Shigatoxin triggers thrombotic thrombocytopenic purpura in genetically susceptible ADAMTS13-deficient mice
Open Access
- 1 October 2005
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 115 (10), 2752-2761
- https://doi.org/10.1172/jci26007
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.Keywords
This publication has 36 references indexed in Scilit:
- Identification of Strain-specific Variants of Mouse Adamts13 Gene Encoding von Willebrand Factor-cleaving ProteasePublished by Elsevier ,2004
- VWF73, a region from D1596 to R1668 of von Willebrand factor, provides a minimal substrate for ADAMTS-13Blood, 2004
- ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditionsBlood, 2002
- Genetic Change Wards Off MalariaScience, 2001
- Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving proteaseBest Practice & Research Clinical Haematology, 2001
- Analysing complex genetic traits with chromosome substitution strainsNature Genetics, 2000
- Fatal haemorrhage and incomplete block to embryogenesis in mice lacking coagulation factor VNature, 1996
- High incidence of malaria in α-thalassaemic childrenNature, 1996
- Inducible secretion of large, biologically potent von Willebrand factor multimersCell, 1986
- Unusually Large Plasma Factor VIII: von Willebrand Factor Multimers in Chronic Relapsing Thrombotic Thrombocytopenic PurpuraNew England Journal of Medicine, 1982