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Enhanced effect of inhibition of thrombin on endothelium in murine endotoxaemia: Specific inhibition of thrombocytopenia

Chen, D, McVey, JH and Dorling, A (2013) Enhanced effect of inhibition of thrombin on endothelium in murine endotoxaemia: Specific inhibition of thrombocytopenia Thrombosis Research, 132 (6). pp. 750-756.

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Abstract

Introduction In systemic endotoxaemia, bacterial lipopolysaccharide causes the rapid expression of tissue factor (TF) and disseminated intravascular coagulation and in animal models, anticoagulants limit pathology and promote survival. Recent studies have emphasised the importance of TF expressed by mononuclear cells for initiating thrombin generation during endotoxaemia and suggested that endothelial cell TF is of little relevance. However, the precise importance of endothelium for intravascular thrombin generation has not been established. In this study, we compared the effect of equivalent levels of hirudin tethered to either endothelium or platelets and monocytes. Materials and Methods CD31-Hir-Tg mice express a vesicle-targeted, membrane-tethered hirudin fusion protein on endothelium, platelets and monocytes. Bone marrow chimeras between these mice and C57BL/6 were generated The level of intravascular hirudin expressed during endotoxaemia was quantified by inhibition studies using an anti-hirudin antibody and reference to the circulating thrombin anti-thrombin complexes generated in control mice given soluble hirudin. Results and Conclusions Antibody inhibition studies indicated that individual chimeras expressed similar levels of hirudin fusion protein on endothelium alone as on platelets and leukocytes combined and accordingly, the levels of thrombin anti-thrombin complexes and fibrinogen in each chimera were similar, indicating equivalent inhibition of thrombin generation. However, mice with hirudin on endothelium alone developed significantly less thrombocytopenia. These results suggest a hitherto unrecognized role of endothelium in thrombin-dependent platelet sequestration during endotoxaemia. The data have implications for the development of therapeutic strategies based on targeted anticoagulation to limit disseminated intravascular coagulation. © 2013 Elsevier Ltd.

Item Type: Article
Authors :
NameEmailORCID
Chen, DUNSPECIFIEDUNSPECIFIED
McVey, JHUNSPECIFIEDUNSPECIFIED
Dorling, AUNSPECIFIEDUNSPECIFIED
Date : 1 December 2013
Identification Number : 10.1016/j.thromres.2013.10.002
Depositing User : Symplectic Elements
Date Deposited : 28 Mar 2017 10:56
Last Modified : 31 Oct 2017 17:48
URI: http://epubs.surrey.ac.uk/id/eprint/809107

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