TY - JOUR T1 - Inhibition of Factor XIa Reduces the Frequency of Cerebral Microembolic Signals Derived from Carotid Arterial Thrombosis in Rabbits JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.116.238600 SP - jpet.116.238600 AU - Xinkang Wang AU - Stan Kurowsk AU - Weizhen Wu AU - Gino A. Castriota AU - Xueping Zhou AU - Lin Chu AU - Kenneth P. Ellsworth AU - Scott Edmondson AU - Donald Chu AU - Amjad Ali AU - Patrick Andre AU - Dietmar Seiffert AU - Mark Erion AU - David E. Gutstein AU - Zhu Chen Y1 - 2016/01/01 UR - http://jpet.aspetjournals.org/content/early/2016/12/29/jpet.116.238600.abstract N2 - Factor XI (FXI) is an integral component of the intrinsic pathway of the coagulation cascade and plays a critical role in thrombus formation. Since its role in the pathogenesis of cerebral microembolic signals (MES) is unclear, this study utilized a potent and selective small molecule inhibitor of FXIa, Compound 1, to assess the effect of FXI blockade in our recently established preclinical model of cerebral MES induced by FeCl3 injury of the carotid artery in male New Zealand White rabbits. Ascending doses of Compound 1 were evaluated simultaneously for both carotid arterial thrombosis by a Doppler flowmeter and MES in the middle cerebral artery by a transcranial Doppler. Plasma drug exposure and pharmacodynamic responses to Compound 1 treatment were also assessed. The effective dose for 50% inhibition (ED50) of thrombus formation was 0.003 mg/kg/h Compound 1, i.v. for the integrated blood flow, 0.004 mg/kg/h for reduction in thrombus weight, and 0.106 mg/kg/h for prevention of MES. The highest dose, 3 mg/kg/h Compound 1, achieved complete inhibition in both thrombus formation and MES. In addition, we assessed potential bleeding liability of Compound 1 (5 mg/kg/h, i.v., >1,250-fold ED50 levels in arterial thrombosis) in rabbit using a cuticle bleeding model, and observed about 2-fold (non-significant) prolongation in bleeding time. In summary, our study demonstrates that Compound 1 produced a robust and dose-dependent inhibition of both arterial thrombosis and MES, suggesting that FXIa blockade may represent a novel therapeutic strategy for the reduction in MES in patients at risk for ischemic stroke. ER -