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Protein S is a vitamin K-dependent plasma glycoprotein synthesized predominantly within the liver. Protein S is also synthesized in endothelial cells and present in platelets. As a part of the plasma anticoagulant system, protein S acts as a necessary cofactor to activated protein C (APC) in the proteolytic inactivation of procoagulant factors Va and VIIIa. About 60% of the total plasma protein S antigen circulates bound to C4b binding protein (C4b-BP), while the remainder circulates as "free" protein S. Only free protein S has anticoagulant activity.
Congenital protein S deficiency is an autosomal codominant disorder that is present in 1% to 3% of patients with venous thromboembolism. Heterozygous protein S deficiency carriers have approximately a 10-fold increased risk of venous thromboembolism. Other phenotypic expressions of heterozygous congenital protein S deficiency include recurrent miscarriage, complications of pregnancy (preeclampsia, abruptio placentae, intrauterine growth restriction, and stillbirth) and possibly arterial thrombosis. Three types of heterozygous congenital protein S deficiency have been described according to the levels of total protein S antigen, free protein S antigen, and protein S (APC cofactor) activity in plasma.
Types of Heterozygous Protein S Deficiency
Protein S Antigen, Free
Protein S Antigen, Total
Type I and III protein S deficiency are much more common than Type II (dysfunctional) protein S deficiency. Type III protein S deficiency appears to be partly due to mutations within the protein S binding region for C4b-BP.
Homozygous protein S deficiency is rare, but can present as neonatal purpura fulminans, reflecting severe intravascular coagulation and fibrinolysis/disseminated intravascular coagulation (ICF/DIC) caused by the absence or near absence of plasma protein S.
Acquired deficiency of protein S is much more common than hereditary protein S deficiency and is generally of unknown hemostatic significance (ie, uncertain thrombosis risk). Among the many causes of acquired protein S deficiency are:
-Vitamin K deficiency
-Oral anticoagulant therapy
-Acute illness (eg, acute thrombosis, recent surgery, or other disorder associated with acute inflammation)
-Thrombotic thrombocytopenic purpura
-Pregnancy, oral contraceptive, or estrogen therapy
-Sickle cell anemia
Second-order testing for diagnosis of congenital or acquired protein S deficiency for example, as an adjunct to initial testing based on results of protein S antigen assay (free protein S antigen, with or without total protein S antigen assay)
Evaluating patients with a history of venous thromboembolism
In Type I and Type III congenital deficiency, free protein S antigen is decreased and protein S functional activity is similarly decreased. In Type II congenital (dysfunctional) protein S deficiency, total and free protein S antigen levels are normal but functional activity is decreased.
Patients with acquired free protein S deficiency associated with inflammation-related increase of C4b-BP typically have decreased free protein S antigen (and protein S activity) and normal (or elevated) total protein S antigen. Acquired protein S deficiency is of uncertain clinical hemostatic significance and is associated with a variety of conditions.
Elevated protein S levels are of uncertain clinical significance.
Very high factor VIII (>250%) activity may cause a spuriously low protein S activity result.
Heparin level >1 U/mL may cause a false-high result.
Activated protein C resistance (eg, heterozygosity or homozygosity for the factor V Leiden mutation) may cause a spuriously low protein S activity result.
The presence of a lupus anticoagulant or a specific factor V inhibitor may cause the protein S activity to appear spuriously normal (or elevated), when protein S activity is truly decreased (or normal).
Coumadin therapy may result in decreased protein S activity (and free protein S antigen).
Acute or chronic inflammation can result in decreased protein S activity (and free protein S antigen).
Interpret protein S activity results with caution when any of the above patient conditions are present.
Protein S antigen assay (free protein S antigen, with concomitant or reflexive total protein S antigen assay), rather than protein S activity (functional) assay, is recommended as the initial testing approach for detecting congenital protein S deficiency, because of the greater variety of patient conditions that can interfere with the accuracy of functional testing as compared to antigen testing.
In general, it is preferable not to test for protein S deficiency during acute illness, pregnancy, or postpartum.
The preferred initial test for protein S is the antigen assay PSTF / Protein S Antigen, Plasma, because other patient conditions can interfere with activity-based assays.
Elective testing for protein S deficiency should be delayed for at least 30 days after cessation of warfarin therapy.
<50 years: 50-160%
> or =50 years: 65-160%
Newborn infants have normal or near-normal free protein S antigen (> or =50%), although total protein S antigen is usually below the adult reference range. There are insufficient data concerning protein S activity in normal neonates, infants, and children; but normal or near-normal activity (> or =50%) probably is present by age 3 to 6 months.
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