The Anticoagulant APC Pathway

The Anticoagulant APC Pathway. TF is the major initiator of the coagulation cascade and can be up-regulated under inflammatory conditions. The activation of the coagulation cascade leads to the formation of thrombin (IIa) and fibrin. Thrombin and fibrin are responsible for the pro-inflammatory effects of coagulation. Thrombin signals through PAR-1 to exert its detrimental effects. APC is generated from the circulating protein C zymogen. Thrombin bound to TM activates protein C. Binding of protein C to the EPCR is responsible for a more efficient activation. After dissociation from EPCR, APC can exert its anticoagulant function. APC cleaves the activated coagulation factors FVa and FVIIIa that become inactive. APC further inactivates the PAI-1 resulting in increased fibrinolysis. These anticoagulant and pro-fibrinolytic characteristics are responsible for the indirect protective effects of APC during inflammatory disorders. APC bound to EPCR is responsible for its direct cytoprotective effects involving PAR-1 signalling. APC, activated protein C; EPCR, endothelial protein C receptor; PAI-1, plasminogen activator inhibitor-1; PAR-1, protease-activated receptor-1; t-PA, tissue-type plasminogen activator; TF, tissue factor; TM, thrombomodulin.

Publication

Protective mechanisms of activated protein C in severe inflammatory disorders. (2009) Arne P Neyrinck, et al. Br J Pharmacol. 2009 Oct;158(4):1034-1047. Figure: F1. Homo sapiens

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