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Mature gamma-carboxylated protein S circulates in two states: free, and bound to the complement component C4b-binding protein (C4b-BP). The free form comprises 30 to 40 percent of total protein S and is the only form of protein S that has cofactor activity for activated protein C
Mature gamma-carboxylated protein S circulates in two states: free, and bound to the complement component C4b-binding protein (C4b-BP). The free form comprises 30 to 40 percent of total protein S and is the only form of protein S that has cofactor activity for activated protein C


[[File:Coagulation cascade.png|none|thumb|600px|Coagulation cascade - Source: Wikipedia]]
[[File:Coagulation cascade.png|none|thumb|600px|Coagulation cascade - Source: Wikipedia <ref name="urlProtein C - Wikipedia">{{cite web |url=https://en.wikipedia.org/wiki/Protein_C |title=Protein C - Wikipedia |format= |work= |accessdate=}}</ref>]]


==Clinical Features==   
==Clinical Features==   

Revision as of 20:03, 19 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:

  • 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. [2]

  • 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. [3] [4]

  • 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

Protein S is produced by the hepatocytes, endothelial cells, and megakaryocytes. It has two methods of action in coagulation; however, it has to first get activated via vitamin K-dependent gamma-carboxylation.


Protein S is a vitamin K-dependent glycoprotein, but it is not a zymogen of a serine protease enzyme. It serves as a cofactor for activated protein C, which inactivates procoagulant factors Va and VIIIa, reducing thrombin generation. Protein S also serves as a cofactor for activated protein C in enhancing fibrinolysis and can directly inhibit prothrombin activation via interactions with other coagulation factors

Mature gamma-carboxylated protein S circulates in two states: free, and bound to the complement component C4b-binding protein (C4b-BP). The free form comprises 30 to 40 percent of total protein S and is the only form of protein S that has cofactor activity for activated protein C

Coagulation cascade - Source: Wikipedia [5]

Clinical Features

Differentiating [disease name] from other Diseases

Epidemiology and Demographics

Age

Gender

Race

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. 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.
  3. 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.
  4. 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.
  5. "Protein C - Wikipedia".