SEARCH:   Advanced

Blood, 15 December 2005, Vol. 106, No. 13, pp. 4024. This Article Full Text (PDF) 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 Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Desch, K. Articles by Motto, D. Search for Related Content PubMed Articles by Desch, K. Articles by Motto, D. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS Comment on Nolasco et al, page 4199 ADAMTS13 and VWF: not just for TTP anymore? Karl Desch, and David Motto UNIVERSITY OF MICHIGAN Shiga toxin stimulates VWF release from endothelial cells and impairs ADAMTS13-mediated VWF proteolysis, demonstrating potential roles for VWF and ADAMTS13 in hemolytic-uremic syndrome (HUS) pathogenesis. Acute diarrhea-associated hemolytic uremic syndrome (D+HUS) is a form of thrombotic microangiopathy (TMA) caused primarily by infection with Shiga toxin–producing bacteria, often Escherichia coli of the O157:H7 serotype. HUS is characterized clinically by microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment, and pathologically by microvascular thrombi in the glomerular arterioles. Familiar to the hematologist, several other TMA-associated disorders exhibit clinical characteristics overlapping those of HUS. In particular, the presentation of the disease thrombotic thrombocytopenic purpura (TTP) can be very similar to that of HUS. However, most cases of TTP are caused by deficiency of the ADAMTS13 von Willebrand factor (VWF)–cleaving protease, whereas most cases of D+HUS do not exhibit severely decreased ADAMTS13 activity. In addition, the nature of the thrombi observed in HUS (fibrin rich) is different from that observed in TTP (platelet and VWF rich). Therefore, these 2 disorders are thought to differ in their mechanisms of pathogenesis, with ADAMTS13 deficiency and VWF playing major roles in the microvascular thrombi formation seen in TTP,1 but not in HUS.2 Additionally, the mechanism by which Shiga toxin induces pathologic coagulation remains the subject of considerable research activity. In this issue of Blood, Nolasco and colleagues provide new evidence implicating VWF and ADAMTS13 in the pathogenesis of Shiga toxin–mediated HUS. Using an elegant flow chamber system of cultured endothelial cells (both human umbilical vein endothelial cells [HUVECs] and human kidney glomerular microvascular endothelial cells [GMVECs]), the authors demonstrate that nanomolar concentrations of Shiga toxin stimulate the release of unusually large VWF (ULVWF) multimers, similar to the known endothelial cell agonist histamine. Furthermore, the authors go on to demonstrate that cleavage of ULVWF by ADAMTS13 is significantly impaired in the presence of Shiga toxin, suggesting a potential inhibitory role of this molecule in ADAMTS13-mediated VWF proteolysis. Thus, the authors hypothesize that Shiga toxin–mediated ULVWF release and impairment of ADAMTS13 activity may promote platelet adhesion to glomerular endothelial cells, thereby contributing to the formation of the fibrin-rich thrombi seen in D+HUS. It is becoming increasingly clear that the mechanism by which Shiga toxin induces the thrombotic events seen in HUS is multifactorial and involves more than just the direct toxic effects originally described for this molecule.2-4 For example, Shiga toxin renders cultured endothelial cells thrombogenic through the up-regulation of cell adhesion molecules, and induces the transcription of proinflammatory genes in endothelial cells and leukocytes.2,4 Whether the newly observed effects of Shiga toxin reported by Nolasco and colleagues play a role in the pathogenesis of D+HUS awaits further study. However, in support of this hypothesis, it recently has been demonstrated that Shiga toxin induces a TTP-like syndrome in ADAMTS13-deficient mice.5 Therefore, independent of its potential inhibitory role in ADAMTS13-mediated VWF proteolysis, Shiga toxin may indeed effect ULVWF release in vivo. Future work is sure to shed more light on the roles that Shiga toxin, VWF, and ADAMTS13 play in HUS, TTP, and other thrombotic microangiopathies. References Moake JL. Thrombotic microangiopathies. N Engl J Med. 2002;347: 589-600.[Free Full Text] Tarr PI, Gordon CA, Chandler W. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet. 2005;365: 1073-1086.[Medline] [Order article via Infotrieve] Konowalchuk J, Speirs JI, Stavric S. Vero response to a cytotoxin of Escherichia coli. Infect Immun. 1977;18: 775-779.[Abstract/Free Full Text] Noris M, Remuzzi G. Hemolytic uremic syndrome. J Am Soc Nephrol. 2005;16: 1035-1050.[Free Full Text] Motto DG, Chauhan AK, Zhu G, et al. Shigatoxin triggers thrombotic thrombocytopenic purpura in genetically susceptible ADAMTS13-deficient mice. J Clin Invest. 2005;115: 2752-2761.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: 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 Blood 2005 106: 4199-4209. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) 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 Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Desch, K. Articles by Motto, D. Search for Related Content PubMed Articles by Desch, K. Articles by Motto, D. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

	Copyright © 2005 by American Society of Hematology         Online ISSN: 1528-0020