Sign in →

Test ID: PSTF Protein S Antigen, Plasma

Reporting Name

Protein S Ag, P

Useful For

Investigation of patients with a history of thrombosis

Profile Information

Test ID Reporting Name Available Separately Always Performed
PSF Protein S Ag, Free, P No Yes

Reflex Tests

Test ID Reporting Name Available Separately Always Performed
PST Protein S Ag, Total, P No No

Testing Algorithm

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

Specimen Type

Plasma Na Cit

Specimen Required

Patient Preparation: Patient must not be receiving heparin or Coumadin. If the patient is being treated with Coumadin, this should be noted. Coumadin will lower protein S.

Specimen Type: Platelet-poor plasma

Collection Container/Tube: Light-blue top (3.2% sodium citrate)

Submission Container/Tube: Plastic vials

Specimen Volume: 1 mL in 2 plastic vials each containing 0.5 mL

Collection Instructions:

1. For complete instructions, see Coagulation Guidelines for Specimen Handling and Processing.
2. Centrifuge, transfer all plasma into a plastic vial, and centrifuge plasma again.
3. Aliquot 0.5 mL of plasma into 2 plastic vials, leaving 0.25 mL in the bottom of centrifuged vial.
4. Freeze plasma immediately (no longer than 4 hours after collection) at -20° C or, ideally ≤-40° C.
5. Send specimens in the same shipping container.

Additional Information: A double-centrifuged specimen is critical for accurate results as platelet contamination may cause spurious results.

Specimen Minimum Volume

0.5 mL

Specimen Stability Information

Specimen Type Temperature Time Special Container
Plasma Na Cit Frozen 14 days

Reference Values


Males: 80-160%


<50 years: 70-160%

≥50 years: 80-160%



Males: 65-160%


<50 years: 50-160%

≥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 (≥50%). Total protein S reaches adult levels by 90 to 180 days postnatal.

Day(s) Performed

Monday through Friday

Test Classification

This test has been modified from the manufacturer's instructions. Its performance characteristics were determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the US Food and Drug Administration.

CPT Code Information


85305-Total (if appropriate)

LOINC Code Information

Test ID Test Order Name Order LOINC Value
PSTF Protein S Ag, P 87557-5


Result ID Test Result Name Result LOINC Value
PSF Protein S Ag, Free, P 27821-8

Clinical Information

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.


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


Table. 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.

Clinical Reference

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; Hemostasis 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 Dec;88(6):975-983

10. Marlar RA, Gausman JN, Tsuda H, Rollins-Raval MA, Brinkman HJM: Recommendations for clinical laboratory testing for S deficiency: Communication from the SCC committee plasma coagulation inhibitors of the ISTH. JThromb Haemost 2021;19:68-74

Report Available

1 to 3 days

Method Name

PSF, PST: Latex Immunoassay (LIA)

Mayo Clinic Laboratories | Hematology Catalog Additional Information: