Correspondence
Endothelial Protein C Activation in Meningococcal Sepsis
N Engl J Med 2001; 345:1776-1777December 13, 2001
- Article
To the Editor:
In the August 9 issue, Faust et al.1 reported that the level of endothelial expression of thrombomodulin and the endothelial protein C receptor was lower in patients with meningococcal sepsis than in control subjects. This finding has clinical implications, because it suggests that therapy with activated protein C2 may be superior to treatment with unactivated protein C3 in patients with sepsis. The conclusions of Faust et al. were based in part on immunohistochemical studies of skin-biopsy specimens. One potential pitfall of this type of analysis is that, depending on the timing of the biopsies and the location of the specimens in relation to the purpuric lesions, decreased staining for thrombomodulin or endothelial protein C receptor could have been a secondary effect caused by tissue necrosis. Decreased staining was seen in both thrombosed and unthrombosed vessels, and ultrastructural studies did not demonstrate widespread loss of endothelial cells, but these observations do not exclude the possibility that the tissue obtained for biopsy was becoming necrotic. Was the decreased expression of thrombomodulin and endothelial protein C receptors a consequence, rather than a cause, of microvascular thrombosis?
The “nonspecific” epidermal staining for thrombomodulin reported by Faust et al. is most likely specific for thrombomodulin, because epidermal keratinocytes express thrombomodulin that can function as a cofactor for the activation of protein C.4,5 Faust et al. might consider reexamining their immunohistochemical specimens to determine whether staining for thrombomodulin in keratinocytes was decreased, as was the case in endothelial cells, in patients with meningococcal sepsis. Such an analysis might yield clues regarding the mechanism of the loss of expression of thrombomodulin.
5 ReferencesWarren W. Piette, M.D.
Steven R. Lentz, M.D., Ph.D.
University of Iowa College of Medicine, Iowa City, IA 522421
Faust SN ,Levin M ,Harrison OB , et al. Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N Engl J Med 2001;345:408-416
Full Text | Web of Science | Medline2
Bernard GR ,Vincent J-L ,Laterre P-F , et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699-709
Full Text | Web of Science | Medline3
White B ,Livingstone W ,Murphy C ,Hodgson A ,Rafferty M ,Smith OP . An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia. Blood 2000;96:3719-3724
Web of Science | Medline4
Raife TJ ,Lager DJ ,Madison KC , et al. Thrombomodulin expression by human keratinocytes: induction of cofactor activity during epidermal differentiation. J Clin Invest 1994;93:1846-1851
CrossRef | Web of Science | Medline5
Peterson JJ ,Rayburn HB ,Lager DJ , et al. Expression of thrombomodulin and consequences of thrombomodulin deficiency during healing of cutaneous wounds. Am J Pathol 1999;155:1569-1575
CrossRef | Web of Science | Medline
To the Editor:
How many of the children studied by Faust et al. had a deficiency of a complement protein? A deficiency of such a protein is a known risk factor for meningococcal disease1 and may have had a role in the pathophysiologic process in these patients.
1 ReferencesNeil Kao, M.D.
1202 E. Butler Rd., Greenville, SC 29607
kaoneilmd@aol.com 1
Ross SC ,Densen P . Complement deficiency states and infection: epidemiology, pathogenesis and consequences of neisserial and other infections in immune deficiency. Medicine (Baltimore) 1984;63:243-273
Web of Science | Medline
To the Editor:
Faust et al. reported decreased expression of thrombomodulin and the endothelial protein C receptor in 21 children with meningococcal sepsis. In addition, no activation of protein C was observed in two patients who received unactivated protein C concentrate (150 IU per kilogram of body weight per day).
We conducted a randomized, controlled trial of protein C concentrate in children with meningococcal sepsis. The study was supported by a grant (IMAG-112) from Baxter, Vienna, Austria. Thirty-eight children were randomly assigned to treatment with protein C concentrate (200, 400, or 600 IU per kilogram per day) or placebo. Increased levels of activated protein C relative to base-line levels were observed in 27 of 28 patients treated with protein C concentrate, and the activated protein C area under the curve (from 0 to 6 hours) was significantly correlated with the dose of protein C concentrate (rank-correlation coefficient=0.41; 95 percent confidence interval, 0.14 to 0.68; P=0.012). These data indicate that the activation of protein C can occur in a dose-dependent manner after the infusion of protein C concentrate in children with meningococcal sepsis.
On the basis of our findings, we suggest that the conclusion drawn by Faust et al., that protein C is not activated in children with meningococcal sepsis, was incorrect, perhaps as a result of the very small number of children (two) analyzed. The suggestion by Faust et al. that protein C concentrate is inferior to activated protein C for the treatment of meningococcal sepsis is premature, since a randomized, controlled comparison of these two agents has not been performed in such patients.
Jan A. Hazelzet, M.D., Ph.D.
Ester D. de Kleijn, M.D., Ph.D.
Ronald de Groot, M.D., Ph.D.
Sophia Children's Hospital, 3000 CB Rotterdam, the Netherlands
hazelzet@alkg.azr. nl Author/Editor Response
The authors reply:
To the Editor: Piette and Lentz raise the possibility that decreased expression of thrombomodulin and the endothelial protein C receptor was a consequence rather than a cause of microvascular thrombosis. This possibility is unlikely, since all our samples were obtained on the first day of disease from the edge of the lesion, near normal skin. Reduced staining for thrombomodulin and the endothelial protein C receptor was seen in both thrombosed and unthrombosed vessels in the absence of histologic features of necrosis. Epidermal keratinocyte staining with antithrombomodulin antibodies has been reported previously. We observed no change in the level of epithelial staining for thrombomodulin in meningococcal disease. This proved to be a useful control when we assessed the level of expression of thrombomodulin by dermal vessel.
Complement protein levels were checked during convalescence in all our patients, and none had a deficiency of C3, C4, or total hemolytic complement. Kao's comment raises the interesting question of the role of innate immune responses in meningococcal disease. Although deficiencies of terminal complement components are associated with meningococcal disease, they are rare. In contrast, we have shown that genetic variants of mannose-binding lectin may account for up to one third of cases of meningococcal disease.1
Finally, Hazelzet and colleagues have presented important data that increase understanding of the role of the protein C pathway in meningococcal disease.2 Their data show wide variation in the levels of activated protein C that are achieved after the administration of fixed doses of unactivated protein C concentrate. The wide confidence interval of their data indicates a spectrum of response, with high levels of activated protein C achieved in some patients and little increase in others. Their data are thus in keeping with our results in severely affected patients, in whom no increase in activated protein C was detectable (limit of sensitivity of assay, 3 ng per milliliter). Our collaborator and co-author Dr. Esmon and colleagues have presented new data to show that in certain adult patients with severe sepsis, protein C was not activated as effectively as would have been anticipated.3
Protein C and activated protein C demonstrate competitive binding to the endothelial protein C receptor.4 In patients with severe purpura fulminans, the administration of protein C concentrate may displace activated protein C from the already reduced number of endothelial protein C receptors on the dermal endothelial vessels and, in doing so, worsen the microvascular thrombosis. Once clinical trials have demonstrated the safety and efficacy of the clinically available proteins, a test that will rapidly measure plasma levels of activated protein C3 should allow more exact tailoring of adjunctive protein C or activated protein C therapy to the needs of individual patients.
4 ReferencesSaul N. Faust, M.R.C.P.
Imperial College School of Medicine at St. Mary's Hospital, London W2 1PG, United KingdomRobert S. Heyderman, M.R.C.P., Ph.D.
University of Bristol, Bristol BS8 1TD, United KingdomMichael Levin, F.R.C.P., Ph.D.
Imperial College School of Medicine at St. Mary's Hospital, London W2 1PG, United Kingdom
m.levin@ic. ac. uk 1
Hibberd ML ,Sumiya M ,Summerfield JA ,Booy R ,Levin M . Association of variants of the gene for mannose-binding lectin with susceptibility to meningococcal disease. Lancet 1999;353:1049-1053
CrossRef | Web of Science | Medline2
Hazelzet JA, de Kleijn ED, de Groot R, Stearns-Kurosawa DJ, Swindle K, Hack CE. Levels of activated protein C and soluble protein C receptor in children with meningococcal sepsis are related to survival. In: The XVIIIth Congress of The International Society of Thrombosis and Haemostasis 2001, Paris, July 6–12. abstract.
3
Liaw PCY, Ferrell GL, Esmon CT. Generation and characterization of a monoclonal antibody against human activated protein C: a major advance in the detection of activated protein C in plasma. In: The XVIIIth Congress of The International Society of Thrombosis and Haemostasis 2001, Paris, July 6–12. abstract.
4
Esmon CT ,Ding W ,Yasuhiro K , et al. The protein C pathway: new insights. Thromb Haemost 1997;78:70-74
Web of Science | Medline
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