Antithrombotic Activity of the Novel Oral Anticoagulant, Tecarfarin [Sodium 3-[4-((1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yloxy) carbonyl) benzyl]-2-oxo-2H-chromen-4-olate] in Animal Models

The antithrombotic activity of tecarfarin, a novel orally active vitamin K epoxide reductase inhibitor, was assessed in canine and rabbit thrombosis models. In dogs, once-daily oral doses of 0.5 mg/kg tecarfarin selectively reduced the levels of the vitamin K-dependent coagulation factors (factors II, VII, IX, and X) and prolonged the prothrombin time (PT). A 4 to 7 day course of oral tecarfarin (0.05 - 0.5 mg/kg) prolonged the PT by 3 to 5-fold and reduced thrombus formation in arterial and venous segments subjected to a combination of electrical injury and flow-limiting constriction. To compare the effects of tecarfarin with those of warfarin, rabbits were given once-daily oral doses of 1 mg/kg tecarfarin, 1.5 mg/kg warfarin, or saline for 2 days. After verifying increases in the PT with tecarfarin and warfarin, blood loss from standardized ear incisions was measured to assess hemorrhagic potential. Then, after intravenous injection of 125I-labeled rabbit fibrinogen, thrombosis was induced in an isolated jugular vein segment by a combination of balloon catheter-induced endothelial denudation and venous occlusion. Compared with the saline control, both tecarfarin and warfarin prolonged the PT, increased blood loss from the ear incisions, and attenuated thrombus formation. Thus, like warfarin, tecarfarin attenuates venous and arterial thrombus formation in animal models by reducing the levels of the vitamin K-dependent coagulation factors.