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 microM, respectively. Consistent with
factor XIa inhibition, the prothrombin time was unaffected at up to 100 microM.
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<0.05), were achieved at a pretreatment dose of 12 mg/kg+12 mg/kg/h which increased the 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<0.05) at a threshold dose of 0.2 mg/kg+0.2 mg/kg/h. In contrast, doses of up to 24 mg/kg+24 mg/kg/h had no effect on either
tissue factor-induced
venous thrombosis or the 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.