Severe hereditary thrombophilia due to congenital protein C deficiency

Severe hereditary thrombophilia due to congenital protein C deficiency (Orphanet code 745) is a rare and life-threatening blood clotting disorder caused by a severe deficiency of protein C, a natural anticoagulant produced by the liver. Protein C plays a critical role in regulating blood coagulation by inactivating clotting factors Va and VIIIa. In the severe form, which typically results from homozygous or compound heterozygous mutations in the PROC gene, affected individuals have little to no functional protein C, leading to uncontrolled clot formation in blood vessels throughout the body. This condition is also known as homozygous protein C deficiency or severe congenital protein C deficiency. The severe form classically presents in the neonatal period with purpura fulminans, a devastating condition characterized by widespread blood clots in small blood vessels of the skin and internal organs, leading to extensive tissue death (necrosis), disseminated intravascular coagulation (DIC), and potentially fatal multi-organ failure. Affected neonates may develop large purplish skin lesions, thrombosis of major veins (including cerebral venous thrombosis), and damage to the eyes, brain, kidneys, and other organs. Without prompt treatment, the condition is often fatal in the first days to weeks of life. Treatment requires immediate replacement of protein C, which can be achieved through fresh frozen plasma or, preferably, protein C concentrate (Ceprotin®), which has been specifically approved for this indication. Long-term management involves lifelong anticoagulation therapy, typically with warfarin, often in combination with periodic protein C concentrate infusions. Liver transplantation has been considered in some cases as a potential curative approach, as the liver is the primary site of protein C synthesis. Early diagnosis and aggressive treatment are essential to prevent irreversible organ damage and death. Heterozygous carriers of PROC mutations may have a milder thrombophilia phenotype with an increased risk of venous thromboembolism in adulthood, but the severe neonatal form is specifically associated with near-complete protein C deficiency.

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