Antithrombotic and hemostatic effects of a small molecule factor XIa inhibitor in rats

Abstract The effect of inhibiting activated blood coagulation factor XIa was determined in rat models of thrombosis and hemostasis. BMS-262084 is an irreversible and selective small molecule inhibitor of factor XIa with an IC 50 of 2.8 nM against human factor XIa. BMS-262084 doubled the activated thromboplastin time in human and rat plasma at 0.14 and 2.2 μM, respectively. Consistent with factor XIa inhibition, the prothrombin time was unaffected at up to 100 μM. BMS-262084 administered as an intravenous loading plus sustaining infusion was effective against FeCl 2 -induced thrombosis in both the vena cava and carotid artery. Maximum thrombus weight reductions of 97 and 73%, respectively ( P ex vivo activated thromboplastin time to 3.0 times control. This dose level also arrested growth of venous and arterial thrombi when administered after partial thrombus formation. BMS-262084 was most potent in FeCl 2 -induced venous thrombosis, decreasing thrombus weight 38% ( P ex vivo prothrombin time. Doses of up to 24 mg/kg + 24 mg/kg/h also did not significantly prolong bleeding time provoked by either puncture of small mesenteric blood vessels, template incision of the renal cortex, or cuticle incision. These results demonstrate that pharmacologic inhibition of factor XIa achieves antithrombotic efficacy with minimal effects on provoked bleeding.