Severe hereditary thrombophilia due to congenital protein S deficiency

Severe hereditary thrombophilia due to congenital protein S deficiency is a rare, inherited blood clotting disorder caused by mutations in the PROS1 gene, which encodes protein S — a vitamin K-dependent anticoagulant glycoprotein that serves as a cofactor for activated protein C in the inactivation of clotting factors Va and VIIIa. When protein S is severely deficient, the body loses a critical natural anticoagulant mechanism, leading to an increased tendency to form dangerous blood clots (thrombophilia). This severe form typically results from homozygous or compound heterozygous mutations in PROS1. The condition primarily affects the vascular and hematologic systems. In its most severe form, it can present in the neonatal period with life-threatening purpura fulminans — a condition characterized by widespread intravascular clotting, hemorrhagic skin necrosis, and disseminated intravascular coagulation (DIC). Affected neonates may develop extensive skin necrosis, thrombosis of large and small vessels, and multi-organ damage. Older patients with severe deficiency are at markedly increased risk of deep vein thrombosis (DVT), pulmonary embolism, and cerebral venous thrombosis, often occurring at a young age or spontaneously without typical provoking factors. Treatment of the severe neonatal form requires urgent intervention, including fresh frozen plasma or protein S concentrate to replace the missing protein, along with anticoagulation therapy (typically heparin). Long-term management usually involves lifelong oral anticoagulation with warfarin or other vitamin K antagonists. In some cases, direct oral anticoagulants may be considered, though evidence in this specific population is limited. Genetic counseling is recommended for affected families. Heterozygous carriers (partial protein S deficiency) may have a milder thrombotic phenotype but still carry an elevated risk of venous thromboembolism compared to the general population.

Common questions about Severe hereditary thrombophilia due to congenital protein S deficiency