The effects of ximelagatran and warfarin on the prophylaxis of a caval vein thrombosis and bleeding in the anaesthetized rat

The antithrombotic and bleeding properties of the oral direct thrombin inhibitor ximelagatran and of warfarin were investigated in an experimental venous thrombosis and bleeding model in anaesthetized rats. Rats were randomized to receive ximelagatran (1-20 micromol/kg), warfarin (0.20-0.82 micromol/kg), or vehicle (tap water) once daily orally for 4 days before surgery. Thrombosis was induced by partial stenosis and application of ferric chloride to the wall of the abdominal vena cava under anaesthesia. Sixty minutes after thrombus induction, rats were sacrificed, thrombi harvested, and their fresh weight determined. Bleeding was determined as haemoglobin in fluid collected from the abdominal cavity. Blood samples were taken before thrombus induction and sacrifice for determination of coagulation parameters and plasma concentrations of melagatran, the active form of ximelagatran. Ximelagatran and warfarin dose-dependently reduced thrombus formation. The highest doses of ximelagatran and warfarin almost completely prevented thrombus formation; however, the increase in bleeding (versus vehicle) was significantly lower with the highest dose of ximelagatran than with the highest dose of warfarin. The oral direct thrombin inhibitor ximelagatran is thus as at least as effective as warfarin in the prevention of thrombus formation in this animal model, but with a wider separation between antithrombotic effects and bleeding.