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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 (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 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 Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 26, 2005 Accepted August 17, 2005 Hemolytic uremic syndrome-associated Shiga toxins promote endothelial cell secretion and impair ADAMTS-13 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* Hematology, Baylor College of Medicine, Houston, Texas, USA Dept. of Bioengineering, Rice University, Houston, Texas, USA Thrombosis Research Sections, Dept. of Medicine, Baylor College of Medicine, Houston, Texas, USA University of Texas Medical School at Houston, Houston, Texas, USA Hematology, Baylor College of Medicine, Houston, Texas, USA; Thrombosis Research Sections, Dept. of Medicine, Baylor College of Medicine, Houston, Texas, USA; Dept. of Bioengineering, Rice University, Houston, Texas, USA * Corresponding author; email: jmoake{at}rice.edu. Shiga toxin (Stx)-1 and Stx-2 produced by enterohemorrhagic E. 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 (ADAMTS-13) 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 milimolar concentrations (0.1-20 mM) of histamine. The rate of ULVWF-platelet string cleavage by plasma or recombinant ADAMTS-13 was delayed by 3-10 minutes (or longer) in the presence of 10 nM Stx-1 or Stx-2, compared to 20 mM histamine. Stx-induced formation of ULVWF-strings, and impairment of ULVWF-platelet string cleavage by ADAMTS-13, 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: A. Taranta, A. Gianviti, A. Palma, V. De Luca, L. Mannucci, M. A. Procaccino, G. M. Ghiggeri, G. Caridi, D. Fruci, S. Ferracuti, et al. Genetic risk factors in typical haemolytic uraemic syndrome Nephrol. Dial. Transplant., June 1, 2009; 24(6): 1851 - 1857. [Abstract] [Full Text] [PDF] 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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