Protein S Deficiency

(See also Overview of Thrombotic Disorders.)

Protein S, a vitamin K–dependent protein, is a cofactor for activated protein C–mediated cleavage of factors Va and VIIIa. Protein S and protein C are, therefore, components of a natural plasma anticoagulant system. Free protein S is the active form unbound to the protein S carrier molecule, C4-binding protein, and serves as the primary cofactor for activated protein C in the inactivation of factors Va and VIIIa. Reduced levels of protein S, thereby inhibit coagulation.

Heterozygous deficiency of plasma protein S predisposes to venous thrombosis. Heterozygous protein S deficiency is similar to heterozygous protein C deficiency in genetic transmission, prevalence, laboratory testing, treatment, and precautions.

Homozygous deficiency of protein S can cause neonatal purpura fulminans that is clinically indistinguishable from that caused by homozygous deficiency of protein C.

Acquired deficiencies of protein C (and, soon thereafter, protein S) occur in patients with:

• Disseminated intravascular coagulation (DIC)

• Liver disease

• Vitamin K deficiency

• Warfarin therapyWarfarin therapy

Protein S deficiency can also occur when patients use estrogen replacement therapy or contraception and during pregnancy due to the influence of estrogen on free protein S levels. Estrogen increases C4-binding protein, which binds to free protein S and reduces its level Inflammation results in decreased protein S activity through a similar mechanism.

Diagnosis is based on antigenic assays of total or free plasma protein S (free protein S is the form unbound to the protein S carrier molecule, C4-binding protein). Protein S activity can also be measured, but the assay is technically difficult and is associated with a high false-positive rate (10 to 15%) so more reproducible antigen assays are favored.