Version July 2025
ALGORITHM —
INITIAL EVALUATION —
Plasma protein S is measured as part of an evaluation for inherited thrombophilia in selected patients with venous thromboembolism (VTE) and features suggestive of an inherited thrombophilia, such as a strong family history of VTE, known familial protein S deficiency, first VTE before age 50, VTE in an unusual site (eg, portal, mesenteric, or cerebral vein), or recurrent VTE. Individuals who have not had a VTE but have a known family history of protein S deficiency are also candidates for testing. (See "Protein S deficiency", section on 'Overview of evaluation and diagnosis'.)
Protein S deficiency can be inherited or acquired. Protein S deficiency is the most difficult of the hereditary thrombophilias to diagnose with certainty. Genetic testing for the multiple mutations that cause protein S deficiency is not readily available outside of a research setting. There are different tests to measure protein S (eg, free protein S antigen, total protein S antigen, protein S functional assay). However, protein S levels in the general population vary widely, and there is no ideal cutoff level that distinguishes between individuals with and without protein S deficiency. The value used depends on the assay, the clinical setting, and the age of the patient. In addition, acquired causes of low protein S (table 1) are more common than inherited causes and should be considered prior to inferring that the protein S deficiency is hereditary. (See "Protein S deficiency".)
Free protein S antigen level (measured with an immunoassay) is the preferred screening test for diagnosing hereditary protein S deficiency. Obtain hematology consultation to help interpret abnormal test results and to guide further evaluation (see "Protein S deficiency", section on 'Diagnosis' and "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors", section on 'Patients without a family history of VTE'):
●If the initial test result was a low free protein S antigen and testing was performed in an asymptomatic individual with a positive family history for protein S deficiency, the patient has protein S deficiency, and there is no need to repeat the test. Provide education about VTE prophylaxis. Inform first-degree relatives about diagnosis and need for testing if not yet performed.
●If the initial test result was a low free protein S antigen and the family history is negative for protein S deficiency, obtain a repeat free protein S antigen level.
●If a different assay (eg, total protein S antigen or protein S functional activity) shows reduced protein S, obtain a free protein S antigen to confirm the results.
The timing of testing for protein S deficiency is important. Testing may be deferred if the results do not immediately impact management:
●Vitamin K antagonists (eg, warfarin) may reduce protein S levels:
•Obtain a free protein S antigen after cessation of vitamin K antagonist for at least two weeks.
•For individuals who cannot discontinue their vitamin K antagonist and whose management would be altered by the results of protein S testing, it may be possible to substitute a different anticoagulant (eg, heparin, a direct oral anticoagulant) for two weeks and repeat the testing.
●Acute thrombosis, liver disease, pregnancy, or any comorbid illness that causes an acute phase response can lower the level of free protein S, resulting in erroneous diagnosis of hereditary protein S deficiency:
•Obtain free protein S antigen testing after recovery from any condition that can cause a decrease in protein S concentration (table 1).
•If this is not possible, it may be reasonable to retest the individual now and base subsequent decisions on the results and how the diagnosis would impact management. As an example, a normal free protein S antigen in an individual with liver or kidney disease excludes the diagnosis of protein S deficiency. For those with borderline or low protein S levels on retesting, other approaches to testing (eg, testing family members) may be discussed with the consulting hematologist.
REFERENCE RANGE —
Protein S levels in the general population vary widely. The lower limit of normal depends on the assay, the clinical setting, and the age of the patient. Levels of total or free protein S antigen <60 to 65 international units/dL in an individual with VTE or a strong family history suggest deficiency. Levels of free protein S <33 units/dL are predictive of increased VTE risk in an individual with a first VTE and a negative family history. Interpretation of a specific result should be based upon the reference range reported by the laboratory.
CITATIONS —
The supporting references for this content are accessible in the linked topics.
