Prevention of vascular graft occlusion and thrombus-associated thrombin generation by inhibition of factor XI

The protease thrombin is required for normal hemostasis and pathologic throm- bogenesis. Since the mechanism of co- agulation factor XI (FXI)-dependent thrombus growth remains unclear, we investigated the contribution of FXI to thrombus formation in a primate thrombo- sis model. Pretreatment of baboons with a novel anti-human FXI monoclonal anti- body (aXIMab; 2 mg/kg) inhibited plasma FXI by at least 99% for 10 days, and suppressed thrombin-antithrombin (TAT) complex and β-thromboglobulin (βTG) formation measured immediately down- stream from thrombi forming within collagen-coated vascular grafts. FXI inhi- bition with aXIMab limited platelet and fibrin deposition in 4-mm diameter grafts without an apparent increase in D-dimer release from thrombi, and prevented the occlusion of 2-mm diameter grafts with- out affecting template bleeding times. In comparison, pretreatment with aspirin (32 mg/kg) prolonged bleeding times but failed to prevent graft occlusion, support- ing the concept that FXI blockade may of- fer therapeutic advantages over other an- tithrombotic agents in terms of bleeding complications. In whole blood, aXIMab prevented fibrin formation in a collagen- coated flow chamber, independent of fac- tor XII and factor VII. These data suggest that endogenous FXI contributes to arte- rial thrombus propagation through a strik- ing amplification of thrombin generation at the thrombus luminal surface.