PatientPlus articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use, so you may find the language more technical than the condition leaflets.
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. A deficiency of Protein S predisposes to recurrent venous thromboembolism and fetal loss.
Protein S is a co-factor for the action of activated Protein C (APC) on activated factor V and activated factor VIII. 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, but it has become evident that some individuals with inherited or acquired APC resistance have been incorrectly diagnosed as having type II Protein S deficiency.
- 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.
Causes of Protein S deficiency
- Inherited: autosomal dominant
- Acute thrombosis
- Vitamin K deficiency
- 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.
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- Prevalence is 0.03-0.13% of the normal population.
- Prevalence is 3% in patients with venous thromboembolism.
- Available evidence suggests that the effect of Protein S deficiency is the result of interaction with other defects.
- 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.
- 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.
- 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, free Protein S 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.
- Patient bleeding risks must be assessed on an individual basis for any prophylactic recommendations, and no single prescription fits all cases.
- Prevention of thrombosis: avoid any drugs that predispose to thrombosis (eg, combined oral contraceptives). See the separate article on Prevention of Venous Thromboembolism.
- Acute thrombosis: see the separate articles on Deep Vein Thrombosis and Pulmonary Embolism.
- Pregnancy: see the separate article on Venous Thromboembolism in Pregnancy.
- 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.
Further reading & references
- Castoldi E, Hackeng TM; Regulation of coagulation by protein S. Curr Opin Hematol. 2008 Sep;15(5):529-36.
- 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 Jan;101(1):93-9.
- ten Kate MK, van der Meer J; Protein S deficiency: a clinical perspective. Haemophilia. 2008 Nov;14(6):1222-8. doi: 10.1111/j.1365-2516.2008.01775.x. Epub 2008 May 7.
- Protein S, PROS1; Online Mendelian Inheritance in Man (OMIM)
- Clinical guidelines for testing for heritable thrombophilia; British Committee for Standards in Haematology (January 2010)
- Middeldorp S; Is thrombophilia testing useful? Hematology Am Soc Hematol Educ Program. 2011;2011:150-5. doi: 10.1182/asheducation-2011.1.150.
- Marlar RA, Gausman JN; Protein S abnormalities: a diagnostic nightmare. Am J Hematol. 2011 May;86(5):418-21. doi: 10.1002/ajh.21992.
- 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-Sep;3(3):235-8.
Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.
Dr Colin Tidy
Dr Colin Tidy
Prof Cathy Jackson