A 43-year-old African American female went to the ICU at our institution with Streptococcus pneumoniae sepsis, which was complicated by disseminated intravascular coagulation.
The patient developed extensive ecchymotic lesions on her lower extremities. These lesions progressed to tender hyperpigmented macules with surrounding erythema, subsequently turned into large bullous lesions and eventually led to full thickness necrosis extending from the tibial tuberosity to the digits bilaterally.
A skin biopsy confirmed the diagnosis. In addition to receiving levofloxacin (Levaquin, Janssen Pharmaceuticals) and vancomycin for Streptococcus pneumoniae sepsis, the patient began IV heparin and warfarin (Coumadin, Bristol-Myers Squibb) for anticoagulation and to maximize tissue perfusion.
Wound care consisted of surgical and enzymatic debridement of necrotic tissue. The final surgical intervention included debridement of all remaining necrotic tissue, digital amputations and application of synthetic wound grafts.
Key Questions To Consider
1. What are the main characteristics of this condition?
2. What is the most likely diagnosis?
3. What is your differential diagnosis?
4. How can one make a definitive diagnosis?
5. What is the treatment?
Answering The Key Diagnostic Questions
1. The main characteristics of purpura fulminans are cutaneous hemorrhage and necrosis, most commonly associated with severe infection.
2. The most likely diagnosis is acute infectious purpura fulminans.
3. Differential diagnoses include thrombotic thrombocytopenic purpura, Henoch-Schönlein purpura and post-infectious thrombocytopenic purpura.
4. Definitive diagnosis of purpura fulminans occurs via skin biopsy.
5. Treatment of purpura fulminans is complex and one must tailor it to individual patients. Supportive treatment and the replacement of deficient blood components with fresh frozen plasma and clotting factors are the mainstays of treating this disorder.
What You Should Know About Purpura Fulminans
Purpura fulminans is a rare disorder of rapidly progressive cutaneous hemorrhage and necrosis of the skin. It is characterized by a petechial rash, which progresses to large, rapidly spreading skin hemorrhages and skin necrosis. It frequently occurs along with disseminated intravascular coagulopathy, fever and shock. The most common cause of purpura fulminans is severe infection but this disorder has also occurred in association with benign infections and deficiency of natural anticoagulants protein S and protein C.1 The pathogenesis of purpura fulminans results from the impairment of natural anticoagulant and fibrinolytic pathways, and activation of procoagulant pathways. Purpura fulminans most commonly occurs in children with fewer reported cases in adults.2-5
There are three types of purpura fulminans classified by their triggering mechanism: neonatal, idiopathic and acute infectious.2 Neonatal purpura fulminans is associated with a hereditary deficiency in anticoagulant factors protein C, protein S and antithrombin III. Idiopathic purpura fulminans most commonly happens after a benign illness. This form is the rarest type of this disorder and arises most commonly in pediatric patients. In idiopathic purpura fulminans, thrombi formation remains localized to the skin without organ involvement.6
Acute infectious purpura fulminans represents the most common form of this disorder. It most commonly occurs with meningococcal sepsis but authors have also reported this condition in association with other bacterial and viral infections.7 Acute infectious purpura fulminans is characterized by large purpuric skin lesions, fever, hypotension and disseminated intravascular coagulation.
Essential Diagnostic Pointers On Purpura Fulminans
The clinical presentation of purpura fulminans starts as a petechial rash that accompanies a severe infection. This petechial rash progresses to rapidly spreading purpura followed by widespread cutaneous hemorrhage. The affected areas are painful and indurated. The cutaneous changes progress to irregular areas of blue-black hemorrhagic necrosis with a surrounding erythematous border. In some cases, vesicles and hemorrhagic bulla are present.6,8 The distribution is symmetrical and affects the peripheral upper and lower extremities with lower extremity involvement being more common. Necrosis may be confined to the dermal tissues or may extend to muscle and bone. Healing occurs with scarring and frequently auto-amputation of the digits occurs.8 The cutaneous pathology of purpura fulminans is accompanied by fever, shock and frequently disseminated intravascular coagulopathy.
Differential diagnoses of purpura fulminans include thrombotic thrombocytopenic purpura, Henoch-Schönlein purpura and post-infectious thrombocytopenic purpura. These purpuric disorders exhibit significantly less severe skin necrosis than in purpura fulminans.6 Additionally, purpura fulminans shows less of an inflammatory component than these other vasculitic skin disorders.
A Closer Look At The Causes And Pathogenesis Of The Condition
Several bacteria reportedly lead to acute infectious purpura fulminans including Meningococcus, Staphylococcus, Escherichia coli, Streptococcus, Neisseria and Enterobacter. Meningococcus is the most common infectious etiology of purpura fulminans in the pediatric population while Streptococcus is the most common infectious cause in the adult population.2,3,5Meningococcus is the most common cause of acute infectious purpura fulminans due to its predisposition to cause dysfunction of the endothelial protein C activation pathway.9,10 Viral infections, Varicella and measles are reportedly causes of purpura fulminans.6
Factors predisposing patients to purpura fulminans include recent upper respiratory infection, recent surgery, recent childbirth, young age and asplenism or functional hyposplenism.11,12 It remains unclear as to why purpura fulminans develops in some patients while other patients with sepsis of the same severity fail to develop this disorder.
The pathogenesis of purpura fulminans results from the impairment of natural anticoagulant and fibrinolytic pathways, and activation of procoagulant pathways. Authors have identified several coagulation abnormalities in purpura fulminans.1,7,13 These abnormalities include decreased protein C, decreased protein S and decreased antithrombin III. Protein C and protein S deficiency can be due to homozygous or compound heterozygous genetic deficiencies, or acquired deficiency secondary to infection. Acquired deficiencies of protein C, protein S and antithrombin are due to coagulative consumption of these proteins during sepsis.
Key Insights On Effective Treatment
Given the multiple types of purpura fulminans and variable causes, one must tailor treatment of purpura fulminans to individual patients. Management of this disorder includes aggressive resuscitation, immediate volume expansion, ventilatory and inotropic support, antibiotic administration, and replacement of blood products and clotting factors.
Transfusion and plasmapheresis. Improvement in skin necrosis has reportedly occurred after the use of whole blood and plasma supply anticoagulant factors protein C, protein S and antithrombin III.8 Large quantities of blood and plasma are frequently needed to replace losses of clotting factors to the affected skin. Plasmapheresis can help control fluid balance when an excessive volume of blood products is necessary. Additionally, plasmapheresis removes circulating endotoxins and inflammatory cell mediators.6
Heparin. Heparin inhibits thrombus formation, halts the consumption of coagulation factors and can slow or stop the process of skin necrosis.8 I recommend heparin to reverse the disseminated intravascular coagulation component of the disease and promote tissue perfusion.3
Protein C. Research has shown that both genetic and acquired deficiencies in the natural anticoagulant protein C contribute to the development of purpura fulminans.14 Several studies have shown the clinical benefit of protein C supplementation with recombinant human activated protein C.12,15-18 Smith and colleagues showed administration of protein C in patients with purpura fulminans produced a 0 percent mortality rate despite a published mortality rate for purpura fulminans ranging from 40 to 80 percent.15
Antithrombin III. Administration of antithrombin III has the potential to reverse the procoagulant state that occurs in purpura fulminans. Studies have shown that antithrombin III has anti-inflammatory properties and decreases the inflammatory response of mononuclear cells and endothelial cells.19
Topical nitroglycerin. Topical nitroglycerin can convert to nitric oxide, a powerful natural vasodilator. Several studies have shown improved blood flow to the skin with topical nitroglycerin application.20,21 Reduction in pain resulting from poor tissue perfusion can also occur with topical nitroglycerin use.6
Surgical management. Researchers have proposed that aggressive fluid resuscitation and endotoxin-induced fluid shifts lead to tissue edema and subsequent compartment syndrome, which further decreases the blood supply in tissue already subject to vascular compromise. Warner and coworkers showed that performing fasciotomies early in the management of patients with purpura fulminans reduced the depth of necrosis and decreased the extent of amputations.4
Surviving patients typically require surgical treatment of skin necrosis and extremity gangrene. One manages skin necrosis similarly to frostbite and burns by delaying amputation until maximal collateral circulation has developed and demarcation of non-viable tissue has taken place.3 Researchers have described multiple techniques for the treatment of full thickness skin necrosis including skin grafting, synthetic skin grafts and amputation.2-4,22
What About The Prognosis Of Patients With Purpura Fulminans?
While the mortality rate of purpura fulminans has decreased with current treatment modalities, it remains a disabling condition with complex wounds complicated by secondary infections, often requiring major amputations.
A study by Warner and colleagues reviewing 70 cases of purpura fulminans showed a 40 percent mortality rate, 90 percent of patients required surgical intervention with skin grafting/amputation and 25 percent of patients required amputations of upper and lower extremities.4 Davis and coworkers reported 12 cases of purpura fulminans associated with peripheral gangrene with a 25 percent mortality rate, a 67 percent single limb amputation rate and a 33 percent four-limb amputation rate.23 Childers and colleagues reported a mortality rate of 43 percent in patients with purpura fulminans.5 Researchers have shown that rapid diagnosis, ICU management and early surgical intervention can decrease mortality in patients with purpura fulminans.5
Dr. Hoffman is in private practice in Boulder, Colo.
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