Test Catalog

Test ID: S_FX    
Protein S Activity, Plasma

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

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

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

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

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: 65-160%


<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.

Interpretation Provides information to assist in interpretation of the test results

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.

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

Direct acting oral anticoagulants (eg, direct thrombin inhibitors: DTI, such as dabigatran [Pradaxa], argatroban [Acova], bivalirudin [Angiomax]) and direct factor Xa inhibitors (eg, rivaroxaban [Xarelto], apixaban [Eliquis], edoxaban [Savaysa]) may cause the protein S activity to appear spuriously normal (or elevated), when protein S activity is truly decreased (or normal). Clinical correlation is suggested, and in the absence of anticoagulation therapy, consider repeating the protein S activity and antigen assay.


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. Elective testing for protein S deficiency should be delayed for at least 30 days after cessation of warfarin therapy.

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. 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

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