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Enzymatically-oxidized phospholipids restore thrombin generation in coagulation factor deficiencies

Slatter, David, Percy, Charles, Allen-Redpath, Keith, Gajsiewicz, J M, Brooks, N J, Clayton, Aled, Tyrrell, Victoria, Rosas, Marcela, Lauder, Sarah, Watson, Andrew, Dul, Maria, Garcia-Diaz, Y, Aldrovandi, MacEler, Heurich-Sevcenco, Meike, Hall, Judith, Morrissey, J H, Lacroix-Desmazes, P S, Delignat, S, Jenkins, P V, Collins, Peter and O'Donnell, Valerie 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: Medicine
Pharmacy
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: 05 Nov 2019 03:41
URI: http://orca.cf.ac.uk/id/eprint/109234

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