Protein S Genomics and Proteomics Refine Thrombosis Risk

Protein S is a vitamin K–dependent protein named after Seattle, where it was isolated and characterized. Subsequently recognized as a multifunctional enzyme that plays a critical role in the regulation of coagulation, protein S limits excessive clot formation through its action on clot initiation and clot propagation. As a cofactor for tissue factor pathway inhibitor, protein S limits clot initiation by inactivating extrinsic factor Xa, and as a cofactor for activated protein C, protein S limits clot propagation by inactivating intrinsic factors Va and VIIIa. In individuals with protein S deficiency, regulation of coagulation is impaired and the risk of thrombosis is increased. A clinically important manifestation of protein S deficiency is neonatal purpura fulminans, a rare and potentially fatal disorder characterized by microvascular thrombosis and skin necrosis. The relevance of protein S regulation of coagulation is further underscored by the recent development of a silencing RNA that inhibits protein S as a novel approach to restore hemostasis and reduce bleeding in hemophilia.