Antithrombotic Activity of a Small Molecule Factor XIa Inhibitor in Rats with Limited Effects on Bleeding Time

Abstract number: P1228

Schumacher W, Seiler S, Steinbacher T, Stewart A, Hartl K, Liu E, Ogletree M

Factor XIa (FXIa) inhibition was evaluated in animal models of thrombosis and hemostasis. BMS-262084 is a 4-carboxy-2-azetidinone-containing mechanism-based inhibitor of FXIa (IC₅₀= 2.8 nMolar) that is selective for FXIa relative to other blood coagulation and fibrinolysis proteases in plasma. In human and rat plasma it doubled the APTT at 0.6 and 2.1 µMolar, respectively, but had no effect on prothrombin time at up to 100 µMolar. BMS-262084 was given intravenously as a loading infusion prior to experimental intervention followed by a continuous infusion. BMS-262084 was effective in vena cava thrombosis induced by either partial stasis of blood flow plus hypotonic saline infusion or by topical FeCl₂, and in carotid artery thrombosis induced by topical FeCl₂. Maximum thrombus weight reductions (p < 0.05) in these models were 64, 97 and 78%, respectively, achieved at a 12 mg/kg loading plus 12 mg/kg/h sustaining dose (12 + 12) which increased the APTT to 2.8 times control. A lower dose level of 6 + 6 showed comparable efficacy in stasis venous thrombosis, but was ineffective in arterial thrombosis. BMS-262084 was most potent in FeCl₂-induced venous thrombosis with a 38% thrombus reduction (p < 0.05) achieved at a dose level of 0.2 + 0.2. In contrast, BMS-262084 had no effect on either tissue factor-induced venous thrombosis or the ex vivo prothrombin time at a dose levels of up to 24 + 24. BMS-262084 did not significantly prolong bleeding time in rats provoked by puncture of small mesenteric blood vessels or by template incision of the renal cortex at a dose levels of up to 24 + 24. However, a 10 mg/kg dose of aspirin prolonged (p < 0.05) both mesenteric (26%) and renal bleeding times (36%). These results suggest that a small molecule FXIa inhibitor may be useful for prevention of thrombosis at doses that have less than aspirin-like effects on bleeding time.