The antithrombotic effects of warfarin and heparin following infusions of tissue thromboplastin in rabbits: clinical implications.

An animal model for the production of stasis thrombi was employed to obtain the data reported in this study. Rabbits treated with warfarin (1.5 mg/kg/day) exhibited a maximal increase in prothrombin time and decreases in factor VII, factor X, and prothrombin within 48 hr with no additional changes occurring after 10 days of drug administration. In contrast, Xa inhibitory activity was unchanged after 48 hr of warfarin treatment but was significantly increased by the tenth day. When thrombosis was induced by infusions of 60 micrograms of tissue thromboplastin, the warfarin regimen produced an antithrombotic effect by the sixth hour, which increased to significance by day 2 and was further significantly increased by day 10. These three stages correspond to the initial depletion of the vitamin K-dependent clotting factors, the maximal depletion of these proteins, and the maximal increase in Xa inhibitory activity, respectively. Thus these experiments separate the antithrombotic potential of warfarin into two components: an early effect related to the decrease in factor VII and a delayed augmentation of Xa inhibitory acticity. Intravenous heparin alone (5 U/kg) did not protect against infusions of 60 micrograms of tissue thromboplastin but did provide an antithrombotic effect against 45 micrograms of the same infusate. Higher doses of heparin, however, did protect against infusion of 60 micrograms of tissue thromboplastin. After 48 hr of warfarin treatment, 5 U/kg heparin increased protection against 60 micrograms of tissue thromboplastin to a degree equivalent to that provided after 10 days of warfarin therapy alone.