Protein S deficiency

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Protein S deficiency
ICD-9 289.81
OMIM 176880
DiseasesDB 10814
MedlinePlus 000559
MeSH D018455

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Roukoz A. Karam, M.D.[2]

Synonyms and keywords: Protein S deficiency disease


Protein S deficiency is an autosomal dominant thrombophilia, which leads to an increased risk of thromboembolic events. Protein S is a vitamin K-dependent glycoprotein and plays a role in anticoagulation. It is mainly a cofactor to the activated protein C (APC), which inactivates coagulation factors Va and VIIIa and thereby controlling the coagulation cascade.

Historical Perspective


Protein S deficiency can be subdivided into three types depending on whether the abnormality affects total protein S level, free protein S level, and/or protein S function:[3][4][5][6]

Type Total Protein S Free Protein S Protein S Function Characteristics Genetics
Type I Classic form Usually results from missense or nonsense mutations
Type II Rare qualitative defect Linked to missense mutations
Type III Quantitative defect Unknown


Coagulation cascade - Source: Wikipedia [7]


Differentiating Protein S Deficiency From Other Diseases

Protein S deficiency must be differentiated from other diseases that cause symptoms of DVT and pulmonary embolism such as:

For more information on differentiating protein S deficiency, click here.

Epidemiology and Demographics


  • Patients of all age groups may be diagnosed with protein S deficiency.[20]
  • It is, however, more commonly observed among patients younger than 40 to 50 years old.



  • Protein S deficiency usually affects the individuals of the Asian race.[20]
  • Caucasian individuals are less likely to develop protein S deficiency.

Risk Factors

  • There are no established risk factors for protein S deficiency.
  • Family history of thrombosis poses increased risk for a mutation.[21]


Natural History, Complications, and Prognosis


Diagnostic Study of Choice

History and Symptoms

Physical Examination

Laboratory Findings



Echocardiography or Ultrasound

CT scan


  • There are no MRI findings associated with protein S deficiency.

Other Imaging Findings

  • There are no other imaging findings associated with protein S deficiency.

Other Diagnostic Studies

  • There are no other diagnostic studies associated with protein S deficiency.


Medical Therapy


  • Surgical intervention is not recommended for the management of protein S deficiency.

Primary Prevention

  • There are no established measures for the primary prevention of protein S deficiency.

Secondary Prevention


  1. Di Scipio RG, Hermodson MA, Yates SG, Davie EW (1977). "A comparison of human prothrombin, factor IX (Christmas factor), factor X (Stuart factor), and protein S." Biochemistry. 16 (4): 698–706. PMID 836809.
  2. Comp PC, Nixon RR, Cooper MR, Esmon CT (1984). "Familial protein S deficiency is associated with recurrent thrombosis". J Clin Invest. 74 (6): 2082–8. doi:10.1172/JCI111632. PMC 425398. PMID 6239877.
  3. Gandrille S, Borgel D, Sala N, Espinosa-Parrilla Y, Simmonds R, Rezende S; et al. (2000). "Protein S deficiency: a database of mutations--summary of the first update". Thromb Haemost. 84 (5): 918. PMID 11127877.
  4. Schwarz HP, Fischer M, Hopmeier P, Batard MA, Griffin JH (1984). "Plasma protein S deficiency in familial thrombotic disease". Blood. 64 (6): 1297–300. PMID 6238642.
  5. Simmonds RE, Ireland H, Kunz G, Lane DA (1996). "Identification of 19 protein S gene mutations in patients with phenotypic protein S deficiency and thrombosis. Protein S Study Group". Blood. 88 (11): 4195–204. PMID 8943854.
  6. Gandrille S, Borgel D, Eschwege-Gufflet V, Aillaud M, Dreyfus M, Matheron C; et al. (1995). "Identification of 15 different candidate causal point mutations and three polymorphisms in 19 patients with protein S deficiency using a scanning method for the analysis of the protein S active gene". Blood. 85 (1): 130–8. PMID 7803790.
  7. "Protein C - Wikipedia".
  8. 8.0 8.1 Esmon CT (1992). "Protein S and protein C Biochemistry, physiology, and clinical manifestation of deficiencies". Trends Cardiovasc Med. 2 (6): 214–9. doi:10.1016/1050-1738(92)90027-P. PMID 21239244.
  9. Rezende SM, Simmonds RE, Lane DA (2004). "Coagulation, inflammation, and apoptosis: different roles for protein S and the protein S-C4b binding protein complex". Blood. 103 (4): 1192–201. doi:10.1182/blood-2003-05-1551. PMID 12907438.
  10. Dahlbäck B (2011). "C4b-binding protein: a forgotten factor in thrombosis and hemostasis". Semin Thromb Hemost. 37 (4): 355–61. doi:10.1055/s-0031-1276584. PMID 21805441.
  11. Ploos van Amstel JK, van der Zanden AL, Bakker E, Reitsma PH, Bertina RM (1987). "Two genes homologous with human protein S cDNA are located on chromosome 3". Thromb Haemost. 58 (4): 982–7. PMID 2895503.
  12. Schmidel DK, Tatro AV, Phelps LG, Tomczak JA, Long GL (1990). "Organization of the human protein S genes". Biochemistry. 29 (34): 7845–52. PMID 2148110.
  13. 13.0 13.1 Marlar RA, Gausman JN (2011). "Protein S abnormalities: a diagnostic nightmare". Am J Hematol. 86 (5): 418–21. doi:10.1002/ajh.21992. PMID 21523802.
  14. Heeb MJ, Mosher D, Griffin JH (1989). "Activation and complexation of protein C and cleavage and decrease of protein S in plasma of patients with intravascular coagulation". Blood. 73 (2): 455–61. PMID 2521800.
  15. Comp PC, Doray D, Patton D, Esmon CT (1986). "An abnormal plasma distribution of protein S occurs in functional protein S deficiency". Blood. 67 (2): 504–8. PMID 2935211.
  16. Matsuzaka T, Tanaka H, Fukuda M, Aoki M, Tsuji Y, Kondoh H (1993). "Relationship between vitamin K dependent coagulation factors and anticoagulants (protein C and protein S) in neonatal vitamin K deficiency". Arch Dis Child. 68 (3 Spec No): 297–302. PMC 1590375. PMID 8466266.
  17. Comp PC, Thurnau GR, Welsh J, Esmon CT (1986). "Functional and immunologic protein S levels are decreased during pregnancy". Blood. 68 (4): 881–5. PMID 2944555.
  18. Gilabert J, Fernandez JA, España F, Aznar J, Estelles A (1988). "Physiological coagulation inhibitors (protein S, protein C and antithrombin III) in severe preeclamptic states and in users of oral contraceptives". Thromb Res. 49 (3): 319–29. PMID 2966452.
  19. Vigano-D'Angelo S, D'Angelo A, Kaufman CE, Sholer C, Esmon CT, Comp PC (1987). "Protein S deficiency occurs in the nephrotic syndrome". Ann Intern Med. 107 (1): 42–7. PMID 2954500.
  20. 20.0 20.1 20.2 20.3 Pintao MC, Ribeiro DD, Bezemer ID, Garcia AA, de Visser MC, Doggen CJ; et al. (2013). "Protein S levels and the risk of venous thrombosis: results from the MEGA case-control study". Blood. 122 (18): 3210–9. doi:10.1182/blood-2013-04-499335. PMID 24014240.
  21. 21.0 21.1 Engesser L, Broekmans AW, Briët E, Brommer EJ, Bertina RM (1987). "Hereditary protein S deficiency: clinical manifestations". Ann Intern Med. 106 (5): 677–82. PMID 2952034.
  22. Wu O, Robertson L, Twaddle S, Lowe G, Clark P, Walker I; et al. (2005). "Screening for thrombophilia in high-risk situations: a meta-analysis and cost-effectiveness analysis". Br J Haematol. 131 (1): 80–90. doi:10.1111/j.1365-2141.2005.05715.x. PMID 16173967.
  23. Wu O, Robertson L, Langhorne P, Twaddle S, Lowe GD, Clark P; et al. (2005). "Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study". Thromb Haemost. 94 (1): 17–25. doi:10.1160/TH04-11-0759. PMID 16113779.
  24. Dalen JE (2008). "Should patients with venous thromboembolism be screened for thrombophilia?". Am J Med. 121 (6): 458–63. doi:10.1016/j.amjmed.2007.10.042. PMID 18501222.
  25. Alshaikh NA, Rosing J, Thomassen MCLGD, Castoldi E, Simioni P, Hackeng TM (2017). "New functional assays to selectively quantify the activated protein C- and tissue factor pathway inhibitor-cofactor activities of protein S in plasma". J Thromb Haemost. 15 (5): 950–960. doi:10.1111/jth.13657. PMID 28211163.
  26. Faioni EM, Franchi F, Asti D, Sacchi E, Bernardi F, Mannucci PM (1993). "Resistance to activated protein C in nine thrombophilic families: interference in a protein S functional assay". Thromb Haemost. 70 (6): 1067–71. PMID 8165605.
  27. Hwang ET, Kang WS, Park JW, Lee JH, Han HJ, Shin SY; et al. (2014). "[Portal-splenic-mesenteric venous thrombosis in a patients with protein S deficiency due to novel PROS1 gene mutation]". Korean J Gastroenterol. 64 (2): 110–4. PMID 25168054.
  28. Simioni P, Zanardi S, Prandoni P, Girolami A (1992). "Combined inherited protein S and heparin co-factor II deficiency in a patient with upper limb thrombosis: a family study". Thromb Res. 67 (1): 23–30. PMID 1440513.
  29. Lijfering WM, Mulder R, ten Kate MK, Veeger NJ, Mulder AB, van der Meer J (2009). "Clinical relevance of decreased free protein S levels: results from a retrospective family cohort study involving 1143 relatives". Blood. 113 (6): 1225–30. doi:10.1182/blood-2008-08-174128. PMID 18945960.

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