Melagatran with aspirin and/or clopidogrel was evaluated for prevention of arterial thrombosis in a model of vessel wall injury. Thirty-five dogs were randomized to receive placebo (n=14), aspirin (7 to 8 mg/kg, p.o. q12 h for three doses with the last dose administered 12 hours before surgery, n=7), clopidogrel (1 mg/kg p.o. QDx3, n=7), or aspirin+clopidogrel (n=7). The right carotid artery (RCA) was the control vessel, whereas the left carotid artery (LCA) was subjected to injury after administration of Melagatran (0.033 mg/kg i.v.+0.1 mg/kg/h). Clopidogrel, but not aspirin pretreatment, increased time (135.6+/-13.5 vs. 116.1+/-27.8 minutes) to RCA thrombosis versus placebo (88.1+/-10.5 minutes). Melagatran prolonged time to occlusion (min) in the LCA (192.4+/-10.9) versus the placebo-treated RCA (88.1+/-10.5). Addition of Melagatran plus aspirin or clopidogrel prevented formation of occlusive thrombosis, in all LCAs. A two-fold increase in tongue bleeding time was observed after aspirin+Melagatran (178.6+/-14.7 to 347.1+/-87.3 seconds) or clopidogrel+Melagatran (279.9+/-97.3 to 437.1+/-142.5 seconds). However, the combination of aspirin and clopidogrel prevented occlusive thrombosis in the RCA and the subsequent addition of Melagatran did not further increase bleeding time. The combination of Melagatran+aspirin or clopidogrel can reduce formation of occlusive arterial thrombosis without eliciting a significant increase in bleeding-time.