Protein S (PROS) is a vitamin K-dependent plasma protein that inhibits blood clotting by serving as a cofactor for activated protein C (APC) and facilitates clearance of early apoptotic cells. In the plasma, circulating Protein S becomes inactive upon complexing with C4b-binding protein (C4BP); 60-70% of Protein S circulates in complex with C4BP. Calcium-dependent association of C4BP-Protein S with apoptotic cells influences the regulation of complement activation. Protein S has APC-independent anticoagulant activity through direct inhibition of prothrombin activation via interactions with Factor X A, Factor V A and phospholipids. Autosomal dominant Protein S deficiency (levels 15 to 37% of normal) correlates with severe recurrent venous thrombosis.