Protein S deficiency

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 coagulation¹. A deficiency of protein S predisposes to recurrent venous thromboembolism and fetal loss²³.

Protein S is a co-factor for the action of activated protein C (APC) on activated factor V and activated factor VIII⁴. 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 deficiency⁵.

• 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 disorder⁵.

Etiologia

• Inherited: autosomal dominant.

• Acute thrombosis.

• Vitamin K deficiency.

• Warfarin.

• Nephrotic syndrome.

• Doença hepática.

• 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 therapy⁵.

• Prevalence is 0.03-0.13% of the normal population⁶.

• Prevalence is 3% in patients with venous thromboembolism⁵.

• Available evidence suggests that the effect of protein S deficiency is the result of interaction with other defects⁵.

• 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 thrombosis⁷.

• 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 stroke⁸.

• Family history of thrombosis.

• Postphlebitic syndrome: chronic complication of thrombosis; pain, swelling, and possibly skin ulceration and induration in the leg.

Outras causas de 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 .

• Acute thrombosis: see separate Deep Vein Thrombosis e Pulmonary Embolism artigos.

• Pregnancy: see separate 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.