Effect of a novel thrombin active-site inhibitor on arterial and venous thrombosis

Abstract

The effects of a thrombin active-site inhibitor on arterial and venous thrombosis, and thrombin-induced thrombocytopenia were determined in anesthetized rats. Desamino D-Phe-Pro-Arg-aldehyde (BMY 44621) was administered before experimental intervention as a loading i.v. dose plus continuous i.v. infusion. Carotid artery thrombosis was produced by transmural vessel injury and vena cava thrombosis was produced by partial stasis of blood flow combined with endothelial injury. Thrombocytopenia was induced by an i.v. injection of human α-thrombin. BMY 44621 inhibited arterial and venous thrombosis in a dose-dependent manner. Its threshold antithrombotic dose for venous thrombosis was half of that for arterial thrombosis. Maximum reductions in thrombus weight were greater for venous (> 90%) compared to arterial (57%) thrombosis and correlated with 2-and 9-fold prolongation of ex vivo thrombin clotting time, respectively. A 40% reduction in platelet counts induced by thrombin injection was abolished by the threshold dose of BMY 44621 for inhibiting venous thrombosis. These experiments demonstrate that thrombin's active-site is an effective target for inhibiting venous and arterial thrombosis, although venous thrombosis is more sensitive to this therapeutic strategy than arterial thrombosis.