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http://bura.brunel.ac.uk/handle/2438/29145
Title: | Enzymatically oxidized phospholipids restore thrombin generation in coagulation factor deficiencies |
Authors: | Slatter, DA Percy, CL Allen-Redpath, K Gajsiewicz, JM Brooks, NJ Clayton, A Tyrrell, VJ Rosas, M Lauder, SN Watson, A Dul, M Garcia-Diaz, Y Aldrovandi, M Heurich, M Hall, J Morrissey, JH Lacroix-Desmazes, S Delignat, S Jenkins, PV Collins, PW O'Donnell, VB |
Issue Date: | 22-Mar-2018 |
Publisher: | American Society for Clinical Investigation |
Citation: | Slatter, D.A. et al. (2018) 'Enzymatically oxidized phospholipids restore thrombin generation in coagulation factor deficiencies', JCI insight, 2018, 3 (6), e98459, pp. 1 - 18. doi: 10.1172/jci.insight.98459. |
Abstract: | Hemostatic defects are treated using coagulation factors; however, clot formation also requires a procoagulant phospholipid (PL) surface. Here, we show that innate immune cell-derived enzymatically oxidized phospholipids (eoxPL) termed hydroxyeicosatetraenoic acid-phospholipids (HETE-PLs) restore hemostasis in human and murine conditions of pathological bleeding. HETE-PLs abolished blood loss in murine hemophilia A and enhanced coagulation in factor VIII- (FVIII-), FIX-, and FX-deficient human plasma . HETE-PLs were decreased in platelets from patients after cardiopulmonary bypass (CPB). To explore molecular mechanisms, the ability of eoxPL to stimulate individual isolated coagulation factor/cofactor complexes was tested in vitro. Extrinsic tenase (FVIIa/tissue factor [TF]), intrinsic tenase (FVIIIa/FIXa), and prothrombinase (FVa/FXa) all were enhanced by both HETE-PEs and HETE-PCs, suggesting a common mechanism involving the fatty acid moiety. In plasma, 9-, 15-, and 12-HETE-PLs were more effective than 5-, 11-, or 8-HETE-PLs, indicating positional isomer specificity. Coagulation was enhanced at lower lipid/factor ratios, consistent with a more concentrated area for protein binding. Surface plasmon resonance confirmed binding of FII and FX to HETE-PEs. HETE-PEs increased membrane curvature and thickness, but not surface charge or homogeneity, possibly suggesting increased accessibility to cations/factors. In summary, innate immune-derived eoxPL enhance calcium-dependent coagulation factor function, and their potential utility in bleeding disorders is proposed. |
Description: | Supplemental data are available online at: https://insight.jci.org/articles/view/98459#sd . |
URI: | https://bura.brunel.ac.uk/handle/2438/29145 |
DOI: | https://doi.org/10.1172/jci.insight.98459 |
Other Identifiers: | ORCiD: Keith Allen-Redpath https://orcid.org/0009-0004-7213-2675. e98459 |
Appears in Collections: | Dept of Life Sciences Research Papers |
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FullText.pdf | Copyright: © 2018 Slatter et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/). | 5.47 MB | Adobe PDF | View/Open |
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