Background: While it is established that mechanical heart valves (MHVs) damage blood elements during leakage and forward flow, the role in thrombus formation of platelet activation by high shear flow geometries remains unclear. In this study, continuously recalcified blood was used to measure the effects of blood flow through orifices, which model MHVs, on the generation of procoagulant thrombin and the resulting formation of thrombus. The contribution of platelets to this process was also assessed. Method of Approach: 200, 400, 800, and orifices simulated the hinge region of bileaflet MHVs, and 200, 400, and wide slits modeled the centerline where the two leaflets meet when the MHV is closed. To assess activation of coagulation during blood recirculation, samples were withdrawn over and the plasmas assayed for thrombin-antithrombin-III (TAT) levels. Model geometries were also inspected visually. Results: The 200 and round orifices induced significant TAT generation and thrombosis over the study interval. In contrast, thrombin generation by the slit orifices, and by the 800 and round orifices, was negligible. In additional experiments with nonrecalcified or platelet-depleted blood, TAT levels were markedly reduced versus the studies with fully anticoagulated whole blood . Conclusions: Using the present method, a significant increase in TAT concentration was found for 200 and orifices, but not 800 and orifices, indicating that these flow geometries exhibit a critical threshold for activation of coagulation and resulting formation of thrombus. Markedly lower TAT levels were produced in studies with platelet-depleted blood, documenting a key role for platelets in the thrombotic process.