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Blood, 1 September 2004, Vol. 104, No. 5, pp. 1344-1349. Prepublished online as a Blood First Edition Paper on May 4, 2004; DOI 10.1182/blood-2003-12-4365. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-12-4365v1 104/5/1344    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 Chen, D. Articles by Dorling, A. Search for Related Content PubMed PubMed Citation Articles by Chen, D. Articles by Dorling, A. Related Collections Hemostasis, Thrombosis, and Vascular Biology Signal Transduction Free Research Articles Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Inhibition of intravascular thrombosis in murine endotoxemia by targeted expression of hirudin and tissue factor pathway inhibitor analogs to activated endothelium Daxin Chen, Konstantinos Giannopoulos, Paul G. Shiels, Zoe Webster, John H. McVey, Geoff Kemball-Cook, Edward Tuddenham, Marilyn Moore, Robert Lechler, and Anthony Dorling From the Department of Immunology, Imperial College London, United Kingdom; PPL Therapeutics, Edinburgh, United Kingdom; Transgenic Facility, Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, United Kingdom; and Haemostasis and Thrombosis Unit, MRC Clinical Sciences Centre, Imperial College, London, United Kingdom. We have generated transgenic mice expressing the leech anticoagulant hirudin and human tissue factor pathway inhibitor tethered to the cell surface by fusion with fragments of human CD4 and P-selectin. Expression of the transgenes is under the control of the CD31 (platelet endothelial cell adhesion molecule [PECAM]) promoter, limiting expression to endothelial cells, monocytes, and platelets. In addition, the P-selectin sequence directs expression to secretory granules. Functional cell surface expression only occurs when the cells are activated. In a mouse model of systemic lipopolysaccharide (LPS)–induced endotoxemia, we show that expression of either anticoagulant on activated endothelium inhibits the widespread intravascular thrombosis, thrombocytopenia, and consumptive coagulopathy associated with endotoxemia. Importantly, non– LPS-treated transgenic mice had normal baseline bleeding times. We speculate that targeted delivery of anticoagulants to the endothelium may be a strategy worth pursuing in clinical sepsis to improve efficacy of systemic anticoagulation while minimizing potential hemorrhagic side effects. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Cell surface–targeted anticoagulation in systemic infection and inflammation Marcel Levi Blood 2004 104: 1231-1232. [Full Text] [PDF] This article has been cited by other articles: D. Chen, A. Carpenter, J. Abrahams, R. C. Chambers, R. I. Lechler, J. H. McVey, and A. Dorling Protease-activated receptor 1 activation is necessary for monocyte chemoattractant protein 1-dependent leukocyte recruitment in vivo J. Exp. Med., July 7, 2008; (2008) jem.20071427. [Abstract] [Full Text] [PDF] B. D. Sachs, G. S. Baillie, J. R. McCall, M. A. Passino, C. Schachtrup, D. A. Wallace, A. J. Dunlop, K. F. MacKenzie, E. Klussmann, M. J. Lynch, et al. p75 neurotrophin receptor regulates tissue fibrosis through inhibition of plasminogen activation via a PDE4/cAMP/PKA pathway J. Cell Biol., July 30, 2007; 177(6): 1119 - 1132. [Abstract] [Full Text] [PDF] Y. Banz, O. M. Hess, S. C. Robson, D. Mettler, P. Meier, A. Haeberli, E. Csizmadia, E. Y. Korchagina, N. V. Bovin, and R. Rieben Locally targeted cytoprotection with dextran sulfate attenuates experimental porcine myocardial ischaemia/reperfusion injury Eur. Heart J., November 1, 2005; 26(21): 2334 - 2343. [Abstract] [Full Text] [PDF] H. G. Nguyen, G. Yu, M. Makitalo, D. Yang, H.-X. Xie, M. R. Jones, and K. Ravid Conditional overexpression of transgenes in megakaryocytes and platelets in vivo Blood, September 1, 2005; 106(5): 1559 - 1564. [Abstract] [Full Text] [PDF]

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