Analysis of the Protein S Gene in Protein S Deficiency

Protein S (PS) is a 71-kDa vitamin K-dependent glycoprotein first identified in human plasma by DiScipio and colleagues in 1977 (1 ), a year after the discovery of the anticoagulant protein C (PC) (2 ,3 ). A few years later, Walker demonstrated that PS acts as a cofactor for activated protein C (APC) in the proteolytic inactivation of the procoagulant factors Va and VIIIa (4 ,5 ) and in 1984, the first families with hereditary PS deficiency and venous thrombotic disease were identified (6 ,7 ). This demonstrated the physiological importance of PS as an antithrombotic protein, which has been further confirmed by the identification of many other families in which the heterozygotes for PS deficiency have an increased risk of developing venous thrombosis in early adulthood (8 –10 ). PS deficient homozygotes with severe thrombotic events and purpura fulminans in the neonatal period have also been described (11 ,12 ). Although the molecular mechanism by which PS enhances APC activity has not yet been completely elucidated (2 ,3 ), it has been proposed that PS increases the affinity of APC for the phospholipid membranes where the inactivation complex will form and the inactivation reactions take place (13 ). PS might also have APC independent anticoagulant properties through direct inhibition of prothrombin and factor X activation (14 –16 ).