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*Although another gene, ''PROS2,'' has been isolated on the same chromosome 3, it does not seem to have any relevance and has since been classified as a pseudogene.<ref name="pmid2895503">{{cite journal| author=Ploos van Amstel JK, van der Zanden AL, Bakker E, Reitsma PH, Bertina RM| title=Two genes homologous with human protein S cDNA are located on chromosome 3. | journal=Thromb Haemost | year= 1987 | volume= 58 | issue= 4 | pages= 982-7 | pmid=2895503 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2895503  }} </ref><ref name="pmid2148110">{{cite journal| author=Schmidel DK, Tatro AV, Phelps LG, Tomczak JA, Long GL| title=Organization of the human protein S genes. | journal=Biochemistry | year= 1990 | volume= 29 | issue= 34 | pages= 7845-52 | pmid=2148110 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2148110  }} </ref>
*Although another gene, ''PROS2,'' has been isolated on the same chromosome 3, it does not seem to have any relevance and has since been classified as a pseudogene.<ref name="pmid2895503">{{cite journal| author=Ploos van Amstel JK, van der Zanden AL, Bakker E, Reitsma PH, Bertina RM| title=Two genes homologous with human protein S cDNA are located on chromosome 3. | journal=Thromb Haemost | year= 1987 | volume= 58 | issue= 4 | pages= 982-7 | pmid=2895503 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2895503  }} </ref><ref name="pmid2148110">{{cite journal| author=Schmidel DK, Tatro AV, Phelps LG, Tomczak JA, Long GL| title=Organization of the human protein S genes. | journal=Biochemistry | year= 1990 | volume= 29 | issue= 34 | pages= 7845-52 | pmid=2148110 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2148110  }} </ref>
*In addition to the common hereditary form of protein S deficiency, there are rare circumstances in which acquired causes can result in diminished protein S levels:
*In addition to the common hereditary form of protein S deficiency, there are rare circumstances in which acquired causes can result in diminished protein S levels:
**Pregnancy
**Pregnancy<ref name="pmid2944555">{{cite journal| author=Comp PC, Thurnau GR, Welsh J, Esmon CT| title=Functional and immunologic protein S levels are decreased during pregnancy. | journal=Blood | year= 1986 | volume= 68 | issue= 4 | pages= 881-5 | pmid=2944555 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2944555  }} </ref>
**Liver disease
**Liver disease<ref name="pmid2935211">{{cite journal| author=Comp PC, Doray D, Patton D, Esmon CT| title=An abnormal plasma distribution of protein S occurs in functional protein S deficiency. | journal=Blood | year= 1986 | volume= 67 | issue= 2 | pages= 504-8 | pmid=2935211 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2935211  }} </ref>
**Vitamin K deficiency
**Vitamin K deficiency
**Oral hormonal contraceptives
**Oral hormonal contraceptives<ref name="pmid2966452">{{cite journal| author=Gilabert J, Fernandez JA, España F, Aznar J, Estelles A| title=Physiological coagulation inhibitors (protein S, protein C and antithrombin III) in severe preeclamptic states and in users of oral contraceptives. | journal=Thromb Res | year= 1988 | volume= 49 | issue= 3 | pages= 319-29 | pmid=2966452 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2966452  }} </ref>
**Disseminated intravascular disease
**Disseminated intravascular disease<ref name="pmid2521800">{{cite journal| author=Heeb MJ, Mosher D, Griffin JH| title=Activation and complexation of protein C and cleavage and decrease of protein S in plasma of patients with intravascular coagulation. | journal=Blood | year= 1989 | volume= 73 | issue= 2 | pages= 455-61 | pmid=2521800 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2521800  }} </ref>
**Nephrotic syndrome
**Nephrotic syndrome<ref name="pmid2954500">{{cite journal| author=Vigano-D'Angelo S, D'Angelo A, Kaufman CE, Sholer C, Esmon CT, Comp PC| title=Protein S deficiency occurs in the nephrotic syndrome. | journal=Ann Intern Med | year= 1987 | volume= 107 | issue= 1 | pages= 42-7 | pmid=2954500 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2954500  }} </ref>
**
 
==Clinical Features==   
==Clinical Features==   


Revision as of 19:43, 20 September 2018


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

Overview

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 VIIa and thereby controlling the coagulation cascade.

Historical Perspective

  • Protein S was first discovered and purified in Seattle, Washington in 1979, and it was arbitrarily named protein S after the city it was discovered in.
  • The function of this protein was still unknown; however, it was hypothesized that protein S plays a role in activating protein C.
  • Protein S deficiency was first discovered in 1984 when two related individuals with recurrent thromboembolic events and normal coagulation tests were studied. At the time, protein C deficiency was usually associated with recurrent familial thrombosis. These individuals were found to have diminished anticoagulation activity with normal coagulation tests (including a normal protein C level), and when purified human protein S was added to their plasma, effective anticoagulation was restored. [1]

Classification

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:[2]

  • Type I: Reduced total protein S, free protein S, and protein S function

It is the classic form of hereditary protein S deficiency. Total protein S levels drop to approximately 50% of normal values while free protein S levels collapse to almost 15% of the normal. On a genetic level, type I deficiency usually results from missense or nonsense mutations. On few occasions, microinsertions, microdeletions, and splice site mutations have occurred with this type. [3]

  • Type II: Normal total and free protein S, reduced protein S function

This form results from a qualitative defect and is very rare. The genetics behind this type isn't certain; however, some reports have linked it to missense mutations affecting the protein S's ability to bind to the activated protein C. [4] [5]

  • Type III: Normal total protein S, reduced free protein S and protein S function

This is a quantitative defect.

Type Total Protein S Free Protein S Protein S Function
I ↓ ↓ ↓
II ↔ ↔ ↓
III ↔ ↓ ↓

Pathophysiology

Coagulation cascade - Source: Wikipedia [6]
  • Protein S is a natural anticoagulant that works with other proteins to regulate coagulation in the body.
  • After it gets produced by the hepatocytes, endothelial cells, and megakaryocytes, protein S undergoes activation via vitamin K-dependent gamma-carboxylation. [7]
    • The vitamin K-dependent gamma-carboxyalse enzyme acts by modifying the glutamic acid residues in protein S to gamma-carboxyglutamic acid residues.
    • These gamma-carboxyglutamic acid residues are needed to ensure calcium-dependent binding to membrane surfaces.
  • The now mature and activated protein S will circulate in the blood in two states:
    • Free protein S
      • This form constitutes 30 to 40 percent of the total protein S in the body.
      • It is the only form that will take part in the coagulation cascade.[8]
    • C4b-bound protein S
      • There is a high affinity interaction between protein S and C4b-binding protein.
      • C4b-binding protein is a complement regulator; hence, it is responsible for controlling the activity of protein S.
      • Around 70 percent of circulating protein S is in the bound form. [9]
  • The activated free protein S acts as a cofactor to activated protein C, and with the help of phospholipids and Ca2+, it inactivates procoagulant factor Va and factor VIIIa thereby reducing thrombin formation.[7]
  • Protein S deficiency is a hereditary disease that results from mutations in the PROS1 gene, located on chromosome 3.
  • This disease usually occurs due to heterozygous gene mutations in the PROS1 gene; however, rare cases of homozygous protein S deficiencies have been reported.
  • Although another gene, PROS2, has been isolated on the same chromosome 3, it does not seem to have any relevance and has since been classified as a pseudogene.[10][11]
  • In addition to the common hereditary form of protein S deficiency, there are rare circumstances in which acquired causes can result in diminished protein S levels:
    • Pregnancy[12]
    • Liver disease[13]
    • Vitamin K deficiency
    • Oral hormonal contraceptives[14]
    • Disseminated intravascular disease[15]
    • Nephrotic syndrome[16]

Clinical Features

Differentiating [disease name] from other Diseases

Epidemiology and Demographics

  • The prevalence of protein S deficiency in the general population is unknown.
  • However, its prevalence in individuals with a history of venous thromboembolism is approximately 900 per 100,000 individuals worldwide. [17]

Age

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

Gender

  • There is no difference in the prevalence of the disease between men and women.

Race

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

Risk Factors

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Criteria

Symptoms

Physical Examination

Laboratory Findings

Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Surgery

Prevention

References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ "Protein C - Wikipedia".
  7. ↑ 7.0 7.1 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
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