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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 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 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 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 Hemostasis, Thrombosis, and Vascular Biology Immunobiology Red Cells Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY 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 From the Institute for Environmental Medicine, the Department of Pathology and Laboratory Medicine, and the Department of Pharmacology and Targeted Therapeutics Program of the Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia; the Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville; Elusys Therapeutics, Pine Brook, NC; and Centro Nacional De Investigationes Cardiovasculares (CNIC), Madrid, Spain. Plasminogen activators (PAs) are not used for thromboprophylaxis due to rapid clearance, bleeding, and extravascular toxicity. We describe a novel strategy that overcomes these limitations. We conjugated tissue-type PA (tPA) to a monoclonal antibody (mAb) against complement receptor type 1 (CR1) expressed primarily on human RBCs. Anti-CR1/tPA conjugate, but not control conjugate (mIgG/tPA), bound to human RBCs (1.2 x 103 tPA molecules/cell at saturation), endowing them with fibrinolytic activity. In vitro, RBC-bound anti-CR1/tPA caused 90% clot lysis versus 20% by naive RBCs. In vivo, more than 40% of anti-CR1/125I-tPA remained within the circulation (90% bound to RBCs) 3 hours after injection in transgenic mice expressing human CR1 (TgN-hCR1) versus less than 10% in wild-type (WT) mice, without RBC damage; approximately 90% of mIgG/125I-tPA was cleared from the circulation within 30 minutes 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 rebleeding in TgN-hCR1 mice than the same dose of tPA. CR1-directed immunotargeting of PAs to circulating RBCs 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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