Effects of a factor Xa inhibitor, DX-9065a, in a novel rabbit model of venous thrombosis

The objective of this study was to evaluate the effects of DX-9065a, a nonp eptide, direct inhibitor of factor Xa (FXa), in a novel experimental model of venous thrombosis. The experiments were conducted on anesthetized rabbit s in which a veno-venous shunt with cotton threads was inserted into the ve na cava. DX-9065a was administered intravenously to the rabbits as an initi al bolus followed by a maintenance infusion using the following dosing sche dules: DX-I: 0.25 mg/kg + 3 mu g/kg/min.; DX-II: 0.75 mg/kg + 9 mu g/kg/min .; DX-III: 1.5 mg/kg + 18 mu g/kg/min.; DX-IV: 3.0 mg/kg + 36 mu g/kg/min.; DX-V: 6.0 mg/kg + 72 mu g/kg/min. DX-9065a induced a dose-dependent increa se in the time to occlusion and a dose-dependent decrease in thrombus weigh t. Because of the unique character of the model, we were also able to show a dose-dependent increase in blood flow through the shunt. In addition, the re were dose-dependent increases in prothrombin time (PT) and activated coa gulation time (ACT) with more variable responses in the activated partial t hromboplastin time (APTT). DX-9065a had little effect on thrombin time (TT) or bleeding time at all doses tested. In conclusion, dose-dependent antith rombotic efficacy was documented with DX-9065a in this new model of venous thrombosis. Although the in vivo potency of the compound was not striking, the results support the utility of FXa inhibition in venous thrombosis and demonstrate the utility of this experimental model for evaluating the effic acy of novel anticoagulants.