Hypercoagulability can occur after severe tissue injury, that is likely related to tissue factor exposure and impaired endothelial release of tissue plasminogen activator (tPA). In contrast, when shock and hypoperfusion occur, activation of the protein C pathway and endothelial tPA release induce a shift from a procoagulant to a hypocoagulable and hyperfibrinolytic state with a high risk of bleeding. Both thrombotic and bleeding phenotypes are associated with increased mortality and are influenced by the extent and severity of tissue injury and degree of hemorrhagic shock. Response to trauma is a complex, dynamic process in which risk can shift from bleeding to thrombosis depending on the injury pattern, hemostatic treatment, individual responses, genetic predisposition, and comorbidities. Based on this body of knowledge, we will review and consider future directions for the management of severely injured trauma patients.