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Protein S

Protein S, together with Protein C, constitutes one of the major naturally occurring anticoagulant mechanisms. It is a vitamin K dependent protein that is synthesized predominantly in the liver, but also in endothelial cells, megakaryocytes, Leydig cells and the brain. Protein S acts as a cofactor that enhances the activity of activated Protein C in the degradation of factors Va and VIIIa. Protein S can also directly inhibit prothombinase and tenase by binding factors Va, VIIIa, and Xa.

Heterozygous Protein S deficiency is an uncommon hypercoagulable disorder with a prevalence of 0.2-0.5% in the general population and 1-2% in patients with venous thrombosis. Heterozygous protein S deficiency carriers have approximately a 10 fold increased risk of thrombosis, particularly venous thromboembolism. The first episode of venous thrombosis usually occurs at an average age of 26 years. Fifty percent of individuals with Protein S deficiency have their first thrombosis by age 40 and 85% by age 50. Other clinical manifestations may include recurrent miscarriage, preeclampsia, and abruptio placentae.  Rare cases of arterial thrombosis have been reported. Homozygous Protein S deficiency is rare, but can present as neonatal purpura fulminans.

Acquired protein S deficiency is much more common than the hereditary form and is seen in the following conditions:

  • Inflammatory disorders
  • Pregnancy
  • Estrogen therapy
  • Thrombosis
  • DIC
  • Liver disease
  • Vitamin K deficiency
  • Warfarin therapy

In view of the high incidence of acquired protein S deficiency in hospitalized patients, it is preferable to perform the assay when a patient is clinically stable, ideally several weeks after an acute event. Factor VIII is often increased above 200% many of these conditions and may be useful in deciding if a low Protein S level is inherited or acquired. If the decrease in Protein S is consistent with the amount of factor VIII elevation, the low functional Protein S is likely to be acquired.

Protein S is a vitamin K dependent protein and treatment with warfarin or vitamin K deficiency results in decreased levels. A reliable protein S assay cannot be performed in a patient on warfarin anticoagulation. If anticoagulation cannot be discontinued, consideration should be given to stopping warfarin for 10 days prior to performing the assay, while the patient is temporarily anticoagulated with standard or low molecular weight heparin.

Since acquired deficiencies of Protein S occur frequently in hospitalized patients, it is preferable to perform the assays at a time when the patient is in stable condition, and ideally in remission from thrombotic events. In general, a diagnosis of hereditary deficiency of Protein S should only be made when a low value has been obtained after repeated testing (after a 4-6 week interval), and the possibility of acquired deficiency has been excluded. Testing of family members may be helpful in confirming the diagnosis.

Indications for Protein S testing include the investigation of any patient with unexplained thromboembolism, especially venous, particularly if the thrombotic episodes occur at a relatively young age, are recurrent, or are associated with a positive family history of thrombotic disease.

 In plasma, 60-70% of Protein S is bound to C4b binding protein. The remaining free Protein S is the functionally active component. The binding of Protein S to C4b complicates the measurement and interpretation of Protein S concentration in plasma because C4b binding protein is an acute phase reactant. There are three ways to measure protein S in the plasma:

  • Immunological assays for total S antigen
  • Immunological assay for free protein S antigen
  • Functional assay for protein S activity.

The functional assay has a high rate of false positive results due to the presence of Activated Protein C resistance, Factor Five Leiden, lupus anticoagulant and high concentrations of prothrombin, factor VIIIa, and factor VIIa. Testing for free and total Protein S antigen is more reliable for detection of most cases of Protein S deficiency. Free protein S is more labile than total and may be falsely decreased if specimen handling is not optimal.

Three varieties of hereditary protein S deficiency have been described, as shown in the following table. Type I deficiency is a quantitative deficiency that is identified by low levels of free and total Protein S antigen with low levels of Protein S activity. Type II is a qualitative deficiency characterized by normal levels of total and free antigen with decreased functional activity. Type III deficiency is caused by excessive binding of Protein S to C4b and is characterized by normal to low levels of total Protein S antigen, low free antigen and low functional activity.



Relative Frequency

Total Protein S Antigen

Free Protein S Antigen

Protein S Activity

Type I





Type II





Type III





Reference ranges are:


Reference Range

Protein S Antigen total

70 – 140%

Protein S Antigen free

57 – 120%

Protein S Activity

57 – 140%

Adult Protein S concentrations vary with age, sex, and hormonal status.

  • Protein S levels are higher in men compared with women.
  • Protein S levels increase with age in women, but not men.
  • Protein S levels are lower in women before menopause, while taking oral contraceptives or hormone replacement therapy and during pregnancy.

If screening for Protein S deficiency in pregnancy is necessary, cutoff values for free protein S antigenhave been identified as less than 30% in the second trimester and less than 24% in the third trimester.

In full term infants, the mean Protein S level is 35% and increases to adult levels by one year of age.

Specimen requirement is one pale blue top tube of blood. Specimen should be drawn after a 5 mL plain red top discard tube.  The tube should be delivered to the laboratory within 2 hours. 

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