achieved by immuno-suppressive regimens using steroids and/or cytotoxic agents, IgIV and interferon-alpha. The selection of the appropriate treatment depends upon the associated medical condition, likelihood of spontaneous remission, risk of toxicities of therapy and cost. Determining the efficacy and safety of new treatment modalities for factor VIII auto-antibodies and other coagulation factor inhibitors will require multicentre randomized clinical trials.

Topics: Adult; Aging; Animals; Antibodies, Anti-Idiotypic; Autoantibodies; Autoimmune Diseases; Blood Coagulation Disorders; Blood Coagulation Factors; Deamino Arginine Vasopressin; Factor VIIa; Factor VIII; Female; Hemophilia A; Hemorrhage; Humans; Immunization; Immunoglobulin G; Immunoglobulins, Intravenous; Immunosuppressive Agents; Incidence; Interferon-alpha; Isoantibodies; Male; Plasma Exchange; Plasmapheresis; Pregnancy; Prothrombin; Puerperal Disorders; Recombinant Proteins; Swine

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

Hemophilias A and B are inherited disorders of clotting-factor production that are characterized by low levels of factor VIII- or IX-coagulant activity. The clinical course of patients with hemophilia is marked by episodes of hemorrhage, some spontaneous and some related to trauma or medical procedures. The physical well-being of patients with hemophilia is maintained by the prevention of bleeding when possible and by prompt, effective treatment of bleeding when it occurs. Factor-replacement therapy continues to be the mainstay of hemophilia treatment, but like pharmacotherapy for other disease states, it is most effective when provided within the framework of a well-designed, individualized therapeutic plan. Currently available factor concentrates have a much greater safety profile than older products, but they are not free of adverse effects. Patients with inhibitors continue to present a challenge in restoring hemostasis. Pharmacists can play an important role in the pharmaceutical care of patients with hemophilia.

Topics: Antifibrinolytic Agents; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Hemophilia B; Humans

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

One patient with an acquired factor VIII inhibitor is reported in which an acute lower intestinal hemorrhage was successfully managed using Desmopressin (DDAVP). The patient initially had a factor VIII level of 10% with a inhibitor titer of 1.9 Bethesda units. Following administration of DDAVP the factor VIII level rose to 86% and there was a decrease in the number and volume of bloody stools. The inhibitor disappeared following treatment with corticosteroids, however the patient ultimately expired due to complications of ischemic colitis. This case and 21 previously reported cases of acquired hemophilia treated with DDAVP are reviewed. The data support a role for DDAVP in the treatment of non life threatening hemorrhage in patients with acquired hemophilia and low titer factor VIII inhibitors (< 5 Bethesda units or factor VIII > or = 5%).

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Child; Deamino Arginine Vasopressin; Factor VIII; Female; Hemophilia A; Hemorrhage; Humans; Intestinal Diseases; Male; Middle Aged

Over the past few years considerable progress has been made in elucidating the molecular genetics of hemophilia A, in carrier detection and prenatal diagnosis, and in the production of safer clotting factor concentrates. Recombinant FVIII, shown to be safe and effective in ongoing prelicensure clinical trials that began in the spring of 1987, should soon be licensed and commercially available. There is now considerable interest in beginning prophylactic therapy regimens at 1 or 2 years of age, in an attempt to prevent chronic joint disease and other complications of serious bleeding episodes. The possibility of gene insertion therapy for persons with hemophilia now seems to be a realistic one--perhaps achievable in the 1990s. Although many problems remain--major problems resulting from HIV, HCV, and HBV infections; how to deal with existing musculoskeletal problems; how to pay for the higher-priced new technologies; high titer inhibitors; just to name a few--the many recent scientific advances and their clinical applications make this an exciting time. This is truly, as indicated in the title of the proceedings of the XIX Congress of the World Federation of Hemophilia, a new decade of hopes and challenges.

Topics: Child, Preschool; Deamino Arginine Vasopressin; Dental Care; Factor VIII; Fetal Diseases; Hemarthrosis; Hemophilia A; Hemorrhage; Humans; Infant; Infant, Newborn; Prenatal Diagnosis; Prevalence; Recombinant Proteins; Virus Diseases

A broad, open, inquisitive, and semiskeptical mind must be used when approaching the bleeding patient. As in most endeavors in medicine, the history and physical examination provide an important baseline. Key laboratory tests must be quickly ordered and interpreted. Using this data base, one can quickly determine whether the hemorrhagic disorder is congenital or acquired, severe or mild, and progressive or stable. Hemostasis may fail owing to deficiencies of platelets, the plasma coagulation protein system, or endothelial disturbances. A precise diagnosis and appreciation of the tempo of the disorder will guide specific therapy.

Topics: Blood Coagulation Factors; Deamino Arginine Vasopressin; Diagnosis, Differential; Hemophilia A; Hemorrhage; Hemorrhagic Disorders; Humans

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

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

Topics: Deamino Arginine Vasopressin; Factor IX; Factor VIII; Female; Genetic Carrier Screening; Hemophilia A; Hemorrhage; Hepatitis B; HIV Infections; Humans; Infant, Newborn; Pregnancy; Prenatal Diagnosis; Recombinant Proteins

Topics: Animals; Antigens; Autoantibodies; Autoimmune Diseases; Deamino Arginine Vasopressin; Factor IX; Factor VIII; Female; Hemophilia A; Hemorrhagic Disorders; Humans; Immunoglobulin G; Immunosuppressive Agents; Isoantibodies; Plasmapheresis; Postpartum Period; Pregnancy; Swine

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

Topics: Antigens; Deamino Arginine Vasopressin; Endothelium, Vascular; Factor VIII; Hemophilia A; Hemorrhagic Disorders; Hemostasis; Hemostasis, Surgical; Hemostatics; Humans; Receptors, Angiotensin; Receptors, Vasopressin; Thrombosis; von Willebrand Factor

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

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

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

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

Haemophilia is a congenital, life-long disorder that may cause major disabilities. The goal of comprehensive care is to prevent problems when possible, to treat early in order to minimize morbidity, and to restore function to disabled patients. The co-ordinated efforts of many experts are needed for success.

Topics: Aminocaproic Acid; Analgesics; Animals; Anti-Inflammatory Agents; Arthritis; Blood Coagulation Factors; Blood Transfusion; Deamino Arginine Vasopressin; Dental Care; Estrogens; Factor IX; Factor IXa; Factor VIII; Hemophilia A; Hemophilia B; Hemorrhage; Humans; Oral Hygiene; Plasma; Progesterone; Self Administration; Surgical Procedures, Operative; Swine; Synovitis

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

Persons with mild hemophilia A (HA) may use intranasal desmopressin prior to sports participation. Desmopressin is expensive and can cause vomiting, headache, palpitation, and occasionally seizures. Our group has previously documented a 2.3-fold increase in factor VIII activity (FVIII:C) in adolescents with mild HA after moderate-intensity aerobic exercise. Herein, we report principal findings of a randomized trial of intranasal desmopressin vs a standardized, moderate-intensity aerobic exercise regimen in adolescents with mild HA. Our primary objective was to compare the change in FVIII:C associated with these 2 interventions. We also examined changes in hemostatic parameters arising from their sequential administration. The study was conducted simultaneously at the Hospital for Sick Children, Canada, and Nationwide Children's Hospital, USA. Thirty-two eligible male adolescents (mean age ± standard deviation: 16.1 ± 2.6 years) with mild HA (mean baseline FVIII:C: 27.9% ± 18.4%) were randomized to 1 of 4 study arms (desmopressin followed by exercise, desmopressin alone, exercise followed by desmopressin, and exercise alone). Blood work was obtained at baseline and at 3 subsequent time-points. Participants randomized to exercise cycled on an ergometer for approximately 12 minutes, with the final 3 minutes at 85% of their predicted maximum heart rate. Standard weight-based dosing of desmopressin was used. Mean immediate increase in FVIII:C was 1.7-fold with exercise compared with 1.9-fold with desmopressin (noninferiority, P = .04). Exercise-induced improvement in hemostatic parameters including FVIII:C was brief compared with more sustained improvements seen with desmopressin. More than 60% of participants randomized to receive both exercise and desmopressin achieved normal (>50%) FVIII:C, 75 and 135 minutes into the study protocol.

Topics: Adolescent; Deamino Arginine Vasopressin; Exercise Therapy; Factor VIII; Hemophilia A; Hemostatics; Humans; Male

Haemophilia A is an inherited bleeding disorder characterised by factor VIII (FVIII) deficiency. In patients with non-severe haemophilia A, surgery and bleeding are the main indications for treatment with FVIII concentrate. A recent study reported that standard dosing frequently results in FVIII levels (FVIII:C) below or above FVIII target ranges, leading to respectively a bleeding risk or excessive costs. In addition, FVIII concentrate treatment carries a risk of development of neutralising antibodies. An alternative is desmopressin, which releases endogenous FVIII and von Willebrand factor. In most patients with non-severe haemophilia A, desmopressin alone is not enough to achieve FVIII target levels during surgery or bleeding. We hypothesise that combined pharmacokinetic (PK)-guided administration of desmopressin and FVIII concentrate may improve dosing accuracy and reduces FVIII concentrate consumption.. In the DAVID study, 50 patients with non-severe haemophilia A (FVIII:C ≥0.01 IU/mL) with a bleeding episode or undergoing surgery will receive desmopressin and FVIII concentrate combination treatment. The necessary dose of FVIII concentrate to reach FVIII target levels after desmopressin administration will be calculated with a population PK model. The primary endpoint is the proportion of patients reaching FVIII target levels during the first 72 hours after start of the combination treatment. This approach was successfully tested in one pilot patient who received perioperative combination treatment.. The DAVID study was approved by the medical ethics committee of the Erasmus MC. Results of the study will be communicated trough publication in international scientific journals and presentation at (inter)national conferences.. NTR5383; Pre-results.

Topics: Bayes Theorem; Deamino Arginine Vasopressin; Drug Administration Schedule; Drug Dosage Calculations; Elective Surgical Procedures; Factor VIII; Hemophilia A; Hemostasis; Humans; Multicenter Studies as Topic; Netherlands; Perioperative Care; Prospective Studies; Treatment Outcome

Cirrhosis frequently affects multiple components of hemostasis. Reversal of the coagulopathy of these patients is frequently required in case of bleeding episodes, or as prophylaxis before invasive procedures. Although 1-deamino-8-D-arginine vasopressin (DDAVP) is widely used as a pro-hemostatic agent in patients with cirrhosis, it is unclear whether DDAVP truly enhances hemostasis in these patients. Here we investigated the hemostatic effects of a single bolus of DDAVP in patients with cirrhosis.. Ten patients with cirrhosis (child B or C) and ten patients with mild haemophilia A received an intravenous single bolus of 0.3 microgram/kg DDAVP. Plasma was collected prior to and at 1, 3, 6, and 24 h after DDAVP administration. Levels of Von Willebrand factor (VWF), VWF propeptide, factor VIII (FVIII), and ADAMTS13 were measured in all plasma samples, whereas VWF multimers and functional VWF-dependent platelet adhesion were determined in the samples pre- and 1 h after DDAVP administration.. Following DDAVP administration, VWF, FVIII, and VWF propeptide levels increased in patients with haemophilia, while patients with cirrhosis only showed an increase in VWF propeptide and FVIII levels. High molecular weight VWF multimers and VWF-dependent platelet adhesion increased in patients with haemophilia one hour after DDAVP administration, but did not change in the patients with cirrhosis. Levels of ADAMTS13 were unaffected in both patient groups after DDAVP.. The lack of relevant effects of DDAVP on laboratory indices of primary hemostasis in patients with cirrhosis is in line with previous clinical study results in these patients.

Topics: ADAM Proteins; ADAMTS13 Protein; Adult; Biomarkers; Deamino Arginine Vasopressin; Factor VIII; Female; Hemophilia A; Hemostasis; Hemostatics; Humans; Infusions, Intravenous; Liver Cirrhosis; Male; Middle Aged; Netherlands; Time Factors; Treatment Outcome; von Willebrand Factor

Increase of factor VIII activity (FVIII) after physical exercise has been reported in healthy subjects and small-scale studies in patients with coagulopathies. The aim was to study whether moderate and mild haemophilia A patients are able to increase their endogenous FVIII activity levels by physical activity. We studied changes in FVIII activity levels after high-intensity exercise in 15 haemophilia A patients, 20-39 years, eight with moderate, seven with mild haemophilia. Patients cycled until volitional exhaustion, blood samples were drawn before and 10 min after the exercise test. FVIII activity increased 2.5 times (range 1.8-7.0 times), for both severities. Absolute increases were markedly different: median 7 IU dL(-1) (range 3-9 IU dL(-1) ) in patients with moderate, compared to 15 IU dL(-1) (range 6-62 IU dL(-1) ) in mild haemophilia patients. VWF and VWFpp increased independently of severity; median 50% (range 8-123%) and median 165% (range 48-350%), respectively, reflecting acute release of VWF. These observations may be used to promote high-intensity activities before participating in sports for moderate and mild haemophilia A patients, to reduce bleeding risk. Further studies are warranted to fully appreciate the clinical significance of exercise on different levels of intensity in patients with mild and moderate haemophilia A.

Topics: Adult; Blood Coagulation; Deamino Arginine Vasopressin; Exercise; Factor VIII; Hemophilia A; Humans; Nature; Pilot Projects; Young Adult

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

The relationship of the biologic response to desmopressin with the F8 mutation and physiological characteristics has been poorly investigated in patients with mild hemophilia A.. We prospectively assessed the molecular and phenotypic determinants of the biologic response to desmopressin in a cohort of 50 patients with mild hemophilia A.. Up to 24 h after desmopressin, blood samples were serially obtained and factor (F)VIII and von Willebrand factor (VWF) measured. The promoter region, all exons and exon-intron boundaries of the F8 gene were screened using denaturing high-performance liquid chromatography (DHPLC). Direct sequencing was done when DHPLC screening was normal. Genomic DNA was also sequenced for exons 18-21, 24 and 27 of VWF.. Mean basal FVIII:C was 19 +/- 9 IU dL(-1) (range 6-37) and the median postdesmopressin peak increase was 2.5-fold (range 1.1-7.1). Eleven patients with a cross-reacting material positive (CRM(+)) phenotype had similar basal levels and relative increases of FVIII:C to the remaining patients with low FVIII:Ag. Using multivariate regression, FVIII:C half-life was positively related to basal and peak VWF:Ag levels (P = 0.008) and patient age (P = 0.004). Eleven patients had evidence of reduced FVIII survival. While 27 different gene mutations were identified in 41 patients, nine patients had no detectable mutation. These patients had significantly smaller peaks and smaller relative increase of postdesmopressin FVIII:C (median FVIII:C 26 IU dL(-1) vs. 54 IU dL(-1); P < 0.001; fold 1.8 +/- 0.6 vs. 2.9 +/- 0.8; P = 0.002).. In this cohort of patients with mild hemophilia A, a poor biologic response to desmopressin was frequently associated with the absence of detectable F8 mutations.

Topics: Adult; Aged; Cohort Studies; Deamino Arginine Vasopressin; Factor VIII; Gene Components; Hemophilia A; Humans; Middle Aged; Mutation; Phenotype; Prospective Studies; Treatment Outcome; von Willebrand Factor; Young Adult

The authors conducted a prospective clinical study to see whether the need for and the cost of factor substitution after circumcision can be reduced using a novel device for bloodless circumcision in boys with hemophilia.. Forty-five boys with hemophilia (age range, 1.5 to 25 years; median age, 11; 40 with hemophilia A, 5 with hemophilia B; weight range, 9 to 75 kg; median weight, 30 kg) were circumcised in our department between 1996 and 2001. Severity of the disease was mild in 9 cases, moderate in 11, and severe in 25. After starting systemic prophylaxis including factor substitution and DDAVP (desmopressin acetate) in reduced doses, all patients underwent circumcision under local anesthesia using a modified straight clamp and a battery-operated diathermic knife specially designed for bloodless circumcision. Duration of factor replacement ranged between 7 and 18 days, and the hospitalization period was 2 to 5 days according to severity of the disease. The last 19 patients were given tranexamic acid orally for 7 days after surgery.. Transient minimal bleeding was observed in 5 patients and easily responded to factor administration. Moderate edema and hyperemia along the excision line owing to the diathermic effect of the device lasted for 3 to 4 days. Normal cosmetic appearance was regained within 7 to 21 days. Excellent patient and family satisfaction was reported. The average cost of the operation was calculated as 81 dollars, 144 dollars, and 243 dollars per kilogram in mild, moderate, and severe cases, respectively.. Bloodless circumcision with "diathermic knife" is a practical and reliable alternative for boys with hemophilia. Enhancement of local hemostasis using such an alternative device may reduce the need for factor substitution and, accordingly, the cost of circumcision in hemophiliacs, down to 50%.

Topics: Adolescent; Adult; Child; Child, Preschool; Circumcision, Male; Cost-Benefit Analysis; Deamino Arginine Vasopressin; Electrocoagulation; Equipment Design; Hemophilia A; Humans; Infant; Male; Postoperative Hemorrhage; Premedication; Prospective Studies; Wound Healing

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

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

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

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

We report a study undertaken to test the biological effect of intranasal 1-deamino-8-D-arginine vasopressin (DDAVP) and its efficacy in the treatment of bleedings in patients with mild factor VIII deficiency. The biological study was carried out in 20 patients: an increase of factor VIII:C and von Willebrand factor antigen levels was observed after inhalation of DDAVP at average post/pre inhalation ratios of 2.80 and 1.72, respectively. No relevant alterations of fibrinolysis were noted. In fact, we only observed a simultaneous increase of tissue plasminogen activator and plasminogen activator inhibitor, without modification of D-dimer. In 10 cases intranasal DDAVP has been used in the prevention or in the treatment of bleeding complications: no bleedings were observed.

Topics: Administration, Intranasal; Adolescent; Adult; Child; Deamino Arginine Vasopressin; Drug Evaluation; Factor VIII; Fibrinolysis; Hemophilia A; Hemorrhage; Humans; Immunologic Factors; Middle Aged

When desmopressin (DDAVP) is given to mild and moderate hemophiliacs intravenously (i.v.) or subcutaneously (s.c.), there is a very large between-patient variability for peak levels of factor VIII coagulant activity (VIII:C). To evaluate whether or not between-patient variability is related to DDAVP levels achieved in plasma, we measured drug levels in 14 hemophilic volunteers (VIII:C 2 to 31 U/dL) who were randomly given 0.3 micrograms/Kg of i.v. or s.c. DDAVP and crossed-over to the other treatment after an interval of 15-30 days. Peak DDAVP levels (Cmax) were higher for i.v. DDAVP (p less than 0.02), times to peak levels (tmax) were shorter for i.v. DDAVP (p less than 0.001). There was no difference between the i.v. and s.c. routes for plasma DDAVP time curve (AUC) and half-life (t 1/2), but there was much larger variability for pharmacokinetic parameters with i.v. than with s.c. DDAVP. Post-DDAVP VIII:C increased 3.4 +/- 1.6 fold (i.v.) and 3.3 +/- 1.3 fold (s.c.) over baseline levels, with no significant correlation between peak VIII:C and DDAVP levels for either route of administration. These findings establish the s.c. route of DDAVP administration to be bioequivalent in effect to the i.v. route, albeit with less variability. At the DDAVP dosage used in this study and currently recommended for therapy, the VIII:C response is neither a function of the rate of absorption of the compound nor of the magnitude of its plasma concentration.

Topics: Deamino Arginine Vasopressin; Factor VIII; Half-Life; Hemophilia A; Humans; Injections, Intravenous; Injections, Subcutaneous; Male

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

The treatment of haemophilia has been dramatically improved since the introduction of factor VIII and IX concentrates, however these concentrates have brought new problems such as hepatitis and A.I.D.S. An oral agent which could raise endogenous levels of factor VIII and IX would be of great benefit. Danazol, an anabolic steroid, has recently been shown to increase levels of factors VIII and IX in haemophilia. We therefore studied the effect of stanozolol, a closely related anabolic steroid, in 15 patients with haemophilia A or Christmas disease over a 2-4 week period. There was no consistent change in factor VIIIc or factor IX, and fibrinolysis was significantly enhanced. No effect was apparent on the incidence of spontaneous bleeds. However serum aminotransferases which were abnormal in 11 of the 15 patients at the start of the study fell significantly with stanozolol therapy. This raises the interesting possibility that anabolic steroids may be beneficial in patients with chronic liver diseases.

Topics: Blood Viscosity; Clinical Trials as Topic; Deamino Arginine Vasopressin; Factor IX; Factor VIII; Fibrinolysis; Hemophilia A; Hemophilia B; Humans; Kinetics; Male; Stanozolol

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

Topics: Arginine Vasopressin; Clinical Trials as Topic; Deamino Arginine Vasopressin; Drug Evaluation; Factor VIII; Hemophilia A; Humans; Kinetics; Male

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

Data are limited on prostate cancer (PC) management in patients with haemophilia (PWH).. To describe PC screening and diagnosis, treatment modalities and bleeding complications in a group of unselected PWH followed at French Haemophilia Treatment Centres (HTCs) PATIENTS AND METHODS: PC screening, management and bleeding complications were retrospectively investigated at 14 French HTCs between 2003 and 2018.. Among> 1549 > 50-year-old PWHs, 73 (4.7%) underwent PC screening (median age 71.1 years; 67/6 HA/HB, 17/56 severe-moderate/mild). At diagnosis, haematuria was infrequent. Prophylaxis was administered during 76/86 (88%) prostate biopsies (PB) (n = 67 clotting factor concentrates, CFC; n = 9 desmopressin; n = 17 associated with tranexamic acid, TA). Bleeding (11/86, 12.8%) occurred mainly post-prophylaxis (median delay: 7 days): haematuria (9/11, 81.8%), and rectal bleeding (2/11, 18.2%) including one major (1.2%). PC was confirmed in 50/86 PB and in two prostatectomy specimens (total n = 50 patients, n = 6 with only active surveillance). Surgery (n = 28/44 patients) was managed with CFC. Fifteen patients had radiotherapy/brachytherapy, 10 had hormone therapy; CFC-based prophylaxis was only prescribed for brachytherapy (n = 2). Major bleedings occurred in 3/28 (10.7%) and 2/15 (13.3%) patients who underwent surgery and radio/brachytherapy, respectively. No bleeding risk factor was found.. Our data indicate that PB requires prophylaxis for atleast 7 days, using CFC, desmopressin or TA in function of haemophilia severity. PC surgery should be considered at high bleeding risk. Long-term post-procedural CFC or oral TA could be discussed. Radiotherapy/brachytherapy also should be managed with prophylaxis (CFC or TA).

Topics: Aged; Biopsy; Deamino Arginine Vasopressin; Hematuria; Hemophilia A; Hemorrhage; Humans; Male; Middle Aged; Prostate; Prostatic Neoplasms; Retrospective Studies

Patients with a bleeding tendency with normal laboratory tests have been described as having an unclassified bleeding disorder or bleeding disorder of unknown cause (BDUC). There are very little data available on how to manage pregnancy.. To study management and outcomes of these patients at four United Kingdom hemophilia comprehensive care centers.. Retrospective case note review from 2010-2020.. Sixty deliveries in 36 patients were recorded. The median International Society on Thrombosis and Haemostasis bleeding assessment tool score was 9. In 54 cases for which data were available, the odds ratio for post partum hemorrhage (PPH) was 6.3 for no primary hemostatic prophylaxis versus prophylaxis (95% confidence interval 1.2-34.2, p < .05); 7/9 (78%) versus 16/45 (36%) PPH incidence for the groups, respectively. Hemostatic prophylaxis was with tranexamic acid but some patients received desmopressin or platelet infusions. Secondary PPH was seen in 5/60 (8%) of cases. No neonatal bleeding complications or maternal thromboembolic complications were noted. Avoidance of regional anesthesia and fetal delivery precautions were commonly advised, but in the small number of cases in which they occurred no complications were noted.. Despite hemostatic prophylaxis PPH was commonly seen. Further prospective studies of BDUC patients are required to determine optimal management in pregnancy as well as determine the pathophysiological basis of bleeding.

Topics: Deamino Arginine Vasopressin; Female; Hemophilia A; Hemostatics; Humans; Postpartum Hemorrhage; Pregnancy; Prospective Studies; Retrospective Studies; Tranexamic Acid

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

Topics: Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Humans

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

Certain haemophilia carriers demonstrate an increased bleeding tendency, mainly related to clotting factor deficiency. No study has so far formally compared the bleeding phenotype of women and girls with mild FVIII or FIX deficiency and associated management with that of male patients affected by mild haemophilia A and B.. We retrospectively evaluated 44 women and girls with mild FVIII or FIX deficiency (FVIII or FIX 0.05-0.5 IU/mL) and 77 male patients with mild haemophilia A or B and compared them with respect to clotting factor level, age at and trigger for diagnosis, as well as treatment modalities.. After excluding gender-related haemorrhagic symptoms, haemophilia carriers with plasma factor levels in the mild haemophilia range and male patients affected by mild haemophilia present a comparable haemorrhagic profile, mainly characterized by mucocutaneous and postinjury bleeding. Haemophilia carriers with clotting factor deficiency, however, distinguish themselves in terms of later age at diagnosis, higher mean factor levels and trigger for diagnosis.. Women and girls with mild FVIII or FIX deficiency should be considered as mild haemophilia patients and have access to care and management inspired from male haemophilia patients while integrating differences and specificities. Larger international studies comparing the clinical presentation and treatment modalities of mild clotting FVIII and FIX deficiencies in both haemophilia males and females should be encouraged.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Coagulation Factors; Child; Child, Preschool; Deamino Arginine Vasopressin; Female; Hemophilia A; Hemostatics; Heterozygote; Humans; Male; Middle Aged; Young Adult

Approximately 50% of female carriers of hemophilia A have factor VIII (FVIII) levels below 0.5 IU/dL and may be categorized as having mild hemophilia. Females with hemophilia may go undiagnosed for years because the most common symptoms - menorrhagia and bleeding after childbirth - also occur in females without hemophilia. Females with hemophilia can exhibit increased bleeding tendencies despite current guidelines of expected, adequate FVIII levels. The cases described illustrate the clinical variability and presentation of hemophilia in females and highlight the importance of a timely diagnosis, effective management, and monitoring. Prophylactic factor replacement therapy is recommended in females with hemophilia, particularly those with joint disease or gynecologic complications. Affected individuals should receive infusion training and education on treatment options, physical activities, the importance of treatment adherence, and recognizing bleeding symptoms warranting treatment. Further study is needed to increase awareness of hemophilia in females and reassess current guidelines for their management and monitoring.

Topics: Adolescent; Aged; Chromosome Inversion; Deamino Arginine Vasopressin; Disease Management; Drug Substitution; Factor VIII; Female; Hemarthrosis; Hemophilia A; Heterozygote; Humans; Introns; Male; Menorrhagia; Middle Aged; Pedigree; Recombinant Proteins; Tranexamic Acid; Young Adult

Diagnosis, treatment monitoring and assessment of desmopressin effect in haemophilia A patients are performed by measurement of factor VIII activity (FVIII). The two assays commonly applied are the one-stage assay and the chromogenic assay. Especially in non-severe haemophilia A, discrepancies between these assays are common. It is still unestablished which assay corresponds best with bleeding phenotype and desmopressin effect.. To correlate FVIII levels measured by the one-stage assay and by the chromogenic assay with bleeding phenotype and, additionally, to compare FVIII assay discrepancies before and after desmopressin administration.. Factor VIII was measured in 130 non-severe haemophilia A patients during routine visits to the outpatient clinic and/or during desmopressin testing. FVIII was measured by both the one-stage assay and the chromogenic assay. Discrepancies between assays were defined as at least a twofold difference of FVIII or an absolute FVIII difference between measurements of ≥0.10 IU/mL. Bleeding phenotype was defined as annual number of treated bleedings (adjusted ABR).. Hundred and thirty non-severe haemophilia A patients were included. In 31/130 patients, assay results were discrepant. However, FVIII measurements with both assays correlated adequately with adjusted ABR. In addition, in 27/130 patients FVIII measurements at baseline and after desmopressin administration were analysed. In 13/27 patients, all measurements were either equivalent or discrepant when results were compared. In 14/27 patients, this was not the case as both equivalent measurements and discrepant measurements at different time points within one patient were observed.. Neither the one-stage assay nor the chromogenic assay is superior in predicting bleeding phenotype. In addition, equivalent or discrepant FVIII results measured before desmopressin do not always predict FVIII assay results after desmopressin administration.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Humans; Male; Middle Aged; Retrospective Studies; Young Adult

Desmopressin increases endogenous factor VIII levels in hemophilia A. Large inter-individual variation in the response to desmopressin is observed. Patients with a lower baseline factor VIII activity tend to show a reduced response, therefore, desmopressin is less frequently used in moderate hemophilia A patients (baseline factor VIII activity 1-5 international units/deciliter), even though factor VIII levels may rise substantially in some of them. We aim to describe the response to desmopressin in moderate hemophilia A patients and to identify predictors. We selected data on 169 patients with moderate hemophilia from the multicenter Response to DDAVP In non-severe hemophilia A patients: in Search for dEterminants (RISE) cohort study. Adequate response to desmopressin was defined as a peak factor VIII level ≥ 30, and excellent response as ≥ 50 international units/deciliter after desmopressin administration. We used univariate and multiple linear regression techniques to analyze predictors of the peak factor VIII level. Response was considered adequate in 68 patients (40%), of whom 25 showed excellent response (15%). Intravenous administration, age, pre-desmopressin factor VIII activity and von Willebrand factor antigen, peak von Willebrand factor activity and desmopressin-induced rise in von Willebrand factor antigen were significant predictors of peak factor VIII level and explained 65% of the inter-individual variation. In 40% of moderate hemophilia A patients, desmopressin response was adequate, thus it is important not to with-hold this group of patients from desmopressin responsiveness. Among the six predictors that we identified for desmopressin-induced factor VIII rise, factor VIII activity and desmopressin-induced rise in von Willebrand factor antigen had the strongest effect.

Topics: Adolescent; Adult; Child; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Humans; Middle Aged; Mutation; Predictive Value of Tests; Prognosis; Treatment Outcome; von Willebrand Factor; Young Adult

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

Topics: Adult; Arginine Vasopressin; Deamino Arginine Vasopressin; Factor VIII; Female; Hemophilia A; Hemostatics; Humans; Male; Middle Aged; Mutation; Retrospective Studies; Time Factors; Treatment Outcome; Young Adult

Topics: Adult; Child; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Hemostatics; Humans; Male; Mutation, Missense; Severity of Illness Index; Tooth Diseases

The cause of hemophilia A carrier bleeding is not well established. Desmopressin (DDAVP), used clinically to treat or prevent bleeding, can also be used as a medical stress surrogate. This study's objective was to compare the response to DDAVP in hemophilia A carriers with that in normal control patients. Bleeding was assessed by the International Society on Thrombosis and Hemostasis Bleeding Assessment Tool (ISTH-BAT). DDAVP (0.3 μg/kg) was administered either IV or subcutaneously (SC), and blood was drawn at baseline and 1, 2, and 4 hours postadministration. Blood was assessed for factor VIII (FVIII) level, von Willebrand factor (VWF) antigen (VWF:Ag), VWF activity (VWF:RCo or VWF:GPIbM), thromboelastography (TEG), and thrombin generation assay (TGA) at all points, and for VWF propeptide (VWFpp):Ag ratio and ABO blood type at baseline. Carriers were older than control patients (median age, 34 and 21 years, respectively;

Topics: Adult; Deamino Arginine Vasopressin; Female; Hemophilia A; Hemostasis; Humans; Male; Middle Aged

Due to interindividual variation in desmopressin response, non-severe haemophilia A patients require desmopressin testing prior to therapeutic treatment. However, adequate response or frequency of blood sampling is not standardised in international guidelines. Consequently, various definitions and blood sampling protocols are currently applied. Interestingly, sustainability of desmopressin response is not incorporated into these definitions.. To study desmopressin response rates in a cohort of non-severe haemophilia A patients using currently accepted desmopressin response definitions. This, in order to formulate a standardised, uniform response which includes information on sustainability and to design a standardised blood sampling protocol.. Currently used desmopressin responses in non-severe haemophilia A patients were derived from a literature search. Actual desmopressin response rates were individualised in 105 non-severe HA patients from the Erasmus University Medical Centre and classified according to current varying definitions.. Five response definitions were evaluated, three of which included only factor VIII (FVIII):C cut-off levels and two also incorporated FVIII:C-fold increase over baseline.. C-fold increase showed no association with desmopressin response sustainability.. C 1 hour after infusion (<0.30, ≥0.30-0.49, ≥0.50-0.79 and ≥0.80 IU/mL) was, however, indicative of desmopressin response after 6 hours.. We suggest standardised desmopressin response based on clinically relevant FVIII:C levels, e.g. 0.30 and 0.50 IU/mL. In addition, patients with <0.30 IU/mL FVIII:C after 1 hour (non-responder) or ≥0.80 IU/mL (sustained responder) do not require subsequent blood sampling. However, patients with ≥0.30-0.79 IU/mL FVIII:C after 1 hour should undergo blood sampling after 6 hours to additionally determine response sustainability.

Topics: Adolescent; Adult; Aged; Child; Cohort Studies; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Humans; Middle Aged; Outcome Assessment, Health Care; Reference Standards; Time Factors; Young Adult

Essentials Factor VIII levels vary in mild and moderate hemophilia A (MHA) patients with the same mutation. We aimed to estimate the variation and determinants of factor VIII levels among MHA patients. Age and genotype explain 59% of the observed inter-individual variation in factor VIII levels. Intra-individual variation accounted for 45% of the variation in the three largest mutation groups.. Background The bleeding phenotype in patients with mild/moderate hemophilia A (MHA) is inversely associated with the residual plasma concentration of factor VIII (FVIII:C). Within a group of patients with the same F8 missense mutation, baseline FVIII:C may vary, because, in healthy individuals, von Willebrand factor (VWF) levels, ABO blood group and age are also known to influence baseline FVIII:C. Our understanding of the pathophysiologic process of the causative genetic event leading to reduced baseline FVIII:C in MHA patients is still limited. Objectives To estimate the variation and determinants of baseline FVIII:C among MHA patients with the same F8 missense mutation. Methods Three hundred and forty-six patients carrying mutations that were present in at least 10 patients in the cohort were selected from the INSIGHT and the RISE studies, which are cohort studies including data of 3534 MHA patients from Europe, Canada, and Australia. Baseline FVIII:C was measured with a one-stage clotting assay. We used Levene's test, univariate and multivariate linear regression, and mixed-model analyses. Results For 59% of patients, the observed variation in baseline FVIII:C was explained by age and genotype. Compared to FVIII:C in patients with Arg612Cys, FVIII:C was significantly different in patients with eight other F8 missense mutations. Intra-individual variation explained 45% of the observed variance in baseline FVIII:C among patients with the same mutation. Conclusion Our results indicate that baseline FVIII:C levels are not exclusively determined by F8 genotype in MHA patients. Insights into other factors may provide potential novel targets for the treatment of MHA.

Topics: ABO Blood-Group System; Adult; Blood Coagulation; Deamino Arginine Vasopressin; Factor VIII; Genetic Variation; Genotype; Hemophilia A; Hemorrhage; Humans; Male; Middle Aged; Multivariate Analysis; Mutation; Mutation, Missense; Observer Variation; Phenotype; Protein Conformation; Retrospective Studies; von Willebrand Factor; Young Adult

ESSENTIALS: Combined factor V (FV) and factor VIII (FVIII) deficiency (CF5F8D) is an autosomal recessive coagulation disorder. Desmopressin acetate (DDAVP) was intravenously infused in 20 adult patients with CF5F8D. DDAVP can enhance FVIII levels but has no effect on FV levels in patients with CF5F8D. DDAVP can be substituted for FVIII concentrates in patients with CF5F8D.. Combined factor V (FV) and FVIII deficiency (CF5F8D) is a rare inherited autosomal recessive double-gene disorder most frequently seen in the Middle East. Although affected individuals have deficiency of two coagulation factors (range 5-30%), their bleeding tendencies are similar to patients who have deficiency of a single coagulation factor at the same level. The mainstay of their treatment is infusion of FVIII concentrate and fresh frozen plasma. Here, the effect of intravenous infusion of desmopressin acetate (DDAVP) on elevation of coagulation FV and FVIII was investigated through a clinical trial in May 2015.. In a registered controlled trial, DDAVP (dosage 0.3 μg kg(-1) ) was intravenously infused into 20 adult patients with CF5F8D over 20 min. After an hour, blood samples were collected and plasma levels of FV and FVIII were measured.. This study revealed that DDAVP can enhance FVIII levels but has no effect on FV plasma concentration in patients with CF5F8D. Based on these findings, FVIII concentrates may be substituted for DDAVP in patients with CF5F8D.

Topics: Adult; Biomarkers; Blood Coagulation Tests; Deamino Arginine Vasopressin; Factor V; Factor V Deficiency; Factor VIII; Female; Hemophilia A; Hemostasis; Hemostatics; Humans; Infusions, Intravenous; Iran; Male; Middle Aged; Time Factors; Treatment Outcome; Up-Regulation; 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

There are many documented cases of a person with haemophilia successfully receiving a solid organ transplant, including liver and kidney. However, there is no literature reporting live organ donation by a person with haemophilia. Presumably, this is because the associated risks of excessive bleeding, inhibitor development after a period of intensive treatment with factor replacement and the possibility of variant Creutzfeldt-Jakob disease transmission in those previously treated with blood products, are considered excessive. This case describes a 24-year-old man who was diagnosed with mild haemophilia A during his pretransplant work up as a potential live kidney donor to his sister. He then went on to successfully donate his kidney, without complications. To the best of our knowledge, this is the first description of a person with haemophilia being a living organ donor.

Topics: Adult; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Hemostatics; Humans; Kidney Transplantation; Living Donors; Male; Tissue and Organ Harvesting; Young Adult

Topics: Antibodies, Monoclonal, Murine-Derived; Antifibrinolytic Agents; Appendicitis; B-Lymphocytes; Blood Loss, Surgical; Child; Deamino Arginine Vasopressin; Factor VIIa; Factor VIII; Hemophilia A; Humans; Immunosuppressive Agents; Infusions, Intravenous; Isoantibodies; Lymphocyte Count; Male; Mutation, Missense; Peritonitis; Postoperative Hemorrhage; Recombinant Proteins; Rituximab

Topics: Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Humans

Desmopressin (DDAVP) is commonly used in the treatment of patients with type 1 von Willebrand disease (VWD) and mild hemophilia A. A patient's responsiveness to DDAVP based on a 0.3  μg/kg dose determines future therapeutic efficacy of the drug. The aim of the study was to determine whether a capped dose of 15 μg subcutaneous DDAVP is able to achieve the same level of DDAVP responsiveness as previously reported. This is a retrospective chart review of patients from 1995 to 2013 in adults and children with type 1 VWD and hemophilia A weighing more than 50 kg. Levels of factor VIII, ristocetin cofactor, and von Willebrand factor antigen were measured before and after 1 h of administration of 15 μg of DDAVP. In patients with type 1 VWD, the complete response rate was 82.5% with a partial response rate of 12.5% and 5% nonresponders. In patients with mild hemophilia A, the complete response rate was 53.8% with a partial response rate of 38.5% and 7.7% nonresponders. These results using a capped 15-μg dose of DDAVP are similar to previously published reports using the 0.3-μg/kg dose.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Deamino Arginine Vasopressin; Drug Administration Schedule; Drug Monitoring; Factor VIII; Female; Hemophilia A; Hemostatics; Humans; Male; Middle Aged; Retrospective Studies; Severity of Illness Index; von Willebrand Disease, Type 1; von Willebrand Factor

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

Hemophilia A and von Willebrand disease (VWD) are distinct bleeding disorders with a spectrum of clinical phenotypes. They are characterized by mutations in either factor VIII (F8) or von Willebrand factor (VWF) genes, respectively. The pattern of inheritance and appropriate laboratory evaluation differentiates these diseases, and treatment strategies for both are different. Here, we report a male patient with hemophilia A and VWD Type 2 Normandy (N) mutations who presented with life-threatening bleeding. We document his medical history, clinical course, management, and diagnostic work up.

Topics: Biopsy, Needle; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Hemorrhage; Heterozygote; Humans; Male; Middle Aged; Postoperative Hemorrhage; Shock, Hemorrhagic; Treatment Outcome; von Willebrand Disease, Type 2

Topics: Deamino Arginine Vasopressin; Factor IX; Factor VIII; Hemophilia A; Hemophilia B; Hemostatics; Humans

Utilization of the synthetic vasopressin analogue (1-deamino-8-D-arginine-vasopressin, DDAVP) in treatment of mild haemophilia A (MHA, specific clotting factor VIII activity level 0.05-0.4 IU mL(-1) ) is convenient and effective for many but not all patients. Genetic testing for patients with MHA is increasingly recognized as providing valuable information for patient care beyond informing reproductive decisions, and as more patients are genotyped, mutation data can be utilized to individualize treatment decisions. To determine if genetic information informs response to DDAVP, a retrospective chart review was performed under Institutional Review Board approval to extract patient data with MHA, genetic mutation results, and response to DDAVP challenge. 62 patients met inclusion criteria. Complete responses (C) presented in mean value IU mL(-1) (range), were recorded for 32 of 62(52%) subjects: pre 0.19(0.04-0.45) and post 0.78(0.5-1.95); partial responses (P) were recorded for 15 of 62(24%) subjects: pre 0.1(0.06-0.15) and post 0.4(0.3-0.47); responses that were not clinically significant (N) were recorded for 15 of 62(24%) subjects: pre 0.17(0.02-0.34) and post 0.25(0.03-0.44). Subjects (related and unrelated) with the same mutation showed a trend towards a similar response to DDAVP. Eight genotypes were common to two or more subjects (n = 26). Two genotypes were concordant in all subjects [p.Ser2192Ile n = 3(C), p.Ala2220Pro n = 2(P)]. Of mutations in the C1 or C2 domains, 13 of 15(87%) subjects responded to DDAVP [C = 9(60%); P = 4(27%); n = 2(13%)]. Baseline FVIII:C did not predict magnitude of response to DDAVP. Genetic mutation results can assist with predicting DDAVP responsiveness, but baseline FVIII:C may not.

Topics: Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Humans; Mutation; Retrospective Studies

Although desmopressin (DDAVP) is considered as the treatment of choice for many patients with mild hemophilia A, several aspects of DDAVP therapy remain unclear, including the rate and type of response and the molecular determinants of its clinical efficacy. To investigate these issues, we retrospectively studied all patients with mild hemophilia A followed up at the Parma Hemophilia Center. A total of 75 patients were enrolled who underwent a DDAVP test, and out of whom, 76% (57/75) had a complete or partial response. Response to DDAVP was significantly correlated to the patients' age (median age of responders and nonresponders: 24 and 18 y, respectively; p = 0.04) and type of mutation (all the 10 patients with mutations in the promoter region were nonresponders). The median basal factor VIII (FVIII):C level was significantly lower in responders than in nonresponders (0.14 vs. 0.19 IU/mL, respectively; p = 0.01); this was mainly due to nonresponders with promoter region mutations who had higher basal FVIII:C levels. During the 12-year follow-up, 82 of 237 (35%) bleeding episodes occurring in 27 responder patients were treated with 246 DDAVP infusions with complete or partial efficacy in 92% (75/82). Overall, 142 events were managed with 253 prophylactic DDAVP infusions, which were hemostatically effective in 96% of cases. No severe adverse reactions to DDAVP administration were recorded during the study period. These results document the safety and efficacy of DDAVP as a treatment or prevention of bleeding in patients with mild hemophilia A, also in the context of home treatment, and encourage the more widespread use of this product.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Deamino Arginine Vasopressin; Hemophilia A; Humans; Middle Aged; Retrospective Studies; Young Adult

Topics: Asparagine; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Humans; Mutation; Serine

Desmopressin causes two- to six-fold increase of factor VIII (FVIII) in mild or moderate haemophilia A patients. However, responses are variable and little is known whether this is associated with F8 gene mutation. The study objective was to assess the relationship between F8 gene mutation and desmopressin response in haemophilia A patients. Desmopressin response (absolute and relative) was determined in 97 hemophilia A patients. Four amino acid changes (Arg2169His, Pro149Arg, Asn637Ser, and Arg612Cys) and a number of other mutations leading to an aberrant FVIII protein or FVIII deficiency were analysed. Patients with Arg2169His showed significantly lower FVIII levels before and after desmopressin compared to all other mutations (p<0.001). Pro149Arg amino acid change showed significantly lower FVIII levels 1 hour after desmopressin compared to all other mutations (p<0.005). An absolute response with FVIII≥0.50 IU/ml after 1 hour was observed in 41% (9 of 22) of patients with Arg2169His; however, this was not sustainable after 6 hours in any of these subjects. No patients with Pro149Arg mutation (n=6) showed an absolute response with FVIII≥0.50 I U/ml. Patients with other mutations showed significantly more complete and partial responses. Relative responses did not differ between mutations. Our study shows that haemophilia A patients with amino acid change Arg2169His or Pro149Arg have a decreased desmopressin response with regard to FVIII levels as compared to other mutations. Our results indicate that response to desmopressin is dependent on the F8 gene mutation type, despite the fact that multiple factors influence the desmopressin response, even within families.

Topics: Adolescent; Adult; Amino Acids; Child; Deamino Arginine Vasopressin; DNA Mutational Analysis; Factor VIII; Hemophilia A; Hemostatics; Humans; Male; Middle Aged; Mutation; Time Factors; Young Adult

In most individuals with moderate/mild haemophilia A, FVIII:C levels increase following DDAVP administration to a haemostatic range, thus avoiding the need for FVIII concentrates. We sought to determine the relationship between responsiveness to DDAVP in boys (<18 years old) with mild/moderate haemophilia and patient age, haemophilic severity and haemophilic genotype. Our cohort consisted of 13 boys with moderate and 61 boys with mild haemophilia who, between them, had 38 different mutations; 21 had unique mutations not shared by any other clinic patient, whereas 53 shared one of 17 mutations with some other clinic patient (included 26 boys with ≥ 1 haemophilic brother). Patient age and endogenous FVIII:C levels were strong predictors of response to DDAVP. Younger patients responded less well to DDAVP and 10 of the 11 patients, when retested at an older age, showed an improved response to DDAVP. Only 1 patient with moderate haemophilia responded to DDAVP, whereas 80% of patients with mild haemophilia responded (including all patients with an endogenous FVIII:C of >0.15 U mL(-1)). Almost all patients with the same mutation had the same response to DDAVP or only a minor discordance in response. Patient's age, disease severity and genotype all are predictors of response to DDAVP.

Topics: Adolescent; Age Factors; Child; Child, Preschool; Cohort Studies; Deamino Arginine Vasopressin; Factor VIII; Genotype; Hemophilia A; Hemostatics; Humans; Infant; Male; Mutation

Acquired hemophilia A is a rare bleeding disorder caused by autoantibodies to coagulation FVIII. Bleeding episodes at presentation are spontaneous and severe in most cases. Optimal hemostatic therapy is controversial, and available data are from observational and retrospective studies only. The EACH2 registry, a multicenter, pan-European, Web-based database, reports current patient management. The aim was to assess the control of first bleeding episodes treated with a bypassing agent (rFVIIa or aPCC), FVIII, or DDAVP among 501 registered patients. Of 482 patients with one or more bleeding episodes, 144 (30%) received no treatment for bleeding; 31 were treated with symptomatic therapy only. Among 307 patients treated with a first-line hemostatic agent, 174 (56.7%) received rFVIIa, 63 (20.5%) aPCC, 56 (18.2%) FVIII, and 14 (4.6%) DDAVP. Bleeding was controlled in 269 of 338 (79.6%) patients treated with a first-line hemostatic agent or ancillary therapy alone. Propensity score matching was applied to allow unbiased comparison between treatment groups. Bleeding control was significantly higher in patients treated with bypassing agents versus FVIII/DDAVP (93.3% vs 68.3%; P = .003). Bleeding control was similar between rFVIIa and aPCC (93.0%; P = 1). Thrombotic events were reported in 3.6% of treated patients with a similar incidence between rFVIIa (2.9%) and aPCC (4.8%).

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Coagulation Factors; Deamino Arginine Vasopressin; Europe; Factor VIIa; Factor VIII; Female; Hemophilia A; Hemorrhage; Hemostatics; Humans; Incidence; Male; Middle Aged; Recombinant Proteins; Registries; Treatment Outcome; Young Adult

Topics: Adult; Deamino Arginine Vasopressin; Factor V; Factor V Deficiency; Factor VIII; Hemophilia A; Humans; Male; Mutation, Missense; Pedigree; Vesicular Transport Proteins; Young Adult

Desmopressin (DDAVP) testing (DT) in patients (pts) with haemophilia A (HA) and carriers (CHA) is up to now not standardized. This prompted us to evaluate results of DT carried out between 1996 and 2011 in centres of the Competence Network Haemorrhagic Diatheses East.. An increase of the factor VIII activity (FVIII) above 50% or at least the two fold of initial values within 120 min after DDAVP was defined as complete response (CR). Data from 80 patients (31 children, 49 adults) of whom 64 suffered from HA (sub-HA: n=48; mild: n=14; moderate: n=2) and 16 patients CHA were evaluated.. In 34 patients DDAVP was given i.v. (dose range: 0.26-0.6 µg/kg body weight, mean: 0.33), in 31 intranasally (i.n. 300-600 µg) and in 15 s.c. (15-40 µg). The maximal FVIII increase was reached 60 min after DDAVP. For i.v. application the mean FVIII increase was 3.1-fold, for i.n. 2.1-fold and for s.c. 2.4-fold. A CR was detected in 71 patients, a non-response in 9. Mild side effects such as flush, headaches or nausea were observed in 11 patients (14%).. For desmopressin testing in patients with haemophilia A and carriers i.v. application at 0.3 µg/kg body weight and the determination of FVIII before and 60 min after desmopressin infusion is recommended.

Topics: Adolescent; Adult; Aged; Biomarkers; Child; Child, Preschool; Deamino Arginine Vasopressin; Factor VIII; Female; Germany; Hemophilia A; Humans; Male; Middle Aged; Prevalence; Reproducibility of Results; Risk Assessment; Sensitivity and Specificity

Topics: Adult; Cesarean Section; Deamino Arginine Vasopressin; Disease Management; Factor V Deficiency; Female; Genes, Recessive; Hemophilia A; Hemostasis; Humans; Infant, Newborn; Morocco; Partial Thromboplastin Time; Patient Care Team; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy, High-Risk; Prothrombin Time

In about 10% of patients with mild hemophilia A, no candidate gene mutations are apparent after complete gene sequencing.. To analyze factor VIII gene (F8) mRNA for mutations in five families with mild hemophilia A with no apparent genomic mutation and a reduced response to desmopressin.. In four cases, mRNA studies revealed the presence of an abnormal mRNA transcript in addition to normal F8 mRNA. Sequencing of the abnormal transcripts revealed complex abnormalities, which allowed the identification of three different intronic variations (c.2113+1152delA, c.5587-93C>T and c.5999-277G>A) at the DNA level, absent from 387 normal alleles. By in silico analysis, c.2113+1152delA and c.5587-93C>T were strongly predicted to result in the generation of new splice sites with the introduction of premature termination codons, while c.5999-277G>A was predicted to generate a new protein with 30 additional amino acids. However, these predictions were not homogeneous across the different mutations and programs used. The detrimental effect of two mutations was also confirmed by in vitro expression studies. These changes were also identified in related female carriers and in other mild HA patients not included in the original study. No mRNA abnormality was identified in the remaining patient.. Although rare, deep intronic variations may be responsible for mild hemophilia A where no other F8 mutations have been identified and may be associated with a reduced biologic response to desmopressin. F8 mRNA analysis is a useful tool for the identification of deep intronic variation not detectable by standard DNA sequencing.

Topics: Adult; Base Sequence; Blood Coagulation; Case-Control Studies; Deamino Arginine Vasopressin; DNA Mutational Analysis; Factor VIII; Female; Genetic Predisposition to Disease; HEK293 Cells; Hemophilia A; Hemostatics; Heredity; Humans; Introns; Italy; Male; Middle Aged; Molecular Sequence Data; Mutation; Pedigree; Phenotype; RNA Splice Sites; RNA, Messenger; Sequence Analysis, RNA; Severity of Illness Index; Transfection; Young Adult

To study the effects of desmopressin (DDAVP) on coagulation factor Ⅷ (FⅧ) and activated partial thromboplastin time (APTT) in children with mild hemophilia A.. Eighteen children with mild hemophilia A were enrolled. DDAVP (0.3 μg/kg•d) was injected intravenously for 5 days. Plasma FⅧ levels and APTT were measured before and after DDAVP treatment.. In 16 of 18 children with mild hemophilia A, the bleeding symptoms, including the articular or musclar hematoma, were significantly alleviated as a result of DDAVP treatment. The plasma FⅧ levels increased significantly to (27±4)% and APTT was shortened to (66±10)s 60 minutes after the first dose of DDAVP treatment. The plasma FⅧ remained at the levels of 25%-30% during 3-4 days of DDAVP treatment. Five days after DDAVP treatment, the plasma FⅧ levels decreased [(21±3)%], and APTT was prolonged when compared with 1-4 days of DDAVP treatment.. DDAVP treatment can increase plasma FⅧ levels and shorten APTT in children with mild hemophilia A. DDAVP is effective in the treatment of mild hemophilia A. The duration of DDAVP therapy for mild hemophilia A is recommended as 3 to 4 days.

Topics: Child; Child, Preschool; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Humans; Infant; Male; Partial Thromboplastin Time

Despite major advances in diagnosis and treatment, the management of patients with mild haemophilia (MH) remains a major challenge. Mild haemophilia is defined by factor levels between 0.05 and 0.40 IU mL(-1). The bleeding associated with mild haemophilia is most frequently episodic, occurring during surgery or following trauma. Spontaneous bleeding is rare. Diagnosis is sometimes delayed because of insensitivity of screening clotting assays or discrepancies in factor VIII activity as measured by different assays. The treatment of choice in mild haemophilia A is desmopressin, which typically induces a 2-6-fold increase of factor VIII over baseline. However, desmopressin has its limitations in this setting such as the occurrence of tachyphylaxis and failure to respond in an undetermined proportion of patients. Factors underlying poor biological response or magnitude of response to desmopressin are incompletely understood. Inhibitor development in mild haemophilia is particularly distressing. This complication arises at an older age in this patient group because of infrequent need for factor VIII replacement. Inhibitors in mild haemophilia patients often cross-react with endogenous factor VIII resulting in severe spontaneous bleeding frequently in a postoperative setting. Intensive perioperative use of factor VIII and some specific mutations induce a particularly high risk for inhibitor development, but risk factors are incompletely understood. For reasons of the older age of the patients, treatment of bleeding with bypassing agents may cause major thrombotic complications. Data on therapeutic options for inhibitor eradication in patients with mild haemophilia are particularly scarce. With increased life-expectancy for all haemophilia patients, the group of elderly patients with mild haemophilia requiring major surgery will further increase. Prevention of inhibitors, particularly in this patient group, should be a major topic of interest in both clinic and research.

Topics: Blood Coagulation Factor Inhibitors; Blood Coagulation Factors; Blood Coagulation Tests; Deamino Arginine Vasopressin; Hemophilia A; Hemostatics; Humans

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

The efficacy of DDAVP (1-deamino-8-D-arginine-vasopressin, desmopressin) in mild haemophilia A and von Willebrand disease (VWD) has been established and the use of this well tolerated drug has become clinical routine. In case of increased fluid intake and based on very rarely occurring hyponatraemia, the indication of administration of DDAVP intravenously (i. v.) has to be performed diligently in elderly patients and in children below the age of five years. Aim, patients: Due to clinical practice we were interested in finding prospective parameter potentially correlating with adverse reactions of DDAVP and initiated this study. From 2007 to 2008, we included 49 patients suspicious to suffer from mild haemophilia A (n = 1) or VWD (n = 48) and investigated efficacy and safety of DDAVP after intravenous administration (mean: 0.29±0.032 μg/kg body weight). They underwent clinical and laboratory investigation and were questioned with regard to potential adverse reactions immediately and three days after administration of DDAVP.. Most adverse reactions were mild and no serious adverse drug reactions were either observed or reported by the subjects. We identified significant changes of heart rate, blood pressure and leucocytes after conduct of the DDAVP test. The value of these findings has to be investigated in later prospective randomized studies. Further research on identification of prospective parameter is currently ongoing.

Topics: Aged; Child, Preschool; Deamino Arginine Vasopressin; Heart Rate; Hematocrit; Hemophilia A; Hemostatics; Humans; Hyponatremia; Injections, Intravenous; Leukocyte Count; Platelet Count; Prothrombin Time; Safety

Topics: Adenocarcinoma; Aged; Anesthesia, General; Blood Loss, Surgical; Colorectal Neoplasms; Deamino Arginine Vasopressin; Drug Therapy, Combination; Factor VIII; Hemophilia A; Hepatectomy; Humans; Liver Neoplasms; Male; Postoperative Hemorrhage; Preanesthetic Medication; Preoperative Care; Tranexamic Acid

Topics: Deamino Arginine Vasopressin; Factor VIII; Female; Hemophilia A; Humans; Male; Mutation; Pedigree; Promoter Regions, Genetic

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

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

Desmopressin (1-deamino-8-D-arginine vasopressin (DDAVP)) has been shown to be an effective treatment option when administered both intravenously [1,2] and subcutaneously [3] to children with inherited bleeding disorders. We demonstrate here, both the efficacy and acceptability of a new intranasal DDAVP preparation, providing a cost effective treatment with good outcomes for children with bleed disorders.

Topics: Administration, Intranasal; Adolescent; Child; Cohort Studies; Deamino Arginine Vasopressin; Dose-Response Relationship, Drug; Female; Hemophilia A; Hemorrhage; Hemostatics; Humans; Male; Treatment Outcome

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

We report here a case of a 22-year-old female patient with hemophilia A who had a bimaxillary osteotomy operation. Adequate replacement of Factor VIII and DDAVP(1 deamino-8-D-arginine vasopressin) led to the achievement of hemostasis during and after the surgery. Le Fort I maxillary osteotomy and mandibular sagittal split osteotomies were done to correct the facial profile of this hemophiliac patient with a class III malocclusion and posterior open-bite deformity. Careful preoperative evaluation and close cooperation with the hematologist are required if surgery is to be successful. The operation was uneventful and no postoperative complication was observed.

Topics: Adult; Coagulants; Deamino Arginine Vasopressin; Factor VIII; Female; Hemophilia A; Hemostasis, Surgical; Hemostatics; Humans; Malocclusion, Angle Class III; Mandible; Maxilla; Open Bite; Osteotomy; Osteotomy, Le Fort; Patient Care Planning

Dental extraction in hemophiliacs is associated with a high risk of bleeding. It requires a multidisciplinary approach and stringent protocol. The current trend is to simplify these protocols. In this study we review the efficacy of a protocol using systemic treatment--factors/dihydro-D-arginine vasopressin (DDAVP)--and simplified local hemostatic measures to control bleeding, to limit patient discomfort, and to minimize hospital length of stay.. This retrospective study of 55 dental extractions was performed during 19 interventions in 16 patients with hemophilia A or B to assess the efficacy of a protocol combining general management via the injection of factor concentrates or DDAVP and local hemostasis using biological glue and gelatin packing. Compressive, hemostatic splints, which have been in use by some for many years, are replaced by intermittent tranexamic acid compression during the first 3 days after surgery.. We recorded 6 instances of postsurgical bleeding, 4 of which occurred after the compression period. In 2 cases repetition of the local hemostasic measures was required along with the injection of an antihemophilic factor concentrate. In the other 4 cases, the patients' condition reverted to normal following injection of the factor concentrate and the reapplication of the compression.. The adopted protocol produced a reliable outcome, limiting the duration of the hospital stay to 24 hours in most cases, and improving postsurgical comfort thanks to a combination of systemic treatment and local hemostasic measures including intermittent tranexamic acid compression.

Topics: Adolescent; Adult; Aged; Child; Clinical Protocols; Deamino Arginine Vasopressin; Dental Care for Chronically Ill; Factor IX; Factor VIII; Hemophilia A; Hemostatic Techniques; Hemostatics; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Middle Aged; Oral Hemorrhage; Postoperative Hemorrhage; Retrospective Studies; Tissue Adhesives; Tooth Extraction; Tranexamic Acid

Topics: Deamino Arginine Vasopressin; Female; Hemophilia A; Hemostatics; Humans; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Trimester, First

Hemophilia A (HA) is a bleeding disorder caused by factor VIII (FVIII) deficiency. FVIII replacement therapy can reduce bleeding but is expensive, inconvenient, and complicated by development of antibodies that inhibit FVIII activity in 30% of patients. Neonatal hepatic gene therapy could result in continuous secretion of FVIII into blood and might reduce immunological responses. Newborn HA mice and dogs that were injected i.v. with a retroviral vector (RV) expressing canine B domain-deleted FVIII (cFVIII) achieved plasma cFVIII activity that was 139 +/- 22% and 116 +/- 5% of values found in normal dogs, respectively, which was stable for 1.5 yr. Coagulation tests were normalized, no bleeding had occurred, and no inhibitors were detected. This is a demonstration of long-term fully therapeutic gene therapy for HA in a large animal model. Desmopressin (DDAVP; 1-deamino-[d-Arg(8)]vasopressin) is a drug that increases FVIII activity by inducing release of FVIII complexed with von Willebrand factor from endothelial cells. It has been unclear, however, if the FVIII is synthesized by endothelial cells or is taken up from blood. Because the plasma cFVIII in these RV-treated dogs derives primarily from transduced hepatocytes, they provided a unique opportunity to study the biology of the DDAVP response. Here we show that DDAVP did not increase plasma cFVIII levels in the RV-treated dogs, although von Willebrand factor was increased appropriately. This result suggests that the increase in FVIII in normal dogs after DDAVP is due to release of FVIII synthesized by endothelial cells.

Topics: Animals; Animals, Newborn; Cloning, Molecular; Deamino Arginine Vasopressin; DNA, Complementary; Dog Diseases; Dogs; Factor VIII; Genetic Therapy; Genetic Vectors; Hemophilia A; Humans; Liver; Male; Mice; Mice, Inbred C57BL; Retroviridae; von Willebrand Factor

Topics: Adenoidectomy; Child, Preschool; Deamino Arginine Vasopressin; Enuresis; Female; Fluid Therapy; Hemophilia A; Humans; Hyponatremia; Postoperative Care; Postoperative Complications; Renal Agents; Seizures; Tonsillectomy; Water Intoxication

Although hemophilia A, a congenital disorder caused by defective or deficient factor VIII:C (FVIII), is cured by liver transplantation, the exact site of hepatic FVIII production is unknown. Further, while intracellular co-localization of FVIII and von Willebrand factor (VWF) is required for in vitro FVIII secretion, whether it is required for in vivo FVIII secretion is not known. An ideal setting to study this problem is in individuals with hemophilia A following liver transplantation, as their FVIII is synthesized primarily in hepatic, but not extrahepatic endothelial cells, while VWF is synthesized primarily in extrahepatic vascular endothelium. Following liver transplantation for end-stage liver disease, three hemophilic men showed VWF, but no FVIII response to (DDAVP) infusion. By contrast, both VWF and FVIII increased in a non-hemophilic transplant recipient after DDAVP. These findings support a model in which intracellular co-localization of FVIII and VWF is necessary for in vivo FVIII secretion after DDAVP.

Topics: Adult; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Humans; Liver; Liver Transplantation; Male; Middle Aged; Protein Binding; von Willebrand Factor

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

Inherited bleeding disorders can be associated with significant morbidity and mortality. Bleeding episodes can be safely and effectively managed in the majority of patients provided the coagulation defect is identified and corrected with the appropriate replacement therapy. It is imperative that these patients are treated in centres that can provide full coagulation support, and a comprehensive care plan is formulated for each individual.

Topics: Blood Coagulation Disorders, Inherited; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Hemostatics; Humans

Topics: Angioplasty, Balloon, Coronary; Deamino Arginine Vasopressin; Electrocardiography; Hemophilia A; Hemostatics; Humans; Male; Middle Aged; Myocardial Infarction; Perioperative Care; Premedication; Stents

Acquired spontaneous hemophilia is a rare but potentially life-threatening disease, which poses a major challenge to intensive care medicine. We report a case in which the disease occurred postoperatively in a patient following uncomplicated lumbal discectomy. The clinical sequelae involved hemorrhagic shock (cHb 4.1 g/dl; hct 17 %; systolic BP 60 mmHg; HR 130/min; saO2 73 %) due to retroperitoneal hematoma eight days after neurosurgical intervention. While lesions of the retroperitoneal vessels were not found during emergent angiography and laparotomy, the laboratory results showed a slightly prolonged activated prothrombin time (aPTT; 47 s). However, application of fresh frozen plasma (FFP) even prolonged the aPTT (53 s). Analysis of clotting factors proved a deficiency of factor VIII with a reduced activity of about 20 %, which was resistant against therapy with desmopressin (DDAVP) and substitution of factor VIII. Thus, the plasma-mix-test was performed, showing complete inactivation of the factor VIII-activity of the pooled plasma. This evidenced the presence of acquired inhibitors against factor VIII. Hemostasis was successfully and immediately restored with the application of recombinant factor VIIa (rFVIIa), including boluses of 60 - 80 microg/kg every 6th - 8th hour (supplemented with tranexamic acid, 3 x 1 g/d), leading to a continuous infusion of 12 microg/kg per hour. With prednisolone (1 mg/kgBW/d) over the ensuing 8 weeks, the antibodies were sufficiently suppressed and no additional substitution of factor VIII was necessary to maintain normal hemostasis.

Topics: Blood Coagulation Tests; Critical Care; Deamino Arginine Vasopressin; Diskectomy; Factor VIIa; Factor VIII; Hematoma; Hemophilia A; Humans; Laparotomy; Male; Middle Aged; Plasma; Postoperative Complications; Prothrombin Time; Recombinant Proteins; Shock, Hemorrhagic

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

Decompensated hepatitis C virus (HCV)-related cirrhosis is the main indication for liver transplantation. We report the first successful living-related liver transplantation in a 49-year-old hemophilia A patient with end-stage HCV-related cirrhosis using a graft obtained from his 20-year-old daughter, an obligate carrier.. The donor's autologous fresh-frozen plasma rich in factor VIII (FVIII) by treatment with 1-deamino-8-D-arginine vasopressin was prepared before the operation. At induction, 1-deamino-8-D-arginine vasopressin was given to the donor to increase plasma FVIII level. In addition, autologous fresh-frozen plasma containing high FVIII concentrate was infused intraoperatively. The right lobe was harvested from the donor and transplanted orthotopically. The recipient was treated postoperatively with recombinant FVIII and immunosuppressive agents.. The donor did not receive recombinant FVIII or allogenic blood during perioperative periods. No bleeding was encountered in the donor perioperatively. The recipient showed a steady increase in FVIII activity postoperatively and was discharged 40 days after transplantation. Ribavirin and interferon-alpha were provided for 3 months postoperatively to prevent potential recurrence of HCV infection. Serum HCV-RNA by RT-PCR became negative after such treatment.. End-stage liver disease in patients with hemophilia A can be an indication for living-related liver transplantation. Furthermore, a graft from a living-related donor with hemophilia A carrier seems to be suitable provided such individuals receive adequate support for coagulopathies.

Topics: Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Hepatitis C; Humans; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Tissue Donors

Desmopressin may be an efficient haemostatic treatment for mild A haemophiliacs because its infusion raises plasma factor VIII level. We report the use of desmopressin in five mild haemophilia A patients undergoing urological surgery. They all received a preoperative infusion (0.3 microg kg(-1), i.v.) 1 h before incision followed by repeated injections at 12- or 24-h intervals according to the severity of the procedure. Nevertheless, four patients presented a postoperative bleeding requiring again surgery performed for 3 of them under clotting factor concentrate instead of desmopressin. The occurrence of haemorrhage was not always correlated with particularly low plasma factor VIII level. Surgical management of urological procedures with desmopressin in mild haemophilia A patients requires standardized protocols.

Topics: Child; Deamino Arginine Vasopressin; Drug Administration Schedule; Factor VIII; Hemophilia A; Hemostasis, Surgical; Hemostatics; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Middle Aged; Postoperative Hemorrhage; Premedication; Treatment Failure; Urologic Surgical Procedures, Male

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

Hemophilia is a rare disorder affecting 1 in 5,000 males. Because hemophilia-associated hemorrhage may occur at anytime, affected males frequently seek care in the ED. We studied the epidemiology of ED visits by males with hemophilia. The medical records of all identified Coloradan males with hemophilia who sought care in Colorado EDs in 1998 were reviewed. Fifty-one males with hemophilia had a total of 125 ED visits; hemorrhage accounted for 64.8% of visits (95% CI=55.6, 73.1). On 13.0% (95% CI=6.4, 22.6) of visits for hemorrhage, treatment was warranted, but not given. On 12.3% (95% CI=5.5, 22.8) of visits when treatment was given, there were errors in product choice or dose. Documentation of factor concentrate brand and lot number was present for just 13.9% (95% CI=6.5, 24.7) and 24.6% (95% CI=14.8, 36.9) of visits, respectively. There is substantial room for improvement in the prescribing practices and documentation related to hemophilia care in the ED. Available resources should be utilized by ED physicians.

Topics: Adult; Blood Coagulation Tests; Colorado; Deamino Arginine Vasopressin; Documentation; Emergency Service, Hospital; Health Care Surveys; Hemophilia A; Hemostatics; Humans; Male; Medical Audit; Medical Records; Medication Errors

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

Acquired haemophilia was diagnosed following detailed investigation of a post-partum haemorrhage unresponsive to standard management. Circulating factor VIII inhibitors and low factor VIII levels were detected and intravenous DDAVP treatment lead to a resolution of symptoms. This case highlights the importance of haematological investigations in persisting post-partum haemorrhage.

Topics: Adult; Autoantibodies; Deamino Arginine Vasopressin; Factor VIII; Female; Hemophilia A; Hemostatics; Humans; Partial Thromboplastin Time; Postpartum Hemorrhage; Tranexamic Acid

Desmopressin (DDAVP) increases plasma factor VIII coagulant activity (FVIII:C) levels in patients with mild/moderate haemophilia A. In some subjects, FVIII can be increased to haemostatic levels, thereby avoiding use of factor VIII concentrates. We reviewed our hospital's experience with 62 boys with FVIII:C levels 0.01-0.3 IU/ml who had a DDAVP challenge test (i.v. 0.3 microg/kg) following diagnosis. A therapeutic response was defined as a 1 h post-FVIII:C increase at least twofold over baseline and > 0.3 IU/ml. Of the total group, 29 (47%) boys responded to DDAVP, all of them with mild haemophilia (baseline FVIII:C > or = 0.05 IU/ml), yielding a response rate of 57% in this subgroup. Boys who responded to DDAVP had higher baseline FVIII:C levels (mean +/- SEM, 0.17 +/- 0.01 vs 0.10 +/- 0.01 IU/ml, P < 0.01) and were older (5.2 +/- 0.8 vs 3 +/- 0.4 years, P = 0.02) than those who failed to do so. The association between DDAVP response and age, however, remains unclear: seven boys who failed the initial challenge test responded to re-challenge after a mean of 6.3 years (median 4.9, range 0.5-12.5), increasing the response rate in boys with mild haemophilia to 71%. Age and FVIII:C association with DDAVP response are both important in boys with mild/moderate haemophilia A. Absence of response to DDAVP should therefore be confirmed by later re-challenge.

Topics: Adolescent; Age Factors; Child; Child, Preschool; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Hormones; Humans; Infant; Male; Retrospective Studies

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

A wide range of ophthalmic surgical procedures were conducted in five patients with haemophilia of varying severity (one severe and four mild) aged between 8 and 75 years. The operations included intraocular lens implantation, trabeculectomy and vitrectomy. Successful postoperative outcome with haemostasis was achieved in all patients with moderate use of clotting factor concentrates (3000-7000 IU), simultaneous use of oral epsilon amino caproic acid therapy and intravenous deamino-8-D-arginine vasopressin (desmopressin; DDAVP) wherever feasible. None of the patients had circulating inhibitor. One of the patients with milder disease (FVIII 32%) was referred to us after he was operated on for hyphaema elsewhere, without prior knowledge of his diagnosis of haemophilia. Thus, satisfactory eye surgery in patients with haemophilia is possible with a restricted amount of factor concentrates with gratifying results.

Topics: Aged; Aminocaproic Acid; Child; Deamino Arginine Vasopressin; Factor IX; Factor VIII; Hemophilia A; Hemostasis; Hemostatics; Humans; Lens, Crystalline; Male; Middle Aged; Ophthalmologic Surgical Procedures; Trabeculectomy; Vitrectomy

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

We describe two patients with mild hemophilia A (MHA) who developed high titer inhibitor (HTI) following intensive recombinant factor VIII (rFVIII) concentrate replacement for surgery and trauma. Intranasal desmopressin was instituted shortly following immunosuppressive therapy (IST) and activated prothrombin complex concentrate (APCC) in one case, and following APCC alone in the second case. Avoidance of factor VIII (FVIII) coupled with intranasal desmopressin prophylaxis three times a week resulted in undetectable inhibitor levels. Both patients have had no further bleeding episodes and have been maintained on desmopressin prophylaxis prior to activity for the past 2 to 3 years. Recombinant factor VIIa (rFVIIa) was used successfully prior to a second surgery in one patient without complication.

Topics: Adolescent; Autoantibodies; Contraindications; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Hemostatics; Humans; Immunosuppressive Agents; Male; Treatment Outcome

A 12-year-old boy presented with a traumatic hyphaema that failed to settle with the standard treatment. Subsequent investigation showed that despite a normal APTT, he had a low factor VIII:C. Treatment with DDAVP precipitated further bleeding despite correction of the fVIII:C to normal, possibly caused by the vasodilation induced by the therapy. Bleeding was effectively treated with recombinant fVIII concentrate. DDAVP may be contraindicated in mild Haemophilia and von Willebrand patients for treatment of traumatic hyphaema.

Topics: Child; Contraindications; Deamino Arginine Vasopressin; Disease Management; Factor VIII; Hemophilia A; Hemostatics; Humans; Hyphema; Male; Partial Thromboplastin Time; Recombinant Proteins; Wounds and Injuries

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

We report the development of a FVIII inhibitor in a patient with severe, cross reacting material reduced (CRM(R)) haemophilia A. The level of Factor VIII antigen (FVIII:Ag) measured by ELISA using anti-C2 monoclonal and alloantibodies was 1.9 U/dl. This baseline FVIII:Ag level was increased to 8.3 U/dl after administration of DDAVP. The anti-FVIII inhibitor titer was 2.9 Bethesda U/ml. DNA analysis showed a large deletion of the FVIII gene from exon 4 to 7, corresponding to amino acid residues 111-317 included within the A1 domain. The size of the gene deletion was approximately 28 kb. 5' and 3' breakpoints were identified by sequencing in intron 3 and intron 7, respectively. FVIII mRNA was detected in the patient's peripheral lymphocytes and the deletion spanning exon 4 to 7 was confirmed at the RNA level. Immunoprecipitation experiments using 125I labeled A1, A2 and light chain demonstrated that the inhibitor reacted only with the 54 kDa A1 domain. The inhibitor activity was more than 95% neutralized by A1 domain polypeptide. Our findings suggest a close relationship between the inhibitor epitope and the specific gene deletion with regard to the pathogenesis of the inhibitor in this patient.

Topics: Adult; Antigen-Antibody Reactions; Base Sequence; Binding Sites; Deamino Arginine Vasopressin; DNA Mutational Analysis; Epitopes; Factor VIII; Gene Deletion; Hemophilia A; Hemostatics; Humans; Isoantibodies; Male; Molecular Sequence Data; Precipitin Tests; RNA, Messenger

Although it is known that factor VIII (FVIII) plasma levels increase rapidly in response to a number of stimuli, the biological stimuli behind this release is less clear. Previously, we showed that FVIII can traffic together with von Willebrand factor (vWF) into storage granules in a pituitary tumor cell line, AtT-20; however, AtT-20 cells could not be used to address the release or functional activity of released FVIII. To investigate the regulated secretion of stored FVIII, endothelial cells with intact agonist-stimulated release pathways were used. Human umbilical vein endothelial cells (HUVECs) were transduced with retroviral FVIII construct [hFVIII(V)] to create a FVIII/vWF storage pool. Immunofluorescent staining of transduced cells demonstrated FVIII in Weibel-Palade bodies. In contrast, the transduction of hFVIII(V) into HT-1080 and HepG2 cells displayed FVIII only in the cytoplasm. We studied the regulated release of both FVIII and vWF from endothelial cells after agonist-induced stimulation and demonstrated a parallel release of FVIII and vWF proteins. This released FVIII was functionally active. Hence, endothelial cells transduced with hFVIII(V) store FVIII together with vWF in Weibel-Palade bodies, creating a releasable storage pool of both proteins. Because FVIII secretion can be physiologically regulated by agonists in culture, this may explain the pharmacological agonist-induced release of FVIII by drugs such as desmopressin in vivo and suggests vascular endothelium as a reasonable target of gene therapy of hemophilia A.

Topics: Cell Line; Cells, Cultured; Cytoplasm; Deamino Arginine Vasopressin; Endothelium, Vascular; Factor VIII; Fluorescent Antibody Technique, Indirect; Genetic Therapy; Genetic Vectors; Hemophilia A; Hemostatics; Humans; Transduction, Genetic; 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: Blood Transfusion; Contraindications; Deamino Arginine Vasopressin; Emergencies; Factor IX; Factor VIII; Hemophilia A; Hemophilia B; Hemorrhage; Hemostatics; Humans; Male; Risk Factors; Wounds and Injuries

Because native circulating factor VIII (FVIII) is maximally stabilized when it is bound to von Willebrand factor (vWf), increased plasma vWf levels may enhance the infused FVIII concentrate intravascular survival and efficacy in severe haemophiliacs. To assess whether the kinetic characteristics and recovery of high purity, plasma-derived (Monoclate-P, Centeon) and recombinant (Bioclate , Centeon) FVIII concentrates are enhanced by increased plasma vWf concentrations, we compared the pharmacokinetic response to a bolus of FVIII infused alone with the response to a bolus infused 2 h after the intranasal delivery of 300 microg of desmopressin acetate (DDAVP) High Concentration Nasal Spray (Stimate, Centeon) in 10 adult severe haemophiliacs. FVIII activity was determined using a one-stage clotting assay on cryopreserved plasma specimens obtained at baseline and at 14 distinct time points (0.25-48 h) following the FVIII infusions. Ristocetin co-factor activity (RCoFA) and vWf antigen levels were assayed at baseline and 2 h after Stimate. FVIII kinetic parameters were calculated using standard, noncompartmental kinetic methods. Statistical analysis was performed using a paired t-test with 95% confidence limits. The mean rises in RCoFA (0.65+/-0.44 IU mL(-1)) and vWf antigen (0.19+/-0.07 IU mL-1) induced by Stimate were significant (P<0.01 and P<0.0001, respectively). The mean increases in the volume of distribution at steady state (Vss) (13.2+/-9.3 dL) and mean residence time (MRT) (4.4+/-3.9 h) between the FVIII-only arm and the FVIII plus Stimate arm were highly significant (P = 0.0015 and P = 0. 0059, respectively). The mean differences in recovery, area under the curve (AUC), half-life, and clearance (Cl) were not significantly altered. Subgroup analysis revealed statistically significant increases in Vss and MRT (P = 0.025 and P = 0.012, respectively) following the administration of intranasal DDAVP in the Monoclate-P cohort, but not in the Bioclate group. These data suggest that even modest pharmacologically induced increases in plasma vWf can favourably affect the kinetics of high-purity, plasma-derived FVIII concentrates in severe haemophiliacs.

Topics: Administration, Intranasal; Adult; Antibodies, Monoclonal; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Hemostatics; Humans; Linear Models; Recombinant Proteins; von Willebrand Factor

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

Desmopressin (DDAVP) may be used to augment the action of factor VIII in mild haemophilia. Its use has been associated with serious adverse effects. We report a case of a three-year-old child with a family history of haemophilia who suffered complications due to severe acute hyponatraemia following the administration of this drug for post-tonsillectomy bleeding.

Topics: Adenoidectomy; Apnea; Blood Loss, Surgical; Child, Preschool; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Hemostasis, Surgical; Hemostatics; Humans; Hyponatremia; Male; Postoperative Hemorrhage; Seizures; Tonsillectomy

Topics: Aged; Autoantibodies; Deamino Arginine Vasopressin; Drug Therapy, Combination; Factor VIII; Female; Hematoma; Hemophilia A; Hemorrhage; Humans; Immunoglobulins; Prednisone

Topics: Aged; Deamino Arginine Vasopressin; Drug Therapy, Combination; Factor VIII; Female; Hemophilia A; Humans; Immunoglobulins, Intravenous; Prednisone

Twenty six patients with mild or moderate haemophilia A and inhibitors are described. The inhibitor was detected at a median age of 33 years, after a median of 5.5 bleeding episodes. This usually following intensive replacement therapy. The median presenting inhibitor titre was antihuman 11.6 BU/ml, antiporcine 1.45 BU/ml. Plasma basal factor VIII level declined from a median of 0.08 IU/ml to 0.01 IU/ml following the inhibitor development. This caused spontaneous bleeding in 22 and a bleeding pattern similar to acquired haemophilia in 17. Bleeding was often severe and caused two deaths. The inhibitor disappeared spontaneously, or following immune tolerance induction, in 16 cases after a median of 9 months (range 0.5-46), with a return to the original baseline VIIIC level and bleeding pattern accompanied inhibitor loss. The inhibitor persisted in the remainder of the cases over a median period of 99 months (range 17-433 months) of follow-up. Inhibitors are an uncommon complication of mild haemophilia which frequently persist and may be associated with severe, life-threatening, haemorrhage. Forty-one percent of treated haemophilic family members had a history of factor VIII inhibitors, suggesting a familial predisposition to develop inhibitors in these kindreds. Sixteen patients from 11 families were genotyped. Seven different missense mutations affecting the light chain were detected and two in the A2 domain. Five patients from three families had a mutation causing a substitution of Trp2229 by Cys in the C2 domain which appears to predispose to inhibitor formation since 7 of the 18 affected individuals have a history of inhibitor development.

Topics: Adolescent; Adult; Aged; Antibody Specificity; Autoantibodies; Blood Transfusion; Child; Deamino Arginine Vasopressin; DNA Mutational Analysis; Epitopes; Factor VIII; Genotype; Hemophilia A; Hemorrhage; Humans; Male; Middle Aged; Pedigree; Point Mutation; Prevalence; Prospective Studies; Protein Conformation; Retrospective Studies

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

Haemophilia A, the most common of bleeding disorders is characterized by bruising and spontaneous bleeding into the joints but may remain undiagnosed if present in the mild form. A case is discussed where episodes of bruising and joint swelling as a child were misdiagnosed as rheumatic fever and the bleeding disorder was diagnosed following recurrent episodes of bleeding after extraction of an upper molar tooth.

Topics: Adolescent; Deamino Arginine Vasopressin; Dental Care for Chronically Ill; Female; Hemophilia A; Hemostatics; Humans; Male; Oral Hemorrhage; Tooth Extraction

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

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

We found a patient with mild hemophilia A who had no detectable factor VIII antigen (FVIII:Ag), as shown by two-site ELISA using inhibitor alloantibodies (TK). We then analyzed A2, A2/B, and C2 antigen of the patient's DDAVP-induced FVIII using several anti-FVIII monoclonal antibodies. Factor VIII activity (FVIII:C) was increased from 12 to 42 U/dl by the administration of DDAVP. The DDAVP-induced increases in the A2 and A2/B antigens were 40 and 36 U/dl, respectively. However, the increase in the C2 antigen was only 7.5 U/dl. SSCP analysis and subsequent sequencing demonstrated an Arg to Cys transition at codon 2159. The anti-FVIII:C titer of monoclonal antibody, NMC-VIII/5 which recognized the C2 domain, against normal plasma was 450 Bethesda U/mg of IgG. However, the titer against DDAVP-treated patient's plasma was only 15 Bethesda U/mg. We also tested DDAVP-induced increase in the FVIII:Ag in another mild hemophilia A patient with the same mutation at Arg2159. Increase in his C2 antigen levels was only 19% of those in the A2 and A2/B antigen. We designate this abnormal FVIII as FVIII Ise. Our results show that a missense mutation at Arg2159 to Cys modifies the antigenicity of the C2 domain.

Topics: Adolescent; Amino Acid Sequence; Antibodies, Monoclonal; Arginine; Base Sequence; Cysteine; Deamino Arginine Vasopressin; DNA Primers; Enzyme-Linked Immunosorbent Assay; Epitopes; Exons; Factor VIII; Hemophilia A; Humans; Isoantibodies; Male; Point Mutation; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; 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

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

Topics: Adult; Coronary Thrombosis; Deamino Arginine Vasopressin; Fatal Outcome; Hemophilia A; Humans; Male

Topics: Adult; Coronary Thrombosis; Deamino Arginine Vasopressin; Fatal Outcome; Hemophilia A; Hip Prosthesis; Humans; Male; Premedication

Topics: Administration, Intranasal; Adolescent; Adult; Child; Child, Preschool; Cost-Benefit Analysis; Deamino Arginine Vasopressin; Europe; Factor VIII; Female; Health Care Costs; Hemarthrosis; Hemophilia A; Humans; Infant; Infusion Pumps; Injections, Intravenous; Japan; Male; Radiography; Severity of Illness Index; Treatment Outcome; United States; von Willebrand Factor

Inhibitor development in patients with mild hemophilia is a rare event. We report the occurrence of a persistent, high-responding inhibitor in two affected members of a mild hemophilia A family and discuss the therapeutic approaches employed in these patients in terms of their efficacy and effect on antibody titer. Desmopressin was an effective option for bleeding management, because endogenous factor VIII released by DDAVP was less immunogenic than exogenous factor VIII replacement, which invariably triggered anamnestic responses. Genetic analysis performed to investigate whether or not a peculiar molecular lesion accounted for this particular phenotype identified a G-A transversion at nucleotide 6507 in exon 23. This missense mutation has been already described in mild hemophilia A, but not in patients with inhibitors.

Topics: Adult; Deamino Arginine Vasopressin; DNA Mutational Analysis; Exons; Factor VIII; Hemophilia A; Humans; Isoantibodies; Male; Point Mutation; Polymerase Chain Reaction

Topics: Aortic Valve Insufficiency; Blood Component Transfusion; Child; Combined Modality Therapy; Deamino Arginine Vasopressin; Drug Monitoring; Factor V Deficiency; Female; Heart Septal Defects, Ventricular; Hemophilia A; Humans; Plasma; Treatment Outcome

Topics: Blood; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Hepatitis B Vaccines; Humans; Immunologic Deficiency Syndromes; Isoantibodies; Safety; Virus Diseases

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

Topics: Activities of Daily Living; Adolescent; Adult; Blood Component Transfusion; Child; Child, Preschool; Deamino Arginine Vasopressin; Hemophilia A; Humans; Infant; Retrospective Studies; Thailand

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 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

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

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

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

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

Topics: Deamino Arginine Vasopressin; Female; Genetic Carrier Screening; Hemophilia A; Humans; Infusions, Parenteral

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

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

Topics: Adult; Anemia, Sickle Cell; Deamino Arginine Vasopressin; Hemophilia A; Hemorrhage; Humans; Male

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

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 more concentrated desmopressin (DDAVP) preparation (40 micrograms/ml), which required small injection volumes (less than 1 ml), was studied in a double-blind trial in 10 healthy volunteers, 12 patients with haemophilia A, and 8 patients with uraemic bleeding. DDAVP was administered by subcutaneous injection at a dose of 0.4 micrograms/kg body weight. In healthy subjects, peak levels of DDAVP ranging from 480 to 638 pg/ml were reached 1 h after the subcutaneous injection and DDAVP was eliminated with a mean half-life of 3.1 h. DDAVP produced a 2.5-fold (3.0-fold) increase of factor VIII:C (factor VIII:Ag) and a 1.9-fold (2.2-fold) increase of von Willebrand factor:Ag (ristocetin cofactor) over baseline levels. Additionally, a 2.1-fold increase of tissue-type plasminogen activator antigen was observed. Factor VIII and von Willebrand factor were rapidly eliminated with a half-life ranging from 1.3 to 5.7 h and from 1.1 to 11.4 h, respectively. In haemophilia A patients, DDAVP produced a 2.3-fold increase of factor VIII:C 1 h after the injection. DDAVP was given on 8 occasions for management of bleeding, and only in 1 patient did a wound haematoma (after herniotomia) occur. In 7 of the 8 patients with uraemia the bleeding time shortened, and in all patients an increase of platelet retention and a decrease of platelet count was observed (p less than 0.05). No serious local or systemic untoward side effects were observed.

Topics: Adult; Antigens; Bleeding Time; Blood Coagulation Disorders; Deamino Arginine Vasopressin; Drug Evaluation; Factor VIII; Female; Hemophilia A; Heterozygote; Humans; Injections, Subcutaneous; Male; Middle Aged; Uremia; von Willebrand Factor

Sufficient increase in plasma of factor VIII activities with a view to carrying out surgery in mild and moderate Haemophilia A and von Willebrand's disease was achieved by intravenous infusion of 1-desamino-8-D-arginine vasopressin (DDAVP). 15 patients were treated with success and three patients had to be transfused with factor VIII concentrates to control postoperative hemorrhage. DDAVP therapy makes transfusion unnecessary in selected patients. This is an important therapeutic advance as long as the use of blood products does involve danger of infecting the recipient. Another advantage is that DDAVP therapy is much cheaper than factor VIII concentrate.

Topics: Adolescent; Adult; Deamino Arginine Vasopressin; Endothelium, Vascular; Factor VIII; Female; Hemophilia A; Humans; Male; Middle Aged

The introduction of factor VIII and IX concentrates in the early 1960s brought a significant change in the hemophiliac's life. In consequence hemophilia treatment has been improving rapidly since, and today most life-threatening hemorrhages are controlled by replacement therapy. Hemophilic arthropathy through recurrent joint and muscle bleedings occurs later in life and is often limited to one joint only. Major surgery in hemophiliacs involves little more risk than in non-hemophilic patients, provided of course there is close teamwork between surgeon and hematologist. The most frequent causes of death are no longer hemorrhages but blood-product-associated AIDS and hepatic failure. Fortunately these side effects have been overcome by the use of virus-inactivated concentrates which in Switzerland have been generally administered since 1986. Factor VIII and IX concentrates must contain a precisely declared quantity of factor VIII and IX activity respectively, with a high specific activity. High-purity concentrates should be preferred because of the hazardous effect of foreign proteins administered intravenously in large quantities over a long period. Activation of fibrinolysis with consequent failure of hemostasis or even worsening of hemorrhage may be a clinically relevant side-effect of DDAVP therapy. When DDAVP is used for prophylactic treatment before surgery, an interval of one hour between the intravenous administration of DDAVP and surgery ensures the latter is performed at the time of highest factor VIII and von Willebrand factor level but with already decreased t-PA and fibrinolytic activity. If DDAVP is used in case of hemorrhage or postoperatively, however, the whole fibrinolytic potential must be taken into account. In these cases subcutaneous administration is advantageous due to more protracted t-PA release and the subsequent lower fibrinolytic activity, which can more easily be neutralized by tranexamic acid. To prevent hemophilic arthropathy, correct replacement therapy in hemarthroses is essential: it should be performed as early as possible, preferably in a home therapy program; adequate levels of factor VIII or IX should be achieved and maintained over a sufficient length of time. Hemophiliacs who did not receive replacement therapy during childhood often need major surgery because of severely destructed joints. Joint replacement by total knee and hip prostheses has proved very successful if certain special conditions are fulfilled. Surgic

Topics: Acquired Immunodeficiency Syndrome; Adult; Deamino Arginine Vasopressin; Factor VIII; Hemarthrosis; Hemophilia A; Hepatitis, Viral, Human; Humans; Knee Prosthesis; Male

Topics: Acquired Immunodeficiency Syndrome; Blood Coagulation Factors; Blood Transfusion; Deamino Arginine Vasopressin; Genetic Carrier Screening; Hemophilia A; Humans; Patient Care Team; Prenatal Diagnosis

Combined deficiency of factor V and factor VIII, a rare bleeding disorder, was found in a 43 year-old male. He had often presented manifestations of easy bruising since childhood, but none of his family had shown evidence of a bleeding tendency. We examined him and his family as far as we could and his abnormality of blood coagulation was apparent, but the members of his family were normal. The prothrombin time and activated partial thromboplastin time of this patient were prolonged, but his thrombin time was normal. Factor V and factor VIII coagulant activity were low, but von Willebrand factor antigen and activity (ristocetin cofactor activity) levels were normal. Protein C and Protein C inhibitor antigen and activity levels were also found to be normal. Following 1-deamino-8-D-arginine vasopressin (DDAVP) injection, he had immediate increases in factor VIII coagulant activity, but both von Willebrand factor antigen, activity levels and factor V coagulant activity remained low. Moreover, there was no rapid decline in factor VIII complex activity. These findings suggest that the endogenous factor VIII in this patient is metabolized normally and that at least the deficiency of factor VIII does not result from accelerated degradation in plasma.

Topics: Adult; Blood Coagulation; Deamino Arginine Vasopressin; Factor V Deficiency; Hemophilia A; Humans; Male

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

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: Adult; Aged; Deamino Arginine Vasopressin; Factor VIII; Female; Hemophilia A; Humans; Postpartum Hemorrhage; Pregnancy; Suppressor Factors, Immunologic

Derivatives of an antidiuretic hormone raise factor VIII levels in patients with mild or moderate hemophilia A. This case report describes the use of desmo-pressin acetate to raise the factor VIII level in a patient with hemophilia A, before and after extraction of 27 teeth.

Topics: Adult; Aminocaproic Acid; Cellulose, Oxidized; Deamino Arginine Vasopressin; Dental Care for Disabled; Hemophilia A; Humans; Male; Oral Hemorrhage; Tooth Extraction

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

A 63-year-old male had major postoperative bleeding complications following the excision of a basal cell carcinoma. The patient denied a prior history of bleeding complications and had normal coagulation screening studies. After coagulation evaluation, he was found to have mild hemophilia A with 23% of normal Factor VIII C. We discuss an approach to the evaluation of coagulation in patients with perioperative and postoperative bleeding. Also, we outline treatment alternatives for patients with hemophilia A who need cutaneous surgery.

Topics: Blood Coagulation; Carcinoma, Basal Cell; Deamino Arginine Vasopressin; Dermatologic Surgical Procedures; Factor VIII; Hemophilia A; Hemorrhage; Hemostasis, Surgical; Humans; Male; Middle Aged; Platelet Count; Postoperative Complications; Skin Neoplasms

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: Aged; Deamino Arginine Vasopressin; Hemophilia A; Humans; Male; Myocardial Infarction

Topics: Adult; Cyclohexanecarboxylic Acids; Deamino Arginine Vasopressin; Dental Care for Disabled; Hemophilia A; Humans; Male; Tooth Extraction; Tranexamic Acid

Topics: Deamino Arginine Vasopressin; Dental Care for Disabled; Hemophilia A; Humans; Oral Hemorrhage; Oral Hygiene; Tooth Extraction; von Willebrand Diseases

Current factor VIII products expose recipients to many donors and hence to a high risk of acquiring blood-borne infections. Plasma-exchange donation of cryoprecipitate can reduce donor exposure by repeatedly obtaining large yields of factor VIII from individual donors. In this study, donor factor VIII levels were stimulated with desmopressin before donation. Mean yield per donation increased from 1399 +/- 425 IU in controls to 3818 +/- 1350 IU in stimulated donations (p less than 0.001), and mean factor VIII concentration in the cryoprecipitate increased from 8.2 +/- 3 IU/mL to 24 +/- 12 IU/mL (p less than 0.001). A new packaging system dispenses assayed aliquots of stimulated cryoprecipitate in plastic vials. The direct cost of production for this material is $.065 per unit. The cryoprecipitate is hemostatically active and convenient to use, and the aggregate yields from sequential donations by stimulated persons are high enough to allow long-term, single-donor support of many adults with hemophilia.

Topics: Blood Component Removal; Chemical Precipitation; Costs and Cost Analysis; Deamino Arginine Vasopressin; Drug Packaging; Factor VIII; Hemophilia A; Humans; Plasma Exchange

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

This study was carried out to evaluate the pharmacological efficacy of a new concentrated 1 Deamino - (8-D-arginine)-vasopressin (DDAVP) preparation. Concentrated DDAVP (C-DDAVP), (40 micrograms/mL) was given subcutaneously (s.c.) in hemophilia and von Willebrand Disease (vWD), and the response was evaluated in terms of factor VIII/vWF (VIII/von Willebrand Factor) complex response. This response was also compared to that obtained using the currently available commercial preparation (4 micrograms/mL) given either s.c. or intravenously (i.v.). The maximal f. VIII response after s.c. C-DDAVP was reached one hour after the injection (means:3.5 times the resting values) with an average decline of 15% at two hours. The response to s.c. C-DDAVP in patients with hemophilia was slightly better than that obtained with the diluted brand, but the difference did not reach any statistical significance even when the schedules were compared in the same patients. In type I (platelet normal subtype) vWD, a higher response in terms of factor VIII:C increase in comparison with hemophiliacs was obtained. Both Ristocetin co-factor activity (RiCof) and bleeding time responded to this vasopressin analogue, when administered subcutaneously.

Topics: Deamino Arginine Vasopressin; Drug Administration Schedule; Factor VIII; Hemophilia A; Humans; Injections, Intravenous; Injections, Subcutaneous

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

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

Factor VIII amidolytic activity was measured by a commercially available method and compared with clotting activity measured in a one-stage assay. Parallel assays with both methods were used for plasma samples from 40 blood donors with normal or high Factor VIII levels, 22 patients with hemophilia before or after treatment with Factor VIII concentrates, 10 patients with chronic liver disease, and 10 normal subjects with high Factor VIII levels after treatment with desmopressin. The results obtained with the amidolytic assay were highly correlated (r = 0.97) with those obtained in the one-stage clotting assay. There were no significant differences in the results with the two methods in any of the patient groups, although in two cases of mild hemophilia the amidolytic assay gave lower values than the clotting assay. The reproducibility of the amidolytic assay (coefficient of variation = 6%) was better than that of the clotting assay (12%) at both normal and low levels of Factor VIII.

Topics: Adult; Amides; Blood Coagulation Tests; Deamino Arginine Vasopressin; Factor VIII; Female; Hemophilia A; Humans; Liver Diseases; Male; Middle Aged

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

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

Topics: Arginine Vasopressin; Blood Coagulation Factors; Deamino Arginine Vasopressin; Electrochemistry; Hemophilia A; Humans; Immunochemistry; Plasminogen Activators; 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: Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Humans; Male; von Willebrand Diseases; von Willebrand Factor

Sixteen patients with mild and moderate hemophilia were given Desmopressin (DDAVP) subcutaneously in the absence of any actual bleeding. The response to the drug - in terms of factor VIII coagulant activity rise - became apparent 15 min after the injection, reaching the maximal response after one hour (means 3.2 times the baseline levels; SD 1.21). This response was not different from that elicited using the intravenous route in 18 hemophiliacs of comparable severity after the same time interval. No local or general side-effects were recorded after the subcutaneous administration of DDAVP. We therefore conclude that the subcutaneous route adds further evidence to the reliability of this alternative treatment in mild factor VIII deficiencies, thus making home treatment with this vasopressin analogue possible.

Topics: Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Humans; Injections, Intravenous; Injections, Subcutaneous; Time Factors

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

The effect of D.D.A.V.P. (desamino-cys'-D-arg8-Vaso-pressin) on the survival characteristics of transfused VIII concentrate was studied in six severe, adolescent, haemophiliacs (VIII:C 1 iu/dl). D.D.A.V.P. was administered at a concentration of 0.3 ug/kg immediately following or 24 hours post infusion. No significant alteration in the half disappearance (1/2 d) or biological half-life (t 1/2) was detected for either VIII procoagulant (VIII:C) or its antigenic counterpart VIII:C Ag. As anticipated there was a significant (if sub-optimal) increase in VIII:R Ag within 2-4 hours of D.D.A.V.P. administration.

Topics: Blood Transfusion; Deamino Arginine Vasopressin; Drug Stability; Factor VIII; Hemophilia A; Humans; Kinetics

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

Topics: Administration, Intranasal; Deamino Arginine Vasopressin; Hemophilia A; Humans; Male

Topics: Deamino Arginine Vasopressin; Hemophilia A; Humans; Minor Surgical Procedures

Topics: Adult; Arginine Vasopressin; Cyclohexanecarboxylic Acids; Deamino Arginine Vasopressin; Dental Care for Disabled; Hemophilia A; Hemostasis, Surgical; Humans; Male; Molar, Third; Tooth Extraction; Tooth, Impacted; Tranexamic Acid

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

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

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

We studied the differential increase in FVIIIc and FVIII R:Ag after the intravenous infusion of 0.30 micrograms/kg DDAVP in 20 obligate hemophilia A carriers and in 20 female controls. FVIIIc increased in carriers (59.5 +/- 23.1 to 137.5 +/- 45.9) and in controls (98.0 +/- 20.7 to 259.9 +/- 57.4) (P less than 0.001), but the magnitude of the FVIIIc increase in carriers was less than that in controls by 51.9% (P less than 0.001). FVIII R:Ag increased comparably in carriers (105.2 +/- 30.4 to 171.9 +/- 25.4) and controls (92.1 +/- 33.0 to 165.2 +/- 20.6). Using the post-DDAVP instead of the standard FVIIIc/FVIII R:Ag ratio, hemophilia carrier detection was increased from 85% (with 10% false positive and 20% false negative assignments) to 95% (with 5% false positive and 5% false negative assignments). Toxicity associated with DDAVP infusion correlated linearly with doses greater than 10.5 +/- 1.3 micrograms/m2 (P less than 0.02) and with total doses greater than 17.0 +/- 4.5 micrograms (P less than 0.02). The use of DDAVP improves carrier detection in factor VIII-deficient hemophilia.

Topics: Adolescent; Adult; Analysis of Variance; Antigens; Arginine Vasopressin; Child; Deamino Arginine Vasopressin; Drug Evaluation; Factor VIII; False Negative Reactions; False Positive Reactions; Female; Genetic Carrier Screening; Headache; Hemophilia A; Humans; Male; Middle Aged; von Willebrand Factor

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

Twenty-one patients suffering from mild von Willebrand's disease (vWd) and patients suffering from mild or moderate hemophilia A received 1-desamino-8-D-arginine vasopressin (DDAVP) (Minirin, Ferring AG) s.c. at a dose of 0.4 microgram/kg body weight. Additionally, two hemophiliacs and 22 patients with vWd received DDAVP i.v. Within the observation period of 3 h Factor (F) VIII:C levels increased 2.4 X baseline levels in hemophiliacs, and the maximal effect was observed 3 h post DDAVP s.c. In patients with vWd post DDAVP s.c. (i.v.) a 2.7 (3.4), 2.1 (1.9) and 2.2 (2.8) fold increase for F VIII: C, F VIIIR:Ag and F VIII:Rcof was observed. In eight patients suffering from vWd with additional F XII deficiency a small and transitory but significant increase of F XII levels was detected post DDAVP s.c. No local or systemic side effects were observed. In five patients with vWd tooth extractions were performed without bleeding complications under DDAVP s.c. treatment. Two patients practiced self-treatment by injecting the drug s.c. at home. We thus conclude that s.c. DDAVP is an effective, reliable, and cost-reducing form of treatment that does not bring with it the risk of transmitting infectious diseases in patients with vWd and hemophilia and that can be administered at home.

Topics: Arginine Vasopressin; Blood Coagulation Disorders; Deamino Arginine Vasopressin; Hemophilia A; Humans; Injections, Intravenous; Injections, Subcutaneous

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

Classic hemophilia or factor VIII deficiency is a recessive, sex-linked bleeding diathesis. The primary clinical problem is hemorrhage, which can be severe and often life threatening, even in the presence of only minor trauma. In the past this inadequate hemostasis has been treated with transfusions of cryoprecipitate, fresh frozen plasma, or commercially prepared factor VIII concentrate. Unfortunately, such treatment carries with it a number of risks, including the development of hepatitis B or hemolytic anemia and the formation of anti-factor VIII antibodies. Because of hemorrhage severity and the risks of conventional treatment, elective surgery in general and oral surgery in particular have often been neglected in patients with hemophilia. This article reviews a drug, 1-desamino-8-d-arginine (DDAVP), heretofore not discussed in the dental literature, and reports on its use in conjunction with epsilon-aminocaproic acid (EACA), a synthetic antifibrinolytic agent, in the surgical dental treatment of a patient with hemophilia A. The results suggest that certain dental surgical procedures can be performed in the presence of subclinical and mild hemophilia without conventional factor VIII replacement therapy with its associated costs and risks.

Topics: Adult; Aminocaproic Acid; Arginine Vasopressin; Deamino Arginine Vasopressin; Dental Care for Disabled; Drug Combinations; Hemophilia A; Humans; Male; Oral Hemorrhage; Oral Surgical Procedures, Preprosthetic

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

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: Blood Coagulation Factors; Blood Proteins; Deamino Arginine Vasopressin; Factor V Deficiency; Female; Glycoproteins; Hemophilia A; Humans; Protein C

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

The effect of a single standard dose of intranasal DDAVP (260 micrograms) was investigated in healthy subjects and in patients with mild deficiencies of VIII:C. Changes in FVIII/VWF activities were measured from baseline after 30, 60, 120 and 360 min of administration of the drug. Intranasal DDAVP was followed by a two-fold increase of VIII:C in both groups studied. VIIIR:AG and VIIIR:RCo increased to a lesser extent. Even though FVIII/VWF activities reached their maximum after 60-120 min, a significant increase over baseline was still observed after 360 min. The rise of VIII:C was unrelated to the body weight of the patients and was proportional to the baseline levels of this factor. In two sisters with combined deficiencies of FV/FVIII, the responses in all activities of FVIII/VWF were similar to those seen in mild hemophiliacs. Factor V did not undergo any variation. No alteration in serum osmolarity and no consistent variation in blood pressure or pulse rate were noted. It is concluded that the i.n. administration of a single high dose of DDAVP might be adopted to provide an emergency aid in bleeding patients with mild to moderate haemophilia A and to yield higher VIII:C levels in blood donors.

Topics: Administration, Intranasal; Adolescent; Adult; Arginine Vasopressin; Blood Coagulation Factors; Body Weight; Deamino Arginine Vasopressin; Factor V Deficiency; Factor VIII; Female; Hemophilia A; Humans; Male; 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: Administration, Intranasal; Arginine Vasopressin; Blood Coagulation; Deamino Arginine Vasopressin; Fibrinolysis; Hemophilia A; Humans

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; Blood Coagulation; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Humans

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: Arginine Vasopressin; Child; Deamino Arginine Vasopressin; Hemophilia A; Humans; Male; Oral Hemorrhage; Preoperative Care; Tooth Extraction

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: Arginine Vasopressin; Congresses as Topic; Deamino Arginine Vasopressin; Factor VIII; Germany, West; Hemophilia A; Humans

Topics: Arginine Vasopressin; Blood Preservation; Cryoglobulins; Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Humans; Infusions, Parenteral; Male; Refrigeration; Tranexamic Acid

DDAVP, a synthetic vasopressin analogue, causes a sustained increase of factor VIII in blood. The drug (0.4 micrograms/kg) was repeatedly infused into 13 hemophilics and 5 healthy men in order to study the kinetics of the elicited antihemophilic factor (AHF). The AHF increase and disappearance were found to be strictly related to the severity of the coagulation defect. Thus, data were obtained which will form a basis for rational therapeutic use of DDAVP in hemophilia. The DDAVP effect was completely independent of the presence of AHF in the circulation and was not associated with activation of clotting or platelets.

Topics: Arginine Vasopressin; Deamino Arginine Vasopressin; Evaluation Studies as Topic; Factor VIII; Hemophilia A; Humans; Male; von Willebrand Factor

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: Administration, Intranasal; Adolescent; Adult; Arginine Vasopressin; Deamino Arginine Vasopressin; Hemophilia A; Humans; Male

Topics: Adult; Child; Deamino Arginine Vasopressin; Hemophilia A; Hemostasis; Humans; Middle Aged; Vasopressins

Topics: Adult; Arginine Vasopressin; Blood Coagulation; Deamino Arginine Vasopressin; Factor XIII; Fibrinolysis; Hemophilia A; Humans; Male; Middle Aged

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

Topics: Deamino Arginine Vasopressin; Factor VIII; Hemophilia A; Hemostasis, Surgical; Humans; Infusions, Parenteral; Male; Middle Aged; Postoperative Care; Preoperative Care; Tooth Extraction; Vasopressins

Topics: Adult; Deamino Arginine Vasopressin; Hemophilia A; Hemostasis, Surgical; Humans; Hyponatremia; Male; Tooth Extraction; Vasopressins; Water Intoxication