Inhibition of Factor XI Decreases Thrombin Production and Prevents Vascular Occlusion in Experimental Thrombosis in Primates. (2007)

Abstract Animal studies suggest that factor XI (FXI) substantially contributes to thrombus growth and stability, presumably by promoting thrombin generation upon the flow surface of thrombi. To further elucidate the role of FXI in thrombus development, we investigated the effect of FXI inhibition in baboons on the time course of thrombogenic marker generation and platelet activation, as measured in samples taken locally from the peripheral blood intraluminal boundary layer (IBL) that superfused forming experimental thrombi. We also tested whether FXI inhibition would reduce thrombus stability under flow and/or prevent thrombotic vessel occlusion. Thrombogenesis was initiated by placement of collagen coated clinical vascular grafts (polytetrafluoroethylene, 4 mm i.d. and 2 mm i.d.) as extension segments within a chronic arteriovenous shunt. Blood flow was controlled at 100 mL/min, producing wall shear rates of 265 sec−1 and 2120 sec−1 within the 4 mm and 2 mm devices, respectively. Deposition of 111In-labelled platelets onto collagen was measured by gamma camera imaging for 60 min. Fibrin accumulation was measured using 125I-labelled fibrinogen. Template bleeding times were used to assess hemostatic impairment. FXI was blocked by a single bolus i.v. injection of an anti-human FXI monoclonal antibody (aXIMab, 2 mg/kg), which neutralized more than 95% of circulating FXI-related procoagulant activity for at least 7 days. aXIMab administration reduced platelet and fibrin deposition by 39–59% and 83–89%, respectively (N=3), in the 4 mm grafts vs. untreated controls (N=8). IBL thrombin/antithrombin III (TAT) and β-thromboglobulin (βTG) levels were reduced by aXIMab treatment at all time points after initiation of thrombus, up to 38-fold and 7-fold respectively. In control experiments, local TAT and βTG levels peaked at about 30 min and then decreased, correlating with the time course of platelet deposition. Inhibition of FXI significantly reduced thrombus stability under high shear, enhancing distal thrombo-embolization with large reductions in thrombus volume. In contrast, significant thromboembolization was not seen in control experiments. While 2 mm grafts consistently occluded within 30 min in control studies, thrombo-occlusion was prevented by aXIMab treatment over the 1 hour study interval. Local D-dimer levels were not affected by FXI blockade, nor were bleeding times prolonged by the antibody. These findings demonstrate that inhibition of FXI can dramatically attenuate thrombin production at sites of forming thrombus, thereby reducing platelet activation, fibrin formation and vascular occlusion without compromising primary hemostasis as assessed by measurements of bleeding time. The lack of D-dimer elevation over the study interval did not, however, support a mechanism of enhanced thrombolysis during FXI inhibition in primates. Since inhibition of FXI with aXIMab prevented graft occlusion without apparent compromise of hemostasis in primates, this strategy may prove an attractive one for antithrombotic applications in man.