Comparison of YM150, an Oral, Direct Factor Xa Inhibitor, with Other Antithrombotic Agents in Rodent Venous and Arterial Thrombosis Models.

YM150, an oral, direct factor Xa inhibitor, is currently being evaluated in Phase II studies as prophylaxis for venous thromboembolism in patients undergoing orthopedic surgery. In the present study, we compared the antithrombotic effect of YM150 with the effects of antithrombin-dependent indirect factor Xa inhibitors, enoxaparin and fondaparinux, and a direct thrombin inhibitor, ximelagatran, in ferric chloride (FeCl₃)-induced venous and arterial thrombosis models in rats. We also evaluated the bleeding time in a rat tail transection model. Prior to any experimentation, male Sprague-Dawley rats, which had been fasting for at least 12 h, were anesthetized with urethane (1 g/kg, i.p.) or sodium pentobarbital (50 mg/kg, i.p.). YM150 and ximelagatran were administered intra-duodenally, and both enoxaparin and fondaparinux were given subcutaneously, 30 min prior to induction of thrombus or tail transection. All animals were kept warm with a heating pad during the experiments. Venous and arterial thromboses were produced, respectively, by the 5 min application of 8% FeCl₃ soaked filter paper to the external surface of the inferior vena cava and 35% FeCl₃ soaked filter paper to the abdominal aorta. The venous thrombosis model was supplemented by using a silk thread venous stenosis. To measure bleeding time, the tail was transected 5 mm from its tip. Blood was carefully blotted each 30 sec with a filter paper. Once a blood stain was observed, we defined bleeding as blood flow sustained over 30 sec. Bleeding time was defined as the sum of the bleeding periods during the 60 min observation in each animal. Administration of intra-duodenal YM150 significantly inhibited both venous and arterial thrombus formation at doses of 10 mg/kg or greater, and 3 mg/kg or greater, respectively. This indicated that YM150 promoted an antithrombotic effect at similar dose ranges for venous and arterial thromboses. In contrast, YM150 did not prolong the bleeding time at doses up to 30 mg/kg. Venous thrombus formation was inhibited by subcutaneous enoxaparin at doses of 100 IU/kg or greater and fondaparinux at doses of 0.03 mg/kg or greater. Arterial thrombus formation was inhibited by subcutaneous administration of 1000 IU/kg enoxaparin and 3 mg/kg fondaparinux. The results indicated that 10–100 times higher doses of these antithrombotics were needed to inhibit arterial thrombosis. Furthermore, enoxaparin at doses of 300 IU/kg or greater and fondaparinux at doses of 1 mg/kg or greater, significantly prolonged the bleeding time, suggesting that these two medications may be associated with increased risk of hemorrhage at concentrations used to prevent arterial thrombosis. At doses of 1 mg/kg or greater, intra-duodenal ximelagatran inhibited both venous and arterial thrombus formation. The dose-response curve for ximelagatran tended to be steeper than that for other anticoagulants tested. Antithrombotic doses of ximelagatran (1 mg/kg or greater), produced similar prolongations of bleeding time as those seen with administration of enoxaparin and fondaparinux. In conclusion, YM150, an oral direct factor Xa inhibitor, shows promise as an antithrombotic drug with potentially wider safety margins than current antithrombin-dependent factor Xa inhibitors and a thrombin inhibitor.