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Protein S Deficiency

Protein S Deficiency is a topic covered in the 5-Minute Clinical Consult.

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Basics

Description

  • Protein S is a vitamin K–dependent glycoprotein, produced mainly in 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 (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
  • 0.3% of general population
  • Found in 3% of persons with venous thrombosis (VT)

Etiology and Pathophysiology

  • It is an autosomal dominant disease.
  • Only the free form of protein S (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; DIC, liver disease, nephrotic syndrome, HIV, L-asparaginase chemotherapy, and acute thrombosis
  • Transient autoantibodies can develop against protein S in patients with acute varicella (1)[C].

Genetics
  • Is due to heterozygous mutations in the PROS1 gene
  • Heterozygotes have an odds ratio (OR) of VT 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 HRT increase the risk of VT in patients with protein S deficiency (2)[A].
  • Patients with protein S deficiency and other prothrombotic states, have further increased rate of thrombosis (2)[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 (2)[A].

Pregnancy Considerations
Increased thrombotic risk and pregnancy losses

General Prevention

There are no preventive measures.

Commonly Associated Conditions

  • Deep and superficial VT, 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 (3)
  • High prevalence of mental disorders was described (4).

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Citation

Stephens, Mark B., et al., editors. "Protein S Deficiency." 5-Minute Clinical Consult, 27th ed., Wolters Kluwer, 2019. Medicine Central, im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116493/all/Protein_S_Deficiency.
Protein S Deficiency. In: Stephens MB, Golding J, Baldor RA, et al, eds. 5-Minute Clinical Consult. 27th ed. Wolters Kluwer; 2019. https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116493/all/Protein_S_Deficiency. Accessed April 24, 2019.
Protein S Deficiency. (2019). In Stephens, M. B., Golding, J., Baldor, R. A., & Domino, F. J. (Eds.), 5-Minute Clinical Consult. Available from https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116493/all/Protein_S_Deficiency
Protein S Deficiency [Internet]. In: Stephens MB, Golding J, Baldor RA, Domino FJ, editors. 5-Minute Clinical Consult. Wolters Kluwer; 2019. [cited 2019 April 24]. Available from: https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116493/all/Protein_S_Deficiency.
* Article titles in AMA citation format should be in sentence-case
TY - ELEC T1 - Protein S Deficiency ID - 116493 ED - Stephens,Mark B, ED - Golding,Jeremy, ED - Baldor,Robert A, ED - Domino,Frank J, BT - 5-Minute Clinical Consult, Updating UR - https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116493/all/Protein_S_Deficiency PB - Wolters Kluwer ET - 27 DB - Medicine Central DP - Unbound Medicine ER -