Test Catalog

Test ID: PST    
Protein S Antigen, Total, Plasma

Useful For Suggests clinical disorders or settings where the test may be helpful

Investigation of patients with a history of thrombosis

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Protein S is a vitamin K-dependent glycoprotein present in platelets and synthesized within the liver and endothelial cells. Protein S works as part of the natural anticoagulant system by acting as a cofactor to activated protein C (APC) in the proteolytic inactivation of procoagulant factors Va and VIIIa. In addition, protein S has direct APC-independent anticoagulant activity by inhibiting formation of the prothrombin and tenase complexes, possibly due to its high affinity for anionic phospholipid membranes. In human plasma, protein S forms a complex with the compliment regulatory protein, C4b-binding protein (C4bBP). Of the total plasma protein S, approximately 60% circulates bound to C4bBP, while the remaining 40% circulates as free protein S. Only free protein S has anticoagulant function. C4bBP is composed of 6 or 7 alpha-chains and 1 or no beta-chain (C4bBP-beta). Different C4bBP isoforms are present in plasma, but only C4bBP-beta binds protein S.


Congenital protein S deficiency is an autosomal dominant disorder that is present in 2% to 6% of patients with venous thrombosis. Patients with protein S deficiency have an approximately 10-fold increased risk of venous thrombosis. In addition they may also experience recurrent miscarriage, complications of pregnancy (preeclampsia, abruptio placentae, intrauterine growth restriction, and stillbirth) and possibly arterial thrombosis.


Three types of protein S deficiency have been described according to the levels of total protein S antigen, free protein S antigen, and protein S activity in plasma. Types 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 C4bBP-beta.


Homozygous protein S deficiency is rare, but can present as neonatal purpura fulminans, reflecting severe disseminated intravascular coagulation/intravascular coagulation and fibrinolysis (DIC/ICF) caused by the absence of plasma protein S.


Acquired deficiency of protein S has causes that are generally of unknown hemostatic significance (ie, uncertain thrombosis risk), and is much more common than hereditary protein S deficiency. Acquired protein S deficiency can present through vitamin K deficiency, oral anticoagulant therapy, liver disease, DIC/ICF, thrombotic thrombocytopenia purpura, pregnancy or estrogen therapy, nephritic syndrome, and sickle cell anemia. As an acute-phase reactant, plasma C4bBP levels increase with acute illness and may cause acquired free protein S deficiency.


Measurement of plasma free protein S antigen is performed as the initial testing for protein S deficiency. When the free protein S antigen level is below the age- and sex-adjusted normal range, reflexive testing will be performed for total plasma protein S antigen.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

Only orderable as part of a profile. For more information see PSTF / Protein S Antigen, Plasma.


Males: 80-160%


<50 years: 70-160%

> or =50 years: 80-160%

Normal, full-term newborn infants or healthy premature infants may have decreased levels of total protein S (15%-50%), but because of low levels of C4bBP, free protein S may be normal or near the normal adult level (> or =50%). Total protein S reaches adult levels by 90-180 days postnatal.*

*See Pediatric Hemostasis References section in Coagulation Guidelines for Specimen Handling and Processing in Special Instructions.

Interpretation Provides information to assist in interpretation of the test results

Protein S values vary widely in the normal population and are age- and sex-dependent.


Types of Heterozygous Protein S Deficiency


Protein S Antigen Free

Protein S Antigen Total

Protein S Activity














Protein S and C4bBP are coordinately regulated, and an increased total protein S antigen and low free protein S antigen most commonly reflect acute or chronic inflammation or illness with an associated increase in plasma C4bBP.


For patients in whom hereditary protein S deficiency is strongly suspected and the free plasma protein S antigen level is normal, consideration should be given to testing of free protein S activity, S_FX / Protein S Activity, Plasma, for detecting type II protein S deficiency (which is rare).


An increased total protein S antigen is of uncertain clinical significance because free protein S antigen levels are usually normal, in such situations. However, the total protein S antigen level may be helpful in distinguishing acquired versus congenital protein S deficiency. High normal or increased total protein S antigen and reduced free protein S antigen suggests acquired protein S deficiency, as may be seen in pregnancy or inflammation. In contrast, low normal or decreased total protein S antigen and reduced free protein S antigen suggests vitamin K deficiency or a warfarin effect, but also could reflect congenital protein S deficiency (type I or III).


Vitamin K deficiency, oral anticoagulant therapy, the presence of liver disease, or disseminated intravascular coagulation/intravascular coagulation and fibrinolysis (DIC/ICF) are common acquired causes of protein S deficiency, which is of uncertain significance when such conditions are present. Concomitant assay of coagulation factor II activity may be helpful in differentiating congenital protein S deficiency from oral anticoagulation effects, but supportive data are currently suboptimal.


Differentiation of congenital and acquired protein S deficiency requires clinical correlation and may require repeated laboratory study of the patient and selected family members in some instances. DNA-based testing may be helpful, but is generally not yet available.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Total protein S antigen results are potentially affected by:

-Heparin (unfractionated or low molecular weight) >4 U/mL

-Hemoglobin >2 g/L

-Bilirubin >100 mg/L; Rheumatoid factor (RF) >300 IU/mL; may lead to an overestimation of the result

-Anti-rabbit antibodies; certain subjects may have aberrant results

-Lipemia: may lead to an overestimation of level

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Laroche P, Plassart V, Amiral J: Rapid quantitative latex immunoassays for diagnosis of thrombotic disorders. Thromb Haemost 1989:62:379  

2. De Stefano V, Finazzi G, Mannucci PM: Inherited thrombophilia: pathogenesis, clinical syndromes, and management. Blood 1996;87:3531-3544

3. Zoller B, Garci a de Frutos P, Dahlback B: Evaluation of the relation between protein S and C4b-binding protein isoform in hereditary protein S deficiency demonstrating type I and type III deficiencies to be phenotypic variants of the same genetic disease. Blood 1995;85:3524-3531

4. Grandrille S, Borgel D, Ireland H, et al: Protein S deficiency: a database of mutations. Thromb Haemost 1997;77:1201

Special Instructions Library of PDFs including pertinent information and forms related to the test