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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.
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.