Purpura fulminans D65.x

Henoch, 1884; Glanzmann, 1918. Purpura fulminans was first described in 1884 and is still a relatively rare disease, so that most articles about it are case reports and case series.

Purpura fulminans is a rare, acquired, often life-threatening syndrome following an initial infectious episode with consumption coagulopathy, extensive hemorrhages in the skin and internal organs and subsequent extensive but also deep necrosis. This is a genuine dermatological emergency that requires immediate diagnosis and treatment. Patients are often acutely ill, have a fever, bleeding in several places and may suffer from a drop in blood pressure. The disease progresses fulminantly and is often associated with disseminated intravascular coagulation and circulatory collapse.

From a clinical point of view, it is classified as follows:

• Congenital/neonatal form (due to congenital protein C deficiency): Onset of symptoms 3 days after birth
• Idiopathic (post-infectious/autoimmunologic) purpura fulminans
• Acute infectious purpura fulminans: maximum form of the cutaneous form in disseminated intravascular coagulopathy (DIC) caused by a septic process or a hemophagocytic syndrome (Perera TB et al. 2024)

Each form of purpura fulminans has a different prevalence. The hereditary neonatal form with severe protein C deficiency occurs in approximately 1:1,000,000 live births.

Acute infectious purpura fulminans can occur in up to 10 % to 20 % of patients who develop meningococcal sepsis (see also Waterhouse-Fridrichsen syndrome). Acute infectious purpura fulminans occurs more frequently in patients with physical or functional asplenia.

The idiopathic post-infectious form is very rare, only a few hundred cases have been reported.

Purpura fulminans is a fulminant syndrome with microvascular thrombosis and hemorrhagic necrosis of the skin. It is considered a clinical symptom rather than a disease in its own right.

Neonatal purpura fulminans is associated with a hereditary deficiency of the anticoagulants protein C, protein S and antithrombin III. It manifests itself very early in life. Treatment targets the anticoagulant deficiency (Irfan Kazi SG et al. 2018).

Idiopathic purpura fulminans is considered a post-infectious autoimmune disease that occurs about 7 to 10 days after a febrile illness and later leads to rapidly progressive purpura. Varicella or scarlet fever are usually the triggering cause. In this variant, a relative deficiency of protein S is suspected as the cause.

Acute infectious purpura fulminans is the most common form. It manifests as a skin finding in the most severe septic patients and in necrotizing fasciitis with a predisposition to certain infectious agents.

The hallmark clinical symptom of purpura fulminans is acute, rapidly progressive skin hemorrhages with consecutive necrosis caused by dermal vascular thrombosis and disseminated intravascular necrosis. All types of purpura fulminans are associated with a dysfunction of hemostasis leading to a disease state with overwhelming procoagulation.

Acute infectious purpura fulminans occurs during an acute illness, usually sepsis with endotoxin-producing Gram-negative bacteria, and neonatal purpura fulminans is associated with a hereditary deficiency of the anticoagulant proteins C and S. These proteins are vitamin K-dependent. These proteins are vitamin K-dependent cofactors that have a fibrinolytic effect. Protein C is one of the most important inhibitors of the coagulation system, which, when activated, inhibits factors Va and VIIIa, which in turn downregulate thrombin synthesis. Newborns typically show massive venous and arterial thrombosis of the skin and other organs within 5 days of birth.

Acute infectious purpura fulminans is the most common form and is associated with acquired protein C deficiency. The mechanism involves a disturbance of the coagulation balance. Bacterial endotoxins trigger the consumption of protein C and S as well as antithrombin III. This procoagulant state leads to thrombosis of the skin vessels and is associated with disseminated intravascular coagulation. The skin lesions may appear as petechial exanthema at an early stage of the disease. These rapidly confluent into larger ecchymoses. As the disease progresses, hemorrhagic blisters form which, after drying out, lead to extensive hard scabs.

Idiopathic purpura fulminans, the rarest form of the disease, is associated with the formation of anti-protein S antibodies. These antibodies bind to protein S and lead to a loss of function of the molecules concerned, resulting in a transient protein S deficiency, which leads to hypoactivation of the protein C pathway and a hypercoagulable state similar to that described above.

Extensive and petechial hemorrhages and blisters, rapidly turning into necrosis, in a symmetrical arrangement on the extremities, face and trunk.

Severe, possibly febrile general symptoms. The skin findings of purpura fulminans have a characteristic appearance and course. Purpura fulminans begins with erythema, from which irregular central areas of blue-black hemorrhagic necrosis develop. In some cases, vesicles and blisters form. The affected skin is initially painful and indurated, but in later stages there may be a complete loss of sensation. Secondary infection of the gangrenous tissue may occur. The necrosis may spread to deeper layers of tissue.

Note: If the pain is disproportionate to the examination, necrotizing fasciitis should always be considered.

Determination of protein C (<25%).

Ultimately, the disease is caused by an imbalance in the coagulation system. Specific levels of antithrombin III, free protein C and free and total protein S can help to confirm the diagnosis, particularly in the neonatal form of the disease. Otherwise, the assessment of patients with purpura fulminans corresponds to the assessment of the underlying cause.

The search for a causative infection using laboratory tests, cultures and imaging should be performed according to the guidelines for sepsis. If the physician is considering necrotizing fasciitis, the leukocyte count (WBC) and sodium level with or without the other components of the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score can help the surgeon decide on early intervention. Due to the strong association with disseminated intravascular coagulation, thrombocytopenia, increased coagulation factors (PT, PTT), increased D-dimer levels (or serum fibrin degradation products) and a decreasing fibrinogen level should also be investigated.

Calciphylaxis: Rare, severe clinical picture observed almost exclusively in patients with renal insufficiency requiring dialysis (pathognomic is the associated secondary hyperparathyroidism), which is characterized by calcifying dermatitis and panniculitis with thrombotic occlusions and wall calcifications of small and medium-sized vessels of the dermis and often subsequent skin necrosis.

Coumarin necrosis (Coumadin): Rare hypercoagulability with extensive, hemorrhagic necrosis, paradoxically triggered by anticoagulant treatment with vitamin K antagonists (see coumarins below).

Meningococcal sepsis(Waterhouse-Friderichsen syndrome): Peracute bacterial sepsis with microcirculatory disorders, disseminated intravascular coagulation and shock (adrenal insufficiency due to hemorrhagic infarcts) as well as skin and adrenal hemorrhages. The incubation period is 3-4 days. Untreated, the mortality rate is 80%.

Necrotizing fasciitis: Rare, life-threatening, fulminant, deep, phlegmonous infection of the skin, subcutis and fascia, possibly also the muscles, often occurring after banal injuries, no bone involvement.

Thrombotic thrombocytopenic purpura: Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy characterized by microangiopathic haemolytic anaemia, consumption thrombocytopenia and organ damage. It is caused by a severe functional deficiency of ADAMTS13, usually due to autoantibodies against ADAMTS13, therefore also referred to as acquired autoimmune TTP

Toxin shock syndrome: Severe, life-threatening clinical picture triggered by the exotoxin (see also exfoliatins) TSST-1 (toxic shock syndrome toxin 1) produced by certain Staphylococcus aureus strains (see superantigen below) with scarlet fever-like skin symptoms, shock symptoms and multiple organ symptoms (see below).

Vasculopathies (occluding): Non-inflammatory, chronic (not acute!) vascular diseases associated with partial or complete occlusion of a vessel (e.g. livedo racemosa; see below livedovasculopathy).

Intensive medical care with circulatory stabilization, fluid and electrolyte balancing. Stage-appropriate shock treatment.

Anticoagulation can be initiated to prevent further necrosis.

Due to the procoagulable state and DIC, replacement of blood, factors and platelets may be necessary.

Early surgical debridement of necrotic areas is important.

In neonatal purpura fulminans, hydration, platelet transfusions followed by assessment of protein C and S levels and immediately afterward transfusions of fresh frozen plasma are the mainstay of treatment. Heparin and warfarin have been used as anticoagulants, and protein C concentrate can be added later if a deficiency is detected (Kizilocak H et al. 2018).

The treatment of idiopathic purpura fulminans is similar to that described above. Immunomodulation with corticosteroids may also play a role.

In acute infectious purpura fulminans , targeted broad-spectrum antibiotics (e.g. against Neisseria meningitidis, Streptococcus, Staphylococcus and Clostridia species) should be used. Carbapenem or vancomycin in combination with beta-lactam beta-lactamase inhibitors are recommended. IVIg therapy is also used due to the antibodies against these toxins. Activated protein C can be administered to reduce the inflammatory cascade and restore clotting balance, which may slow the progression of purpuric skin lesions. In acute infectious purpura fulminans, the decision to anticoagulate is based on the concomitant presence of disseminated intravascular coagulopathy (DIC).

In all forms of the disease, repeated tissue evaluations with debridement of the affected areas are performed if necessary. Repeated operations are often necessary.

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