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Protein S Deficiency Workup

  • Author: Mohammad Muhsin Chisti, MD, FACP; Chief Editor: Perumal Thiagarajan, MD  more...
Updated: Jan 27, 2016

Laboratory Studies

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[5] :

  • 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. [13]

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.

Contributor Information and Disclosures

Mohammad Muhsin Chisti, MD, FACP Assistant Professor of Hematology and Oncology, Karmanos Cancer Institute, Michigan State University College of Human Medicine

Mohammad Muhsin Chisti, MD, FACP is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Clinical Oncology, American Society of Hematology, Medical Society of the State of New York

Disclosure: Nothing to disclose.


Suma Chinta, MD, MBBS Resident Physician, Department of Internal Medicine, St Joseph Mercy Oakland Hospital

Suma Chinta, MD, MBBS is a member of the following medical societies: American College of Physicians, Medical Council of India

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Perumal Thiagarajan, MD Professor, Department of Pathology and Medicine, Baylor College of Medicine; Director, Transfusion Medicine and Hematology Laboratory, Michael E DeBakey Veterans Affairs Medical Center

Perumal Thiagarajan, MD is a member of the following medical societies: American College of Physicians, American Society for Clinical Investigation, Association of American Physicians, American Society for Biochemistry and Molecular Biology, American Heart Association, American Society of Hematology, Royal College of Physicians

Disclosure: Nothing to disclose.


John E Godwin, MD, MS Professor of Medicine, Chief Division of Hematology/Oncology, Associate Director, Simmons Cooper Cancer Institute, Southern Illinois University School of Medicine

John E Godwin, MD, MS is a member of the following medical societies: American Association for the Advancement of Science, American Heart Association, and American Society of Hematology

Disclosure: Nothing to disclose.

  1. Piccin A, Murphy C, Eakins E, Kinsella A, McMahon C, Smith OP, et al. Protein C and free protein S in children with sickle cell anemia. Ann Hematol. 2012 Oct. 91 (10):1669-71. [Medline].

  2. Castoldi E, Hackeng TM. Regulation of coagulation by protein S. Curr Opin Hematol. 2008 Sep. 15(5):529-36. [Medline].

  3. Soare AM, Popa C. Deficiencies of proteins C, S and antithrombin and activated protein C resistance--their involvement in the occurrence of Arterial thromboses. J Med Life. 2010 Oct-Dec. 3(4):412-5. [Medline]. [Full Text].

  4. Castoldi E, Maurissen LF, Tormene D, Spiezia L, Gavasso S, Radu C, et al. Similar hypercoagulable state and thrombosis risk in type I and type III protein S-deficient individuals from families with mixed type I/III protein S deficiency. Haematologica. 2010 Sep. 95(9):1563-71. [Medline]. [Full Text].

  5. Marlar RA, Gausman JN. Protein S abnormalities: a diagnostic nightmare. Am J Hematol. 2011 May. 86(5):418-21. [Medline].

  6. Heeb MJ, Prashun D, Griffin JH, Bouma BN. Plasma protein S contains zinc essential for efficient activated protein C-independent anticoagulant activity and binding to factor Xa, but not for efficient binding to tissue factor pathway inhibitor. FASEB J. 2009 Jul. 23(7):2244-53. [Medline]. [Full Text].

  7. Lijfering WM, Brouwer JL, Veeger NJ, Bank I, Coppens M, Middeldorp S, et al. Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives. Blood. 2009 May 21. 113(21):5314-22. [Medline].

  8. Brouwer JL, Lijfering WM, Ten Kate MK, Kluin-Nelemans HC, Veeger NJ, van der Meer J. High long-term absolute risk of recurrent venous thromboembolism in patients with hereditary deficiencies of protein S, protein C or antithrombin. Thromb Haemost. 2009 Jan. 101(1):93-9. [Medline].

  9. Edlich RF, Cross CL, Dahlstrom JJ, Long WB 3rd. Modern concepts of the diagnosis and treatment of purpura fulminans. J Environ Pathol Toxicol Oncol. 2008. 27(3):191-6. [Medline].

  10. Alvi AR, Khan S, Niazi SK, Ghulam M, Bibi S. Acute mesenteric venous thrombosis: improved outcome with early diagnosis and prompt anticoagulation therapy. Int J Surg. 2009 Jun. 7(3):210-3. [Medline].

  11. Yilmaz S, Gunaydin S. Inherited risk factors in low-risk venous thromboembolism in patients under 45 years. Interact Cardiovasc Thorac Surg. 2014 Oct 17. [Medline].

  12. Klostermeier UC, Limperger V, Kenet G, Kurnik K, Alhenc Gelas M, Finckh U, et al. Role of protein S deficiency in children with venous thromboembolism. An observational international cohort study. Thromb Haemost. 2014 Oct 2. 113(1):[Medline].

  13. Tripodi A, Asti D, Chantarangkul V, Biguzzi E, Mannucci PM. Interference of factor V Leiden on protein S activity: evaluation of a new prothrombin time-based assay. Blood Coagul Fibrinolysis. 2007 Sep. 18(6):543-6. [Medline].

  14. Adachi T. Protein S and congenital protein S deficiency: the most frequent congenital thrombophilia in Japanese. Curr Drug Targets. 2005 Aug. 6(5):585-92. [Medline].

  15. Baker ME, French FS, Joseph DR. Vitamin K-dependent protein S is similar to rat androgen-binding protein. Biochem J. 1987 Apr 1. 243(1):293-6. [Medline].

  16. Brill-Edwards P, Ginsberg JS, Johnston M, Hirsh J. Establishing a therapeutic range for heparin therapy. Ann Intern Med. 1993 Jul 15. 119(2):104-9. [Medline].

  17. Dahlback B, Villoutreix BO. The anticoagulant protein C pathway. FEBS Lett. 2005 Jun 13. 579(15):3310-6. [Medline].

  18. Dahlbäck B, Stenflo J. High molecular weight complex in human plasma between vitamin K-dependent protein S and complement component C4b-binding protein. Proc Natl Acad Sci U S A. 1981 Apr. 78(4):2512-6. [Medline].

  19. Di Scipio RG, Hermodson MA, Yates SG, Davie EW. A comparison of human prothrombin, factor IX (Christmas factor), factor X (Stuart factor), and protein S. Biochemistry. 1977 Feb 22. 16(4):698-706. [Medline].

  20. Francis RB Jr. Protein S deficiency in sickle cell anemia. J Lab Clin Med. 1988 May. 111(5):571-6. [Medline].

  21. Giri TK, Villoutreix BO, Wallqvist A, Dahlbäck B, de Frutos PG. Topological studies of the amino terminal modules of vitamin K-dependent protein S using monoclonal antibody epitope mapping and molecular modeling. Thromb Haemost. 1998 Nov. 80(5):798-804. [Medline].

  22. Gomez E, Poort SR, Bertina RM, Reitsma PH. Identification of eight point mutations in protein S deficiency type I--analysis of 15 pedigrees. Thromb Haemost. 1995 May. 73(5):750-5. [Medline].

  23. Hackeng TM, Rosing J. Protein S as cofactor for TFPI. Arterioscler Thromb Vasc Biol. 2009 Aug 6. epub ahead of print. [Medline].

  24. Hackeng TM, van 't Veer C, Meijers JC, Bouma BN. Human protein S inhibits prothrombinase complex activity on endothelial cells and platelets via direct interactions with factors Va and Xa. J Biol Chem. 1994 Aug 19. 269(33):21051-8. [Medline].

  25. Heeb MJ, Rosing J, Bakker HM, Fernandez JA, Tans G, Griffin JH. Protein S binds to and inhibits factor Xa. Proc Natl Acad Sci U S A. 1994 Mar 29. 91(7):2728-32. [Medline].

  26. Hillarp A, Dahlback B. Novel subunit in C4b-binding protein required for protein S binding. J Biol Chem. 1988 Sep 5. 263(25):12759-64. [Medline].

  27. Ploos van Amstel HK, Huisman MV, Reitsma PH, Wouter ten Cate J, Bertina RM. Partial protein S gene deletion in a family with hereditary thrombophilia. Blood. 1989 Feb. 73(2):479-83. [Medline].

  28. Ploos van Amstel HK, Reitsma PH, van der Logt CP, Bertina RM. Intron-exon organization of the active human protein S gene PS alpha and its pseudogene PS beta: duplication and silencing during primate evolution. Biochemistry. 1990 Aug 28. 29(34):7853-61. [Medline].

  29. Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med. 1995 Apr 6. 332(14):912-7. [Medline].

  30. Schmidel DK, Nelson RM, Broxson EH Jr, Comp PC, Marlar RA, Long GL. A 5.3-kb deletion including exon XIII of the protein S alpha gene occurs in two protein S-deficient families. Blood. 1991 Feb 1. 77(3):551-9. [Medline].

  31. Schmidel DK, Tatro AV, Phelps LG, Tomczak JA, Long GL. Organization of the human protein S genes. Biochemistry. 1990 Aug 28. 29(34):7845-52. [Medline].

  32. Siddique RM, Siddique MI, Connors AF Jr, Rimm AA. Thirty-day case-fatality rates for pulmonary embolism in the elderly. Arch Intern Med. 1996 Nov 11. 156(20):2343-7. [Medline].

  33. Simmonds RE, Zöller B, Ireland H, Thompson E, de Frutos PG, Dahlbäck B, et al. Genetic and phenotypic analysis of a large (122-member) protein S-deficient kindred provides an explanation for the familial coexistence of type I and type III plasma phenotypes. Blood. 1997 Jun 15. 89(12):4364-70. [Medline].

  34. Tait RC, Walker ID, Reitsma PH, Islam SI, McCall F, Poort SR, et al. Prevalence of protein C deficiency in the healthy population. Thromb Haemost. 1995 Jan. 73(1):87-93. [Medline].

  35. Walker MC, Garner PR, Keely EJ, Rock GA, Reis MD. Changes in activated protein C resistance during normal pregnancy. Am J Obstet Gynecol. 1997 Jul. 177(1):162-9. [Medline].

  36. Watkins PC, Eddy R, Fukushima Y, Byers MG, Cohen EH, Dackowski WR, et al. The gene for protein S maps near the centromere of human chromosome 3. Blood. 1988 Jan. 71(1):238-41. [Medline].

  37. Zhang D, Hao J, Yang N. Protein C and D-dimer are related to portal vein thrombosis in patients with liver cirrhosis. J Gastroenterol Hepatol. 2009 Aug 3. epub ahead of print. [Medline].

A simplified outline of the protein C system.
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