Clinical Information

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.

Congenital protein S deficiency is an autosomal codominant disorder that is present in 1% to 3% of patients with venous thromboembolism. Heterozygous protein S deficiency carriers have, approximately, a 10-fold increased risk of venous thromboembolism. Other phenotypic expressions of heterozygous congenital protein S deficiency include recurrent miscarriage, complications of pregnancy (preeclampsia, abruptio placentae, intrauterine growth restriction, and stillbirth) and, possibly, arterial thrombosis. Three types of heterozygous congenital protein S deficiency have been described according to the levels of total protein S antigen, free protein S antigen, and protein S (APC cofactor) activity in plasma.

 Table. Types of heterozygous protein S deficiency

Type I and III protein S deficiency are much more common than type II (dysfunctional) protein S deficiency. Type III protein S deficiency appears to be partly due to variants within the protein S binding region for C4b-BP.

Homozygous protein S deficiency is rare but can present as neonatal purpura fulminans, reflecting severe intravascular coagulation and fibrinolysis/disseminated intravascular coagulation (ICF/DIC) caused by the absence or near absence of plasma protein S.

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