Antithrombotic effects of YM-60828, a newly synthesized factor Xa inhibitor, in rat thrombosis models and its effects on bleeding time

1 The effects of YM-60828, a newly synthesized factor Xa inhibitor, were investigated to analyse the relationship between its antithrombotic effects and its prolongation of template bleeding time in rats. YM-60828 was compared with argatroban, heparin and dalteparin. All agents were intravenously administered as a bolus. 2 In ex vivo studies, YM-60828 and argatroban prolonged both prothrombin time and activated partial thromboplastin time in a dose-dependent manner, while heparin and dalteparin prolonged only activated partial thromboplastin time. 3 In a venous thrombosis model, all agents exerted antithrombotic effects in a dose-dependent manner. The ID50 values of YM-60828, argatroban, heparin and dalteparin were 0.008 I mg kg(-1), 0.011 mg kg(-1), 6.3 iu kg(-1) and 4.7 iu kg(-1)? respectively. 4 In an arterio-venous shunt model, all agents exerted antithrombotic effects in a dose-dependent manner. The ID50 values of YM-60828, argatroban, heparin and dalteparin were 0.010 mg kg(-1), 0.011 mg kg(-1), 10 iu kg(-1) and 4.2 iu kg(-1), respectively. 5 In bleeding time studies, all agents prolonged template bleeding time in a dose-dependent manner. ED2 values, the doses causing a 2 fold prolongation of bleeding time in the saline group, of YM-60828, argatroban, heparin and dalteparin were 0.76 mg kg(-1), 0.081 mg kg(-1), 18 iu kg(-1) and 25 iu kg(-1), respectively. 6 The ratio (ED2/ID50) of YM-60828 was more than 30 fold greater than that of heparin and more than 10 fold greater than those of argatroban and dalteparin. 7 These data show that YM-60828 can exert its antithrombotic effects with little prolongation of bleeding time compared with the other currently used anticoagulant agents.