Protein S is a vitamin K-dependent plasma glycoprotein synthesized predominantly within the liver. Protein S is also synthesized in endothelial cells and present in platelets. As a part of the plasma anticoagulant system, protein S acts as a necessary cofactor to activated protein C (APC) in the proteolytic inactivation of procoagulant factors Va and VIIIa. About 60% of the total plasma protein S antigen circulates bound to C4b binding protein (C4b-BP), while the remainder circulates as free protein S. Only free protein S has anticoagulant activity. Acquired deficiency of protein S is much more common than hereditary protein S deficiency and is generally of unknown hemostatic significance (ie, uncertain thrombosis risk). Among the many causes of acquired protein S deficiency are: Vitamin K deficiency, Oral anticoagulant therapy, Acute illness (eg, acute thrombosis, recent surgery, or other disorder associated with acute inflammation), Liver disease, ICF/DIC, Thrombotic thrombocytopenic purpura, Pregnancy, oral contraceptive, or estrogen therapy, Nephrotic syndrome, Sickle cell anemia.