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Previous Volume 345:408-416 August 9, 2001 Number 6 Next

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ABSTRACT

Background Impairment of the protein C anticoagulation pathway is critical to the thrombosis associated with sepsis and to the development of purpura fulminans in meningococcemia. We studied the expression of thrombomodulin and the endothelial protein C receptor in the dermal microvasculature of children with severe meningococcemia and purpuric or petechial lesions.

Methods We assessed the integrity of the endothelium and the expression of thrombomodulin and the endothelial protein C receptor in biopsy specimens of purpuric lesions from 21 children with meningococcal sepsis (median age, 41 months), as compared with control skin-biopsy specimens.

Results The expression of endothelial thrombomodulin and of the endothelial protein C receptor was lower in the patients with meningococcal sepsis than in the controls, both in vessels with thrombosis and in vessels without thrombosis. On electron microscopical examination, the endothelial cells were generally intact in both thrombosed and nonthrombosed vessels. Plasma thrombomodulin levels in the children with meningococcal sepsis (median, 6.4 ng per liter) were higher than those in the controls (median, 3.6 ng per liter; P=0.002). Plasma levels of protein C antigen, protein S antigen, and antithrombin antigen were lower than those in the controls. In two patients treated with unactivated protein C concentrate, activated protein C was undetectable at the time of admission, and plasma levels remained low.

Conclusions In severe meningococcal sepsis, protein C activation is impaired, a finding consistent with down-regulation of the endothelial thrombomodulin–endothelial protein C receptor pathway.

Source Information

From the Departments of Paediatrics (S.N.F., M.L., O.B.H., S.K.) and Pathology (R.D.G.), Imperial College School of Medicine at St. Mary's Hospital, London; the Oklahoma Medical Research Foundation, Oklahoma City (M.S.L., C.T.E.); the Departments of Pathology (Z.L., C.T.E.) and Biochemistry and Molecular Biology (C.T.E.), University of Oklahoma Health Sciences Center, Oklahoma City; the Howard Hughes Medical Institute, Oklahoma City (C.T.E.); and the Departments of Pathology and Microbiology, University of Bristol, Bristol, United Kingdom (R.S.H.).

Address reprint requests to Dr. Levin at the Department of Paediatrics, Imperial College School of Medicine at St. Mary's Hospital, Norfolk Pl., London W2 1PG, United Kingdom, or at m.levin{at}ic.ac.uk.

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