title: 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.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Motto
authors.forename: Anil K
authors.initials: AK
authors.lastname: Chauhan
authors.forename: Guojing
authors.initials: G
authors.lastname: Zhu
authors.forename: Jonathon
authors.initials: J
authors.lastname: Homeister
authors.forename: Colin B
authors.initials: CB
authors.lastname: Lamb
authors.forename: Karl C
authors.initials: KC
authors.lastname: Desch
authors.forename: Weirui
authors.initials: W
authors.lastname: Zhang
authors.forename: Han-Mou
authors.initials: HM
authors.lastname: Tsai
authors.forename: Denisa D
authors.initials: DD
authors.lastname: Wagner
authors.forename: David
authors.initials: D
authors.lastname: Ginsburg
mesh_terms: D000071120:ADAMTS13 Protein; D000818:Animals; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008666:Metalloendopeptidases / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011697:Purpura, Thrombotic Thrombocytopenic / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D022621:Shiga Toxin / Q000633:toxicity*; D014841:von Willebrand Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D014841:von Willebrand Factor; D022621:Shiga Toxin; C502939:ADAMTS13 protein, mouse; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein