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

Protein S is a co-factor for the action of activated Protein C (APC) on activated factor V and activated factor VIII². 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: is 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.³
• 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 phenotypic variants of the same genetic disorder.³

Causes of Protein S deficiency

• 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.³

Epidemiology

• Prevalence is 0.03-0.13% of the normal population.⁴
• Prevalence is 3% in patients with venous thromboembolism.³
• Available evidence suggests that the effect of Protein S deficiency is the result of interaction with other defects.³

Presentation

• The homozygous or compound heterozygous state is associated with severe life-threatening neonatal purpura fulminans or massive venous 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
• There is no significant association with arterial thrombosis.
• Family history of thrombosis.
• Postphlebitic syndrome: chronic complication of thrombosis; pain, swelling, and possibly skin ulceration and induration in the leg.⁵

Differential diagnosis

Other causes of thrombophilia.

Investigations

• 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, e.g. 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, chest ventilation/perfusion scan.

Management

• Patient bleeding risks must be assessed on an individual basis for any of these prophylactic recommendations, and no single prescription fits all cases.
• Acute thrombosis
  • Heparin therapy:
    • Should be administered for a minimum of 5 days.
  • Warfarin:
    • Can start on day 1 or 2 of heparin therapy. After a minimum of 5 days of heparin therapy, the patient can continue on warfarin alone.⁵
    • 6-9 months of initial treatment with warfarin is recommended for most patients.⁵
    • Patients may be considered for lifelong warfarin after a first thrombotic event if the event was life threatening or occurred in multiple or unusual sites.
    • If precipitated by an event, e.g. trauma or surgery, then warfarin may be discontinued after 9 months.
      Warfarin treatment may lead to warfarin-induced skin necrosis.⁵
• In asymptomatic carriers of Protein S deficiency the goal is prevention of first thrombosis by:
  • Avoiding drugs that predispose to thrombosis, including oral contraceptives.
  • Prophylaxis with heparin for surgery and following trauma.⁵
• In pregnancy, heparin prophylaxis is recommended; most experts would treat from the second trimester through 4-6 weeks postpartum.⁵

Prognosis

• 10 fold increased risk of thrombosis.⁶
• Venous thromboembolism develops in 60-80% of patients who are heterozygous for Protein S deficiency.
• The remaining patients are asymptomatic, and some heterozygotes never develop a thrombosis.⁵

Document references

1. Castoldi E, Hackeng TM; Regulation of coagulation by protein S. Curr Opin Hematol. 2008 Sep;15(5):529-36. [abstract]
2. Protein S Deficiency, Online Mendelian Inheritance in Man (OMIM).
3. Investigation and management of heritable thrombophilia, British Committee for Standards in Haematology (2001)
4. Dykes AC, Walker ID, McMahon AD, et al; A study of Protein S antigen levels in 3788 healthy volunteers: influence of age, Br J Haematol. 2001 Jun;113(3):636-41. [abstract]
5. Godwin JE; Protein S deficiency. eMedicine, November 2007.
6. Thrombophilia, British Heart Foundation (Factfile), 2002.

Acknowledgements