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Blood, 20 August 2009, Vol. 114, No. 8, pp. 1666-1674. Prepublished online as a Blood First Edition Paper on June 18, 2009; DOI 10.1182/blood-2009-01-195461. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2009-01-195461v1 114/8/1666    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 CrossRef Google Scholar Articles by Raife, T. J. Articles by Zheng, X. L. PubMed PubMed Citation Articles by Raife, T. J. Articles by Zheng, X. L. Related Collections Thrombosis and Hemostasis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  THROMBOSIS AND HEMOSTASIS Leukocyte proteases cleave von Willebrand factor at or near the ADAMTS13 cleavage site Thomas J. Raife1, Wenjing Cao2, Bonnie S. Atkinson3, Bruce Bedell1, Robert R. Montgomery3,4, Steven R. Lentz5, George F. Johnson1, and X. Long Zheng2 1 Department of Pathology, University of Iowa Carver College of Medicine, Iowa City; 2 Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The University of Pennsylvania Medical Center; 3 Blood Research Institute, Blood Center of Wisconsin, Milwaukee; 4 Department of Pediatrics, Medical College of Wisconsin, Milwaukee; and 5 Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City The function of von Willebrand factor (VWF) is regulated by proteolysis, which limits its multimeric size and ability to tether platelets. The importance of ADAMTS13 metalloprotease in VWF regulation is demonstrated by the association between severe deficiency of ADAMTS13 and thrombotic thrombocytopenic purpura (TTP). However, ADAMTS13 activity levels do not always correlate with the clinical course of TTP, suggesting that other proteases could be important in regulating VWF. We identified 4 leukocyte proteases that cleave the synthetic VWF substrate FRETS-VWF73 and multimeric VWF. Elastase and proteinase 3 (PR3) cleave multimeric VWF and FRETS-VWF73 at the V1607-T1608 peptide bond; cathepsin G and matrix metalloprotease 9 cleave VWF substrates at the Y1605-M1606 and M1606-V1607 bonds, respectively. Isolated intact human neutrophils cleave FRETS-VWF73 at the V1607-T1608 peptide bond, suggesting that elastase or PR3 expressed on leukocyte surfaces might cleave VWF. In the presence of normal or ADAMTS13-deficient plasma, cleavage of FRETS-VWF73 by resting neutrophils is abolished. However, activated neutrophils retain proteolytic activity toward FRETS-VWF73 in the presence of plasma. Although the in vivo relevance remains to be established, these studies suggest the existence of a "hot spot" of VWF proteolysis in the VWF A2 domain, and support the possibility that activated leukocytes may participate in the proteolytic regulation of VWF. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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