Effect of vascular injury on inhibition of venous thrombosis with ZK-807834, a direct inhibitor of factor Xa

Inhibition of factor Xa with the small molecule inhibitor ZK-807834 (Mr 527 Da, K _i 0.11 nM) attenuates progression of thrombosis, but the ED ₅₀ is substantially lower for venous compared with arterial thrombosis in experimental animals. To determine whether this reflects differences in the extent of vascular injury, we compared the dose-response of ZK-807834 for inhibition of venous thrombosis induced with a cotton thread and copper wire device in the presence and absence of balloon catheter-induced injury to the vena cava in rabbits. ZK-807834 administration over 2h (total dosages of 0.0023-2.3 (imol kg ^-1, n = 6/group) resulted in dose-dependent reductions in clot weight compared with vehicle controls, but the ED50 was 0.03 (imolkg ^-1 for non-injured veins and 0.42 (irnol kg ^-1 for injured veins. We conclude that vascular injury invokes a tissue factor-mediated response that increases the dose requirements for inhibition of venous thrombosis with ZK-807834.