TY - JOUR AU - Slatter, David A. AU - Percy, Charles L. AU - Allen-Redpath, Keith AU - Gajsiewicz, Joshua M. AU - Brooks, Nick J. AU - Clayton, Aled AU - Tyrrell, Victoria J. AU - Rosas, Marcela AU - Lauder, Sarah N. AU - Watson, Andrew AU - Dul, Maria AU - Garcia-Diaz, Yoel AU - Aldrovandi, Maceler AU - Heurich, Meike AU - Hall, Judith AU - Morrissey, James H. AU - Lacroix-Desmazes, Sebastien AU - Delignat, Sandrine AU - Jenkins, P. Vincent AU - Collins, Peter W. AU - O’Donnell, Valerie B. T1 - Enzymatically oxidized phospholipids restore thrombin generation in coagulation factor deficiencies PY - 2019/03/19/ AB - 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. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.98459 VL - 3 IS - 6 UR - https://doi.org/10.1172/jci.insight.98459 PB - The American Society for Clinical Investigation ER -