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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.
Highlights
Effective hemostasis requires multiple enzyme/cofactor complexes colocated on an electronegative phospholipid (PL) membrane to first generate thrombin, which cleaves fibrinogen to fibrin, forming a stable clot
It shows that the procoagulant action of hydroxyeicosatetraenoic acid-PLs (HETE-PL) that we recently demonstrated in healthy plasma is at least partially dependent on FVIII [25]
In studies designed to look for proof of principles of this hypothesis, we show that coagulation can be enhanced in FVIII, FIX, and FXI-deficient human plasmas in vitro (Figures 1 and 2)
Summary
Effective hemostasis requires multiple enzyme/cofactor complexes colocated on an electronegative phospholipid (PL) membrane to first generate thrombin (factor IIa [FIIa]), which cleaves fibrinogen to fibrin, forming a stable clot. Congenital factor deficiency or acquired hemostatic failure (associated with cardiac surgery) are routinely treated by coagulation factor replacement either individually or as fresh frozen plasma (FFP), while the potential role of procoagulant PLs administered locally has not been considered. Coagulation factor complexes are tissue factor (TF)/FVIIa (extrinsic tenase), FIXa/FVIIIa (intrinsic tenase), and FXa/FVa (prothrombinase), and they all require PL membranes to function [1,2,3]. TF and PLs are implicated in infection-associated coagulation [4,5,6]. Plasma membranes externalize aminoPLs: phosphatidylserine (PS) and phosphatidylethanolamine (PE) [2, 3, 7, 8]. PS is required to support coagulation, while PE enhances PS activity[9,10,11].
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