Formation of a hemostatic clot is essential for minimizing blood loss upon injury and is mediated, in part, by tightly regulated activity of and crosstalk between platelets and plasma proteases of blood coagulation. Dysregulation of this otherwise protective clotting mechanism provokes thrombosis, which is caused by pathologic intravascular progression of some hemostatic mechanisms, and manifests as the common underlying pathology of major cardiovascular diseases. There remains an unmet clinical need for safer therapeutics that are effective while also preserving hemostasis. The present research defines signaling mechanisms underlying the role of platelet and coagulation proteases in hemostasis and vascular inflammation.