Anti-Inflammatory Actions of the Anticoagulant, Activated Protein C

Protein C is a vitamin K–dependent zymogen, discovered in 1976 in bovine plasma (Stenflo, 1976). It is derived from the human PROC gene on chromosome 2 (2q13-q14) which contains 9 exons (Rezaie, 1993). Post-translational modifications include -hydroxylation at Asp71, N-linked glycosylation at residues 97, 248, 313 and 329 and ┛-carboxylation of 9 glutamic acid residues which forms the Gla domain at the amino terminus. Human protein C is 62kD protein and consists of 419 amino acids. The four major moieties that make up the protein C molecule are a Gla domain, two epidermal growth factor (EGF)like regions, a small activation peptide, and an active serine protease domain (Griffin, 2005). Mature 62 000 Da human protein C is cleaved by a furin-like endoprotease that releases Lys156–Arg157 before secretion from liver cells. Protein C is activated on the endothelial surface when thrombin binds to thrombomodulin and cleaves protein C’s activation peptide. This conversion to activated protein C (APC) is augmented by endothelial cell protein C receptor (EPCR) (Fukudome & Esmon, 1994). Protein C circulates in plasma at 70 nM whereas APC is present in much lower concentrations (40 pM or ~ 2.3 ng/mL) (Gruber & Griffin, 1992). APC was first recognized as an anticoagulant. In the presence of its cofactor, protein S, APC degrades the coagulation factors Va and VIIIa and inhibits thrombin generation. The light chain provides anticoagulant activity by having highly specific protein–protein interactions with factors Va and VIIIa followed by proteolytic inactivation of factor Va by cleavage at Arg (506) and Arg (306) and of factor VIIIa by cleavage at Arg (336) and Arg (562) (Zlokovic & Griffin, 2011). In addition, APC promotes fibrinolysis by binding to plasminogen activator inhibitor which prevents inhibition of plasminogen conversion to plasmin. The significance of APC as an anticoagulant is reflected by the findings that deficiencies in protein C result in severe familial disorders of thrombosis (Baker & Bick, 1999). Replenishment of protein C/APC in patients with systemic or local hypercoagulation can reverse the abnormality.