Deficiency of active protein S (protein S activity <60%) leads to decreased anticoagulant activity. Protein S is a vitamin K-dependent protein that acts as a cofactor to activated protein C to accelerate the inactivation of coagulation factors Va and VIIIa. Normally, approximately 60% of protein S is present in a complex with the C4b-binding protein, and only free protein S is available as a cofactor for activated protein C. Protein S deficiency is associated with an increased tendency to have venous thrombosis from the 1st to 4th decade of life. Congenital protein S deficiency is classified as follows:
- Type I: quantitative defect, decreased total and free protein S and protein S activity
- Type II: qualitative defect, decreased protein S activity with a normal concentration of free and total protein S
- Type III: quantitative defect, decreased free protein S and protein S activity with a normal plasma concentration of total protein S
The expression of the clinical phenotype and the age of onset of the disease is influenced by the type and localization of variants in the PROS1 gene. Homozygous or combined heterozygous protein S deficiency is rare and often leads to perinatal purpura fulminans or massive thrombosis with lethal outcomes. Usually, these patients have protein S activity of <5%. It is important to distinguish this from acquired protein S deficiency, which often occurs in association with inflammation, sepsis, burns, polytrauma, vitamin K deficiency, or major surgery. The use of ovulation inhibitors also lowers protein S activity, so in these cases, the lower limit of the normal range for protein S activity is 50%. Molecular genetic testing can detect causative variants in over 60% of patients with suspected congenital protein S deficiency. This corresponds to 1-2% of all patients with deep vein thrombosis. Larger deletions of single exons or more frequently of the entire gene account for approximately 2-5% of all variants. These can be analyzed by MLPA.
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