Protein S Deficiency
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- Protein S is a vitamin K–dependent factor made principally by the liver that acts as a cofactor for protein C.
- Protein C becomes activated when thrombin binds to the endothelial receptor, thrombomodulin.
- Activated protein C, with protein S as a cofactor, inactivates clotting factors Va and VIIIa, and it enhances fibrinolysis.
- Protein S is also able to directly inhibit factors Va, VIIa, and Xa independently of activated protein C.
- Patients with protein S deficiency have a thrombotic disorder that primarily affects the venous system.
- System(s) affected: Cardiovascular; Hematologic/Lymphatic/Immunologic; Pulmonary
- Predominant age: Mean age of 1st thrombosis is the 2nd decade.
- Predominant sex: Male = Female
- 0.3% of normal individuals
- Found in 3% of persons with VT
- Oral contraceptives, pregnancy, and the use of HRT increase the risk of VT in patients with protein S deficiency (1)[A].
- Patients with protein S deficiency and another prothrombotic state, such as factor V Leiden, have further increased rates of thrombosis (1)[A].
- Patients heterozygous for protein S deficiency who are begun 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 (4–8 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].
Autosomal dominant. Heterozygotes have an OR of VT of 1.6–11.5. Arterial thrombosis is more frequent in patients with protein S deficiency who smoke. Homozygotes can have a fulminant thrombotic event in infancy, termed neonatal purpura fulminans. Homozygosity or compound heterozygosity, if untreated, is usually incompatible with adult life.
Increased thrombotic risk in patients with protein C deficiency
Since protein S deficiency is a congenital disease, there are no preventive measures.
- >131 mutations in the protein S gene leading to an inherited protein S deficiency have been described. Protein S reversibly binds to the C4b-binding protein. Only the free form acts as a cofactor for activated protein C. This leads to conditions in which free protein S is low, but total protein S is normal. These individuals are prone to thrombosis.
- Acquired protein S deficiency from decreased free protein S can occur during pregnancy; in patients taking oral contraceptives or warfarin; and in DIC, liver disease, nephrotic syndrome, inflammation, L-asparaginase chemotherapy, and acute thrombosis.
- Transient autoantibodies can develop to protein S in patients with acute varicella (2)[C].
Commonly Associated Conditions
- Deep and superficial VT, often spontaneous
- 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 can be seen in patients on warfarin.