American Society for Clinical Laboratory Science

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September 13, 2021

Do not order a protein S activity assay for measuring protein S function. Instead, order free protein S antigen.

Thrombophilia has numerous causes, including protein S deficiency, of which there are 3 recognized types. Type I and type III are quantitative defects while type II is a qualitative defect.

Types of Heterozygous Protein S Deficiency

Type Free Protein S Antigen  Total Protein S Antigen  Functional Protein S Activity
 I Decreased  Decreased Decreased
II Normal  Normal Decreased
III Decreased Normal Decreased

Type II is extremely rare and is not considered a risk factor for thrombophilia. While functional protein S activity is commonly measured to detect
protein S deficiency, there are problems with this test. It is a clot-based assay and has a large coefficient of variation; the test is affected by patients
who have factor V Leiden mutation or lupus anticoagulant. On the contrary, free protein S antigen assay is more specific for detecting true deficiencies
and only free protein S has anticoagulant activity. Measuring free protein S antigen provides more reliable results, when testing for protein S deficiency
is clinically warranted.

These items are provided solely for informational purposes and are not intended as a substitute for consultation with a medical professional. Patients with any specific questions about the items on this list or their individual situation should consult their physician.

How The List Was Created

George Fritsma, MS, MLS (ASCP), and the late Cindy Johns, MS, MLS (ASCP) hosted a plenary presentation “Enhancing Laboratory Communication to Reduce Extra-analytical Errors” at the ASCLS Clinical Laboratory Educators’ Conference in Boston in February 2017. Their talk referenced the ABIMF Choosing Wisely initiative. Subsequent discussions resulted in the ASCLS Board of Directors appointing a Choosing Wisely task force that evolved to a standing committee. The committee is composed of ASCLS members representing all medical laboratory science disciplines.

The committee collaborated with respective ASCLS Scientific Assemblies in developing and reviewing recommendations, which the Board of Directors reviewed and accepted for publication. The recommendations were subsequently reviewed in collaboration with the ASCP Test Utilization Steering Committee prior to submission.



American Society for Clinical Laboratory Science (ASCLS) recommendations were developed under the leadership of ASCLS’s Choosing Wisely Committee and the ASCLS president and executive vice president. The Committee examined numerous options based on evidence available through an extensive review of  the literature and member proposals. Subject matter experts from the ASCLS Scientific Assemblies reviewed and recommended approval of their respective recommendations, which are subsequently approved by the ASCLS Board of Directors. The recommendations were subsequently reviewed in collaboration with the ASCP Test Utilization Steering Committee prior to submission.


Gandrille S, Borgel D et al. Protein S deficiency: a database of mutations–summary of the first update. Plasma Coagulation Inhibitors Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis Thromb Haemost. 2000;84(5):918.

Bertina RM et al. Heerlen polymorphism of protein S, an immunologic polymorphism due to dimorphism of residue 460. Blood. 1990;76(3):538.

Faioni EM, Franchi F et al. Resistance to activated protein C in nine thrombophilic families: interference in a protein S functional assay. Thromb Haemost. 1993;70(6):1067.

Chandler WL. Protein S deficiency. LabMed. 2017. Goodwin AJ, Rosendaal FR et al. A review of the technical, diagnostic, and epidemiological considerations for protein S assays. Arch Pathol Lab Med. 2002.126:1349-1366.