Protein S Deficiency Workup
- Author: Mohammad Muhsin Chisti, MD, FACP; Chief Editor: Perumal Thiagarajan, MD more...
Protein S deficiency is diagnosed using laboratory tests for the protein S antigen and by using other tests for functional protein S activity (based on clotting assays), as follows :
Protein S antigen: Laboratories can test protein S antigen as total antigen (ie, protein S bound to C4BP plus free protein) or free protein S antigen. The free form of protein S has functional activity, and researchers have developed assays specifically for the free protein S antigen. Both free and total protein S are measured by ELISA methods in the laboratory.
Functional protein S: Assays for functional protein S are indirect and are based on prolongation of blood clotting by the generation of APC and its function in the assay. These functional tests are difficult to perform. In addition, the tests introduce several other factors that can alter the interpretation of test results. Most importantly, a falsely low protein S functional assay value can be observed in patients with factor V Leiden genetic defect, which is another common cause of hereditary thrombophilia that interferes with protein C function. Some new commercial methods for determining protein S deficiency can measure activity in factor V Leiden patients accurately after dilution of test plasma. 
Several clinical conditions affect the blood levels of protein S—both antigenic and functional assays. As one would expect, vitamin K deficiency, liver disease, or antagonism with warfarin reduces protein S levels. In the setting of acute thrombosis, protein S levels fall, sometimes into the deficient range. Pregnancy also results in lower blood levels of protein S, especially as measured by functional assays. As noted previously in the section on genetics of protein S, total protein S levels actually rise with age. Free protein S levels are not affected by age.
Based on the measurement of free and total protein S antigen and functional protein S activity, scientists classify protein S deficiency into the following three phenotypes, using the classification proposed at the 1991 meeting of the Scientific Subcommittee of the International Society on Thrombosis and Haemostasis in Munich, Germany:
Type I deficiency is characterized by a decrease in the total protein S antigen and free protein S antigen together (quantitative deficiency)
Type II deficiency is characterized by normal total and free antigen levels but reduced protein S activity (functional deficiency)
Type III deficiency is characterized by low free protein S levels, whereas the total plasma concentration of protein S is normal
Although reports document a few type II deficiencies, they are rare. The most common types are I and III. The distinction between type I and type III has no clinical implications. In both type I and type III deficiencies, free protein S levels are reduced.
Physicians should request free protein S antigen testing for any patient suspected of having deficiencies of protein S because this test detects most cases (ie, type I or III), and the use of a total protein S assay is not routinely needed. Consider use of the functional assay for protein S deficiency if the other test results are normal and a reliable assay can be performed after excluding other interfering defects.
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