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*Protein S deficiency is a hereditary disease that results from mutations in the ''PROS1'' gene, located on chromosome 3.
*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.
*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.
*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.
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*
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*

Revision as of 18:48, 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.

Clinical Features

Differentiating [disease name] from other Diseases

Epidemiology and Demographics

  • The prevalence of protein S deficiency is approximately 90 per 100,000 individuals worldwide. [10]

Age

  • The age of onset of thromboembolic events varies by heterozygous vs homozygous.
    • The thromboembolic events seen in heterozygous protein S deficiency usually occurs in individuals younger that 40-50 years of age.
    • The homozygous patients have neonatal purpura fulminans at birth.

Gender

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

Race

  • Current data shows that protein S deficiency affects Asians 5 to 10 times more than caucasians.

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. 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.