Protein S Deficiency
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- Protein S is a vitamin K–dependent 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
- 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, oral contraceptives, warfarin, disseminated intravascular coagulation (DIC), liver disease, nephrotic syndrome, HIV, L-asparaginase chemotherapy, acute thrombosis, and acute varicella-zoster virus infection
- 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.
- Oral contraceptives, pregnancy, and the use of 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 K–dependent 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].
Increased thrombotic risk and pregnancy losses
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)