Protein S deficiency

Protein S deficiency is associated with an increased tendency to venous thrombosis from the 1st to the 4th decade of life. Very rare homozygous or compound heterozygous forms frequently lead to perinatal purpura fulminans or massive thrombosis with lethal outcome.

A deficiency of active protein S (protein S activity <60%) leads to reduced anticoagulant activity. Protein S is a vitamin K-dependent protein that acts as a cofactor of activated protein C, accelerating the inactivation of coagulation factors Va and VIIIa. Normally, approximately 60% of protein S is present in a complex with C4b-binding protein, and only free protein S is available as a cofactor for activated protein C.

The expression of the clinical phenotype and the age at onset are influenced by the type and localisation of variants in the PROS1 gene. Homozygous or compound heterozygous protein S deficiency is very rare and usually associated with protein S activity of <5%.

Congenital protein S deficiency is classified as follows:

• Type I: quantitative defect, reduction of total and free protein S as well as protein S activity
• Type II: qualitative defect, reduced protein S activity with normal concentrations of free and total protein S
• Type III: quantitative defect, reduced free protein S and protein S activity with normal plasma concentration of total protein S

Molecular genetic testing can detect causative variants in more than 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 and can be analysed by MLPA.

It is important to distinguish hereditary protein S deficiency from acquired protein S deficiency, which frequently occurs in association with inflammation, sepsis, burns, polytrauma, vitamin K deficiency or major surgery. The use of ovulation inhibitors also lowers protein S activity; in these cases, the lower limit of the normal range for protein S activity is 50%.

• Alhenc-Gelas et al. 2016, Thromb Haemost. 115:570
• Klostermeier et al. 2015, Thromb Haemost 113:426
• Duebgen et al. 2012, Am J Clin Pathol
• Pintao et al. 2010, Hum Genet 127:121
• ten Kate et al. 2008, Hum Mutat 29:939
• Yin et al. 2007, Throm Haemost 98:783
• ten Kate et al 2006, Haematologica 91:1151