Enzymatically oxidized phospholipids restore thrombin generation in coagulation factor deficiencies

JCI Insight. 2018 Mar 22;3(6):e98459. doi: 10.1172/jci.insight.98459.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Blood Coagulation
  • Blood Coagulation Factors / genetics
  • Blood Coagulation Factors / metabolism*
  • Blood Platelets
  • Cardiopulmonary Bypass / adverse effects
  • Carrier Proteins
  • Cysteine Endopeptidases
  • Factor IX / genetics
  • Factor VIII / genetics
  • Factor VIIa / metabolism
  • Factor X / genetics
  • Hemophilia A
  • Hemorrhage / enzymology*
  • Hemorrhage / metabolism*
  • Hemorrhage / prevention & control
  • Hemostasis
  • Humans
  • Hydroxyeicosatetraenoic Acids
  • Lipoproteins / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Neoplasm Proteins
  • Phospholipids / metabolism*
  • Surface Plasmon Resonance
  • Thrombin / metabolism*
  • Thromboplastin / antagonists & inhibitors
  • Thromboplastin / metabolism


  • Blood Coagulation Factors
  • Carrier Proteins
  • Hydroxyeicosatetraenoic Acids
  • Lipoproteins
  • Neoplasm Proteins
  • Phospholipids
  • lipoprotein-associated coagulation inhibitor
  • F8 protein, human
  • Factor VIII
  • Factor IX
  • Factor X
  • Thromboplastin
  • Factor VIIa
  • Thrombin
  • Cysteine Endopeptidases
  • cancer procoagulant