Purpura Fulminans

Background

Purpura fulminans, first described by Guelliot in 1884,[3] is a rare syndrome of intravascular thrombosis and hemorrhagic infarction of the skin that is rapidly progressive and is accompanied by vascular collapse and disseminated intravascular coagulation (DIC).[4] This syndrome usually occurs in children, but it has also been noted in adults.[5] Hogarth et al reported a case study of a male patient aged 60 years who suffered penile necrosis resulting from purpura fulminans. Necrotic purpuric lesions were found on the penile, suprapubic, inguinal, and hip dermis, with the penile necrosis affecting most of the shaft and the glans penis.[6]

Purpura fulminans is classified into the following three types:

• Neonatal

• Idiopathic

• Acute infectious

The three forms have differing presentations and are managed differently.

While three distinct presentations of purpura fulminans are recognized, the underlying pathophysiology stems from a qualitative or quantitative deficiency in protein C, an important regulator of the clotting cascade. When activated, protein C inhibits coagulation by blocking activity of factors V and VIII. If no feedback exists secondary to defective protein C, a prothrombotic state develops and in severe cases leads to DIC.

Protein C deficiency may be hereditary or acquired. Hereditary forms are present in neonatal purpura fulminans, while acquired protein C deficiency predominates in the etiology of idiopathic and acute infectious purpura fulminans.

Neonatal purpura fulminans

Neonatal purpura fulminans is associated with a hereditary deficiency of the natural anticoagulants protein C and protein S, as well as antithrombin III (ATIII). Protein C is synthesized in the liver as a polypeptide. Purified plasma protein C concentrate has been successfully used to treat patients with thrombotic episodes in neonatal purpura fulminans. Hereditary protein C deficiency is caused by homozygous and heterozygous mutations that result in severe coagulopathies.

Homozygosity or compound heterozygosity for protein C mutations results in an absolute deficiency of protein C. Fortunately, such absolute deficiency is exceedingly rare in neonates.[7] The complete lack of plasma protein C activity causes neonatal purpura fulminans, which is characterized by sudden onset of widespread purpuric lesions that progress to gangrenous necrosis and is associated with DIC.

The acquired form of neonatal purpura fulminans, usually recognized in older infants, is a post−meningococcal sepsis syndrome that results in decreased levels of protein C activity. In addition, neonates may be born with an inherited deficiency in either protein S or ATIII that may lead to neonatal purpura fulminans.

Protein S was first purified from plasma by DiScipio et al, who named the protein in honor of the city of its discovery, Seattle.[8] Protein S is synthesized by hepatocytes, neuroblastoma cells, kidney cells, testis, megakaryocytes, and endothelial cells and is found in platelet granules. Hereditary protein S deficiency associated with thrombosis is caused by homozygous and heterozygous mutations.

ATIII is a protein made in the liver. It inhibits coagulation and limits the formation of blood clots. A shortage of ATIII affects the normal process of coagulation and can lead to excessive blood clotting. This protein plays a major role in the regulation of hemostasis by inhibiting thrombin.

ATIII deficiency predisposes patients to venous thromboembolic events by impairing the clearance of anticoagulation factors. The deficiency is usually inherited and affects males and females equally. ATIII deficiency is found in approximately 1 in 2000-5000 individuals. All family members should be tested if the family has a history of the disease.

ATIII deficiencies fall into three categories. In type I deficiency, both ATIII levels and functional activity are reduced, whereas in types II and III deficiency, ATIII levels are normal, but some of the proteins do not function properly.

Patients with ATIII deficiency have thromboembolic problems that usually begin in early adulthood. Clots forming in the legs may cause pain and swelling. Pulmonary embolism (PE) is also encountered. Homozygote-deficient newborns, however, may have a purpura fulminans type of presentation with embolic lesions in the skin. ATIII concentrate has been available commercially since 1974. These vitamin K–dependent ATIII cofactors are profibrinolytic and inactivate clotting factors V and VIII.[9]

Presentation of intense venous thrombosis of the skin and other organs occurs within the first days of life in a patient with neonatal purpura fulminans. These infants with severe genetic protein deficiency experience recurrent episodes of purpura fulminans, despite therapy with long-term high-intensity anticoagulation.

Idiopathic purpura fulminans

Idiopathic or chronic purpura fulminans, first recognized in 1964, typically follows a bacterial or viral infection and occurs after a variable latent period.[10] It usually develops after an initiating febrile illness that manifests with rapidly progressive purpura, which may lead to skin necrosis, gangrene of limbs or digits, and major organ dysfunction. Protein C deficiency is considered central to the pathogenesis of idiopathic purpura fulminans, and DIC is considered the major pathophysiologic mechanism responsible for peripheral gangrene.

Acute infectious purpura fulminans

Acute infectious purpura fulminans, the most common form of purpura fulminans, occurs superimposed on a bacterial infection. In this illness, the balance between anticoagulant and procoagulant endothelial cell activity is disturbed. This disturbance is precipitated by bacterial endotoxin and mediated by various factors, including the inflammatory cytokines interleukin (IL)-12, interferon gamma, tumor necrosis factor (TNF)–α, and IL-1, which consume ATIII as well as proteins C and S.[11]

Microemboli and direct bacterial damage to vessels have also been linked with this process. In a study by Lerolle et al, eight of nine adult purpura fulminans patients tested were found to have bacteria at portions of the vascular walls where damage had occurred, suggesting that vascular wall infection causes endothelial damage and skin lesions in this disease.[12]

The most common cause of acute infectious purpura fulminans is meningococcus, though streptococci, varicella-zoster virus, Gram-negative bacilli, staphylococci, Rickettsia species, and measles virus have also been associated with this form of purpura fulminans. Rare cases of adult purpura fulminans caused by Haemophilus influenzae have also been reported.[13]

ATIII deficiency is found in approximately 1 in 2000-5000 individuals. It is usually inherited and affects males and females equally. Purpura fulminans develops as a complication in approximately 1:500,000 to 1:1,000,000 live births[14] . Meningococcal septicemia, however, may be complicated by purpura fulminans in as many as 10-20% of children.[15] If there is any indication of family history of disease, all family members should undergo genetic testing.

Mortality/Morbidity

Complications of purpura fulminans are frequent and often severe, including sepsis due to superinfection of lesions, vascular compromise, and limb amputation. Similar to burn patients, patients with purpura fulminans require meticulous fluid management and may quickly develop electrolyte derangements and acid-base disorders. Calciphylaxis, if present, is an ominous complication that typically results in death. Treatment adjuncts such as anticoagulation and clotting protein replacement therapy also have inherent risks, including bleeding and systemic thromboses.[16]

Purpura fulminans has historically been associated with a high death rate, with reports ranging from 60% mortality for distal lesions to as high as 90% for truncal and widespread lesions.[17]  With improvements in antibiotic therapy, protein replacement therapy, and adjunctive treatments, a decrease in mortality rates should be expected.

Neonatal purpura fulminans

Neonatal purpura fulminans occurs usually in patients with a deficiency of protein C. Protein C deficiency is usually inherited in an autosomal dominant manner, with heterozygous carriers often remaining asymptomatic until later in life, when they become very susceptible to venous thromboembolism. Autosomal recessive protein C deficiency, which is caused by homozygous or compound heterozygous mutations in protein C, is less common and usually leads to a more severe form of the disease, with onset of thrombotic manifestations at birth.

Within the first 72 hours after birth, a neonate with neonatal purpura fulminans exhibits purpuric lesions over many different skin sites, including the perineal region, the flexor surface of the thighs, and abdominal skin. The skin lesions soon enlarge and become vesiculated, producing hemorrhagic bullae with subsequent necrosis and black eschar formation. The margins of the lesions become erythematous and indurated. Thrombocytopenia is often evident.

The patient may later develop signs of a urinary tract infection (UTI). (For more information on the diagnosis and treatment of UTIs, see Urinary Tract Infection, Females; and Urinary Tract Infection, Males.)

Idiopathic purpura fulminans

Most of idiopathic purpura fulminans cases occur in children, and more than 90% are preceded by infection (commonly varicella or streptococcal infection). The purpura usually begins suddenly, 7-10 days after the onset of the precipitating infection, with the development of progressively enlarging, well-demarcated purplish areas of hemorrhagic cutaneous necrosis with deranged coagulation factors. Lesions begin as erythematous macules that progress within hours to sharply defined areas of purpura.

The illness is often complicated by impaired perfusion of limbs and digits, as well as major organ dysfunction caused by thromboembolic phenomena involving the lungs, the heart, or the kidneys.[18] In some cases, patients have undetectable levels of free protein S, as well as protein C and ATIII, at the time of admission. Procoagulant and anticoagulant factors, including protein C, protein S, and ATIII, must be measured by functional assays.

Acute infectious purpura fulminans

Over time, the term purpura fulminans has come to be applied to cases of purpura fulminans that occur in the face of overwhelming sepsis (ie, sepsis-associated fulminans). The four primary features of this syndrome are as follows:

• Large purpuric skin lesions

• Fever

• Hypotension

• DIC

Meningococci in the bloodstream are generally more predisposed to cause a dysfunction of the activated protein C pathway than other bacteria are. Staphylococcus aureus has been associated with purpura fulminans with accompanying toxic shock syndrome.[19]

Purpura fulminans is frequently associated with shock physiology, including tachycardia, hypotension, fever, and altered mental status. Hallmark dermatologic features of purpura fulminans include the following (see the image below):

• Nonblanching purpura
• Sharply demarcated lesions
• With advanced disease, the development of hemorrhagic bullae with overlying skin sloughing
• Possible coalescence of lesions in branching or angular patterns

With severe advanced disease, multiorgan failure manifests with widespread bleeding, stroke, liver failure, and acute respiratory failure.

Lesion associated with purpura fulminans in an adult patient. Courtesy of DermNet New Zealand.

Once purpura fulminans is suspected, workup should begin immediately to identify the underlying etiology. Laboratory studies are the primary diagnostic tools for working up purpura fulminans and should include the following:

• Complete blood count (CBC) with differential
• Basic metabolic panel
• Liver function tests
• Prothrombin time, international normalized ratio, and activated partial thromboplastin time
• Fibrinogen, D-dimer levels
• Blood cultures
• Qualitative/quantitative coagulation cascade protein assays

Abnormalities in the CBC and coagulation cascade indicate DIC, as highlighted in the table below.

Table 1. (Open Table in a new window)

*Table created using data from: Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol. 2009 Apr;145(1):24-33.

A peripheral blood smear may indicate microangiopathic hemolytic anemia (MAHA) with schistocytes, bite cells, and helmet cells. (See the image below.)

Schistocytes (arrows) on a peripheral smear. Courtesy of Bodhit AN, Stead LG. Altered mental status and a not-so-benign rash. Case Rep Emerg Med. 2011;2011:684572.

A study by Brozyna et al indicated that even in culture-negative cases, acute infectious purpura fulminans can be identified based on its histopathology. The 11 patients in the study were diagnosed with signs of acute infectious purpura fulminans, including sepsis and, histopathologically, intravascular thrombosis and/or DIC. These findings correlated with lesions identified on clinical examination. Focal epidermal ischemia or necrosis was found in most of the 13 skin biopsies, with full-thickness epidermal necrosis demonstrated in three of them. The underlying dermis was seen to feature “fibrin thrombi in superficial and deep blood vessels with acute inflammation,” while five cases revealed changes related to an inflammatory, destructive vasculitis. Bacteria and fungi, however, did not show up on histopathologic examination.[20]

Neonatal purpura fulminans

In a neonate with neonatal purpura fulminans, immediate treatment with platelet concentrate is recommended to reverse the thrombocytopenia and the bleeding manifestations. The neonate often develops disseminated intravascular coagulation (DIC). In the absence of signs of generalized bloodstream infection, deficiencies of the anticoagulant factors protein C, protein S, and antithrombin III (ATIII) remain important considerations. Consequently, the endogenous activity of these anticoagulant factors must be assessed by means of a chromogenic assay.

With a provisional diagnosis of purpura fulminans due to protein C deficiency, fresh frozen plasma (FFP) transfusion must be started. The FFP can later be replaced with low-molecular-weight heparin (LMWH). Subsequently, oral anticoagulation with warfarin must be instituted. Debridement of the dead tissue is mandatory. The protein C, protein S, and ATIII genes must be analyzed both in the patient and in the parents.

These patients require long-term oral anticoagulation, which, if well tolerated, may be sufficient to permit them to remain free of coagulopathy throughout life.[21] If the genetic assays reveal a defect in the protein C or ATIII genes, the protein C or ATIII concentrates may be used to correct this coagulation disorder.

In 2018 guidelines released by the American Society of Hematology (ASH) on the management of venous thromboembolism, the guidelines panel remarked that protein C replacement offers better long-term effectiveness than does anticoagulation in pediatric patients with purpura fulminans arising from homozygous protein C deficiency (although the panel also cited a concern that protein C therapy may be prohibitively expensive). In addition, the ASH guidelines suggested that during an acute episode in such pediatric patients, treatment involve anticoagulation not by itself but in combination with protein C replacement.[22]

Idiopathic purpura fulminans

In 1995, Sheridan et al described a management strategy for idiopathic purpura fulminans with multiple organ failure in children. In three cases in the report, the purpura fulminans involved a large percentage of the patients’ body surface areas. One patient, a 15-year-old boy, had skin lesions on 55% of his body surface area. Another patient, an 11-month-old girl, was affected on 25% of her body surface area. The third patient, a 2-year-old boy, had evidence of purpura fulminans on 55% of his body surface area. The pathogenesis of purpura fulminans was not known but probably involved acute transient decreases in protein C, protein S, or ATIII.[23]

The successful management of meningococcal sepsis in these patients was facilitated by early diagnosis and aggressive antibiotic therapy.[23] Management of purpura fulminans was particularly challenging in these cases because the children had evidence of multiple organ failure.

To better understand the current management of idiopathic purpura fulminans, seven burn centers performed a 10-year retrospective chart review of patients who were diagnosed with idiopathic purpura fulminans.[24] A total of 70 patients were identified, with a mean patient age of 13 years. Neisseria meningitidis[25] was the most common pathogen identified in infants and adolescents, while Streptococcus species predominated in adults.

In the patients studied, acute management consisted of antibiotic treatment, volume resuscitation, and ventilatory and inotropic support.[24] Protein C replacement was performed in only 9% of the cases. One fourth of the patients required amputation of all of the extremities. When performed early, fasciotomies may reduce the depth of soft tissue involvement and the extent of amputation. Although the overall mortality in this study was only 13%, the surgeons believed this number to be inaccurately low because it did not reflect the number of patients who succumbed to sepsis in facilities outside the multicenter study group.

In general, the authors recommend a conservative approach to treatment of idiopathic purpura fulminans that includes excising gangrenous areas after they have been demarcated from purpuric and indeterminate zones. In the presence of infection, however, early aggressive surgical debridement is essential to prevent invasive wound sepsis. When compartment syndrome is suspected in patients with tense limbs and distal ischemia, early fasciotomy is recommended. If established gangrene is present, conservative amputation is warranted.

Manco-Johnson and Knapp-Clevenger described the use of activated protein C (APC) in a 14-year-old girl with protein C deficiency due to idiopathic purpura fulminans.[26] At the end of the APC infusions, all skin lesions of purpura fulminans were resolved. The patient experienced no adverse reactions to APC. The authors concluded that APC is safe and effective for the treatment of purpura fulminans with severe genetic protein C deficiency.

Recognition of the pathophysiologic mechanism of idiopathic purpura fulminans provides a rational basis for treatment with immediate heparinization and infusion of FFP.[18] In some cases complicated by major vessel thrombosis, the use of tissue plasminogen activator (tPA) may reduce thromboembolic complications.

Acute infectious purpura fulminans

Meningococcemia and infection due to S aureus lead to acute infectious purpura fulminans. Patients with these infections have remarkably reduced levels of APC as a result of dysfunction of the endothelial protein C activation pathway. APC not only acts as an anticoagulant but also serves as an important modulator of the inflammatory response.

Patients who present with acute infectious purpura fulminans should receive broad-spectrum intravenous antibiotic therapy with activity against a variety of pathogens, including N meningitidis, streptococci, and methicillin-resistant S aureus (MRSA).

Consideration should also be given to early administration of APC concentrates to minimize purpura skin injury and to reduce the inflammatory cascade before irreparable tissue injury occurs.[27] Finally, because toxic shock syndrome is mediated by strong antigens, intravenous immunoglobulin (IVIg) therapy should be implemented because these preparations contain significant antibodies against the causative exotoxins.[28]

Because patients with DIC are at risk for acute thrombosis and bleeding, it is difficult to predict which will occur in a specific patient. Given these inherent risks and the lack of evidence available, prophylactic anticoagulation is not currently indicated in the treatment of acute infectious purpura fulminans.[29]

Hyperbaric oxygen therapy (HBOT) has rarely been used in the treatment of purpura fulminans and is not currently considered an important part of its therapy.