Shigatoxin triggers thrombotic thrombocytopenic purpura in genetically susceptible ADAMTS13-deficient mice
David G. Motto, … , Denisa D. Wagner, David Ginsburg
David G. Motto, … , Denisa D. Wagner, David Ginsburg
Published October 3, 2005
Citation Information: J Clin Invest. 2005;115(10):2752-2761. https://doi.org/10.1172/JCI26007.
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Research Article Hematology

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

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.

Authors

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

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Figure 4

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Lack of TTP pathology in Adamts13B/129–/– mice. (A and B) Peripheral blo...
Lack of TTP pathology in Adamts13B/129–/– mice. (A and B) Peripheral blood smears from Adamts13B/129+/+ (A) and Adamts13B/129–/– (B) mice appear identical, without evidence of schistocytes, rbc fragments, thrombocytopenia, or nucleated rbc. (C–H) H&E–stained tissue sections from Adamts13B/129+/+ (C, E, and G) and Adamts13B/129–/– (D, F, and H) are indistinguishable, without evidence of the pink-staining “hyaline thrombi” typically seen in affected organs from humans with TTP. Representative sections are shown from kidney (C and D), brain (E and F), and heart (G and H). Magnification, ×1,000 (A and B); ×400 (C and D); ×100 (E and F); and ×200 (G and H).