Shigatoxin triggers thrombotic thrombocytopenic purpura in genetically susceptible ADAMTS13-deficient mice

David G. Motto; Anil K. Chauhan; Guojing Zhu; Jonathon Homeister; Colin B. Lamb; Karl C. Desch; Weirui Zhang; Han-Mou Tsai; Denisa D. Wagner; David Ginsburg

doi:10.1172/JCI26007

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Shigatoxin triggers thrombotic thrombocytopenic purpura in genetically susceptible ADAMTS13-deficient mice

Journal article

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Shigatoxin triggers thrombotic thrombocytopenic purpura in genetically susceptible ADAMTS13-deficient mice

David G. Motto, Anil K. Chauhan, Guojing Zhu, Jonathon Homeister, Colin B. Lamb, Karl C. Desch, Weirui Zhang, Han-Mou Tsai, Denisa D. Wagner and David Ginsburg

The Journal of clinical investigation, Vol.115(10), pp.2752-2761

10/01/2005

DOI: 10.1172/JCI26007

PMCID: PMC1240119

PMID: 16200209

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Abstract

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening illness caused by deficiency of the vWF-cleaving protease ADAMTS13. Here we show that ADAMTS13-deficient mice are viable and exhibit normal survival, although vWF-mediated platelet-endothelial interactions are significantly prolonged. Introduction of the genetic background CASA/Rk (a mouse strain with elevated plasma vWF) resulted in the appearance of spontaneous thrombocytopenia in a subset of ADAMTS13-deficient mice and significantly decreased survival. Challenge of these mice with shigatoxin (derived from bacterial pathogens associated with the related human disease hemolytic uremic syndrome) resulted in a striking syndrome closely resembling human TTP. Surprisingly, no correlation was observed between plasma vWF level and severity of TTP, implying the existence of TTP-modifying genes distinct from vWF. These data suggest that microbe-derived toxins (or possibly other sources of endothelial injury), together with additional genetic susceptibility factors, are required to trigger TTP in the setting of ADAMTS13 deficiency.

Details

Title: Subtitle: Shigatoxin triggers thrombotic thrombocytopenic purpura in genetically susceptible ADAMTS13-deficient mice
Creators: David G. Motto - University of Michigan–Ann Arbor
Anil K. Chauhan - Harvard University
Guojing Zhu - University of Michigan–Ann Arbor
Jonathon Homeister - University of Michigan–Ann Arbor
Colin B. Lamb - Latino Health Institute
Karl C. Desch - University of Michigan–Ann Arbor
Weirui Zhang - University of Michigan–Ann Arbor
Han-Mou Tsai - Yeshiva University
Denisa D. Wagner - Harvard University
David Ginsburg - Institut de Génétique Humaine
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.115(10), pp.2752-2761
Publisher: American Society for Clinical Investigation
DOI: 10.1172/JCI26007
PMID: 16200209
PMCID: PMC1240119
ISSN: 0021-9738
eISSN: 1558-8238
Language: English
Date published: 10/01/2005
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984359672902771

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