Protein S 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 S (PS) is the vitamin K dependent, non-enzymatic cofactor for the serine protease activated protein C (APC) which functions as a regulator of secondary haemostasis by inactivating FVa & FVIIIa within a forming clot. Zymogen protein C (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 & 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.Approximately 60% of PS circulates bound to C4b-binding protein and is largely unavailable for functioning as a cofactor for APC. The remainder is termed free protein S (FPS) and is directly available for APC cofactor function. PS also operates as a cofactor for tissue factor pathway inhibitor. Deficiency of PS reduces the effectiveness of haemostasis regulation and tips the balance towards an increased risk of venous thromboembolism. Protein S deficiency, either congenital or acquired, may lead to serious thrombotic events such as thrombophlebitis, deep vein thrombosis or pulmonary embolism. Two-thirds of patients with a congenital deficiency of free protein S (levels < 50% of normal) may present with venous thrombosis in young adulthood. In patients with a history of thrombosis, the prevalence may be as high as 2-6%. Acquired protein S deficiency may be seen during pregnancy, oral contraceptive and oral anticoagulant therapy, liver disease, antiphospholipid syndrome, diabetes mellitus, postoperative complications, septicaemia and various inflammatory syndromes. A decreased protein S activity may be the result of low concentrations or abnormal function of the protein S molecule. The laboratory diagnosis of protein S deficiency may require both quantitative and functional determination. The measurement of plasma levels, of both free and total protein S, and the protein S activity is useful in determining the type of defect in patients with protein S deficiency. Protein S deficiency can be sub-classified on the basis of Total protein S (TPS), FPS and PS activity assays:- Type I - parallel reduction in FPS and TPS. Type II - normal FPS and TPS with decreased activity, indicative of a circulating variant. Type III - clear reduction of FPS with TPS in the reference range.