refludan and Thrombocytopenia

To prevent thromboembolic events associated with heparin-induced thrombocytopenia (HIT), patients usually are treated with argatroban, lepirudin, and bivalirudin. Here, we conducted a meta-analysis of studies to comparing the treatment of HIT with the following direct thrombin inhibitor: argatroban versus lepirudin and argatroban versus bivalirudin. We systematically searched PubMed, Embase, and Cochrane Library database for relevant studies. The clinical outcomes were thromboembolic complication and bleeding. A total of 589 articles were found and 9 of which were finally included in this meta-analysis. There were no significantly differences of thromboembolic complication between argatroban and hirudin analogues (lepirudin and bivalirudin) in the treatment of HIT (lepirudin: RR = 0.773, 95% CI = 0.449-1.331, P = 0.353; bivalirudin: RR = 0.768, 95% CI = 0.386-1.527, P = 0.452). Moreover, the incidence of clinical bleeding of argatroban was similar to hirudin analogues (lepirudin: RR = 0.755, 95% CI = 0.531-1.073, P = 0.117; bivalirudin: RR = 0.995, 95% CI = 0.673-1.472, P = 0.981). Current evidences show that argatroban has the similar effectiveness and safety with lepirudin and bivalirudin for defending against HIT.

Topics: Arginine; Female; Heparin; Hirudins; Humans; Male; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombocytopenia

Limitations and contraindications of heparins and oral vitamin K antagonists have led to the development of new anticoagulant drugs over the last few years. Argatroban is an intravenous direct thrombin inhibitor currently indicated for the prophylaxis and treatment of thrombosis associated with heparin-induced thrombocytopenia (HIT) and for patients at risk of HIT undergoing percutaneous coronary intervention (PCI). The role of argatroban for the treatment of acute coronary syndrome (ACS) is under evaluation.. This article reviews the potential use of argatroban for the treatment of ACS and presents the pharmacokinetic data currently available. The authors also present the pharmacodynamic literature of agratroban in addition to highlighting the safety and tolerability of the drug.. Theoretically, argatroban's pharmacokinetics makes it an attractive alternative to heparin. Pharmacological advantages of argatroban over heparin include a more-predictable anticoagulant response and the absence of a risk of HIT. Furthermore, argatroban has a fast and predictable dose-dependent anticoagulant effect with low inter-individual variability. It is non-immugenic, not susceptible to degradation by proteases and it is cleared via the liver. These characteristics confer argotroban a different profile from other anticoagulants. Agatroban is an effective alternative for patients when heparin, lepirudin and bivalirudin cannot be used. Its utility in ACS and PCI in non-HIT patients has been evaluated but further studies are warranted to define its role in this context.

Topics: Acute Coronary Syndrome; Animals; Antithrombins; Arginine; Disease Models, Animal; Drug Evaluation; Heparin; Hirudins; Humans; Peptide Fragments; Percutaneous Coronary Intervention; Pipecolic Acids; Randomized Controlled Trials as Topic; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombosis

Incidence of deep vein thrombosis in critically ill patients depends on the underlying disease but may be as high as 60%. The Surviving Sepsis Campaign clearly recommends administering anticoagulation in the absence of specific contraindications in patients with severe sepsis or septic shock. The article discusses risk factor for thromboembolic events in critical illness as well as means of non-pharmacologic and pharmacologic thrombosis prophylaxis. Peripheral vasoconstriction, edema, shock, and administration of catecholamines may reduce the bioavailability and efficacy of subcutaneous administration of low molecular weight heparin. This article further elaborates on the problem and pathophysiology of heparin resistance. Continuous intravenous administration of new anticoagulants may be a promising alternative to indirect anticoagulants. Severity of illness and SAPS II-score determine dosing of the direct thrombin inhibitor argatroban which needs to be about 10-times lower than in patients without critical illness.

Topics: Anticoagulants; Arginine; Biological Availability; Chromosome Breakage; Chromosome Disorders; Critical Care; Dose-Response Relationship, Drug; Drug Resistance; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Infusions, Intravenous; Injections, Subcutaneous; Pipecolic Acids; Recombinant Proteins; Risk Factors; Sepsis; Severity of Illness Index; Shock, Septic; Sulfonamides; Thrombin; Thrombocytopenia; Venous Thrombosis

Heparin-induced thrombocytopenia (HIT) is an important, increasingly recognized antibody-mediated complication of heparin therapy occurring in approximately 0.5-5% of patients receiving heparin for at least 5 days. HIT is a prothrombotic disorder that typically presents with a 50% platelet count drop, thrombotic event manifesting usually 5-14 days after starting heparin, or both. HIT antibodies usually decrease to negative titers/levels within 3 months. When there is clinical suspicion of HIT, heparin should be discontinued and alternative anticoagulation should be considered, as well as laboratory evaluation for HIT.. HIT immunoassay results should be used for clinical decision-making about initial anticoagulation management. Recent data reevaluate the importance of absolute titers of HIT antibodies as a risk factor for clinical occurrence. Although laboratory assays are routinely used, current data suggest that increasing optical densities are more likely associated with a positive 14C-serotonin release assay and HIT. HIT is also associated with a greater risk for adverse events, so even though alternative anticoagulation is used, clinicians should be aware of this hypercoagulable syndrome.. For patients with HIT, alternative anticoagulation is available, but for cardiovascular surgery, if the operation cannot be delayed until HIT antibodies have become negative, alternative anticoagulation strategies are recommended, although patients with HIT are at a greater risk for adverse outcomes.

Topics: Anticoagulants; Arginine; Cardiovascular Surgical Procedures; Heparin; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Platelet Activation; Platelet Count; Platelet Factor 4; Recombinant Proteins; Sulfonamides; Thrombin; Thrombocytopenia

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 an immune-mediated disorder caused by the development of antibodies to platelet factor 4 (PF4) and heparin. The thrombocytopenia is typically moderate, with a median platelet count nadir of approximately 50 to 60 x 10(9) platelets/L. Severe thrombocytopenia has been described in patients with HIT, and in these patients antibody levels are high and severe clinical outcomes have been reported (eg, disseminated intravascular coagulation with microvascular thrombosis). The timing of the thrombocytopenia in relation to the initiation of heparin therapy is critically important, with the platelet count beginning to drop within 5 to 10 days of starting heparin. A more rapid drop in the platelet count can occur in patients who have been recently exposed to heparin (within the preceding 3 months), due to preformed anti-heparin/PF4 antibodies. A delayed form of HIT has also been described that develops within days or weeks after the heparin has been discontinued. In contrast to other drug-induced thrombocytopenias, HIT is characterized by an increased risk for thromboembolic complications, primarily venous thromboembolism. Heparin and all heparin-containing products should be discontinued and an alternative, non-heparin anticoagulant initiated. Alternative agents that have been used effectively in patients with HIT include lepirudin, argatroban, bivalirudin, and danaparoid, although the last agent is not available in North America. Fondaparinux has been used in a small number of patients with HIT and generally appears to be safe. Warfarin therapy should not be initiated until the platelet count has recovered and the patient is systemically anticoagulated, and vitamin K should be administered to patients receiving warfarin at the time of diagnosis of HIT.

Topics: Anticoagulants; Arginine; Autoantibodies; Contraindications; Disseminated Intravascular Coagulation; Fondaparinux; Heparin; Hirudins; Humans; Pipecolic Acids; Platelet Count; Platelet Factor 4; Polysaccharides; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombophilia; Time Factors; Venous Thromboembolism; Vitamin K; Warfarin

Topics: Anticoagulants; Antithrombin III; Arginine; Fondaparinux; Heparin; Hirudins; Humans; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Sulfonamides; Thrombin; Thrombocytopenia

Lepirudin is a recombinant hirudin that exerts its anticoagulant effect by direct inhibition of thrombin. Lepirudin is indicated for anticoagulation in patients with heparin-induced thrombocytopenia (HIT) and associated thromboembolic disease to prevent further thromboembolic complications.. This review addresses various clinical uses of lepirudin including but not limited to FDA approved indication. The objective is to provide an updated overview of the clinical use and pharmacology of the agent. In addition, we address certain areas of controversy especially pertaining to dosing of lepirudin and its use in different clinical situations.. Literature was reviewed using appropriate search terms in Pubmed and Ovid medline databases.. Lepirudin continues to be a valuable anticoagulant in the management of HIT. Lepirudin has the highest recommendation in treatment of HIT based on evidence from clinical trials. Minor modifications in dosing over the standard label recommendations may simplify its use and enhance safety.

Topics: Anticoagulants; Clinical Trials as Topic; Dose-Response Relationship, Drug; Heparin; Hirudins; Humans; Recombinant Proteins; Thrombocytopenia

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

Patients with or at risk of heparin-induced thrombocytopenia (HIT) who are undergoing percutaneous coronary intervention (PCI) are at particular risk of thrombosis due to the prothrombotic nature of HIT and the endovascular disruption from PCI. Patients require aggressive anticoagulation during PCI, and alternative, nonheparin anticoagulation is recommended over heparin in patients with acute or previous HIT. Argatroban, bivalirudin, and lepirudin are nonheparin, fast-acting, parenteral direct thrombin inhibitors (DTIs). Multicenter, prospective studies have demonstrated that argatroban and lepirudin each reduce thrombosis in HIT and that argatroban and bivalirudin each provide adequate anticoagulation during PCI in patients with or at risk of HIT. We review current therapeutic practices with direct thrombin inhibitors in patients with or at risk of HIT during PCI, including individuals requiring periprocedural anticoagulation, and the factors influencing the choice of DTI in this setting.

Topics: Angioplasty, Balloon, Coronary; Antithrombins; Arginine; Drug Interactions; Economics, Pharmaceutical; Fibrinolytic Agents; Hemorrhage; Heparin; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Platelet Aggregation Inhibitors; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombosis

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

Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse effect that typically manifests several days after the start of heparin therapy, although both rapid- and delayed-onset HIT have been described. Its most serious complication is thrombosis. Although not all patients develop thrombosis, it can be life threatening. The risk of developing HIT is related to many factors, including the type of heparin product administered, route of administration, duration of therapy, patient population, and previous exposure to heparin. The diagnosis of HIT is typically based on clinical presentation, exposure to heparin, and presence of thrombocytopenia with or without thrombosis. Antigen and activation laboratory assays are available to support the diagnosis of HIT. However, because of the limited sensitivity and specificity of these assays, bedside probability scales for HIT were developed. When HIT is suspected, prompt cessation of all heparin therapy is necessary, along with initiation of alternative anticoagulant therapy. Two direct thrombin inhibitors--argatroban and lepirudin--are approved for the management of HIT in the United States, and bivalirudin is approved for use in patients with HIT who are undergoing percutaneous coronary intervention. Other agents, although not approved to manage HIT, have also been used; however, their role in therapy requires further evaluation. A comprehensive HIT management strategy involves the evaluation of numerous factors. Many patients, including those undergoing coronary artery bypass surgery, those with acute coronary syndromes, those with hepatic or renal insufficiency, and children, require special attention. Clinicians must become familiar with the available information on this serious adverse effect and its treatment so that optimum patient management strategies may be formulated.

Topics: Anticoagulants; Antithrombins; Arginine; Heparin; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombosis

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

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

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

Repeated exposure to unfractionated heparin is the rule in many congenital heart disease patients. Heparin-induced thrombocytopenia occurs in 1% to 3% of adult cardiac surgeries, and carries high thrombotic morbidity (38% to 81%) and mortality (approximately 28%). Although heparin-induced thrombocytopenia appears to be infrequent in pediatric patients, particularly neonates, our evolving experience suggests postcardiopulmonary bypass congenital heart disease patients may be at increased risk. Diagnostic and therapeutic challenges include frequency of thrombocytopenia after cardiopulmonary bypass, imperfect laboratory testing, lack of established dosing of alternative anticoagulants (such as argatroban and lepirudin), and increased anticoagulant-related bleeding in young children.

Topics: Adolescent; Anticoagulants; Arginine; Autoantibodies; Cardiopulmonary Bypass; Child; Child, Preschool; Clinical Trials as Topic; Fatal Outcome; Female; Heart Defects, Congenital; Heparin; Hirudins; Hospitals, University; Humans; Hypoplastic Left Heart Syndrome; Infant; Infant, Newborn; Male; Multicenter Studies as Topic; Pipecolic Acids; Platelet Factor 4; Postoperative Complications; Postoperative Hemorrhage; Recombinant Proteins; Retrospective Studies; Sulfonamides; Thrombocytopenia; Thromboembolism; Treatment Outcome

Heparins are in widespread use as anticoagulants for the prophylaxis and therapy of thromboembolisms. A dangerous side-effect is heparin-induced thrombocytopenia type II (HIT type II) with the paradox of thromboembolic venous and arterial vascular occlusions. HIT type II is an immunological disease which results in activation of platelets and plasma coagulation. The main symptom is an acute onset of thrombocytopenia with a fall in thrombocytes to less than 50% of the initial value with or without newly arising thromboembolic complications between days 5 and 14 after the start of heparin therapy. Surgery patients are more often affected by subclinical antibody formation as well as by symptomatic HIT type II than clinical patients. In this review we will discuss the difficult diagnosis and the differential diagnosis with special emphasis on postoperative intensive care patients, as well as preventive measures and management on occurrence of HIT type II and associated thrombotic complications.

Topics: Anticoagulants; Blood Platelets; Heparin; Hirudins; Humans; Platelet Function Tests; Recombinant Proteins; Thrombocytopenia

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

Topics: Administration, Oral; Anticoagulants; Arginine; Critical Care; Drug Monitoring; Enzyme-Linked Immunosorbent Assay; Heparin; Hirudins; Humans; International Normalized Ratio; Nurse's Role; Nursing Assessment; Partial Thromboplastin Time; Patient Selection; Pipecolic Acids; Platelet Count; Practice Guidelines as Topic; Recombinant Proteins; Risk Factors; Sulfonamides; Syndrome; Thrombocytopenia; Time Factors

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

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 a pathology manifested as clinically induced destruction of platelets. There are 2 forms of HIT, type I and type II; type II is the more serious. HIT type I is a transient, non-immune-mediated form manifesting with mild thrombocytopenia. Type II is a drug-induced, immune-mediated syndrome that may cause life- or limb-threatening thromboembolic events. Induction of general anesthesia for a person with HIT type II is no different from that for a person in the general population. Treatment modalities vary only if heparin will be used during the case. The initial indicator of HIT is decreased platelet count, with or without thrombosis. Clinical criteria and advanced serological testing are available for the definitive diagnosis of HIT. Clinical suspicion of HIT remains key to early cessation of heparin (all routes) and initiation of alternative treatments.

Topics: Anesthesia, General; Anticoagulants; Arginine; Drug Monitoring; Enzyme-Linked Immunosorbent Assay; Heparin; Hirudins; Humans; Intraoperative Care; Nurse Anesthetists; Pipecolic Acids; Platelet Count; Recombinant Proteins; Risk Factors; Sensitivity and Specificity; Severity of Illness Index; Sulfonamides; Thrombocytopenia; Thrombosis; Time Factors

Heparin-induced thrombocytopenia (HIT) is a potentially devastating complication of therapy with either unfractionated or low-molecular-weight heparin. Thrombocytopenia is no longer essential for the diagnosis of HIT, since a 50% drop in the platelet count may be a more specific indicator. Once HIT is clinically suspected, heparin should be stopped immediately and direct thrombin inhibitor therapy started; waiting for laboratory confirmation may be catastrophic.

Topics: Anticoagulants; Arginine; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Pipecolic Acids; Platelet Count; Practice Guidelines as Topic; Recombinant Proteins; Risk Assessment; Sulfonamides; Thrombocytopenia; Time Factors

Heparin-induced thrombocytopenia (HIT) type II is an immune mediated reaction in which pathologic antibodies develop to a complex composed of heparin and the platelet-derived alpha granule protein, platelet factor 4 (PF4). HIT must be recognized quickly so as to eliminate all heparin exposure from a patient's clinical care. Thrombosis (HIT) may accompany thrombocytopenia resulting in limb and life-threatening complications. Despite a higher incidence of subclinically detectable heparin-PF4 antibody formation in the cardiac care setting, the development of the full clinicopathologic syndrome occurs in approximately 2% to 3% of patients, similar to the incidence in other clinical scenarios.

Topics: Anticoagulants; Arginine; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Heparin, Low-Molecular-Weight; Hirudins; Humans; Male; Pipecolic Acids; Recombinant Proteins; Risk Assessment; Severity of Illness Index; Sulfonamides; Thrombocytopenia; Thrombosis; Treatment Outcome

Unfractionated heparin, derived from porcine intestine, is the prototype of a rapidly acting anticoagulant. It has been used for over 60 years to arrest or prevent thrombus growth. Low-molecular-weight heparins, available in the last 20 years, are manufactured from unfractionated heparin and have superior dose-response relationships because of fewer nonspecific reactions with plasma proteins and cells. Fondaparinux is a recently approved five-saccharide synthetic molecule that carries the evolution of heparin further. It is a pure Xa inhibitor, with minimal nonspecific interactions. It does not appear to elicit the antibody that leads to heparin-induced thrombocytopenia (HIT). All of these agents are given either intravenously or subcutaneously. They act indirectly by activating the natural plasma inhibitor, antithrombin III. Direct thrombin inhibitors bind directly to thrombin's active site without interaction with the cofactor, antithrombin III. Lepirudin (Refludan; Berlex, Wayne, NJ) and argatroban (Argatroban; GlaxoSmithKline, Research Triangle Park, NC) are given intravenously and are usually used in HIT and thrombosis associated with HIT. Bivalirudin (Angiomax; The Medicines Company, Parsippany, NJ) is a parenteral direct thrombin used in place of heparin in percutaneous coronary interventions. Ximelagatran (Exanta; AstraZeneca, Wilmington, DE) is an oral direct thrombin inhibitor under development for both acute and chronic anticoagulation.

Topics: Anticoagulants; Arginine; Azetidines; Benzylamines; Embolism; Enzyme Inhibitors; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Sulfonamides; Thrombin; Thrombocytopenia; Venous Thrombosis

To assess efficacy and safety of lepirudin in patients with heparin-induced thrombocytopenia (HIT) in a prospective study (HAT-3) as well as in a combined analysis of all HAT study data.. Patients with laboratory-confirmed HIT were treated with lepirudin in three different aPTT-adjusted dose regimen and during cardiopulmonary bypass (CPB). Endpoints were new thromboembolic complications (TEC), limb amputations, and death and major bleeding. A historical control group (n = 120) was used for comparison.. After start of lepirudin in 205 patients treated in HAT-3, the combined endpoint occurred in 43 (21.0%). Thirty (14.6%) patients died, 10 (4.9%) underwent limb amputation, and 11 (5.4%) new TECs occurred. Major bleeding occurred in 40 patients (19.5%) (seven during CPB surgery). Combining all prospective HAT trials (n = 403), after start of lepirudin treatment, the combined endpoint occurred in 82 patients (20.3%), with 47 deaths (11.7%), 22 limb amputations (5.5%), 30 new TECs (7.4%), and 71 (17.6%) major bleedings. Compared with the historical control group (log-rank test), the combined endpoint after start of treatment was reduced (29.7% vs. 52.1%, P = 0.0473), primarily because of reduction in new thromboses (11.9% vs. 32.1%, P = 0.0008). Mean lepirudin maintenance doses ranged from 0.07 to 0.11 mg kg(-1) h(-1). Major bleeding was more frequent in the lepirudin-treated patients (29.4% vs. 9.1%, P = 0.0148).. The rate of new TECs in HIT patients is low after start of lepirudin treatment. The rate of major bleeding of 17.6% might be reduced by reducing the starting dose to 0.1 mg kg(-1) h(-1).

Topics: Adult; Aged; Aged, 80 and over; Amputation, Surgical; Anticoagulants; Female; Hemorrhage; Heparin; Hirudins; Humans; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Secondary Prevention; Survival Analysis; Thrombocytopenia; Thromboembolism

Heparin-induced thrombocytopenia (HIT) is a serious complication of heparin therapy that has a high rate of morbidity (thrombosis and amputation) and mortality. In the past, a number of different anticoagulants have been used to treat HIT in an attempt to prevent these complications. More recently, direct thrombin inhibitors have become popular. This systematic review summarizes the risk for thrombosis in HIT patients when heparin therapy is stopped; evidence of the efficacy of thrombin inhibitors in patients with HIT with and without thrombosis; evidence supporting the use of thrombin inhibitors in patients with a history of HIT who require a coronary intervention procedure; and the risk for bleeding when antithrombotic agents are used.

Topics: Anticoagulants; Arginine; Heparin; Hirudins; Humans; Pipecolic Acids; Recombinant Proteins; Risk Assessment; Sulfonamides; Thrombocytopenia; Thrombosis

Heparin-induced thrombocytopenia (HIT) type II is an antibody mediated severe adverse event to heparin with a paradoxical decrease of platelet count and an increased risk for thromboembolic complications. The antibodies are directed against a neoepitop of platelet factor 4 after its binding to heparin. The incidence of HIT type II is lower with low-molecular-weight heparin compared to unfractionated heparin and lower in not operated patients compared to those after major surgery. In patients with HIT type II alternative anticoagulation has to be performed immediately due to the high thrombogenicity of the antibodies. The recombinant hirudin lepirudin (Refludan) is the anticoagulant drug of choice. A long-term anticoagulation has to be performed depending on the concomitant risk factors, intravenous administration followed by subcutaneous lepirudin overlapping with vitamin K antagonists.

Topics: Anticoagulants; Diagnosis, Differential; Heparin; Hirudins; Humans; Recombinant Proteins; Thrombocytopenia

Lepirudin (Refludan), Berlex Laboratories, USA and Canada; Pharmion, all other countries), a recombinant derivative of the naturally occurring leech anticoagulant hirudin, was the first direct thrombin inhibitor to be approved by the European Agency for the Evaluation of Medicinal Products and the US Food and Drug Administration for the treatment of heparin-induced thrombocytopenia. Since its introduction into Europe and the USA, it has been studied in over 7000 patients requiring anticoagulation in conditions including acute coronary syndromes, percutaneous coronary intervention, cardiopulmonary bypass and heparin-induced thrombocytopenia. Three European clinical trials, designated Heparin-Associated Thrombocytopenia (HAT)-1, -2 and -3, demonstrated the efficacy and safety of lepirudin in the prevention and treatment of thrombosis in patients with antibody-confirmed heparin-induced thrombocytopenia. A postmarketing, observational study, termed the Drug-Monitoring Program, evaluated lepirudin in over 1000 patients with heparin-induced thrombocytopenia in the setting of routine clinical practice. In the Drug-Monitoring Program, adverse events were substantially reduced compared with clinical trials, while clinical efficacy was maintained; suggesting that insight gained through clinical experience was translated into improved safety. Here, pharmacotherapy using lepirudin is reviewed, with particular reference to clinical studies in heparin-induced thrombocytopenia, and some recommendations based on this extensive clinical experience with lepirudin are provided. Although only approved for the treatment of heparin-induced thrombocytopenia, the use of lepirudin in acute coronary syndromes, percutaneous coronary intervention, vascular surgery and coronary artery bypass grafting is also discussed. The review concludes with a discussion of pharmacokinetic and clinical data supporting the potential for subcutaneous administration of lepirudin.

Topics: Anticoagulants; Cardiovascular Surgical Procedures; Coronary Disease; Dose-Response Relationship, Drug; Heparin; Hirudins; Humans; Myocardial Infarction; Postoperative Complications; Recombinant Proteins; Thrombin; Thrombocytopenia; Venous Thrombosis

Due to the widespread use of unfractionated (UFH) and low molecular weight heparins (LWH) for prophylaxis and treatment of thrombosis, heparin-induced thrombocytopenia is considered to be the most frequent (and potentially the most devastating) drug-induced thrombocytopenia. Induced by an immune response, excessive activation of platelets and endothelium cells causes massive thrombin generation and, as a result, life-threatening venous and arterial thrombotic vessel occlusion. The rate of mortality and amputation in HIT II is estimated to be 30% and 20%, respectively. The clinical course of HIT II depends highly on early therapeutic intervention consisting of immediate interruption of heparin application and, most important, of compatible thrombin inhibition. All measures implying a potentially procoagulant risk such as begin of oral anticoagulation or platelet substitution may result in disastrous side effects.

Topics: Anticoagulants; Blood Coagulation Tests; Heparin, Low-Molecular-Weight; Hirudins; Humans; Models, Biological; Platelet Count; Recombinant Proteins; Thrombocytopenia; Thromboembolism

Native hirudin is the most potent natural direct thrombin inhibitor currently known; it is capable of inhibiting not only fluid phase, but also clot-bound thrombin. Recombinant technology now allows production of recombinant hirudins (r-hirudins), which are available in sufficient purity and quantity with essentially unaltered thrombin-inhibitory potency. As thrombin is known to play a key role in a number of thrombotic disorders, numerous studies focused on the impact of r-hirudins on the clinical course in these diseases. R-hirudins provided significantly more stable anticoagulation than standard heparin, but demonstrated a relatively narrow therapeutic range with relevant bleeding risk even at clinically effective doses. In doses that are not associated with an increased bleeding risk, r-hirudins often failed to demonstrate significant superiority to heparin. To date, r-hirudins have a definite role in the treatment of heparin-induced thrombocytopenia, where they markedly reduce the high risk of thrombosis. For prophylaxis of deep vein thrombosis, r-hirudins have been shown to be superior to both unfractionated and low molecular weight heparin, but are not extensively used in this indication. In acute coronary syndromes, a definite role of r-hirudins has not yet been firmly established. When applied in an appropriate dose as adjunct to thrombolysis in patients with acute myocardial infarction, randomized, controlled trials did not show a consistent benefit of r-hirudins, especially in the long-term. In patients undergoing coronary balloon angioplasty for acute coronary syndromes, promising effects in the early postprocedural phase did not translate to an improved outcome after 6 months. In patients with unstable angina pectoris, efficacy and safety of r-hirudins as primary antithrombotic therapy are still under debate. In the future, r-hirudins are to be compared with alternative or additional potent antithrombotic agents or treatment strategies. This comparison will ultimately lead to their final placement in the management of thrombotic disorders.

Topics: Clinical Trials as Topic; Coronary Disease; Fibrinolytic Agents; Heparin; Hirudins; Humans; Kidney Failure, Chronic; Partial Thromboplastin Time; Recombinant Proteins; Thrombin; Thrombocytopenia; Tissue Distribution; Venous Thrombosis

Heparin was first discovered in 1916 and at present is used in more than 12 million patients a year. In the 1950s, several physicians noticed an uncommon paradoxical phenomenon in which heparin appeared to function as a procoagulant instead of an anticoagulant. This phenomenon is now known as the immune-mediated heparin-induced thrombocytopenia (HIT) and thrombosis syndrome (HITTS). Our understanding of this syndrome has evolved over the last 2 to 3 decades, and therapeutic options are arising. This article will focus on the most extensively studied therapy for HIT, which is the class of drugs known as the direct thrombin inhibitors. Specifically, we will focus on the mechanisms by which direct thrombin inhibitors may be useful in this syndrome, the evidence for their use, and the unique characteristics of the two FDA-approved agents in this class, lepirudin and argatroban.

Topics: Anticoagulants; Arginine; Binding Sites; Heparin; Hirudins; Humans; Models, Biological; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Syndrome; Thrombin; Thrombocytopenia; Treatment Outcome

The use of unfractionated heparin, the traditional antithrombotic agent during percutaneous coronary interventions (PCI), is associated with the risk of heparin-induced thrombocytopenia, a rare but often fatal clinical condition. This article focuses on several issues related to heparin-induced immune-mediated thrombocytopenia (HIT, type II) and alternative modes of periprocedural anticoagulation in patients with suspected or known HIT. The hypercoagulable state characterizing HIT, along with mechanical plaque disruption resulting from PCI place patients with HIT at particular risk of thrombosis during PCI. Given that a diagnosis of HIT precludes any further use of heparin, other treatment modalities are essential. Direct thrombin inhibitors are the drugs of choice in this challenging situation. These agents offer several advantages as anticoagulants for patients with HIT: (1) the ability to inhibit both thrombin that is bound to fibrin (clot-bound thrombin) and fluid-phase free thrombin; (2) rapid achievement of steady state; and (3) no cross-reactivity with HIT antibodies. Recent data on the use of bivalirudin, lepirudin, and argatroban in the setting of PCI in patients with HIT are encouraging. Optimal dosing regimens for argatroban, lepirudin, and bivalirudin should be further established in PCI patients.

Topics: Anticoagulants; Arginine; Blood Platelets; Heparin; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Skin; Sulfonamides; Thrombin; Thrombocytopenia; Time Factors

One of the most important adverse drug reactions that physicians encounter is the life- and limb-threatening prothrombotic syndrome known as heparin-induced thrombocytopenia (HIT). Unfractionated heparin (UFH), administered during cardiopulmonary bypass (CPB), is highly immunogenic. Heparin-dependent antibodies can develop in 25 to 50% of UFH-treated cardiac surgery patients within 5 to 10 days. These antibodies can activate platelets and are considered the causative agents of HIT. HIT is a relatively common complication, occurring in 1 to 3% of cardiovascular surgery patients when UFH administration is continued postoperatively. It is strongly associated with new thromboembolic events leading to limb amputation and death. In acute or recent (< 100 days) HIT, alternative anticoagulatory regimens are needed during CPB surgery for prevention of HIT-related thrombosis. Treatment options for such patients now generally include the use of alternative anticoagulants such as lepirudin, bivalirudin, or danaparoid, as well as a combined treatment with platelet-function inhibitors and heparin. In patients with a history of HIT and no detectable antibodies, heparin is currently the safest approach for high-dose anticoagulation during CPB. Before and after surgery, however, alternative anticoagulants should be used. The risk of clinical HIT after heart surgery could potentially be reduced by using low-molecular-weight heparins for postsurgery anticoagulation.

Topics: Anticoagulants; Cardiovascular Diseases; Clinical Trials as Topic; Enzyme-Linked Immunosorbent Assay; Heparin; Hirudins; Humans; Platelet Count; Recombinant Proteins; Thrombin; Thrombocytopenia; Time Factors

Topics: Anticoagulants; Aortic Valve Insufficiency; Arginine; Autoantibodies; Autoimmune Diseases; Female; Fingers; Heart Valve Prosthesis Implantation; Heparin; Hirudins; Humans; Ischemia; Middle Aged; Necrosis; Pipecolic Acids; Platelet Activation; Platelet Factor 4; Postoperative Complications; Raynaud Disease; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombosis; Toes; Warfarin

Heparin-induced thrombocytopenia (HIT) is a serious and common complication of heparin therapy that can lead to significant losses of life and limb. It is often under-recognized and, therefore, goes untreated until thrombosis develops. This article is meant to provide specific recommendations for treating patients with immune-mediated HIT, whether or not it is associated with thrombosis. These recommendations are based on our clinical experience treating patients with HIT and our evaluation of the published data on the efficacy and safety of lepirudin and argatroban, the 2 drugs approved by the Food and Drug Administration for treating HIT. Based on these criteria, we consider lepirudin the treatment of choice in all patients with HIT except those with severe or deteriorating renal function.

Topics: Algorithms; Anticoagulants; Antigen-Antibody Complex; Arginine; Clinical Trials as Topic; Diagnosis, Differential; Disease Management; Follow-Up Studies; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Immunoglobulin G; Pipecolic Acids; Platelet Activation; Platelet Count; Platelet Factor 4; Prognosis; Purpura, Thrombocytopenic, Idiopathic; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombophilia; Time Factors

We evaluated a combination therapy using glycoprotein IIb/IIIa receptor antagonism and direct thrombin inhibition in nine patients with heparin-induced thrombocytopenia (HIT) undergoing 10 percutaneous coronary interventions (PCIs). In selected patients with HIT, the combination of a direct thrombin inhibitor, lepirudin, and abciximab, tirofiban, or eptifibatide appears to be a safe and effective anticoagulation strategy for PCI.

Topics: Abciximab; Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; Antibodies, Monoclonal; Anticoagulants; Drug Therapy, Combination; Eptifibatide; Female; Fibrinolytic Agents; Heparin; Hirudins; Humans; Immunoglobulin Fab Fragments; Male; Middle Aged; Peptides; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Proteins; Thrombocytopenia; Tirofiban; Tyrosine

Heparin-induced thrombocytopenia (HIT) is a transient hypercoagulability state initiated, paradoxically, by the anticoagulant, heparin. It is characterized by antibody-induced activation of platelets, leading to thrombin generation. Many patients with HIT develop thrombosis; even when heparin is stopped because of "isolated HIT" detected during routine platelet count monitoring, 25-50% of patients subsequently develop symptomatic thrombosis. Thus, an alternative anticoagulant should be substituted for heparin when HIT is strongly suspected. Two direct thrombin inhibitors (DTIs), lepirudin and argatroban, have been studied for prevention and treatment of thrombosis in HIT patients. Lepirudin is a polypeptide that binds irreversibly to the fibrin-binding and catalytic sites on thrombin (bivalent inhibitor). In contrast, argatroban is a synthetic, small-molecule DTI that binds reversibly to the catalytic site alone (univalent inhibitor). Results of historically controlled clinical trials suggest both agents are effective for preventing and treating thrombosis in HIT. However, these agents have not been compared directly, and important differences in study design limit conclusions from indirect comparison. For example, lepirudin was given for 12-14 days (mean) in treatment studies of thrombosis complicating HIT, whereas argatroban was given only for 6-7 days, a difference that could explain apparent lower thrombosis rates (and greater bleeding) with lepirudin. Recently, the transition from DTI therapy to oral anticoagulation in patients with deep venous thrombosis (DVT) complicating HIT has been identified as a risk period for coumarin-induced venous limb gangrene. Thus, the DTI should be given alone during acute HIT, with oral anticoagulants deferred until substantial resolution of the thrombocytopenia has occurred.

Topics: Anticoagulants; Antithrombins; Arginine; Female; Heparin; Hirudins; Humans; Middle Aged; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombocytopenia

Unfractionated heparin given during cardiopulmonary bypass is remarkably immunogenic, as 25% to 50% of postcardiac surgery patients develop heparin-dependent antibodies during the next 5 to 10 days. Sometimes, these antibodies strongly activate platelets and coagulation, thereby causing the prothrombotic disorder, heparin-induced thrombocytopenia. The risk of heparin-induced thrombocytopenia is 1% to 3% if unfractionated heparin is continued beyond the first postoperative week. When cardiac surgery is urgently needed for a patient with acute or subacute heparin-induced thrombocytopenia, options include an alternative anticoagulant (bivalirudin, lepirudin, or danaparoid) or combining unfractionated heparin with a platelet antagonist (epoprostenol or tirofiban). As heparin-induced thrombocytopenia antibodies are transient, unfractionated heparin alone is appropriate in a patient with previous heparin-induced thrombocytopenia whose antibodies have disappeared.

Topics: Anticoagulants; Cardiac Surgical Procedures; Diagnosis, Differential; Female; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Peptide Fragments; Postoperative Complications; Recombinant Proteins; 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

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

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

Topics: Anticoagulants; Arginine; Azetidines; Benzylamines; Fondaparinux; Heparin; Hirudin Therapy; Hirudins; Humans; Pipecolic Acids; Polysaccharides; Prodrugs; Recombinant Proteins; Sulfonamides; Thrombin; Thrombocytopenia

Clinical applications for recombinant hirudins have been investigated for the past 10 years. The first indication for which a hirudin-lepirudin-has been approved is treatment of heparin-induced thrombocytopenia (HIT). Also, the recently completed trials for use of lepirudin in unstable angina indicate a potentially new indication. This review describes pharmacology and clinical applications of lepirudin with an emphasis on HIT and unstable angina. An overview of usage of lepirudin in acute coronary syndromes is given, as well as a summary of rare indications for lepirudin, such as extracorporeal circulation, for which comprehensive data are lacking.

Topics: Angina, Unstable; Clinical Trials as Topic; Fibrinolytic Agents; Heparin; Hirudin Therapy; Hirudins; Humans; Recombinant Proteins; Thrombocytopenia

Heparin induced thrombocytopenia thrombosis (HIT/T) is associated with a high morbidity and mortality. Diagnosis is essentially clinical and negative results of laboratory assays do not exclude the diagnosis. Treatment involves stopping all heparin immediately and giving an alternative thrombin inhibitor. The adoption of low molecular weight heparins is one reason for the reduced incidence of this disease in recent years.

Topics: Anticoagulants; Arginine; Heparin; Hirudin Therapy; Hirudins; Humans; Pipecolic Acids; Platelet Count; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombosis

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

This meta-analysis focuses on 2 prospective studies in patients with heparin-induced thrombocytopenia (HIT) and thromboembolic complication (TEC) who were treated with lepirudin (n = 113). Data were compared with those of a historical control group (n = 91). The primary endpoint (combined incidence of death, new TEC, and limb amputation) occurred in 25 lepirudin-treated patients (22.1%; 95% CI, 14.5%-29.8%): 11 died (9.7%; 95% CI, 4.9%-16.8%), 7 underwent limb amputation (6.2%; 95% CI, 2.5%-12.3%), and 12 experienced new TEC (10.6%; 95% CI, 5.8%-18.3%). The risk was highest in the period between diagnosis of HIT and the start of lepirudin therapy (combined event rate per patient day 6.1%). It markedly decreased to 1.3% during lepirudin treatment and to 0.7% in the posttreatment period. From the start of lepirudin therapy to the end of follow-up, lepirudin-treated patients had consistently lower incidences of the combined endpoint than the historical control group (P =.004, log-rank test), primarily because of a reduced risk for new TEC (P =. 005). Thrombin-antithrombin levels in the pretreatment period (median, 43.9 microg/L) decreased after the initiation of lepirudin (at 24 hours +/- 6 hours; median, 9.18 microg/L.) During treatment with lepirudin, aPTT ratios of 1.5 to 2.5 produced optimal clinical efficacy with a moderate risk for bleeding, aPTT ratios lower than 1. 5 were subtherapeutic, and aPTT levels greater than 2.5 were associated with high bleeding risk. Bleeding events requiring transfusion were significantly more frequent in patients taking lepirudin than in historical control patients (P =.02). In conclusion, this meta-analysis provides further evidence that lepirudin is an effective and acceptably safe treatment for patients with HIT.

Topics: Aged; Anticoagulants; Clinical Trials as Topic; Female; Heparin; Hirudins; Humans; Infusions, Intravenous; Male; Middle Aged; Recombinant Proteins; Thrombocytopenia; Thromboembolism; Treatment Outcome

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

Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug reaction that is associated with thrombotic events of the venous and arterial circulatory systems stemming from an intense and well-characterized prothrombotic triad of platelet activation, coagulation cascade stimulation and vascular endothelial cell injury. Although heparin (or other sulfated mucopolysaccharide compound) cessation represents a vital first step in management, patients remain susceptible to life-threatening thrombosis for up to several weeks, providing a strong rationale for a 'proactive approach' to care that includes prompt initiation of an alternative anticoagulant strategy throughout the high-risk period. The importance of alternative options for anticoagulation is most evident in clinical situations wherein treatment is a recognized standard of care and prerequisite for an optimal outcome. The following review highlights the use of recombinant hirudin (lepirudin) among patients with suspected HIT requiring precutaneous coronary interventions (PCI) and coronary arterial bypass grafting.

Topics: Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Blood Coagulation Tests; Coronary Artery Bypass; Heparin; Hirudin Therapy; Hirudins; Humans; Recombinant Proteins; Risk; 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

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

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

Critically ill patients often require renal replacement therapy accompanied by thrombocytopenia. Thrombocytopenia during heparin anticoagulation may be due to heparin-induced thrombocytopenia with need for alternative anticoagulation. Therefore, we compared argatroban and lepirudin in critically ill surgical patients.. Following institutional review board approval and written informed consent, critically ill surgical patients more than or equal to 18 years with suspected heparin-induced thrombocytopenia, were randomly assigned to receive double-blind argatroban or lepirudin anticoagulation targeting an activated Partial Thromboplastin Time (aPTT) of 1.5 to 2 times baseline. In patients requiring continuous renal replacement therapy we compared the life-time of hemodialysis filters. We evaluated in all patients the incidence of bleeding and thrombembolic events.. We identified 66 patients with suspected heparin-induced thrombocytopenia, including 28 requiring renal replacement therapy. Mean filter lifetimes did not differ between groups (argatroban 32 ± 25 hours (n = 12) versus lepirudin 27 ± 21 hours (n = 16), mean difference 5 hours, 95% CI -13 to 23, P = 0.227). Among all 66 patients, relevant bleeding occurred in four argatroban- versus eleven lepirudin-patients (OR 3.9, 95% CI 1.1 to 14.0, P = 0.040). In the argatroban-group, three thromboembolic events occurred compared to two in the lepirudin group (OR 0.7, 95% CI 0.1 to 4.4, P = 0.639). The incidence of confirmed heparin-induced thrombocytopenia was 23% (n = 15) in our study population.. This first randomized controlled double-blind trial comparing two direct thrombin inhibitors showed comparable effectiveness for renal replacement therapy, but suggests fewer bleeds in surgical patients with argatroban anticoagulation.. Clinical Trials.gov NCT00798525. Registered 25 November 2008.

Topics: Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Arginine; Critical Illness; Female; Hemorrhage; Heparin; Hirudins; Humans; Male; Middle Aged; Partial Thromboplastin Time; Pipecolic Acids; Recombinant Proteins; Renal Insufficiency; Renal Replacement Therapy; Sulfonamides; Surgical Procedures, Operative; Thrombocytopenia

To evaluate the effectiveness of our institutions heparin-induced thrombocytopenia (HIT) protocol in achieving a therapeutic activated partial thromboplastin time (aPTT) and to evaluate patient outcomes related to bleeding and thrombotic events before and after protocol implementation.. Retrospective, single-center, pre- and post- assessment of a protocol previously approved at our institution.. 400-bed community hospital serving surrounding rural populations with emphasis in cardiothoracic surgery.. Retrospective chart review based on drug charge data identified 29 patients that received either argatroban or lepirudin for greater than 24 hours. Nineteen patients received either argatroban or lepirudin prior to HIT-protocol implementation, while the remaining ten received either drug after the HIT protocol was implemented.. Implementation of HIT protocol occurred in March 2009. Patients were divided into pre-protocol and post-protocol groups.. Primary outcome was to evaluate the number of therapeutic, subtherapeutic, and supratherapeutic aPTTs between two groups. In the pre-protocol group, aPTTs were therapeutic, subtherapeutic, and supratherapeutic 48.5% (164/338), 14.2% (48/338), and 37.2% (126/338) of the time, respectively. Meanwhile aPTTs in the post-protocol group were therapeutic, subtherapeutic, and supratherapeutic 46.6% (89/191), 22% (42/191), and 31.4% (60/191) of the time, respectively. The number of subtherapeutic aPTTs was statistically higher in the post-protocol group compared to the pre-protocol group. Secondary endpoints included the number of bleeding events and number of thrombotic events. None of the secondary endpoints reached statistical significance. Time to therapeutic aPTT was also evaluated: in the pre-protocol group median time (range) was 15 hours (2-108.6) compared to 8.1 hours (2.3-94.2) in the post-protocol group.. Adoption and implementation of HIT protocol at our institution resulted in significantly more subtherapeutic aPTTs as compared to time prior to protocol. Although not statistically significant, the time required to obtain therapeutic aPTT was reduced by almost 50% after protocol implementation, which could be of clinical importance. Larger studies are needed to continue to assess if standardized protocols are effective in treatment of HIT.

Topics: Aged; Anticoagulants; Antithrombins; Arginine; Female; Heparin; Hirudins; Humans; Male; Middle Aged; Partial Thromboplastin Time; Pipecolic Acids; Platelet Aggregation Inhibitors; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Treatment Outcome

The recommended dose (bolus 0.4 mg/kg followed by 0.15 mg/kg per hour) of lepirudin, a direct thrombin inhibitor licensed for treatment of heparin-induced thrombocytopenia (HIT), is too high. Starting in 2001, we omitted the bolus and reduced maintenance dose by at least one-third. Analyzing 53 HIT patients treated between January 2001 and February 2007, we observed that therapeutic anticoagulation intensity already 4 hours after lepirudin start had been reached with the following initial lepirudin doses (median): 0.078 mg/kg per hour [creatinine clearance (CrCl) more than 60 mL/min], 0.040 mg/kg per hour (CrCl 30-60 mL/min), and 0.013 mg/kg per hour (CrCl < 30 mL/min). The efficacy of this treatment was documented by increasing platelets and decreasing D-dimers. Based on this experience, we derived a lepirudin dosing regimen, which was prospectively evaluated treating 15 HIT patients between March 2007 and February 2008. We show that omitting the initial lepirudin bolus and administering 0.08 mg/kg per hour in patients with CrCl more than 60 mL/min, 0.04 mg/kg per hour in patients with CrCl 30-60 mL/min, and 0.01 to 0.02 mg/kg per hour in those with CrCl less than 30 mL/min is efficacious and safe, as documented by increasing platelet counts, decreasing D-dimer levels, and rare thrombotic (1 of 46) and major bleeding (4 of 46) complications.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Blood Cell Count; Blood Platelets; Creatine; Dose-Response Relationship, Drug; Female; Heparin; Hirudins; Humans; Kidney; Male; Metabolic Clearance Rate; Middle Aged; Recombinant Proteins; Renal Insufficiency; Retrospective Studies; Thrombocytopenia; Treatment Outcome

To assess efficacy and safety of lepirudin in patients with heparin-induced thrombocytopenia (HIT) in a prospective study (HAT-3) as well as in a combined analysis of all HAT study data.. Patients with laboratory-confirmed HIT were treated with lepirudin in three different aPTT-adjusted dose regimen and during cardiopulmonary bypass (CPB). Endpoints were new thromboembolic complications (TEC), limb amputations, and death and major bleeding. A historical control group (n = 120) was used for comparison.. After start of lepirudin in 205 patients treated in HAT-3, the combined endpoint occurred in 43 (21.0%). Thirty (14.6%) patients died, 10 (4.9%) underwent limb amputation, and 11 (5.4%) new TECs occurred. Major bleeding occurred in 40 patients (19.5%) (seven during CPB surgery). Combining all prospective HAT trials (n = 403), after start of lepirudin treatment, the combined endpoint occurred in 82 patients (20.3%), with 47 deaths (11.7%), 22 limb amputations (5.5%), 30 new TECs (7.4%), and 71 (17.6%) major bleedings. Compared with the historical control group (log-rank test), the combined endpoint after start of treatment was reduced (29.7% vs. 52.1%, P = 0.0473), primarily because of reduction in new thromboses (11.9% vs. 32.1%, P = 0.0008). Mean lepirudin maintenance doses ranged from 0.07 to 0.11 mg kg(-1) h(-1). Major bleeding was more frequent in the lepirudin-treated patients (29.4% vs. 9.1%, P = 0.0148).. The rate of new TECs in HIT patients is low after start of lepirudin treatment. The rate of major bleeding of 17.6% might be reduced by reducing the starting dose to 0.1 mg kg(-1) h(-1).

Topics: Adult; Aged; Aged, 80 and over; Amputation, Surgical; Anticoagulants; Female; Hemorrhage; Heparin; Hirudins; Humans; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Secondary Prevention; Survival Analysis; Thrombocytopenia; Thromboembolism

This analysis of 3 prospective multicenter trials in patients with laboratory-confirmed acute heparin-induced thrombocytopenia (HIT) without clinically evident thromboembolic complications (TECs), isolated HIT, assessed the combined individual end points of death, new TECs, and limb amputation. Patients with the same inclusion criteria who did not receive lepirudin or danaparoid served as a contemporaneous control group. Ninety-one patients were treated with lepirudin (intravenous infusion 0.10 mg/kg/h, no bolus, activated partial thromboplastin time [aPTT]-adjusted to 1.5-2.5 times baseline) for a median of 11.0 days (range, 1-68 days). During the observation period (median 24 days), 13 (14.3%) deaths, 4 (4.4%) new TECs, 3 (3.3%) limb amputations (combined 18 [19.8%]), and 13 (14.3%) major bleeding events occurred. In comparison to the control group (N = 47), the combined end point (P = .0281) and new TECs (P = .02) were reduced, and major bleeding was not significantly different between groups (P = .5419). In renal impairment, lepirudin did not reach its steady state within 4 hours, and additional monitoring every 4 hours after start of lepirudin until steady state is reached is recommended. Lepirudin seems to be effective in patients with isolated HIT. Dose reductions in renal impairment are important. Keeping the aPTT in the range corresponding to 600 to 700 microg/L lepirudin during treatment may minimize bleeding complications.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Anticoagulants; Antithrombin III; Female; Heparin; Hirudins; Humans; Male; Middle Aged; Partial Thromboplastin Time; Peptide Hydrolases; Recombinant Proteins; Thrombocytopenia; Thrombosis; Treatment Outcome

Heparin-induced thrombocytopenia (HIT) is a well-known complication of heparin exposure and presents a clinical dilemma for patients undergoing percutaneous intervention (PI). Heparin cannot be used for thrombin inhibition and direct thrombin inhibitors offer an attractive alternative to heparin. We report our experience with lepirudin, a recombinant hirudin, used for PI in HIT patients.. Patients undergoing PI with known diagnosis of HIT were assigned to varying doses of lepirudin, often in combination with a platelet glycoprotein (GP) IIb/IIIa inhibitor. Predetermined endpoints of safety and efficacy were assessed prospectively.. Twenty-five patients underwent a total of 36 interventions. Angiographic success was obtained in 100% of patients and clinical success (freedom from death, myocardial infarction, stroke or target vessel revascularization) in 92% of patients. There was 1 procedure-related mortality resulting from a retroperitoneal bleed. Three patients had minor bleeding.. Lepirudin is efficacious as a replacement for heparin in patients with HIT undergoing PI. Caution should be used when using a combination of lepirudin, GP IIb/IIIa inhibitors, clopidogrel and aspirin.

Topics: Abciximab; Angioplasty, Balloon; Antibodies, Monoclonal; Anticoagulants; Drug Therapy, Combination; Eptifibatide; Female; Heparin; Hirudins; Humans; Immunoglobulin Fab Fragments; Male; Peptides; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Prospective Studies; Recombinant Proteins; Thrombocytopenia; Tirofiban; Treatment Outcome; Tyrosine

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

We prospectively investigated lepirudin for further parenteral anticoagulation in patients with heparin-induced thrombocytopenia (HIT).. Patients with confirmed HIT (n=112) received lepirudin according to need for 2 to 10 days (longer if necessary): A1, treatment: 0.4 mg/kg IV bolus, followed by 0.15 mg. kg(-1). h(-1) intravenous infusion, n=65; A2, treatment in conjunction with thrombolysis: 0.2 mg/kg, followed by 0.10 mg. kg(-1). h(-1), n=4; and B, prophylaxis: 0.10 mg. kg(-1). h(-1), n=43. Outcomes from 95 eligible lepirudin-treated patients were compared with those of historical control patients (n=120). Complete laboratory response (activated partial thromboplastin time ratio >1.5 with /=1 outcome (cumulative incidence 30.9% versus 52.1%; relative risk [RR] 0.71; P=0.12, log-rank test). Bleeding events were more frequent in the lepirudin group than the historical control group (cumulative incidence at 35 days, 44.6% versus 27.2%; RR 2.57; P=0.0001, log-rank test). No difference was observed in bleeding events requiring transfusion (cumulative incidence at 35 days, 12.9% versus 9.1%; RR 1.66; P=0.23, log-rank test); no intracranial bleeding was observed in the lepirudin group.. Lepirudin effectively prevents death, limb amputations, and new thromboembolic complications and has an acceptable safety profile in HIT patients. Treatment should be initiated as soon as possible if HIT is suspected.

Topics: Aged; Amputation, Surgical; Anticoagulants; Autoimmune Diseases; Female; Hemorrhage; Heparin; Hirudin Therapy; Hirudins; Humans; Life Tables; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Recurrence; Safety; Survival Analysis; Thrombocytopenia; Thrombosis; Treatment Outcome

Recombinant hirudin (lepirudin) is a potent direct thrombin inhibitor, which has been approved for the treatment of heparin-induced thrombocytopenia type II (HIT). Because the drug is mainly eliminated by the kidneys, a single loading dose of hirudin may induce therapeutic anticoagulation for up to one week in patients with renal insufficiency. Thus, the use of hirudin in critically ill patients with renal failure could markedly increase their bleeding risk. In this study, hirudin was used in critically ill patients with suspected HIT while on continuous venovenous hemodialysis (CVVHD).. Hirudin anticoagulation was performed in seven critically ill patients with suspected HIT. Four patients were initially anuric. Three patients had residual renal function. In all 64 CVVHD treatments (mean duration 12 hr), a polysulfone high-flux hemodialyzer (0.75 m2) with a dialysate flow rate of 1.5 liter/hr and an ultrafiltration rate of up to 200 ml/hr was used. Hirudin was given either as continuous intravenous infusion or as repetitive intravenous boli. Monitoring of anticoagulation was performed by measurements of the systemic activated partial thromboplastin time (aPTT).. Hirudin dosage had to be individualized according to the risk of bleeding or clotting. During CVVHD, a continuous intravenous infusion (0.006 to 0.025 mg/kg body wt/hr, N = 2) or repetitive intravenous boli (0.007 to 0.04 mg/kg, N = 5) were given. Two patients required blood transfusions prior to and during hirudin treatment. In five patients without a high bleeding risk, the hirudin dose was adjusted to achieve the target aPTT (1.5 to 2.0 x baseline) in order to prevent thrombotic complications or frequent clotting in the extracorporal circuit. Hirudin dose requirements depended on residual renal function and extracorporal clearance.. We conclude from these first clinical data that anticoagulation with hirudin in critically ill patients on continuous hemodialysis can be performed without excessive bleeding risk by combining close clinical and laboratory monitoring. The hirudin dose has to be reduced because of renal failure, and may require adjustment for residual or recovering renal function and extracorporal elimination.

Topics: Acute Kidney Injury; Adult; Aged; Anticoagulants; Critical Care; Female; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Platelet Count; Recombinant Proteins; Renal Dialysis; Thrombocytopenia; Treatment Outcome

Monitoring of direct thrombin inhibitors (DTIs) in patients with heparin-induced thrombocytopenia (HIT) is primarily performed using the activated partial thromboplastin time (aPTT). This assay is poorly standardized, reagent dependent, and not DTI specific. We compared aPTT, thrombin time (TT), and prothrombin time (PT) to drug levels obtained by the ecarin chromogenic assay (ECA). We analyzed 495 samples of patients with confirmed or suspected HIT on treatment with either argatroban (n = 37) or lepirudin (n = 80). Mean DTI levels ± standard deviation (SD) were 0.41 ± 0.36 µg/mL for argatroban and 0.20 ± 0.21 µg/mL for lepirudin. Results of aPTT were highly variable: 67 ± 22 seconds for argatroban and 55 ± 20 seconds for lepirudin. Significant correlations ( P < .01) were found between ECA-based DTI level and TT (argatroban, r = .820 and lepirudin, r = .830), PT (argatroban, r = -.544), and aPTT (lepirudin, r = .572). However, there was no correlation of aPTT with argatroban or PT with lepirudin concentration. Multiple regression analyses revealed that the TT predicted 54% of argatroban and 42% of lepirudin levels, but no significant impact was seen for PT or aPTT. The aPTT-guided monitoring of DTI therapy leads to a high percentage of patients with inaccurate plasma levels, hence resulting to either undertreatment or overtreatment. Knowledge of baseline values prior to DTI therapy and inclusion of clinical settings are essential for dosing DTIs when using aPTT. However, due to several limitations of aPTT, monitoring according to exact plasma concentrations as obtained by specific tests such as ECA may be more appropriate.

Topics: Antithrombins; Arginine; Blood Coagulation Tests; Drug Monitoring; Heparin; Hirudins; Humans; Partial Thromboplastin Time; Pipecolic Acids; Prothrombin Time; Recombinant Proteins; Sulfonamides; Thrombin Time; Thrombocytopenia

The rate of heparin-induced thrombocytopenia (HIT) on a population basis is unknown. The objective of this study was to characterize the risk for HIT during antepartum, delivery, and postpartum hospitalizations in the United States.. A large administrative database was used to determine the risk of HIT in hospitalized obstetric patients who received unfractionated heparin (UFH) or low molecular weight heparin (LMWH). Patients were presumed to have HIT if they were exposed to UFH or LMWH, received a diagnosis of HIT, and were administered a medication for the treatment of HIT including bivalirudin, argatroban, fondaparinux, or lepirudin. We queried severe complications of HIT including arterial thrombosis, limb amputation, heart failure, and death.. We identified 66,468 antepartum hospitalizations, 66,741 delivery hospitalizations, and 16,325 postpartum readmissions where women received pharmacologic prophylaxis. Of these, 10 antepartum admissions, 1 delivery admission, and 14 postpartum readmissions involved a diagnosis of HIT with treatment of bivalirudin, argatroban, fondaparinux, or lepirudin. There were no deaths and no diagnoses of arterial thrombosis, limb amputation, heart failure, and death.. Risk for HIT among hospitalized obstetric patients is low. In this cohort, no cases of death or severe complications were noted in relation to the diagnosis.

Topics: Adolescent; Adult; Arginine; Databases, Factual; Delivery, Obstetric; Female; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Hospitalization; Humans; Middle Aged; Peptide Fragments; Pipecolic Acids; Postpartum Period; Pregnancy; Recombinant Proteins; Risk Assessment; Sulfonamides; Thrombocytopenia; United States; Young Adult

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

Recent studies reveal a high occurrence of overdiagnosis of heparin-induced thrombocytopenia in surgical patients with critical illness. The optimal criteria for diagnosis of heparin-induced thrombocytopenia remain unclear, contributing to unnecessary treatment. We reviewed patients who were admitted to surgical ICUs and were suspected of heparin-induced thrombocytopenia to identify how often patients were correctly treated.. In this clinical prospective study, data were collected including age, sex, antiplatelet factor 4/heparin enzyme-linked immunosorbent assay, serotonin release assay, and Warkentin 4Ts scores. Heparin-induced thrombocytopenia-positive patients were defined as those with both positive antiplatelet factor 4/heparin enzyme-linked immunosorbent assay (optical density, ≥ 0.40) and positive serotonin release assay results.. Urban tertiary medical center.. Patients admitted to the surgical and cardiac ICU who were presumed to have heparin-induced thrombocytopenia and underwent antiplatelet factor 4/heparin enzyme-linked immunosorbent assay and serotonin release assay testing between January 1, 2011, and August 1, 2014.. None.. A total of 135 patients had 4Ts, antiplatelet factor 4/heparin enzyme-linked immunosorbent assay, and serotonin release assay scores. A total of 11 patients (8.1%) had positive serotonin release assay and 80 patients had positive antiplatelet factor 4/heparin enzyme-linked immunosorbent assay; 10 patients were identified as heparin-induced thrombocytopenia positive. Positive serotonin release assay was noted in nine of 11 patients (81.8%) with antiplatelet factor 4/heparin enzyme-linked immunosorbent assay optical density greater than or equal to 2.0, compared with one of 22 patients (4.5%) with optical density values of 0.85-1.99, and one of 102 patients (1.0%) with optical density values of 0-0.84. Out of 135 patients, 29 patients (21.5%) received treatment with argatroban, lepirudin, or fondaparinux: 10 of 10 heparin-induced thrombocytopenia-positive patients (100%) compared with 19 of 125 heparin-induced thrombocytopenia-negative patients (15%).. Overtreatment of heparin-induced thrombocytopenia in the surgical ICU continues even with recent increased caution encouraging a higher antiplatelet factor 4/heparin enzyme-linked immunosorbent assay optical density threshold before initiating treatment. More stringent criteria should be used to determine when to order serologic testing and when the results of such testing should prompt a change in anticoagulant treatment. If antiplatelet factor 4/heparin enzyme-linked immunosorbent assay is used to consider immediate treatment, an optical density greater than or equal to 2.0 may be a more appropriate threshold.

Topics: Academic Medical Centers; Aged; Antibodies; Anticoagulants; Antithrombins; Arginine; Enzyme-Linked Immunosorbent Assay; Female; Fondaparinux; Heparin; Hirudins; Humans; Intensive Care Units; Male; Medical Overuse; Middle Aged; Pipecolic Acids; Platelet Factor 4; Polysaccharides; Prospective Studies; Recombinant Proteins; Serotonin; Sulfonamides; Thrombocytopenia

To evaluate the safety, effectiveness, and dosing of off-label bivalirudin to argatroban and lepirudin in patients with heparin-induced thrombocytopenia (HIT) using a new pharmacist driven protocol.. Retrospective cohort study of forty eight patients treated with lepirudin, argatroban, or bivalirudin from November 2010 to February 2012 for suspected HIT. Patients were excluded if the bivalirudin therapy was being used for acute coronary syndrome or if the treatment duration was less than 24 hours. The primary endpoint was time to therapeutic activated partial thromboplastin time (aPTT 50-90 seconds for argatroban and bivalirudin and 50-85 seconds for lepirudin). The secondary endpoints were elevation in international normalized ratio (INR), bleeding episodes, and percent time in aPTT target range.. Patients receiving bivalirudin reached a therapeutic aPTT more quickly than those receiving argatroban and lepirudin (3.7 hours vs. 14.2 hours vs. 14.7 hours, p <0.001). The INR was increased more in patients treated with argatroban than lepirudin and bivalirudin (1.3 vs. 0.3 vs. 0.4, p = 0.4). Clinically significant bleeding in patients treated with bivalirudin was significantly lower than that observed with argatroban or lepirudin (7% vs. 22% vs. 56%, p = 0.02). The average percentage of therapeutic aPTTs drawn was higher for patients treated with bivalirudin than those patients treated with argatroban and lepirudin (90% vs. 66% vs. 67%, p = 0.2).. A pharmacist-driven protocol for bivalirudin provided a significantly shorter time to therapeutic aPTT and lower bleeding rate for patients being treated for HIT when compared to lepirudin and argatroban. A larger study should be considered to confirm the results of this single center study.

Topics: Aged; Anticoagulants; Antithrombins; Arginine; Dose-Response Relationship, Drug; Female; Hemorrhage; Heparin; Hirudins; Humans; International Normalized Ratio; Male; Middle Aged; Partial Thromboplastin Time; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Retrospective Studies; Sulfonamides; Thrombocytopenia

Parenteral direct thrombin inhibitors (DTIs) may be used in pediatric patients with contraindications to heparin therapy, such as heparin-induced thrombocytopenia. Few data exist regarding the use of DTIs in pediatric patients.. To characterize the use of DTIs in pediatric patients, including monitoring strategies and bleeding complications.. A retrospective descriptive study was designed and the Pediatric Health Information System database was queried from 2004 to 2011 for pediatric patients receiving a parenteral DTI. Patient demographic and hospital data, mortality, disease state, and procedure information (from International Classification of Diseases, Ninth Revision codes) were collected from the query. DTI monitoring information was also collected. Patients were divided into 2 time periods (2004-2007, 2008-2011) to evaluate trends.. Two hundred eight patients met study criteria (50.9% male, 64.4% white), and children (2-12 years of age) represented 34.6% of the population. Congenital heart disease was present in 43.8% and cardiovascular surgical procedure occurred in 28.4%. Argatroban was most commonly used (73.1%) and bivalirudin use increased (P < .001). Bleeding complications were present in 37.9% of patients and mortality was 19.7%. Bleeding complications were associated with lepirudin (62.5%) and argatroban (41.7%) more often as compared with bivalirudin (18.8%) (P < .001). Activated partial thromboplastin time and prothrombin time were used more often in patients receiving argatroban and lepirudin in comparison with bivalirudin, and thrombin time was used more often in patients receiving lepirudin (P < .001). Activated clotting time use increased over time (5.1% versus 17.5%, P = .02).. Pediatric use of DTIs is infrequent and occurs in patients with high morbidity and mortality.

Topics: Adolescent; Age Factors; Antithrombins; Arginine; Child; Child, Preschool; Databases, Factual; Female; Health Information Systems; Hemorrhage; Hirudins; Humans; Incidence; Infant; Infant, Newborn; Infusions, Parenteral; Male; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Retrospective Studies; Sulfonamides; Thrombocytopenia; Young Adult

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

Topics: Aged; Antithrombins; Aortic Valve Stenosis; Coronary Angiography; Coronary Thrombosis; Echocardiography; Enzyme-Linked Immunosorbent Assay; Female; Heart Valve Prosthesis Implantation; Heparin; Hirudins; Humans; Intra-Aortic Balloon Pumping; Recombinant Proteins; Thrombocytopenia

A quality initiative to improve the management of heparin-induced thrombocytopenia (HIT) at an academic medical center, including the development of guidelines on the use of direct thrombin inhibitors (DTIs), is described.. In keeping with the Joint Commission's National Patient Safety Goal (NPSG) for anticoagulant therapy (goal 03.05.01), a multidisciplinary working group conducted a needs assessment to identify areas for improvement in the center's HIT management practices, particularly the use of DTI therapy (an issue not specifically addressed by NPSG 03.05.01). The resulting action steps included (1) the implementation of a detailed protocol for the recognition and management of HIT, as well as guidelines on the use of the DTIs argatroban and lepirudin, (2) more efficient use and optimized documentation of initial and confirmatory tests in the electronic medical record (EMR), and (3) the education of pharmacists, nurses, and physicians on the use of the HIT protocol, with initial and ongoing case-based competency testing of pharmacy staff. Early postimplementation experience indicated that the protocol and associated activities have resulted in improved DTI prescribing and dosing, HIT documentation, and patient education practices while expanding pharmacists' involvement in ensuring optimal, cost-effective management of patients with HIT.. In one institution, an HIT working group extended the scope of NPSG 03.05.01 to include the parenteral DTIs. The implementation of the HIT protocol has resulted in greater compliance with appropriate DTI dosing and improved EMR documentation of HIT.

Topics: Academic Medical Centers; Anticoagulants; Antithrombins; Arginine; Heparin; Hirudins; Humans; Joint Commission on Accreditation of Healthcare Organizations; Patient Education as Topic; Pharmacists; Pipecolic Acids; Practice Guidelines as Topic; Quality Assurance, Health Care; Recombinant Proteins; Sulfonamides; Thrombin; Thrombocytopenia; United States

Patients with central nervous system (CNS) malignancies have a substantial risk for developing both thrombotic and bleeding disorders. The risk of venous thromboembolism (VTE) is substantially higher in these patients, both in the perioperative period and throughout their disease course. Patients with CNS malignancy harbor a latent hypercoagulability, which predisposes to VTE, as do postoperative immobility, hemiparesis, and other factors. The management of VTE in these patients is complex, given the significant morbidity and mortality associated with intratumoral hemorrhage. In the past, the perceived risk of intracranial hemorrhage limited the use of anticoagulation for the management of VTE with many favoring nonpharmacologic methods for prophylaxis and treatment. Inferior vena cava (IVC) filters have since lost favor at many centers given significant complications, which appear to be more frequent in patients with CNS malignancy. Recent studies have demonstrated safe and efficacious use of anticoagulation in these patients with a low incidence of intracranial hemorrhage. Treatment of established VTE is now recommended in this population with many centers favoring low-molecular-weight heparin (LMWH) versus oral warfarin for short- or long-term treatment. We advocate a multimodality approach utilizing compression stockings, intermittent compression devices, and heparin in the perioperative setting as the best proven method to reduce the risk of VTE. In the absence of a strict contraindication to systemic anticoagulation, such as previous intracranial hemorrhage or profound thrombocytopenia, we recommend LMWH in patients with newly diagnosed VTE and a CNS malignancy.

Topics: Antibodies, Monoclonal, Humanized; Anticoagulants; Arginine; Bevacizumab; Central Nervous System Neoplasms; Fondaparinux; Glioblastoma; Glioma; Hemorrhage; Heparin, Low-Molecular-Weight; Hirudins; Humans; Pipecolic Acids; Polysaccharides; Postoperative Complications; Pulmonary Embolism; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Vena Cava Filters; Venous Thromboembolism; Venous Thrombosis; Warfarin

The clinical outcomes of patients receiving renal replacement therapy (RRT) and treated with direct thrombin inhibitors (DTIs) for the management of heparin-induced thrombocytopenia (HIT) were compared.. A retrospective evaluation of clinical outcomes of patients receiving RRT with a presumed diagnosis of HIT treated with lepirudin, argatroban, or bivalirudin was conducted. Inpatients at the University of Pittsburgh Medical Center from January 1, 1995, through March 1, 2008, were included if they were receiving either continuous or intermittent RRT and argatroban, bivalirudin, or lepirudin; were exposed to heparin within the preceding 100 days (including a heparin-treated pulmonary artery catheter) or had a documented heparin allergy; and had at least one of following: (1) an absolute platelet count of <150,000 cells/μL, (2) a decline in platelets of >50% from baseline before exposure to heparin, or (3) a documented diagnosis of thrombocytopenia. The primary outcome assessed was a triple composite endpoint of thrombosis, hemorrhage, and inhospital mortality. A secondary assessment compared the pharmacodynamic relationship between activated partial thromboplastin time and the triple composite.. For the primary endpoint, there was no statistically significant difference observed among DTIs. In patients receiving RRT, a lack of a previous heparin allergy, the degree of International Normalized Ratio elevation, and lower serum albumin were significantly correlated with increased morbidity and the occurrence of the composite endpoint.. No differences in adverse events or other clinical outcomes were observed in this retrospective evaluation of DTI use in patients receiving RRT with presumed HIT.

Topics: Adult; Aged; Anticoagulants; Antithrombins; Arginine; Female; Heparin; Hirudins; Humans; International Normalized Ratio; Male; Middle Aged; Peptide Fragments; Pipecolic Acids; Platelet Count; Recombinant Proteins; Renal Replacement Therapy; Retrospective Studies; Serum Albumin; Sulfonamides; Thrombocytopenia

Topics: Aged, 80 and over; Fibrinolytic Agents; Heparin; Hirudins; Humans; Kidney Diseases; Male; Recombinant Proteins; Thrombocytopenia; Time Factors; Treatment Outcome; Warfarin

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

In this case series, we describe our successful use of a reduced hirudin dosage as an anticoagulant during cardiac surgery using minimized extracorporeal circulation in patients with heparin-induced thrombocytopenia.

Topics: Aged; Anticoagulants; Blood Loss, Surgical; Blood Transfusion, Autologous; Coronary Artery Bypass; Erythrocyte Transfusion; Extracorporeal Circulation; Female; Fibrinolytic Agents; Heparin; Hirudins; Humans; Male; Middle Aged; Monitoring, Intraoperative; Partial Thromboplastin Time; Plasma; Postoperative Care; Recombinant Proteins; Thrombocytopenia; Whole Blood Coagulation Time

Patients with heparin-induced thrombocytopenia (HIT) require anticoagulation with alternative immediate acting anticoagulants such as lepirudin. Lepirudin may generate antibodies that increase risk of bleeding. Fondaparinux, on the other hand, is structurally too short to induce antibody formation, and therefore, it could be a useful agent for the treatment of HIT.. University teaching hospital in Saudi Arabia.. A retrospective study was conducted at a university teaching hospital on HIT cases which were diagnosed between January 2006 and December 2009. The diagnosis was based on clinical findings consistent with HIT presentation (i.e., a confirmed fall in the platelet count to <100 × 10(9)/L or a 50% reduction from baseline, four or more days after starting heparin therapy, with exclusion of other causes of thrombocytopenia) and a positive immunoassay test.. Twelve HIT patients (6 males and 6 females) met the inclusion criteria. Fondaparinux was given to five subjects while lepirudin was utilized in seven patients. The median age was 65 years in the fondaparinux group, and 55 years in the lepirudin group. Nine patients (75%) were on heparin infusion, while three (25%) were on subcutaneous heparin or heparin flushes prior to HIT diagnosis. Frequencies of concomitant chronic diseases as well as other treatments including antiplatelets were similar between the two groups (P > 0.05). The time for platelets recovery was similar between the two groups (Median = 4 days for both arms; P = 0.736). Furthermore, fondaparinux therapy was associated with bigger area under platelet count compared to lepirudin (8,179 vs. 5,768 cell × 10(9)*day/L; P = 0.0303), and higher nadir counts (89 vs. 44 cell × 10(9)/L; P = 0.061).. The current study suggests that fondaparinux is a potential alternative treatment for HIT. Further larger studies are needed to confirm our findings.

Topics: Aged; Anticoagulants; Female; Fibrinolytic Agents; Fondaparinux; Heparin; Hirudins; Hospitals, University; Humans; Male; Middle Aged; Platelet Count; Polysaccharides; Recombinant Proteins; Retrospective Studies; Saudi Arabia; Thrombocytopenia; Treatment Outcome

Type II heparin-induced thrombocytopenia (HIT) is a potentially severe adverse effect of heparin treatment triggered by an immune response. Although most cases occur in patients receiving unfractioned heparin, HIT can also arise after low-molecular-weight heparin (LMWH). We report a case of HIT in a postoperative orthopedic 75-year-old woman in treatment with LMWH (nadroparin) complicated by pulmonary embolism and treated successfully with recombinant hirudin. Early recognition and proper treatment are fundamental for the management of this life-threatening disorder.

Topics: Aged; Antibodies; Female; Fibrinolytic Agents; Fractures, Bone; Hirudins; Humans; Nadroparin; Orthopedic Procedures; Platelet Count; Pulmonary Embolism; Recombinant Proteins; Thrombocytopenia; Tomography, X-Ray Computed; Treatment Outcome

A 57-year-old man developed transient global amnesia within an hour of bolus unfractionated heparin administration on day 4 post-mitral valve replacement. Both immunoglobulin G-specific enzyme-linked immunosorbent assay and serotonin release assay were strongly positive for the antibodies that cause heparin-induced thrombocytopenia. The patient's cognitive functions returned to normal following discontinuation of unfractionated heparin and warfarin and commencement of lepirudin infusion.

Topics: Amnesia, Transient Global; Anticoagulants; Heart Valve Prosthesis Implantation; Heparin; Hirudins; Humans; Male; Middle Aged; Mitral Valve; Recombinant Proteins; Thrombocytopenia; Time Factors; Warfarin

Topics: Anticoagulants; Female; Fondaparinux; Hematocrit; Heparin; Hirudins; Humans; Middle Aged; Platelet Count; Polysaccharides; Recombinant Proteins; Thrombocytopenia; Ultrasonography; Venous Thrombosis

Topics: Anticoagulants; Antithrombins; Arginine; Fibrinolytic Agents; Heparin; Hirudins; Humans; Pipecolic Acids; Platelet Aggregation Inhibitors; Recombinant Proteins; Sulfonamides; Thrombectomy; Thrombocytopenia; Time Factors; Venous Thrombosis

Heparin-Induced Thrombocytopenia (HIT), if left untreated, can lead to thrombocytopenia, thromboembolic complications and even death. Two thrombin inhibitors, lepirudin and argatroban, have been shown to improve clinical outcomes compared to historical controls in the management of HIT. The purpose of this retrospective study was to compare the effects of lepirudin and argatroban in the management of HIT.. Adult subjects with a positive anti-heparin platelet factor 4 (PF4) antibody test and >50% decrease in platelet count during the first 30 days of admission over a period of 2 years were included in the study. Patient demographics, platelet counts, choice of antithrombin therapy, occurrence of thrombosis, length of hospital stay, and date and cause of death, if applicable, were collected for each patient.. Eighty-two patients met inclusion criteria: 41 patients did not receive any thrombin inhibitors after the diagnosis of HIT, 24 patients received lepirudin and 17 patients received argatroban. Subjects treated with a thrombin inhibitor were more likely to experience platelet count recovery (87.5% for the lepirudin group and 82.4% for the argatroban group) compared to those who did not receive antithrombin therapy (51.2%) after the diagnosis of HIT was made (P < 0.001). The thrombosis rate for subjects who did not receive antithrombin therapy after the diagnosis of HIT was 26.8%, compared to 8.3% for the lepirudin group and 5.9% for the argatroban group (P < 0.01). The incidence of death was also higher in the group of subjects that did not receive antithrombin therapy (48.8%) compared with the lepirudin group (16.7%) or the argatroban group (23.5%), P < 0.01.. Our findings suggest that thrombin inhibitors can improve the outcomes of patients with HIT by decreasing the incidence of morbidity and mortality relating to HIT. No significant difference could be determined in outcomes between argatroban and lepirudin therapy.

Topics: Aged; Anticoagulants; Arginine; Female; Heparin; Hirudins; Humans; Male; Middle Aged; Pipecolic Acids; Recombinant Proteins; Retrospective Studies; Sulfonamides; Thrombocytopenia

Up to 3% of patients receiving unfractioned heparin develop heparin-induced thrombocytopenia (HIT). We report on a polytrauma patient who developed severe HIT with bilateral pulmonary embolism. Lepirudin treatment resulted initially in rapid improvement. Ten days after discharge the patient complained of abdominal pain. A large subcapsular hepatic hematoma was diagnosed, requiring repeat surgery and ending in secondary sclerosing cholangitis. This process can potentially be avoided by regular tests of lepirudin concentration and coagulation.

Topics: Anticoagulants; Aortic Rupture; Blood Coagulation Tests; Cholangiopancreatography, Endoscopic Retrograde; Cholangitis, Sclerosing; Female; Heparin; Hernia, Diaphragmatic, Traumatic; Hirudins; Humans; Liver; Liver Diseases; Middle Aged; Multiple Trauma; Patient Readmission; Platelet Count; Postoperative Complications; Postoperative Hemorrhage; Recombinant Proteins; Reoperation; Thrombocytopenia; Tomography, X-Ray Computed

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

A case of lepirudin-induced thrombocytopenia is reported.. A 61-year-old white man arrived at the emergency department with complaints of pain in his left thigh that worsened with walking. His medical history was significant for extensive thromboses over a period of six months. He had recently been discharged from the hospital for suspected heparin-induced thrombocytopenia (HIT) while on enoxaparin. A venous duplex scan revealed two new deep venous thromboses in the left common, superficial, and popliteal veins. The patient was admitted and initiated on aspirin 325 mg and warfarin sodium 2 mg daily. Intravenous lepirudin with an activated partial thromboplastin time (aPTT) goal of 60-80 seconds was also started. Because of his recurrent thrombotic event, a new International Normalized Ratio (INR) goal of 3.0-3.5 was established for warfarin therapy. Eighteen days after admission, the patient's INR and aPTT were high; therefore, his warfarin dose was reduced and i.v. lepirudin was changed to subcutaneous administration. The patient was transferred to the intensive care unit (ICU) and, 5 days later, he developed melena. During the 7 days of treatment with subcutaneous lepirudin, a drop in platelet counts was observed. Subcutaneous lepirudin was discontinued after resolution of melena, and i.v. lepirudin was restarted. After 15 days, his platelet counts increased and he was switched back to subcutaneous lepirudin, which again led to a drop in platelets. After 27 days in the ICU, the patient's INR and aPTT remained high. Lepirudin was discontinued and i.v. bivalirudin was initiated. His platelet count increased and he was discharged. Eleven days later, the patient was found unresponsive with left-sided fasciculations. The patient died secondary to respiratory arrest as a consequence of intracranial hemorrhage.. A 61-year-old white man with a history of thromboses and suspected HIT developed thrombocytopenia possibly associated with receiving two courses of subcutaneous lepirudin. Careful monitoring of platelet counts are warranted in patients who have a history of HIT and are receiving subcutaneous lepirudin.

Topics: Fatal Outcome; Hirudins; Humans; Injections, Subcutaneous; Male; Middle Aged; Recombinant Proteins; Thrombocytopenia

Heparin-induced thrombocytopenia (HIT II) in childhood is rare. Suspected HIT II requires immediate diagnostic and therapeutic measures in order to avoid potentially life threatening complications. Heparin must be stopped immediately. We report on a 6-year old boy who required cardiac surgery due to tetralogy of Fallot. To our knowledge he had been exposed to heparin for the first time during cardiac catheterization on the day before surgery. Preoperatively, platelet count was normal. Postoperatively (3 days after heparin exposure), he developed pulmonary and renal failure and required inotropic cardiac support and dialysis. He also developed progressive (severe) thrombocytopenia under heparin therapy on day 2-3 postoperatively. The dialysis filter required daily exchanges due to clotting despite increasing heparin doses. The first ELISA for HIT on postop day 4 was negative. 3 days later a repeated test was positive. Von Willebrand factor antigen and D-dimers were markedly increased. The patient was immediately switched to lepirudin and subsequently stabilized slowly. No major systemic thrombosis occurred. After lepirudin treatment for 6 weeks the patient was fully recovered and HIT II-testing was negative again.. In children with progressive thrombocytopenia in the setting of heparin exposure and signs of major or micro thrombosis HIT II must be ruled out. Even if a first early test turns out negative repeated testing should be performed. Lepirudin anticoagulation is effective and should be monitored correctly. Platelet transfusion should be avoided in HITII.

Topics: Anticoagulants; Child; Heparin; Hirudins; Humans; Male; Postoperative Period; Recombinant Proteins; Tetralogy of Fallot; Thrombocytopenia; Treatment Outcome

Topics: Anticoagulants; Antiphospholipid Syndrome; Cerebral Hemorrhage; Drug Administration Schedule; Half-Life; Heparin; Hirudins; Humans; Lupus Erythematosus, Systemic; Male; Middle Aged; Recombinant Proteins; Renal Insufficiency; Thrombocytopenia; Treatment Outcome

Topics: Anticoagulants; Autoantibodies; Enzyme-Linked Immunosorbent Assay; Fibrinolytic Agents; Heparin; Hirudins; Humans; Microsurgery; Platelet Aggregation; Recombinant Proteins; Surgical Flaps; Thrombocytopenia; Treatment Outcome; Vascular Surgical Procedures

Lepirudin (r-hirudin) is one of the two alternative anticoagulants licensed to treat patients with heparin-induced thrombocytopenia (HIT). Manufacturer's guidelines state that lepirudin should be monitored using the activated partial thromboplastin time (APTT) ratio. However, several studies have demonstrated a plateau effect of higher concentrations of lepirudin on APTT ratios and variable results when comparing different APTT reagents. This study compares APTT ratios (using two different APTT reagents) with two other commercially available methods for directly quantifying plasma lepirudin levels: ecarin chromogenic assay and prothrombinase-induced clotting time in 95 samples from five patients receiving lepirudin anticoagulation for HIT.

Topics: Anticoagulants; Blood Coagulation; Blood Coagulation Tests; Endopeptidases; Fibrinolytic Agents; Heparin; Hirudins; Humans; Partial Thromboplastin Time; Recombinant Proteins; Thrombocytopenia; Thromboplastin

Anticoagulation management of patients with recent heparin-induced thrombocytopenia (HIT) requiring cardiopulmonary bypass (CPB) surgery is a serious challenge, and especially difficult in patients requiring urgent heart transplantation. As nonheparin anticoagulants during CPB bear a high risk of major bleeding, these patients are at risk of being taken off the transplant list. Short-term use of unfractionated heparin (UFH) for CPB, with restriction of UFH to the surgery itself, is safe and effective in patients with a history of HIT who test negative for antiplatelet factor 4 (PF4)/heparin antibodies. We present evidence that it is safe to expand the concept of UFH reexposure to patients with subacute HIT (ie, those patients with recent HIT in whom the platelet count has recovered but in whom anti-PF4/heparin IgG antibodies remain detectable) requiring heart transplantation, if they test negative by a sensitive functional assay using washed platelets. This can be lifesaving in patients with end-stage heart failure.

Topics: Adult; Anticoagulants; Arginine; Autoantibodies; Heart Failure; Heart Transplantation; Heparin; Hirudins; Humans; Male; Middle Aged; Pipecolic Acids; Platelet Factor 4; Recombinant Proteins; Sulfonamides; Thrombocytopenia

Treatment of patients with heparin-induced thrombocytopenia type II (HIT II) and thrombosis in some cases that represents a clinical challenge, which, if unrecognized, may lead to treatment delay or disease progression with potentially lethal outcome. We present a case of a 19-year-old patient with antiphospholipid syndrome, factor V (FV) Leiden mutation in heterozygous state, and venous thromboembolism. The patient was subjected to intravenous infusions of unfractionated heparin (UFH), and 16 days after the beginning of the treatment, his condition worsened, with thrombocytopenia and extension of thrombosis. Whereas the patient had a high clinical score for HIT II, functional and antigenic assays for the presence of HIT antibodies were negative. After repeated negative functional and antigenic assays, pseudo-HIT was suspected and nadroparin was introduced, which resulted in further worsening of the clinical presentation. Disease remission, along with complete normalization of platelet count, was finally accomplished with the introduction of lepirudin. The presence of multiple comorbid states, such as antiphospholipid syndrome, can potentially make laboratory confirmation of disease more difficult in patients with HIT II. In our opinion, it is of great importance that HIT II diagnosis be primarily clinical and that laboratory test results are carefully interpreted, especially when HIT is indicated by high clinical score values.

Topics: Administration, Oral; Adult; Antibodies; Anticoagulants; Antiphospholipid Syndrome; Diagnosis, Differential; Factor V; Heparin; Hirudins; Humans; Infusions, Intravenous; Male; Mutation; Nadroparin; Platelet Count; Recombinant Proteins; Thrombocytopenia; Venous Thromboembolism

Topics: Acute Disease; Anticoagulants; Arginine; Blood Coagulation; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Heparin; Hirudins; Humans; International Normalized Ratio; Pipecolic Acids; Platelet Count; Polysaccharides; Recombinant Proteins; Research Design; Sulfonamides; Thrombin; Thrombocytopenia; Treatment Outcome; Venous Thrombosis; Warfarin

An evidence-based heparin- induced thrombocytopenia (HIT) treatment protocol to standardize the management of confirmed or suspected HIT was developed.. In a retrospective review of 10 patients with known or suspected HIT over a two-year period, medical records were evaluated for baseline laboratory results, treatment selection, initial dosing and monitoring, discontinuation of heparin, and alternative therapies chosen. Six of 10 patients had antibody-confirmed HIT at admission. Nine patients received alternative anticoagulation therapy with one of two formulary direct thrombin inhibitor (DTI) agents, lepirudin and argatroban; 1 patient was given fondaparinux. Medical record analyses revealed deficiencies in both initial and transitional dose administration and renal function monitoring, order omissions, infusion-related medication errors, and treatments that were unsubstantiated, inappropriate, or lacking in regulatory approval. The new treatment protocol developed to assist physicians, pharmacists, and nurses with HIT management focused primarily on the two agents labeled for HIT, lepirudin and argatroban. The protocol established baseline levels for the selection of anticoagulation therapy as well as guidance in DTI selection, use, and monitoring. Guidelines for initial dosing and continuous infusion rates based on weight and detailed instructions in all aspects of therapy discontinuation (transition) were included. HIT treatments unsupported by data ensuring the efficacy and safety of therapies were excluded. Careful review of the relevant literature led to the inclusion of alternative anticoagulant treatments based on issues of safety, efficacy, cost, and convenience of dose forms.. A treatment protocol for HIT was developed and implemented in a tertiary care hospital in an effort to improve the management of patients suffering from this complication.

Topics: Anticoagulants; Arginine; Clinical Protocols; Evidence-Based Medicine; Fondaparinux; Heparin; Hirudins; Humans; Pipecolic Acids; Platelet Count; Platelet Function Tests; Polysaccharides; Recombinant Proteins; Retrospective Studies; Sulfonamides; Thrombocytopenia

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 is an immunologically mediated syndrome that is associated with potentially life-threatening arterial and venous thrombosis. Re-exposing patients who have heparin-induced thrombocytopenia to heparin during cardiopulmonary bypass may be hazardous. We describe the re-exposure to unfractionated heparin of a patient with a left ventricular assist device and evidence of heparin-induced thrombocytopenia who needed cardiac transplantation, which was accomplished without complications.

Topics: Anticoagulants; Cardiomyopathy, Dilated; Cardiopulmonary Bypass; Female; Fibrin Fibrinogen Degradation Products; Fibrinogen; Heart Transplantation; Heart-Assist Devices; Heparin; Hirudins; Humans; Intraoperative Period; Middle Aged; Recombinant Proteins; Thrombocytopenia

The authors present the case of a patient with heparin induced thrombocytopaenia who needed anticoagulation during the perioperative period of a third repeat cardiac operation without transfusions. Prostacyclin pretreatment was contraindicated because of critical aortic stenosis, heparinoids could not have been used due to necessity of postoperative anticoagulation. Recombinant hirudin was applied and its effect was monitored with ekarin coagulation time. Hirudin anticoagulation was continued until the proper INR was reached in the postoperative period. There were no intra- and postoperative complications detected, and there was no need for transfusion either. On his long-term follow-up, 6.5 years after the last cardiac surgery the patients was feeling well and had no complaints.. Open heart operation of a patient with heparin induced thrombocythopenia can be performed safely by total anticoagulation with lepirudin if it is conducted by ecarin clotting time.

Topics: Anticoagulants; Blood Coagulation Tests; Cardiac Surgical Procedures; Endopeptidases; Heparin; Hirudin Therapy; Hirudins; Humans; International Normalized Ratio; Male; Middle Aged; Postoperative Period; Recombinant Proteins; Reoperation; Thrombocytopenia; Treatment Outcome

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 is commonly used in the intensive care unit for preventing and treating thromboembolic disease. One of its more significant complications is heparin-induced thrombocytopenia (HIT), an immune-mediated disorder which can provoke an extreme prothrombotic state. We describe an unusual presentation of HIT, where thrombocytopenia was absent.

Topics: Adult; Anticoagulants; Calcitonin; Female; Follow-Up Studies; Heparin; Hirudins; Humans; Intensive Care Units; Partial Thromboplastin Time; Platelet Count; Protein Precursors; Recombinant Proteins; Stroke; Thrombocytopenia; Thrombosis; Time Factors; Tomography, X-Ray Computed

Topics: Aged; Anticoagulants; Heparin; Hirudins; Humans; Kidney Failure, Chronic; Male; Recombinant Proteins; Renal Dialysis; Thrombocytopenia; Time Factors

Topics: Anticoagulants; Cardiomyopathy, Hypertrophic; Cardiopulmonary Bypass; Female; Heart Failure; Heart Transplantation; Hemofiltration; Heparin; Hirudins; Humans; Middle Aged; Recombinant Proteins; Thrombocytopenia

Topics: Arginine; Female; Headache; Heparin, Low-Molecular-Weight; Hirudins; Humans; Middle Aged; Pipecolic Acids; Recombinant Proteins; Seizures; Sulfonamides; Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) type II (HIT II), is an immune-mediated complication of heparin therapy, associated with arterial and venous thrombosis. Herein we have reported a case of a 23-year-old woman who developed HIT following a living related donor, preemptive, renal transplantation. The patient was preoperatively exposed to both unfractionated and low-molecular-weight heparin as she underwent five hemodialysis sessions. HIT caused right common and external iliac vein and renal graft artery thrombosis, resulting in graft loss. Heparin-free hemodialysis was continued, and the patient was successfully treated with anticoagulation by the direct thrombin inhibitor lepirudin for both the thromboses and for hemodialysis. Finally, she was accepted for the continuous ambulatory peritoneal dialysis program. This report highlighted the importance of clinical awareness as far as previous heparin exposure is concerned for establishing an early diagnosis and delivering treatment of this life-threatening prothrombotic complication of heparin administration.

Topics: Adult; Anticoagulants; Female; Hematocrit; Heparin, Low-Molecular-Weight; Hirudins; Humans; Kidney Transplantation; Living Donors; Platelet Count; Pulmonary Embolism; Recombinant Proteins; Renal Dialysis; Thrombocytopenia; Treatment Outcome

Type II heparin-induced thrombocytopenia (HIT) is a rare but well-recognised and potentially life-threatening complication of unfractionated heparin therapy, and has been reported in association with heparin locks for central venous lines. We report a case of type II HIT complicated by iliofemoral deep venous thrombosis and pulmonary embolism in a 43-year-old woman in the course of plasma exchange for myasthenia gravis. A Gamcath central venous line had been inserted femorally due to poor peripheral venous access, and this was locked with heparin 5000 U/ml between procedures. Twelve days after initial heparin exposure, she presented with new-onset thrombocytopenia, a painfully swollen right leg, and pleuritic pain. Deep venous thrombosis and pulmonary embolism were confirmed radiologically, and serology for heparin/PF4 antibodies was unequivocally positive. The line was removed, and she was successfully managed with intravenous lepirudin, switching to warfarin on platelet recovery. This case demonstrates that Type II HIT can occur in association with heparin line locks in the course of plasmapheresis, despite previous reports of successful use of plasma exchange to treat Type II HIT.

Topics: Adult; Catheterization, Central Venous; Female; Heparin; Hirudins; Humans; Myasthenia Gravis; Plasma Exchange; Pulmonary Embolism; Recombinant Proteins; Thrombocytopenia; Venous Thrombosis; Warfarin

Topics: Anticoagulants; Female; Fibrinolytic Agents; Heparin; Hirudins; Humans; Middle Aged; Recombinant Proteins; Renal Artery Obstruction; Renal Insufficiency; Syndrome; Thrombocytopenia; Thrombosis

Topics: Anticoagulants; Arginine; Heparin; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Platelet Factor 4; Recombinant Proteins; Sulfonamides; Thrombocytopenia

A patient with triple heart valve disease, heparin-induced thrombocytopenia, and terminal renal insufficiency was treated successfully using lepirudin for anticoagulation of cardiopulmonary bypass (CPB) and during the postoperative course. Anticoagulatory monitoring was performed with ecarin clotting time during CPB and aPTT postoperatively.

Topics: Aged; Anticoagulants; Cardiopulmonary Bypass; Female; Follow-Up Studies; Heart Failure; Heparin; Hirudins; Humans; Kidney Failure, Chronic; Myocardial Ischemia; Recombinant Proteins; Thrombocytopenia

To evaluate the efficacy, safety, and associated costs of anticoagulation with argatroban, bivalirudin, and lepirudin for managing patients with heparin-induced thrombocytopenia (HIT) or presumed HIT.. Retrospective medical record review.. University-affiliated teaching hospital.. Forty-two patients who were hospitalized between January 1 and December 31, 2004, and who were treated with bivalirudin, argatroban, or lepirudin for at least 24 hours.. The primary outcome was the time to reach the desired goal for activated partial thromboplastin time (aPTT). Secondary outcomes were the number of aPTT measurements within the therapeutic range, costs, treatment duration, clinical outcomes, and adverse events. Of the 42 patients who met the inclusion criteria, 24 received bivalirudin, 13 received argatroban, and 5 received lepirudin. Patients receiving bivalirudin who reached therapeutic aPTTs attained them sooner than those receiving either argatroban or lepirudin (8.5 vs 14 and 24 hrs, respectively, p=0.124). Average percentage of therapeutic aPTTs/patient was greatest in the argatroban group (62%), followed by the bivalirudin (57%) and lepirudin (29%) groups (p=0.062). Average drug cost/day/patient was greater in the lepirudin group than the other groups, whereas average laboratory costs were similar among groups. Treatment duration was longer with argatroban than with bivalirudin or lepirudin. Bleeding rates were similar in the argatroban and bivalirudin groups, but higher than in the lepirudin group. A composite of clinical outcomes (deep vein thrombosis, nonfatal myocardial infarction, nonfatal stroke, limb amputation, and all-cause mortality) were similar among the three groups.. All three drugs were effective as anticoagulants for patients with HIT or presumed HIT. Based on average use and average wholesale price, bivalirudin cost less per day than the other two agents. Although not yet approved by the United States Food and Drug Administration for management of HIT, bivalirudin appears to be a viable treatment alternative for anticoagulation therapy.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Arginine; Female; Heparin; Hirudins; Humans; Male; Middle Aged; Partial Thromboplastin Time; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Retrospective Studies; Sulfonamides; Thrombin; Thrombocytopenia; Time Factors; Treatment Outcome

A 56-year-old man with heparin-induced thrombocytopenia with thrombosis syndrome (HITTS) received anticoagulation with recombinant hirudin (lepirudin) for emergency coronary artery bypass graft (CABG) surgery and aortic valve replacement. The patient experienced life-threatening refractory bleeding that was successfully treated with recombinant factor VIIa. He had a history of infective endocarditis that resulted in severe aortic insufficiency, three-vessel coronary artery disease, and acute renal failure requiring hemodialysis. The patient was transferred from another hospital for the emergency surgery, but before his transfer, he developed HITTS secondary to therapeutic heparin for a deep vein thrombosis of the lower extremity. The presence of HITTS, the urgent nature of the case, and the availability of the direct thrombin inhibitor led the surgical team to select lepirudin for anticoagulation to facilitate cardiopulmonary bypass. After separation from cardiopulmonary bypass, the patient was in a coagulopathic state due to the inability to reverse the lepirudin and the slowed elimination of the drug secondary to inadequate renal function. As a result, the patient experienced excessive generalized oozing that was unresponsive to traditional therapies and blood product transfusions. Recombinant factor VIIa 35 microg/kg was given as rescue therapy. The bleeding slowed, which allowed placement of chest tubes and closing of the sternum. The patient was transferred to the intensive care unit in stable condition with no evidence of thrombosis in the freshly placed bypass grafts or on the bioprosthetic valve. Recombinant factor VIIa appears to be a suitable option as salvage therapy in patients with refractory bleeding secondary to anticoagulation with a direct thrombin inhibitor during cardiac surgery.

Topics: Acute Kidney Injury; Anticoagulants; Coronary Artery Bypass; Factor VII; Factor VIIa; Heparin; Hirudins; Humans; Male; Middle Aged; Postoperative Hemorrhage; Recombinant Proteins; Thrombin; Thrombocytopenia; Thrombosis

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

The antithrombotic efficacy of lepirudin in patients with heparin-induced thrombocytopenia (HIT) is compromised by an increased risk for bleeding. A retrospective observational analysis in 181 patients (median age, 67 years) with confirmed HIT treated in routine practice with lepirudin was performed to identify predictive factors for thrombotic and bleeding complications. Lepirudin was administered at a mean (+/- SD) dose of 0.06 +/- 0.04 mg/kg/h (compared with a recommended initial dose of 0.15 mg/kg/h). Mean activated partial thromboplastin time was greater than 1.5 times baseline value in 99.4% of patients. Median treatment duration was 7.7 days. Until discharge from the hospital, 13.8% and 20.4% of patients experienced a thrombotic or a major bleeding event, respectively. On multivariate analysis, mean lepirudin dose was not a significant predictive factor for thrombosis. In contrast, mean lepirudin dose greater than 0.07 mg/kg/h, long duration of lepirudin treatment, and moderate to severe renal impairment were significant positive factors for major bleeding. Overall, these results suggest that the recommended dose of lepirudin in patients with HIT is too high; the use of reduced doses may be safer with regard to bleeding risk and does not compromise antithrombotic efficacy.

Topics: Adolescent; Adult; Aged; Female; Hemorrhage; Heparin; Hirudins; Humans; Male; Middle Aged; Recombinant Proteins; Retrospective Studies; Thrombocytopenia; Treatment Outcome

A 21-month-old boy received anticoagulation with lepirudin for heparin-induced thrombocytopenia (HIT) after undergoing cardiac surgery and receiving extracorporeal membrane oxygenation (ECMO). This report illustrates the significance of HIT in pediatric patients after cardiac surgery and the successful administration of lepirudin in this setting. To our knowledge, this is the first published report of lepirudin administered to treat HIT in a child after cardiac surgery and ECMO. Although guidelines exist that suggest the potential administration of lepirudin as treatment for children with HIT, further studies are needed to determine the safest yet most effective dosage for this population.

Topics: Anticoagulants; Cardiac Surgical Procedures; Child, Preschool; Echocardiography; Extracorporeal Membrane Oxygenation; Fontan Procedure; Heparin; Hirudins; Humans; Hypoplastic Left Heart Syndrome; Male; Platelet Count; Postoperative Complications; Recombinant Proteins; Thrombocytopenia

Heparin-induced thrombocytopenia is a potentially limb- and life-threatening response to heparin exposure. Direct thrombin inhibitors (DTIs) have been reported to provide anti-coagulation for cardiopulmonary bypass; however, clot formation within the cardiopulmonary bypass circuit has been reported after the administration of DTIs. We present a case of thrombosis of the cardiopulmonary bypass circuit and, ultimately, death after argatroban administration. An in vitro thrombelastographic assessment of the effects of DTIs on clot kinetics was consequently performed to determine potential causes for this complication.. Normal human plasma was unmodified or exposed to heparin (1, 2, 3 U/ml), argatroban (5, 10, 50 microg/ml), bivalirudin (12, 20, 120 microg/ml), or lepirudin (3, 6, 10 microg/ml) before activation with tissue factor/kaolin in a thrombelastograph. Clot initiation (R, reaction time), propagation (MTG, maximum thrombus generation), and strength (MG, maximum elastic modulus) were determined. Analysis of variance was performed, with p < 0.05 considered significant.. Compared with unmodified plasma, heparin significantly prolonged R and essentially reduced MTG and MG to the limits of detection in an activity-dependent fashion. In general, the DTIs tested prolonged R in a concentration-dependent fashion but did not diminish MTG or MG nearly as well as heparin. The only exception was 10 microg/ml lepirudin, which eliminated coagulation.. DTIs demonstrated a significant prolongation of clot initiation but poor attenuation of propagation and strength. Further in vitro and clinical investigations to design a heparin-equivalent regimen to provide anti-coagulation for patients with heparin-induced thrombocytopenia are indicated.

Topics: Anticoagulants; Antithrombins; Arginine; Cardiopulmonary Bypass; Child; Dose-Response Relationship, Drug; Fatal Outcome; Female; Fibrinolytic Agents; Heart Transplantation; Heparin; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Platelet Aggregation Inhibitors; Recombinant Proteins; Sulfonamides; Thrombelastography; Thrombocytopenia; Treatment Failure; Whole Blood Coagulation Time

Topics: Antibodies; Anticoagulants; Aprotinin; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Child; Drug Therapy, Combination; Heart Valve Prosthesis Implantation; Hemostatics; Heparin; Hirudins; Humans; Male; Mitral Valve; Phenprocoumon; Platelet Aggregation Inhibitors; Platelet Factor 4; Recombinant Proteins; Reoperation; Thrombocytopenia; Tirofiban; Tyrosine; Ventricular Outflow Obstruction

Topics: Adult; Anticoagulants; Drug Administration Schedule; Drug Monitoring; Female; Heparin; Hirudins; Humans; Recombinant Proteins; Renal Dialysis; Thrombocytopenia

The management of heparin-induced thrombocytopenia (HIT) in pregnancy represents a medical challenge. The advent of new antithrombotic agents that do not cross-react with platelet factor 4 and heparin antibodies represents an important progress, and they are of utmost interest in special situations such as early pregnancy, a situation where the teratogenicity of warfarin precludes its use.

Topics: Anticoagulants; Female; Heparin; Hirudins; Humans; Platelet Factor 4; Pregnancy; Pregnancy Trimester, First; Recombinant Proteins; Thrombocytopenia; Warfarin

Heparin induced thrombocytopenia (HIT) is a life-threatening complication that can be seen in the course of heparin treatment. The syndrome is much likely to be seen during treatment with standard heparin but it can also be seen due to low molecular weight heparins. In this article, we presented a case of HIT who was given low molecular weight heparin for prophylaxis that developed massive pulmonary thromboembolism. The patient was successfully treated with lepirudin infusion and no complications due to treatment was seen.

Topics: Anticoagulants; Diagnosis, Differential; Female; Heparin, Low-Molecular-Weight; Hirudins; Humans; Infusions, Intravenous; Middle Aged; Pulmonary Embolism; Radiography; Recombinant Proteins; Thrombocytopenia

We report a patient who developed type II heparin-induced thrombocytopenia (HIT) and accidentally received a recombinant hirudin (r-hirudin) overdosage. Treatment with hemodialysis (HD) using high-flux polysulfone dialyzer and hemofiltration was performed. Length of treatment was adjusted, monitoring activated partial thromboplastin time (aPTT) to 1.5-2.5 times the mean of the normal range. She developed deep venous thrombosis and occlusion of vascular access. Only after cessation of heparin lock catheter, platelet count began to increase. After one year of treatment with acenocoumarol and additional low-dose r-hirudin, neither bleeding nor thrombotic episodes have been reported.

Topics: Aged; Drug Overdose; Female; Hemofiltration; Heparin; Hirudin Therapy; Hirudins; Humans; Recombinant Proteins; Renal Dialysis; Renal Insufficiency; Thrombocytopenia

We identified the incidence of heparin-induced thrombocytopenia and the antiheparin-platelet factor 4 (PF4) antibody in pediatric patients undergoing cardiac surgery and documented the differences in the anticoagulation management for the extracorporeal circulation.. Between January 2001 and September 2003, 559 cardiac procedures with extracorporeal circulation in 415 patients with congenital heart defects were performed in our institution. Because the development of heparin-induced thrombocytopenia requires previous exposition to heparin, only the 144 patients undergoing a scheduled second procedure on extracorporeal circulation were screened preoperatively. Of these 144 patients, 41 underwent also a third procedure and were screened before each procedure for presence of antiheparin-PF4 antibodies and for clinical signs of heparin-induced thrombocytopenia.. The incidence of antiheparin-PF4 antibodies during the study period was 1.4% (2 of 144 patients). Patients with clinically significant heparin-induced thrombocytopenia could not be identified. Outside the study protocol, 2 more patients with antiheparin-PF4 antibodies were found. In these 4 patients, surgery was performed using lepirudin (Schering, Berlin, Germany) instead of the usual heparin management for extracorporeal circulation. Three of these 4 patients had an uneventful procedure and postoperative course. In 1 patient after total cavopulmonary connection, a reoperation was necessary on the seventh postoperative day owing to partial thrombosis of the lateral tunnel.. The incidence of heparin-induced thrombocytopenia and of antiheparin-PF4 antibodies in patients undergoing repeated cardiac surgery is low. In antiheparin-PF4 antibody positive patients, the complete avoidance of heparin can be achieved and may account for an uneventful perioperative course.

Topics: Anticoagulants; Cardiac Surgical Procedures; Contraindications; Extracorporeal Circulation; Heart Defects, Congenital; Heparin; Hirudins; Humans; Incidence; Infant; Kidney Failure, Chronic; Platelet Factor 4; Postoperative Complications; Preoperative Care; Recombinant Proteins; Reoperation; Retrospective Studies; Thrombocytopenia

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

Delayed-onset heparin-induced thrombocytopenia is a syndrome in which thrombocytopenia and thrombosis begin several days after heparin discontinuation. Delayed-onset heparin-induced thrombocytopenia is caused by immunoglobulin G antibodies that are reactive against the heparin-platelet factor 4 complex in the absence of circulating heparin. We describe 2 patients with delayed-onset heparin-induced thrombocytopenia who presented to the emergency department. An 88-year-old man and a 62-year-old man experienced thrombocytopenia and thrombosis 9 or more days after heparin cessation and demonstrated a further decrease in platelet count on reexposure to heparin. Delayed-onset heparin-induced thrombocytopenia should be included in the differential diagnosis of a patient with recent heparin exposure who presents with thrombosis or thrombocytopenia.

Topics: Aged; Aged, 80 and over; Anticoagulants; Emergency Service, Hospital; Heparin; Hirudins; Humans; Male; Middle Aged; Platelet Factor 4; Recombinant Proteins; Thrombocytopenia; Time Factors; Venous Thrombosis

To retrospectively assess the signs and symptoms indicative of adverse reactions to repeated exposures to lepirudin in patients with heparin-induced thrombocytopenia who received at least 2 courses of lepirudin therapy.. Medical records were retrospectively assessed from adult patients who received at least 2 courses of lepirudin therapy separated by at least 1 week between January 1999 and June 2002 at The Cleveland Clinic, Cleveland, Ohio. We evaluated the list of 289 low-level terms for possible signs and symptoms of anaphylactic reactions In the medical dictionary for regulatory activities as well as patient vital signs to detect manifestations of immediate hypersensitivity reactions. Vital signs from the day before initiation of lepirudin therapy were compared with those from days 1 and 2 after exposure.. No cases of anaphylaxis or allergic reaction related to lepirudin administration were identified among 43 adult patients. On day 1 of lepirudin, 10 patients had lower systolic blood pressures (by > or =20 mm Hg) than pre-lepirudin values, and 4 patients had systolic blood pressures of less than 100 mm Hg.. Isolated asymptomatic decreases in blood pressure after patient reexposure to lepirudin most likely do not reflect anaphylaxis due to lepirudin. We believe that isolated and uncommon cases of anaphylaxis temporally related to lepirudin exposure should not preclude its use in patients with heparin-induced thrombocytopenia and past lepirudin exposure.

Topics: Adult; Aged; Aged, 80 and over; Anaphylaxis; Anticoagulants; Female; Heparin; Hirudins; Humans; Injections, Intravenous; Male; Middle Aged; Recombinant Proteins; Retrospective Studies; Risk Factors; Thrombocytopenia

There are few reports of the management of pediatric patients with heparin-induced thrombocytopenia (HIT) requiring cardiac surgery using currently available anticoagulants. We report a case of an infant with HIT requiring a bidirectional Glenn shunt who was successfully managed using lepirudin (r-hirudin, Refludan; Aventis, Bridgewater, NJ). Dosing and monitoring of anticoagulation were difficult, and we suggest caution in the use of lepirudin for cardiac surgery unless reliable monitoring of the degree of anticoagulation becomes available.

Topics: Anticoagulants; Blood Coagulation Tests; Cardiac Catheterization; Cardiac Surgical Procedures; Hemodynamics; Heparin; Hirudins; Humans; Hypoplastic Left Heart Syndrome; Infant; Male; Monitoring, Intraoperative; Partial Thromboplastin Time; Recombinant Proteins; Thrombocytopenia; Thrombosis

Patients with heparin-induced thrombocytopenia (HIT) type II require anticoagulation with non-heparin immediate acting anticoagulants. Danaparoid may cross react with HIT-antibodies and lepirudin may generate anti-lepirudin antibodies influencing anticoagulation. We hypothesised, that the synthetic small molecular thrombin inhibitor argatroban does not induce immunoglobulins reacting towards lepirudin in patients with anti-lepirudin antibodies in the history and that titration of the anticoagulation may be easier with argatroban. We report on the treatment of four patients of a study, which was terminated prematurely due to official warnings for a repeated use of lepirudin. Two patients each received argatroban and lepirudin intravenously. A blinded assessor adjusted the doses of the anticoagulants to 1.5-3.0 fold prolongation of the aPTT. Ecarin clotting time (ECT), concentrations of lepirudin (ELISA) and of argatroban (gas-chromatography with mass spectrometry), and the generation of lepirudin antibodies (ELISA) were measured. APTT-adjusted dosages for argatroban was 2.0-2.6 microg/kg.min and for lepirudin 48-149 microg/kg.h. ECT was prolonged 2.1 to 4.5-fold with lepirudin and 4 to 7-fold with argatroban. The concentration of lepirudin ranged between 750 and 1500 ng/ml and of argatroban between 400 and 1100 ng/ml. Patients on argatroban did not generate immunoglobulin IgG reacting towards lepirudin in contrast to both patients on lepirudin who developed anti-lepirudin antibodies. Both treatments were well tolerated. Despite the low number of patients argatroban seems to lead to a more stable anticoagulant response than lepirudin resulting in a lower variability of the dosage for prophylaxis or treatment of thromboembolism of patients with a history of HIT and lepirudin antibodies.

Topics: Aged; Antibodies; Anticoagulants; Arginine; Enzyme-Linked Immunosorbent Assay; Female; Heparin; Hirudin Therapy; Hirudins; Humans; Immunoglobulin G; Male; Middle Aged; Pipecolic Acids; Platelet Aggregation Inhibitors; Recombinant Proteins; Sulfonamides; Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) type II is typically characterized by a decrease in platelet count to values between 20 and 120 x 10 (9)/L or a platelet count fall of greater than 50%. We report on a patient who developed a HIT syndrome, thrombosis of the vena cava, and fulminant pulmonary embolism during heparin treatment after cesarean section, without a significant decrease in platelet count. Lepirudin anticoagulation and ecarin clotting time (ECT) monitoring were used successfully during cardiopulmonary bypass.

Topics: Adult; Anticoagulants; Cardiopulmonary Bypass; Cesarean Section; Combined Modality Therapy; Female; Follow-Up Studies; Hirudins; Humans; Platelet Count; Pregnancy; Pulmonary Embolism; Recombinant Proteins; Reference Values; Risk Assessment; Thrombocytopenia; Treatment Outcome

The potential risk for heparin-induced thrombocytopenia should be suspected in postoperative patients who develop thrombocytopenia in the presence of heparin and low-molecular weight heparin agents.

Topics: Anticoagulants; Arginine; Heparin; Hirudins; Humans; Pipecolic Acids; Platelet Aggregation Inhibitors; Recombinant Proteins; Sulfonamides; Thrombocytopenia

A 6-year-old girl required argatroban at dosages up to 18 mug/kg/minute for treatment of heparin-induced thrombocytopenia (HIT) type 2; however, her activated partial thromboplastin time (aPTT) values remained subtherapeutic. Treatment was converted to lepirudin, which resulted in therapeutic aPTT values, and later to long-term warfarin therapy; no further thromboembolic incidents occurred. The reporting of cases of HIT in prepubertal patients has generally been scarce. Argatroban and lepirudin dosing and pharmacokinetics have not yet been established for young children. The argatroban dosage for this patient exceeded the upper limit of the dose range for adults. Several possible explanations for why argatroban did not illustrate typical first-order pharmacokinetics in this patient are discussed, and the pharmacokinetics and pharmacodynamics of argatroban are compared with those of lepirudin, with special consideration given to the pediatric population.

Topics: Anticoagulants; Arginine; Child; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Female; Heparin; Hirudins; Humans; Partial Thromboplastin Time; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombocytopenia

To evaluate diagnostic tests for heparin-induced thrombocytopenia (HIT), a serious drug reaction that can occur in patients receiving heparin, and to evaluate treatment with direct thrombin inhibitors-the only initial drug therapy that decreases the risk of thromboembolism associated with immune-mediated HIT.. Retrospective cohort study.. University teaching hospital.. Patients with HIT treated with argatroban or lepirudin between January 1, 2000, and December 31, 2003.. Patients were assessed for dosage and duration of argatroban or lepirudin therapy, HIT diagnostic tests, and clinically significant adverse events. Thirty-four patients received argatroban, 42 received lepirudin. Mean+/-SD doses of argatroban and lepirudin were 1.2+/-0.9 microg/kg/minute and 0.09+/-0.11 mg/kg/hour, respectively; both were 40% lower than the recommended doses. Mean duration of therapy was 10+/-9 days. Supratherapeutic activated partial thromboplastin times were observed in 30 (39%), 10 (13%) , and six (8%) of 76 patients on days 1, 2, and 3, respectively (p<0.0001). Clinically significant bleeding occurred in 6% of patients receiving argatroban and in 5% of those receiving lepirudin (p=0.99); all patients had an activated partial thromboplastin time of longer than 100 seconds. Although platelet-aggregation tests were ordered in 55 (72%) of 76 patients, they were not useful in 16 (29%) because of equivocal or contradictory results.. Due to supratherapeutic activated partial thromboplastin times, our patients often required doses of argatroban and lepirudin lower than those usually recommended. Thus, direct thrombin inhibitors should be started at low initial doses and titrated to target activated partial thromboplastin times to achieve appropriate efficacy and to avoid increasing the risk of bleeding. Platelet-aggregation tests were least useful for evaluating HIT. Appropriate diagnostic strategies should be used to avoid unnecessary drug use.

Topics: Anticoagulants; Arginine; Cohort Studies; Female; Heparin; Hirudins; Humans; Male; Middle Aged; Partial Thromboplastin Time; Pipecolic Acids; Platelet Activation; Platelet Aggregation; Recombinant Proteins; Retrospective Studies; Sulfonamides; Thrombocytopenia

Bivalirudin is a synthetic antithrombin sharing a sequence of 11 amino acids with the recombinant hirudin lepirudin. We investigated whether antilepirudin antibodies recognize epitopes on bivalirudin. Antilepirudin antibody-positive sera of 43 patients, treated with lepirudin for heparin-induced thrombocytopenia, were analyzed. Lepirudin- and bivalirudin-coated microtiter plates were used for antibody testing in an enzyme-linked immunosorbent assay (ELISA) system. Of the 43 sera-containing antibodies binding to lepirudin, 22 (51.2%) contained antibodies that also recognized bivalirudin. Binding of these antibodies to bivalirudin was inhibited by more than 70% by preincubation with high doses of bivalirudin. However, if lepirudin-coated microtiter plates were used, high concentrations of bivalirudin inhibited only 2 of the 43 positive sera by more than 30%. Therefore antihirudin antibodies must be polyspecific. The clinical consequences of this cross-reactivity are unknown but bivalirudin, targeted by antibodies of patients treated with lepirudin previously, could potentially boost antibody titers in such patients or even trigger an immune response by itself. Clinically significant antibody formation in response to bivalirudin monotherapy has not been observed, however. Yet, as lepirudin and antilepirudin antibodies have recently been implicated in severe anaphylactic reactions, caution is warranted when using bivalirudin in patients previously treated with lepirudin.

Topics: Amino Acid Sequence; Antibody Specificity; Binding Sites; Cross Reactions; Epitopes; Heparin; Hirudins; Humans; Molecular Sequence Data; Peptide Fragments; Protein Conformation; Recombinant Proteins; Thrombocytopenia

To report a case of probable acute venous thrombosis caused by heparin-induced thrombocytopenia (HIT) in a pediatric patient with a normal platelet count after prolonged enoxaparin therapy.. An 11-year-old African American female with Crohn's disease developed extensive vena cava thrombosis. Her deep vein thrombosis (DVT) was treated with intravenous unfractionated heparin followed by extended outpatient warfarin therapy. Four months later, the warfarin was stopped and subcutaneous enoxaparin 1.5 mg/kg once daily was substituted prior to an elective colonoscopy. She was readmitted 6 weeks later with acute DVT with a platelet count of 233 x 10(3)/mm3, significantly lower than the count of 550-700 x 10(3)/mm3 5 months previously and the count of 433 x 10(3)/mm3 3 months earlier. An enzyme-linked immunosorbent assay for heparin-platelet factor 4 antibodies was strongly positive and a d-dimer was elevated at 2.9 mg/L (normal <1.5). She was treated with lepirudin followed by warfarin when repeat d-dimer on day 3 was normal. An ultrasound at that time showed no clot extension, and the platelet count had risen to >300 x 10(3)/mm3. Over the next 4 months, there was no further thrombosis.. HIT appears to be rare in the pediatric population, and only a few cases treated with a direct thrombin inhibitor have been reported. This is the first case report to our knowledge of a pediatric patient developing HIT secondary to enoxaparin. An interesting feature of this case is the development of HIT in the face of a normal platelet count, which is rare but has been reported in adults.. Pediatric patients receiving low-molecular-weight heparin are still at risk for developing HIT. Treatment of HIT should involve the initial use of a direct thrombin inhibitor to manage thrombosis until the platelet count returns to higher values. Once the platelet count returns, warfarin can be used for long-term thrombosis management.

Topics: Anticoagulants; Child; Enoxaparin; Female; Heparin, Low-Molecular-Weight; Hirudins; Humans; Platelet Count; Recombinant Proteins; Thrombocytopenia

To report a case of a patient with antiphospholipid antibody syndrome and multiple thromboses who developed heparin-induced thrombocytopenia (HIT) and subsequent international normalized ratio (INR) prolongation possibly due to antiphospholipid antibodies.. A 56-year-old white woman with a history of antiphospholipid antibody syndrome and thrombosis taking chronic warfarin was admitted for gastrointestinal concerns and found to have an INR >14. Warfarin was discontinued, vitamin K was administered, and a heparin infusion was initiated. Over the next 2 days, thrombocytopenia, hypotension, tachycardia, hyponatremia, and progressive abdominal pain developed. Upon transfer to a tertiary care center, HIT was diagnosed, and a lepirudin infusion was initiated. Subsequently, a sudden elevation of the INR occurred (>14) with low prothrombin (factor II) activity. After INR values declined to 2-3, warfarin was reinitiated with dosing adjusted using factor X and II activity levels. Clotting factors II and X activities were measured to monitor long-term warfarin therapy, with no evidence of complications after 7 months.. Typically, the INR is used to assess the intensity of anticoagulation. The INR value represents the reduction of clotting factors II, VII, and X. In rare circumstances, an independent inhibitor or interfering substance can interfere with the process of measuring the INR. In such situations, an alternative approach can be direct measurement of clotting factor concentrations.. Factor II and/or factor X activity levels provided an alternative means for measuring the anticoagulant effects of warfarin in the presence of a significant inhibitor (antiphospholipid antibodies) that biased the INR measurements.

Topics: Anticoagulants; Antiphospholipid Syndrome; Factor VII; Factor X; Female; Hirudins; Humans; International Normalized Ratio; Middle Aged; Platelet Count; Prothrombin; Recombinant Proteins; Thrombocytopenia; Warfarin

To report a case of intermediate-probability suspected heparin-induced thrombocytopenia (HIT) treated with lepirudin in a patient requiring continuous extracorporeal membranous oxygenation (ECMO).. A 17-year-old girl was admitted with multiple traumatic injuries including severe bilateral pulmonary contusions. Within 48 hours, she developed progressive pulmonary failure despite mechanical ventilation, and was placed on ECMO. Anticoagulation of the ECMO circuit was facilitated by unfractionated heparin (UFH). The platelet count of 116 x 10(3)/mm(3) after initiation of ECMO gradually decreased over 5 days to 44 x 10(3)/mm(3). On ECMO day 5, a highly positive enzyme-linked immunosorbent assay for HIT antibodies was reported, and the UFH infusion was discontinued. Lepirudin was immediately started with a bolus of 0.1 mg/kg, followed by an infusion of 0.12 mg/kg/h, with a target activated partial thromboplastin time (aPTT) ratio approximately 2 times control. The ECMO circuit was maintained without any unexpected bleeding complications or thrombosis for 6 additional days until the patient died secondary to pulmonary failure after ECMO was removed.. Use of ECMO typically requires continuous infusion of UFH to keep the circuit from clotting. In patients with HIT, alternative anticoagulation using a direct thrombin inhibitor may be warranted. Lepirudin was effectively used to maintain the circuit despite continued presence of heparin molecules impregnated into the ECMO circuit tubing. The aPTT was successfully used to monitor and adjust the lepirudin infusion.. In patients requiring ECMO in the presence of HIT, anticoagulation of the ECMO circuit may be accomplished using a continuous infusion of a direct thrombin inhibitor such as lepirudin.

Topics: Adolescent; Anticoagulants; Extracorporeal Membrane Oxygenation; Fatal Outcome; Female; Heparin; Hirudins; Humans; Recombinant Proteins; Thrombocytopenia

Heparin-induced thrombocytopenia with thrombosis (HITT) is a rare complication of cardiac surgery with cardiopulmonary bypass. We report two cases of HITT treated with the direct thrombin inhibitor Lepirudin. Immediate diagnosis was essential to prompt heparin discontinuation and successful early Lepirudin administration in the first case. In the second, the presence of an intra-aortic balloon pump delayed HITT recognition, and Lepirudin infusion could not prevent limb amputation. In both cases HITT occurred earlier (< 5 days after heparin exposure) than its usual presentation.

Topics: Adult; Aged; Amputation, Surgical; Anticoagulants; Aorta; Aortic Aneurysm; Aortic Dissection; Aortic Valve; Blood Vessel Prosthesis Implantation; Combined Modality Therapy; Coronary Artery Bypass; Early Diagnosis; Fibrinolytic Agents; Heart Valve Prosthesis Implantation; Heparin; Hirudins; Humans; Intra-Aortic Balloon Pumping; Ischemia; Leg; Male; Marfan Syndrome; Mitral Valve; Postoperative Complications; Recombinant Proteins; Thrombocytopenia; Thrombophlebitis

We report herein a patient with coronary artery disease that developed heparin-induced thrombocytopenia after coronary artery bypass graft with resulting thrombosis of multiple saphenous vein grafts and myocardial infarction after heparin exposure. The patient required lepirudin and a cardiac catheterization with placement of stents.

Topics: Angina Pectoris; Angioplasty, Balloon; Anticoagulants; Autoantibodies; Autoantigens; Autoimmune Diseases; Cardiac Catheterization; Coronary Artery Bypass; Coronary Restenosis; Drug Therapy, Combination; Eptifibatide; Heparin, Low-Molecular-Weight; Hirudins; Humans; Internal Mammary-Coronary Artery Anastomosis; Male; Middle Aged; Myocardial Infarction; Peptides; Platelet Factor 4; Postoperative Complications; Recombinant Proteins; Recurrence; Saphenous Vein; Stents; Thrombocytopenia; Thrombosis

Topics: Adult; Anticoagulants; Female; Fibrinolytic Agents; Heparin; Hirudins; Humans; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Complications, Hematologic; Pregnancy Trimester, First; Recombinant Proteins; Thrombocytopenia; Thrombosis; Warfarin

Approximately 40% of patients who receive lepirudin for 5-10 days develop antihirudin antibodies. These antibodies lead to decreased renal elimination of lepirudin, ultimately resulting in elevated activated partial thromboplastin times (aPTTs). A small percentage of patients with antihirudin antibodies develop hypersensitivity reactions to lepirudin with reexposure. Thus, patients who are reexposed to lepirudin must be monitored closely for hypersensitivity. A 45-year-old African-American woman received lepirudin for anticoagulation after being diagnosed with heparin-induced thrombocytopenia type II. She developed supratherapeutic aPTTs after 10 days of lepirudin therapy. Lepirudin was then withheld for 6 days, during which her aPTT remained supratherapeutic. After lepirudin infusion was restarted, the patient developed an anaphylactic reaction. She was treated appropriately with an antihistamine, a corticosteroid, and an anxiolytic agent. After the reaction resolved, the patient was rechallenged with lepirudin, and the anaphylactic reaction recurred.

Topics: Anaphylaxis; Anticoagulants; Female; Heparin; Hirudins; Humans; Middle Aged; Recombinant Proteins; Thrombocytopenia

Topics: Adenocarcinoma; Adult; Anticoagulants; Arterial Occlusive Diseases; Autoimmune Diseases; Drug Resistance; Female; Heparin; Heparin, Low-Molecular-Weight; Hepatitis C, Chronic; Hirudins; Humans; Inflammatory Bowel Diseases; Male; Middle Aged; Neoplasms, Unknown Primary; Platelet Aggregation Inhibitors; Portal Vein; Pulmonary Embolism; Recombinant Proteins; Recurrence; Thrombocytopenia; Vena Cava, Inferior; Venous Thrombosis; Warfarin

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

This report describes a 72-year-old woman with atrial fibrillation who presented with lower extremity ischemia secondary to thromboembolism. After lower extremity thrombectomy, the patient developed heparin-induced thrombocytopenia with thrombosis (HITT). Her postoperative course was complicated by recurrent supraventricular and ventricular tachycardia, secondary to a mobile thrombus in the right atrium extending into the right ventricle. Because administration of heparin was contraindicated, the patient underwent off-pump right atrial thrombectomy during a brief period of inflow occlusion. Postoperatively, she was placed on lepirudin. Her platelet count normalized without any further thrombotic episodes, and she was discharged on warfarin.

Topics: Aged; Atrial Fibrillation; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Combined Modality Therapy; Female; Follow-Up Studies; Heart Atria; Heparin; Hirudins; Humans; Lower Extremity; Postoperative Period; Recombinant Proteins; Risk Assessment; Thrombectomy; Thrombocytopenia; Thromboembolism; Treatment Outcome; Venous Thrombosis

Lepirudin is an alternative anticoagulant therapy in heparin-induced thrombocytopenia (HIT) during cardiopulmonary bypass (CPB). We report a case of a female patient with HIT referred for aortocoronary bypass graft despite persistence of antibodies to platelet factor 4-heparin complexes. Anticoagulation management is described. Whole blood hirudin concentration attempted during CPB was above 4 microg ml(-1). To obtain this concentration, lepirudin administration was managed as follows: 0.1 mg kg(-1) h(-1) lepirudin during preoperative course, 0.2 mg kg(-1) bolus just before CPB and 0.2 mg kg(-1) in the priming solution, complementary boluses of 5 and 10 mg during procedure (according to whole blood ecarin clotting time). Aprotinin was administered simultaneously according to Royston protocol. Anticoagulation was monitored with whole blood ecarin time performed in the operation room (patient's whole blood was diluted one half and one third with normal whole blood; in vitro calibration curve was constructed using normal whole blood spiked with lepirudin). CPB duration was 73 min. When measured, whole blood hirudin concentration was 3.8-5.8 microg ml(-1). Total lepirudin administration was 44 mg. No haemorrhagic or thrombotic events were observed during surgical procedure and postoperative course. Despite lepirudin administration is not yet clearly precise for CPB procedure, its use seems adapted and safe in subjects without renal insufficiency but requiring precise coordination for anaesthesiological, surgical and biological teams.

Topics: Aged; Antibodies; Anticoagulants; Aprotinin; Calibration; Cardiopulmonary Bypass; Hemostatics; Heparin; Hirudins; Humans; Male; Platelet Factor 4; Recombinant Proteins; Thrombocytopenia; Whole Blood Coagulation Time

A patient with antiphospholipid antibody syndrome (APS) and a history of heparin-induced thrombocytopenia required lepirudin therapy. The patient had an abnormal baseline activated partial thromboplastin time (aPTT), complicating management of his therapy. We investigated whether an alternative monitoring system, using a dry reagent technology [Thrombolytic Assessment System (TAS)], could be used to monitor the patient's whole blood ecarin clot time (ECT) and aPTT. Baseline values for the ECT and aPTT were normal with this system. During a continuous infusion of lepirudin, the patient's whole blood ECT was maintained between a desired range of 150-200 s for 73% of the time. Similarly, his whole blood aPTT was maintained between 60 and 80 s for 80% of the time. In contrast, the patient's plasma-based aPTT by standard methods was consistently > 150 s. The patient underwent surgical procedures without complications. To further investigate the finding that the patient's antibody did not affect the aPTT with this system, we performed the ECT and the aPTT assays on the TAS Analyzer with plasma samples from 10 patients with APS and abnormal aPTTs. All 10 samples had plasma ECT values within the normal range. Four patients had normalization of the aPTT, suggesting that a subset of patients with APS may benefit from the TAS aPTT assay when monitoring heparin or other anticoagulation therapy.

Topics: Anticoagulants; Antiphospholipid Syndrome; Drug Monitoring; Endopeptidases; Heparin; Hirudins; Humans; Male; Middle Aged; Partial Thromboplastin Time; Recombinant Proteins; Thrombocytopenia; Whole Blood Coagulation Time

Lepirudin (Refludan) is a hirudin derivative. It is a direct thrombin inhibitor obtained by recombinant technology from the medicinal leech and is approved for treatment of heparin-induced thrombocytopenia complicated by thrombosis. Because 3 cases of fatal anaphylaxis possibly associated with use of lepirudin have been reported, we initiated an investigation of putative lepirudin-associated anaphylaxis.. Aided by the manufacturer (Schering AG, Berlin, Germany), we used the lepirudin study databases to identify all patients in whom possible anaphylaxis/severe allergy was recorded from 1994 to September 2002. The 26 possible cases identified were reviewed independently by 2 investigators. After excluding patients with mild skin reactions, reactions likely caused by concomitant medications, poorly documented cases, and reactions that did not correspond temporally with lepirudin use, there remained 9 patients judged to have had severe anaphylaxis in close temporal association with lepirudin. All reactions occurred within minutes of intravenous lepirudin administration, with 4 fatal outcomes (3 acute cardiorespiratory arrests, 1 hypotension-induced myocardial infarction). In these 4 cases, a previous uneventful treatment course with lepirudin was identified (1 to 12 weeks earlier). We recorded high-titer IgG-anti-lepirudin antibodies in an additional patient with anaphylaxis. Because lepirudin has been used in approximately 35 000 patients, the risk of anaphylaxis is approximately 0.015% (5 of 32 500) on first exposure and 0.16% (4 of 2500) in reexposed patients (7.5% estimated reexposures).. Lepirudin can cause fatal anaphylaxis, particularly in patients who are treated within 3 months of a previous exposure. The overall risk/benefit assessment of lepirudin as a treatment for heparin-induced thrombocytopenia remains favorable.

Topics: Aged; Aged, 80 and over; Anaphylaxis; Anticoagulants; Cardiovascular Diseases; Databases, Factual; Female; Fibrinolytic Agents; Heparin; Hirudins; Humans; Male; Middle Aged; Product Surveillance, Postmarketing; Recombinant Proteins; Risk Assessment; Thrombocytopenia; Thromboembolism

Appropriate management, as well as efficacy and safety, of heparin-induced thrombocytopenia (HIT) and prevention of severe consequences with argatroban and lepirudin are discussed. Heparin-induced thrombocytopenia, a serious immune-mediated drug reaction, can occur as an isolated incident (isolated HIT) or with acute thrombosis sometimes referred to as HIT and associated thrombosis syndrome (HITTS). Due to the severe consequences associated with HIT, appropriate management is critical. Argatroban and lepirudin, two direct thrombin inhibitors (DTIs), are currently FDA approved for use in patients with HIT. The clinical experience with these agents is critically examined in this article. The safety and efficacy of argatroban in management of HIT were the subject of a single published clinical trial. The study was designed to reflect conventional clinical practice, whereby treatment of patients with HIT was initiated upon clinical suspicion. In several of these patients, HIT antibodies could not be demonstrated. Compared to historical controls, argatroban demonstrated efficacy in patients with isolated HIT; however, no differences were observed in HIT patients with acute thrombosis. Rates of bleeding episodes did not differ between argatroban and control. The clinical efficacy and safety of lepirudin have been the subject of three clinical trials and one large drug monitoring program. Lepirudin has demonstrated benefit in HIT patients with or without existing thromboembolism. Bleeding rates were higher than in the historical control. However, bleedings requiring transfusion did not differ. Although no direct head-to-head comparison trials of argatroban and lepirudin have been conducted, parallels can be drawn between the agents based on careful review of published clinical trials. Consistently, rates of new thrombosis, limb amputation, and death appear to be lower in patients treated with lepirudin as compared with those treated with argatroban, whereas the risk for major bleeding per patient day seems to be similar with both DTIs.

Topics: Antithrombins; Arginine; Heparin; Hirudins; Humans; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombosis; United States

Topics: Aged; Anticoagulants; Dose-Response Relationship, Drug; Heparin; Hirudins; Humans; Recombinant Proteins; Renal Insufficiency; Thrombocytopenia; United States

Topics: Antibody Formation; Anticoagulants; Heparin; Hirudin Therapy; Hirudins; Humans; Multicenter Studies as Topic; Recombinant Proteins; Thrombocytopenia

Topics: Anticoagulants; Arginine; Heparin; Hirudins; Humans; International Normalized Ratio; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombin; Thrombocytopenia; Warfarin

We report two patients with deep-vein thrombosis complicating immune heparin-induced thrombocytopenia who developed venous limb gangrene during overlapping therapy with a direct thrombin inhibitor (lepirudin or argatroban) and warfarin. In both patients, therapy with the direct thrombin inhibitor was interrupted during persisting severe athrombocytopenia while warfarin administration continued. Both patients exhibited the typical feature of a supratherapeutic international normalized ratio (INRs, 5.9 and 7.3) that has been linked previously with warfarin-associated venous limb gangrene. These data suggest that warfarin anticoagulation be postponed in patients with acute heparin-induced thrombocytopenia until substantial recovery of the platelet count has occurred.

Topics: Aged; Aged, 80 and over; Amputation, Surgical; Anticoagulants; Arginine; Autoimmune Diseases; Catheterization, Central Venous; Contraindications; Drug Administration Schedule; Drug Therapy, Combination; Female; Gangrene; Heparin; Hirudin Therapy; Hirudins; Humans; International Normalized Ratio; Leg; Male; Middle Aged; Necrosis; Pipecolic Acids; Protein C Deficiency; Recombinant Proteins; Sulfonamides; Surgical Wound Infection; Thrombin; Thrombocytopenia; Thrombophlebitis; Warfarin

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

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

This is a case series of 5 patients who were treated with the direct antithrombin agents (lepirudin or argatroban) for known or suspected heparin-induced thrombocytopenia thrombosis syndrome (HITTs). Coincidentally all had evidence of disseminated intravascular coagulation (DIC). The DIC parameters improved with treatment and each patient was successfully discharged from the hospital. These observations provide evidence that the direct antithrombin inhibitors, lepirudin and argatroban, can improve DIC. Moreover the presence of DIC in a patient with suspected HlTTs should not mitigate against the use of these agents.

Topics: Adult; Aged; Arginine; Disseminated Intravascular Coagulation; Female; Fibrinolytic Agents; Heparin; Hirudins; Humans; Male; Middle Aged; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a common complication of heparin therapy. There are three types of HIT. In the majority of patients, thrombocytopenia is modest and resolves without sequelae (HIT I). In a smaller number of patients, the thrombocytopenia is severe (HIT II), and in still others, the thrombocytopenia is also associated with thrombosis (HITT). Administration of heparin to this latter group of patients causes platelet aggregation, thromboembolism, and thrombocytopenia. It is advisable that heparin not be administered in any form to patients with documented or suspected HIT II or HITT. This situation, of course, poses a problem for those patients requiring cardiopulmonary bypass (CPB) surgery. In this report, we summarize our experience with Lepirudin (Hoechst, Frankfurt Ammain, Germany), which is a recombinant hirudin (r-hirudin), as an alternative to heparin for systemic anticoagulation, as well as the use of the ecarine clotting time (ECT) for monitoring anticoagulation status during CPB.

Topics: Aged; Aged, 80 and over; Anticoagulants; Cardiopulmonary Bypass; Female; Heparin; Hirudins; Humans; Male; Recombinant Proteins; Risk Factors; Thrombocytopenia; Thrombosis

Lepirudin is a specific thrombin inhibitor that is used for anticoagulation in patients with heparin-induced thrombocytopenia who are also undergoing cardiopulmonary bypass (CPB). Monitoring of lepirudin during CPB has been carried out with activated clotting time and ecarin clotting time. Correlation is poor with the former method, whereas ecarin clotting time is not widely available. A patient is described with heparin-induced thrombocytopenia who underwent CPB, where coagulation monitoring was accomplished with the Thrombelastograph. This more widely available method may be useful in such patients.

Topics: Anticoagulants; Cardiopulmonary Bypass; Drug Monitoring; Heparin; Hirudins; Humans; Male; Middle Aged; Recombinant Proteins; Thrombelastography; Thrombocytopenia; Thrombosis

We report the case of a 71 old woman presenting a bilateral massive pulmonary embolism with intraventricular right thrombus complicating heparin induced thrombocytopenia (HIT) persistent after one month of conventional anticoagulant processing. We underline the effectiveness of lepirudin (Refludan) in the curative processing of pulmonary embolism allowing here to avoid a complex surgical thromboembolectomy. We evoke the place of this molecule in the curative therapeutic strategy of HIT with thrombotic phenomena.

Topics: Aged; Female; Fibrinolytic Agents; Heparin; Hirudins; Humans; Pulmonary Embolism; Recombinant Proteins; Thrombocytopenia; Treatment Outcome

Topics: Acute Kidney Injury; Aged; Anticoagulants; Creatinine; Drug Monitoring; Heparin; Hirudins; Humans; Infusions, Intravenous; International Normalized Ratio; Male; Platelet Count; Recombinant Proteins; Renal Dialysis; Thrombocytopenia

Topics: Aged; Arterial Occlusive Diseases; Diagnosis, Differential; Fibrinolytic Agents; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Recombinant Proteins; Thrombocytopenia

Lepirudin is indicated for anticoagulation in patients with heparin-induced thrombocytopenia (HIT). We describe 2 cases of HIT and thrombosis in children with heart disease, including one that required extracorporeal membrane oxygenation. Lepirudin, dosed in the recommended adult weight--based fashion, was an effective antithrombotic agent in pediatric patients with HIT.

Topics: Anticoagulants; Cardiomyopathy, Dilated; Child; Child, Preschool; Extracorporeal Membrane Oxygenation; Female; Hirudin Therapy; Hirudins; Humans; Recombinant Proteins; Thrombocytopenia

The method of anticoagulation in patients undergoing major vascular surgery with a history of heparin-induced thrombocytopenia (HIT) is controversial. We present two cases in which a bolus only technique using recombinant hirudin (Lepirudin or Refludan) was used successfully in patients with HIT scheduled for vascular surgery.

Topics: Aged; Anticoagulants; Heparin; Hirudins; Humans; Male; Middle Aged; Partial Thromboplastin Time; Recombinant Proteins; Thrombocytopenia; Vascular Surgical Procedures

We report here a case of recurrent venous and arterial thromboembolism, Trousseau's syndrome, in a cancer patient who developed heparin-induced thrombocytopenia. She was treated with lepirudin and after establishing the patient-specific half-life for subcutaneous lepirudin, she was successfully maintained on this therapy for more than eight months. To our knowledge this case represents the longest reported use of subcutaneous lepirudin.

Topics: Anticoagulants; Arterial Occlusive Diseases; Female; Heparin; Hirudins; Humans; Injections, Subcutaneous; Kinetics; Middle Aged; Paraneoplastic Syndromes; Partial Thromboplastin Time; Recombinant Proteins; Recurrence; Thrombocytopenia; Thromboembolism; Venous Thrombosis

Heparin-induced thrombocytopenia (HIT) is a well-documented complication of heparin anticoagulation therapy. Heparin's frequent use in the cardiovascular population poses a significant challenge for managing patients with HIT in need of percutaneous coronary intervention (PCI). We describe four patients with HIT who successfully underwent PCI without thrombotic or hemorrhagic complications while on lepirudin.

Topics: Aged; Angioplasty, Balloon, Coronary; Anticoagulants; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Recombinant Proteins; Thrombocytopenia

The purpose of this study was to determine whether lepirudin, a direct thrombin inhibitor, is a safe and effective anticoagulant for patients with heparin-associated antiplatelet antibodies (HAAbs).. The charts of HAAb-positive patients who received lepirudin were reviewed. Lepirudin use was analyzed for indication, duration, and effectiveness of anticoagulation, and for adverse events. HAAb presence was determined by platelet aggregation.. Eighteen HAAb-positive patients received lepirudin: 9 had previous documentation of HAAb, 6 had thrombocytopenia while receiving heparin; and 3 had HAAb after a thrombotic event. The indications for lepirudin anticoagulation included thromboembolism prophylaxis (5), arterial thromboses (5), pulmonary embolus (3) or deep venous thrombosis (1), and one each for atrial fibrillation, myocardial infarction, artificial heart valves, and hemodialysis access. The average duration of therapy was 4.04 days. Fifteen patients achieved adequate anticoagulation (activated partial thromboplastin time [aPTT] ratio > 2.0) with lepirudin. Seven patients had aPTTs that were sometimes supratherapeutic (aPTT > 100 seconds) but did not bleed. In all patients who had heparin-induced thrombocytopenia, platelet counts were normalized while they received lepirudin. There were two complications: one patient fell and had a calf hematoma (aPTT ratio 3.24), and one patient who received lepirudin during nine separate hospitalizations had epistaxis (aPTT ratio 2.86) during her ninth hospitalization. Another patient received lepirudin during two hospitalizations without an adverse event.. Lepirudin is a safe and effective anticoagulant for patients with HAAbs. The platelet counts of all patients with heparin-induced thrombocytopenia were normalized while they received lepirudin. Careful monitoring of the aPTT and avoidance of trauma while patients are receiving lepirudin are recommended.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies; Anticoagulants; Female; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Partial Thromboplastin Time; Platelet Count; Recombinant Proteins; Retrospective Studies; Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is described as an allergy-like adverse reaction to heparin. It is a potentially severe complication of heparin therapy that can result in serious or life-threatening venous or arterial thromboembolic events. In the United States, lepirudin (Aventis Pharma AG, Strasbourg, France) is an approved therapy for anticoagulation in patients with HIT requiring anticoagulation. Lepirudin is a recombinant form of hirudin, a leech enzyme that is a highly specific direct inhibitor of thrombin. Lepirudin monitoring during surgery can be managed with ecarin clotting time (ECT) (Cardiovascular Diagnostics, Inc., Raleigh, NC), which has recently been approved as a humanitarian device exemption (HDE) for use in the United States in the management of HIT with cardiopulmonary bypass. This case report describes a patient with HIT who was managed successfully with lepirudin and ECT during coronary artery bypass grafting.

Topics: Anticoagulants; Blood Coagulation Tests; Cardiopulmonary Bypass; Endopeptidases; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Pennsylvania; Recombinant Proteins; Thrombocytopenia

An 81-year-old woman with a history of prior coronary artery bypass surgery, heparin-induced thrombocytopenia with "white clot" syndrome, and renal insufficiency presented with unstable angina. She was referred for cardiac catheterization. Complex percutaneous revascularization of the native circumflex coronary artery was performed using stents. A combination of tirofiban and lepirudin was used with dosing adjusted for renal insufficiency. The hospital course was uncomplicated and the patient was discharged on the fourth hospital day. This is only the second report of the combination use of direct thrombin inhibitor and glycoprotein IIb/IIIa receptor inhibitor.

Topics: Aged; Aged, 80 and over; Anticoagulants; Combined Modality Therapy; Coronary Artery Disease; Coronary Thrombosis; Drug Therapy, Combination; Female; Fibrinolytic Agents; Heparin; Hirudin Therapy; Hirudins; Humans; Platelet Aggregation Inhibitors; Recombinant Proteins; Renal Insufficiency; Stents; Thrombocytopenia; Tirofiban; Tyrosine

Treatment of critically ill patients who have heparin-induced thrombocytopenia and thrombosis (HITT) and also renal failure is a challenge. Recombinant hirudin (Refludan, Hoechst Marion Roussel) is a direct thrombin inhibitor indicated for anticoagulation in HITT and approved by the United States Food and Drug Administration. Because this drug is renally cleared, a single dose of hirudin may induce prolonged (up to one week) unpredictable anticoagulation in patients with renal insufficiency. There are a few case reports of patients with renal failure and suspected heparin-induced thrombocytopenia (HIT) in which patients were anticoagulated with Refludan for catheter thrombosis. There is no literature on the therapeutic use of Refludan to treat HITT in patients with diffuse thrombosis and renal failure. The authors report the case of a 44-year-old female dialysis patient with HITT and extensive life-threatening thrombosis. The patient developed common iliac vein occlusion extending to the right atrium with progressive right internal jugular vein thrombus developing while on heparin. Her platelet count dropped to 60,000/microL. She was lethargic and hemodynamically unstable. Refludan was initially given as a bolus of 0.2 mg/kg (total, 12 mg) at a 50% dose reduction based on the patient's ideal body weight. This dose was based on the published pharmacokinetics of Refludan in patients with renal failure. Only 2 additional boluses of 6 mg and 3 mg were needed to extend the duration of therapeutic anticoagulation (measured by PTT) to 140 hours. The patient improved both clinically and radiographically after the treatment with Refludan. There were no additional thromboembolic events or bleeding complications. The platelets returned to normal within a few days. The patient was transitioned to coumadin and discharged from the hospital. She remains stable at 1-year follow-up.

Topics: Adult; Anticoagulants; Female; Heparin; Hirudin Therapy; Hirudins; Humans; Kidney Failure, Chronic; Recombinant Proteins; Thrombocytopenia; Thrombosis; Warfarin

A 61-year-old male with a history of severe heparin-induced thrombocytopenia (HIT) type II after aorto-femoral bypass surgery presented to the emergency department within 8 hours of development of substernal chest pain radiating to the left arm. Electrocardiogram (ECG) on arrival and at 3 hours showed no acute changes; cardiac enzymes revealed minimal MB elevation. Echocardiogram showed normal left ventricular systolic function with mild mitral and tricuspid regurgitation and trace aortic insufficiency. Five hours after arrival, the patient reported a recurrence of severe chest pain. ECG showed marked ST elevations consistent with acute myocardial infarction. Reteplase was administered with concomitant lepirudin. Follow-up ECG showed improvement in ST-segment elevation and eventual resolution to pre-event tracing; cardiac enzymes showed slight elevations. Catheterization revealed 90% midstenosis of the left anterior descending artery, which was successfully treated with percutaneous transluminal coronary angioplasty (PTCA) and stent placement. Repeat PTCA was performed 10 days postdischarge due to intraluminal stent occlusion. The patient was doing well at 6 months follow-up.

Topics: Angioplasty, Balloon, Coronary; Drug Therapy, Combination; Electrocardiography; Heparin; Hirudins; Humans; Male; Middle Aged; Myocardial Infarction; Recombinant Proteins; Thrombocytopenia; Tissue Plasminogen Activator

Heparin induced thrombocytopenia with thrombosis (HITT) is a rare but dangerous complication related to the application of unfractionated heparin or low molecular weight heparin. Due to an antibody dependent in vivo platelet activation, severe thromboembolic episodes may occur. We present the case of a patient with HITT following implantation of an aortobifemoral graft secondary to bilateral common iliac artery stenoses. An arterial clot developed and led to a partial occlusion of the graft to the right external iliac artery. Heparin was replaced by Lepirudin, a recombinant hirudin. A bolus of 0.4 mg/kg body weight was given, thereafter 0.15 mg/kg body weight per hour was administered continuously i.v. to maintain the aPTT 2- to 2.5-fold above the baseline value. The platelet count (minimum 47 G/l) normalised within two days. During thrombectomy of the right common femoral artery we used Lepirudin intraoperatively (bolus injection of 0.2 mg/kg body weight) to prevent any further platelet and coagulation activation during the clamping phase. Six months later the patient underwent two further bypass operations due to severe stenoses of both superficial femoral arteries. Due to the high risk of thromboembolism if HITT recurred, a bolus of 0.2 mg/kg body weight of Lepirudin was given during each intervention. No bleeding complications occurred. In addition Lepirudin appeared to decrease platelet consumption in the absence of active thrombosis. Direct thrombin inhibitors such as Lepirudin possess no heparin-like immunological properties and seem to have become the therapeutic "gold-standard" in patients with HITT. Our experience suggests that the repetitive intraoperative use of Lepirudin is safe and effective.

Topics: Anticoagulants; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Platelet Count; Postoperative Complications; Recombinant Proteins; Thrombocytopenia; Thromboembolism

Topics: Anticoagulants; Cardiopulmonary Bypass; Fatal Outcome; Heart Valve Prosthesis Implantation; Heparin; Hirudin Therapy; Hirudins; Humans; Intraoperative Period; Male; Middle Aged; Mitral Valve; Multiple Organ Failure; Partial Thromboplastin Time; Postoperative Complications; Recombinant Proteins; Thrombocytopenia; Thrombosis

To report the case of a patient with HIT that received a prolonged infusion of r-hirudin (lepirudin; Refludan; Hoechst, France) before, during and after cardiopulmonary bypass (CPB) for aortic surgery. Although administration of r-hirudin for CPB anticoagulation has previously been reported, many questions persist concerning the best therapeutic regimen for CPB anticoagulation as well as the time of onset and the doses for postoperative anticoagulation.. A 65-yr-old man was admitted for surgery of aortic stenosis after an episode of acute pulmonary edema complicated by deep venous thrombosis in the context of documented HIT. The patient received r-hirudin for 13 dy before surgery at doses (0.4 mg x kg(-1) bolus followed by 0.15 mg x kg(-1) x hr(-1) continuous infusion) that maintained activated partial thromboplastin time (aPTT) ratios between 2 and 2.5. Anticoagulation for CPB was performed with r-hirudin given as 0.1 mg x kg(-1) i.v. bolus and 0.2 mg kg(-1) in the CPB priming volume. Anticoagulation during CPB was monitored with the whole blood activated coagulation time and ecarin clotting time (ECT) performed in the operating room with values corresponding to r-hirudin concentrations >5 microg x ml(-1) during CPB. Anticoagulation during CPB was uneventful. Two bleeding episodes, related to the r-hirudin regimen and necessitating allogeneic blood transfusion, occurred after surgery.. This case report confirms previous experience of the use of r-hirudin for anticoagulation during CPB and provides additional information in the context of prolonged r-hirudin infusion before and after CPB.

Topics: Aged; Anticoagulants; Aortic Valve; Aortic Valve Stenosis; Blood Coagulation; Blood Transfusion; Cardiopulmonary Bypass; Endopeptidases; Fibrinolytic Agents; Follow-Up Studies; Heart Valve Prosthesis Implantation; Heparin; Hirudin Therapy; Hirudins; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Postoperative Hemorrhage; Recombinant Proteins; Thrombocytopenia; Venous Thrombosis; Whole Blood Coagulation Time

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

A 60-year-old man was admitted to the hospital with aortic dissection. An operative excision and replacement with a Y-graft was performed. Postoperatively he developed multiple organ dysfunction and required intermittent haemofiltration (anticoagulation with heparin). An ischemia of the left leg occurred at the third postoperative day. The initial platelet count was 99,000/microliter. Continuous haemofiltration (CVVH) was started three days later. Thrombotic obstructions of haemodialysis filters and catheters occurred frequently and heparin-induced thrombocytopenia (HIT II) was suspected. Antibodies against heparin were found in the HIPA test. Despite heparin free citrate dialysis and anticoagulation with danaparoid thrombotic obstructions of filters and catheters continued. Therefore the anticoagulation therapy during CVVH was changed to recombinant hirudin (lepirudin). Starting dose was a bolus of 0.01 mg/kg bw followed by the same amount as maintenance dose per hour. Anticoagulation was adjusted to an increase of aPTT (activated partial thromboplastin time) to 1.5-2 times its normal value. A dose of 0.005 mg/kg bw/h lepirudin was sufficient to maintain adequate anticoagulation. After changing to lepirudin no further catheter obstructions were observed and the platelets recovered slowly. Renal function improved and five weeks after admission endogenous creatinine clearance showed a value of 25 ml/min. We conclude that lepirudin is an effective anticoagulant during CVVH in patients with HIT II. In partly permeable polysulfon filters a dose of 0.005 mg/kg bw/h lepirudin is sufficient to maintain adequate anticoagulation. Monitoring anticoagulation by measuring the increase of aPTT (factor 1.5-2.0) seems to be safe. However, optimally the r-hirudin concentration should be measured directly using the Ecarin clotting time.

Topics: Anticoagulants; Aortic Aneurysm, Abdominal; Aortic Dissection; Blood Vessel Prosthesis Implantation; Hemodiafiltration; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Multiple Organ Failure; Recombinant Proteins; Thrombocytopenia; Treatment Outcome

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

Hirudin, a potent and specific thrombin inhibitor, is a protein of nonhuman origin and therefore potentially immunogenic. The primary objectives of this investigation were to determine the incidence of antihirudin antibodies (ahir-ab) in patients with heparin-induced thrombocytopenia (HIT) who received lepirudin as parenteral anticoagulation and to determine the incidence of death, limb amputation, new thromboembolic complications (TECs), and major hemorrhage in patients who had ahir-ab, compared with patients who were ahir-ab negative. The investigation used data from 2 prospective multicenter studies with the same study protocol, in which HIT patients received 1 of 4 intravenous lepirudin dosage regimens. The treatment duration was 2 to 10 days. Ahir-ab were determined by a newly developed enzyme-linked immunosorbent assay (ELISA). Eighty-seven of 196 evaluable patients (44.4%) had ahir-ab of the IgG class. Development of ahir-ab was dependent on the duration of treatment (ahir-ab-positive patients 18.6 days vs ahir-ab-negative patients 11.8 days; P =.0001). Fewer ahir-ab-positive than ahir-ab-negative patients died (P =.001). Ahir-ab did not cause an increase in limb amputation (P =.765), new TECs (P >.99), or major bleedings (P =.549). In 23 of 51 (45.1%) evaluable patients in whom ahir-ab developed during treatment with lepirudin ( = 12% of all lepirudin treated patients), the ahir-ab enhanced the anticoagulatory effect of lepirudin. Ahir-ab are frequent in patients treated with lepirudin for more than 5 days. Ahir-ab are the first example for a drug-induced immune response causing enhanced activity of a drug. Therefore, during prolonged treatment with lepirudin, anticoagulatory activity should be monitored daily to avoid bleeding complications.

Topics: Amputation, Surgical; Antibodies; Anticoagulants; Extremities; Hemorrhage; Heparin; Hirudin Therapy; Hirudins; Humans; Immunoglobulin G; Partial Thromboplastin Time; Recombinant Proteins; Thrombocytopenia; Thromboembolism; Time Factors

A case of 68 years old women suffering from chronic anemia, myelodysplastic syndrome and treated with progestogen due to endometrial hypertrophy is presented. Initially she was admitted to a regional hospital because of progressive weakness and exertional dyspnea. Three months earlier she reported an episode of acute dyspnea and chest pain. On the basis of clinical symptoms and perfusion lung scintigraphy pulmonary embolism (PE) was diagnosed. Patient received i.v. heparin which was changed to s.c. nadroparine subcutaneously. Platelet count dropped to 55,000'/ml on fifth day of treatment from initial level of about 200,000'/ml. Heparin induced thrombocytopenia was diagnosed, heparin was stopped and ticlopidine was recommended. After 3 weeks symptoms suggesting recurrent PE were observed. The patient was transferred to National Tuberculosis and Lung Diseases Research Institute. Recombinant hirudine (Refludan) was administrated (bolus 0.4 mg/kg and initial dose of infusion 0.1 mg/kg/h) overlapping with acenocoumarol from second day. Dose of r-hirudine was adjusted to achieve APTT prolongation 1.5 to 2.5 times of mid-normal range. During treatment with r-hirudine no bleeding and new thromboembolic complications occurred. Platelets count remained within normal range. After 14 days clinical improvement was observed, though symptoms of right ventricular overload and hypoxemia were still present after 6 months of treatment with oral anticoagulants suggesting chronic thromboembolic pulmonary hypertension.

Topics: Aged; Anemia; Anticoagulants; Dyspnea; Female; Heparin; Hirudin Therapy; Hirudins; Humans; Injections, Intravenous; Myelodysplastic Syndromes; Pulmonary Embolism; Recombinant Proteins; Recurrence; Thrombocytopenia

Topics: Aged; Anticoagulants; Appendectomy; Female; Fibrinolytic Agents; Hirudin Therapy; Hirudins; Humans; Nadroparin; Perioperative Care; Phenprocoumon; Recombinant Proteins; Thrombocytopenia

Heparin-induced thrombocytopenia type II (HIT type II) is the most serious complication of heparin treatment apart from bleeding, which is the most common side effect. Eleven days after coronary bypass grafting, a 71 year old patient showed a posterolateral myocardial infarction and a thrombocytopenia of 80,000/microliter. This was considered a postoperative thrombocytopenia. Coronary angiography revealed closed venous bypass grafts. The right coronary artery (RCA) was revascularized by percutaneous transluminal coronary angioplasty (PTCA) and stent placement. During both coronary angiography and PTCA, heparin was administered to the patient. The platelet number did not change. Four days later the patient showed an inferior myocardial infarction and an AV-block III degrees and a syncope. The following coronary angiography revealed RCA stent occlusion. HIT type II was presumed and recanalization was carried out using Lepirudin (Refludan) as the anticoagulant. After placing the guide wire, thrombi could be seen in the proximal RCA. Abciximab (Reo pro), a monoclonal antibody against the glycoprotein IIb/IIIa receptor was additionally administered. Coronary angiography on the next day revealed only a small remaining thrombus. The AV-block disappeared immediately after revascularization. The diagnosis of HIT type II was confirmed through heparin-induced-platelet-activation-test (Hipa-test) and immunoassay (PF 4/heparin-ELISA). This case report illustrates the complicated diagnosis of HIT type II and the successful simultaneous use of Lepirudin (Refludan) and Abciximab (Reo pro). The number of platelets should be checked daily during heparin treatment. In the case of a thrombocytopenia, the treatment should be stopped immediately, and Hipa-test and PF 4/heparin-ELISA should be carried out.

Topics: Abciximab; Aged; Angioplasty, Balloon, Coronary; Antibodies, Monoclonal; Coronary Artery Bypass; Heparin; Hirudin Therapy; Hirudins; Humans; Immunoglobulin Fab Fragments; Male; Myocardial Infarction; Postoperative Complications; Recombinant Proteins; Stents; Thrombocytopenia; Thrombosis

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: Catheters, Indwelling; Heparin; Hirudins; Humans; Male; Middle Aged; Recombinant Proteins; Recurrence; Renal Dialysis; Thrombocytopenia; 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

Topics: Anticoagulants; Coumarins; Female; Fibrinolytic Agents; Heparin; Hirudin Therapy; Hirudins; Humans; Middle Aged; Phenprocoumon; Pulmonary Embolism; Recombinant Proteins; Thrombocytopenia; Thrombophlebitis; Time Factors

A serious retroperitoneal bleeding occurred in a 56-year-old male patient receiving unfractionated heparin due to multiple pulmonary embolism. After reducing the heparin dose, the patient developed a new pulmonary embolism and a large thrombus in the right atrium. Concomitantly, the platelet count dropped to a value of 29 g/l. Heparin-induced thrombocytopenia (HIT) was confirmed by a functional assay, the heparin-induced platelet activation (HIPA) assay, whereas the results of a platelet factor 4/heparin complex ELISA were repeatedly negative. This indicated that the patient's HIT antibodies were directed towards an antigen other than platelet factor 4/heparin complexes. For treatment of the atrial thrombus, an ultra-low-dose lysis with rt-PA (2 mg/h, intravenously) was administered for a period of 52 h, overlapping with systemic treatment with recombinant hirudin (Lepirudin, Refludan, 0.06-0.14 mg/kg/h intravenously). The aim was to enhance lysis of the thrombus without increasing the haematoma, and at the same time keep the risk of fulminant pulmonary embolism due to thrombus fragmentation as low as possible. The cardiac thrombus disappeared within 48 h, without new signs of pulmonary embolism. Platelet counts normalized within nine days.

Topics: Anticoagulants; Arrhythmias, Cardiac; Autoimmune Diseases; Heart Atria; Heart Diseases; Hemorrhage; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Phenprocoumon; Plasminogen Activators; Pulmonary Embolism; Recombinant Proteins; Retroperitoneal Space; Thrombocytopenia; Thrombolytic Therapy; Thrombosis; Tissue Plasminogen Activator; Vena Cava Filters

Topics: Anticoagulants; Drug Approval; Fibrinolytic Agents; Heparin; Hirudin Therapy; Hirudins; Humans; Recombinant Proteins; Thrombocytopenia; Thromboembolism; United States; United States Food and Drug Administration

Topics: Anticoagulants; Heparin; Hirudin Therapy; Hirudins; Humans; Recombinant Proteins; Surveys and Questionnaires; Thrombocytopenia

Topics: Anticoagulants; Clinical Trials as Topic; Dose-Response Relationship, Drug; Fees, Pharmaceutical; Heparin; Hirudin Therapy; Hirudins; Humans; Recombinant Proteins; Thrombocytopenia

A 60-year-old woman was admitted because of acute ischemia of the right leg. The patient had been immobilized during diagnostic procedures for a thoracic paraspinal space-occupying lesion and over 5 days had received unfractionated sodium heparin by subcutaneous injection. The pedal pulses were no longer palpable.. The thrombocyte count had fallen from 207,000/microliter to 45,000/microliter. Angiography revealed occlusion of the common femoral artery. Heparin-induced platelet aggregation (HIPA) test demonstrated type II heparin-induced thrombocytopenia. Thrombectomy was performed and intraoperatively an i.v. bolus of the recombinant hirudin, lepirudin (Refludan), was given (0.2 mg/kg body weight), continual lepirudin infusion being continued postoperatively. Normal blood flow was re-established in the limb and the pedal pulse was palpable. There were no complications.. Recombinant hirudin is the only alternative licensed in Germany to heparin and seem to be suitable also for the intraoperative bolus administration in heparin-induced thromboembolic vascular occlusions.

Topics: Angiography, Digital Subtraction; Anticoagulants; Arterial Occlusive Diseases; Female; Femoral Artery; Heparin; Hirudin Therapy; Hirudins; Humans; Infusions, Intravenous; Injections, Intravenous; Intraoperative Care; Ischemia; Leg; Middle Aged; Platelet Aggregation; Platelet Count; Postoperative Care; Recombinant Proteins; Thrombectomy; Thrombocytopenia

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

Topics: Anticoagulants; Female; Femoral Artery; Heparin; Hirudin Therapy; Hirudins; Humans; Middle Aged; Recombinant Proteins; Thrombocytopenia; Thromboembolism