A mechanistic model of key platelet functions in inflammatory hemostasis. (A) Proinflammatory mediators, such as exogenous LPS or endogenous cytokines prime platelets to express a distinct set of receptors, facilitating their adhesion to the inflamed vessel wall and migration is initiated by lamellipodium formation. (B) Through migration and haptotaxis-mediated sensing of density gradients of deposited fibrinogen, platelets detect neutrophil transmigrations sites, which cause vascular breaches and subsequent leakage of red blood cells. (C) Exposed ECM proteins trigger further activation, such as degranulation and PA. Single platelets physically plug injury sites and influence leukocyte recruitment through direct receptor interaction and endothelial-platelet cross talk. Secretion of soluble mediators such as angiopoietin-1 (Angpt1) stabilizes endothelial cell junctions, preventing leukocyte transmigration. Plasmatic coagulation factors such as fibrinogen and thrombin are recruited to the surface of PS–positive procoagulant platelets, which foster local fibrin deposition and act as a single hemostatic plug that further seal endothelial microlesions. We note that this mechanistic model has been shown in LPS-induced acute lung injury and inflammation of both the peritoneum and the cremasteric microcirculation; its relevance in other models of inflammatory bleeding is yet to be examined.