Dysfunction of endothelial protein C activation in severe meningococcal sepsis

N Engl J Med. 2001 Aug 9;345(6):408-16. doi: 10.1056/NEJM200108093450603.


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, 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antithrombin III
  • Antithrombins / metabolism
  • Bacteremia
  • Biopsy
  • Blood Coagulation Factors*
  • Case-Control Studies
  • Child, Preschool
  • Down-Regulation
  • Endothelium / chemistry
  • Endothelium / diagnostic imaging
  • Endothelium / metabolism
  • Humans
  • IgA Vasculitis / etiology
  • IgA Vasculitis / pathology*
  • Meningococcal Infections / complications
  • Meningococcal Infections / metabolism*
  • Meningococcal Infections / pathology*
  • Microscopy, Electron
  • Neisseria meningitidis
  • Peptide Hydrolases / blood
  • Protein C / metabolism*
  • Protein S / metabolism
  • Receptors, Cell Surface / analysis*
  • Receptors, Cell Surface / blood
  • Skin / chemistry*
  • Skin / diagnostic imaging
  • Skin / pathology
  • Thrombomodulin / analysis*
  • Thrombomodulin / blood
  • Ultrasonography


  • Antithrombins
  • Blood Coagulation Factors
  • Protein C
  • Protein S
  • Receptors, Cell Surface
  • Thrombomodulin
  • activated protein C receptor
  • antithrombin III-protease complex
  • Antithrombin III
  • Peptide Hydrolases