Protein S Deficiency

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Protein S is a vitamin K-dependent anticoagulant protein. The mechanism of protein S has been one of the least understood amongst the vitamin K-dependent coagulation proteins but it has a central role in the regulation of coagulation[1]. A deficiency of protein S predisposes to recurrent venous thromboembolism and fetal loss[2, 3].

Protein S is a co-factor for the action of activated protein C (APC) on activated factor V and activated factor VIII[4]. 60% of protein S in the plasma is inactive, being bound to a binding protein. Protein S deficiency is associated with an increased risk of thrombosis. Both quantitative and qualitative abnormalities of protein S have been identified. Excessive binding of protein S to C4b-binding protein may result in a deficiency of active protein S in the plasma. Three types of protein S deficiency have been described:

  • Type I: a quantitative defect caused by genetic abnormalities which result in the reduced production of structurally normal protein. Both total and free protein S antigen levels are reduced.
  • Type II: a qualitative (functional) defect; however, it has become evident that some individuals with inherited or acquired APC resistance have been incorrectly diagnosed as having type II protein S deficiency[5].
  • Type III deficiency: free protein S antigen is reduced; the total protein S antigen level is normal.

It has been suggested that type I and type III protein S deficiencies may be phenotypical variants of the same genetic disorder[5].

  • Inherited: autosomal dominant.
  • Acute thrombosis.
  • Vitamin K deficiency.
  • Warfarin.
  • Nephrotic syndrome.
  • Liver disease.
  • Antiphospholipid antibodies.
  • Disseminated intravascular coagulation.

Protein S levels fall progressively during pregnancy and are reduced to a lesser extent in women using oestrogen-containing oral contraceptives or hormone replacement therapy[5].

  • Prevalence is 0.03-0.13% of the normal population[6].
  • Prevalence is 3% in patients with venous thromboembolism[5].
  • Available evidence suggests that the effect of protein S deficiency is the result of interaction with other defects[5].
  • The homozygous state is associated with severe life-threatening neonatal purpura fulminans or massive venous thrombosis.
  • Heterozygous deficiency of protein S also increases the risk for developing thrombosis[7].
  • Purpura fulminans (widespread severe purpura with extensive tissue damage and sloughing of skin) in neonates with homozygous defect.
  • Venous thrombosis: during early life in homozygotes; includes deep vein thrombosis, pulmonary embolus, cerebral venous thrombosis.
  • The inherited hypercoagulable syndromes primarily affect veins and only rarely cause arterial thrombosis. There are only conflicting and inconclusive data regarding the implications of protein S deficiency with arterial stroke[8].
  • Family history of thrombosis.
  • Postphlebitic syndrome: chronic complication of thrombosis; pain, swelling, and possibly skin ulceration and induration in the leg.

Other causes of thrombophilia.

  • A family history is essential in assessing the association of a patient's deficiency with the patient's risk of thrombotic disease.
  • Protein S antigen:
    • Over-diagnosis of protein S deficiency (false positives) is a risk.
    • Laboratories can test protein S antigen as total antigen (includes protein-bound fraction) or free protein S antigen. Both free and total protein S are measured by ELISA methods.
    • Total protein S levels rise with age but free protein S levels are not affected by age.
    • The free protein S antigen should be tested for any patient suspected of having deficiencies of protein S and the total protein S assay is not routinely needed.
    • Functional protein S:
      • Difficult to perform and other factors may influence the results - eg, factor V Leiden genetic defect, which is another common cause of hereditary thrombophilia that interferes with protein C function.
      • Functional assay for protein S deficiency should be considered if the other test results are normal and a reliable assay can be performed after excluding other interfering defects.
  • Coagulation tests: including APTT, prothrombin time, fibrinogen level, fibrin degradation, D-dimer test.
  • Tests for other thrombotic risk factors, including antithrombin level, a plasma-based test for APC resistance, or a genetic test for factor V Leiden and prothrombin G20210A. Tests for plasminogen, dysfibrinoginaemia, lupus anticoagulant and an anticardiolipin antibody may be required.
  • Investigation of thrombotic disease, including Doppler, contrast venography, MRI, and chest ventilation/perfusion scan.
  • Inherited: people who are homozygous and many who are heterozygous have an increased risk of thrombosis. However, some people who are heterozygous will never develop a thrombosis.
  • The prognosis therefore depends on early diagnosis, effective measures to prevent thrombosis and effective management of any thrombosis that does occur.
  • The prognosis for non-inherited protein S deficiency will largely depend on the nature of the underlying cause.

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Further reading and references

  1. Castoldi E, Hackeng TM; Regulation of coagulation by protein S. Curr Opin Hematol. 2008 Sep15(5):529-36.

  2. Brouwer JL, Lijfering WM, Ten Kate MK, et al; High long-term absolute risk of recurrent venous thromboembolism in patients with hereditary deficiencies of protein S, protein C or antithrombin. Thromb Haemost. 2009 Jan101(1):93-9.

  3. ten Kate MK, van der Meer J; Protein S deficiency: a clinical perspective. Haemophilia. 2008 Nov14(6):1222-8. doi: 10.1111/j.1365-2516.2008.01775.x. Epub 2008 May 7.

  4. Protein S, PROS1; Online Mendelian Inheritance in Man (OMIM)

  5. Clinical guidelines for testing for heritable thrombophilia; British Committee for Standards in Haematology (January 2010)

  6. Middeldorp S; Is thrombophilia testing useful? Hematology Am Soc Hematol Educ Program. 20112011:150-5. doi: 10.1182/asheducation-2011.1.150.

  7. Marlar RA, Gausman JN; Protein S abnormalities: a diagnostic nightmare. Am J Hematol. 2011 May86(5):418-21. doi: 10.1002/ajh.21992.

  8. Soare AM, Popa C; Deficiencies of proteins C, S and antithrombin and factor V Leiden and the risk of ischemic strokes. J Med Life. 2010 Jul-Sep3(3):235-8.