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Blood, 15 September 2006, Vol. 108, No. 6, pp. 1895-1902. Prepublished online as a Blood First Edition Paper on May 30, 2006; DOI 10.1182/blood-2005-11-012336. This Article Full Text (PDF) All Versions of this Article: blood-2005-11-012336v1 108/6/1895    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 Zaitsev, S. Articles by Muzykantov, V. R. Search for Related Content PubMed PubMed Citation Articles by Zaitsev, S. Articles by Muzykantov, V. R. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 9, 2005 Accepted May 4, 2006 Human complement receptor type 1-directed loading of tissue plasminogen activator on circulating erythrocytes for prophylactic fibrinolysis Sergei Zaitsev, Kristina Danielyan, Juan-Carlos Murciano, Kumkum Ganguly, Tatiana Krasik, Ronald P. Taylor, Steven Pincus, Steven Jones, Douglas B Cines, and Vladimir R. Muzykantov* Institute for Environmental Medicine, University of Pennsylvania Cardiovascular Research Center, Madrid Department of Biochemistry and Molecular Genetics, University of Virginia Elusys Therapeutics Department of Pathology and Laboratory Medicine, University of Pennsylvania * Corresponding author; email: muzykant{at}mail.med.upenn.edu. Plasminogen activators (PA) are not used for thromboprophylaxis due to rapid clearance, bleeding and extravascular toxicity. We describe a novel strategy that overcomes these limitations. We conjugated tPA to a monoclonal antibody (mAb) against complement receptor-1 (CR1) expressed primarily on human RBC. Anti-CR1/tPA conjugate, but not control conjugate (mIgG/tPA), bound to human RBC (1.2x103 tPA molecules/cell at saturation), endowing them with fibrinolytic activity. In vitro, RBC- bound anti-CR1/tPA caused 90% clot lysis vs 20% by naive RBC. In vivo, >40% of anti-CR1/125I-tPA remained within the circulation (~90% bound to RBC) 3 hours after injection in transgenic mice expressing human CR1 (TgN- hCR1) vs <10% in WT mice, without RBC damage; ~90% of mIgG/125I-tPA was cleared from the circulation within 30 min in both WT and TgN-hCR1 mice. Anti-CR1/tPA accelerated lysis of pulmonary emboli and prevented stable occlusive carotid arterial thrombi from forming after injection in TgN-hCR1 mice, but not in WT mice, whereas soluble tPA and mIgG/tPA were ineffective. Anti- CR1/tPA caused 20-fold less re-bleeding in TgN-hCR1 mice than the same dose of tPA. CR1-directed immunotargeting of PAs to circulating RBC provides a safe and practical means to deliver fibrinolytics for thromboprophylaxis in settings characterized by a high imminent risk of thrombosis CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Change erythrocytes into thrombolytic agents Soichi Kojima Blood 2006 108: 1789-1790. [Full Text] [PDF] This article has been cited by other articles: K. Danielyan, K. Ganguly, B.-S. Ding, D. Atochin, S. Zaitsev, J.-C. Murciano, P. L. Huang, S. E. Kasner, D. B. Cines, and V. R. Muzykantov Cerebrovascular Thromboprophylaxis in Mice by Erythrocyte-Coupled Tissue-Type Plasminogen Activator Circulation, September 30, 2008; 118(14): 1442 - 1449. [Abstract] [Full Text] [PDF] K. Ganguly, J.-C. Murciano, R. Westrick, J. Leferovich, D. B. Cines, and V. R. Muzykantov The Glycocalyx Protects Erythrocyte-Bound Tissue-Type Plasminogen Activator from Enzymatic Inhibition J. Pharmacol. Exp. Ther., April 1, 2007; 321(1): 158 - 164. [Abstract] [Full Text] [PDF]

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