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Blood, 15 December 2005, Vol. 106, No. 13, pp. 4199-4209. Prepublished online as a Blood First Edition Paper on August 30, 2005; DOI 10.1182/blood-2005-05-2111. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-05-2111v1 106/13/4199    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Nolasco, L. H. Articles by Moake, J. L. Search for Related Content PubMed PubMed Citation Articles by Nolasco, L. H. Articles by Moake, J. L. Related Collections Hemostasis, Thrombosis, and Vascular Biology Cell Adhesion and Motility Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Hemolytic uremic syndrome–associated Shiga toxins promote endothelial-cell secretion and impair ADAMTS13 cleavage of unusually large von Willebrand factor multimers Leticia H. Nolasco, Nancy A. Turner, Aubrey Bernardo, Zhenyin Tao, Thomas G. Cleary, Jing-fei Dong, and Joel L. Moake From the Hematology and Thrombosis Research Sections, Department of Medicine, Baylor College of Medicine, Houston, TX; Department of Bioengineering, Rice University, Houston, TX; and the University of Texas Medical School at Houston, Houston, TX. Shiga toxin 1 (Stx-1) and Stx-2 produced by enterohemorrhagic Escherichia coli cause the diarrhea-associated hemolytic uremic syndrome (HUS). This type of HUS is characterized by obstruction of the glomeruli and renal microvasculature by platelet-fibrin thrombi, acute renal failure, thrombocytopenia, microvascular hemolytic anemia, and plasma levels of von Willebrand factor (VWF)-cleaving protease (ADAMTS13) activity that are within a broad normal range. We investigated the mechanism of initial platelet accumulation on Stx-stimulated endothelial cells. Stx-1 or Stx-2 (1-10 nM) stimulated the rapid secretion of unusually large (UL) VWF multimeric strings from human umbilical vein endothelial cells (HUVECs) or human glomerular microvascular endothelial cells (GMVECs). Perfused normal human platelets immediately adhered to the secreted ULVWF multimeric strings. Nanomolar concentrations (1-10 nM) of the Shiga toxins were as effective in inducing the formation of ULVWF-platelet strings as millimolar concentrations (0.1-20 mM) of histamine. The rate of ULVWF-platelet string cleavage by plasma or recombinant ADAMTS13 was delayed by 3 to 10 minutes (or longer) in the presence of 10 nM Stx-1 or Stx-2 compared with 20 mM histamine. Stx-induced formation of ULVWF strings, and impairment of ULVWF-platelet string cleavage by ADAMTS13, may promote initial platelet adhesion above glomerular endothelial cells. These processes may contribute to the evolution of glomerular occlusion by platelet and fibrin thrombi in diarrhea-associated HUS. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: ADAMTS13 and VWF: not just for TTP anymore? Karl Desch and David Motto Blood 2005 106: 4024. [Full Text] [PDF] This article has been cited by other articles: M.-C. Chung, T. G. Popova, S. C. Jorgensen, L. Dong, V. Chandhoke, C. L. Bailey, and S. G. Popov Degradation of Circulating von Willebrand Factor and Its Regulator ADAMTS13 Implicates Secreted Bacillus anthracis Metalloproteases in Anthrax Consumptive Coagulopathy J. Biol. Chem., April 11, 2008; 283(15): 9531 - 9542. [Abstract] [Full Text] [PDF] K. C. Desch and D. G. Motto Thrombotic Thrombocytopenic Purpura in Humans and Mice Arterioscler. Thromb. Vasc. Biol., September 1, 2007; 27(9): 1901 - 1908. [Abstract] [Full Text] [PDF] K. Desch and D. Motto Is There a Shared Pathophysiology for Thrombotic Thrombocytopenic Purpura and Hemolytic-Uremic Syndrome? J. Am. Soc. Nephrol., September 1, 2007; 18(9): 2457 - 2460. [Abstract] [Full Text] [PDF] R. De Cristofaro, F. Peyvandi, L. Baronciani, R. Palla, S. Lavoretano, R. Lombardi, E. Di Stasio, A. B. Federici, and P. M. Mannucci Molecular Mapping of the Chloride-binding Site in von Willebrand Factor (VWF): ENERGETICS AND CONFORMATIONAL EFFECTS ON THE VWF/ADAMTS-13 INTERACTION J. Biol. Chem., October 13, 2006; 281(41): 30400 - 30411. [Abstract] [Full Text] [PDF]

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