Combination of FXI Antisense Oligonucleotide and Plavix® Treatment Results in Enhanced Antithrombotic Activity without Increased Risk of Bleeding in Mouse Models of Thrombosis.

Abstract 4173

Factor XI (FXI) is a serine protease produced in the liver that contributes to thrombin generation via the intrinsic coagulation pathway. Also, it is a key component of an amplification pathway that is thought to sustain thrombin production at a wound site to maintain fibrin clot integrity. Loss of function mutations in the human FXI gene results in FXI deficiency, a disorder which is associated with only mild bleeding. In addition, high levels of FXI are a risk factor for thrombosis. We have previously presented the antithrombotic efficacy and safety of antisense oligonucleotide (ASO) mediated FXI depletion in various animal models of thrombosis. We have demonstrated that in combination with Lovenox®, FXI ASO treatment increases antithrombotic activity but does not increase bleeding risk. The purpose of the current study was to evaluate the relative risk/benefit of ASO mediated Factor XI depletion in combination with the platelet antagonist Plavix®. The “risk” component was bleeding tendency as measured by blood volume loss following tail nick, and the “benefit” component was antithrombotic effect in arterial and venous mouse models of thrombosis. Our study investigated a 20 mg/kg dose of FXI ASO in combination with a dose response of Plavix® and indicates that antisense mediated FXI depletion provides enhanced antithrombotic protection when given in combination with Plavix®. The combination of FXI ASO and Plavix® did not result in increased bleeding tendency. In contrast, treatment with a small molecule inhibitor of factor Xa in combination with Plavix® significantly increased bleeding. The approach used in this study is being used to define the ability of FXI ASO to combine with standard of care agents for the treatment of thrombosis.