Protein C activity

The complex orchestration of cellular and molecular participants of haemostasis achieves a crucial yet fine balance of procoagulant and anticoagulant mechanisms. Deficiencies of natural anticoagulant regulators of secondary haemostasis, such as antithrombin, protein C and protein S, and gain of function mutations in genes for FII and FV, are heritable disorders that can shift this balance and increase the risk of venous thromboembolic disease.Protein C (PC) is the vitamin K dependent zymogen of the serine protease activated protein C (APC), which functions as a regulator of secondary haemostasis by inactivating FVa & FVIIIa within a forming clot. PC attaches to vessel endothelium via a specific receptor, endothelial PC receptor (EPCR) and then migrates across the endothelial surface 'in search' of its activator. If a clot is being formed, some of the thrombin leaks onto the endothelial surface and encounters membrane-bound thrombomodulin (TM), whereupon they form a complex that induces a conformational change in thrombin such that it loses procoagulant activity and instead adopts an anticoagulant role by activating PC. The APC/EPCR complex then dissociates from the TM-throbmin complex and the APC is released to migrate onto the surface of an activated platelet. PC & its non-enzymatic cofactor protein S (PS) are vitamin K dependent and so bind to surface phospholipid and PS orientates the active site of PC above the platelet surface to facilitate inactivation of substrates by cleavage of a small number of peptide bonds. Inactivation of FVIIIa additionally requires zymogen FV to operate synergistically with PS in a cofactor role.

Deficiency of PC can be qualitative or quantitative and reduces the effectiveness of haemostasis regulation, thus tipping the balance towards an increased risk of venous thromboembolism.