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JCI Insight. 2018 Mar 22;3(6). pii: 98459. doi: 10.1172/jci.insight.98459.

Enzymatically oxidized phospholipids restore thrombin generation in coagulation factor deficiencies.

Author information

1
Systems Immunity Research Institute and Division of Infection and Immunity, Cardiff University, Cardiff, United Kingdom.
2
Departments of Biological Chemistry and Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
3
Faculty of Natural Science, Department of Chemistry, Imperial College London, London, United Kingdom.
4
Institute of Cancer and Genetics, Velindre Cancer Centre, School of Medicine, and.
5
School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, United Kingdom.
6
School of Chemistry, Vanderbilt University, Nashville, Tennessee, USA.
7
INSERM UMRS 1138, Centre de Recherche des Cordeliers, Paris, France.
8
Haematology Department, University Hospital of Wales, Cardiff, United Kingdom.

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.

KEYWORDS:

Coagulation; Hematology

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