Relationship between the antithrombotic effect of YM-75466, a novel factor Xa inhibitor, and coagulation parameters in rats

The relationship between the antithrombotic effects of intravenous infusions of YM-75466 [N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N-[(7-amidino-2-naph thyl)methyl] sulfamoyl]acetic acid monomethanesulfonate), a novel Factor Xa (FXa) inhibitor, and various coagulation parameters (prothrombin time, activated partial thromboplastin time, thrombin-antithrombin III complex (TAT), anti-FXa activity and anti-thrombin activity) in rats was studied and compared with results for heparin. In the arterio-venous shunt model, both agents exerted antithrombotic effects in a dose-dependent manner. Coagulation parameters were studied simultaneously with antithrombotic effects. YM-75466 did not prolong coagulation time even at the dose which exerted significant antithrombotic effects, while it decreased TAT level in plasma in a dose-dependent manner. YM-75466 exerted anti-FXa activity but not anti-thrombin activity. In contrast, heparin prolonged activated partial thromboplastin time in a dose-dependent manner and decreased TAT level in plasma with increasing inhibition of thrombus formation. Heparin exerted both anti-FXa and anti-thrombin activity in a dose-dependent manner. These results suggest that TAT is a suitable parameter for monitoring the antithrombotic effect of YM-75466 in the arterio-venous shunt model in rats and that YM-75466, unlike heparin, exerts its antithrombotic effect through specific inhibition of FXa without any effect on Thrombin.