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DC Field | Value | Language |
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dc.contributor.author | Slatter, DA | - |
dc.contributor.author | Percy, CL | - |
dc.contributor.author | Allen-Redpath, K | - |
dc.contributor.author | Gajsiewicz, JM | - |
dc.contributor.author | Brooks, NJ | - |
dc.contributor.author | Clayton, A | - |
dc.contributor.author | Tyrrell, VJ | - |
dc.contributor.author | Rosas, M | - |
dc.contributor.author | Lauder, SN | - |
dc.contributor.author | Watson, A | - |
dc.contributor.author | Dul, M | - |
dc.contributor.author | Garcia-Diaz, Y | - |
dc.contributor.author | Aldrovandi, M | - |
dc.contributor.author | Heurich, M | - |
dc.contributor.author | Hall, J | - |
dc.contributor.author | Morrissey, JH | - |
dc.contributor.author | Lacroix-Desmazes, S | - |
dc.contributor.author | Delignat, S | - |
dc.contributor.author | Jenkins, PV | - |
dc.contributor.author | Collins, PW | - |
dc.contributor.author | O'Donnell, VB | - |
dc.date.accessioned | 2024-06-10T12:04:17Z | - |
dc.date.available | 2024-06-10T12:04:17Z | - |
dc.date.issued | 2018-03-22 | - |
dc.identifier | ORCiD: Keith Allen-Redpath https://orcid.org/0009-0004-7213-2675. | - |
dc.identifier | e98459 | - |
dc.identifier.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. | en_US |
dc.identifier.uri | https://bura.brunel.ac.uk/handle/2438/29145 | - |
dc.description | Supplemental data are available online at: https://insight.jci.org/articles/view/98459#sd . | en_US |
dc.description.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. | en_US |
dc.description.sponsorship | Wellcome Trust (094143/Z/10/Z) and British Heart Foundation (RG/12/11/29815) (VBOD, PWC), European Research Council (VBOD), British Heart Foundation Research Fellowship (FS/11/42/28753) (CLP) and NIH R35 HL135823 to JM. | en_US |
dc.format.extent | 1 - 18 | - |
dc.format.medium | Electronic | - |
dc.language.iso | en_US | en_US |
dc.publisher | American Society for Clinical Investigation | en_US |
dc.rights | 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/). | - |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | - |
dc.title | Enzymatically oxidized phospholipids restore thrombin generation in coagulation factor deficiencies | en_US |
dc.type | Article | en_US |
dc.date.dateAccepted | 2018-02-16 | - |
dc.identifier.doi | https://doi.org/10.1172/jci.insight.98459 | - |
dc.relation.isPartOf | JCI insight | - |
pubs.issue | 6 | - |
pubs.publication-status | Published | - |
pubs.volume | 3 | - |
dc.identifier.eissn | 2379-3708 | - |
dc.rights.license | https://creativecommons.org/licenses/by/4.0/legalcode.en | - |
dc.rights.holder | Slatter et al. | - |
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 |
This item is licensed under a Creative Commons License