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A potentially fatal clinical syndrome that typically presents with necrosis of the skin and underlying soft tissue.
Its marked hemorrhagic component accounts for the lesions purpuric appearance.
There is inflammation of the microvasculature, combined with formation of micro thrombi, leading to capillary occlusion , tissue ischemia, and necrosis.
Etiologies include: disseminated intravascular coagulation due to sepsis, trauma, malignancy, or obstetric complications.
Congenital thrombophilia, such as homozygous proteins C or S deficiency is important cause in the neonatal period.
Acquired deficiencies can occur when antibodies to natural anticoagulants are produced in a response to a viral infection.
Refers to an acute, often fatal, thrombotic disorder which manifests as blood spots, bruising and discoloration of the skin resulting from coagulation in small blood vessels within the skin and rapidly leads to skin necrosis and disseminated intravascular coagulation.
Purpura fulminans is rare and most commonly occurs in babies and small children but can also be a rare manifestation in adults when it is associated with severe infections.
It is caused by defects in the protein C anticoagulant pathway.
Congenital defects in protein C activity are autosomal dominant.
Loss of protein C may be partial or a severe loss of function.
Hundreds of mutations of the protein C gene (PROC) have been identified.
Acquired protein C deficiency is caused by either depletion of available protein C in plasma or decreased protein C synthesis.
Decreased protein C synthesis is caused by administration of vitamin K antagonists, severe liver failure or complications of prematurity.
It is a presenting feature of severe acute sepsis, particularly in individuals with asplenia.
In some cases, a combination of sepsis and a partial congenital defect in the protein C anticoagulant pathway initiates the process.
Rarely, it is an autoimmune manifestation against protein C or protein S after normally benign infections, such as chicken pox.
Sometimes its cause remains unknown.
The mechanism of disease is similar for all cases, deficiency in protein C concentration or decrease in protein C activity which promotes blood clotting.
With severe sepsis there is activation of the acute systemic inflammatory response, including activation of the coagulation and complement pathways, as well as endothelial dysfunction.
Activated protein C binds to endothelial protein C receptor and subsequently cleaves the endothelial cell protease activated receptor-1.
Activated protein C alters coagulation profiles by down-regulating pro-inflammatory and pro-apoptotic mediators, up-regulates anti-inflammatory and anti-apoptotic pathways and stabilizes the endothelial cell barrier functions.
Activated protein C helps regulate the systemic inflammatory response.
The inflammatory cytokines, interleukin-1 and tumor necrosis factor during sepsis effect systemic inflammatory response, resulting in decreased synthesis of the regulatory proteins antithrombin, protein C and protein S, with increased synthesis of prothrombotic proteins Factor VIII, von Willebrand factor, and fibrinogen.
As systemic coagulation activation leads to depletion of circulating coagulation factors and platelets, bleeding results.
In early purpura fulminans, the histological appearance is of blockage of small skin blood vessels with blood clots causing capillary dilation and congestion with red blood cells.
In later stage lesions, irreversible endothelial ischemic injury with extravasation of blood cells into the dermis and gangrenous necrosis, sometimes with secondary infection occur.
Subsequently, depletion of anticoagulant and anti-inflammatory proteins, in particular, protein C and its co-factor, protein S, may also promote thrombus formation, inhibit fibrinolysis and lead to further activation of the inflammatory pathways.
Early disease looks similar to traumatic skin bleeds or purpuric rashes, such as immune thrombocytopenic purpura or thrombotic thrombocytopenic purpura.
Purpura fulminans, however, will rapidly progress to necrosis whereas other purpuric rashes do not.
The initial appearance of purpura fulminans is of well-demarcated erythematous lesions which progress rapidly to central areas of blue-black haemorrhagic necrosis.
Hemorrhage into the necrotic skin causes purpura fulminans lesions to become painful, dark and raised, sometimes with vesicle or blister formation.
Purpura fulminans due to sepsis typically develops in the distal extremities and progresses proximally or appears as a generalized rash affecting the whole body surface.
With severe inheritable protein C deficiency, and disseminated intravascular coagulation can manifest within a few hours or days after birth.
The cardinal features: prolonged plasma clotting times, thrombocytopenia, reduced plasma fibrinogen concentration, increased plasma fibrin-degradation products and occasionally microangiopathic hemolysis.
Protein C replacement therapies are available.
Protein C replacement is often in combination with anticoagulation therapy of injectable low molecular weight heparin or oral warfarin.
The amount of fresh frozen plasma required to reverse disseminated intravascular coagulation associated with purpura fulminans may lead to complications of fluid overload and death, especially in neonates.
Purpura fulminans may also lead to severe large vessel venous thrombosis.
It is often accompanied by micro-vascular thrombosis and hemorrhagic infarction in other tissues, such as the lungs, kidneys, central nervous system and adrenal glands, leading to multiple organ failure, and causes initial high mortality and long-term morbidity in survivors.
Purpura fulminans secondary to severe infection is self-limiting.
Treatment addresses the removal of the underlying cause and clotting abnormalities, with supportive treatment of antibiotics, fluid expansion, oxygenation, and aggressive management of the septic state.
Purpura fulminans with disseminated intravascular coagulation is emergently treated with fresh frozen plasma, 10–20 mL/kg every 8–12 hours, and/or protein C concentrate to replace pro-coagulant and anticoagulant plasma proteins that have been depleted by the DIC process.
Protein C in plasma in the steady state has a half life of 6- to 10-hours.
Patients with severe protein C deficiency and presenting with purpura fulminans can be treated acutely with an initial bolus of protein C concentrate 100 IU/kg followed by 50 IU /kg every 6 hours.
A total of 1 IU/kg of protein C concentrate or 1 mL/kg of fresh frozen plasma will increase the plasma concentration of protein C by 1 IU/dL.
Surgical removal of the dead tissue, fasciotomy, amputation or reconstructive surgery may be required for tissue necrosis.
The process often progresses within 24 to 48 hours to full-thickness skin necrosis or soft-tissue necrosis.
Full thickness skin necrosis, leaves large scars, with healing taking between 4–8 weeks.
Necrotic soft tissue may become gangrenous, leading to loss of limbs.
With homozygous protein C deficiency, episodes of purpura fulminans and other thrombotic events are recurrent.
Meningococcal septicemia is complicated by purpura fulminans in 10–20% of cases among children.
Purpura fulminans associated with congenital protein C deficiency occurs in 1:500,000–1,000,000 live births.