Protein S Deficiency

Protein S is a vitamin K-dependent anticoagulant protein. It is a co-factor for the action of activated protein C on activated factor V and activated factor VIII¹. 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 deficiency².
• 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 disorder².

• Inherited: autosomal dominant
• Acute thrombosis
• Protein S levels fall progressively during pregnancy and are reduced to a lesser extent in women using oestrogen-containing oral contraceptives or hormone replacement therapy²
• Vitamin K deficiency
• Warfarin
• Nephrotic syndrome
• Liver disease
• Antiphospholipid antibodies
• Disseminated intravascular coagulation

• Prevalence is 2% of the normal population³
• Prevalence is 3% in patients with venous thromboembolism²
• Available evidence suggests that the effect of protein S deficiency is the result of interaction with other defects².

• 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 possiblly skin ulceration and induration in the leg⁴

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, 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, dysfibrinogenemia, lupus anticoagulant and an anticardiolipin antibody may be required.
• Investigation of thrombotic disease including doppler, contrast venography, MRI, chest ventilation/perfusion scan.

• 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 alone⁴.
    • 6-9 months of initial treatment with warfarin is recommended for most patients⁴.
    • 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 necrosis⁴
• Asymptomatic carriers of protein S deficiency
• Avoid drugs that predispose to thrombosis, including oral contraceptives.
• Prophylaxis with heparin for surgery and following trauma.
• In pregnancy, heparin prophylaxis is recommended; most experts would treat from the second trimester through 4-6 weeks postpartum⁴.

• 10 fold increased risk of thrombosis³
• 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 thrombosis⁴.