Antihirudin antibodies following low-dose subcutaneous treatment with desirudin for thrombosis prophylaxis after hip-replacement surgery: incidence and clinical relevance

Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating IgG antibodies that recognize platelet factor 4 (PF4) bound to heparin. Immunogenicity of heparins differs in that unfractionated heparin (UFH) induces more anti-PF4/heparin antibodies than low-molecular-weight heparin (LMWH) and UFH also causes more HIT. Fondaparinux, a synthetic anticoagulant modeled after the antithrombin-binding pentasaccharide, is believed to be nonimmunogenic. We tested 2726 patients for anti-PF4/heparin antibodies after they were randomized to receive antithrombotic prophylaxis with fondaparinux or LMWH (enoxaparin) following hip or knee surgery. We also evaluated in vitro cross-reactivity of the IgG antibodies generated against PF4 in the presence of UFH, LMWH, danaparoid, or fondaparinux. We found that anti-PF4/heparin antibodies were generated at similar frequencies in patients treated with fondaparinux or enoxaparin. Although antibodies reacted equally well in vitro against PF4/UFH and PF4/ LMWH, and sometimes weakly against PF4/danaparoid, none reacted against PF4/fondaparinux, including even those sera obtained from patients who formed antibodies during fondaparinux treatment. At high concentrations, however, fondaparinux inhibited binding of HIT antibodies to PF4/polysaccharide, indicating that PF4/ fondaparinux interactions occur. No patient developed HIT. We conclude that despite similar immunogenicity of fondaparinux and LMWH, PF4/fondaparinux, but not PF4/ LMWH, is recognized poorly by the antibodies generated, suggesting that the risk of HIT with fondaparinux likely is very low.

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“…16,17 The plasma samples for assessment of anti-PF4/heparin antibodies were obtained between postoperative days 5 to 9 (median, day 6).…”

Section: Introductionmentioning

confidence: 99%

Anti–platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin

Warkentin

Cook

Marder

et al. 2005

Blood

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256

177

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“…Lepirudin antibodies reduce or prolong aPTT or ECT coagulation times and interact with the hirudin ELISA antibody [8] and may influence the biological elimination half-life of lepirudin in animals [10]. Cross-reactions of lepirudin antibodies have been described with desirudin in about 10% of patients on prophylaxis of postoperative thromboembolism [11]. In contrast, argatroban did not generate antibodies [7].…”

Section: Discussionmentioning

confidence: 95%

Treatment of Patients with a History of Heparin-Induced Thrombocytopenia and Anti-Lepirudin Antibodies with Argatroban

Harenberg

Jörg

Fenyvesi

et al. 2005

J Thromb Thrombolysis

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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.

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“…(12) Alguns estudos mostram sua maior eficácia do que a enoxaparina na profilaxia de TVP em cirurgias ortopédicas, sem haver diferenças significativas nas complicações, como sangramentos. (14) Várias formas comerciais de hirudina são fabricadas através do emprego de biotecnologia recombinante. (15) A lepirudina é uma hirudina recombinante dissulfatada, estando indicada no tratamento da plaquetopenia induzida por heparina, promovendo uma rápida e sustentada recuperação da contagem de plaquetas, indicando uma ausência de reação cruzada, com risco de sangramento semelhante ao da heparina.…”

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Medicamentos alternativos e novos fármacos

2010

J. bras. pneumol.

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Antihirudin antibodies following low-dose subcutaneous treatment with desirudin for thrombosis prophylaxis after hip-replacement surgery: incidence and clinical relevance

Cited by 59 publications

References 17 publications

Anti–platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin

Anti–platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin

Treatment of Patients with a History of Heparin-Induced Thrombocytopenia and Anti-Lepirudin Antibodies with Argatroban

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