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Protein S deficiency
Other Resources UpToDate PubMed

Protein S deficiency

Contributors: Nina Haghi MD, Paritosh Prasad MD, Susan Burgin MD
Other Resources UpToDate PubMed


Protein S deficiency is a condition in which there is a quantitative or qualitative defect in vitamin K-dependent coagulation cofactor protein S that impairs the normal fibrinolysis mechanism and results in increased risk of thromboembolism. The prevalence of protein S deficiency is unknown; however, within patients with history of venous thromboembolism (VTE), the prevalence is less than 1%.

Protein S deficiency has autosomal dominant inheritance and results from mutations in the PROS1 gene on chromosome 3. Most patients are heterozygous for the PROS1 mutation; however, homozygous or compound heterozygous patients have been described. Protein S deficiency is further categorized on how the mutation affects total protein S levels, free protein S levels, or protein S function. Type 1 refers to decreased total protein S, free protein S, and reduced function. Type 2 is when total and free protein S levels are normal but function is reduced. Type 3 is isolated free protein S deficiency with normal total protein S and normal function.

The primary presentation of protein S deficiency is the development of VTE, with deep vein thrombosis and pulmonary embolism being the most common presentations.


D68.59 – Other primary thrombophilia

1563006 – Protein S deficiency disease

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Diagnostic Pearls

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Differential Diagnosis & Pitfalls

  • Antiphospholipid antibody syndrome
  • Other inherited thrombophilias (factor V Leiden mutation, protein G20210A mutation, Protein C deficiency, Antithrombin deficiency)
  • Myeloproliferative neoplasm
  • Warfarin use
  • Human immunodeficiency virus disease
  • Nephrotic syndrome
  • Liver disease
  • L-asparaginase chemotherapy
  • Pregnancy
  • Oral hormonal contraceptive use
  • Disseminated intravascular coagulation

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Management Pearls

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Drug Reaction Data

Below is a list of drugs with literature evidence indicating an adverse association with this diagnosis. The list is continually updated through ongoing research and new medication approvals. Click on Citations to sort by number of citations or click on Medication to sort the medications alphabetically.

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Last Reviewed:09/10/2019
Last Updated:01/23/2022
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Protein S deficiency
A medical illustration showing key findings of Protein S deficiency : Ecchymosis, Rash or multiple lesions
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