Enzymatically oxidized phospholipids restore thrombin generation in coagulation factor deficiencies
| Autor: | Slatter, David A., Percy, Charles L., Allen-Redpath, Keith, Gajsiewicz, Joshua M., Brooks, Nick J., Clayton, Aled, Tyrrell, Victoria J., Rosas, Marcela, Lauder, Sarah N., Watson, Andrew, Dul, Maria, Garcia-Diaz, Yoel, Aldrovandi, Maceler, Heurich, Meike, Hall, Judith, Morrissey, James H., Lacroix-Desmazes, Sebastien, Delignat, Sandrine, Jenkins, P. Vincent, Collins, Peter W., O'Donnell, Valerie B. |
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| Přispěvatelé: | Department of Oncology - Pathology, Cancer Center Karolinska [Karolinska Institutet] (CCK), Karolinska Institutet [Stockholm]-Karolinska Institutet [Stockholm], NASA Ames Research Center (ARC), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Cardiac Medicine, National Heart and Lung Institute, Imperial College London, École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Adult
Blood Platelets Male Lipoproteins Hemorrhage Factor VIIa Hemophilia A Thromboplastin Factor IX Mice Hydroxyeicosatetraenoic Acids Animals Humans Blood Coagulation Phospholipids Aged Aged 80 and over Hemostasis Cardiopulmonary Bypass Factor VIII Thrombin Middle Aged Surface Plasmon Resonance Blood Coagulation Factors Neoplasm Proteins Mice Inbred C57BL Cysteine Endopeptidases Factor X [SDV.IMM]Life Sciences [q-bio]/Immunology lipids (amino acids peptides and proteins) Carrier Proteins Research Article circulatory and respiratory physiology |
| Zdroj: | JCI Insight JCI Insight, American Society for Clinical Investigation, 2018, 3 (6), ⟨10.1172/jci.insight.98459⟩ |
| ISSN: | 2379-3708 |
| DOI: | 10.1172/jci.insight.98459⟩ |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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