Protein S Deficiency, hereditary [I82.9]
Dr. rer. nat. Christoph Marschall
A deficiency in active, anticoagulant protein S (protein S activity < 60%) results in decreased fibrinolytic activity. Protein S is a vitamin K-dependent protein which, as a co-factor of the activated protein C, accelerates the inactivation of the coagulation factors Va and VIIIa. Usually, there is approx. 60% of protein S in complex with C4b binding protein; only free protein S is available as co-factor for the activated protein C. Protein S deficiency has been associated with increased risk of venous thrombosis from the 1st to the 4th decade of life.
Hereditary protein S deficiency has been classified as follows:
- Type I: Quantitative defect, decrease in total and free protein S as well as protein S activity
- Type II: Qualitative defect, decreased protein S activity with normal concentration of free and total protein S
- Type III: Quantitative defect, free protein S and protein S activity decreased but with normal plasma concentration of total protein S
The clinical phenotype and the age of onset are influenced by the type and the location of the mutations in the PROS1 gene. Homozygous or compound heterozygous protein S deficiency, which frequently results in perinatal purpura fulminans or severe thrombosis with lethal outcome, is very rare. Usually, these patients have a protein S activity of < 5%. It is important to distinguish hereditary protein S deficiency from the acquired protein S deficiency, which frequently occurs in association with infections, sepsis, burnings, polytraumata, vitamin K deficiency or major surgeries. The intake of ovulation inhibitors also lowers the protein S activity; in these cases the lowest normal level of protein S activity is 50%. In 60% of all patients suspected to have congenital protein S deficiency causative mutations can be detected by molecular genetic diagnostics. This is an equivalent of 1-2% of all patients with deep vein thromboses. The mutations are usually point mutations. About 2-5% of all mutations are larger deletions of single exons or, more often, of the entire gene. They can be analyzed by MLPA.