*6.2.1. Protein C (PC)*

PC is a vitamin K dependent serine protease majorly synthesized by liver and its expression has also been identified in epididymis, kidney, lung, brain and male reproductive organ. PC is a single polypeptide of 461 amino acids, consist one Gla domain, a helical aromatic segment, two epidermal growth factor (EGF)-like domains, an activation peptide and a trypsin-like serine protease domain [117]. In the presence of Calcium, PC binds to the endothelial membrane through its Gla domain and interacts with its receptor (endothelial PC receptor: EPCR) [117]. The complex of PC-EPCR facilitates the activation of PC by thrombin, thrombomodulin complex where, thrombin cleaves PC at Arg169-Leu170. This cleavage removes activation peptide from PC. Activated Protein C (APC) cleaves FV and FVIII, and inactivates them. Zymogen PC circulates in the blood at a concentration of 63 nM with a half-life of 2–3 hours whereas, plasma APC concentration is 40 pM with a half-life of 20 min. APC function is increased in presence of Protein S (PS) as PS acts as a cofactor for APC. Reduction of plasma APC antigen levels or loss of APC function is one of the causes for thrombosis. Causes for PC deficiency include congenital/ hereditary deficiencies due to mutations in PC gene. Till date 380 mutations are reported in PC gene (http://www.hgmd.cf.ac.uk/ac/gene.php?gene=PROC). Hereditary PC deficiency is treated by a protein C zymogen concentrate derived from human plasma known as Protexel® (Raosevich et al. 2003). Low plasma PC antigen levels (<10 IU/dl) are also caused by acquired PC deficiency. Acquired PC deficiency is caused by consumption of vitamin K antagonist or severe hepatic dysfunction. A recombinant analogue to the physiologic human activated PC (Drotrecogin alpha activated/ Xigris®) is used to treat the acquired PC deficiency. Thrombosis is also observed due to loss of APC function (APC resistance). APC resistance is observed due to mutations in FV (FV leiden) or APC resistance is acquired by smoking, chronic alcoholism and obesity [118].
