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Blood, 1 October 2000, Vol. 96, No. 7, pp. 2373-2378
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Antihirudin antibodies in patients with heparin-induced
thrombocytopenia treated with lepirudin: incidence, effects on aPTT,
and clinical relevance
Petra Eichler,
Heinz-Juergen Friesen,
Norbert Lubenow,
Bernd Jaeger, and
Andreas Greinacher
From the Institute for Immunology and Transfusion
Medicine and Institute for Biometry and Medical Informatics,
Ernst-Moritz-Arndt-University, Greifswald, Germany;
Hoechst Marion Roussel Deutschland GmbH, Marburg, Germany.
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.
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