Please use this identifier to cite or link to this item: 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

Files in This Item:
File Description SizeFormat 
FullText.pdfCopyright: © 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 MBAdobe PDFView/Open


This item is licensed under a Creative Commons License Creative Commons