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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.
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Submitted December 22, 2003
Accepted April 14, 2004
Inhibition of intravascular thrombosis in murine endotoxaemia by targeted expression of hirudin and tissue factor pathway inhibitor analogues 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*
Department of Immunology, Imperial College London, London, United Kingdom
PPL Therapeutics plc, Edinburgh, United Kingdom
Transgenic Facility, MRC Clinical Sciences Centre, Imperial College London, London, United Kingdom
Haemostasis and Thrombosis Unit, MRC Clinical Sciences Centre, Imperial College London, London, United Kingdom
* Corresponding author; email: a.dorling{at}imperial.ac.uk.
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 (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 endotoxaemia we show that expression of either anticoagulant on activated endothelium inhibits the widespread intravascular thrombosis, thrombocytopenia and consumptive coagulopathy associated with endotoxaemia. 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 minimising potential haemorrhagic side effects.
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