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- Hematologic emergency characterized by dermal hemorrhagic necrosis and disseminated intravascular coagulation (DIC)
- Associated with a congenital or acquired protein C and/or protein S deficiency
- Life-threatening condition that requires prompt diagnosis and judicious replacement therapy to decrease morbidity and mortality
- Neonatal purpura fulminans related to homozygous protein C deficiency: 1 in 2–4 million births
- Clinical protein C deficiency: 1 in 20,000 individuals
- Homozygous protein S deficiency is exceptionally rare.
- Predicted prevalence of severe protein C deficiency is 1 in 40,000–250,000 individuals. Significantly less seen in practice, likely due to associated high rate of fetal loss and perinatal mortality
- Deficiencies of protein C and protein S are autosomally inherited with variable penetrance.
- Over 150 different genetic mutations of protein C have been described, leading to both qualitative and quantitative defects of the proteins.
- Homozygous protein C or S deficiency and compound heterozygous states are associated with severe deficiency, <1% normal activity level.
- Neonatal purpura fulminans is associated with a severe protein C or S deficiency.
- Coinheritance with other thrombophilias may also contribute to the risk of developing purpura fulminans.
- Heterozygous protein C and S deficiency are associated with a lifetime increased risk of venous and arterial thrombosis.
Common features of purpura fulminans:
- DIC: Endothelial injury from bacterial endotoxin or other trigger may initiate secretion of inflammatory cytokines or activation of coagulation and complement proteins.
- Purpura: due to perivascular hemorrhage
- Dermal vascular thrombosis: formation of microthrombosis in blood vessels of the skin, leading to hemorrhage in the skin (purpura), necrosis of skin, and gangrene
- Acquired causes:
- Severe acute bacterial infections: Neisseria meningitidis most common
- Postinfectious fulminans: most commonly associated with varicella and Streptococcus infections. Caused by cross-reacting IgG antibodies that increase protein S clearance from the circulation. Consider in an otherwise well child with new-onset purpura fulminans and DIC.
- Warfarin (Coumadin)-induced skin necrosis
- Antiphospholipid antibodies
- Cardiac bypass
- Severe liver dysfunction
- Severe congenital heart disease
- Inherited protein C pathway defects
- Predisposes to a reduced capacity to inhibit thrombin formation and therefore a hypercoagulable state
- Inherited defect of coagulation presenting as neonatal purpura fulminans
- Protein C slows (“brakes”) the coagulation cascade at two steps: by degrading activated factor V and activated factor VIII.
- Also plays a role in inflammatory cascade
- Protein S is a cofactor for protein C.