Perspectives of Activated Protein C in the Vasculature: Update on Proposed Roles of the Protein C Pathway

S.   H.   Slofstra; H.   T.   Cate

Abstract

The protein C anticoagulant pathway serves as a vitally important system limiting the coagulation response. The pathway is triggered by thrombin allowing the trombin-thrombomodulin (TM)-endothelial protein C receptor (EPCR) complex to activate protein C. The discovery of the protein C pathway and genetic defects affecting the system in relation to the risk of venous thrombosis directed most research attention towards its anti-coagulatory properties. The observation that activated protein C (APC) has potentially important functions in controlling inflammation and functioning as a natural defence against sepsis, redirected research into its cellular functions. Intracellular signaling effects in endothelial cells induced by APC depend on the presence of the endothelial protein C receptor and protease activated receptor-1 and involves a variety of distinct signal transduction pathways engaged in various biological activities. However, the exact mechanism by which the protein C pathway controls inflammation during sepsis and to what extend the signaling capacity of APC contributes to its pro-survival effects remains elusive. Other essential factors of the protein C pathway, like EPCR and TM may themselves be directly involved in regulating inflammation, underlining the importance of the complete pathway.

Keywords: Activated protein C pathway, regulation of coagulation, intracellular signaling effects, endothelial protein C receptor, thrombomodulin, fibrinolysis, sepsis

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