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Coagulation factor V (FV) is distributed in plasma and platelet pools, which are distinguished by physical and functional differences. FV has been extensively studied for its roles in coagulation. The roles of FV in other physiologic pathways remain understudied.Hind limb ischemia was produced in transgenic mice by femoral artery ligation, with different levels of FV gene expression restricted to the plasma or platelets.Hind limb blood flow perfusion in mice with higher platelet FV was significantly increased. The expression of major angiogenesis-related factors was correlated with the level of FV during ischemia. Furthermore, a platelet depletion and transfusion procedure showed that the transfusion of platelets with higher levels of FV into transgenic mice with undetectable platelet FV significantly rescued the ischemia-mediated impairments in blood flow perfusion. Immunohistochemistry analysis also indicated markedly increased capillary formation in the ischemic muscle of mice with higher platelet FV. Moreover, thrombin activity was significantly higher in the mice with higher platelet FV. Platelets expressing higher levels of FV stimulated increased endothelial cell migration. Hind limb blood flow perfusion was significantly blocked by thrombin inhibitor.These findings suggest that platelet-derived FV contributes to the control of angiogenesis and is likely associated with thrombin generation.Platelets and the fibrinolytic system contain many regulators of angiogenesis. Studying the specific roles of individual hemostatic proteins in angiogenesis could lead to novel therapeutic approaches by targeting the angiogenesis functions of the hemostatic proteins. However, the roles of factor V (FV) in angiogenesis have not been reported. This study suggests that platelet-derived FV has an important role in angiogenesis. The stimulation could be partially associated with thrombin generation due to platelet-derived FV.