{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nEndothelial protein C receptor (EPCR, encoded by PROCR) is pivotal in regulating vascular homeostasis. By binding protein C, EPCR accelerates its activation by the thrombin–thrombomodulin complex so that activated protein C (APC) can exert potent anticoagulant, anti‐inflammatory, and cytoprotective effects. EPCR engagement also modulates protease‐activated receptor 1 (PAR1) signaling—shifting it from disruptive, proinflammatory cascades toward protective responses that stabilize endothelial barrier function and regulate intracellular Ca²⁺ flux. In addition, EPCR can serve as a platform for interactions with coagulation factors such as factor VIIa, thereby contributing to receptor‐mediated endocytosis and further downstream cell signaling responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its central role in coagulation, EPCR is exploited by pathogens and immune cells alike. In severe malaria, specific PfEMP1 variants expressed by Plasmodium falciparum–infected erythrocytes bind EPCR, thereby interfering with its natural protein C interactions and contributing to microvascular coagulation and endothelial dysfunction. In parallel, EPCR is recognized by certain γδ T‐cell receptors—linking coagulation pathways with immunosurveillance of stressed or infected tissues—and also binds coagulation factor VIIa to facilitate its endocytosis. These multifaceted interactions underscore EPCR’s role at the nexus of immunity, infection, and hemostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEPCR function is further refined by regulated proteolytic shedding and genetic variation. Metalloproteinase‐mediated cleavage releases soluble EPCR (sEPCR) into the circulation—a process that is influenced by inflammatory cytokines and can impair local protein C activation. Several PROCR gene polymorphisms (including the Ser219Gly “A3” variant) markedly affect EPCR expression and the extent of its shedding, thereby modulating risks for thrombotic disorders, myocardial infarction, and adverse pregnancy outcomes. In addition, autoantibodies against EPCR and alternative EPCR splice isoforms further contribute to its complex regulation on both endothelial and epithelial cells, affecting local hemostatic balance and tissue repair."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "36"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "James H Finigan, Steven M Dudek, Patrick A Singleton, et al. 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