Pharmacologic inhibition of platelet activation and aggregation is a mainstay for reducing the incidence of arterial thrombosis, whereas anticoagulation is the primary approach for preventing the development of venous thrombosis. The effect of standard pharmacologic agents on their reciprocal vessel – anticoagulants on arterial thrombosis and platelet inhibitor on venous thrombosis – is relatively understudied. This study was designed to evaluate murine large-vessel arterial or venous thrombosis under conditions of either fibrin or platelet inhibition. In this study, heparin and clopidogrel were used as standard anticoagulant and platelet inhibitor, respectively, evaluating both large artery and vein thrombosis in mice, using in-vivo fluorescence imaging to simultaneously measure fibrin and platelet levels at the thrombus induction site. Heparin reduced both fibrin and platelet development in both arteries and veins, with stronger influences on fibrin accrual. Clopidogrel had a stronger effect in arteries, reducing both platelet and fibrin accumulation. Clopidogrel also reduced platelet accumulation with venous thrombosis, but the reductions in fibrin formation did not reach statistical significance. These findings illustrate the interactive role of platelet activity and coagulation in the development of large-vessel thrombosis, with inhibition of one thrombotic component showing profound effects on the other component in both arterial and venous thrombosis.