Test Catalog

Test ID: PSTF    
Protein S Antigen, Plasma

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

Investigation of patients with a history of thrombosis

Testing Algorithm Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

If this test result is decreased, then total plasma protein S antigen will be performed at an additional charge.

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 variants 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, 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.


Males: 80-160%


<50 years: 70-160%

> or =50 years: 80-160%



Males: 65-160%


<50 years: 50-160%

> or =50 years: 65-160%

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 C4b-binding protein, free protein S may be normal or near the normal adult level (> or =50%). Total protein S reaches adult levels by 90 to 180 days postnatal.

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 C4b-binding protein (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 (Coumadin) effect, but also could reflect congenital protein S deficiency (type I or III).


Vitamin K deficiency, oral anticoagulant therapy, 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; see PRSNG / Protein S Deficiency, PROS1 Gene, Next-Generation Sequencing, Varies.

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


Protein S total 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 >300 IU/mL; may lead to an overestimation of the result

-Antirabbit antibodies; certain subjects may have aberrant results

-Lipemic specimen may lead to an overestimation of level



Free protein S antigen results are potentially affected by:

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

-Hemoglobin >200 mg/dL

-Bilirubin >25 mg/dL

-Triglycerides >1500 mg/dL

-Platelets >10(10)/L

-Rheumatoid factor >900 IU/mL

-Factor V Leiden variant (APC-R)

Supportive Data

A retrospective review of Mayo Special Coagulation Laboratory data found that of 584 patients tested sequentially, only 4 patients demonstrated a pattern of normal free protein S antigen with decreased total protein S antigen. Three of these patients were receiving oral anticoagulant therapy and 1 had liver disease. There were 8 patients with probable congenital protein S deficiency. Of this group, all had significantly reduced levels of free protein S antigen and normal or mildly reduced levels of total protein S antigen. We conclude that omission of routine measurement of total protein S antigen and substituting measurement of free protein S antigen with reflexive testing of total protein S antigen only for decreased free protein S antigen would not decrease clinical sensitivity of this assay system for detecting hereditary protein S deficiency.

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

1. Borgel D, Gandrille S, Aiach M: Protein S deficiency. Thromb Haemost. 1997 July;78(1):351-356

2. De Stefano V, Finazzi G, Mannucci PM: Inherited thrombophilia: pathogenesis, clinical syndromes, and management. Blood. 1996 May 1;87(9):3531-3544

3. Zoller B, Garcia de Frutos P, Dahlback B: Evaluation of the relationship between protein S and C4b-binding protein isoforms in hereditary protein S deficiency demonstrating type I and type III deficiencies to be phenotypic variants of the same genetic disease. Blood. 1995 June 15;85(12):3524-3531

4. Grandrille S, Borgel D, Ireland H, et al: Protein S deficiency: a database of mutations. For the Plasma Coagulation Inhibitors Subcommittee for the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost. 1997 June;77(6):1201-1214

5. Wolf M, Boyer-Neumann C, Peynaud-Debayle E, Marfaing-Koka A, Amiral J, Meyer D: Clinical applications of a direct assay of free protein S antigen using monoclonal antibodies. A study of 59 cases. Blood Coagul Fibrinolysis. 1994 Apr;5(2):187-192

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

7. Goodwin AJ, Rosendaal FR, Kottke-Marchant K, Bovill EG: A review of the technical, diagnostic, and epidemiologic considerations for protein S assays. Arch Pathol Lab Med. 2002 Nov;126(11):1349-1366

8. Sales M, Begona A, Rosen S: IL Test Free Protein S: A diagnostic tool for protein S deficiency. Instrumentation Laboratories; Hemostaisis Monograph

9. Serra J, Sales M, Chitolie A, et al: Multicentre evaluation of IL Test Free PS: a fully automated assay to quantify free protein S. Thromb Haemost. 2002;88:975-983

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