Thrombin generation can be driven by prothrombin activation on the surface of myosin, which binds factors Xa and Va. The intrinsic and extrinsic coagulation pathways converge at the generation of factor Xa, which is the key enzyme that activates prothrombin. As depicted here, both factor Xa and its cofactor, factor Va, bind to myosin, which potently promotes prothrombin activation to generate thrombin. Extensive data in this report lead to this novel scheme for prothrombin activation, which may occur on the surface of myosin independent of any particular cell surface.