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.