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Test ID: S_FX Protein S Activity, Plasma

Reporting Name

Protein S Activity, P

Useful For

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

Specimen Type

Plasma Na Cit

Specimen Required

See Coagulation Guidelines for Specimen Handling and Processing in Special Instructions.


Patient Preparation: Patient must not be receiving Coumadin.

Specimen Type: Platelet-poor plasma

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

Submission Container/Tube: Plastic vial

Specimen Volume: 1 mL

Collection Instructions:

1. Centrifuge, transfer all plasma into a plastic vial, and centrifuge plasma again.

2. Aliquot plasma into a plastic vial leaving 0.25 mL in the bottom of centrifuged vial.

3. Freeze specimen immediately (no longer than 4 hours after collection) at ≤-40° C, if possible.

Additional Information:

1. Double-centrifuged specimen is critical for accurate results as platelet contamination may cause spurious results.

2. Each coagulation assay requested should have its own vial.

Specimen Minimum Volume

0.5 mL

Specimen Stability Information

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

Reference Values

Males: 65-160%


<50 years: 50-160%

≥50 years: 65-160%

Newborn infants have normal or near-normal free protein S antigen (≥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 (≥50%) probably is present by age 3 to 6 months.

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


LOINC Code Information

Test ID Test Order Name Order LOINC Value
S_FX Protein S Activity, P 27822-6


Result ID Test Result Name Result LOINC Value
S_FX Protein S Activity, P 27822-6

Clinical Information

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

Protein Activity














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)

-Liver disease


-Thrombotic thrombocytopenic purpura

-Pregnancy, oral contraceptive, or estrogen therapy

-Nephrotic syndrome

-Sickle cell anemia


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-binding protein (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.

Clinical Reference

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

2. Faioni EM: Protein S activity. In Laboratory Techniques in Thrombosis-A Manual. Second edition. Kluwer Academic Publishers, Boston, MA, 1999, pp 153-161

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

4. 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

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

6. 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 November;126(11):1349-1366

7. Yohe S, Olson J: Thrombophilia: Assays and Interpretation. In Laboratory Hematology Practice. Edited by K Kottke-Marchant. Wiley Blackwell Publishing 2012;38:492-508

Report Available

1 to 4 days

Method Name

Optical Clot-Based

Mayo Clinic Laboratories | Hematology Catalog Additional Information: