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Blood, 22 January 2009, Vol. 113, No. 4, pp. 936-944. Prepublished online as a Blood First Edition Paper on October 22, 2008; DOI 10.1182/blood-2008-06-163675. This Article Full Text (PDF) All Versions of this Article: blood-2008-06-163675v1 113/4/936    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 Tucker, E. I Articles by Hanson, S. R Search for Related Content PubMed PubMed Citation Articles by Tucker, E. I Articles by Hanson, S. R Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 19, 2008 Accepted October 6, 2008 Prevention of vascular graft occlusion and thrombus-associated thrombin generation by inhibition of factor XI Erik I Tucker, Ulla M Marzec, Tara C White, Sawan Hurst, Sandra Rugonyi, Owen JT McCarty, David Gailani, Andras Gruber*, and Stephen R Hanson Department of Biomedical Engineering, Oregon Health & Science University School of Medicine, Portland, OR, United States Department of Cell and Developmental Biology, Oregon Health & Science University School of Medicine, Portland, OR, United States Departments of Pathology and Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States Department of Medicine, Oregon Health & Science University School of Medicine, Portland, OR, United States Oregon National Primate Research Center, Beaverton, OR, United States * Corresponding author; email: grubera{at}ohsu.edu. The protease thrombin is required for normal hemostasis and pathologic thrombogenesis. Since the mechanism of coagulation factor XI (FXI)-dependent thrombus growth remains unclear, we investigated the contribution of FXI to thrombus formation in a primate thrombosis model. Pre-treatment of baboons with a novel anti-human FXI monoclonal antibody (aXIMab - 2 mg/kg), inhibited plasma FXI by 99% for 10 days, and suppressed thrombin-antithrombin (TAT) complex and -thromboglobulin (TG) formation measured immediately downstream from thrombi forming within collagen-coated vascular grafts. FXI inhibition with aXIMab limited platelet and fibrin deposition in 4 mm diameter grafts without an apparent increase in D-dimer release from thrombi, and prevented the occlusion of 2 mm diameter grafts without affecting template bleeding times. In comparison, pre-treatment with aspirin (32 mg/kg) prolonged bleeding times but failed to prevent graft occlusion, supporting the concept that FXI blockade may offer therapeutic advantages over other antithrombotic agents in terms of bleeding complications. In whole blood, aXIMab prevented fibrin formation in a collagen-coated flow chamber, independent of factor XII and factor VII. These data suggest that endogenous FXI contributes to arterial thrombus propagation through a striking amplification of thrombin generation at the thrombus luminal surface. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. C. White-Adams, M. A. Berny, E. I. Tucker, J. M. Gertz, D. Gailani, R. T. Urbanus, P. G. de Groot, A. Gruber, and O. J.T. McCarty Identification of Coagulation Factor XI as a Ligand for Platelet Apolipoprotein E Receptor 2 (ApoER2) Arterioscler Thromb Vasc Biol, October 1, 2009; 29(10): 1602 - 1607. [Abstract] [Full Text] [PDF] D. V. Kravtsov, A. Matafonov, E. I. Tucker, M.-f. Sun, P. N. Walsh, A. Gruber, and D. Gailani Factor XI contributes to thrombin generation in the absence of factor XII Blood, July 9, 2009; 114(2): 452 - 458. [Abstract] [Full Text] [PDF]

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