COMPARISON OF THROMBIN ACTIVE-SITE AND EXOSITE INHIBITORS AND HEPARININ EXPERIMENTAL-MODELS OF ARTERIAL AND VENOUS THROMBOSIS AND BLEEDING

Different pharmacological approaches to thrombin inhibition were compa red for their effects on thrombosis and bleeding time in anesthetized rats. Thrombosis was induced in the carotid artery by transmural vesse l injury and in the vena cava by partial blood flow stasis combined wi th mild endothelial disruption. Small mesenteric arteries were punctur ed with a hypodermic needle to measure the bleeding time. Dose-respons e relationships were determined with a thrombin active site inhibitor, N-methyl D-Phe-Pro-Arg-aldehyde (GYKI 14,766); a thrombin exosite inh ibitor, -Glu-Pro-Ile-Pro-Glu-Glu-Tyr-cyclohexylalanine-Gln (BMS 180,74 2); and heparin. BMS 180,742 interferes with fibrinogen binding to the thrombin exosite but, unlike GYKI 14,766, it does not block thrombin' s catalytic site. The effects on thrombosis and bleeding time were cor related with ex vivo clotting times using the activated partial thromb oplastin time for heparin and the thrombin time for GYKI 14,766 and BM S 180,742. Venous thrombosis was inhibited more than 90% by all three inhibitors at doses that either produced threshold increases or had no effect on bleeding and clotting times. Arterial thrombosis was inhibi ted 82% by GYKI 14,766 and 63% by heparin but it was not inhibited by BMS 180,742. These antithrombotic activities were accompanied by a max imal activated partial thromboplastin time increase and doubling of th e bleeding time with heparin and a maximal thrombin time prolongation and 35% increase in bleeding time with GYKI 14,766. These results sugg est that thrombin inhibitors, which act at the active site or exosite or through antithrombin III, are equally efficacious against venous th rombosis but active site inhibitors are the most effective against art erial thrombosis.