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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. 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. 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.
- 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.
- 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.
- 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, 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. No single prescription fits all cases.
- Prevention of thrombosis: avoid any drugs that predispose to thrombosis (eg, combined oral contraceptives). See separate Prevention of Venous Thromboembolism article.
- Acute thrombosis: see separate Deep Vein Thrombosis and Pulmonary Embolism articles.
- Pregnancy: see separate Venous Thromboembolism in Pregnancy article.
- 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 and references
Castoldi E, Hackeng TM; Regulation of coagulation by protein S. Curr Opin Hematol. 2008 Sep15(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 Jan101(1):93-9.
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.
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. 20112011:150-5. doi: 10.1182/asheducation-2011.1.150.
Marlar RA, Gausman JN; Protein S abnormalities: a diagnostic nightmare. Am J Hematol. 2011 May86(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-Sep3(3):235-8.
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