Inhibition of Heparin-Resistant Microarterial Thrombosis by Recombinant Hirudin

Abstract

The effects of heparin boluses comparable with those commonly used during angioplasty procedures were compared with equal gravimetric doses of recombinant desulfatohirudin (CGP 39393) in a rabbit model of microarterial thrombosis. Seven-millimeter segments of the central arteries of the ears were isolated between microvascular clamps and subjected to arteriotomy and deep vessel wall trauma. Arteriotomies were closed with continuous 10-0 sutures. Five minutes before vascular reperfusion (opening of vascular clamps), boluses of heparin (1.00 mg/kg), hirudin (1.00 mg/kg), hirudin (0.25 mg/kg), or vehicle (saline) were administered to groups of 10 rabbits in a blind, random fashion. Neither agent prolonged arteriotomy bleeding times relative to vehicle. All active agents significantly increased patency rates versus vehicle at 30 minutes after reperfusion, though reduced vessel patency was noted in a substantial portion of vessels in the groups receiving 0.25 mg hirudin or 1.00 mg/kg heparin. Patency rates at 120 minutes were only improved by the 1.00 mg/kg hirudin dose, and in accord, thrombus weights were significantly reduced only by the 1.00 mg/kg dose of hirudin. In contrast, the anticoagulant response (measured as the activated partial thromboplastin time and anti-IIa and anti-Xa activities) was considerably more pronounced and of longer duration after administration of heparin and hirudin. This is consistent with the hypothesis that the inactivation of clot-bound thrombin that is produced by specific thrombin inhibition (hirudin) but not by cofactor-mediated thrombin inhibition (heparin) is of pivotal importance in achieving a profound and sustained antithrombotic effect following vascular trauma. While heparin boluses seem to be of doubtful value, hirudin seems a promising strategy in context with angioplasty procedures.