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Cited by 554

The DOI matches its Crossref record; 45 of the 45 references it cites were found in a registry or an index.

Thrombomodulin Mutations in Atypical Hemolytic–Uremic Syndrome

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Delvaeye, Mieke, Noris, Marina, De Vriese, Astrid, Esmon, Charles T., Esmon, Naomi L., Ferrell, Gary, Del-Favero, Jurgen, Plaisance, Stephane, Claes, Bart, Lambrechts, Diether, Zoja, Carla, Remuzzi, Giuseppe, Conway, Edward M.·2009·New England Journal of Medicine
DOI 10.1056/nejmoa0810739
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Abstract

BACKGROUND: The hemolytic-uremic syndrome consists of the triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. The common form of the syndrome is triggered by infection with Shiga toxin-producing bacteria and has a favorable outcome. The less common form of the syndrome, called atypical hemolytic-uremic syndrome, accounts for about 10% of cases, and patients with this form of the syndrome have a poor prognosis. Approximately half of the patients with atypical hemolytic-uremic syndrome have mutations in genes that regulate the complement system. Genetic factors in the remaining cases are unknown. We studied the role of thrombomodulin, an endothelial glycoprotein with anticoagulant, antiinflammatory, and cytoprotective properties, in atypical hemolytic-uremic syndrome. METHODS: We sequenced the entire thrombomodulin gene (THBD) in 152 patients with atypical hemolytic-uremic syndrome and in 380 controls. Using purified proteins and cell-expression systems, we investigated whether thrombomodulin regulates the complement system, and we characterized the mechanisms. We evaluated the effects of thrombomodulin missense mutations associated with atypical hemolytic-uremic syndrome on complement activation by expressing thrombomodulin variants in cultured cells. RESULTS: Of 152 patients with atypical hemolytic-uremic syndrome, 7 unrelated patients had six different heterozygous missense THBD mutations. In vitro, thrombomodulin binds to C3b and factor H (CFH) and negatively regulates complement by accelerating factor I-mediated inactivation of C3b in the presence of cofactors, CFH or C4b binding protein. By promoting activation of the plasma procarboxypeptidase B, thrombomodulin also accelerates the inactivation of anaphylatoxins C3a and C5a. Cultured cells expressing thrombomodulin variants associated with atypical hemolytic-uremic syndrome had diminished capacity to inactivate C3b and to activate procarboxypeptidase B and were thus less protected from activated complement. CONCLUSIONS: Mutations that impair the function of thrombomodulin occur in about 5% of patients with atypical hemolytic-uremic syndrome.

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Metadata

Authors
Delvaeye, M., Noris, M., De Vriese, A., Esmon, C. T., Esmon, N. L., Ferrell, G., Del-Favero, J., Plaisance, S., Claes, B., Lambrechts, D., Zoja, C., Remuzzi, G., & Conway, E. M.
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2009-07-23
Volume
361
Issue
4
Pages
345-357
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa0810739
OpenAlex
W2008607429
Cited by
554
References
45
FWCI
16.80
Type
journal article
Language
en
Open access
bronze

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CoChat. (2026). Citation check: Thrombomodulin Mutations in Atypical Hemolytic–Uremic Syndrome. https://app.cochat.ai/papers/10.1056/nejmoa0810739
The paper
Delvaeye, M., Noris, M., De Vriese, A., Esmon, C. T., Esmon, N. L., Ferrell, G., Del-Favero, J., Plaisance, S., Claes, B., Lambrechts, D., Zoja, C., Remuzzi, G., & Conway, E. M. (2009). Thrombomodulin Mutations in Atypical Hemolytic–Uremic Syndrome. New England Journal of Medicine. https://doi.org/10.1056/nejmoa0810739

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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.