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. (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.
- 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 (2,3,4).
- 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 visa 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