Protein S Deficiency

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

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

• ~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

• Is 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 (1)[A].
• Patients with protein S deficiency and other prothrombotic states have further increased rate of thrombosis (1)[A].
• 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 (1)[A].

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 (2)