heparitin-sulfate and Thrombocytopenia

Heparin-induced thrombocytopaenia (HIT) is a severe and potentially life-threatening adverse drug reaction. Patients become extremely hypercoagulable, and this can lead to life-threatening and limb-threatening thrombosis with a mortality of 5%-10%. HIT is an antibody-mediated process in which platelet activation occurs. Diagnosis requires a high index of suspicion along with a scoring system and laboratory testing. Patients suspected of having HIT must not receive any further heparin or low-molecular weight heparin and must be started on an alternative anticoagulant such as argatroban or danaparoid. Fondaparinux may also be considered but is not licenced for this indication.

Topics: Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Fondaparinux; Heparin; Heparitin Sulfate; Humans; Pipecolic Acids; Polysaccharides; Sulfonamides; Thrombocytopenia

In the context of inpatient and increasingly ambulatory thrombosis prophylaxis, heparins have been recognised as standard therapy for decades. In addition to the therapeutic benefit, therapy with heparins also entails the risk of undesirable side effects, such as bleeding and thrombocytopenia. Heparin-induced thrombocytopenia (HIT II) is deemed a serious side effect.. In the following work, HIT II is subjected to a medico-economic consideration (treatment, pharmaceuticals, subsequent costs due to possible complications) and, with regard to a possible HIT II prophylaxis, aspects of increasingly respected patient safety are also considered.. In the context of a literature search the active ingredients argatroban and danaparoid, which are approved for HIT II treatment, were evaluated.. HIT II - especially in combination with thromboembolic complications - represents a medical-economic burden for the hospital. Although this is only an orientation guide, it shows that HIT II syndrome is not adequately cost-covered by the G‑DRG system. An early thrombosis prophylaxis with argatroban/danaparoid for HIT II risk patients should therefore be taken into account for medical-related as well as patient safety-relevant aspects. According to experience, the pharmaceutical supply for these medically needed products (anticoagulants) should be ensured for reasons of patient safety.. The risk of an immunological response to heparin therapy is known. Within the context of increased patient safety, thrombosis prophylaxis should be issued with a risk-adjusted prophylaxis.

Topics: Arginine; Chondroitin Sulfates; Costs and Cost Analysis; Dermatan Sulfate; Germany; Hemorrhage; Heparin; Heparitin Sulfate; Hospitalization; Humans; Pipecolic Acids; Risk Factors; Sulfonamides; Thrombocytopenia; Thrombosis; Treatment Outcome

Topics: Anticoagulants; Antithrombins; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Female; Heparin; Heparitin Sulfate; Humans; Middle Aged; Pipecolic Acids; Practice Guidelines as Topic; Sulfonamides; Thrombocytopenia

Topics: Antibodies; Anticoagulants; Antithrombins; Arthroplasty, Replacement, Knee; Chondroitin Sulfates; Dermatan Sulfate; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Humans; Immunoglobulin G; Male; Middle Aged; Platelet Activation; Platelet Count; Platelet Factor 4; Polysaccharides; Practice Guidelines as Topic; Thrombocytopenia; Venous Thrombosis; Vitamin K

Type II heparin-induced thrombocytopenia is currently managed by withdrawing heparin and replacing it with danaparoid sodium. Argatroban, a direct thrombin inhibitor anticoagulant (like lepirudin), is now authorised for this indication in France, following authorisation in several other countries since the early 2000s. Argatroban has not been compared with danaparoid in clinical trials. About 700 patients treated with argatroban in 2 trials were compared to historical controls managed by simple withdrawal of heparin and, in some cases, switching to an oral anticoagulant. Argatroban had no apparent advantages in terms of death or the need for amputation. Argatroban did not appear to increase the risk of bleeding in these trials, but evidence provided by historical comparisons is weak. The adverse effect profile includes hepatic disorders (notably fulminant hepatitis). The risk of pharmacokinetic interactions appears to below. In practice, given the absence of a proven therapeutic advantage, it is better to continue to use danaparoid for first-line treatment, reserving argatroban for the rare situations in which danaparoid is inappropriate.

Topics: Anticoagulants; Antithrombins; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Drug Interactions; Drug Substitution; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Patient Selection; Pipecolic Acids; Risk Assessment; Risk Factors; Sulfonamides; Thrombocytopenia; Treatment Outcome; Venous Thrombosis

Topics: Anticoagulants; Arginine; Autoantibodies; Chondroitin Sulfates; Dermatan Sulfate; Drug Monitoring; Fondaparinux; Heparin; Heparitin Sulfate; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Platelet Count; Platelet Factor 4; Polysaccharides; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombosis; Warfarin

Thrombocytopenia following heparin administration can be associated with an immune reaction, now referred to as heparin-induced thrombocytopenia (HIT). HIT is essentially a prothrombotic disorder mediated by an IgG antiplatelet factor 4/heparin antibody, which induces platelet, endothelial cell, monocyte, and other cellular activation, leading to thrombin generation and thrombotic complications. Indeed, HIT can also be regarded as a serious adverse drug effect. Importantly, HIT can be a life-threatening and limb-threatening condition frequently associated with characteristically severe and extensive thromboembolism (both venous and arterial) rather than with bleeding. This article provides an overview of HIT, with an emphasis on the clinical diagnosis and management.

Topics: Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Female; Heparin; Heparitin Sulfate; Hirudins; Humans; Male; Monitoring, Physiologic; Peptide Fragments; Pipecolic Acids; Platelet Aggregation Inhibitors; Platelet Count; Prognosis; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Factors; Safety Management; Severity of Illness Index; Sulfonamides; Survival Rate; Thrombocytopenia; Thrombosis; Time Factors

Heparin-induced thrombocytopenia (HIT) is a serious adverse effect of heparin exposure that can progress to severe thrombosis, amputation, or death. HIT is an immune response in which antibodies cause platelet activation, platelet aggregation, the generation of procoagulant platelet microparticles, and activation of leukocytes and endothelial cells. Early diagnosis based on a comprehensive interpretation of clinical and laboratory information is important to improve clinical outcomes. However, limitations of the laboratory assays and atypical clinical presentations can make the diagnosis difficult. Clinical management of patients with HIT is with a non-heparin anticoagulant such as a direct thrombin inhibitor or danaparoid followed by a vitamin K antagonist for long-term treatment. The new anti-factor Xa drugs (fondaparinux, rivaroxaban, apixaban) and other non-heparin antithrombotic agents can potentially be used for the treatment of HIT if clinically validated. Important drug-specific limitations and dosing and monitoring guidelines must be respected for patient safety. Issues still exist regarding the optimal clinical management of HIT.

Topics: Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Enzyme-Linked Immunosorbent Assay; Factor Xa Inhibitors; Heparin; Heparitin Sulfate; Hirudins; Peptide Fragments; Pipecolic Acids; Platelet Factor 4; Platelet Function Tests; Recombinant Proteins; Sulfonamides; Thrombin; Thrombocytopenia

Topics: Ancrod; Anticoagulants; Arginine; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Chondroitin Sulfates; Dermatan Sulfate; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Platelet Aggregation Inhibitors; Recombinant Proteins; Sulfonamides; Thrombocytopenia

To summarize new information on frequency of heparin-induced thrombocytopenia (HIT) in patients treated in intensive care units (ICU), developments in the interpretation of assays for detecting anti-PF4/heparin antibodies, and treatment of HIT patients.. All data on the frequency of laboratory-confirmed HIT in ICU patients were included; for laboratory testing of HIT and treatment of patients, this review focuses on recent data that became available in 2005 and 2006.. HIT is a potentially life-threatening adverse effect of heparin treatment caused by platelet-activating antibodies of immunoglobulin G class usually recognizing complexes of platelet factor 4 and heparin. HIT is more often caused by unfractionated heparin than low-molecular-weight heparin and is more common in postsurgical than in medical patients. In the ICU setting, HIT is uncommon (0.3-0.5%), whereas thrombocytopenia from other causes is very common (30-50%). For laboratory diagnosis of HIT antibodies, both antigen assays and functional (platelet activation) assays are available. Both tests are very sensitive (high negative predictive value) but specificity is problematic, especially for the antigen assays, which also detect nonpathogenic immunoglobulin M and immunoglobulin A class antibodies. Detection of immunoglobulin M or immunoglobulin A antibodies could potentially lead to adverse events such as bleeding if a false diagnosis of HIT prompts replacement of heparin by an alternative anticoagulant. For treatment of HIT, three alternative anticoagulants are approved: the direct thrombin inhibitors, lepirudin and argatroban, and the heparinoid, danaparoid (not approved in the United States). Recent data indicate that the approved dosing regimens of the direct thrombin inhibitors are too high, especially in ICU patients.. HIT affects <1% of ICU patients even though 30-50% develop thrombocytopenia. The choice of the optimal alternative anticoagulant depends on patient characteristics. Many ICU patients require lower doses of alternative anticoagulant than those recommended by the manufacturer.

Topics: Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Extracorporeal Circulation; Heparin; Heparitin Sulfate; Hirudins; Humans; Intensive Care Units; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombin; Thrombocytopenia; Thrombosis

World wide, heparins are the most commonly used anticoagulants for renal replacement therapy (RRT). In the intensive care unit (ICU) keeping the RRT circuit patent is more difficult than during routine outpatient hemodialysis, as ICU patients typically have sepsis and/or inflammation resulting in activation of the procoagulant pathways, with reduced antithrombin. One important cause of repeated RRT circuit clotting is heparin-induced thrombocytopenia (HIT), which should not be overlooked in patients with a reduced platelet count. If HIT is clinically suspected then all heparins should be withdrawn, and the patient systemically anticoagulated with either a direct thrombin inhibitor, such as argatroban and/or hirudin, or the heparinoid danaparoid. The availability and licensing of these alternative anticoagulants varies from country to country. Argatroban has to be continuously infused, which is an advantage for continuous RRT, but not for intermittent RRT, and can be monitored by activated partial thromboplastin time. Hirudin has a prolonged half life, which is extended by hirudin antibodies, and requires specialist monitoring to prevent over anticoagulation. Although the half life of danaparoid is increased in renal failure, it can be given as boluses for intermittent and continuous RRT, or by continuous infusion during continuous RRT, but requires factor Xa monitoring.

Topics: Acute Kidney Injury; Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Extracorporeal Circulation; Heparin; Heparitin Sulfate; Hirudin Therapy; Humans; Intensive Care Units; Pipecolic Acids; Renal Replacement Therapy; Sulfonamides; Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) and heparin induced thrombocytopenia with thrombosis (HITT) ar rare complications associated with use of unfractionate heparin (UFH) or low-molecular-weight heparin (LMWH) HIT is a benign clinical condition characterized by a mil drop in platelet count with no clinical significance. HIT is an immune-mediated reaction associated with a wide spread "hypercoagulable" state resulting in arterial an venous thrombosis. There is a higher incidence of HIT with UFH use than with LMWH use. Orthopedic surger patients are at higher risk for developing HITT than are patients who receive prophylactic heparin for cardiovascular surgery or medical reasons. Therapy for patients suspected of having HITT should begin with immedi ate discontinuation of heparin in any form followed by pharmacologic inhibition with thrombin (e.g., recombinant hirudin [lepirudin], argatroban, danaparoid sodium).

Topics: Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Heparin; Heparitin Sulfate; Hirudins; Humans; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombosis

Heparin-induced thrombocytopenia (HIT) is a potentially devastating immune mediated adverse drug reaction caused by the emergence of antibodies that activate platelets in the presence of heparin. Despite thrombocytopenia, bleeding is rare; rather, HIT is strongly associated with thromboembolic complications involving both the arterial and venous systems. A number of laboratory tests are available to confirm the diagnosis; however, when HIT is clinically suspected, treatment should not be withheld pending the result. Fortunately, therapeutic strategies have been refined, and new and effective therapeutic agents are available. Treatment options are focused on inhibiting thrombin formation or direct thrombin inhibition. Warfarin should not be used until the platelet count has recovered.

Topics: Anticoagulants; Arginine; Cardiovascular Surgical Procedures; Chondroitin Sulfates; Dermatan Sulfate; Fibrinolytic Agents; Hemorrhage; Heparin; Heparitin Sulfate; Hirudins; Humans; Pipecolic Acids; Recombinant Proteins; Renal Dialysis; Sulfonamides; Thrombocytopenia; Warfarin

Accomplishing a successful percutaneous coronary intervention in a patient with a suspected or diagnosed heparin-induced thrombocytopenia (HIT) requires the selection of an appropriate alternative anticoagulant and a thorough assessment of bleeding and thrombotic risks. In this review, we suggest an evidence-based management algorithm that takes into account the clinical phase of HIT (acute, recent, and remote HIT) and the associated risk when patients present with acute coronary syndrome. The algorithm also integrates preventive measures directed at decreasing the bleeding risk associated with the antithrombotic and invasive therapies used for HIT and percutaneous coronary intervention.

Topics: Algorithms; Angioplasty, Balloon, Coronary; Anticoagulants; Arginine; Chondroitin Sulfates; Comorbidity; Dermatan Sulfate; Drug Therapy, Combination; Fibrinolytic Agents; Fondaparinux; Heparin; Heparinoids; Heparitin Sulfate; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Sulfonamides; Syndrome; Thrombocytopenia; Vitamin K

Heparin induced thrombocytopenia (HIT) in addition to bleeding complications are the most serious and dangerous side effects of heparin treatment. HIT remains the most common antibody-mediated, drug-induced thrombocytopenic disorder and a leading cause of morbidity and mortality. Two types of HIT are described: Type I is a transitory, slight and asymptomatic reduction of platelet count occurring during 1-2 days of therapy. HIT type II, which has an immunologic origin, is characterized by a thrombocytopenia that generally onset after the fifth day of therapy. Despite thrombocytopenia, haemorrhagic complications are very rare and HIT type II is characterized by thromboembolic complications consisting in venous and arterial thrombosis. The aim of this paper is to review new aspects of epidemiology, pathophysiology, clinical features, diagnosis and therapy of HIT type II. There is increasing evidence that platelet factor 4 (PF4) displaced from endothelial cells, heparan sulphate or directly from the platelets, binds to heparin molecule to form an immunogenic complex. The anti-heparin/PF4 IgG immune-complexes activates platelets through binding with the Fcgamma RIIa (CD32) receptor inducing endothelial lesions with thrombocytopenia and thrombosis. Cytokines are generated during this process and inflammation could play an additional role in the pathogenesis of thromboembolic manifestations. The onset of HIT type II is independent from dosage, schedule, and route of administration of heparin. A platelet count must be carried out prior to heparin therapy. Starting from the fourth day, platelet count must be carried out daily or every two days for at least 20 days of any heparin therapy regardless of the route of the drug administration. Patients undergoing orthopaedic or cardiac surgery are at higher risk for HIT type II. The diagnosis of HIT type II should be formulated on basis of clinical criteria and confirmed by in vitro demonstration of heparin-dependent antibodies detected by functional and antigen methods. However, the introduction of sensitive ELISA tests to measure anti-heparin/PF4 antibodies has showed the immuno-conversion in an higher number of patients treated with heparin such as the incidence of anti-heparin/PF4 exceeds the incidence of the disease. If HIT type II is likely, heparin must be immediately discontinued, even in absence of certain diagnosis of HIT type II, and an alternative anticoagulant therapy must be started followed by oral dicuma

Topics: Animals; Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Heparin; Heparitin Sulfate; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Postoperative Complications; Recombinant Proteins; Sulfonamides; Thrombocytopenia

Hemorrhage is the most common and best-recognized complication of heparin treatment. However, a potentially more dangerous complication is the development of heparin-induced thrombocytopenia (HIT). All patients exposed to heparin, irrespective of the dose and route of administration, are at risk of developing HIT. It is due to the formation of antibodies against the heparin-platelet factor 4 complex, which cause secondary activation of platelets, coagulation and, finally, increased thrombin production. The main symptom is the sudden onset of thrombocytopenia involving a drop in the platelet count to less than 50% of the basal level, with or without the appearance of thrombotic complications some 5 to 14 days after the start of heparin therapy. Heparin-induced thrombocytopenia can be detected early in patients receiving heparin by monitoring the platelet count. Demonstration of heparin-dependent platelet activation using an antigen or functional assay confirms the clinical diagnosis. Once the diagnosis of HIT has been confirmed serologically or there is a high level of suspicion of HIT, heparin must be suspended and treatment with an alternative anticoagulant should be considered. This review contains a discussion of the diagnosis and treatment of this syndrome.

Topics: Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Fibrinolytic Agents; Fondaparinux; Heparin; Heparitin Sulfate; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Sulfonamides; Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is an antibody-mediated syndrome associated with heparin exposure, a falling platelet count and a high risk of thrombosis. Cardiovascular patients are at increased risk of HIT due to wide use of heparin in this population. Should HIT be suspected, heparin must be avoided in most situations, and anticoagulation with an alternative anticoagulant should be instituted. Preferred agents include the direct thrombin inhibitors argatroban and lepirudin, whilst bivalirudin or desirudin (other direct thrombin inhibitors) can be used in some situations. The indirect thrombin inhibitors, danaparoid and fondaparinux, can also be considered at times. These agents and their use in cardiac patients, including patients with acute coronary syndrome, percutaneous coronary interventions, acute ST elevation myocardial infarction or cardiac surgery, will be reviewed.

Topics: Angioplasty, Balloon, Coronary; Anticoagulants; Arginine; Cardiovascular Diseases; Chondroitin Sulfates; Dermatan Sulfate; Drug Administration Schedule; Factor Xa Inhibitors; Fondaparinux; Heparin; Heparitin Sulfate; Hirudins; Humans; Pipecolic Acids; Polysaccharides; Postoperative Complications; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Recombinant Proteins; Sulfonamides; Thrombin; Thrombocytopenia

Clinical outcomes of 1,478 danaparoid treatment case reports for HIT (involving 1,418 patients) treated between 1982 and mid-2004 are analysed. Treatment in 1,291 episodes was for current HIT. Thromboembolism due to HIT was present in 39.4%. The patients include 33 children and 32 pregnancies. Two hundred twenty-six patients required extra-corporeal circuit use for renal failure, 241 patients had a concomitant thrombophilic disorder, and 351 major operations were performed. Clinical outcomes were assessed during danaparoid treatment (range one day to 3.5 years) plus three months of follow-up. Of the danaparoid-treated patients 83.8% survived; 63.7% had no or minor adverse events and 20.1% suffered serious non-fatal adverse events. New thromboses occurred during 9.7% of treatment episodes, and 16.4% of treatment episodes had an inadequate treatment response (i. e. developed one or more of the following: new/extended thrombosis, persistent/new platelet count reduction, unplanned amputation during treatment and follow-up). Major bleeding was reported in 8.1% of treatment episodes. Clinical cross-reactivity of danaparoid (new/persistent platelet count reduction and/or new/extended thrombosis) was confirmed serologically in 23 of 36 patients with positive pretreatment serological danaparoid cross-reactivity and in 22 of 32 additional patients tested at the time of the new event, i.e. a total of 45 patients (3.2%). Clinical outcomes of these case reports of patients given danaparoid because of suspected or confirmed HIT appear to be comparable with those reported by others who used direct thrombin inhibitors, especially when a sufficient danaparoid dosing intensity was used in patients with isolated HIT. Post-operative bleeding limits danaparoid use for cardiopulmonary by-pass surgery. Routine clinical and platelet count monitoring are required to minimise adverse reactions due to cross-reactivity.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Anticoagulants; Child; Child, Preschool; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Drug Administration Schedule; Exanthema; Female; Fibrinolytic Agents; Heparin; Heparitin Sulfate; Humans; Infant; Male; Middle Aged; Postoperative Hemorrhage; Practice Guidelines as Topic; Thrombocytopenia; Thromboembolism

Topics: Anticoagulants; Arginine; Cardiac Surgical Procedures; Cardiovascular Diseases; Chondroitin Sulfates; Dermatan Sulfate; Diagnosis, Differential; Fondaparinux; Heparin; Heparitin Sulfate; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Platelet Aggregation Inhibitors; Platelet Factor 4; Polysaccharides; Recombinant Proteins; Sensitivity and Specificity; Sulfonamides; Thrombocytopenia; Thrombosis

Thrombocytopenia is a common occurrence in critical illness, reported in up to 41% of patients. Systematic evaluation of thrombocytopenia in critical care is essential to accurate identification and management of the cause. Although sepsis and hemodilution are more common etiologies of thrombocytopenia in critical illness, heparin-induced thrombocytopenia (HIT) is one potential etiology that warrants consideration.. This review will summarize the pathogenesis and clinical consequences of HIT, describe the diagnostic process, and review currently available treatment options.. MEDLINE/PubMed search of all relevant primary and review articles.. HIT is a clinicopathologic syndrome characterized by thrombocytopenia (>/=50% from baseline) that typically occurs between days 5 and 14 after initiation of heparin. This temporal profile suggests a possible diagnosis of HIT, which can be supported (or refuted) with a strong positive (or negative) laboratory test for HIT antibodies. When considering the diagnosis of HIT, critical care professionals should monitor platelet counts in patients who are at risk for HIT and carefully evaluate for, a) temporal features of the thrombocytopenia in relation to heparin exposure; b) severity of thrombocytopenia; c) clinical evidence for thrombosis; and d) alternative etiologies of thrombocytopenia. Due to its prothrombotic nature, early recognition of HIT and prompt substitution of heparin with a direct thrombin inhibitor (e.g., argatroban or lepirudin) or the heparinoid danaparoid (where available) reduces the risk of thromboembolic events, some of which may be life-threatening.

Topics: Anticoagulants; Arginine; Chondroitin Sulfates; Clinical Trials as Topic; Critical Care; Dermatan Sulfate; Heparin; Heparinoids; Heparitin Sulfate; Hirudins; Humans; Pipecolic Acids; Platelet Count; Recombinant Proteins; Risk Factors; Sulfonamides; Thrombin; Thrombocytopenia

There has been a recent change in the management guidelines for patients with heparin-induced thrombocytopenia with the addition of a recommendation to commence parenteral anticoagulation in patients with isolated HIT without evidence of thrombosis. We assessed the evidence supporting this recommendation, to answer the following questions: in a patient with isolated HIT, should alternative anticoagulation be commenced, what alternative agent should be used, what is the recommended duration of anticoagulation, and when should warfarin be used?. We searched MEDLINE (using keywords "heparin-induced thrombocytopenia", "heparin induced thrombocytopaenia", "HIT" and "HITTS") and PubMed (using MeSH terms "thrombocytopenia" and "heparin") from 1966 to 2006 and selected articles for further assessment according to specified criteria.. We assessed 12 non-randomised studies, five large case series and multiple small case series.. Although patients with isolated HIT are at considerable risk of new thrombosis, there is limited evidence to support or reject the use of non-heparin anticoagulation in this group. Non-randomised, historically controlled trials support the use of lepirudin and argatroban; evidence favouring danaparoid is limited to large case series and one retrospective observational study. Duration of parenteral anticoagulation and warfarin use are guided by consensus opinion alone.

Topics: Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Evidence-Based Medicine; Heparin; Heparitin Sulfate; Hirudins; Humans; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombocytopenia

Pregnant patients with acute venous thrombosis or a history of thrombosis may need alternative anticoagulation, when heparin intolerance occurs. Only limited data on the use of the heparinoid danaparoid are available in literature. We reviewed the use of danaparoid in 51 pregnancies of 49 patients identified in literature between 1981 and 2004. All patients had developed heparin intolerance (32 due to heparin-induced thrombocytopenia, 19 mainly due to heparin-induced skin rashes) and had a current and/or past history of thromboembolic complications. The initial danaparoid dose regimens ranged from 1000 to 7500 U/day administered s.c. or i.v.. The median duration of danaparoid use was 10 weeks. Danaparoid was used until delivery of a healthy infant in 37 pregnancies. In the remaining 14 pregnancies it was stopped earlier, because anticoagulant treatment was no longer required (3/14) or an adverse event led to a treatment discontinuation (11/14). Four maternal bleeding events were recorded during pregnancy, delivery or postpartum, two of them were fatal due to placental problems. Three fetal deaths were recorded, all associated with maternal complications antedating danaparoid use. Danaparoid cross-reactivity was suspected in 4 HIT patients and 5 non-HIT patients with skin reactions and was confirmed serologically in one of the two HIT patients tested. In none of five fetal cord blood- and three maternal breast milksamples anti-Xa activity transfer was observed. In conclusion danaparoid can be used as an alternative antithrombotic agent in pregnant women with high thrombotic risk and intolerance to heparins.

Topics: Adult; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Drug Evaluation; Drug Hypersensitivity; Exanthema; Female; Hemorrhage; Heparin; Heparitin Sulfate; Humans; MEDLINE; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Retrospective Studies; Thrombocytopenia; Thrombosis

For patients with heparin-induced thrombocytopenia (HIT), reexposure to heparin is generally not recommended. However, these patients are likely to require anticoagulation therapy at some point in the future. During acute HIT, when thrombocytopenia and anti-heparin-platelet factor 4 antibodies (or HIT antibodies) are present, therapy with heparin must be avoided. In patients with subacute HIT, when platelets have recovered but HIT antibodies are still present, therapy with heparin should be avoided. In patients with a remote history of HIT, when HIT antibodies have cleared, heparin reexposure may be safe, although recurrent HIT has been described in some patients. For all of these patients, the use of alternate anticoagulant agents, including direct thrombin inhibitors and anti-Xa agents, is preferable. There is an increasing amount of data supporting the use of these alternative agents in a wide variety of clinical circumstances, including thromboprophylaxis and treatment of acute thrombosis. Except for a few clinical situations, it is generally possible to avoid heparin reexposure in patients with a history of HIT.

Topics: Angina, Unstable; Antibodies; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Female; Fondaparinux; Heparin; Heparitin Sulfate; Hirudins; Humans; Male; Multiple Organ Failure; Platelet Factor 4; Polysaccharides; Pregnancy; Preoperative Care; Recombinant Proteins; Thrombin; Thrombocytopenia; Venous Thrombosis

Recommendations for transitioning from therapy with heparin or a low-molecular-weight heparin preparation to therapy with an oral anticoagulant in patients with acute venous or arterial thromboembolism have undergone several changes during the last two decades. Physicians are now comfortable with beginning treatment with an oral anticoagulant once the diagnosis is confirmed, and loading doses are no longer considered to be necessary. Exceptions to early transition may be necessary in patients with an extensive iliofemoral or axillary-subclavian vein thrombosis or pulmonary embolism where thrombolytic agents may be indicated, or in individuals who require surgery or other invasive procedures, or if there are concerns about bleeding. The avoidance of early transition to oral anticoagulants in patients with acute heparin-induced thrombocytopenia also has been advised because of the potential for further thrombotic complications, including venous limb gangrene and warfarin-induced skin necrosis.

Topics: Administration, Oral; Anticoagulants; Arginine; Blood Coagulation; Blood Coagulation Factors; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Gangrene; Heparin; Heparitin Sulfate; Hirudins; Humans; Ischemia; Leg; Necrosis; Pipecolic Acids; Recombinant Proteins; Skin; Sulfonamides; Thrombocytopenia; Thrombosis; Warfarin

Heparin-induced thrombocytopenia (HIT) is caused by heparin-dependent, platelet-activating IgG antibodies that increase thrombin generation in vivo, producing a prothrombotic phenotype. In addition to platelet activation, there is in vitro evidence that activation of endothelium and monocytes occurs, perhaps directly by HIT antibodies, but more likely through activated platelet (or microparticle)-endothelial-leukocyte interactions. Patients with cardiac disease receiving heparin present important diagnostic and therapeutic issues when unexpected thrombocytopenia arises. Concomitant vascular disease burden and intravascular catheter use further increase risk of HIT-associated arterial thrombosis in this patient population. Whether arterial thrombosis simply reflects the "hypercoagulability state" of HIT interacting with diseased or injured arteries, or whether arterial "white clots" reflect additional prothrombotic effects of HIT via endothelial and monocyte activation, remains uncertain. Patients with HIT can also develop deep-vein thrombosis, which can progress to limb loss if coumarin (warfarin) leads to severe protein C depletion (coumarin-induced venous limb gangrene). Therapy for patients strongly suspected to have HIT should focus on inhibiting thrombin (or its generation) pharmacologically. Two direct thrombin inhibitors (lepirudin, argatroban) are approved for treating HIT. When using these agents, coumarin anticoagulation should be delayed pending substantial resolution of thrombocytopenia, before cautiously introducing overlapping coumarin therapy.

Topics: Antibodies; Anticoagulants; Cardiovascular Diseases; Coumarins; Heparin; Heparitin Sulfate; Humans; Immunoglobulin G; Models, Biological; Monocytes; Phenotype; Platelet Activation; Platelet Factor 4; Thrombin; Thrombocytopenia; Thrombosis

Topics: Anticoagulants; Antithrombins; Arginine; Blood Coagulation; Blood Coagulation Tests; Chondroitin Sulfates; Critical Care; Dermatan Sulfate; Drug Combinations; Drug Costs; Drug Monitoring; Heparin; Heparitin Sulfate; Hirudins; Humans; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombocytopenia

Several counterintuitive treatment paradoxes complicate the management of immune heparin-induced thrombocytopenia (HIT). For example, simple discontinuation of heparin often fails to prevent subsequent HIT-associated thrombosis. Thus, current treatment guidelines recommend substituting heparin with a rapidly acting alternative anticoagulant (eg, danaparoid, lepirudin, or argatroban) even when HIT is suspected on the basis of thrombocytopenia alone ("isolated HIT"). Another paradox-coumarin (warfarin) anticoagulation-can lead to venous limb gangrene in a patient with HIT-associated deep-vein thrombosis. Thus, warfarin is not recommended during acute thrombocytopenia secondary to HIT. However, warfarin can be given as overlapping therapy with an alternative anticoagulant, provided that (1) initiation of warfarin is delayed until substantial platelet count recovery has occurred (to at least above 100 x 10(9)/L); (2) low initial doses of warfarin are used; (3) at least 5 days of overlapping therapy are given; and (4) the alternative agent is maintained until the platelet count has normalized. It has recently been recognized that HIT antibodies are transient and usually do not recur upon subsequent re-exposure to heparin. This leads to a further paradox-patients with previous HIT can be considered for a brief re-exposure to heparin under exceptional circumstances; for example, heart surgery requiring cardiopulmonary bypass, if HIT antibodies are no longer detectable using sensitive assays. For patients with acute or recent HIT who require urgent heart surgery, other approaches include use of alternative anticoagulants (eg, lepirudin or danaparoid) for cardiopulmonary bypass or antiplatelet agents (eg, tirofiban or epoprostenol) to permit intraoperative use of heparin.

Topics: Anticoagulants; Antithrombins; Arginine; Autoimmune Diseases; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Heparin; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Warfarin

Because patients with heparin-induced thrombocytopenia (HIT) have an extremely high frequency of developing thrombosis, treatment options other than heparin are essential. Prophylaxis against thrombosis should also be considered. The current American College of Chest Physicians guidelines for the treatment of acute heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) include the use of danaparoid, lepirudin or argatroban, alone or in combination with warfarin. For documented clinical thrombosis associated with HIT, patients should be treated with a direct thrombin inhibitor at therapeutic activated partial thromboplastin time for 7 to 10 days. Warfarin should not be used during the acute phase of HIT, unless a thrombin inhibitor is being used simultaneously. Conversion to warfarin can be done when the acute phase of HIT has passed. Due to the high likelihood of cross-reactivity, the use of low molecular weight heparins in patients with HIT is not recommended. For prophylactic treatment of HIT patients, despite a lack of other indications for anticoagulation, a direct thrombin inhibitor can be initiated with a low level of anticoagulation until the thrombocytopenia resolves. This regimen is continued until laboratory evidence is provided that the HIT antibody is no longer detectable. HIT patients, in addition to needing anticoagulation to treat thrombosis, can require anticoagulation for non HIT-related events, such as for the treatment of myocardial infarction, unstable angina and long-term anticoagulation for heart valves or atrial fibrillation. For these situations, and if immediate anticoagulation is needed, the use of a direct thrombin inhibitor with switch-over to warfarin is a useful option. However, optimal dosing regimens have not been established in all cases.

Topics: Animals; Anticoagulants; Antithrombins; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Fibrinolytic Agents; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudins; Humans; Pipecolic Acids; Platelet Aggregation Inhibitors; Recombinant Proteins; Sulfonamides; Thrombocytopenia

Danaparoid (danaparoid sodium) is a low molecular weight heparinoid which has undergone clinical study for use as continued anticoagulant therapy in patients with heparin-induced thrombocytopenia (HIT), for the prophylaxis and treatment of deep vein thrombosis (DVT), and for the treatment of disseminated intravascular coagulation (DIC). A nonblind study in patients with HIT has reported that complete clinical resolution is significantly more likely in patients receiving danaparoid than in patients receiving dextran 70. In addition, retrospective analyses and noncomparative data support the use of danaparoid for continued anticoagulant therapy in patients with HIT. Studies in patients undergoing hip surgery have shown that danaparoid significantly reduces the incidence of postoperative DVT compared with aspirin, warfarin, dextran 70 and heparin-dihydroergotamine, while additional data suggest no difference between danaparoid, enoxaparin and dalteparin. In patients undergoing abdominal or thoracic surgery for removal of a malignancy, danaparoid reduced the incidence of postoperative DVT compared with placebo, but showed no significant difference when compared with unfractionated heparin (UFH). Two studies have compared danaparoid with UFH in the prophylaxis of DVT following acute ischaemic stroke; twice daily danaparoid was significantly superior to UFH whereas there was no significant difference between a once-daily dosage and UFH. Danaparoid did not differ from UFH in terms of efficacy in the treatment of existing DVT. In all comparative studies examining the efficacy of danaparoid in the prophylaxis or treatment of DVT (versus warfarin, dextran 70, enoxaparin, dalteparin, aspirin, heparin-dihydroergotamine, UFH and placebo), the incidence of haemorrhagic complications did not differ between treatment groups. In patients with DIC, 61.9% of those patients receiving danaparoid experienced either disappearance or reduction of symptoms of DIC whereas 62% of those receiving UFH showed either no change or aggravation of their symptoms. There was no significant difference between treatment groups in tolerability or overall improvement of DIC.. Danaparoid is an effective anticoagulant agent which has undergone clinical evaluation in a wide range of disease indications. Current guidelines support the use of danaparoid in prophylaxis of DVT following ischaemic stroke, and in patients who develop HIT. Danaparoid has shown efficacy in DIC, and for DVT prophylaxis in patients undergoing hip surgery although further data are required to establish the role of danaparoid in these indications. In particular, double-blind trials comparing danaparoid with such recommended therapies as the low molecular weight heparins will provide more definitive data on the place of danaparoid in the clinical management of these conditions and ultimately lead to improved patient outcomes.

Topics: Anticoagulants; Biological Availability; Chondroitin Sulfates; Dermatan Sulfate; Disseminated Intravascular Coagulation; Drug Combinations; Heparitin Sulfate; Humans; Injections, Intravenous; Injections, Subcutaneous; Randomized Controlled Trials as Topic; Thrombocytopenia; Treatment Outcome; Venous Thrombosis

Heparin-induced thrombocytopenia (HIT), a serious side effect of heparin treatment, requires alternative anticoagulation in most affected patients. The recombinant hirudin (r-hirudin) lepirudin has been approved for this purpose after two prospective trials in laboratory-confirmed HIT patients. Other drugs available for this purpose are danaparoid sodium (a heparinoid) and argatroban, a synthetic direct thrombin inhibitor. In this article, recommendations for optimal use of r-hirudin in HIT are given, covering therapy in uncomplicated patients as well as in special situations such as heparin reexposure of HIT patients. Because lepirudin's half-life depends on renal function, it may vary between 1 and 200 hours, which requires individual dose adjustments. Lepirudin compares favorably with danaparoid, based on retrospective data. No direct comparisons of lepirudin with argatroban are available, but argatroban might offer advantages in patients with renal failure, because it is mainly eliminated hepatically. Major hemorrhage, the main risk of lepirudin treatment, occurring in about 15% of patients, makes close monitoring important. New monitoring tools, such as the ecarin clotting time (ECT), might further reduce bleeding risks. Antihirudin antibodies, which can alter the pharmacokinetics as well as the pharmacodynamics of hirudin, can also be countered by close monitoring and appropriate dose adjustments. Whereas hirudins have not yet managed to gain importance in non-HIT indications such as unstable coronary syndromes, they have a major role to play in the treatment of HIT. The choice between the available drugs for HIT, namely lepirudin, danaparoid, and argatroban, has to be made according to the clinical presentation of the patient.

Topics: Anticoagulants; Antithrombins; Arginine; Blood Coagulation; Chondroitin Sulfates; Clinical Trials as Topic; Dermatan Sulfate; Drug Combinations; Fibrinolytic Agents; Heparin; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombosis; Time Factors

Heparin-induced thrombocytopenia (HIT) appears rarely in pregnant patients who are being treated with heparin. When HIT is suspected, heparin treatment should be discontinued and alternative anticoagulation should be started. The heparinoid danaparoid appears to be the drug of choice for acute treatment and prophylaxis because of its low placental permeability. Between the 12th and 36th weeks of pregnancy, either danaparoid may be continued or warfarin may be used after recovery of platelet counts. Before and during delivery, danaparoid should be preferred over warfarin in order to avoid bleeding complications in mother and infant. Hirudin should only be used when either cross-reactivity with heparin-induced antibodies or cutaneous allergy against heparinoids are observed. Postpartum warfarin seems to be the treatment of choice because breast-feeding can be continued. Alternative treatment with either danaparoid or hirudin is possible, but data on treatment with these reagents in lactating mothers are very limited.

Topics: Adult; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Female; Heparin; Heparitin Sulfate; Humans; Lactation; Pregnancy; Pregnancy Complications; Thrombocytopenia; Warfarin

To describe heparin-induced thrombocytopenia (HIT or HIT-2), an immune-mediated adverse reaction to heparin or low-molecular-weight heparin. Available treatment options and considerations in developing a therapy approach are discussed.. A search of the National Library of Medicine (1992-June 2001) was done to identify pertinent literature. Additional references were reviewed from selected articles.. Articles related to laboratory recognition and treatment options of HIT, including the use of agents in selected clinical conditions, were reviewed and included.. HIT is a rare but potentially severe adverse reaction to heparin that was, until recently, poorly understood and had limited treatment options. Recent advances describing the recognition and clinical manifestations of immune-mediated HIT, including recently available antithrombotic treatment options, have dramatically changed outcomes for patients having this syndrome.

Topics: Animals; Anticoagulants; Arginine; Chondroitin Sulfates; Clinical Trials as Topic; Coronary Disease; Dermatan Sulfate; Drug Combinations; Female; Heparin; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Pipecolic Acids; Pregnancy; Rabbits; Recombinant Proteins; Sulfonamides; Thrombocytopenia

Review of the frequency, clinical and biological features and treatment of type II heparin-induced thrombocyopenia.. Case report and literature review.. A 65 years old woman received as antithrombotic prophylaxis low molecular weight heparin (LMWH) after prosthetic knee replacement. Day 8, asymptomatic deep vein thrombosis was discovered after systematic echodoppler examination. Curative anticoagulation was started with LMWH. A fall in the platelet count (17 G/L) was noted day 12. Danaparoid was immediately introduced and heparin discontinued. However, day 16 a massive pulmonary embolism occurred which required transfer to an intensive care unit. Danaparoid was changed for lepirudin the same day. It took longer than three weeks for platelet count to return to normal value after heparin discontinuation. The suspicion of heparin-induced thrombocyopenia was confirmed by specific tests.. HIT type II are rare but life-threatening and thrombosis events are the most frequent complications. The diagnosis is a high probability proved by both clinical and biological patterns. The treatment consists in alternative thrombin inhibitors such as danaparoid and lepirudin. The platelet count usually requires less than ten days to recover normal values after heparin withdrawal. Cases in which the delay to a normal platelet count exceeds 3 weeks have been reported specially after LMWH therapy.. Type II HIT are rare but life-threatening events can occur. The platelet count check-up during heparin therapy must be systematic.

Topics: Aged; Anticoagulants; Arthroplasty, Replacement, Knee; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Female; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Humans; Thrombocytopenia; Thrombosis

Most patients with heparin-induced thrombocytopenia (HIT), a serious adverse effect of heparin mediated by platelet-activating heparin-dependent antibodies, require alternative anticoagulation. This is because HIT is highly prothrombotic and is characterized by markedly increased thrombin generation. Unfractionated heparins seem to induce HIT more often than low molecular weight heparins. There are three anticoagulants for which there is an emerging consensus for their efficacy in management of HIT, and which are currently approved for treatment of HIT in several countries: the recombinant hirudin, lepirudin, a direct thrombin inhibitor; the synthetic direct thrombin inhibitor, argatroban; and the heparinoid, danaparoid sodium, mainly exhibiting antifactor-Xa activity. Recommendations for optimal use of these drugs in HIT are given in this review stressing the need for immediate treatment of patients with HIT without awaiting laboratory diagnosis. Hirudin, the drug for which most data from prospective trials exists, can be safely and effectively used in patients with HIT, its dramatically increased elimination half-life in patients with renal failure being the most important drawback. Argatroban, which is mainly eliminated by the liver, could be used preferentially in such patients with renal impairment. Interference with the international normalized ratio makes oral anticoagulation, which is necessary in many patients with HIT, problematic. Activated partial thromboplastin time is sufficient to monitor lepirudin and argatroban treatment in most cases. Danaparoid sodium, with an antifactor-X activity half-life of about 24 hours seems to be best suited for thrombosis prophylaxis in patients with HIT. In some patients monitoring by determining antifactor-Xa activity is necessary. No antidote is available for any of the drugs discussed, and bleeding complications are the most important adverse effects. In situations such as hemodialysis or cardiopulmonary bypass, not only the characteristics of the drug in use itself, but also availability of monitoring methods play an important role. Adjunctive treatments have not been systematically evaluated and should be used cautiously. Recent data suggest that re-exposure of patients with a history of HIT with heparin, for example during cardiopulmonary bypass, can be well tolerated provided no circulating HIT antibodies are detectable at the time of re-exposure, and heparin is strictly avoided pre- and postoperatively

Topics: Animals; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Heparin; Heparitin Sulfate; Hirudin Therapy; Humans; Thrombin; Thrombocytopenia; Thrombosis

We report the case of a patient who underwent two cardiopulmonary bypass (CPB) procedures with Orgaran because of heparin-induced thrombocytopenia. A 38 years-old man with ischemic mitral insufficiency was operated for coronary artery bypass and valvular replacement. The CPB was carried out with heparin. Heparin-induced thrombocytopenia occured and was proven immunologically. Two months later, a new valvular replacement was performed because of paravalvular leak due to endocarditis. The Orgaran-CPB protocol was as follows: 5,000 units before cardiopulmonary bypass, 5,000 units in the priming volume, anti-Xa level between 0.9 and 1.1 units/mL, with injection of 1,500 units if necessary, no administration of protamine. One month later, a new valvular replacement was necessary and performed with the same protocol using Orgaran. No bleeding or thrombotic complication occurred. Orgaran is a safe and reliable anti-thrombotic substitute if anti-Xa activity is closely monitored.

Topics: Adult; Anticoagulants; Cardiopulmonary Bypass; Chondroitin Sulfates; Coronary Artery Bypass; Dermatan Sulfate; Endocarditis; Heart Valve Prosthesis; Heart Valve Prosthesis Implantation; Heparin; Heparin Antagonists; Heparitin Sulfate; Humans; Male; Mitral Valve Insufficiency; Prosthesis Failure; Protamines; Reoperation; Thrombocytopenia; Treatment Outcome

Despite the progress made in the development of cardiopulmonary bypass (CPB) equipment, systemic anticoagulation with unfractionated heparin and post-bypass neutralization with protamine are still used in most perfusion procedures. However, there are a number of situations where unfractionated heparin, protamine or both cannot be used for various reasons. Intolerance of protamine can be addressed with extracorporeal heparin removal devices, perfusion with (no) low systemic heparinization and, to some degree, by perfusion with alternative anticoagulants. Various alternative anticoagulation regimens have been used in cases of intolerance to unfractionated heparin, including extreme hemodilution, low molecular weight heparins, danaparoid, ancrod, r-hirudin, abciximab, tirofiban, argatroban and others. In the presence of heparin-induced thrombocytopenia (HIT) and thrombosis, the use of r-hirudin appears to be an acceptable solution which has been well studied. The main issue with r-hirudin is the difficulty in monitoring its activity during CPB, despite the fact that ecarin coagulation time assessment is now available. A more recent approach is based on selective blockage of platelet aggregation by means of monoclonal antibodies directed to GPIIb/IIIa receptors (abciximab) or the use of a GPIIb/IIIa inhibitor (tirofiban). An 80% blockage of the GPIIb/IIIa receptors and suppression of platelet aggregation to less than 20% allows the giving of unfractionated heparin and running CPB in a standard fashion despite HIT and thrombosis. Likewise, at the end of the procedure, unfractionated heparin is neutralized with protamine as usual and donor platelets are transfused if necessary. GPIIb/IIIa inhibitors are frequently used in interventional cardiology and, therefore, are available in most hospitals.

Topics: Abciximab; Ancrod; Antibodies, Monoclonal; Anticoagulants; Arginine; Cardiopulmonary Bypass; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Drug Combinations; Drug Hypersensitivity; Factor Xa Inhibitors; Hemodilution; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudin Therapy; Humans; Immunoglobulin Fab Fragments; Perfusion; Pipecolic Acids; Platelet Aggregation Inhibitors; Protamines; Sulfonamides; Thrombocytopenia; Thrombophilia; Thrombosis; Tirofiban; Tyrosine

The numerous drugs to which the acutely ill are exposed place these patients at a significant risk of developing drug-induced thrombocytopenia. Such patients tend to have preexisting hemostatic defects that place them at additional risk of complications as a result of the drug-induced thrombocytopenia. The clinical challenge is to provide rapid identification and removal of the offending agent before clinically significant bleeding or, in the case of heparin, thrombosis results. Drug-induced thrombocytopenic disorders can be classified into three mechanisms: bone marrow suppression, immune-mediated destruction, and platelet aggregation. Clinical characteristics, preliminary laboratory findings, and drug history specific to the mechanisms can assist clinicians in rapidly isolating the causative drug.

Topics: Acute Disease; Anticoagulants; Antineoplastic Agents; Chondroitin Sulfates; Critical Care; Dermatan Sulfate; Disease Management; Drug Combinations; Fibrinolytic Agents; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Interleukin-11; Recombinant Proteins; Thrombocytopenia; Thrombopoietin

Deep-vein thrombosis (DVT) and pulmonary embolism are among the most common complications of heparin-induced thrombocytopenia (HIT), an antibody-mediated adverse effect of heparin that leads paradoxically to in vivo activation of platelets and the coagulation system. Inappropriate treatment of HIT-associated DVT with warfarin can cause the DVT to progress to limb gangrene: this results from impaired ability of the protein C natural anticoagulant pathway to down-regulate thrombin generation, thus leading to microvascular thrombosis and tissue necrosis. Appreciation of the importance of coagulation system activation in HIT provides a rationale for treatments that reduce thrombin generation, either via inhibiting factor Xa (danaparoid) or via inhibiting thrombin directly (lepirudin). Clinicians should know how to distinguish HIT from other thrombocytopenic disorders: for example, thrombocytopenia associated with pulmonary embolism can mimic HIT (pseudo-HIT), and acute dyspnea that can mimic acute pulmonary embolism can result from acute in vivo platelet activation in a patient with HIT antibodies who receives heparin bolus therapy (pseudo-pulmonary embolism).

Topics: Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Gangrene; Heparin; Heparitin Sulfate; Humans; Leg; Pulmonary Embolism; Thrombocytopenia; Venous Thrombosis; Warfarin

Heparin therapy has two potential adverse effects: bleeding and heparin-induced thrombocytopenia (HIT). There are two types of HIT: type I is more common but less severe; type II occurs less frequently but involves severe thrombocytopenia and a high risk for thrombotic events. Treatment involves discontinuing heparin, allowing the platelet count to return to normal, and treating any thrombosis. Lepirudin (Refludan) is the only agent currently approved for the treatment of HIT-related thrombosis, but other agents may have a role in combination therapy. Prevention includes using low molecular weight heparin instead of unfractionated heparin and limiting unfractionated heparin therapy to less than 5 days.

Topics: Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Epoprostenol; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Platelet Aggregation Inhibitors; Recombinant Proteins; Thrombocytopenia; Thrombosis

Topics: Anticoagulants; Antithrombins; Arginine; Chondroitin Sulfates; Clinical Trials as Topic; Critical Pathways; Dermatan Sulfate; Drug Combinations; Fibrinolytic Agents; Heparin; Heparinoids; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombocytopenia

Heparin-induced thrombocytopenia (HIT), a drug-induced immunohaematological adverse reaction, is a rare but potentially very severe condition. The main problem for this complex syndrome is its recognition and management, which should be as early as possible to avoid the development of life-threatening complications. Most studies have reported heterogeneous populations of patients with other diseases that potentially induce thrombocytopenia. There is no gold standard diagnostic criteria, and we have established a score with anamnestic criteria that allows us to evaluate the likelihood of HIT. In clinical practice, the diagnosis is based on the analysis of clinical features and laboratory tests. Platelet aggregation test (PAT) and an ELISA test (heparin platelet-induced antibodies) are generally performed by expert laboratories to confirm the occurrence of HIT. In our experience, both tests are concordant in the majority of patients. PAT seems to correlate better with the clinical features while ELISA appears more specific. Regarding their limits, both are complementary in the determination of HIT diagnosis coupled to the clinical score system. The treatment often requires a multidisciplinary approach. Danaparoid (Orgaran) or lepirudin (Refludan) are the two alternative treatments for HIT patients with marketing approval. To avoid further exposure to heparin, every HIT patient should carry a written document that confirms the immunoallergy.

Topics: Animals; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Disease Models, Animal; Drug Combinations; Fibrinolytic Agents; Heparin; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Immunoassay; Platelet Activation; Recombinant Proteins; Thrombocytopenia

Danaparoid sodium (Orgaran, Organon) is a heparinoid glycosamino-glycuronan antithrombotic agent approved for the prophylaxis of post-operative deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE) in patients undergoing elective hip replacement surgery. Danaparoid is a low molecular weight heparinoid consisting of a mixture of heparan sulphate (84%), dermatan sulphate (12%) and small amounts of chondroitin sulphate (4%), whose antithrombotic activity has been well established. Its pharmacological effect is exerted primarily by inhibiting Factors Xa (FXa) and IIa (FIIa) at a ratio greater than heparin, with a minimal effect on platelet function. Danaparoid exhibits low cross-reactivity with heparin-induced antibodies when compared with heparin or low molecular weight heparins (LMWH), thereby making it an excellent choice for the management of heparin-induced thrombocytopenia (HIT). It has excellent bioavailability following s.c. injection. Danaparoid has little effect on routine coagulation tests (activated partial thromboplastin time [aPTT], prothrombin time [PT], and thrombin time [TT]). Patients with elevated serum creatinine should be monitored carefully. For its FDA approved indication (DVT prophylaxis during hip replacement surgery), its cost per day is approximately eight times more than LMWH. Even though monitoring is not routinely necessary according to the manufacturer for its approved indication, monitoring is frequently necessary when it is used in other clinical scenarios. Its higher cost than comparable therapies for DVT prophylaxis and the low availability of the FXa assay in most non-tertiary care hospitals has limited the widespread use of danaparoid. Danaparoid has been found to be effective in the treatment of HIT although this is an off label use, despite being the most frequent reason why danaparoid is used.

Topics: Anticoagulants; Blood Coagulation Disorders; Chondroitin Sulfates; Clinical Trials as Topic; Dermatan Sulfate; Drug Combinations; Fibrinolytic Agents; Heparitin Sulfate; Humans; Thrombocytopenia

Heparin-induced thrombocytopenia remains a topical subject for at least two reasons. The first reason is the increasing prescription of low molecular weight heparins (LMWH) rather than unfractionated heparins, with limited laboratory surveillance, raising the question concerning the need for twice-weekly platelet counts, according to the recommendations of the Vidal drug directory. The second reason is the recent release onto the market of two products, danaparoid (Orgaran) and lepirudin (Refludin) for this precise indication of heparin-induced thrombocytopenia. These products greatly facilitate the management of this complication. Many basic research teams are trying to optimize the detection of heparin-dependent antibodies and to more clearly elucidate the mechanism of this particular thrombocytopenia, which carries a risk of very severe thrombotic complications when the diagnosis is delayed.

Topics: Antibodies; Anticoagulants; beta-Thromboglobulin; Chondroitin Sulfates; Dermatan Sulfate; Drug Monitoring; Drug Utilization; Enzyme-Linked Immunosorbent Assay; Heparin; Heparitin Sulfate; Hirudins; Humans; Interleukin-8; Peptides; Platelet Count; Platelet Factor 4; Recombinant Proteins; Risk Factors; Thrombocytopenia; Time Factors

The past decade has seen many important advances in the pathogenesis, clinical and laboratory diagnosis, and management of heparin-induced thrombocytopenia (HIT), one of the most common immune-mediated adverse drug reactions. HIT is caused by IgG antibodies that recognize complexes of heparin and platelet factor 4, leading to platelet activation via platelet Fc gamma IIa receptors. Formation of procoagulant, platelet-derived microparticles, and, possibly, activation of endothelium generate thrombin in vivo. Thrombin generation helps to explain the strong association between HIT and thrombosis, including the newly recognized syndrome of warfarin-induced venous limb gangrene. This syndrome occurs when acquired protein C deficiency during warfarin treatment of HIT and deep venous thrombosis leads to the inability to regulate thrombin generation in the microvasculature. The central role of HIT antibodies in causing HIT, as well as refinements in laboratory assays to detect these antibodies, means that HIT should be considered a clinicopathologic syndrome. The diagnosis can be made confidently when one or more typical clinical events (most frequently, thrombocytopenia with or without thrombosis) occur in a patient with detectable HIT antibodies. The central role of thrombin generation in this syndrome provides a rationale for the use of anticoagulants that reduce thrombin generation (danaparoid) or inhibit thrombin (lepirudin).

Topics: Antibodies; Anticoagulants; Antithrombin III; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Fibrinolytic Agents; Gangrene; Heparin; Heparinoids; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Immunoglobulin G; Leg; Platelet Activation; Platelet Factor 4; Protein C Deficiency; Receptors, IgG; Recombinant Proteins; Retrospective Studies; Syndrome; Thrombin; Thrombocytopenia; Venous Thrombosis; Warfarin

Heparin-induced thrombocytopenia (HIT) may be complicated by severe thrombotic complications and death. Currently no specific laboratory test is available to make the diagnosis. When HIT is clinically suspected, heparin should be discontinued immediately. While no specific therapy for HIT exists, there is increasing evidence that acute antithrombin therapy may significantly reduce morbidity and mortality. Among several agents, the direct antithrombins, such as r-hirudin and argatroban, look the most promising for acute treatment.

Topics: Ancrod; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Fibrinolytic Agents; Forecasting; Gangrene; Hemorrhage; Heparin; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Pipecolic Acids; Platelet Aggregation; Protein C; Recombinant Proteins; Sulfonamides; Thrombin; Thrombocytopenia; Warfarin

Topics: Adult; Anticoagulants; Child; Chondroitin Sulfates; Clinical Trials as Topic; Combined Modality Therapy; Dermatan Sulfate; Drug Combinations; Female; Heparin; Heparitin Sulfate; Hirudins; Humans; Male; Pregnancy; Thrombocytopenia

Topics: Adult; Ancrod; Antibodies; Anticoagulants; Antigen-Antibody Complex; Antithrombins; Child; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Drug Combinations; Extracorporeal Circulation; Female; Heparin; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Platelet Factor 4; Pregnancy; Pregnancy Complications, Hematologic; Thrombocytopenia; Thrombolytic Therapy; Thrombosis

The immunological form of heparin-induced thrombocytopenia (HIT) is a potentially life-threatening adverse reaction of heparin medication. It is mediated by multimolecular complexes consisting of platelet factor 4 (PF4)-heparin-IgG which bind to platelets via platelet Fc gamma receptors. Cross-linking of multiple Fc gamma receptors results in platelet activation, platelet aggregation and enhanced thrombin generation with a increasing risk of developing new thrombosis. In children, data on HIT are sparse. This review of the literature reports on 8 children aged 3 months to 15 years and 14 newborns suffering from HIT. Additionally, we report one new case treated with danaparoid sodium. Thrombotic complications were venous (n = 12) and arterial (n = 15). The children received heparin either for a spontaneous thrombotic event, for severe cardiac diseases or to maintain patency of intravascular catheters which are used for nutrition, blood sampling, and for application of medication. After diagnosis of HIT they were further anticoagulated with aspirin, warfarin, danaparoid sodium, lepirudin or low molecular weight heparin.. Although HIT is less frequently reported in newborns and children, paediatricians should be aware of HIT in childhood as a potential complication of heparin application. The widespread practice of flushing catheters with heparin should also be debated in view of the risk of triggering the primary immune-response of HIT. In 1999, treatment options for further parenteral anticoagulation of HIT patients are danaparoid sodium (a low-molecular weight heparinoid) and lepirudin (a direct thrombin inhibitor).

Topics: Adolescent; Anticoagulants; Child; Child, Preschool; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Female; Heparin; Heparinoids; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Infant; Infant, Newborn; Male; Recombinant Proteins; Thrombocytopenia

Thrombosis is a common and potentially serious complication of immune-mediated heparin-induced thrombocytopenia (HIT). Discontinuation of heparin is a simple and important maneuver in patients with suspected HIT. Unfortunately, thrombosis often occurs even in those patients in whom heparin was discontinued because of thrombocytopenia alone ("isolated" HIT). It therefore is reasonable to consider prophylactic anticoagulation with an alternate anticoagulant in patients with suspected HIT, especially if their initial indication for anticoagulation persists. For patients with thrombosis complicating HIT, conventional treatment options often have important limitations. Warfarin has a slow onset of action, and its use in patients with acute HIT and deep venous thrombosis has been associated with the devastating syndrome of venous limb gangrene. Ancrod, a defibrinogenating snake venom with thrombin-like activity, has also been used to treat HIT. However, this agent does not inhibit thrombin generation in HIT, which could explain why some patients who have been treated with this agent have developed certain adverse clinical events, such as warfarin-associated venous limb gangrene. The use of low-molecular-weight heparin (LMWH) to treat patients with HIT is limited by their high rate (up to 100%) of in vitro cross-reactivity with HIT sera, and the relatively frequent occurrence of new or recurrent thrombocytopenia or thrombosis during treatment of HIT with this class of agents. In contrast, the mixture of anticoagulant glycosamingoglycans known as danaparoid sodium has a much lower frequency of in vitro cross-reactivity with HIT sera (10% to 40%, depending upon the sensitivity of the assay). Moreover, clinically significant cross-reactivity during treatment with danaparoid appears to be uncommon, even in patients in whom in vitro cross-reactivity is demonstrable.

Topics: Ancrod; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Humans; Thrombocytopenia; Warfarin

A rapidly acting anticoagulant that can either inhibit thrombin generation or inhibit thrombin itself is the optimum therapy for acute thrombosis associated with heparin-induced thrombocytopenia (HIT). In this review, the newer treatment approaches that fulfill this requirement are discussed. These newer treatments include hirudin and argatroban, direct thrombin inhibitors, and danaparoid, which inhibits thrombin generation. Preliminary outcome results from the extensive compassionate-use program for danaparoid in HIT and from a recently completed randomized clinical trial that compared danaparoid with dextran in patients with HIT are provided. Based on these data, danaparoid appears to be a useful and safe replacement for heparin in patients who develop HIT.

Topics: Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Heparin; Heparitin Sulfate; Hirudin Therapy; Humans; Pipecolic Acids; Randomized Controlled Trials as Topic; Sulfonamides; Thrombocytopenia

After 10 days of intravenous heparin treatment of a 25-year-old woman with recurrent pulmonary emboli, thrombocytopenia occurred with a platelet drop from 1.52 x 10(5)/microliter to 3.6 x 10(4)/microliter. Heparin-induced platelet activation assays confirmed the diagnosis of heparin-induced thrombocytopenia (HIT). The detected heparin-dependent antibodies exhibited in vitro cross-reactivity with low-molecular-weight heparins, but not with danaparoid.. After heparin was stopped and platelet counts were normal, a massive thrombosis of the iliofemoral veins and the inferior vena cava occurred. Under protection of a temporary vena cava filter, systemic anticoagulation with danaparoid (anti-factor Xa-activity 0.4-0.8 U/ml) and transcatheter thrombolysis with urokinase (70,000 U/h) was initiated. Within 8 days of treatment a complete recanalisation of the occluded iliofemoral and caval veins was achieved. Oral anticoagulation with phenprocoumon was started and the patient has since then been free of symptoms.. The case demonstrates successful treatment of massive iliofemoral and caval thrombosis in the HIT syndrome achieved by combined transcatheter administration of urokinase and systemic infusion of danaparoid.

Topics: Adult; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Female; Femoral Vein; Heparin; Heparinoids; Heparitin Sulfate; Humans; Iliac Vein; Plasminogen Activators; Pulmonary Embolism; Recurrence; Thrombocytopenia; Thrombolytic Therapy; Thrombosis; Urokinase-Type Plasminogen Activator; Vena Cava Filters; Vena Cava, Inferior

Danaparoid, a low molecular weight heparinoid consisting of a mixture of heparan, dermatan and chondroitin sulfates, has well established antithrombotic activity. The drug has a high antifactor Xa to antifactor IIa (thrombin) activity ratio, a low tendency to cause bleeding and minimal effects on the fibrinolytic system. Danaparoid has a low cross-reactivity rate with heparin-associated antiplatelet antibodies (0 to 20%; mean approximately 10%). This represents a significant advantage over low molecular weight heparins (LMWHs) as a potential replacement agent for unfractionated heparin (UFH) in patients with immune-mediated (type II) heparin-induced thrombocytopenia (HIT). In a worldwide compassionate-use programme involving a total of 667 patients with HIT to date, 93% of danaparoid treatment courses were considered to be successful. Thrombocytopenia resolved in 91% of episodes. In a multicentre randomised comparative trial of danaparoid and dextran in patients with HIT plus thrombosis (HITT), significantly more danaparoid than dextran recipients had resolution of thromboses, and an effective clinical response was achieved in significantly more danaparoid recipients. Results of a retrospective case-controlled study of danaparoid and ancrod in patients with HITT showed significantly fewer new or progressive thromboses with danaparoid. In the compassionate-use programme, danaparoid was associated with a mortality rate of 10.4% during treatment (up to 3.5 years) and 7.8% during the follow-up period (3 months). 14 of 114 deaths during the follow-up period were considered to be related to danaparoid therapy. A mortality rate of 23.5% was reported in patients accepted for but not treated with, danaparoid. Mortality rates with danaparoid, ancrod and dextran in the comparative studies were similar (7, 11 and 12%, respectively). Severe bleeding was reported in 3.1% of patients in the compassionate-use programme, persistent or recurrent thrombocytopenia in 2.6% and new thromboembolic events/extension of existing thrombosis in 1.7%. The incidence of bleeding was similar with danaparoid and dextran in a comparative trial. Although in vitro cross-reactivity does not always translate into clinical cross-reactivity, testing is currently recommended, when possible, before initiation of danaparoid therapy. Thus, danaparoid appears to be an effective and well tolerated replacement agent for UFH in many patients with HIT who require further anticoagulation. The drug has lo

Topics: Blood Coagulation; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Heparin; Heparinoids; Heparitin Sulfate; Humans; Thrombocytopenia

The development of heparin-induced thrombocytopenia in patients who require systemic anticoagulation for cardiac and vascular operations poses a therapeutic dilemma because no alternative anticoagulants are generally available. Heparinoid (Org 10172) has been used as an alternative anticoagulant under protocol or on a compassionate use basis, and has recently been approved by the Food and Drug Administration. There is, however, no heparinoid antagonist to reverse the anticoagulation. This report describes the combined use of heparinoid anticoagulation and adjunctive fibrin sealant for topical hemostasis in a patient with heparin-induced thrombocytopenia. Recommendations for perioperative monitoring of heparinoid anticoagulation are provided.

Topics: Anticoagulants; Chondroitin Sulfates; Coronary Artery Bypass; Dermatan Sulfate; Fibrin Tissue Adhesive; Heparin; Heparinoids; Heparitin Sulfate; Humans; Male; Middle Aged; Thrombocytopenia

On the basis of the results of the 11 studies reviewed, thromboprophylaxis with unfractionated heparin, low molecular weight (LMW) heparin or a heparinoid (danaparoid sodium; Org 10172) in patients undergoing total hip replacement did not show any important clinical differences with respect to the tolerability profiles of the different compounds. However, as a result of the great variability in the presentation and evaluation of blood losses and bleeding complications in these studies, it is mandatory to perform a direct comparison of the different compounds in question in a double-blind, prospective clinical study.

Topics: Chondroitin Sulfates; Dermatan Sulfate; Fibrinolytic Agents; Hemorrhage; Heparin; Heparinoids; Heparitin Sulfate; Hip Prosthesis; Humans; Molecular Weight; Postoperative Complications; Thrombocytopenia; Thrombosis; Wound Infection

Topics: Animals; Autoantibodies; Blood Platelets; Cattle; Cohort Studies; Glycosaminoglycans; Hemorrhagic Disorders; Heparin; Heparinoids; Heparitin Sulfate; Humans; Immunoglobulin G; Prospective Studies; Structure-Activity Relationship; Swine; Thrombocytopenia; Thrombosis

Topics: Animals; Anticoagulants; Blood Coagulation; Cerebrovascular Disorders; Chondroitin Sulfates; Dermatan Sulfate; Drug Evaluation, Preclinical; Fibrinolytic Agents; Glycosaminoglycans; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Incidence; Mammals; Molecular Weight; Platelet Aggregation; Postoperative Complications; Rabbits; Renal Dialysis; Thrombocytopenia; Thrombophlebitis; Thrombosis

There are three distinct syndromes of heparin-induced thrombocytopenia: an acute reversible from seen immediately after intravenous bolus injection, a delayed-onset antibody-mediated form seen several days after the initiation of therapy, and an intermediate type characterized by mild thrombocytopenia developing just a few days after starting therapy. Delayed-onset heparin-induced thrombocytopenia, clinically the most important form, results from the formation of heparin-dependent antibodies that are directed against the platelet membrane. In the presence of heparin, these antibodies may induce in vitro or in vivo platelet aggregation. Consequently, the course may be complicated by arterial thromboses. Treatment of this syndrome includes the prompt cessation of heparin. Since continued or future anticoagulation is usually necessary, alternative means of anticoagulation have been explored. Oral anticoagulation is often started but requires several days to take effect. Other options include low-molecular-weight heparins, antiplatelet agents, prostacyclin analogues, and low-molecular-weight dextran. In vitro laboratory tests may be helpful in guiding alternative therapy in some, but not all cases. Unfortunately, none of these agents have proved to be uniformly effective and additional agents and clinical investigation are needed before a definitive option becomes available.

Topics: Aspirin; Cardiopulmonary Bypass; Chondroitin Sulfates; Dermatan Sulfate; Epoprostenol; Fibrinolytic Agents; Glycosaminoglycans; Heparin; Heparinoids; Heparitin Sulfate; Humans; Iloprost; Necrosis; Platelet Aggregation Inhibitors; Skin; Skin Diseases; Thrombocytopenia; Thrombosis

Topics: Animals; Cardiopulmonary Bypass; Chondroitin Sulfates; Clinical Trials as Topic; Dermatan Sulfate; Factor X; Factor Xa; Fibrinolytic Agents; Glycosaminoglycans; Heparin; Heparinoids; Heparitin Sulfate; Humans; Kinetics; Molecular Weight; Postoperative Complications; Rats; Renal Dialysis; Thrombocytopenia; Thrombosis; Uremia

During the use of fractionated or unfractionated heparin adverse events frequently occur that can endanger the continuation of therapy. Especially in pregnant patients with thromboembolic complications it may be difficult to find a suitable alternative anticoagulant when heparin-induced thrombocytopenia type II (HIT II) or allergic skin reactions occur. There are still limited data on the use of danaparoid in pregnancy. The main reason for heparin intolerance in the 59 reviewed pregnancies were either HIT II, described in 37/59 (62.7%) pregnancies, or cutaneous adverse effects in 19/22 (86.4%) of non-HIT-associated pregnancies (22/59, 37.3%).. 40/59 pregnancies were carried to term under use of danaparoid and resulted in the delivery of a healthy infant. In 16/19 pregnancies, danaparoid was stopped due to a major adverse event. Five patients showed bleeding complications, seven fetal losses were documented, but there was no association with the use of danaparoid. In 31/59 (52.5%) pregnancies adverse events were documented, 14/31 (45.2%) could be attributed to danaparoid. Anti-Xa-activity was not detected in five fetal cord blood samples and in four maternal breast-milk samples.. Danaparoid can be used as an alternative anticoagulant in pregnant women with high risk for thrombosis and heparin intolerance.

Topics: Adult; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Factor Xa Inhibitors; Female; Heparin; Heparitin Sulfate; Humans; Infant, Newborn; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Thrombocytopenia; Thrombosis

The incidence of heparin-induced thrombocytopenia is increasing, and the thrombin inhibitor danaparoid could be a useful alternative. The objective of the present study was to compare danaparoid and heparin in patients undergoing off-pump coronary artery bypass grafting.. In a prospective, randomized, double-blind clinical trial comparing heparin (bolus of 1 mg/kg) with danaparoid (bolus of 40 U/kg), 71 patients underwent off-pump coronary artery bypass grafting with one of the study drugs. The amount of blood lost, the number of homologous blood products transfused, the troponin T levels, and the amount of anti-Xa activity were monitored.. Thirty-four patients underwent 2.6 +/- 0.7 bypasses with danaparoid, and 37 patients underwent 2.5 +/- 0.9 grafts with heparin (P =.8). Postoperative blood losses averaged 1394 +/- 1033 mL in patients receiving danaparoid and 1130 +/- 868 mL in patients receiving heparin (P =.2). The number of homologous blood products transfused averaged 3.6 +/- 7 units in patients receiving danaparoid and 1.9 +/- 4.4 units in patients receiving heparin (P =.2). The number of patients requiring homologous blood transfusion was higher in patients receiving danaparoid (18/34 [53%]) than in patients receiving heparin (10/37 [27%], P =.03). Serum anti-Xa activity averaged 1.6 +/- 0.6 U/mL in patients receiving danaparoid and 1.9 +/- 0.8 U/mL in patients receiving heparin 30 minutes after injection of the drugs (P =.1) and 0.3 +/- 0.1 and 0.04 +/- 0.08 U/mL, respectively, 12 hours after coronary artery bypass grafting (P =.001). Troponin serum levels were similar 48 hours after coronary artery bypass grafting (0.5 +/- 0.6 and 0.4 +/- 0.6 microg/L, respectively).. Although off-pump coronary artery bypass grafting with danaparoid versus heparin increases the number of patients exposed to homologous blood transfusion (relative risk, 2; 95% confidence limits, 1-4), off-pump coronary artery bypass grafting with danaparoid is a valuable alternative to heparin in patients with thrombocytopenia requiring surgical intervention.

Topics: Aged; Analysis of Variance; Anticoagulants; Blood Loss, Surgical; Blood Transfusion; Chondroitin Sulfates; Coronary Artery Bypass; Coronary Disease; Dermatan Sulfate; Double-Blind Method; Drug Combinations; Drug Monitoring; Factor Xa Inhibitors; Female; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Prospective Studies; Risk Factors; Severity of Illness Index; Thrombocytopenia; Troponin T

Heparin-induced thrombocytopenia (HIT) is a rare but dangerous complication of heparin prophylaxis or treatment. The present laboratory tests to measure heparin-associated antibodies are not specific. The diagnosis of HIT mainly depends on the decrease in platelet count and on clinical symptoms. To evaluate clinical outcome, bleeding complications and platelet counts were evaluated in 45 patients with HIT type II (HIT II) treated prophylactically (subcutaneous injections) or therapeutically (intravenous infusion) with danaparoid. Group I included 24 patients with HIT II without thromboembolic complications who received danaparoid twice daily subcutaneously (10 IU/kg) for a mean of 16 days. Group II included 21 patients with thromboembolic complications. They were treated with intravenous danaparoid (2.6 IU/kg/h +/- 1.1) for a mean of 17 days. During subcutaneous prophylaxis, mean anti-Xa levels of 0.2 U/mL and during intravenous treatment, mean anti-Xa levels of 0.4 U/mL were reached. No deaths, amputations, or serious bleeding complications occurred, and no new thromboses were observed in both patient groups. Treatment with danaparoid led to a fast normalization of the platelet counts. This normalization occurred earlier and the concentration of platelets was higher in patients treated with intravenous doses. Danaparoid with subsequent vitamin K-antagonist treatment effectively prevents thromboembolic complications in patients with HIT.

Topics: Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Female; Heparin; Heparitin Sulfate; Humans; Injections, Subcutaneous; Male; Middle Aged; Patient Selection; Platelet Count; Platelet Factor 4; Thrombocytopenia; Treatment Outcome

Heparin-induced thrombocytopenia (HIT) is a hypercoagulable syndrome strongly associated with thrombosis that is usually treated with drugs that inhibit factor Xa (danaparoid) or thrombin (lepirudin). In the present study the outcome of HIT-patients treated with danaparoid or lepirudin was compared using the single or combined endpoints of new thromboembolic complications (new TECs), amputations and/or death, and major bleeding. HIT-patients treated with lepirudin were enrolled in two prospective trials and patients, who were identified in the same two laboratories during the same time period, who were not enrolled into these studies but treated with danaparoid, were assessed retrospectively according to a standardized questionnaire. 126 danaparoid (60.3% female) and 175 lepirudin treated patients (58.3% female) fulfilled the same inclusion and exclusion criteria. In a time-to-event-analysis the cumulative risk of combined endpoint was higher in HIT-patients without thromboembolic complication at baseline treated with danaparoid (usually in prophylactic dose 750 anti-factor Xa units b.i.d. or t.i.d.s.c.) as compared to lepirudin (aPTT adjusted) (P = 0.020). Whereas HIT-patients with TEC at baseline who were usually treated with therapeutic dose had a similar outcome in both treatment groups (P = 0.913). Major bleeding occurred in 2.5% (95% CI 0.5-7.0%) of danaparoid treated patients as compared to 10.4% (95% CI 6.3-15.9%) of lepirudin treated patients until day 42 (P = 0.009). This indicates that the efficacies of therapeutic doses of danaparoid or lepirudin in preventing death, amputation or new TEC in HIT-patients do not differ largely, but the risk of bleeding seems to be higher in lepirudin treated patients. The prophylactic dose of danaparoid approved in the European Union for HIT without TEC at baseline seems suboptimal. A prospective comparative trial is required to verify these preliminary conclusions.

Topics: Age Factors; Aged; Amputation, Surgical; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Drug Evaluation; Female; Hemorrhage; Heparin; Heparitin Sulfate; Hirudins; Humans; Incidence; Male; Middle Aged; Recombinant Proteins; Retrospective Studies; Surveys and Questionnaires; Thrombocytopenia; Thromboembolism; Treatment Outcome

To compare clinical outcomes in a randomised comparison of treatment with danaparoid sodium (a heparinoid), or dextran 70, for heparin-induced thrombocytopaenia (HIT) plus thrombosis.. Forty-two patients with recent thrombosis and a clinical diagnosis of probable HIT who presented at ten Australian hospitals during a study period of six and one half years were randomly assigned to open-label treatment with intravenous danaparoid or dextran 70, each combined with oral warfarin. Thirty-four patients (83%) had a positive platelet aggregation or 14C-serotonin release test for HIT antibody. Twenty-five received danaparoid as a bolus injection of 2400 anti-Xa units followed by 400 units per hour for 2 h, 300 units per hour for 2 h, and then 200 units per hour for five days. Seventeen received 1000 mL dextran 70 on day one and then 500 mL on days 2-5. Patients were reviewed daily for clinical evidence of thrombus progression or resolution, fresh thrombosis or embolism, bleeding or other complications. The primary trial endpoint was the proportion of thromboembolic events with complete clinical resolution by the time of discharge from hospital.. With danaparoid, there was complete clinical recovery from 56% of thromboembolic events compared to 14% after dextran 70 (Odds Ratio 10.53, 95% Confidence Interval 1.6-71.4; p = 0.02). Clinical recovery with danaparoid was complete or partial in 86% of thromboembolic events compared with 53% after dextran 70 (Odds Ratio 4.55, 95% Confidence Interval 1.2-16.7; p = 0.03). Overall clinical effectiveness of danaparoid was rated as high or moderate in 88% of patients compared with 47% for dextran 70 (p = 0.01). One patient given danaparoid died of thrombosis compared with three patients given dextran 70. The platelet count returned to normal after a mean of 6.7 days with danaparoid and 7.3 days with dextran 70. There was no major bleeding with either treatment.. danaparoid plus warfarin treatment for HIT with thrombosis is effective, safe, and superior to dextran 70 plus warfarin.

Topics: Aged; Chondroitin Sulfates; Dermatan Sulfate; Dextrans; Drug Combinations; Drug Therapy, Combination; Female; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Prospective Studies; Survival Rate; Therapeutic Equivalency; Thrombocytopenia; Thrombosis; Treatment Outcome; Warfarin

To assess the cross-reactivity of danaparoid sodium in patients undergoing cardiovascular surgery.. Prospective investigation.. A major European heart center and university hospital.. 81 patients who underwent cardiovascular surgery during the period between January 1998 and April 1999 and were diagnosed with heparin-induced thrombocytopenia (HIT) II.. Testing was performed in patients who revealed a decrease in the platelet count >30% or a platelet count <100,000/microL during heparin therapy. Testing for HIT was performed by the use of the heparin-induced platelet-aggregation assay. Patients were evaluated as positive if an agglutination occurred in two of four of the 0.2 IU/mL heparin chambers. Patients were judged to be cross-reactive with danaparoid sodium when an agglutination occurred in two of four chambers that contained 0.2 IU/mL Orgaran.. 281 patients (5.4% of the patients who underwent surgery during the period of the investigation) were tested for HIT II. Of these, 81 (1.5% of the total) gave a positive heparin-induced platelet-aggregation assay and 23 (28%) revealed a cross-reactivity with danaparoid sodium.. Cross-reactivity with heparin-induced platelet antibodies occurred in 28% of the patients who tested positive for heparin-platelet antibodies. In these patients, Orgaran would not have been a safe option. In patients with HIT II undergoing cardiac surgery, cross-reactivity with danaparoid sodium must be excluded before initiation of therapy with Orgaran, otherwise, or in cases of cross-reactivity, other options such as r-hirudin are preferred.

Topics: Anticoagulants; Blood Platelets; Cardiovascular Surgical Procedures; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Drug Combinations; Drug Interactions; Heparin; Heparitin Sulfate; Humans; Platelet Aggregation; Platelet Count; Thrombocytopenia

To evaluate the effectiveness and the safety of danaparoid sodium in the treatment of critically ill patients with standard unfractionated heparin-induced thrombocytopenia (HIT) or low-molecular-weight HIT.. University hospital.. Retrospective analysis of 42 consecutive critically ill patients who were admitted for HIT between October 1992 and February 1997 and were treated either with therapeutic or prophylactic doses of danaparoid sodium.. Among the 26 patients treated with therapeutic doses, neither new thrombotic complications nor thrombosis extension was clinically suspected. Two deaths were directly related to lower limb acute arterial thrombosis associated with HIT. Two major hemorrhagic complications were observed when aspirin in addition to danaparoid sodium was administered. When danaparoid sodium was used in prophylactic doses (20 courses of treatment) to prevent either postsurgical or medical thrombotic complications, no thrombotic event was observed. No death related to HIT or danaparoid sodium treatment was observed. One aggravation of a postsurgical cerebral lesion was observed. During danaparoid sodium treatment, a persistence or a recurrence of thrombocytopenia was observed in 6.5% of patients without thrombotic complications.. Danaparoid sodium appears to be an efficient and safe treatment in critically ill patients with HIT. The concomitant use of aspirin in addition to danaparoid sodium seems to represent an important additional hemorrhagic risk that should be avoided in patient management.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Aspirin; Blood Coagulation Factors; Chondroitin Sulfates; Critical Illness; Dermatan Sulfate; Drug Therapy, Combination; Female; Fibrinolytic Agents; Follow-Up Studies; Heparin; Heparitin Sulfate; Humans; Injections, Subcutaneous; Male; Middle Aged; Platelet Aggregation Inhibitors; Platelet Count; Recurrence; Retrospective Studies; Safety; Thrombocytopenia; Treatment Outcome

Topics: Anticoagulants; Antithrombins; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Heparin; Heparitin Sulfate; Pipecolic Acids; Platelet Aggregation Inhibitors; Sulfonamides; Thrombocytopenia

Type II of heparin-associated thrombocytopenia (HAT) is well known, but the cardinal symptom, thrombocytopenia, is rarely adequately considered. Serious and potential lethal complications such as pulmonary embolism, cerebral stroke, or limb gangrene are often falsely regarded as insufficient anticoagulation. Guided diagnosis and therapy are of vital importance for the patient's outcome. Based on the experience of patients with HAT Type II treated in the intensive care unit, a diagnostic and therapeutic approach to the cardinal symptom thrombocytopenia is presented. A recently developed heparin-induced platelet activation assay (HIPAA) seems to be a highly sensitive laboratory test. The first therapeutic principle in case of presumed and diagnosed HAT is the cessation of unfractioned or low-molecular-weight heparins. ORG 10172 (Orgaran), a low-sulfated heparinoid with a low cross-reactivity (10%) to heparins, can be regarded as the most effective anticoagulant in patients with HAT Type II.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Arterial Occlusive Diseases; Chondroitin Sulfates; Dermatan Sulfate; Diagnosis, Differential; Female; Gangrene; Heparin; Heparitin Sulfate; Humans; Middle Aged; Phenprocoumon; Platelet Activation; Platelet Aggregation; Platelet Count; Pulmonary Embolism; Recurrence; Systemic Inflammatory Response Syndrome; Thrombocytopenia; Thromboembolism; Thrombophlebitis

Patients who develop heparin-induced thrombocytopenia (HIT) frequently need further anticoagulation to treat an ongoing thromboembolic problem or to prevent one. Orgaran (Org 10172), a low-molecular-weight (LMW) glycosaminoglycuronan, has shown a low frequency (10%) of cross-reactivity in vitro with sera containing the HIT antibody, in contrast to the much higher frequency of cross-reactivity (approximately 80%) shown by the LMW heparins. This paper summarises the results of intravenous or subcutaneous Orgaran treatment in 57 of 67 Australian patients, in whom the diagnosis of HIT was reasonably confirmed by exclusion of other causes of thrombocytopenia and by objective tests. The presenting indications for Orgaran were: continuous venovenous haemofiltration and haemodialysis (n = 21), thrombo-embolism treatment (n = 23), thrombo-embolism prophylaxis (n = 10), and anticoagulation for coronary artery by-pass graft (n = 4), peripheral by-pass graft surgery and plasmapheresis (n = 1 each). The results showed Orgaran to be a safe, well-tolerated, effective (successful treatment in over 90% of patients) anticoagulant in patients with a high thrombotic and/or bleeding risk even if critically ill and requiring haemofiltration. The complete results of the world-wide study in 161 patients confirmed not only these clinical findings in the subgroup of 57 Australian patients, but also the low cross-reactivity (12%) of Orgaran with the HIT serum factor.

Topics: Antibody Specificity; Autoantibodies; Autoimmune Diseases; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Drug Evaluation; Glycosaminoglycans; Hemofiltration; Heparin; Heparinoids; Heparitin Sulfate; Humans; Postoperative Complications; Thrombocytopenia; Thromboembolism

Topics: Animals; Cardiopulmonary Bypass; Chondroitin Sulfates; Clinical Trials as Topic; Dermatan Sulfate; Factor X; Factor Xa; Fibrinolytic Agents; Glycosaminoglycans; Heparin; Heparinoids; Heparitin Sulfate; Humans; Kinetics; Molecular Weight; Postoperative Complications; Rats; Renal Dialysis; Thrombocytopenia; Thrombosis; Uremia

Heparin is widely used to prevent clotting of the extracorporeal circuit during haemodialysis (HD). Heparin-induced thrombocytopenia (HIT) is a potentially devastating immune mediated adverse drug reaction caused by the emergence of antibodies that activate platelets in the presence of heparin, leading to a pro-thrombotic state. Danaparoid is an alternative anticoagulant used in patients on HD with HIT but its dosing recommendations in obese patients on HD are relatively scarce.. We report a case of a 48-year-old morbidly obese patient who received weight-based dosing of danaparoid for HD with monitoring of anti-Xa activity. However, despite the patient's anti-Xa level being within the therapeutic range at various time points, the circuit lines kept clotting during HD.. The report provides evidence that the manufacturer's recommendations on dosing danaparoid based on body weight may lead to sub-optimal therapeutic benefit and highlight the need for higher than recommended weight-based dosing in obese individuals on dialysis.

Topics: Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Dose-Response Relationship, Drug; Female; Heparin; Heparitin Sulfate; Humans; Obesity, Morbid; Renal Dialysis; Thrombocytopenia; Thrombosis

Topics: Aged; Anticoagulants; Chondroitin Sulfates; Computed Tomography Angiography; Dermatan Sulfate; Diagnosis, Differential; Female; Heparin; Heparitin Sulfate; Humans; Platelet Count; Syndrome; Thrombectomy; Thrombocytopenia; Thrombosis

Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction mediated by platelet-activating antibodies that target complexes of platelet factor 4 and heparin. Patients are at markedly increased risk of thromboembolism.. These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in their decisions about diagnosis and management of HIT.. ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations, which were subject to public comment.. The panel agreed on 33 recommendations. The recommendations address screening of asymptomatic patients for HIT, diagnosis and initial management of patients with suspected HIT, treatment of acute HIT, and special situations in patients with acute HIT or a history of HIT, including cardiovascular surgery, percutaneous cardiovascular intervention, renal replacement therapy, and venous thromboembolism prophylaxis.. Strong recommendations include use of the 4Ts score rather than a gestalt approach for estimating the pretest probability of HIT and avoidance of HIT laboratory testing and empiric treatment of HIT in patients with a low-probability 4Ts score. Conditional recommendations include the choice among non-heparin anticoagulants (argatroban, bivalirudin, danaparoid, fondaparinux, direct oral anticoagulants) for treatment of acute HIT.

Topics: Administration, Oral; Anticoagulants; Arginine; Cardiovascular Surgical Procedures; Chondroitin Sulfates; Dermatan Sulfate; Evidence-Based Medicine; Fondaparinux; Heparin; Heparitin Sulfate; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Platelet Count; Recombinant Proteins; Renal Replacement Therapy; Sulfonamides; Thrombocytopenia; Venous Thromboembolism

Life-threatening heparin-induced thrombocytopenia (HIT) is treated with the alternative nonheparin anticoagulants argatroban, lepirudin, or danaparoid. Frequently, the pentasaccharide fondaparinux is used off-label.. The authors sought to investigate the safety and efficacy of the different anticoagulants for treating HIT.. In a national, multicenter registry study, hospitalized patients who were diagnosed with HIT, an at least intermediate clinical HIT-risk (4Ts score ≥4 points), and received treatment with ≥1 dose of the aforementioned anticoagulants were included. Main outcome measures were the incidences of HIT-specific complications (thromboembolic venous/arterial events, amputations, recurrent/persistent thrombocytopenia, skin lesions) and bleedings.. Of 195 patients, 46 (23.6%), 4 (2.1%), 61 (31.3%), and 84 (43.1%) had been treated first-line with argatroban, lepirudin, danaparoid, and fondaparinux, respectively. The composite endpoint of HIT-specific complications (thromboembolic events, amputation, skin necrosis) occurred in 11.7% of patients treated with approved alternative anticoagulation and in 0.0% of fondaparinux-treated patients. The all-cause in-hospital mortality rates were 14.4% during approved alternative anticoagulation and 0.0% during fondaparinux treatment. Bleeding complications occurred in alternatively anticoagulated patients and in fondaparinux-treated patients in 6.3% and 4.8%, respectively. Post hoc analysis of clinical and laboratory features confirmed "true" HIT in at least 74 of 195 (38.0%) patients; 35 of 74 (47.3%) were treated with fondaparinux.. Fondaparinux is effective and safe in suspected acute HIT; no HIT-specific complications occurred in the fondaparinux-treated patients, even among those with a high clinical HIT probability. Further data from randomized controlled trials are urgently needed because lepirudin was recalled from the market; danaparoid access has been limited and is not approved in the United States; and argatroban is contraindicated in patients with impaired liver function, and activated partial thromboplastin time confounding may interfere with monitoring. (Retrospective Registry of Patients With Acute Heparin-induced Thrombocytopenia Type II; NCT01304238).

Topics: Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Factor Xa Inhibitors; Female; Fondaparinux; Hemorrhage; Heparin; Heparitin Sulfate; Hirudins; Hospital Mortality; Hospitalization; Humans; Male; Necrosis; Off-Label Use; Partial Thromboplastin Time; Patient Safety; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Registries; Retrospective Studies; Sulfonamides; Thrombocytopenia; Thromboembolism; Treatment Outcome

Clinical suspicion of immune heparin-induced thrombocytopenia (HIT) requires cessation of heparin and initiation of an alternative anticoagulant. The platelet count will subsequently recover. This case report describes the clinical course of a patient after a cardiovascular surgery. HIT was clinically and biologically confirmed. Unexpectedly, the platelet count did not recover despite the arrest of heparin. Danaparoid was initiated, and thrombocytopenia persisted. Danaparoid cross-reactivity was suspected, and laboratory assay was performed. Results were misinterpreted because no comparative buffer control was performed to ensure that the platelet aggregation was caused by danaparoid. Moreover, plasma/serum must be diluted to demonstrate this effect. Danaparoid cross-reactivity was incorrectly concluded, and the patient was switched to bivalirudin. The severe thrombocytopenia persisted. Plasmapheresis was started, and platelet count finally increased. The clinical course suggested a delayed-onset HIT. This case report illustrates the need for appropriate testing to differentiate drug cross-reactivity from delayed-onset HIT.

Topics: Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Thrombocytopenia

Management of heparin-induced thrombocytopenia (HIT) entails cessation of heparin and initiation of a nonheparin parenteral anticoagulant such as danaparoid. Danaparoid cross-reactivity with HIT antibodies is an uncommon complication of treatment of HIT. We report the case of confirmed HIT and in vivo cross-reactivity with danaparoid, complicating severe sepsis due to an infectious endocarditis treated by cardiac surgery.

Topics: Anticoagulants; Cardiac Surgical Procedures; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Heart Valve Diseases; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a potentially life-threatening prothrombotic complication following heparin administration. We describe a patient, known with idiopathic dilating cardiomyopathy, presenting nine days after a biventricular ICD implantation with dyspnoea and thrombocytopenia. Thirteen days after administration of a single heparin flush during ICD implantation, the patient developed venous thrombosis in two extremities and pulmonary embolism caused by HIT. HIT is the development of thrombocytopenia, caused by IgG antibodies against complexes of platelet factor 4 and heparin, leading to platelet aggregation. HIT may be accompanied by thrombosis in 20-50% of patients and untreated mortality rates are high. Once HIT is suspected, heparin should be replaced by an alternative anti-factor Xa or anti-factor II therapy. Regardless of the low incidence of HIT, because of the widespread use of heparin and the potentially life-threatening course of HIT, all physicians should be aware of it.

Topics: Antibodies; Anticoagulants; Cardiomyopathy, Dilated; Chondroitin Sulfates; Defibrillators, Implantable; Dermatan Sulfate; Female; Follow-Up Studies; Heparin; Heparitin Sulfate; Humans; Immunoglobulin G; Middle Aged; Platelet Aggregation; Platelet Factor 4; Postoperative Complications; Pulmonary Embolism; Thrombocytopenia; Treatment Outcome; Venous Thromboembolism

Early clinical signs of heparin induced thrombocytopenia (HIT) are nonspecific and include a sudden drop in the number of platelets as well as formation of arterial and venous thromboses. Regional citrate anticoagulation (RCA) is increasingly used as a very effective modality to prevent filter clotting during renal replacement therapy (RRT). We report the first case where repeated premature filter clotting despite RCA indicated a manifestation of HIT.. A 71-year old woman admitted to the ICU for a compartment syndrome of the leg developed septic shock with acute kidney injury requiring continuous veno-venous hemodialysis (CVVHD). Because of unexpected and repeated premature filter clotting during CVVHD using RCA, HIT was suspected.. The diagnosis of HIT was confirmed by the presence of IgG antibodies against heparin and platelet factor (PF) 4 complexes and six points in the 4T score. Discontinuation of heparin administration and initiation of systemic anticoagulation with danaparoid sodium resulted in the normalization of platelet count and hemofilter lifetime.. RCA does not seem to be sufficient to prevent hemofilter clotting during HIT. Thus, in case of repeated premature filter clotting despite RCA, one should suspect HIT and prompt diagnostic workup as well as a switch to alternative anticoagulation.

Topics: Acute Kidney Injury; Aged; Anticoagulants; Chondroitin Sulfates; Citrates; Dermatan Sulfate; Equipment Failure; Female; Heparin; Heparitin Sulfate; Humans; Immunoglobulin G; Platelet Factor 4; Renal Dialysis; Shock, Septic; Thrombocytopenia; Thrombosis

Patients can develop thrombocytopenia during heparin therapy.The most frequent form, type I heparin-induced thrombocytopenia, does not require cessation of therapy. Type II heparin-induced thrombocytopenia is immune-mediated. It can cause venous or arterial thrombosis, which may be fatal or require amputation. Type II thrombocytopenia typically develops 5 to 10 days after initiation of treatment, sometimes earlier in patients previously exposed to heparins. The recommendations on platelet-count monitoring during heparin therapy are not based on high-level evidence. The main risk factors for type II thrombocytopenia must be taken into account: unfractionated heparin, previous heparin exposure, surgery, female patient. For patients considered at high risk for heparin-induced thrombocytopenia, platelet-count monitoring is usually recommended at least twice a week for at least 2 weeks. The treatment of immune-mediated heparin-induced thrombocytopenia is based on stopping heparin and replacing it with danaparoid or argatroban. In practice, the decision to initiate treatment with unfractionated or low-molecular-weight heparin is not a trivial one. In addition to the bleeding risk, the risk of type II thrombocytopenia in the short- term, or during subsequent heparin therapy, should be taken into account when assessing the harm-benefit balance.

Topics: Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Heparin; Heparitin Sulfate; Humans; Pipecolic Acids; Platelet Aggregation Inhibitors; Platelet Count; Sulfonamides; Thrombocytopenia; Venous Thrombosis

The authors present the case of a nulliparous 34-year-old patient. At the tenth week of gestation, she developed phlebothrombosis of veins of the right leg and massive pulmonary embolism. After thrombolytic and heparin therapy she developed rethrombosis and heparin-induced thrombocytopenia type II. Lepirudin was introduced in therapy and in the 12th week of gestation acenocumarol was added. After the 34th week, she received danaparoid sodium. After a week, by cesarean section, a healthy and mature female was delivered.

Topics: Acenocoumarol; Adult; Anticoagulants; Cesarean Section; Chondroitin Sulfates; Dermatan Sulfate; Female; Fibrinolytic Agents; Gestational Age; Heparin; Heparitin Sulfate; Hirudins; Humans; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pulmonary Embolism; Recombinant Proteins; Thrombocytopenia; Venous Thrombosis

There is no in vitro data on the comparison of the effects of danaparoid, argatroban and fondaparinux on thrombin generation in patients with heparin-induced thrombocytopenia. It was the study objective to compare the in vitro anticoagulant potential of argatroban, danaparoid and fondaparinux using a thrombin generation assay TGA on a mixture of control platelet-rich plasma (PRP) and HIT patient platelet-poor plasma (PPP). The plasma of seven patients with a clear HIT diagnosed at our institution was selected. Mixtures of donor PRP and patient PPP were incubated with unfractionated heparin 0.2 U.mL⁻¹, argatroban at 600 ng.mL⁻¹, argatroban at 400 ng.mL⁻¹, danaparoid at 0.65 IU.mL⁻¹ and fondaparinux at 1 μg.mL⁻¹. Thrombin generation was assessed by calibrated thrombinography. The percentage of inhibition of the endogenous thrombin potential observed with argatroban at 600 ng.mL⁻¹ was statistically significantly higher compared with those observed with fondaparinux (median: 53.6% vs. 3.9%; p=0.031) but not compared with argatroban at 400 ng.mL⁻¹ and danaparoid. The percentage of inhibition of the thrombin peak observed with argatroban at 600 ng.mL⁻¹ was statistically significantly higher compared with those observed with danaparoid (median: 71.2 vs. 56.8; p=0.031) and fondaparinux (mean: 71.2 vs. 30; p=0.031) but not with argatroban at 400 ng.mL⁻¹. In conclusion, the in vitro effect of argatroban and danaparoid on thrombin generation seems to corroborate the results of clinical studies of these drugs in the treatment of HIT in term of efficiency. Fondaparinux showed a very small effect on thrombin generation evaluated by calibrated thrombinography.

Topics: Aged; Aged, 80 and over; Anticoagulants; Arginine; Blood Platelets; Calibration; Chondroitin Sulfates; Dermatan Sulfate; Female; Fondaparinux; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Pipecolic Acids; Plasma; Platelet-Rich Plasma; Polysaccharides; Recombinant Proteins; Sulfonamides; Thrombin; Thrombocytopenia; Time Factors

This study presents a case of bifrontal intracerebral haemorrhage in a patient with heparin-induced thrombocytopenia type II (HIT II). HIT II was induced by treatment with low-molecular-weight heparin for recurrent deep vein thrombosis caused by essential thrombocytosis and accompanied by hepatic thromboembolism. This patient was treated with platelet substitution and neurosurgical haematoma evacuation. Anticoagulation with 2500 units danaparoid per day was sufficient for therapy of thrombosis and no rebleeding occurred.

Topics: Aged; Anticoagulants; Blood Coagulation Disorders; Cerebral Hemorrhage; Chondroitin Sulfates; Chromosome Breakage; Chromosome Disorders; Dermatan Sulfate; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Humans; Male; Thrombocytopenia; Treatment Outcome

This case describes the medical history of a 61-year-old woman treated for cerebral venous thrombosis (CVT) leading to diagnosis of essential thrombocythemia (ET). During treatment with unfractionated heparin, after initial improvement of clinical state, signs of cerebral hypertension reappeared. Although the platelet count decreased, heparin-induced thrombocytopenia (HIT) was only suspected 2 days later when it dropped below the standard 150 × 10(9) L(-1) threshold. HIT diagnosis was confirmed by the presence of anti-PF4/heparin IgG. This late finding was the cause of the extension of CVT with worsening of cerebral hypertension necessitating decompressive craniectomy. Elevated basal platelet count due to ET can delay diagnosis and treatment of HIT. In this case, physicians should be more attentive to platelet count variations rather than thrombocytopenia threshold.

Topics: Anticoagulants; Cerebral Veins; Chondroitin Sulfates; Decompressive Craniectomy; Dermatan Sulfate; Female; Heparin; Heparitin Sulfate; Humans; Intracranial Hypertension; Middle Aged; Platelet Count; Radiography; Thrombocythemia, Essential; Thrombocytopenia; Thrombosis; Treatment Outcome; Venous Thrombosis

Topics: Aged, 80 and over; Anticoagulants; Aortic Valve Stenosis; Chondroitin Sulfates; Dermatan Sulfate; Echocardiography, Transesophageal; Female; Fibrinolytic Agents; Heart Valve Prosthesis; Heparin; Heparitin Sulfate; Humans; Middle Aged; Thrombocytopenia; Thrombosis; Tomography, X-Ray Computed

Heparin-induced thrombocytopenia (HIT, type II) is an immune-mediated disorder due to antibodies formed against heparin-platelet factor 4 complexes, usually appearing at days 5 to 14 after initiation of heparin. It is important to recognize HIT because heparin prophylaxis or treatment paradoxically associates with new venous and/or arterial thrombosis. Early clinical suspicion and diagnosis together with proper pharmacotherapy and close laboratory monitoring are the cornerstones for successful management. This includes monitoring of Thrombocytopenia, its Timing to heparin administration, appearance of new Thrombosis or resistance to treatment, and differential diagnosis by exclusion of o Ther causes (the 4T's). Specific attention should be paid to the absence or presence of thrombosis and to tailoring thromboprophylaxis or anticoagulant therapy with a nonheparin alternative. Even in the absence of HIT-associated thrombosis, an active policy for prolonged thromboprophylaxis is demanded. Rapid and reliable assays should be developed for diagnosis and anticoagulation monitoring to secure safe management with nonheparins. Semiquantitative testing for on-call hours should be available and later confirmed as clinically needed. Alternative therapeutic options are available, but because their use is infrequent, experienced coagulation treatment centers should provide guidance in the treatment and in laboratory monitoring. Most of the evidence in HIT is grade IC, and thus the best evidence is provided by clinical experience. New anticoagulants and platelet inhibitors may offer future alternatives in the management of HIT, but the current treatment options provide the best experience and benefit. The joint clinical and laboratory guidelines provided in this article along with two practical case scenarios were prepared by a Nordic expert panel. They will be valuable for hematologists and colleagues who do not routinely encounter HIT.

Topics: Aged; Anticoagulants; Arginine; Cardiac Catheterization; Cardiac Surgical Procedures; Chondroitin Sulfates; Dermatan Sulfate; Female; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudins; Humans; Male; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Vascular Surgical Procedures; Vitamin K; Young Adult

Topics: Antibodies; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Female; Fondaparinux; Heparin; Heparitin Sulfate; Humans; Male; Platelet Activation; Platelet Factor 4; Polysaccharides; Serotonin; Thrombocytopenia; Thromboembolism

We undertook a survey of French university hospital hematological laboratories to ascertain the clinical characteristics of patients with suspected HIT, the laboratory tests performed, and the therapeutic strategy adopted in current practice.. A standardized medical records database for patients with suspected HIT was sent to 19 laboratories. During two months, all consecutive patients for whom a biological test was performed were included.. 169 patients were included, 27 (16%) patients having a final diagnosis of HIT. At the time HIT was suspected, the heparin duration and the level of thrombocytopenia were similar in HIT- positive and HIT-negative groups. The use of unfractionated heparin, a therapeutic heparin dose regimen and the presence of thrombotic complications were significantly more frequent in HIT-positive patients. When the heparin dose regimen was taken into account, only thrombotic complications under a therapeutic dose regimen were significantly increased in HIT-positive patients. Eighty-six percent of patients presented at least one alternative diagnosis of thrombocytopenia without significant difference between the two groups. Laboratory tests were performed after a mean of 0.3days and mainly consisted of antigen assays. At the time HIT was suspected, heparin was stopped in 56 (33%) patients, being replaced mainly by danaparoid. Only three laboratories declared they usually received all the necessary clinical information to establish the likelihood of HIT.. In current practice in France, the clinical probability of HIT is rarely established, leading to systematic requests for laboratory HIT tests.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Chondroitin Sulfates; Clinical Laboratory Techniques; Data Collection; Dermatan Sulfate; Female; France; Heparin; Heparitin Sulfate; Hospitals, University; Humans; Male; Medical Records; Middle Aged; Practice Patterns, Physicians'; Thrombocytopenia; Thrombosis; Young Adult

Heparin treatment can cause an immune-mediated thrombocytopenia: HIT. HIT antibodies can be detected by various methods, but laboratory analyses are not specific or sensitive and may delay the diagnostic process. It is therefore important to initiate alternative treatment based on the clinical findings, and a clinical score system for evaluating the risk of HIT has been suggested. When HIT is likely, treatment consists of immediate replacement of heparin with alternative anticoagulation treatment and refrainment from warfarin therapy and platelet infusion.

Topics: Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Fibrinolytic Agents; Heparin; Heparitin Sulfate; Hirudins; Humans; Pipecolic Acids; Recombinant Proteins; Risk Factors; Sulfonamides; Thrombocytopenia

Prognostic factors for unfavorable clinical outcome in patients with heparin-induced thrombocytopenia (HIT) are largely unknown.. In this multicenter, retrospective, case-control study, all HIT patients were treated with danaparoid. Study cases were HIT patients with an unfavorable clinical outcome. Controls were HIT patients who were not study cases. Unfavorable clinical outcome was defined as the occurrence of at least one of the following clinical events: death within 60 days after HIT start date, or venous or arterial thromboembolism, amputation, major bleeding, or disseminated intra-vascular coagulation between 48 hours and 60 days after HIT start date.. Compared with controls (n=65), thrombotic episodes within 48 hours of HIT start date were more frequent (59.2% versus 32.3%; p=0.004), the median time between HIT start date and initiation of danaparoid infusion was longer (3.0 versus 1.0 days; p=0.001), and this treatment was more frequently underdosed (43.8% versus 18.8%; p=0.004) in study cases (n=49). Upon multivariate analysis, all these three parameters were significant predictive factors for unfavorable clinical outcome. The adjusted odds ratios [95% confidence interval] were 6.6 [2.5-17.3] for time between HIT start date and danaparoid initiation over 48 hours, 4.3 [1.5-12.0] for danaparoid underdosing, and 3.2 [1.3-8.0] for presence of a thromboembolic episode at HIT start date.. This study supports the recommendations concerning the management of HIT patients, namely discontinuation of all heparin administration once the diagnosis is suspected and prompt initiation of an alternative anticoagulant drug with a strict adherence to doses specifically recommended for these patients.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Case-Control Studies; Chondroitin Sulfates; Dermatan Sulfate; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Multivariate Analysis; Prognosis; Retrospective Studies; Risk Factors; Thrombocytopenia; Treatment Outcome; Young Adult

Heparin-induced thrombocytopenia (HIT) might be life-threatening in patients undergoing open heart surgery, due to thromboembolic events, thrombocytopenia and bleeding. If cardiac surgery with cardiopulmonary bypass (CPB) is necessary, anticoagulation therapy will be based on usage of danaparoid or direct thrombin inhibitors. Female patient was switched from per oral anticoagulant therapy to low molecular heparin therapy preparing for reredo mitral valve replacement due to endocarditis and artificial valve thrombosis. In next 10 days, thrombocytopenia was obvious (Tr 302,000 mm3 to 11,000 mm3) , and diagnoses of HIT were done. Anticoagulant therapy was continued with danaparoid, 750 IU/12 h sc. During the surgery, reredo mitral valve replacement and aortocoronary bypass on anterior descending coronary artery, blood salvage technique with rhirudin (intravenous bolus 0.4 mg/kg, in CPB prajming solution 0.4 mg/kg and continuous infusion during CPB 0.15 mg/kg/h) during cardiopulmonary bypass was used. Active coagulation time and +++ were monitored, without any sign of micro thrombosis in circuit. Postoperatively, per oral anticoagulation therapy was initiated with prolonged postoperative treatment due to basic disease, endocarditis. Patient was discharged from hospital on 21st postoperative day without any complication.

Topics: Anticoagulants; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Chondroitin Sulfates; Dermatan Sulfate; Female; Heparin; Heparin Antagonists; Heparitin Sulfate; Humans; Middle Aged; Postoperative Care; Preoperative Care; Thrombocytopenia

Topics: Anticoagulants; Antithrombins; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Heparinoids; Heparitin Sulfate; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Platelet Aggregation; Recombinant Proteins; Thrombocytopenia

The case of a 21-year old man who died due to an intracranial thrombosis just after diagnosis of Goodpasture's disease, is reported. Discussion deals with the putative mechanisms, which could be responsible for the thrombosis.

Topics: Anti-Glomerular Basement Membrane Disease; Anticoagulants; Chondroitin Sulfates; Combined Modality Therapy; Dermatan Sulfate; Diabetes Insipidus, Neurogenic; Disseminated Intravascular Coagulation; Enoxaparin; Fatal Outcome; Headache; Heparin; Heparitin Sulfate; Humans; Immunosuppressive Agents; Male; Methylprednisolone; Plasma Exchange; Platelet Factor 4; Sinus Thrombosis, Intracranial; Thrombocytopenia; Young Adult

This chapter describes the pharmacology of approved parenteral anticoagulants, including the indirect anticoagulants, unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), fondaparinux, and danaparoid as well as the direct thrombin inhibitors hirudin, bivalirudin, and argatroban. UFH is a heterogeneous mixture of glycosaminoglycans that bind to antithrombin via a unique pentasaccharide sequence and catalyze the inactivation of thrombin factor Xa and other clotting factors. Heparin also binds to cells and other plasma proteins, endowing it with unpredictable pharmacokinetic and pharmacodynamic properties, and can lead to nonhemorrhagic side effects, such as heparin-induced thrombocytopenia (HIT) and osteoporosis. LMWHs have greater inhibitory activity against factor Xa than thrombin and exhibit less binding to cells and proteins than heparin. Consequently, LMWH preparations have more predictable pharmacokinetic and pharmacodynamic properties, have a longer half-life than heparin, and have a lower risk of nonhemorrhagic side effects. LMWHs can be administered once or twice daily by subcutaneous injection, without anticoagulant monitoring. Based on their greater convenience, LMWHs have replaced UFH for many clinical indications. Fondaparinux, a synthetic pentasaccharide, catalyzes the inhibition of factor Xa, but not thrombin, in an antithrombin-dependent fashion. Fondaparinux binds only to antithrombin; therefore, HIT and osteoporosis are unlikely to occur. Fondaparinux has excellent bioavailability when administered subcutaneously, has a longer half-life than LMWHs, and is given once daily by subcutaneous injection in fixed doses, without anticoagulant monitoring. Three parenteral direct thrombin inhibitors and danaparoid are approved as alternatives to heparin in HIT patients.

Topics: Anticoagulants; Arginine; Biological Availability; Chondroitin Sulfates; Dermatan Sulfate; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudins; Humans; Infusions, Parenteral; Injections, Subcutaneous; Peptide Fragments; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Sulfonamides; Thrombocytopenia

Treatment of heparin-induced thrombocytopenia (HIT), a disorder in which anti-platelet factor 4 (PF4)-heparin antibodies cause platelet activation and hypercoagulability, requires alternative (non-heparin) anticoagulation. Treatment options include direct thrombin inhibitors [lepirudin and argatroban (approved), and bivalirudin], danaparoid (approved) (mixture of anticoagulant glycosaminoglycans), or fondaparinux (synthetic heparin-mimicking pentasaccharide). PF4-heparin complexes form at optimal stoichiometric ratios.. To compare the effects of these various non-heparin anticoagulants in disrupting the formation of PF4-heparin complexes, and PF4-containing immune complexes.. Sera were obtained from patients with serologically confirmed HIT. The effects of the alternative anticoagulants on PF4 and PF4-heparin complex interactions with platelets, as well as HIT antibody binding and platelet activation, were investigated.. Danaparoid at very low concentrations increased PF4 binding to platelets. In therapeutic concentrations, however, it decreased PF4 binding to platelets (P = 0.0004), displaced PF4-heparin complexes from platelets (P = 0.0033) and PF4 from the surface of a PF4-transfected HEK-293 EBNA cell line expressing the PF4 receptor CXCR3-B (P = 0.0408), reduced PF4-heparin complex size (P = 0.025), inhibited HIT antibody binding to PF4-heparin complexes (P = 0.001), and prevented platelet activation by HIT antibodies (P = 0.046). Although fondaparinux also interfered with PF4 binding to platelets, HIT antibody binding to PF4-heparin complexes, and activation of platelets by HIT antibodies, these effects occurred only at supratherapeutic concentrations. The direct thrombin inhibitors had no effect at any concentrations.. Danaparoid uniquely interferes with the pathogenesis of HIT by disrupting PF4-containing immune complexes at therapeutic dose concentrations. It is possible that these effects contribute to its therapeutic efficacy.

Topics: Antibodies; Antibody Affinity; Cells, Cultured; Chondroitin Sulfates; Dermatan Sulfate; Fondaparinux; Heparin; Heparitin Sulfate; Humans; Platelet Activation; Platelet Factor 4; Polysaccharides; Protein Binding; Serine Proteinase Inhibitors; Thrombin; Thrombocytopenia

During extracorporeal membrane oxygenation, anticoagulation therapy is usually achieved with unfractionated heparin. We report on an extracorporeal membrane oxygenation with danaparoid sodium for a patient with severe respiratory failure due to massive pulmonary embolism and suspected type 2 heparin-induced thrombocytopenia. Danaparoid, a low molecular weight heparinoid, is an alternative to heparin for patients who develop type 2 heparin-induced thrombocytopenia. Danaparoid was given at 400 IU/h with an objective of antifactor Xa activity of 0.6-0.8 U/mL, which was monitored twice a day. No excessive bleeding or clotting of the circuit was noted. The patient was weaned from extracorporeal membrane oxygenation after 9 days of treatment.

Topics: Adult; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Echocardiography, Transesophageal; Extracorporeal Membrane Oxygenation; Factor Xa; Heparitin Sulfate; Humans; Iliac Vein; Male; Portal Vein; Pulmonary Embolism; Thrombocytopenia; Thrombosis; Tomography, X-Ray Computed

Topics: Abortion, Habitual; Adult; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Factor V; Factor V Deficiency; Female; Heparin; Heparitin Sulfate; Homozygote; Humans; Infant, Newborn; Male; Platelet Count; Point Mutation; Pregnancy; Pregnancy Complications, Hematologic; Thrombocytopenia; Translocation, Genetic; Venous Thrombosis

The decision for an anticoagulant for renal replacement therapy (RRT) in patients with acute renal failure and heparin-induced thrombocytopenia (HIT) has to be made carefully. Based on results from the literature argatroban is favoured in patients without hepatic dysfunction, referring to its short halftime and easy feasable monitoring. In the case of coexsisting hepatic disorder, danaparoid provides a safe alternative therapy. However, long halftime and the difficult elimination of the substance are unfavourable. Lepirudin represents another possible anticoagulant therapy. Bleeding complications and monitoring of the ecarin clotting time imposes limitations. Experiences with bivalirudin, fondaparinux and prostaglandines are limited and future trials will have to determine the significance of their application in RRT in HIT patients. Furthermore it has to be proven whether the combination of alternative anticoagulants with citrate prolongates circuit halftime of CVVH.

Topics: Acute Kidney Injury; Anticoagulants; Arginine; Blood Coagulation Tests; Chondroitin Sulfates; Citrates; Critical Care; Dermatan Sulfate; Diagnostic Errors; Dose-Response Relationship, Drug; Epoprostenol; Fondaparinux; Hemofiltration; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudins; Humans; Iloprost; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Sodium Citrate; Sulfonamides; Thrombocytopenia; Thrombosis

Heparin-induced thrombocytopenia (HIT) represents a serious side effect caused by an atypical immune response to platelet factor 4 leading to platelet activation and thrombin formation. These patients are at high risk of thromboembolism, with a rapid drop in platelet count between days 5 and 14 after the initiation of heparin treatment. In single cases, especially after major surgery, platelet count reduction might be absent or hidden by preceding thrombocytosis. Different clinical manifestations of HIT include unspecific skin reactions with potential necrosis at the site of heparin injection, mostly after the application of unfractionated heparin but also with low molecular weight heparin. In heparin-induced skin necrosis, administration of unfractionated or low molecular weight heparin is contraindicated and heparin therapy should be stopped immediately. Instead, an alternative anticoagulant in the form of a direct thrombin inhibitor such as argatroban, and respectively lepirudin, or danaparoid sodium must be administered. Due to frequent misinterpretations of heparin-induced unspecific skin reactions, especially in the absence of thrombocytopenia, we present two case reports which should increase the awareness of HIT's various clinical pictures.

Topics: Adult; Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Drug Eruptions; Female; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudins; Humans; Male; Pipecolic Acids; Platelet Count; Platelet Factor 4; Postoperative Complications; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombosis; Time Factors

Heparin-induced thrombocytopenia (HIT) is a serious immune complication of heparin therapy and presents a risk of severe thromboembolic events. Withdrawal of heparin together with administration of an alternative antithrombotic agent is always necessary in patients with suspected HIT. Diagnosis of this complication, however, is often difficult, particularly in hospitalized patients. The aim of this study was to evaluate the impact of multidisciplinary consultation on the appropriate prescription of danaparoid, widely used as an alternative antithrombotic treatment in HIT.. Multidisciplinary consultation between clinician, hematologist, and pharmacist called for reassessment of the HIT diagnosis at day 3 and between day 3 and 10 after the beginning of danaparoid treatment. Continuation or stopping treatment depended on their joint conclusion. All danaparoid prescriptions were evaluated according to this procedure for one year.. HIT was suspected in 26 in-patients. The multidisciplinary approach made it possible to reassess the HIT diagnosis on day 3 and stop the alternative treatment in 42.3% of cases. Danaparoid use decreased by 52% compared with the previous year.. Multidisciplinary consultations between clinician, hematologist, and pharmacist appear useful for minimizing inappropriate prescription of this alternative treatment in cases of suspected HIT.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Prescriptions; Fibrinolytic Agents; Heparin; Heparitin Sulfate; Hospitalization; Humans; Middle Aged; Patient Care Team; Platelet Count; Probability; Referral and Consultation; Retrospective Studies; Thrombocytopenia; Time Factors

In patients with suspected heparin-induced thrombocytopenia (HIT) who need renal replacement therapy, a nonheparin anticoagulant has to be chosen to prevent thrombosis in the extracorporeal circuit. Danaparoid, a low-molecular-weight heparinoid consisting of heparan sulphate, dermatan sulphate, and chondroitin sulphate, is recommended for systemic anticoagulation in patients with HIT. However, there are few data on the use of danaparoid in patients with acute renal failure, especially in patients dependent on renal replacement therapy such as continuous venovenous hemofiltration (CVVH). In the present study, we analyzed the pharmacokinetics and pharmacodynamics of danaparoid during CVVH in patients with suspected HIT.. Based on a mathematical model, a dosing scheme for danaparoid was designed, aiming at anti-Xa levels of 0.5 to 0.7 U/mL, with a maximum of 1.0 U/mL. This dosing scheme was prospectively tested in the first CVVH run of a cohort of five patients with suspected HIT. CVVH with a blood flow rate of 150 mL/minute and a substitution rate of 2,000 mL/hour was performed with a cellulose triacetate membrane. Danaparoid was administered as a continuous infusion of 100 anti-Xa-U/hour after a loading dose of 3,500 anti-Xa-U. Serial measurements of anti-Xa activity and prothrombin fragment F1+2 were performed at baseline, at t = 5, 15, and 30 minutes, and at t = 1, 2, 4, 8, 16, and 24 hours after the danaparoid loading dose.. The median anti-Xa activity reached a maximum of 1.02 (0.66 to 1.31) anti-Xa-U/mL after 15 minutes and gradually declined to 0.40 (0.15 to 0.58) anti-Xa-U/mL over the span of 24 hours. Target anti-Xa levels were reached from 2 to 12 hours after the loading dose. Median prothrombin fragment F1+2 gradually decreased from 432 (200 to 768) to 262 (248 to 317) pmol/L after 24 hours. No bleeding or thromboembolic events occurred throughout the described treatment period.. Danaparoid administered by a continuous infusion of 100 anti-Xa-U/hour after a loading dose of 3,500 anti-Xa-U elicited target anti-Xa levels from 2 to 12 hours after the loading dose, without bleeding or thromboembolic events during the described CVVH treatment in patients with suspected HIT.

Topics: Aged; Anticoagulants; Chondroitin Sulfates; Cohort Studies; Dermatan Sulfate; Dose-Response Relationship, Drug; Female; Hemofiltration; Heparitin Sulfate; Humans; Infusions, Intravenous; Male; Pilot Projects; Prospective Studies; Thrombocytopenia; Treatment Outcome

The patient was a 55-year-old female. On the diagnosis of the right acoustic tumor, a subtotal extirpation was performed. Heparinized solution was administered, and on postoperative day 7, an occlusion of the left common femoral artery was confirmed. A continuous administration of heparin was initiated after a thrombectomy. On the following day, the platelet count decreased. Following confirmation of the recurrence of thromboembolism, we again performed a thrombectomy. Considering the possibility of heparin-induced thrombocytopenia (HIT), we terminated the administration of heparin, and treatment with danaparoid and argatroban was initiated. Two days later, she redeveloped thromboembolism. After the administration of danaparoid was terminated, the platelet count improved.

Topics: Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Female; Heparin; Heparitin Sulfate; Humans; Leg; Middle Aged; Pipecolic Acids; Recurrence; Sulfonamides; Thrombectomy; Thrombocytopenia; Thromboembolism

Randomized controlled trials evaluating treatment of acute, transient, but uncommon diseases are difficult to perform. The prothrombotic adverse drug reaction, heparin-induced thrombocytopenia (HIT), is such an example. During the mid-1980s, the defibrinogenating snake venom, ancrod (+/-warfarin, Canada), or coumarin (warfarin, Canada; phenprocoumon, Germany) alone, were often used to treat HIT. During the 1990s, danaparoid+/-coumarin began to replace ancrod (+/-coumarin), or coumarin alone, for treating HIT, despite danaparoid not being approved for treatment of HIT.. We performed a retrospective evaluation of treatment outcomes from 1986 to 1999, comparing danaparoid+/-coumarin (n=62) versus ancrod+/-coumarin or coumarin alone (controls, n=56).. The predefined composite endpoint of adjudicated new, progressive, or recurrent thrombosis (including thrombotic death), or limb amputation, at day 7 (maximum, one event per patient) was significantly lower in danaparoid-treated patients, compared with controls: 8/62=12.9% (95% CI, 4.3-21.5) vs. 22/56=39.3% (95% CI, 26.1-52.5); p=0.0014. We also found a lower frequency of the composite endpoint at end of study (day 35) in danaparoid-treated patients: 12/62=19.4% vs. 24/56=42.9% (p=0.0088). Major bleeding (by day 7) occurred in 7/62 (11.3%) and 16/56 (28.6%) of danaparoid-treated and control patients, respectively (p=0.0211).. The replacement of ancrod+/-coumarin, or coumarin alone, by danaparoid (+/-coumarin) in the mid-1990s for the treatment of HIT was justified by improved efficacy and safety.

Topics: Aged; Ancrod; Canada; Chondroitin Sulfates; Cohort Studies; Coumarins; Dermatan Sulfate; Female; Germany; Heparin; Heparitin Sulfate; Humans; Male; Outcome Assessment, Health Care; Platelet Count; Practice Patterns, Physicians'; Retrospective Studies; Survival Analysis; Thrombocytopenia

The Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology has produced a concise practical guideline to highlight the key issues in the management of heparin-induced thrombocytopenia (HIT) for the practicing physician in the UK. The guideline is evidence-based and levels of evidence are included in the body of the article. All patients who are to receive heparin of any sort should have a platelet count on the day of starting treatment. For patients who have been exposed to heparin in the last 100 d, a baseline platelet count and a platelet count 24 h after starting heparin should be obtained. For all patients receiving unfractionated heparin (UFH), alternate day platelet counts should be performed from days 4 to 14. For surgical and medical patients receiving low-molecular-weight heparin (LMWH) platelet counts should be performed every 2-4 d from days 4 to 14. Obstetric patients receiving treatment doses of LMWH should have platelet counts performed every 2-4 d from days 4 to 14. Obstetric patients receiving prophylactic LMWH are at low risk and do not need routine platelet monitoring. If the platelet count falls by 50% or more, or falls below the laboratory normal range and/or the patient develops new thrombosis or skin allergy between days 4 and 14 of heparin administration HIT should be considered and a clinical assessment made. If the pretest probability of HIT is high, heparin should be stopped and an alternative anticoagulant started at full dosage unless there are significant contraindications while laboratory tests are performed. Platelet activation assays using washed platelets have a higher sensitivity than platelet aggregation assays but are technically demanding and their use should be restricted to laboratories experienced in the technique. Non-expert laboratories should use an antigen-based assay of high sensitivity. Only IgG class antibodies need to be measured. Useful information is gained by reporting the actual optical density, inhibition by high concentrations of heparin, and the cut-off value for a positive test rather than simply reporting the test as positive or negative. In making a diagnosis of HIT the clinician's estimate of the pretest probability of HIT together with the type of assay used and its quantitative result (enzyme-linked immunosorbent assay, ELISA, only) should be used to determine the overall probability of HIT. Clinical decisions should be made following consideration of the ris

Topics: Anticoagulants; Cardiac Surgical Procedures; Chondroitin Sulfates; Dermatan Sulfate; Evidence-Based Medicine; Heparin; Heparitin Sulfate; Hirudins; Humans; Perioperative Care; Platelet Count; Platelet Function Tests; Recombinant Proteins; Thrombocytopenia

Type 2 heparin-induced thrombocytopenia is an uncommon but often fatal complication of heparin, frequently difficult to diagnose after cardiac surgery. In this series, we record the clinical presentation, temporal relationship, and treatment outcome of patients diagnosed with heparin-induced thrombocytopenia postoperatively.. Thirty-three consecutive patients (1.1%) with a diagnosis of heparin-induced thrombocytopenia established by a greater than 50% drop in platelet count with or without a thrombotic event and a positive platelet factor-4 assay were reviewed. We recorded the clinical presentation, the time to presentation, treatment, and outcome (thrombosis, mortality). Univariate analysis was performed on 13 preoperative, operative, and postoperative variables.. The cohort was at increased mortality risk as a result of age (69.4 years), reduced cardiac function (46.8%), nonbypass operations (57.6%), emergency surgery (21.2%), and implantation of three assist devices. The mean time to suspect heparin-induced thrombocytopenia postoperatively was 5.4 days, with 22 cases (66.6%) occurring within 5 days. All patients had previous (within 3 months) exposure to heparin, and 66.6% had ongoing treatment with heparin before surgery. Overall mortality was 33%; thrombotic complications occurred in 15 patients (45.5%), with a mortality of 7 (46.6%) despite immediate cessation of heparin and treatment with a nonheparin analog. Thrombocytopenia without thrombosis occurred in 18 patients (54.5%), but a subgroup of 5 patients with nonthrombotic complications accounted for the 4 (22.2%) deaths.. Heparin-induced thrombocytopenia after cardiac surgery is uncommon but may occur within 5 days of surgery, further complicating diagnosis and treatment. Thrombotic complications result in a high mortality despite treatment with a nonheparin analog, and a subgroup of patients with thrombocytopenia fared poorly.

Topics: Aged; Aged, 80 and over; Anticoagulants; Autoantibodies; Cardiac Surgical Procedures; Chondroitin Sulfates; Cohort Studies; Dermatan Sulfate; Diabetes Complications; Female; Gangrene; Heparin; Heparitin Sulfate; Hospital Mortality; Humans; Ischemia; Male; Middle Aged; Platelet Factor 4; Postoperative Complications; Postoperative Period; Retrospective Studies; Risk Factors; Thrombocytopenia; Thrombosis; Time Factors; Treatment Outcome

Topics: Anticoagulants; Cardiac Surgical Procedures; Chondroitin Sulfates; Contraindications; Dermatan Sulfate; Heparin; Heparitin Sulfate; Humans; Platelet Count; Platelet Factor 4; Postoperative Complications; Postoperative Period; Serotonin; Thrombocytopenia; Time Factors; Treatment Outcome

Patients with heparin-induced thrombocytopenia requiring urgent cardiac surgery present a unique challenge that must be addressed by the use of nonheparin alternatives for anticoagulation during cardiopulmonary bypass. Although isolated cases have been presented involving the use of antithrombin III independent thrombin inhibitor hirudin in this situation, its ability to completely inhibit thrombin activity has not been demonstrated. In this report we describe the efficacy of this drug in inhibiting thrombin during a case requiring prolonged cardiopulmonary bypass.

Topics: Aged; Anticoagulants; Blood Coagulation; Cardiopulmonary Bypass; Chondroitin Sulfates; Contraindications; Dermatan Sulfate; Endarterectomy; Female; Heparin; Heparitin Sulfate; Hirudins; Humans; Hypertension, Pulmonary; Plasma; Platelet Transfusion; Pulmonary Embolism; Recombinant Proteins; Thrombectomy; Thrombin; Thrombocytopenia; Time Factors; Warfarin

Topics: Aged; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Heparin; Heparitin Sulfate; Humans; Male; Sinus Thrombosis, Intracranial; Thrombocytopenia

We report a case of Budd-Chiari syndrome revealing a polycythemia vera and complicated by heparin-induced thrombocytopenia. A surgical porto-caval shunt was inserted with danaparoid as anticoagulant during the peri-operative period. The doses of danaparoid were as follows: a continuous intravenous infusion of 200 U/h with a target between 0.5 et 0.8 U/ml antifactor Xa activity during the preoperative period, followed by 100 U/h with a target of 0.3 U/ml during the peroperative period; an increase in doses of danaparoid to 150 and 200 U/h with a target above 0.5 U/ml was used during the postoperative period. This case report is a rare situation of hypercoagulable state, in a surgical context, treated with danaparoid.

Topics: Adult; Anticoagulants; Budd-Chiari Syndrome; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Factor Xa Inhibitors; Female; Heparin; Heparitin Sulfate; Humans; Infusions, Intravenous; Platelet Aggregation; Thrombocytopenia

In the past 10 years numerous reports of cases referring to complications and their outcome with heparin-induced thrombocytopenia type II (HIT II) have been published. Clinically these symptoms are manifested as a combination of arterial and venous thromboembolisms. Mostly affected are the vessels of the limbs, the abdomen, kidneys and coronary arteries. We present the most rare initial manifestations of cerebral symptoms with headache, nausea, change of character and generalised convulsion, which have found their origin in sinus vein thrombosis and the treatment with the heparinoid danaparoid.

Topics: Aged; Anticoagulants; Anticonvulsants; Blood Cell Count; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Heparin; Heparitin Sulfate; Humans; Male; Mental Disorders; Postoperative Complications; Seizures; Sinus Thrombosis, Intracranial; Thrombocytopenia; Tomography, X-Ray Computed

Heparin-induced thrombocytopenia (HIT) is the most common form of drug-induced immune-mediated thrombocytopenia. HIT may be aggravated by life-threatening arterial and venous thrombosis and, to a lesser extent, hemorrhagic complications. We investigated the incidence of thromboembolic and hemorrhagic complications in critically ill patients with the multiple organ dysfunction syndrome and HIT.. Case-control study.. A 33-bed general intensive care unit in a university-affiliated teaching hospital.. Twenty consecutive patients with laboratory-proven HIT compared with 20 contemporary, consecutive patients without HIT.. Unfractionated heparin or low-molecular-weight heparin were replaced by danaparoid sodium in patients with HIT.. Heparin-induced thrombocytopenia was proven by a positive platelet aggregation test. The HIT group consisted of 14 males and 6 females aged 65.2+/-10.8 years (mean +/- standard deviation) with APACHE II scores of 26.7+/-5.4. Thrombocytopenia less than 100 x 10(9)/l developed within 6.4+/-7.0 days. In 12 patients thrombocytopenia resolved after discontinuation of unfractionated heparin in 8.8+/-6.4 days. Arterial and venous thromboembolic complications occurred more frequently in HIT patients than in non-HIT patients (10/20 (50%) versus 0/20 (0%); chi-square p<0.001). Hemorrhagic complications also occurred more frequently in HIT patients than in non-HIT patients (17/20 (85%) versus 7/20 (35%); chi-square p=0.001).. In critically ill patients with HIT, the incidence of thromboembolic complications and hemorrhagic complications was remarkably high.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Case-Control Studies; Chondroitin Sulfates; Critical Illness; Dermatan Sulfate; Drug Combinations; Female; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Incidence; Intensive Care Units; Male; Middle Aged; Multiple Organ Failure; Risk Factors; Thrombocytopenia; Venous Thrombosis

Heparin-induced thrombocytopenia (HIT) is a common immunological drug reaction. After exposure to heparin, some patients develop heparin dependent antibodies with no evidence of thrombosis, while others are at risk of thrombocytopenia, thrombosis, limb loss, and death. We conducted a retrospective chart review on all patients serologically positive for HIT by HPIA ELISA in a single tertiary-care hospital, to determine whether patients with malignancy had an increased risk of thrombotic complications. Medical records of 55 patients who tested positive for HIT and met clinical criteria for HIT were analyzed. All patients had been treated with unfractionated heparin. Malignancy was diagnosed in 11 patients, either at surgery or post-mortem examination. A higher rate of venous thrombosis and pulmonary embolism was observed in patients with HIT and malignant disease when compared to patients with no underlying malignancy (odds ratio 13.6, 95% CI 2.9-63.8).

Topics: Aged; Aged, 80 and over; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Female; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Neoplasms; Pulmonary Embolism; Retrospective Studies; Risk Factors; Thrombocytopenia; Thrombosis; Venous Thrombosis

To describe a case of heparin-induced thrombocytopenia (HIT) in a premature infant and the doses of danaparoid and lepirudin needed to achieve appropriate therapeutic endpoints.. A 30-week gestational age infant was diagnosed with HIT with heparin antibodies. Danaparoid 2.0-2.4 units/kg/h achieved anti-Xa levels of 0.2-0.4 U/mL, but thrombocytopenia failed to resolve. Lepirudin was started in place of danaparoid. Lepirudin doses of 0.03-0.05 mg/kg/h achieved target activated partial thromboplastin time values of 1.5-2.0 times baseline.. Dosing information for danaparoid in neonates is limited, and information for lepirudin appears only in German literature at this time. HIT is well documented in newborns, and lepirudin use in these situations is likely to increase. This report provides some guidance for optimal dosing. It also provides some guidance for HIT evaluation in preterm infants, in whom blood volume for laboratory tests is a major issue.. HIT is an important and potentially fatal problem in neonates. Lepirudin may be the drug of choice, especially since danaparoid is now unavailable. Initial lepirudin dosing should not exceed 0.05 mg/kg/h.

Topics: Chondroitin Sulfates; Dermatan Sulfate; Dose-Response Relationship, Drug; Drug Combinations; Heparin; Heparitin Sulfate; Hirudins; Humans; Infant, Newborn; Infant, Premature; Male; Platelet Count; Recombinant Proteins; Thrombocytopenia

We describe a case where danaparoid was used prophylactically in a high-risk twin pregnancy following the development of heparin-allergy while on prophylactic dalteparin. Danaparoid was substituted for dalteparin at 20 weeks of pregnancy following the development of a severe skin reaction while on the low molecular weight heparin. Although there was no significant fall in platelet count, an aggregation assay for heparin-induced thrombocytopaenia was positive. The skin lesions rapidly resolved following the change to subcutaneous danaparoid. Delivery was by emergency caesarian section at 35 weeks under a general anaesthetic, as a dose of danaparoid had been given 6 h prior to delivery. A sample of breast milk showed no anti-activated factor X activity. Danaparoid was continued post-delivery until the patient was fully warfarinized. To our knowledge, there are no previous reports of the use of danaparoid in this setting.

Topics: Adult; Anticoagulants; Cesarean Section; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Drug Eruptions; Emergencies; Female; Heparin; Heparitin Sulfate; Humans; Infant, Newborn; Injections, Subcutaneous; Platelet Count; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy, High-Risk; Pregnancy, Multiple; Puerperal Disorders; Pulmonary Embolism; Thrombocytopenia; Thrombosis; Warfarin

Patients with heparin-induced thrombocytopenia (HIT) (with or without thrombosis) require alternative anticoagulation because of their extreme risk of new thromboembolic complications. The first effective agent for this purpose may be danaparoid, a less-sulfated low molecular weight heparinoid. Recently, direct thrombin inhibitors have been used.. Five HIT patients, who developed new thromboembolic complications while receiving danaparoid, were analyzed to consider possible reasons for treatment failure and to promulgate strategies that improve efficacy.. Three patients had acute HIT, one had recent HIT, and one with remote HIT was re-exposed to heparin during heart surgery. Danaparoid was started as intravenous bolus and infusion in one patient, and as 1250 units subcutaneously twice daily in four patients. The new complications that emerged on danaparoid were new venous thrombi in three patients (one with pulmonary emboli), lower extremity arterial thrombosis in one, myocardial ischemia in one, thromboembolic cardiovascular accidents in one, and fatal bowel necrosis in one (two patients suffered more than one complication). Platelet counts did not improve or worsened in four, improved partially in the other, and parameters of disseminated intravascular coagulation failed to improve in one patient. Four patients responded relatively dramatically when direct thrombin inhibitors were substituted. Possible reasons for danaparoid failure include that: 1) no treatment is expected to completely prevent complications, 2) antithrombin III consumption can blunt efficacy in some patients, 3) low or intermediate doses may be insufficient, and 4) there was clinically significant cross-reactivity of the pathogenic HIT antibodies.. It is emphasized that the possibility of clinically significant antibody cross-reactivity and that low or intermediate dosage may be inadequate when using danaparoid in therapy of HIT. The latter problem probably extrapolates to other anticoagulants used for HIT.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Disseminated Intravascular Coagulation; Drug Combinations; Female; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Platelet Count; Thrombocytopenia; Thrombosis; Treatment Failure

Topics: Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Female; Heparin; Heparitin Sulfate; Humans; Pregnancy; Pregnancy Complications, Hematologic; Thrombocytopenia

Thrombosis prophylaxis using heparins is mandatory in most trauma patients. However, heparins can induce heparin-induced thrombocytopenia (HIT), the most common and clinically important immune-mediated drug-dependent thrombocytopenia. Affected patients are at risk of developing new thromboembolic complications. HIT has to be considered if platelet counts decrease >50% between day 5-10 of heparin therapy that cannot be explained alternatively or if new thromboses occur in a sufficiently heparinised patient. Immediately changing the anticoagulant to danaparoid or lepirudin is most important. Proof of anti-platelet-factor-4/heparin antibodies secures the diagnosis, usually retrospectively. Diagnosis and therapy are demonstrated in a typical HIT patient. HIT usually occurs in the second week of heparin administration. Heparin-reexposure within 100 days can lead to HIT before day 5. For early recognition of HIT, platelet counts should be monitored regularly. Because of earlier discharge of patients to rehabilitation or outpatient care, the problem of HIT-diagnosis and therapy gains increasing relevance in these sectors.

Topics: Adult; Anticoagulants; Autoantibodies; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Fractures, Bone; Heparin; Heparitin Sulfate; Hirudins; Humans; Male; Multiple Trauma; Platelet Count; Platelet Factor 4; Postoperative Complications; Recombinant Proteins; Thrombocytopenia; Thromboembolism

Several low molecular weight (LMW) heparin preparations, including dalteparin, enoxaparin and nadroparin, as well as the heparinoid danaparoid sodium, are approved for use in Australia. LMW heparins are replacing unfractionated heparin for the prevention and treatment of venous thromboembolism and the treatment of non-ST-segment-elevation acute coronary syndromes. The advantages of LMW heparins over unfractionated heparin include a longer half-life (allowing once-daily or twice-daily subcutaneous dosing), high bioavailability and predictable anticoagulant response (avoiding the need for dose adjustment or laboratory monitoring in most patients), and a low risk of heparin-induced thrombocytopenia and osteoporosis. Laboratory monitoring of LMW heparin therapy should be considered in newborns and children, patients with renal impairment, those who are pregnant, and those at the extremes of bodyweight (eg, < 40 kg or > 100 kg). LMW heparins should: be avoided or used with caution in patients undergoing neuraxial anaesthesia, owing to the potential for epidural haematoma formation; not be used (ie, are contraindicated) in patients with immune heparin-induced thrombocytopenia, as they may cross-react with anti-heparin antibodies. Conventional unfractionated heparin retains a role in the management of patients at high risk of bleeding, undergoing invasive procedures, and patients with renal failure owing to its shorter half-life, reversibility with protamine sulfate, and extrarenal metabolism. The heparinoid danaparoid sodium is effective for the treatment of heparin-induced thrombocytopenia.

Topics: Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Heparin; Heparin, Low-Molecular-Weight; Heparinoids; Heparitin Sulfate; Humans; Myocardial Infarction; Thrombocytopenia; Venous Thrombosis

HIT is a common, potentially catastrophic syndrome. Awareness and early diagnosis allow effective therapeutic intervention. Ineffective strategies include stopping heparin only and starting warfarin early. Use of alternative anticoagulants is improving patient outcomes. Lepirudin, argatroban, and danaparoid each have advantages and disadvantages; treatment should be tailored to each patient.

Topics: Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Heparin; Heparinoids; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombocytopenia

Topics: Adult; Anticoagulants; Antithrombin III; Aspirin; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Female; Heparin; Heparitin Sulfate; Humans; Pregnancy; Pregnancy Complications, Hematologic; Thrombocytopenia; Treatment Outcome

A case of successful regional anticoagulation with trisodium citrate in a patient who developed heparin-induced thrombocytopenia while on continuous hemofiltration is described. Immediate citrate anticoagulation allowed for maintenance of extracorporeal circulation until effective danaparoid therapy could be established. Recommended plasma antifactor Xa levels for hemodialysis may be inadequate in some cases. Values similar to those in use during cardiopulmonary bypass could be required.

Topics: Anticoagulants; Chondroitin Sulfates; Citric Acid; Dermatan Sulfate; Dose-Response Relationship, Drug; Drug Combinations; Emergencies; Factor Xa Inhibitors; Female; Heart Failure; Hemofiltration; Heparin; Heparitin Sulfate; Humans; Middle Aged; Platelet Aggregation; Platelet Count; Thrombocytopenia

Owing to the disadvantage of radioactivity of the carbon 14 serotonin release assay and the time-consuming procedure of the enzyme immunoassay, we developed a high-pressure liquid chromatography (HPLC) method to detect serotonin released from donor platelets in the presence of heparins and serum samples from patients with heparin-induced thrombocytopenia (HIT). Samples were analyzed from 60 healthy control subjects, 19 patients with HIT, and 20 patients without HIT after incubation with heparin, low-molecular-weight heparin (LMWH), and danaparoid. Serotonin release was measured from platelets, 300 x 10(3)/microL, by HPLC. Serotonin eluted as a single peak from the HPLC column. Serum samples from patients with HIT released 5.5 to 352.5 and 6.6 to 1,533.3 ng/mL of serotonin from platelets in the presence of 0.2 IU/mL of heparin and LMWH, respectively. In the presence of 0 IU/mL of heparin, LMWH, danaparoid, and control samples, less than 2.5 ng/mL of serotonin were released. The HPLC method permits a rapid, sensitive, and quantitative determination of serotonin released from donor platelets for laboratory confirmation of HIT.

Topics: Anticoagulants; Blood Platelets; Chondroitin Sulfates; Chromatography, High Pressure Liquid; Dermatan Sulfate; Drug Combinations; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Humans; Predictive Value of Tests; Sensitivity and Specificity; Serotonin; Single-Blind Method; Thrombocytopenia

Pathogenesis, frequency, and management of heparin-induced thrombocytopaenia are well-known. They may be related with both unfractioned heparin and low-molecular weight heparin. Suspected heparin must be discontinued as soon as the diagnosis is established. Orgaran (danaparoid sodium) may be used for management of patients with heparin-associated thrombocytopaenia but can itself be associated with a thrombocytopaenia. Our case report allows us to catch in mind such a crossed complication.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Anticoagulants; Captopril; Carotid Stenosis; Chondroitin Sulfates; Dermatan Sulfate; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Drug Combinations; Female; Heparin; Heparitin Sulfate; Humans; Hypertension; Stroke; Thrombocytopenia

The use of cardiopulmonary bypass (CPB) in patients with a history of type II heparin-induced thrombocytopenia (HIT) may be associated with complications related to their anticoagulation management.. Between January 1997 and December 1999, among 4,850 adults patients who underwent cardiac surgery in our institution, 10 patients presented with preoperative type II HIT. In 4 patients, anticoagulation during CPB was achieved with danaparoid sodium. In 6 other patients, heparin sodium was used after pretreatment with epoprostenol sodium.. No significant change in platelet count occurred in any patient. No intraoperative thrombotic complication was encountered. Total postoperative chest drainage ranged from 250 to 1,100 ml in patients pretreated with epoprostenol and 1,700 to 2,470 ml in patients who received danaparoid sodium during CPB (p < 0.05, Mann-Whitney U test).. During CPB, inhibition of platelet aggregation by prostacyclin may be a safe anticoagulation approach in patients with type II HIT.

Topics: Aged; Aged, 80 and over; Anticoagulants; Cardiopulmonary Bypass; Chondroitin Sulfates; Coronary Artery Bypass; Dermatan Sulfate; Drug Combinations; Epoprostenol; Female; Heart Valve Prosthesis Implantation; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Premedication; Thrombocytopenia

Heparin-induced thrombocytopenia (HIT), with or without thrombosis, is a common and often serious complication of heparin therapy. Platelet-activating, heparin-induced antibodies characteristic of HIT are thought to be specific for complexes formed between platelet factor 4 (PF4) and heparin, and such complexes are routinely used for antibody detection. We studied the binding of HIT antibodies to PF4 complexed with heparin fractions of uniform molecular size or linear polyanions other than heparin and found that many compounds other than heparin form complexes with PF4 that are suitable for antibody detection, provided they carry strong negative charges spaced about 0.5 nm apart along the molecular backbone and are of sufficient length to span about 40% of the circumference of the PF4 tetramer. Polyvinyl phosphonate was among the compounds that were equivalent to heparin. Thus neither a polysaccharide chain nor sulfate side groups--the hallmarks of heparin structure--are required for HIT antibody detection. The findings support the view that antibodies associated with HIT are specific for conformational changes that take place in the positively charged PF4 molecule when it reacts with a suitable, linear polyanion.

Topics: Antibody Specificity; Anticoagulants; Antigen-Antibody Reactions; Blood Platelets; Epitopes; Heparin; Heparitin Sulfate; Humans; In Vitro Techniques; Platelet Activation; Platelet Factor 4; Polyelectrolytes; Polymers; Polysaccharides; Polyvinyls; Thrombocytopenia; Thrombosis

We report on four children with heparin-induced thrombocytopenia type II. In three patients, therapy with unfractionated heparin was associated with development of cardiac thrombi or with thrombosis progression up to the inferior vena cava or with aggravation of peripheral arterial occlusion. In the fourth child, the disease was recognized early on, and no complication occurred. Heparin-induced thrombocytopenia type II was confirmed by heparin-induced platelet activation assay and/or heparin/platelet factor 4-ELISA. Concomitant elevated antiphospholipid antibodies were seen in all patients. Danaparoid sodium applied at a dosage of between 1.2 and 7.1 U/kg/h stopped the disease progression in each patient. Three children had a clinical recovery with partial recanalization, but for the child with peripheral arterial occlusion disease, amputation of some of the toes became necessary.. Our data indicate that heparin-induced thrombocytopenia type II is a potential life-threatening disease in children and danaparoid sodium is beneficial in this age group.

Topics: Adolescent; Antibodies, Antiphospholipid; Anticoagulants; Child; Chondroitin Sulfates; Dermatan Sulfate; Female; Heparin; Heparitin Sulfate; Humans; Male; Thrombocytopenia; Thrombosis; Treatment Outcome

Heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) is an immune-mediated drug reaction that occurs 5-14 d after initiation of heparin therapy and is a potentially life-threatening thrombotic complication. The antibody-heparin-PF4 complexes cause platelet activation and generation of platelet microparticles. The need for anticoagulant treatment in asymptomatic thrombocytopenia is uncertain. However, treatment is warranted in HITTS, as illustrated in the case reported here. Danaparoid, r-Hirudin and argatroban are effective drugs. Danaparoid has a 10-50% in vitro cross-reactivity rate with the HIT antibodies, but has been proven to be clinically efficacious even in these cases. Here, we report a case of in vivo cross-reactivity with danaparoid, the patient showed an excellent recovery with r-Hirudin.

Topics: Aged; Antibodies; Anticoagulants; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Drug Combinations; Factor Xa; Heparin; Heparitin Sulfate; Hirudin Therapy; Humans; International Normalized Ratio; Male; Platelet Count; Syndrome; Thrombocytopenia; Thrombosis

Topics: Chondroitin Sulfates; Dermatan Sulfate; Dose-Response Relationship, Drug; Drug Administration Schedule; Heparin; Heparitin Sulfate; Hirudin Therapy; Humans; Otorhinolaryngologic Diseases; Risk Factors; Thrombocytopenia; Thromboembolism

A type II heparin-induced thrombocytopenia (HIT) was diagnosed in a 64-year-old woman at day 20 of intravenous unfractionated heparin (UFH) therapy, given after myocardial infarction treated by angioplasty and intracoronary stent. The infarction was complicated by a mitral insufficiency that led to a mitral valve replacement. Cardiopulmonary bypass was successfully performed with sodium danaparoid (Orgaran), as an alternative to UFH, without thrombotic or haemorrhagic complications and the follow-up was uneventful.

Topics: Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Extracorporeal Circulation; Female; Heart Valve Prosthesis; Heparin; Heparitin Sulfate; Humans; Middle Aged; Mitral Valve Insufficiency; Thrombocytopenia

Topics: Aged; Angina, Unstable; Anticoagulants; Cardiopulmonary Bypass; Chondroitin Sulfates; Coronary Disease; Dermatan Sulfate; Drug Combinations; Heparin; Heparitin Sulfate; Humans; Male; Reoperation; Thrombocytopenia; Thrombosis; Treatment Failure

Heparin-induced thrombocytopenia type II (HIT II) is a rare but life-threatening side effect of heparin therapy. We describe the perioperative anticoagulative management of patients tested positive for HIT II and requiring implantation of a left ventricular assist device (LVAD).. We report on 3 patients with a different perioperative anticoagulative management (preoperative, intraoperative, and postoperative anticoagulation with danaparoid-sodium; preoperative anticoagulation with recombinant hirudin, anticoagulation with danaparoid-sodium intraoperatively and postoperatively; preoperative anticoagulation with recombinant hirudin, intraoperative anticoagulation with heparin, and postoperative anticoagulation with danaparoid-sodium) and discuss the difficulties of the treatment.. Anticoagulation with alternative drugs such as recombinant hirudin and danaparoid-sodium led to serious and life-threatening bleeding complications as well as to thromboembolic events in the first 2 patients. Therefore the third patient underwent LVAD implantation using heparin for intraoperative anticoagulation to avoid administration of high doses of recombinant hirudin or danaparoid-sodium. Despite very low anti-factor Xa activities, when using danaparoid-sodium postoperatively, the patient suffered from a bleeding complication on the 4th day after LVAD implantation requiring reexploration.. In selected cases (negative heparin-induced platelet aggregation (HIPA) test at the time of LVAD implantation and continuation of postoperative anticoagulation with recombinant hirudin or danaparoid-sodium), heparin may be used for LVAD implantation in HIT II patients to reduce bleeding complications.

Topics: Adult; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Female; Heart-Assist Devices; Heparin; Heparitin Sulfate; Hirudin Therapy; Humans; Male; Middle Aged; Thrombocytopenia

Topics: Ancrod; Anticoagulants; Antithrombins; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Recombinant Proteins; Thrombocytopenia; Thrombosis; Warfarin

Topics: Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Enoxaparin; Female; Heparitin Sulfate; Humans; Middle Aged; Platelet Count; Radionuclide Imaging; Thrombocytopenia; Warfarin

Topics: Ancrod; Anticoagulants; Aprotinin; Cardiopulmonary Bypass; Chondroitin Sulfates; Coronary Disease; Dermatan Sulfate; Drug Combinations; Heparin; Heparitin Sulfate; Humans; Serine Proteinase Inhibitors; Thrombocytopenia; Thrombosis; Treatment Failure

We report two pediatric patients with end-stage renal failure who developed heparin-induced thrombocytopenia type II (HIT II) on hemodialysis (HD). Both developed acute respiratory distress and chest pain within 30 min of initiating the 5th HD session. The platelets dropped during HD from 168 to 38x10(9)/l and from 248 to 109x10(9)/l, respectively. Marked clots were observed in the dialyzers. Substitution of heparin with the low molecular weight heparin dalteparin had no effect. Switching from anticoagulation to the heparinoid danaparoid resulted in immediate disappearance of all adverse effects, and further long-term HD was uneventful. HIT II was diagnosed clinically; heparin-induced platelet activation test (HIPA) and serum IgG, IgA, and IgM to heparin-platelet factor 4 complexes (HPF4) were both negative. We conclude that HIT II may occur in children on HD. HIT II is essentially a clinical diagnosis, as HIPA and antibodies to HPF4 are not always positive. Once HIT II is suspected, heparin (and low-molecular-weight heparins) should be stopped immediately. Long-term anticoagulation with danaparoid is a valuable option for patients on HD.

Topics: Adolescent; Anticoagulants; Child; Chondroitin Sulfates; Dalteparin; Dermatan Sulfate; Drug Combinations; Heparin; Heparitin Sulfate; Humans; Kidney Failure, Chronic; Male; Platelet Count; Renal Dialysis; Thrombocytopenia

Topics: Antibodies; Anticoagulants; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Drug Combinations; Female; Heparin; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Middle Aged; Recombinant Proteins; Thrombocytopenia

Management of anticoagulation in patients with heparin-induced thrombocytopenia (HIT) undergoing surgery requiring cardiopulmonary bypass (CPB), such as cardiac transplantation, represents a difficult clinical problem and no clear management strategy exists. The cases of 2 patients with HIT who underwent cardiac transplantation using differing anticoagulation strategies are presented with a discussion of potential advantages and pitfalls of each approach used.

Topics: Adult; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Fatal Outcome; Female; Heart Transplantation; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Partial Thromboplastin Time; Platelet Count; Thrombocytopenia; Warfarin

There is no consensus concerning thromboembolic prophylaxis in high-risk pregnant women with a previous history of heparin-induced thrombocytopenia. An alternative anticoagulant therapy is danaparoïd, whereas unfractioned and low-molecular-weight heparin therapy is contraindicated. We report a case of successful thrombosis prophylaxis using danaparoïd in a high-thrombosis-risk pregnant woman with a history of heparin-induced thrombocytopenia during a previous pregnancy and Widal's disease.

Topics: Adult; Anticoagulants; Aspirin; Asthma; Cephalosporins; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Drug Hypersensitivity; Female; Heparin; Heparinoids; Heparitin Sulfate; Humans; Pregnancy; Pregnancy Complications, Hematologic; Risk Factors; Thrombocytopenia; Thromboembolism

Topics: Anticoagulants; Body Weight; Chondroitin Sulfates; Contraindications; Dermatan Sulfate; Drug Monitoring; Heparin; Heparitin Sulfate; Humans; Kidney Failure, Chronic; Renal Dialysis; Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) has become more prevalent in today's cardiac setting and has resulted in the need for alternative anticoagulant therapies. Danaparoid sodium, one alternative to heparin, has been used in six cardiopulmonary bypass procedures in this hospital. This clinical experience has resulted in the progressive refinement of a protocol for the 'safe' clinical use of danaparoid sodium. Although there were six positive outcomes with the use of danaparoid sodium, alternatives must be explored in order to find the optimal anticoagulant for the treatment of HIT.

Topics: Adult; Aged; Anticoagulants; Cardiopulmonary Bypass; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Female; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Postoperative Complications; Thrombocytopenia

Topics: Adult; Aged; Anticoagulants; Cardiopulmonary Bypass; Chondroitin Sulfates; Coronary Artery Bypass; Coronary Disease; Dermatan Sulfate; Drug Combinations; Female; Heart-Lung Transplantation; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Thrombocytopenia

Topics: Anticoagulants; Aprotinin; Chondroitin Sulfates; Coronary Artery Bypass; Dermatan Sulfate; Hemostatics; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Thrombocytopenia

The authors describe a case of heparin-induced skin reaction due to two preparations of low molecular weight heparin in a pregnant woman. The main characteristics of heparin-related cutaneous allergy are reported. The use of an heparinoid, usually indicated for patients with heparin-induced thrombocytopenia, appeared to be efficient and safe for the mother and her fetus. An epidural analgesia was performed for labor analgesia, 24 hours after the last injection of danaparid of sodium.

Topics: Adult; Analgesia, Epidural; Analgesia, Obstetrical; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Drug Eruptions; Drug Hypersensitivity; Female; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Humans; Pregnancy; Pregnancy Complications; Thrombocytopenia

Topics: Anticoagulants; Chondroitin Sulfates; Critical Care; Dermatan Sulfate; Drug Combinations; Heparitin Sulfate; Humans; Thrombocytopenia

Topics: Anticoagulants; Antithrombin III; Antithrombins; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Femoral Vein; Fibrinolytic Agents; Heparin; Heparinoids; Heparitin Sulfate; Hirudin Therapy; Humans; Iliac Vein; Thrombocytopenia; Thrombolytic Therapy; Vena Cava, Inferior; Venous Thrombosis

Heparin-induced thrombocytopenia is a relatively uncommon but severe side-effect of heparin therapy. Heparin-induced IgG antibody has been elucidated to be the main isotype and the most pathogenic antibody in the pathophysiology. As affected patients are at high risk of developing thrombotic events, confirmation of the clinical diagnosis and avoidance of heparin re-exposure are important and desirable.. In the present study, heparin-induced IgG was measured by the binding of neoantigens, which were prepared by incubating FITC-heparin with platelet factor 4 present in normal serum. The cross-reactivities of heparin-induced IgG with low-molecular-weight heparin and danaparoid were analysed by competitive binding.. A total of 81 clinically suspected heparin-induced thrombocytopenia type II patients were analysed. Thirty-seven of 38 heparin-induced thrombocytopenia type II patients, in whom thromboembolism was confirmed by objective methods, had elevated relative fluorescence intensity ratios (patient normal control) and 36 had positive heparin-induced platelet activation results. The prevalence of heparin-induced IgG in heparin-induced thrombocytopenia type II patients was 97.4%. Positive heparin-induced IgG results were: 0/319 healthy volunteers, 0/38 other thrombo-cytopenia and 2/56 heparin/low-molecular-weight heparin-receiving patients without thrombocytopenia, 2/41 hyperbilirubinaemic patients and 2/50 hyperlipidaemic patients. A small amount of cross-reaction assays showed similar results as obtained in heparin-induced platelet activation.. Our results suggest that a very high frequency of heparin-induced IgG in heparin-induced thrombocytopenia type II patients can be detected using a novel antigen assay. The rapid determination of pathogenic heparin-induced IgG may be a useful tool for the rapid diagnosis of heparin-induced thrombocytopenia type II that could facilitate further management of the patients.

Topics: Adult; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Drug Combinations; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Humans; Immunoglobulin G; Sensitivity and Specificity; Thrombocytopenia

Only few reports exist addressing the problem of temporary pacemaker leads associated with thromboembolic disease. We report the case of a 67-year-old patient who required a temporary transfemoral pacemaker due to AV block grade III. The patient developed extensive right atrial and ventricle thrombus formation attached to the pacing wire, as well as venous thrombosis at the insertion site due to heparin-induced thrombocytopenia type II (HIT type II). After short-term thrombolysis with 1 mg rt-PA/kg b.w. complete resolution of all clots could be shown by B-mode sonography and transthoracic, as well as transesophageal echocardiography.

Topics: Aged; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Fibrinolytic Agents; Heart Atria; Heart Diseases; Heart Ventricles; Heparin; Heparinoids; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Pacemaker, Artificial; Thrombocytopenia; Thrombolytic Therapy; Thrombosis; Tissue Plasminogen Activator

No data exist regarding the inter-laboratory reproducibility of the heparin-induced-platelet-activation (HIPA) test, the most widely used functional assay in Germany for the detection of heparin-induced thrombocytopenia (HIT) antibodies.. Nine laboratories used an identical protocol to test eight different sera with the HIPA test. Five laboratories also tested the sera with a platelet factor 4 (PF4)/heparin-complex ELISA. Cross-reactivity with danaparoid-sodium was assessed using 0.2 aFXa units instead of heparin in the HIPA test.. Two of nine laboratories had no discrepant HIPA test results. Four laboratories differed in one sample, one reported two discrepant results, and two laboratories reported more than two discrepant results. Cross-reactivity with danaparoid-sodium test results differed among laboratories. PF4/heparin ELISA results were identical in all five laboratories.. The HIPA test requires strict quality control measures. Using both a sensitive functional assay (HIPA test) and a PF4/heparin ELISA will allow detection of antibodies directed to antigens other than PF4/heparin complexes as well as detection of IgM and IgA antibodies with PF4/heparin specificity.

Topics: Antibodies; Anticoagulants; Antigens, Human Platelet; Blood Donors; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Drug Combinations; Enzyme-Linked Immunosorbent Assay; False Negative Reactions; False Positive Reactions; Heparin; Heparitin Sulfate; Humans; Methods; Platelet Activation; Platelet Factor 4; Reproducibility of Results; Thrombocytopenia

Due to the extensive use of unfractionated heparins in France, there is considerable experience with heparin-induced thrombocytopenia (HIT). It is recommended that platelet counts be performed twice a week for three weeks when patients are treated with any form of heparin. A drop in platelet counts can, however, occur not only in HIT patients but also for other unrelated reasons. For diagnosing HIT, all laboratories in France use platelet aggregometry inspite of poor sensitivity. Both false positive and false negative results are obtained. The serotonin release test is not used in France. The ELISA test for HIT does not always correlate with the platelet aggregation test and many patients with a positive ELISA test do not necessarily have other evidence for HIT. This is especially true in patients following cardiopulmonary bypass surgery. None of the available laboratory tests reliably identify patients with HIT. Patients with HIT should not be managed with low-molecular-weight heparins, but danaparoid, argatroban and ancrod are viable options. Also, recombinant hirudin has been employed. All have advantages and disadvantages. At present, the diagnosis and management of patients with HIT remains difficult and properly designed clinical studies are needed to obtain answers to several open questions.

Topics: Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Enzyme-Linked Immunosorbent Assay; France; Heparin; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Platelet Aggregation; Platelet Function Tests; Recombinant Proteins; Thrombocytopenia

Topics: Adult; Anticoagulants; Bone Marrow Transplantation; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Enzyme Activation; Female; Fibrinolytic Agents; Heparin; Heparinoids; Heparitin Sulfate; Hirudin Therapy; Humans; Protein C; Recombinant Proteins; Thrombocytopenia

Cutaneous heparin-induced allergic reactions to subcutaneous heparin may begin 2-5 days after administration. The relation of the delayed-type hypersensitivity and a systemic immunologic response is controversial. The present investigation aimed to analyze the occurrence of thromboembolic complication, pathologic heparin-induced platelet activation (HIPA), and the presence of circulating heparin-induced IgG in patients with heparin-induced skin reactions.. Intracutaneous tests, HIPA assay, and heparin-heparin IgG antibodies were performed in nine patients with heparin-induced skin lesions.. Six of eight patients showed positive intracutaneous tests to heparin and to four low-molecular-weight heparins. Three of six heparin-positive patients presented hypersensitivity to a heparinoid, too. Two of three patients had a positive HIPA test and elevated heparin-induced IgG antibodies. Both patients developed complications presenting as heparin-induced skin necrosis or arterial thrombosis. Two of nine patients were treated with danaparoid, 4/9 patients received r-hirudin, and 1/9 received oral coumarin. In 2/9 patients, anticoagulant therapy was stopped, but these patients will receive r-hirudin if indicated.. On the basis of the coincidence of local and systemic hyperreactivity to heparin and danaparoid, patients with heparin-induced skin lesions should receive r-hirudin, a nonheparin compound, for anticoagulant treatment.

Topics: Adult; Aged; Anticoagulants; Antithrombins; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Drug Eruptions; Female; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Hypersensitivity, Delayed; Immunoglobulin G; Injections, Subcutaneous; Male; Middle Aged; Platelet Activation; Skin Tests; Thrombocytopenia

Heparin-induced thrombocytopenia is a rare and serious complication of anticoagulation therapy. There remains a paucity of information pertaining to alternative anticoagulation strategies for use during cardiopulmonary bypass concomitant with heparin-induced thrombocytopenia, especially in children. We report the successful treatment of heparin-induced thrombocytopenia and subsequent hemorrhagic complications postoperatively in a 2-year-old child with Danaparoid (orgaran). Emergent conduit revision with cardiopulmonary bypass was required for a thrombosed systemic-venous to pulmonary-arterial connection (completion modified Fontan procedure). Required doses of Danaparoid were consistently twofold that previously reported for adults.

Topics: Anticoagulants; Cardiopulmonary Bypass; Child, Preschool; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Female; Heart Defects, Congenital; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Thrombocytopenia; Thrombosis

Four classes of anticoagulants are now available: vitamin K antagonists, heparin, Orgaran and hirudin. For each of these classes the mechanism of the anticoagulant effect, the usual doses and biological monitoring are described. Each low molecular weight heparin must be considered as an original product. Orgaran and hirudin are new antithrombotic agents allowing to solve the dramatic problems raised by heparin-induced thrombocytopenia.

Topics: Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Heparin; Heparitin Sulfate; Hirudin Therapy; Humans; Thrombocytopenia; Vitamin K

An 80-year-old woman had been hospitalized in a psychiatric clinic where, on the 22nd day, she sustained a fracture of the neck of the left femur, which was treated by internal screw fixation. The postoperative course was at first without complication. But 9 days postoperatively her platelet count had fallen to 59,000/microliter. As heparin induced type II thrombocytopenia (HIT II) was suspected, the thrombosis prophylaxis with low-molecular heparin was replaced by sodium danaparoid (twice 750 units subcutaneously). Despite this, ischaemia of the right lower leg developed and required amputation. On the following day the left lower leg and foot also became ischemic, where upon she was admitted to the author's hospital (37 days after her admission to the psychiatric clinic).. The patient was in a reduced general condition (body-mass index 19.5 kg/m2). She was disoriented as to place and time. Her blood pressure was 140/80 mmHg, her pulse irregular with a ventricular rate of 100/min. The skin below the middle of the left lower leg was cold and livid and the pedal pulses were not palpable.. Haemoglobin content was 9.7 g/dl, the white cell count 9,200/microliter, and platelet count 54,000/microliter. Electrolytes and creatinine were within normal limits.. Thrombendarterectomy was performed once via the left groin under danaparoid anticoagulation. There was no re-occlusion and the patient was able to walk again.--It was ascertained subsequently, she had already been given ordinary heparin in the psychiatric clinic for 20 days. Her platelet count of around 70,000/microliter returned to normal even though heparin administration was continued.. A reduction in platelet count by more than half during heparin treatment suggests heparin-induced thrombocytopenia, in which case heparin should be discontinued at once. In high-risk patients adequate treatment should be initiated with other anticoagulants even before the occurrence of thromboembolism.

Topics: Aged; Aged, 80 and over; Amputation, Surgical; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Endarterectomy; Female; Heparin; Heparinoids; Heparitin Sulfate; Humans; Ischemia; Leg; Recurrence; Thrombocytopenia; Thromboembolism; Thrombosis

Two types of thrombocytopenia occur during treatment with heparin: type I and type II heparin-induced thrombocytopenia (HIT). Type I HIT is due to a direct interaction between heparin and platelets. They are asymptomatic, occur early, mild and transitory. Type II HIT which is immunoallergic in nature is the most important complication of this treatment. The thrombocytopenia has a different presentation, acute with a fall in platelets over 30 per cent and is often associated with the occurrence or worsening of a venous or arterial thrombotic episode. The major problems of this secondary type are threefold: its recognition, its confirmation and its management should be as early as possible to avoid the development of often dramatic complications which compromise the prognosis. Laboratory investigations are required by highly reliable specialist laboratories following a careful clinical history. The natural history of the platelet count should enable the difficult diagnosis of HIT to be made more accurately. The treatment of confirmed HIT and/or symptomatic HIT often requires a multidisciplinary approach from a specialized team involving clinicians and hematologists. Two therapies with the benefit of large experience have just been obtained in France with marketing approval (AMM) for the management of HIT: danaparoid (Orgaran) and recombinant hidurin, lepirudin (Refludan). A declaration to the regional drugs monitoring center should not be omitted. In addition, each patient should be given a certificate confirming the immunallergy thus avoiding any further exposure with potentially dramatic consequences.

Topics: Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Diagnosis, Differential; Drug Combinations; Heparin; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Recombinant Proteins; Thrombocytopenia

Danaparoid sodium is an antithrombin composed of 3 glycosaminoglycans: heparan sulfate, dermatan sulfate and chondroitin sulfate. Similar to heparin, danaparoid operates by activating antithrombin 3, but does not contain heparin or heparin fragments, and is therefore antigenically distinct. Danaparoid has been advocated as a safe and effective anticoagulant for heparin-associated thrombocytopenia. However, there is little experience in its use as a substitute for heparin in hemodialysis. We report 2 men, aged 82 and 73 years, respectively, who developed thrombocytopenia while undergoing hemodialysis with heparin, and who subsequently underwent successful dialysis with danaparoid. There was a rise in platelet levels in both while receiving danaparoid, and dialysis was completed without hemorrhagic or thrombotic complications. Danaparoid is a safe and effective substitute for heparin, and may be used as an anticoagulant in hemodialysis.

Topics: Aged; Aged, 80 and over; Antithrombin III; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Heparin; Heparitin Sulfate; Humans; Kidney Failure, Chronic; Male; Nephrotic Syndrome; Platelet Aggregation; Renal Dialysis; Thrombocytopenia

Patients with cardiovascular disorders frequently need anticoagulation for diagnostic studies, surgical procedures, and therapy. Heparin-induced thrombocytopenia is a relatively common complication of heparin therapy that can result in thrombosis and subsequent limb loss or death, necessitating use of alternative anticoagulants.. Two patients who needed cardiac surgery had thrombocytopenia induced by exposure to heparin and heparin-coated tubing. Several assays were examined for their ability to monitor intraoperative anticoagulation of a factor Xa inhibitor, danaparoid sodium.. In vitro, celite and kaolin activated dotting times and activated partial thromboplastin time were prolonged linearly in the presence of increasing concentrations of danaparoid sodium. Aprotinin did not alter the linearity of the response but did alter its slope. In vivo, activated clotting times and activated partial thromboplastin time were insensitive to clinically significant changes in danaparoid sodium plasma levels during cardiopulmonary bypass. Correction in activated partial thromboplastin time lagged 2 hours behind clinically important changes in anti-factor Xa levels. Only anti-factor Xa levels were adequate to monitor intraoperative danaparoid sodium levels.. Anticoagulation for cardiopulmonary bypass can be successfully performed with danaparoid sodium and intraoperative anti-factor Xa monitoring.

Topics: Adult; Anticoagulants; Blood Coagulation Tests; Chondroitin Sulfates; Coronary Artery Bypass; Dermatan Sulfate; Drug Combinations; Drug Monitoring; Factor Xa Inhibitors; Female; Heart Transplantation; Heparin; Heparinoids; Heparitin Sulfate; Humans; Male; Middle Aged; Monitoring, Intraoperative; Platelet Activation; Thrombocytopenia; Time Factors

Two types of heparin-associated thrombopenia can be distinguished. Patients with the type II condition present a particularly difficult management problem when they require full anticoagulation. There is no consensus about the proper anticoagulation management for type II patients who have to undergo cardiopulmonary bypass. The case is reported of a type II heparin-associated thrombopenia patient who underwent successful aortocoronary saphenous vein grafting. Sodium-danaparoid was used for anticoagulation. The anti-factor Xa level was kept below the value reported in the literature for patients undergoing cardiopulmonary bypass. No fibrin formation was observed during the time of cardiopulmonary bypass, nor was any severe postoperative haemorrhage seen, as is frequently described in the literature.

Topics: Aged; Anticoagulants; Cardiopulmonary Bypass; Chondroitin Sulfates; Coronary Artery Bypass; Coronary Disease; Dermatan Sulfate; Drug Combinations; Heparin; Heparinoids; Heparitin Sulfate; Humans; Intraoperative Care; Male; Postoperative Hemorrhage; Saphenous Vein; Thrombocytopenia

Heparin is the standard anticoagulant for patients undergoing cardiopulmonary bypass. There are some patients for whom heparin is unsuitable and ancrod (a defibrinogenating enzyme) has been used as an alternative. We present a patient with heparin-induced thrombocytopenia in whom treatment ancrod was ineffective. The addition of danaparoid sodium (a heparinoid) allowed safe cardiopulmonary bypass. We discuss the reasons for this and suggest that the combination of ancrod and danaparoid sodium is a logical one in such cases.

Topics: Ancrod; Anticoagulants; Aortic Valve Stenosis; Cardiopulmonary Bypass; Chondroitin Sulfates; Coronary Disease; Dermatan Sulfate; Drug Combinations; Drug Therapy, Combination; Female; Heparin; Heparinoids; Heparitin Sulfate; Humans; Middle Aged; Thrombocytopenia

Topics: Aged; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Female; Hemofiltration; Heparitin Sulfate; Humans; Thrombocytopenia

Topics: Aged; Anticoagulants; Arteries; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Fatal Outcome; Heparinoids; Heparitin Sulfate; Humans; Male; Pulmonary Embolism; Thrombocytopenia; Thrombosis

Topics: Adult; Antithrombin III; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Female; Heparitin Sulfate; Humans; Obstetric Labor Complications; Pregnancy; Pregnancy Complications, Cardiovascular; Thrombocytopenia; Thrombophlebitis; Ultrasonography, Doppler

Heparin is considered necessary during percutaneous coronary interventions; however, heparin is contraindicated in patients with heparin-induced thrombocytopenia and/or heparin antibodies. We describe the successful use of the heparinoid Orgaran (danaparoid sodium) in addition to abciximab (ReoPro) in a patient with heparin antibodies who required rotational atherectomy.

Topics: Abciximab; Antibodies; Antibodies, Monoclonal; Anticoagulants; Atherectomy, Coronary; Blood Coagulation; Chondroitin Sulfates; Coronary Angiography; Coronary Disease; Dermatan Sulfate; Heparin; Heparinoids; Heparitin Sulfate; Humans; Immunoglobulin Fab Fragments; Intraoperative Period; Male; Middle Aged; Thrombocytopenia

Topics: Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Fibrinolytic Agents; Heparin; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Recombinant Proteins; Thrombocytopenia; Thrombophlebitis

Topics: Acute Kidney Injury; Aged; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Lung Diseases; Male; Phlebography; Renal Dialysis; Thrombocytopenia; Venous Thrombosis

Topics: Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Fibrinolytic Agents; Heparin; Heparitin Sulfate; Humans; Thrombocytopenia

Heparin-associated thrombocytopenia occurred in a patient during continuous renal replacement therapy (CRRT), resulting in repeated clotting of the extracorporeal circuit and spontaneous hemorrhage. The peripheral platelet count initially appeared to improve by changing to prostacyclin and dalteparin. However, repeated CRRT circuit clotting recurred, and the platelet count decreased once again. This time the synthetic heparinoid, Orgaran (danaparoid), was used and was associated with successful CRRT and return of the platelet count.

Topics: Adult; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Female; Heparin; Heparitin Sulfate; Humans; Kidney; Multiple Trauma; Platelet Count; Pregnancy; Recurrence; Renal Replacement Therapy; Rupture; Suicide, Attempted; Thrombocytopenia

Topics: Aged; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Heparin; Heparitin Sulfate; Humans; Male; Thrombocytopenia; Thrombosis

Heparin-induced thrombocytopenia is an immuno-mediated life-threatening side effect of heparin therapy which poses difficulties in diagnosis and major therapeutic problems. Heparin must be instantly discontinued. We describe the case of a 60-year-old male patient with type II heparin-induced thrombocytopenia, complicated by progressive deep venous thrombosis and pulmonary embolism. He failed to improve when therapy was continued with a low molecular weight heparin (Fragmin) and high doses of intravenous immunoglobulins were administered. The test for heparin-dependent platelet aggregation was positive for unfractionated heparin and low molecular weight heparin, but negative for the heparinoid Org 10172. During subsequent anticoagulant therapy with Org 10172 for seven days the number of platelets increased rapidly and the patient recovered. Nine months later Org 10172 was used again in this patient for thrombosis prophylaxis without any adverse effects. In patients with heparin-induced thrombocytopenia requiring immediately acting anticoagulant therapy, Org 10172 can be considered as an effective alternative drug to unfractionated and low molecular weight heparins.

Topics: Anticoagulants; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Dose-Response Relationship, Drug; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Humans; Infusions, Intravenous; Male; Middle Aged; Platelet Aggregation; Pulmonary Embolism; Thrombocytopenia; Thrombophlebitis

Topics: Anticoagulants; Cardiopulmonary Bypass; Chondroitin Sulfates; Dermatan Sulfate; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Plasmapheresis; Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) together with simultaneously occurring thromboembolism is a serious complication of heparin treatment. At present an immunologic cause of this side effect of heparin is equivocally accepted. However, further anticoagulation of these patients is still debated. The present article summarizes the treatment of 20 patients with such complications. Two of these patients did not develop thrombocytopenia but presented cutaneous allergy or necrosis. All patients were treated either with intravenous heparinoid (Orgaran) or with low-molecular-weight heparin without/with simultaneous intravenous high-dose immunoglobulins or with intravenous r-hirudin. Based on these experiences the treatment of choice depends at present on the availability of the anticoagulants and on the local experience with the different anticoagulants. In the future r-hirudins and other nonheparin thrombin inhibitors may become the drugs of choice in this indication. Surgical intervention has to be considered additionally.

Topics: Adult; Aged; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Female; Heparin; Heparin, Low-Molecular-Weight; Heparinoids; Heparitin Sulfate; Humans; Injections, Intravenous; Male; Middle Aged; Thrombocytopenia; Thromboembolism

We report a case of heparin-induced thrombocytopenia with in vitro antibody cross-reactivity by platelet aggregometry to both low molecular weight heparin and the heparinoid Org 10172 (Orgaran). The in vitro reactivity with Orgaran was only present at the upper limit of concentrations that would normally be used therapeutically. Low dose Orgaran therapy was initiated, allowing successful renal replacement therapy without invoking further thrombocytopenia or thrombosis. Interestingly, in vitro platelet aggregometry following treatment did not reveal increasing sensitivity to Orgaran. This case indicates that negative in vitro platelet aggregometry at defined lower concentrations of Orgaran may predict in vivo safety at the same levels despite positive platelet aggregometry reactions at higher concentrations of Orgaran.

Topics: Aged; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Dose-Response Relationship, Drug; Heparin; Heparitin Sulfate; Humans; Male; Platelet Aggregation; Reproducibility of Results; Thrombocytopenia

Topics: Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Enoxaparin; Heparin; Heparinoids; Heparitin Sulfate; Humans; Thrombocytopenia

Anticoagulation for cardiopulmonary bypass in patients with heparin-induced thrombocytopenia requires the use of other anticoagulants. We report a case in whom this was achieved using the heparinoid danaparoid (Orgaran). Based on our experience and a review of the literature, we provide guidelines for managing these rare patients. A danaparoid dose substantially lower than that recommended by the manufacturer may minimize bleeding complications.

Topics: Anticoagulants; Cardiopulmonary Bypass; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Humans; Male; Middle Aged; Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is frequently associated with antibodies (Abs) to heparin-PF4 complexes (H-PF4). In order to investigate whether there are variations in specificity of Abs, we studied 63 samples from patients with suspected HIT. Two groups of samples were separated after comparing their reactivity against H-PF4 or recombinant PF4 (r-PF4) using ELISA. In group Ab1 (n = 46), Abs only or mainly bound to H-PF4 complexes and thus most of the epitopes recognized probably involved both heparin and PF4. In group Ab2 (n = 17), Abs exhibited similar reactivity to r-PF4 and H-PF4, and the antigens recognized were possibly neoepitopes mainly expressed by modified PF4 and by H-PF4 complexes. Platelet activation tests were positive with 56 samples containing high titres of Abs to H-PF4. Most samples (n = 59) contained IgG antibodies, often associated with IgA antibodies which were more frequently found in group Ab2, and/or IgM. With unfractionated heparin treatment, HIT was associated with Ab1 or Ab2 antibodies, whereas only Ab1 antibodies were detected after low-molecular-weight heparin (LMWH). Furthermore, cross-reactivity with danaparoid sodium was present only in group Ab1 and mainly involved LMWH-treated patients.

Topics: Adult; Aged; Aged, 80 and over; Antibodies; Antibody Specificity; beta-Thromboglobulin; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Enzyme-Linked Immunosorbent Assay; Female; Heparin; Heparitin Sulfate; Humans; Interleukin-8; Male; Middle Aged; Peptides; Platelet Activation; Platelet Factor 4; Thrombocytopenia

Topics: Abdomen; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Humans; Randomized Controlled Trials as Topic; Thrombocytopenia; Thrombophlebitis

Heparin-induced thrombocytopenia type II (HIT-II) is a serious complication in heparin treatment. Because of arterial and/or venous thromboembolism, HIT-II quite often takes a life-threatening course. This article describes the clinical course of seven trauma patients, who developed HIT-II during thromboembolism prophylaxis with unfractionated heparin (UFH, Heparin-Natrium-Nattermann, 250,000 I.E., Rhone-Poulenc Rorer GmbH), given subcutaneously. Thromboembolic complications occurred in 5 out of 7 cases (71.4%). One case took a fatal course (14.3%). UFH was replaced by Orgaran when HIT-II was suspected or diagnosed. There were no more complications. Thrombocyte count increased to normal values within 3 to 9 days. The importance of HIT-II in heparin therapy during in- and outpatient therapy is discussed with reference to the current literature.

Topics: Aged; Aged, 80 and over; Anticoagulants; Arthroplasty, Replacement, Hip; Chondroitin Sulfates; Dermatan Sulfate; Female; Femoral Neck Fractures; Heparin; Heparitin Sulfate; Hip Fractures; Humans; Male; Middle Aged; Multiple Trauma; Osteoarthritis, Hip; Platelet Count; Postoperative Complications; Thrombocytopenia; Thromboembolism

Topics: Aged; Anticoagulants; Blood Coagulation; Cardiopulmonary Bypass; Chondroitin Sulfates; Dermatan Sulfate; Heparin; Heparitin Sulfate; Humans; Male; Thrombocytopenia

An 84-year-old patient with heparin-induced thrombocytopenia (HIT), global cardiac decompensation, and acute renal failure underwent a cardiosurgical intervention using an extracorporeal circuit. For systemic anticoagulation danaparoid (Orgaran) was applied as a heparin substitute preoperatively and maintained for systemic anticoagulation during ECC despite it being eliminated by the kidney. The postoperative recovery was prolonged due to bleeding complications. During cardiopulmonary bypass (216 min) the target level of anti-factor Xa was 1.5 UI/ml. This required continuous infusion and an occasional bolus of danaparoid. Coagulation in the extracorporeal circuit was observed twice at plasma levels below 1.4 IU/ml. There were no thromboembolic or neurologic events. We did not retransfuse blood from the extracorporeal circuit or the cardiotomy reservoir after bypass, but because elimination of danaparoid was impaired in this patient and there is no neutraliser available antifactor Xa postoperatively exceeded 0.6 IU/ml for 30 hours. Diffuse bleeding with tamponade resulted. Weaning the patient from the respirator was achieved 12 hours after the last re-exploration. From the 4th postoperative day 750 IU of danaparoid were administered twice daily subcutaneously for thrombosis prevention. On the 6th postoperative day discharge from the ICU was possible. We conclude that the application of danaparoid for cardiopulmonary bypass in patients suffering from acute renal failure may be complicated by hemorrhage.

Topics: Acute Kidney Injury; Aged; Aged, 80 and over; Anticoagulants; Chondroitin Sulfates; Coronary Artery Bypass; Coronary Disease; Dermatan Sulfate; Drug Combinations; Female; Heparin; Heparinoids; Heparitin Sulfate; Humans; Thrombocytopenia

The treatment of heparin-induced thrombocytopenia in pregnancy is uncertain. Warfarin is contraindicated and ancrod is of unknown safety. Low-molecular-weight heparin should not be used because of cross-reactivity with unfractionated heparin. We report a case of heparin-induced thrombocytopenia during pregnancy treated successfully with danaparoid.. A 25-year-old woman pregnant with twins developed heparin-induced thrombocytopenia after starting heparin therapy for a deep vein thrombosis. Treatment was initiated with danaparoid by subcutaneous injection and was continued until the time of delivery. Treatment was completed with 6 weeks of warfarin therapy postpartum. No fetal or maternal ill effects were observed.. Danaparoid, which has low cross-reactivity for heparin-dependent antibodies and no known fetopathic effects, was used successfully to treat our patient, who developed heparin-induced thrombocytopenia during pregnancy. Danaparoid may be the treatment of choice for this difficult clinical situation in which there are limited therapeutic options.

Topics: Adult; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Female; Heparin; Heparinoids; Heparitin Sulfate; Humans; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy, Multiple; Thrombocytopenia; Twins; Venous Thrombosis

In patients with heparin-induced thrombocytopenia undergoing cardiac operations, anticoagulation with heparin should be avoided. The low-molecular-weight glycosaminoglycan Orgaran has been used as an alternative, but the overall experience is limited.. Two patients with heparin-induced thrombocytopenia underwent cardiopulmonary bypass using Orgaran for anticoagulation. A 30-year-old woman suffered from emboli to her brain through a secondary atrial septal defect, a 14-year-old boy from ischemia of his left leg due to recurrent embolism originating from the mitral valve. In both cases, cardiopulmonary bypass was performed in a routine manner, except for using low-dose Orgaran instead of heparin. Anticoagulation was monitored during cardiopulmonary bypass by measuring Orgaran plasma levels and activated clotting time.. No thromboembolic or bleeding complications occurred during and after atrial septal defect repair and mitral valve replacement, respectively. In the former case, thrombotic material from the inferior vena cava was removed during hypothermic circulatory arrest within the same procedure. Activated clotting time did not correlate with plasma levels of Orgaran.. Orgaran might be a useful alternative for anticoagulation during extracorporeal circulation. Adequate dosages and measurement of plasma levels are recommended for its use in cardiopulmonary bypass.

Topics: Adolescent; Adult; Anticoagulants; Cardiopulmonary Bypass; Chondroitin Sulfates; Dermatan Sulfate; Female; Heart Septal Defects, Atrial; Heart Valve Diseases; Heparin; Heparitin Sulfate; Humans; Male; Mitral Valve; Thrombocytopenia; Thromboembolism; Treatment Outcome

Heparin-induced thrombocytopenia (HIT) with thrombosis is a rare, but important complication of heparin therapy. We describe the case of a 53-year-old patient hospitalized with complicated pelvic fracture. Intravenous infusion of unfractionated heparin (15'000 IU/24 h) was given for thrombosis prevention. After 11 days' treatment the patient developed deep venous thrombosis of the left calf, complicated 2 days later by massive bilateral pulmonary embolism. Simultaneous with these thromboembolic events, thrombocytopenia, signs of activated coagulation, and antibodies to heparin occurred. In the context of this case the diagnostic and therapeutic possibilities of HIT, and in particular treatment with the heparinoid danaproid (Orgaran), are discussed.

Topics: Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Fractures, Bone; Heparin; Heparinoids; Heparitin Sulfate; Humans; Male; Middle Aged; Pelvic Bones; Pulmonary Embolism; Thrombocytopenia; Thrombosis

A 15-year-old boy developed deep vein thrombosis of the right leg 9 days after appendectomy. In spite of three courses of thrombolysis with streptokinase and effective heparinization the thrombosis progressed with additional occlusion of the left iliac vein. Although platelet counts were constantly normal, heparin-associated thrombocytopenia was suspected as the cause of the new venous occlusions. This diagnosis was confirmed by detecting heparin-associated antibodies with the heparin-induced platelet activation test. Therapy was instituted replacing heparin by the low molecular weight heparinoid Orgaran. Bilateral recanalization occurred within 6 days.. Heparin-associated thrombocytopenia must be considered if thrombosis occurs or progresses despite effective heparinization even in the absence of thrombocytopenia.

Topics: Adolescent; Chondroitin Sulfates; Dermatan Sulfate; Diagnosis, Differential; Fibrinolytic Agents; Heparin; Heparitin Sulfate; Humans; Male; Platelet Activation; Thrombocytopenia; Thrombophlebitis

Topics: Adult; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Heparin; Heparitin Sulfate; Humans; Male; Renal Dialysis; Thrombocytopenia

We report the cases of two patients who last lims as a result of heparin-induced thrombocytopenia (HIT). On the basis of these cases, the incidence, pathophysiology and the diagnosis of HIT are reviewed. For the diagnosis of HIT, the platelet aggregation test and ELISA are used. For HIT prophylaxis and treatment of thromboembolic complications is recommended Orgaran. Exact dosage schedules are provided.

Topics: Aged; Amputation, Surgical; Arm; Chondroitin Sulfates; Dermatan Sulfate; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Female; Fibrinolytic Agents; Heparin; Heparitin Sulfate; Humans; Middle Aged; Platelet Aggregation; Risk Factors; Thrombocytopenia; Thrombosis

Deep vein thrombosis of the right leg occurred in a 77-year-old woman after percutaneous cardiac catheterization via the right femoral vein, performed to assess mitral valve disease with atrial fibrillation. She thereupon received intravenous heparin (1,000 IU/h; partial thromboplastin time 60-70s). 13 days later she developed a transient incomplete right brachiofacial hemiparesis with motor aphasia. Transthoracic echocardiography revealed a fresh left atrial thrombus. Platelet count fell from initially normal levels to 20 x 10(9)/l. Because type II heparin-associated thrombocytopenia was suspected heparin administration was discontinued and phenprocoumon administered. Heparin-dependent antibodies were demonstrated with the heparin-induced platelet activation test. Cross reactions occurred in vitro against all low-molecular heparins and heparinoid ORG 10172. The platelet count had become normal 17 days later, the leg veins had recanalized and the intraatrial thrombus had become much smaller. The patient declined cardiac surgery and was discharged on the 41st hospital day in satisfactory general condition on maintenance anticoagulant dosage.

Topics: Aged; Antibodies; Anticoagulants; Atrial Fibrillation; Cardiac Catheterization; Chondroitin Sulfates; Coronary Thrombosis; Dermatan Sulfate; Echocardiography; Female; Heparin; Heparinoids; Heparitin Sulfate; Humans; Mitral Valve Stenosis; Partial Thromboplastin Time; Phenprocoumon; Platelet Count; Thrombocytopenia; Thrombophlebitis

Topics: Aged; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Embolism; Female; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Thrombocytopenia

Heparin-associated thrombocytopenia (HAT) is a relative frequent complication of thromboembolic prophylaxis and therapy. There is good evidence that the more severe HAT Type II is caused by an antibody dependent on polysulfated oligosaccharide epitopes. At present, low molecular weight heparins are used with varying success in patients with HAT that require further anticoagulation, although there are several known cases of cross reactivity between standard and low molecular weight heparins. Using our present case as an example, we show that the In-vitro- diagnostic of cross-reactivity is an indispensable precondition for any sufficient therapy. Additionally, we give support to previous findings that the low-grade sulfated heparinoid Org 10,172 shows no (or less) cross reactivity with standard or low molecular weight heparins. Thus, it might be the most appropriate choice if an anticoagulation is necessary before the results of In-vitro-diagnostics are available.

Topics: Adult; Anticoagulants; Cesarean Section; Chondroitin Sulfates; Cross Reactions; Dalteparin; Dermatan Sulfate; Dose-Response Relationship, Drug; Female; Heparin; Heparitin Sulfate; Humans; Platelet Count; Pre-Eclampsia; Pregnancy; Puerperal Disorders; Thrombocytopenia; Thromboembolism

Topics: Aged; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Heparin; Heparitin Sulfate; Humans; Male; Thrombocytopenia; Treatment Failure

The 29-year-old, heroin-addicted patient received an aortic valve prosthesis (SJM) 10 years ago because of aortic valve stenosis III. One year after surgical treatment he refused to take Phenprocoumon and thus received no anticoagulation for 9 years. The patient was hospitalized due to cardial decompensation and thrombosis of the aortic valve prosthesis was diagnosed. Under heparinization, he developed heparin-induced thrombocytopenia type II, which disappeared after changing the medication to Danaparoid-Sodium. In order to avoid any further heparin exposure, we also carried out the surgical replacement of the aortic valve prosthesis under anticoagulation with Danaparoid-Sodium.

Topics: Adult; Aortic Valve Stenosis; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Heart Valve Prosthesis; Heparin; Heparitin Sulfate; Heroin Dependence; Humans; Male; Platelet Count; Postoperative Complications; Prosthesis Failure; Reoperation; Thrombocytopenia; Thrombosis

A 48-yr-old patient was admitted to the ICU for cardiogenic shock and acute renal failure after coronary artery bypass graft surgery. A heparin-induced thrombocytopenia (HIT) occurred during haemodialysis with unfractioned heparin (UFH) as the anticoagulant. The dialysers, the circuits and the catheters were recurrently thrombosing and the platelet count decreased to 9 G.L-1 on postoperative day 7. UFH was discontinued. Attempts to substitute UFH with a low molecular weight heparin (LMWH) failed, due to the presence of a high cross-reactivity rate of LMWH with the heparin-dependent antibody. Intermittent haemodialysis without anticoagulation using a predilution of the dialysers failed also and resulted in recurrent clotting. After informed consent of the patient, a new natural heparinoid Orgaran (Org 10172, Organon, Oss Holland) was administered. This agent is a mixture of several non heparin low molecular weight glycosaminoglycans, with proven anticoagulant efficacy, low cross-reactivity with the HIT antibody, and a half-time prolonged over 18-25 hours. The treatment regimen consisted in a i.v. bolus of 40-45 IU.kg-1 prior to each dialysis procedure, performed every two days. The platelet count increased to 200 G.L-1, seven days after discontinuing heparin injection, and remained stable during the administration of Orgaran. No other thrombosis occurred again. Each procedure of four hours duration was monitored with the plasma anti-Xa activity and APTT test. The mean anti-Xa plasma concentrations (0.44 +/- 0.55 IU.mL-1, 30 min after injection of Orgaran) were well correlated with APTT test (r = 0.73, p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Anticoagulants; Blood Coagulation Tests; Chondroitin Sulfates; Critical Care; Dermatan Sulfate; Factor Xa Inhibitors; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Platelet Count; Renal Dialysis; Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a severe complication of heparin therapy. Life-threatening thromboembolism (HITT) may occur in a large number of patients with HIT. In this article diagnostic problems and the clinical course of 4 typical patients are described. Diagnosis was based on the occurrence of thrombocytopenia during heparin therapy and was confirmed in vitro by an ELISA to heparin-platelet factor 4 antibodies, heparin-induced platelet activation assay (HIPAA) or the platelet aggregation assay (PAA). Thrombotic complications developed in 2 patients, one of whom suffered a fatal embolism after accidentally rechallenging with low-dose heparin which was used to maintain the patency of an intravascular catheter. After discontinuation of heparin the thrombocyte count rapidly increased to normal values during treatment with the heparinoid danaparoid (Orgaran) without complications.

Topics: Aged; Blood Coagulation Tests; Chondroitin Sulfates; Dermatan Sulfate; Diagnosis, Differential; Drug Combinations; Female; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Platelet Count; Platelet Function Tests; Thrombocytopenia

The incidence of cross-reactivity between unfractionated heparin and LMWH, fragmin, in patients with HIT is significantly lower (6/15, 40%) than hitherto reported in the literature. 7/9 patients with a negative cross-reactivity test were treated with dalteparin sodium (Fragmin) without any untoward events.

Topics: Adult; Aged; Aged, 80 and over; Chondroitin Sulfates; Dalteparin; Dermatan Sulfate; Drug Interactions; Female; Heparin; Heparin, Low-Molecular-Weight; Heparinoids; Heparitin Sulfate; Humans; Male; Middle Aged; Thrombocytopenia

Topics: Cells, Cultured; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Drug Combinations; Fibrinolytic Agents; Heparin; Heparitin Sulfate; Humans; Platelet Aggregation; Polysaccharides; Thrombocytopenia

A simple rapid platelet aggregation test was used to evaluate cross-reactivity of four low molecular weight heparins and the heparinoid ORG 10172 in three patients with heparin-induced thrombocytopenia. The low molecular weight heparins cross-reacted in 11 out of 12 tests. The heparinoid ORG 10172 did not cross-react in any of the patients. One patient was treated with ORG 10172 and thrombocytopenia resolved.

Topics: Adult; Aged; Anticoagulants; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Female; Glycosaminoglycans; Heparin; Heparin, Low-Molecular-Weight; Heparinoids; Heparitin Sulfate; Humans; Platelet Aggregation; Thrombocytopenia

Topics: Adolescent; Adult; Aged; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Female; Heparin; Heparinoids; Heparitin Sulfate; Humans; Male; Middle Aged; Thrombocytopenia; Treatment Outcome; Warfarin

Topics: Aged; Chondroitin Sulfates; Dermatan Sulfate; Female; Glycosaminoglycans; Heparin; Heparinoids; Heparitin Sulfate; Humans; Kidney Failure, Chronic; Molecular Weight; Renal Dialysis; Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) with thrombosis occurs in about 1 in 2,000 heparin-treated patients. The arterial or venous thromboses may threaten life and limb hence alternative anticoagulation is needed. Some alternative treatments are possible i.e. LMWH, Ancrod, prostacyclin analogues, Dextran, aspirin and oral anticoagulants, but each has its drawbacks. This report reviews treatment of HIT patients with Orgaran (Org 10172), a low molecular weight heparinoid. Because of its proven antithrombotic activity Orgaran was used to treat 230 HIT patients. One hundred and fifty, nine patients presented with at least one thrombotic problem, which in 88 was due to the heparin use. 92.8% of the patients were considered to have adequately responded to Orgaran during the treatment period. Fifty-nine deaths (25.7%) occurred of which 7 (3.0%) were attributed to Orgaran use. The remaining 52 deaths, 27 of which occurred after Orgaran treatment was successfully terminated, were due to the severe underlying disorders in these patients. These results and the lower cross-reactivity rate (approximately 10%) with the heparin-induced antibody compared with that of the LMWH (> 90%) suggest that although problems remain, Orgaran can be a valuable alternative treatment for patients who suffer from HIT and who require anticoagulation.

Topics: Adult; Aged; Anticoagulants; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Drug Therapy, Combination; Female; Glycosaminoglycans; Hematologic Tests; Heparin; Heparinoids; Heparitin Sulfate; Humans; Incidence; Male; Middle Aged; Platelet Count; Pregnancy; Pregnancy Complications, Hematologic; Thrombocytopenia; Treatment Outcome

A pregnant woman treated with unfractionated heparin for pelvic vein thrombosis in the 26th week of her first pregnancy developed heparin-associated thrombocytopenia. Diagnosis was verified by the heparin induced platelet activation (HIPA) assay, which revealed cross reactivity to various LMW heparins, but not to the LMW heparinoid Org 10172. Upon intravenous (i.v.) anticoagulation with the heparinoid Org 10172 the platelet count returned to normal within 6 days and remained stable throughout the entire treatment period. After 3 weeks i.v. treatment with Org 10172, administration was changed to the subcutaneous route. At term a healthy boy was delivered spontaneously. No Org 10172 was detected in the cord blood, while therapeutic levels were measured in the maternal blood. The infant's platelet count was normal, but serum from the cord blood induced platelet activation in the presence of heparin, indicating the transplacental passage of heparin-dependent maternal antibodies.

Topics: Adult; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Embryonic and Fetal Development; Female; Glycosaminoglycans; Heparin; Heparinoids; Heparitin Sulfate; Humans; Infant, Newborn; Male; Pregnancy; Pregnancy Complications, Hematologic; Prospective Studies; Thrombocytopenia

Low molecular weight heparin (LMWH) and heparinoids have been offered as alternatives to unfractionated heparin (UH) to patients with heparin-associated antiplatelet antibodies (HAAb) and heparin-induced thrombocytopenia syndrome (HIT). Some of these patients have had continued HIT in the presence of the UH substitutes. It would seem important to know whether the heparin substitute is likely to cause patients' platelets to aggregate before administering the substitute to patients with HAAb.. Patients with HIT were identified as having HAAb by positive platelet aggregometry testing with commercial UH. Plasmas from 51 patients with HAAb were tested for the ability to aggregate platelets in the presence of two LMWHs (Mono-Embolex NM and Fragmin) and one heparinoid (Org 10172).. The proportions of plasmas reacting to each UH substitute are Mono-Embolex NM, 60.8%; Fragmin, 25.5%; and Org 10172, 19.6%. Although Fragmin and Org 10172 aggregated platelets in the presence of HAAb significantly less often than Mono-Embolex NM (p < 0.001), a patient with HAAb has a substantial chance of reacting to one of these UH substitutes.. Before giving a LMWH or heparinoid to a patient with HAAb, one should determine with in vitro testing that the patient's HAAb will not cause platelet aggregation in the presence of the heparin substitute.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies; Chondroitin Sulfates; Dalteparin; Dermatan Sulfate; Dihydroergotamine; Drug Combinations; Female; Glycosaminoglycans; Heparin; Heparin, Low-Molecular-Weight; Heparinoids; Heparitin Sulfate; Humans; Male; Middle Aged; Platelet Aggregation; Thrombocytopenia

A patient suffering from heparin-associated thrombocytopenia (HAT), recurrent arteriothromboses, and acute renal failure after treatment with standard heparin is described. He failed to improve when therapy was continued with low-molecular-weight (LMW) heparin (Fragmin, Kabi Pfrimmer, Erlangen, FRG). By means of the in vitro heparin-induced platelet activation (HIPA) assay it was shown that standard heparin and the LMW heparins Fragmin and Fraxiparin (Sanofi Labaz, Munich, FRG), as well as the enoxaparine Clexane (Nattermann, Cologne, FRG), all induced platelet activation with the patient's serum. In contrast, the LMW heparinoid Org 10172 (Organon, Oss, The Netherlands) did not cause platelet activation. When the patient was subsequently treated by parenteral administration of Org 10172 as anticoagulant over a period of several weeks the number of platelets rapidly increased and the patient almost completely recovered. This case shows that strong in vivo and in vitro cross-reactivity between standard heparin and LMW heparins may occur, but can be avoided by the use of a novel heparinoid, Org 10172. The HIPA assay provides a simple and sensitive laboratory method for the choice of an innocuous heparin or heparinoid for continued parenteral anticoagulation.

Topics: Aged; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Fibrinolytic Agents; Glycosaminoglycans; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Humans; Male; Thrombocytopenia

Progressive thrombocytopenia may develop in as many as 5% of patients receiving heparin anticoagulation. In these patients, the risk of thromboembolic complications as well as continued thrombocytopenia necessitates discontinuation of heparin and initiation of an alternative anticoagulant when indicated. The heparinoid Lomoparan (Org 10172) is a mixture of several non-heparin low molecular weight glycosaminoglycans with proven anticoagulant efficacy that is generally non-reactive with platelets in the presence of plasma from patients with heparin induced thrombocytopenia, whereas standard heparin will induce platelet aggregation. We evaluated the role of heparinoid as a potential alternative anticoagulant in patients with heparin induced thrombocytopenia. During a 6 month period, we identified six patients with heparin induced thrombocytopenia who required an alternative parenteral anticoagulant, four as primary treatment for specific medical problem, and two as anticoagulation during a necessary surgical procedure. Heparinoid was used successfully in both medical and surgical patients requiring parenteral anticoagulation. In no case was there an exacerbation of the thrombocytopenia nor thromboembolic complications while on heparinoid therapy. Three of our patients sustained hemorrhagic complications, predominantly in the post-surgical setting in association with elevated anti-factor Xa levels and additional anticoagulant agents. We feel that these results confirm the utility of heparinoid anticoagulation in a select subset of patients with heparin induced thrombocytopenia who require continued parenteral anticoagulation.

Topics: Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Female; Glycosaminoglycans; Heparin; Heparinoids; Heparitin Sulfate; Humans; Infusions, Intravenous; Male; Middle Aged; Platelet Aggregation; Thrombocytopenia; Thrombosis

Topics: Antibodies, Monoclonal; Anticoagulants; Chondroitin Sulfates; Coronary Artery Bypass; Dermatan Sulfate; Factor Xa; Glycosaminoglycans; Heparin; Heparitin Sulfate; Humans; Monitoring, Physiologic; Partial Thromboplastin Time; Thrombocytopenia

We report two cases of heparin induced thrombocytopenia (HIT), in patients who required anticoagulation for extracorporeal procedures (haemodialysis and cardiopulmonary bypass) one associated with recurrent thrombosis of the artificial circuits. Resolution of thrombocytopenia and successful anticoagulation were achieved using a low molecular weight heparinoid (LMWH) Org 10172. Anticoagulation was monitored using estimations of plasma anti-factor Xa activity. These cases demonstrate that LMWH provides safe and effective anticoagulation in patients in whom unfractionated heparin has caused HIT.

Topics: Aged; Cardiopulmonary Bypass; Chondroitin Sulfates; Dermatan Sulfate; Female; Fibrinolytic Agents; Glycosaminoglycans; Heparin; Heparinoids; Heparitin Sulfate; Humans; Renal Dialysis; Thrombocytopenia; Thrombosis

The management of pregnant patients with coagulopathies and heparin induced thrombocytopenia is difficult and poorly defined. We report the case of a patient who was treated with a low molecular weight heparinoid. The treatment was complicated by the delayed occurrence of thrombocytopenia and a thrombotic event. This is the first report of thrombocytopenia caused by heparinoid. It is possible that this complication could have been avoided by a shorter duration of treatment with heparinoid and the use of Vitamin K antagonists during the second trimester of pregnancy.

Topics: Adult; Blood Coagulation Disorders; Blood Coagulation Factors; Chondroitin Sulfates; Dermatan Sulfate; Female; Glycosaminoglycans; Heparin; Heparinoids; Heparitin Sulfate; Humans; Lupus Coagulation Inhibitor; Pregnancy; Pregnancy Complications, Hematologic; Thrombocytopenia

Topics: Chondroitin Sulfates; Critical Illness; Dermatan Sulfate; Extracorporeal Circulation; Female; Glycosaminoglycans; Hemofiltration; Heparinoids; Heparitin Sulfate; Humans; Male; Middle Aged; Multiple Organ Failure; Renal Dialysis; Thrombocytopenia

Topics: Chondroitin Sulfates; Dermatan Sulfate; Fibrinolytic Agents; Glycosaminoglycans; Hemofiltration; Heparin; Heparitin Sulfate; Humans; Renal Dialysis; Thrombocytopenia

Three different assay systems were studied to determine the effect of dermatan sulfate and heparan sulfate on the activation of platelets. These studies were conducted on an equigravimetric basis for the three glycosaminoglycans. Concentrations were chosen at which differential effects of the three agents could be discerned (10 to 25 micrograms/ml for the HIPA and HIT systems). In the AIPA system where only minimal effects were observed, a higher concentration of 100 micrograms/ml was used. This higher level corresponded to the circulating levels of dermatan sulfate and heparan sulfate required for antithrombotic activity in an animal model (Fareed et al, data not shown). Heparin and saline systems were used as positive and negative controls. Human platelets were studied in a CPDA-1 anticoagulated PRP system. A PRP system was used because it is more physiologic than a washed platelet system. PRP contains all the plasma components and platelet-associated proteins that are present in vivo. One disadvantage, however, is the removal of calcium by the anticoagulant CPDA-1, which may induce a nonphysiologic aberration in the aggregation effect. Overall, these three platelet system studies revealed little to no platelet aggregation response in the presence of dermatan or heparan. Heparin, on the other hand, produced variable but measurable increases, particularly in the heparin-induced thrombocytopenia platelet aggregation system. In the HIPA system (no agonist), only a slight increase was found with heparin, whereas no increase in platelet response was noted with either dermatan or heparan.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cattle; Dermatan Sulfate; Heparin; Heparitin Sulfate; Humans; Platelet Activation; Platelet Aggregation; Swine; Thrombocytopenia

Studies were performed to determine the cross-reaction rate of the heparin-dependent antibody with Org 10172, a new low molecular weight heparinoid, and to investigate the effect of Org 10172 on platelet activation induced by the antibody. The plasmas of 17 patients with thrombocytopenia induced by standard heparin were shown, by platelet aggregation studies, to contain the heparin-dependent antibody. Of these 17 patient plasmas, only three cross-reacted with the heparinoid, producing a cross-reaction rate of 18%. When Org 10172 was added to a reaction mixture containing normal platelet-rich plasma, patient plasma, and standard heparin with non-cross-reacting plasmas, it inhibited platelet aggregation and thromboxane B2 production induced by the antibody, provided that the ratio of Org 10172 concentration (anti-Xa U/mL) to standard heparin concentration (IU/mL) exceeded 2.5 to 5.0. This inhibitory effect was observed only with platelet activation mediated by the antibody, but not by collagen (2 micrograms/mL) or ADP (5.0 mumol/L). Additionally, three of 17 patients with serious thrombosis, whose plasma showed no cross-reaction with the heparinoid, received Org 10172 treatment with a good response in each case. These findings suggest that Org 10172 may be a useful drug for the treatment of heparin-induced thrombocytopenia.

Topics: Antigen-Antibody Reactions; Blood Platelets; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Glycosaminoglycans; Heparin; Heparitin Sulfate; Humans; In Vitro Techniques; Molecular Weight; Platelet Aggregation Inhibitors; Thrombocytopenia; Thrombosis; Thromboxane B2

We studied the possibility that immune injury to endothelial cells may have a role in the development of thrombosis in some patients with heparin-associated thrombocytopenia. Serum samples from each of 27 patients who had this clinical diagnosis contained heparin-dependent platelet antibodies and deposited more than normal amounts of IgG, IgA, or IgM on endothelial cells, stimulating the production of tissue factor. Binding of immunoglobulins to endothelial cells was no longer detected when the patients were studied after heparin was withdrawn, but reappeared within several days upon reexposure to heparin in a patient who experienced a clinical recurrence. Binding of immunoglobulin to endothelial cells was partially reduced by the preadsorption of serum samples with heparin or heparan sulfate bound to Sepharose or by enzymatic cleavage of cell-bound heparan sulfate, and was augmented by the addition of heparan sulfate. Thus, serum from some patients with heparin-associated thrombocytopenia may contain antibodies that react with heparin bound to endothelial cells or with heparan sulfate synthesized by endothelial cells. Immune injury to both platelets and endothelial cells may play a part in the development of thrombosis in some patients after heparin therapy.

Topics: Blood Platelets; Blood Vessels; Endothelium; Heparin; Heparitin Sulfate; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; In Vitro Techniques; Thrombocytopenia; Thrombosis

Topics: Aged; Chondroitin Sulfates; Dermatan Sulfate; Female; Glycosaminoglycans; Heparin; Heparitin Sulfate; Humans; Thrombocytopenia; Thrombophlebitis

We have previously demonstrated that platelets obtained from patients with anorexia nervosa or severe peripheral vascular disease are hyperaggregable. Since conventional heparins are known to activate platelets in vitro and occasionally induce thrombosis and consumptive thrombocytopenia in vivo, we have investigated the direct effect of a conventional heparin on platelets obtained from patients with anorexia nervosa or severe peripheral vascular disease. Heparin at therapeutic concentrations was found to induce platelet aggregation of such platelets in vitro. In contrast, a recently developed low molecular weight heparinoid (Org 10172), at therapeutic concentrations, had no effect on these hyperaggregable platelets. We conclude that: heparin may be potentially harmful to patients with hyperaggregable platelets; thrombocytopenia and thrombosis associated with heparin therapy may be mediated through a direct effect of heparin on platelets; it is unlikely that heparin induced thrombocytopenia is always mediated by classical immunological mechanisms, especially in patients with hyperaggregable platelets; and low molecular weight heparinoids may be safer anticoagulants in patients with platelet hyperaggregability.

Topics: Adolescent; Adult; Aged; Anorexia Nervosa; Blood Platelets; Chondroitin Sulfates; Collagen; Dermatan Sulfate; Epinephrine; Female; Glycosaminoglycans; Heparin; Heparitin Sulfate; Humans; Immunoglobulin G; In Vitro Techniques; Male; Middle Aged; Platelet Aggregation; Thrombocytopenia; Thromboembolism; Thromboxane B2; Vascular Diseases

Topics: Chondroitin Sulfates; Dermatan Sulfate; Fibrinolytic Agents; Glycosaminoglycans; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Pulmonary Embolism; Thrombocytopenia; Thrombosis