Antihirudin antibodies in patients with heparin-induced thrombocytopenia treated with lepirudin: incidence, effects on aPTT, and clinical relevance

Hirudin, a potent and specific thrombin inhibitor, is a protein of nonhuman origin and therefore potentially immunogenic. The primary objectives of th is investigation were to determine the incidence of antihirudin antibodies (ahir-ab) in patients with heparin-induced thrombocytopenia (HIT) who recei ved lepirudin as parenteral anticoagulation and to determine the incidence of death, limb amputation, new thromboembolic complications (TECs), and maj or hemorrhage in patients who had ahir-ab, compared with patients who were ahir-ab negative. The investigation used data from 2 prospective multicente r studies with the same study protocol, in which HIT patients received 1 of 4 intravenous lepirudin dosage regimens. The treatment duration was 2 to 1 0 days. Ahir-ab were determined by a newly developed enzyme-linked immunoso rbent assay (ELISA). Eighty-seven of 196 evaluable patients (44.4%) had ahi r-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 pati ents 11.8 days; P = .0001). Fewer ahir-ab-positive than ahir-ab-negative pa tients died (P = .001). Ahir-ab did not cause as increase in limb amputatio n (P = .765), new TECs (P > .99), or major bleedings (P = .549). In 23 of 5 1 (45.1%) evaluable patients in whom ahir-ab developed during treatment wit h lepirudin ( = 12% of all lepirudin treated patients), the ahir-ab enhance d 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. Th erefore, during prolonged treatment with lepirudin, anticoagulatory activit y should be monitored daily to avoid bleeding complications. (Blood. 2000;9 6: 2373-2378) (C) 2000 by The American Society of Hematology.