Description

• Protein S is a vitamin Kdependent glycoprotein, produced mainly in the liver that acts as a cofactor for protein C. It is also produced by megakaryocytes and endothelial cells.
• Protein C becomes activated when thrombin binds to the endothelial receptor, thrombomodulin.
• Activated protein C, with protein S (a cofactor), inactivates clotting factors Va and VIIIa enhancing fibrinolysis.
• Protein S is also able to directly inhibit factors Va, VIIa, and Xa independently of activated protein C.
• Protein S deficiency is a congenital thrombophilia, which increases the risk of thromboembolism.
• It primarily affects the venous system.
• System(s) affected: cardiovascular, hematologic/immunologic, pulmonary

Epidemiology

Incidence

• Mean age of first thrombosis: 2nd decade
• Predominant sex: male = female

Prevalence

• ~0.2% of general population
• Found in ~1% of persons with venous thrombosis embolism (VTE)

Etiology and Pathophysiology

• It is an autosomal dominant disease.
• Only the free form of protein S (30–40%) acts as a cofactor for activated protein C. Protein S reversibly binds to the C4b protein, which leads to conditions in which free protein S is low, but total protein S is normal. These individuals are prone to thrombosis.
• Conditions with reduced protein S: pregnancy, disseminated intravascular coagulation (DIC), liver disease, nephrotic syndrome, HIV, acute thrombosis, and acute varicella-zoster virus infection
• Drugs: oral contraceptives, warfarin, and L-asparaginase chemotherapy

Genetics

• Due to mutations in the PROS1 gene on chromosome 3; most individuals are heterozygous.
• Heterozygotes have an odds ratio (OR) of VTE of 1.6 to 11.5.
• Homozygosity or compound heterozygosity, if untreated, is usually incompatible with adult life.
• Homozygotes can have a fulminant thrombotic event in infancy, termed neonatal purpura fulminans.

Risk Factors

• Oral contraceptives, pregnancy, and the use of hormone replacement therapy (HRT) increase the risk of VTE in patients with protein S deficiency.
• Patients with protein S deficiency and other prothrombotic states have further increased rate of thrombosis.
• Arterial thrombosis is more frequent in patients with protein S deficiency who smoke.
• Patients heterozygous for protein S deficiency who are initiated on warfarin without concomitant heparin can develop warfarin-induced skin necrosis because the half-life of other vitamin Kdependent clotting factors (e.g., prothrombin, factor IX, and factor X) is much longer than the anticoagulant protein S (4 to 8 hours), leading to a transient hypercoagulable state when protein S becomes depleted. These patients develop extremely low levels of protein S and develop necrosis of the skin over central areas of the body such as the breast, abdomen, buttocks, and genitalia.

Pregnancy Considerations
Increased thrombotic risk and pregnancy losses

General Prevention

There are no preventive measures.

Commonly Associated Conditions

• Deep and superficial VTE, often unprovoked
• Up to 50% of homozygotes will have thrombosis.
• Homozygosity is associated with catastrophic thrombotic complications at birth: neonatal purpura fulminans.
• Sites of thrombosis can be unusual, including the mesentery, cerebral veins, and axillary veins.
• Arterial thrombosis is rare but reported in several case reports.
• Skin necrosis in patients treated with warfarin
• Recurrent pregnancy losses