refludan and Thromboembolism

Type-2 heparin-induced thrombocytopenia (HIT) is a not infrequent complication of treatment with heparins which can lead to fatal outcomes if not recognized and timely treated. Over the last years new epidemiological knowledge, new diagnostic approaches and new therapeutic options have become available. In the present review such novelties will be briefly discussed in the frame of Italian Health System. In Italy only one drug is approved for use in HIT patients differently from other countries. Alternative possible therapeutic options will be discussed based on the scarce available evidence.

Topics: Fondaparinux; Heparin; Hirudins; Humans; Italy; Platelet Activation; Platelet Factor 4; Polysaccharides; Purpura, Thrombocytopenic, Idiopathic; Recombinant Proteins; Thromboembolism

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

The coagulation cascade, and particularly thrombin, plays a very important role in arterial and venous thrombosis. Thereby, it is clear that thrombin inactivation is an optimal strategy for thrombotic disease prevention and treatment. The direct thrombin inhibitors are a new class of anticoagulant drugs directly binding thrombin and blocking its interaction with fibrinogen. The group of direct thrombin inhibitors includes recombinant hirudin (lepirudin and desirudin), bivalirudin, melagatran and its oral precursor, ximelagatran, argotraban and dabigatran. These drugs have several advantages compared to other anticoagulant drugs, and the particular pharmacokinetic properties of some of them could be very important for future management of thromboembolic prophylaxis. The efficacy and safety of these new drugs are evaluated in several clinical trials; however today only few clinical indications are available for the majority of them.

Topics: Anticoagulants; Antithrombins; Azetidines; Benzylamines; Clinical Trials as Topic; Drug Therapy, Combination; Fibrinolytic Agents; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Thromboembolism; 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

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

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

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

Topics: Anticoagulants; Drug Administration Schedule; Drug Monitoring; Hirudins; Humans; Practice Guidelines as Topic; Recombinant Proteins; Retrospective Studies; Thromboembolism

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

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

Edoxaban is a novel, potent and orally active direct Factor Xa (FXa) inhibitor under development for prophylaxis and treatment of thromboembolic diseases. Properties of dose response and margin of safety of anticoagulants are the key factors for a positive risk/benefit of novel oral anticoagulants.. To compare the dose response of antithrombotic effect and margin of safety between antithrombotic and hemorrhagic effects of edoxaban with conventional anticoagulants, unfractionated heparin (UFH), dalteparin (low molecular weight heparin), lepirudin, and warfarin in rat models of thrombosis and hemorrhage.. Rats were treated with edoxaban, UFH, dalteparin, and lepirudin by continuous intravenous (iv) infusion, or with oral warfarin for 4 days before inducing thrombosis or bleeding. Thrombosis was induced by inserting a platinum wire into the inferior vena cava for 60 minutes. Tail template bleeding time was measured after making an incision on the tail.. In rats, iv infusion of edoxaban inhibited venous thrombosis in a dose-dependent manner. The other anticoagulants also exerted dose-dependent antithrombotic effects. The slopes of the dose-response curves of edoxaban were significantly shallower than the slopes of UFH, dalteparin, and warfarin. At supratherapeutic doses, edoxaban prolonged bleeding time in a rat tail bleeding model. To determine bleeding risk, the margins between antithrombotic and bleeding-time prolongation were compared. The margins of safety of edoxaban were wider than those of UFH, dalteparin, lepirudin, and warfarin.. These results suggest that edoxaban may be more easily controlled and has the potential for a more positive risk/benefit ratio compared to conventional anticoagulants.

Topics: Animals; Anticoagulants; Disease Models, Animal; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Heparin; Hirudins; Male; Pyridines; Rats; Rats, Wistar; Recombinant Proteins; Thiazoles; Thromboembolism; Warfarin

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 (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

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

Outpatient treatment of deep venous thrombosis has gained widespread acceptance and is facilitated by the use of subcutaneous low molecular weight heparins (LMWH). We report two patients in whom subcutaneous lepirudin was used for long term anticoagulation after heart transplant or surgical pulmonary embolectomy because treatment with LMWH or warfarin was contraindicated, unsuccessful, or impractical. Neither bleeding complications nor recurrent thromboses developed. Subcutaneous lepirudin may be safely and effectively employed for the outpatient treatment of venous thrombosis in selected cases including patients with heparin-induced thrombocytopenia and in those who fail LMWH.

Topics: Adult; Ambulatory Care; Anticoagulants; Embolectomy; Heart Transplantation; Hirudins; Humans; Injections, Subcutaneous; Male; Postoperative Complications; Pulmonary Embolism; Recombinant Proteins; Thromboembolism; Treatment Outcome; Venous Thrombosis

The pathogenesis of allergic reactions to heparin is poorly understood. Clinically, this phenomenon is relevant because of its increasing incidence and the resulting therapeutic challenges due to various cross-reactions between unfractionated and low-molecular weight heparins as well as between heparins and heparinoids. A 44-year-old female patient had developed a delayed-type hypersensitivity to certoparin-sodium. Diagnostic allergy testing revealed various cross-reactions between different heparins as well as an intolerance to heparinoids. After subcutaneous challenge with the recombinant hirudin lepirudin (Refludan) the patient developed a local Arthus reaction at the injection site. In general, recombinant hirudins do not cross-react with high- or low-molecular weight heparins and heparinoids because of a different molecular structure and are therefore an alternative in case of adverse reactions to heparins and heparinoids. Whereas a local Arthus reaction has already been described twice for low-molecular weight heparins, this is to the best of our knowledge the first observation of a superficial leukocytoclastic vasculitis due to s.c. applied lepirudin. Intravenous administration of heparins and heparinoids in case of hypersensitivity to these drugs following topical application risks a generalized eczematous reaction in patients with delayed-type allergy to both groups of substances. In our patient with delayed-type hypersensitivity to heparins and heparinoids and superficial vasculitis due to lepirudin, the intravenous challenge with heparin and a heparinoid was justified as an ultima ratio measure and proved to be the useful therapeutical alternative.

Topics: Adult; Anticoagulants; Arthus Reaction; Female; Heparin; Heparinoids; Hirudins; Humans; Hypersensitivity, Delayed; Infusions, Intravenous; Postoperative Complications; Recombinant Proteins; Thromboembolism

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 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

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

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

To assess morbidity and mortality in patients treated with Refludan for heparin-induced thrombocytopenia type II in comparison with controls.. One hundred thirteen patients with heparin-induced thrombocytopenia were treated with Refludan in two studies, HAT1 and HAT2. Clinical outcome was assessed in a meta analysis and compared to results in 91 control patients from a former series. Patients with no associated thrombolytic treatment were given an intravenous bolus injection of Refludan (0.4 mg/kg) then a continuous infusion of Refuldan (0.15 mg/kg/h). When a thrombolytic treatment was associated, patient were given a 0.2 mg/kg) bolus followed by a 0.10 mg/kg/h infusion.. The rate of thromboembolism complications, amputations and death was significantly lower in patients treated with Refludan than in controls. There was a clinically acceptable increase in episodes of bleeding with Refludan. The benefit/risk ratio was optimum for APTT between 1.5 and 3.

Topics: Amputation, Surgical; Anticoagulants; Blood Transfusion; Heparin; Hirudin Therapy; Hirudins; Humans; Meta-Analysis as Topic; Neutropenia; Recombinant Proteins; Thromboembolism

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