How is protein S deficiency diagnosed?

Updated: Jan 03, 2021
  • Author: Mohammad Muhsin Chisti, MD, FACP; Chief Editor: Perumal Thiagarajan, MD  more...
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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 [32] :

  • 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 enzyme-linked immunosorbent assay (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 activated protein C (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, 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. [33, 34]

Several clinical conditions affect the blood levels of protein S on 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 Overview/Pathophysiology, total protein S levels actually rise with age. Free protein S levels are not affected by age.

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