Sandbox:Roukoz

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.

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.

• 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.

• 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

• 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.
  • 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.
  • 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.

• 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.
• 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.

Epidemiology and Demographics

• The prevalence of protein S deficiency is approximately 140 per 100,000 individuals worldwide.

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.