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Title
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Thrombomodulin mutations in atypical hemolyticuremic syndrome
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Author
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Abstract
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| Background The hemolyticuremic 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 toxinproducing bacteria and has a favorable outcome. The less common form of the syndrome, called atypical hemolyticuremic 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 hemolyticuremic 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 hemolyticuremic syndrome. Methods We sequenced the entire thrombomodulin gene (THBD) in 152 patients with atypical hemolyticuremic 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 hemolyticuremic syndrome on complement activation by expressing thrombomodulin variants in cultured cells. Results Of 152 patients with atypical hemolyticuremic 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 Imediated 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 hemolyticuremic 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 hemolyticuremic syndrome. |
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Language
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English
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Source (journal)
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The New England journal of medicine. - Boston, Mass., 1928, currens
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Publication
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Boston, Mass.
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2009
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ISSN
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0028-4793
[print]
1533-4406
[online]
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DOI
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10.1056/NEJMOA0810739
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Volume/pages
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361
:4
(2009)
, p. 345-357
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ISI
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000268184500005
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Full text (Publisher's DOI)
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