Purpura fulminans – It’s Not Always Sepsis

A 3-year-old boy developed purpuric lesions a few days after a respiratory viral infection. The purpura enlarged rapidly and affected the lower limbs, nose, ear and lumbar area ([Fig. 1]). At admittance to hospital he had no fever and was cardiorespiratory stable. Laboratory tests showed DIC with prolonged aPTT (47 s [22–34 s]), low PT (40% [70–120%]), high D-Dimer levels (155 μg/ml [≤0,6 μg/ml]) and a low platelet count (47 G/l [195–464 G/l]). Antithrombin (AT) levels were always normal. Inflammatory laboratory parameters were low or negative (CRP 2.3 mg/dl [≤0.5 mg/], PCT 0.24 ng/ml [≤0.5 ng/ml]) and no acute viral or bacterial infection was found. There was no history of a thrombophilic disorder or varicella infection. Fresh frozen plasma and PC-concentrate were given immediately and platelets and fibrinogen concentrate were substituted. A therapeutic anticoagulation with low molecular weight heparin (LMWH, enoxaparin – 2 mg/kg/d) was started. Test results received later showed undetectable PC and PS levels prior to substitution and only PC levels raised after PC substitution. Therefore, autoantibodies against PS were suspected despite plasma mixing studies were not conclusive and measuring of PS antibodies is not established routinely [Regnault et al. J. Thromb Haemost 2005; 3:1243–1249, Thomson et al. Blood Coagul Fibrinolysis 2010;21:598–600]. Administration of rituximab (375 mg/m²) and continuous plasmapheresis using FFP over several days was necessary to achieve stable PS levels>50%. At admission thrombotic microangiopathy (TMA) was considered as differential diagnosis and eculizumab (600 mg) was administered twice ([Fig.] [2]).

Fig. 1 Disseminated Purpura fulminans in a patient with acquired Protein S deficiency due to autoantibodies.

Fig. 2 Clinical course of PF with PC, PS levels and D- dimers and therapeutic procedures – substitution of fresh frozen plasma (FFP), Protein C concentrate (PC), plasmapheresis (PEX), rituximab (RIT, 375 mg/m²) and ecolizumab (ECO, 600 mg).

The child survived and only amputation of the right lower limb was necessary. Testing for inherited thrombophilia was negative, including genetics for PS deficiency. Since Protein C levels after substitution were stable within normal ranges no Protein C genetics was performed.

Purpura fulminans (PF) is a rare and rapidly progressive syndrome resulting from intravascular thrombosis and hemorrhagic skin necrosis associated with disseminated intravascular coagulation (DIC). Mortality and morbidity including limb amputations is high. [Chalmers et al. Arch Dis Child 2011; 96:1066–1071] In PF, thrombus formation, inhibition of fibrinolysis and activation of inflammatory pathways are associated with a massive consumption of anticoagulant and anti-inflammatory PC and its co-factor PS. Physiologically, PC and PS inhibit factor Va and VIIIa reducing the formation of tenase complex. Additionally the tissue factor pathway inhibitor (TFPI) mediated inhibition of factor Xa is promoted by Protein S [Thomson et al. Blood Coagul Fibrinolysis 2010;21:598–600].

In most instances, PF occurs with severe bacterial sepsis most commonly meningococcemia. Rarely, PF is the first manifestation of severe hereditary protein C (PC) or protein S (PS) deficiency in the neonatal period. It might also occur due to acquired antibodies against PC/PS. Commonly idiopathic PF is preceded by varicella or streptococcal infection. [Francis et a. Semin Thromb Hemost 1990;16:310–325]. Therapy consists of substitution of PC-concentrate in PC-deficiency, fresh frozen plasma which supplies PS in PS-deficiency, antibiotic therapy in case of sepsis or elimination of antibodies by plasmapheresis and immunomodulation with immunoglobulins and steroid or rituximab in antibody-mediated disease [Thomson et al. Blood Coagul Fibrinolysis 2010;21:598–600].

Our case shows that post-infectious PF due to autoantibodies against PS should be considered, especially in the absence of severe acute infection or a positive family history for thrombosis. Immediate treatment with supply of PS by administration of FFP, elimination of suspected autoantibodies by plasmapheresis and anticoagulation is necessary.