title: Antihirudin antibodies in patients with heparin-induced thrombocytopenia treated with lepirudin: incidence, effects on aPTT, and clinical relevance.
abstract: 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.
authors.affiliation: Institute for Immunology and Transfusion Medicine and Institute for Biometry and Medical Informatics, Ernst-Moritz-Arndt-University, Greifswald, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Eichler
authors.forename: H J
authors.initials: HJ
authors.lastname: Friesen
authors.forename: N
authors.initials: N
authors.lastname: Lubenow
authors.forename: B
authors.initials: B
authors.lastname: Jaeger
authors.forename: A
authors.initials: A
authors.lastname: Greinacher
mesh_terms: D000671:Amputation, Surgical; D000906:Antibodies / Q000097:blood*; D000925:Anticoagulants / Q000276:immunology / Q000627:therapeutic use*; D005121:Extremities; D006470:Hemorrhage / Q000276:immunology; D006493:Heparin / Q000009:adverse effects*; D024764:Hirudin Therapy; D006629:Hirudins / Q000031:analogs & derivatives* / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D010314:Partial Thromboplastin Time; D011994:Recombinant Proteins / Q000276:immunology / Q000627:therapeutic use; D013921:Thrombocytopenia / Q000139:chemically induced / Q000188:drug therapy* / Q000401:mortality; D013923:Thromboembolism / Q000276:immunology; D013997:Time Factors
chemical_list: D000906:Antibodies; D000925:Anticoagulants; D006629:Hirudins; D007074:Immunoglobulin G; D011994:Recombinant Proteins; D006493:Heparin; C083544:lepirudin