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Blood, 15 March 2006, Vol. 107, No. 6, pp. 2339-2345. Prepublished online as a Blood First Edition Paper on December 1, 2005; DOI 10.1182/blood-2005-04-1758. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-04-1758v1 107/6/2339    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 Hassenpflug, W. A. Articles by Schneppenheim, R. Search for Related Content PubMed PubMed Citation Articles by Hassenpflug, W. A. Articles by Schneppenheim, R. Related Collections Hemostasis, Thrombosis, and Vascular Biology Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Impact of mutations in the von Willebrand factor A2 domain on ADAMTS13-dependent proteolysis Wolf Achim Hassenpflug, Ulrich Budde, Tobias Obser, Dorothea Angerhaus, Elke Drewke, Sonja Schneppenheim, and Reinhard Schneppenheim From the University Medical Center Hamburg-Eppendorf, Department of Pediatric Hematology and Oncology, Hamburg; and the Lab Association Prof Arndt and Partners, Coagulation Laboratory, Hamburg, Germany. Classical von Willebrand disease (VWD) type 2A, the most common qualitative defect of VWD, is caused by loss of high-molecular-weight multimers (HMWMs) of von Willebrand factor (VWF). Underlying mutations cluster in the A2 domain of VWF around its cleavage site for ADAMTS13. We investigated the impact of mutations commonly found in patients with VWD type 2A on ADAMTS13-dependent proteolysis of VWF. We used recombinant human ADAMTS13 (rhuADAMTS13) to digest recombinant full-length VWF and a VWF fragment spanning the VWF A1 through A3 domains, harboring 13 different VWD type 2A mutations (C1272S, G1505E, G1505R, S1506L, M1528V, R1569del, R1597W, V1607D, G1609R, I1628T, G1629E, G1631D, and E1638K). With the exception of G1505E and I1628T, all mutations in the VWF A2 domain increased specific proteolysis of VWF independent of the expression level. Proteolytic susceptibility of mutant VWF in vitro closely correlated with the in vivo phenotype in patients. The results imply that increased VWF susceptibility for ADAMTS13 is a constitutive property of classical VWD type 2A, thus explaining the pronounced proteolytic fragments and loss of HMWM seen in multimer analysis in patients. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Could shear stress be the answer? Miguel A. Cruz Blood 2006 107: 2218. [Full Text] [PDF] This article has been cited by other articles: W. Gao, P. J. Anderson, and J. E. Sadler Extensive contacts between ADAMTS13 exosites and von Willebrand factor domain A2 contribute to substrate specificity Blood, September 1, 2008; 112(5): 1713 - 1719. [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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