(A) At the site of arterial injury, platelets roll, adhere, and aggregate to arrest bleeding through integrin α_IIbβ₃. The activation of GPVI by collagen drives integrin activation. Activated platelets release secondary mediators such as ADP and TxA₂, leading to recruitment of circulating platelets and formation of a platelet-fibrin-fibrinogen plug. The resulting thrombus is composed of a densely packed, fibrin-rich core and a looser outer shell of platelets. The diffusion of ligands from the core to the outer shell determines the size of the thrombus. Fibrin and fibrinogen bind to and activate GPVI, which may serve to propagate and stabilize the thrombus. (B) At the site of inflammation, platelets prevent hemorrhaging independent of α_IIbβ₃. The contribution of platelet receptors to the inflammatory hemostasis is stimulus- and organ-dependent. During immune complex–mediated dermatitis, endothelial and stromal cell activation promotes recruitment, activation, and transmigration of neutrophils to the inflamed skin. Single platelets rapidly adhere and seal the neutrophil-mediated vascular damage through GPVI. The bleeding in GPVI-deficient mice is limited by the interaction of CLEC-2 with podoplanin on macrophages and stromal cells. In the absence of both receptors, a severe loss of vascular integrity is observed, with increased bleeding in the inflamed skin.