Elsevier

The Journal of Pediatrics

Volume 127, Issue 3, September 1995, Pages 355-363
The Journal of Pediatrics

Postinfectious purpura fulminans caused by an autoantibody directed against protein S,☆☆,,★★

https://doi.org/10.1016/S0022-3476(95)70063-3Get rights and content

Abstract

Objective. To determine the mechanism responsible for idiopathic purpura fulminans, we investigated the procoagulant and anticoagulant pathways in five consecutive patients, four after varicella, and the fifth after a nonspecific infection. Methods. Procoagulant and anticoagulant factors, including protein C, protein S, and antithrombin III, were measured by quantitative or functional assays. Anti–protein S autoantibodies were identified by dot blotting and Western blotting, and quantified serially by enzyme-linked immunosorbent assay. Clinical and laboratory data were collated retrospectively. Results. In each case the disease began 7 to 10 days after the onset of the precipitating infection, with rapidly progressive purpura leading to extensive areas of skin necrosis. The illness was complicated by impaired perfusion of limbs or digits (two patients), peripheral gangrene resulting in an above-knee amputation (one patient), and major organ dysfunction caused by thromboembolic phenomena involving the lungs (two patients), the heart (one patient), or the kidneys (one patient). Protein S levels were virtually undetectable at the time of admission and failed to respond to infusions of fresh frozen plasma, despite correction of other procoagulant and anticoagulant factors. All five children had anti–protein S IgM and IgG autoantibodies, which persisted for less than 3 months after admission. Decline in the anti–protein S IgG antibody concentration was associated with normalization of the plasma protein S levels. Conclusions. Autoimmune protein S deficiency may be a common mechanism causing postinfectious idiopathic purpura fulminans. Recognition of the pathophysiologic mechanism may provide a rational basis for treatment. Immediate heparinization, infusions of fresh frozen plasma, and, in cases complicated by major vessel thrombosis, the use of tissue-type plasminogen activator may limit thromboembolic complications. (J PEDIATR 1995;127:355-63)

Section snippets

Patient 1

A previously healthy boy aged 6.4 years was transferred to us because of rapidly developing purpura. Five days before admission, fever, malaise, and a vesicular rash over his groin had begun. During the next 3 days he remained intermittently febrile, but his condition seemed to be improving symptomatically until the onset of a generalized macular eruption, which progressed to purpura. He had had chickenpox 1 year previously. There was no family history of thromboembolism. On examination he was

METHODS

Plasma coagulation tests (PT, activated partial thromboplastin time, fibrinogen, and D-dimer concentrations) were determined by standard methods. Total and free protein S concentrations were measured by ELISA as previously described.20 Protein S activity was measured by a clotting assay (Staclot Protein S, Diagnostica-Stago, Asnieres, France). Plasma concentration of complement C4b binding protein was measured by Laurell Rocket electrophoresis by means of a C4bBP-specific antiserum (Nordic

RESULTS

All five patients had virtually undetectable levels of free protein S at the time of admission, together with markedly reduced levels of total protein S (Fig. 1). In all cases, despite daily infusions of up to 60 ml FFP per kilogram of body weight, free protein S levels remained markedly reduced for 1 to 2 weeks after admission and thereafter rose slowly to within the normal range. Total protein S levels recovered more quickly than free protein S but remained below normal for several days after

DISCUSSION

Reviews by Hjort et al.3 and Francis4 delineated the characteristic features of idiopathic PF. Most cases occur in children. More than 90% are preceded by infection, commonly varicella or a streptococcal infection.4 The disease begins suddenly with the development of progressively enlarging, well-demarcated purplish black areas of haemorrhagic cutaneous necrosis with deranged coagulation factors. The overall mortality rate in cases reported before 1964 was more than 50%.3 In more recent reports

CONCLUSION

Postinfectious purpura fulminans after varicella, mediated by autoantibodies against protein S, appears to be a distinct clinical and pathophysiologic entity. Recognition of this disorder may facilitate appropriate treatment. Although it is possible that postinfectious purpura fulminans may be mediated by other mechanisms, recognition of autoimmune protein S deficiency in five consecutive patients with PF indicates that this mechanism may be common.

We are grateful for expert help and advice

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  • Cited by (0)

    From the Paediatric Infectious Diseases Unit, Department of Paediatrics, and the Department of Haematology, St. Mary's Hospital Medical School, London, and the Haemostasis Research Unit, University College, London, United Kingdom

    ☆☆

    Supported by the Max Friedman Trust (Dr. Eley) and the Wellcome Trust (Dr. Heyderman).

    Reprint requests: Michael Levin, FRCP, PhD, Paediatric Infectious Disease Unit, Queen Elizabeth the Queen Mother Wing, St. Mary's Hospital Medical School, South Wharf Road, London W2 1NY, United Kingdom.

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    0022-3476/95/$5.00 + 0 09/20/66744

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