Protein S


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Subject: Protein S

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  • Protein S is a plasma protein synthesized in the liver and dependent on vitamin K for its functionality. It has an anticoagulant function, serving as a cofactor for activated protein C. Together they inhibit the activities of activated factors V and VIII. Protein S circulates in a free form, free protein S (about 40% of the protein), where the major cofactor function resides, and as bound to complement C4b, bound protein S. The bound form may also play a role in the natural anticoagulation mechanism, this possibility being under active investigation.

  • Normal range: “free” or “total.”

  • Free protein S (measured functionally): 60–140% in males, slightly lower in females but increases with age.

  • Total protein S (measured as antigen by enzyme immunoassay): 60–140%, lower in females but increases with age.

  • During the first year of life, the total PS is low (free PS level is identical with that of adults). Adult levels of total PS are reached by 1 year of life.


  • Protein S, both free and total, should be requested in patients with unprovoked venous thrombosis suspected of congenital thrombophilia.

  • Protein S should not be performed in patients on vitamin K antagonist therapy. It is necessary to wait for 2 weeks after cessation of therapy.

  • It is advisable to request protein S together with protein C, because both are affected by therapy with vitamin K antagonists, but they have different half-lives. Comparing the two facilitates the interpretation.

  • If the functional assay for free protein S is decreased, an immunoassay for free protein S is recommended for confirmation.


Decreased In

  • Congenital condition. Prevalence of the congenital deficiency of protein S is 1 in 500 for the Caucasian population. It predisposes to venous thromboembolism. The rare homozygous type may cause severe neonatal purpura fulminans.

  • Acquired: oral anticoagulants or vitamin K deficiency; pregnancy, hormone replacement therapy, oral contraceptives; young age; liver disease; acute-phase reaction situations (decreased free protein S but increased total protein S); proteinuria; DIC; and l-asparaginase therapy


  • Very elevated (>250%) factor VIII decreases the activity of protein S.

  • High titers of rheumatoid factor may lead to overestimation of protein S.

  • Heparin (up to 1 IU/mL), high bilirubin, or hemolyzed blood do not interfere with measurements, but elevated values may be seen artificially during high-dose heparin therapy.