Purpura Fulminans

Purpura fulminans is a rapidly progressive thrombotic disorder with haemorrhagic skin necrosis and disseminated intravascular coagulation, caused by acquired or congenital deficiency of protein C and protein S activity. It may lead to limb loss and multiple organ failure.

Epidemiology. Acute infectious purpura fulminans occurs in about 10 to 20% of severe meningococcal disease, and may arise with pneumococcal, staphylococcal, streptococcal and other infections, especially after splenectomy. Neonatal purpura fulminans reflects severe congenital protein C deficiency (about 1 in 4 million births).

Types.

• Acute infectious.
• Idiopathic or post-infectious (1 to 3 weeks after infection, with antibodies against protein S).
• Neonatal, from homozygous or compound heterozygous protein C or protein S deficiency.
• Warfarin induced skin necrosis in protein C deficiency.

Pathophysiology. Infection or deficiency depletes protein C and S, and antithrombin, causing unopposed thrombin generation, microvascular thrombosis in the skin and soft tissue, haemorrhage and gangrene.

Presentation is sudden, painful, well demarcated erythematous, then purpuric and black necrotic lesions with bullae, on the limbs, trunk and face, with fever, shock and bleeding. Limb ischaemia and compartment syndrome may follow. Neonates have lesions within hours or days of birth, often with intracranial and ocular thrombosis.

Red flags.

• Rapidly spreading purpura with fever and shock.
• Platelets and fibrinogen falling quickly, with prolonged clotting.
• A neonate with purpura and a family history of thrombosis.

Full blood count, coagulation tests (prolonged prothrombin time and activated partial thromboplastin time), fibrinogen (low), D-dimer (high), blood film (fragmented red cells), protein C, protein S and antithrombin levels (before replacement), lactate, creatinine and cultures. Use skin biopsy (fibrin thrombi in small vessels) when diagnosis is unclear. Test for factor V Leiden and antiphospholipid antibodies in post-infectious disease. In neonates, test parents and genes.

Differential diagnosis. Meningococcaemia without necrosis, heparin induced thrombocytopenia, thrombotic thrombocytopenic purpura, antiphospholipid syndrome, vasculitis, calciphylaxis and warfarin necrosis.

Treat the cause. Antibiotics at once for infection: ceftriaxone 2 g IV every 12 hours (adults) with vancomycin if staphylococcal infection is possible. Resuscitate shock with fluid and vasopressors.

Replace natural anticoagulants (specialist).

• Protein C concentrate 100 to 120 units/kg IV bolus, then 60 to 80 units/kg every 6 hours for 3 doses, then 45 to 60 units/kg every 6 to 12 hours, aiming for a protein C activity over 100% at first and over 25% in trough levels, in congenital deficiency and in severe infection where available.
• If concentrate is unavailable, give fresh frozen plasma 10 to 20 mL/kg every 8 to 12 hours, which supplies protein C and S, with attention to volume overload.

Coagulopathy and anticoagulation.

• Replace platelets (over 50 x 10^9/L when bleeding or needing procedures), fibrinogen (cryoprecipitate to over 1.5 g/L) and plasma.
• Unfractionated heparin 10 units/kg/h, adjusted to anti-factor Xa, only in thrombotic dominant disease and under specialist direction, with attention to bleeding.

Surgery. Fasciotomy for compartment syndrome. Delay amputation and debridement until demarcation, usually weeks, unless there is sepsis or gangrene.

Wound care. Debride only dead tissue, apply dressings, give analgesia and prevent infection. Provide tetanus cover.

Long term. For congenital deficiency, lifelong protein C replacement or anticoagulation: warfarin only after stabilisation and with overlap by heparin, and consider liver transplantation.

Monitoring. Coagulation tests every 6 to 12 hours, protein C level, skin progression, limb perfusion and compartment status.

Referral and escalation. Intensive care, haematology, plastic and orthopaedic surgery.

Special groups. In neonates, ophthalmic and neuroimaging assessment. In pregnancy, discuss anticoagulants with haematology and obstetrics.