Inhibition of factor Xia reduces the frequency of cerebral Microembolic signals derived from carotid arterial thrombosis in Rabbits

Xinkang Wang, Stan Kurowski, Weizhen Wu, Gino A. Castriota, Xueping Zhou, Lin Chu, Kenneth P. Ellsworth, Donald Chu, Scott Edmondson, Amjad Ali, Patrick Andre, Dietmar Seiffert, Mark Erion, David E. Gutstein, Zhu Chen

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Factor XI (FXI) is an integral component of the intrinsic pathway of the coagulation cascade and plays a critical role in thrombus formation. Because its role in the pathogenesis of cerebral microembolic signals (MES) is unclear, this study used 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 the potential bleeding liability of compound 1 (5 mg/kg/h, i.v., .1250-fold ED50 levels in arterial thrombosis) in rabbits using a cuticle bleeding model, and observed about 2-fold (not statistically significant) prolongation in bleeding time. 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.

Original languageEnglish
Pages (from-to)476-483
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
StatePublished - Mar 2017
Externally publishedYes


Dive into the research topics of 'Inhibition of factor Xia reduces the frequency of cerebral Microembolic signals derived from carotid arterial thrombosis in Rabbits'. Together they form a unique fingerprint.

Cite this