Enzymatically oxidized phospholipids restore thrombin generation in coagulation factor deficiencies

Slatter, David A., Percy, Charles L., Allen-Redpath, Keith, Gajsiewicz, Joshua M., Brooks, Nick J., Clayton, Aled ORCID: https://orcid.org/0000-0002-3087-9226, Tyrrell, Victoria J., Rosas, Marcela ORCID: https://orcid.org/0000-0002-9442-9638, Lauder, Sarah N., Watson, Andrew, Dul, Maria ORCID: https://orcid.org/0000-0002-0192-2280, Garcia-Diaz, Yoel, Aldrovandi, Maceler, Heurich, Meike, Hall, Judith ORCID: https://orcid.org/0000-0002-6770-7372, Morrissey, James H., Lacroix-Desmazes, Sebastien, Delignat, Sandrine, Jenkins, P. Vincent, Collins, Peter W. ORCID: https://orcid.org/0000-0002-6410-1324 and O'Donnell, Valerie B. ORCID: https://orcid.org/0000-0003-4089-8460 2018. Enzymatically oxidized phospholipids restore thrombin generation in coagulation factor deficiencies. JCI Insight 3 (6) , e98459. 10.1172/jci.insight.98459

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy Medicine
Additional Information:	This work is licensed under the Creative Commons Attribution 4.0 International License.
Publisher:	American Society for Clinical Investigation
ISSN:	2379-3708
Date of First Compliant Deposit:	19 February 2018
Date of Acceptance:	16 February 2018
Last Modified:	23 May 2024 01:05
URI:	https://orca.cardiff.ac.uk/id/eprint/109234

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