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Enzymatically oxidized phospholipids restore thrombin generation in coagulation factor deficiencies

DOI: 10.1172/jci.insight.98459 DOI Help

Authors: David A. Slatter (Cardiff University) , Charles L. Percy (Cardiff University) , Keith Allen-Redpath (Cardiff University) , Joshua M. Gajsiewicz (University of Michigan Medical School) , Nick J. Brooks (Imperial College London) , Aled Clayton (Cardiff University) , Victoria J. Tyrrell (Cardiff University) , Marcela Rosas (Cardiff University) , Sarah N. Lauder (Cardiff University) , Andrew Watson (Cardiff University) , Maria Dul (Cardiff University) , Yoel Garcia-Diaz (Vanderbilt University) , Maceler Aldrovandi (Cardiff University) , Meike Heurich (Cardiff University) , Judith Hall (Cardiff University) , James H. Morrissey (University of Michigan Medical School) , Sebastien Lacroix-Desmazes (Centre de Recherche des Cordeliers) , Sandrine Delignat (Centre de Recherche des Cordeliers) , P. Vincent Jenkins (University Hospital of Wales) , Peter W. Collins (Cardiff University) , Valerie B. O'Donnell (Cardiff University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Jci Insight , VOL 3

State: Published (Approved)
Published: March 2018

Open Access Open Access

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.

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials

Instruments: I22-Small angle scattering & Diffraction

Added On: 28/03/2018 10:59


Discipline Tags:

Health & Wellbeing Life Sciences & Biotech

Technical Tags:

Scattering Small Angle X-ray Scattering (SAXS)