Circulating membrane aminophospholipids contribute to thrombotic risk in rheumatoid arthritis.
| Title: | Circulating membrane aminophospholipids contribute to thrombotic risk in rheumatoid arthritis. |
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| Authors: | Costa DO; Division of Infection and Immunity, Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff, UK. Electronic address: costad2@cardiff.ac.uk.; Protty MB; Division of Infection and Immunity, Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff, UK.; Tyrrell VJ; Division of Infection and Immunity, Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff, UK.; Hajeyah AA; Division of Infection and Immunity, Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff, UK.; Morgan BH; Division of Infection and Immunity, Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff, UK.; Mead B; School of Optometry and Vision Sciences, Cardiff University, Cardiff, UK.; Giera M; Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, Netherlands.; Collins PW; Division of Infection and Immunity, Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff, UK; Hematology Department, University Hospital of Wales, Cardiff, UK.; Jenkins PV; Hematology Department, University Hospital of Wales, Cardiff, UK.; Choy E; Division of Infection and Immunity, Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff, UK.; Jones SA; Division of Infection and Immunity, Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff, UK.; O'Donnell VB; Division of Infection and Immunity, Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff, UK. Electronic address: o-donnellvb@cardiff.ac.uk. |
| Source: | Journal of lipid research [J Lipid Res] 2025 Jul; Vol. 66 (7), pp. 100842. Date of Electronic Publication: 2025 Jun 14. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Elsevier Country of Publication: United States NLM ID: 0376606 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1539-7262 (Electronic) Linking ISSN: 00222275 NLM ISO Abbreviation: J Lipid Res Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2021- : [New York] : Elsevier; Original Publication: Memphis, Lipid Research, inc. |
| MeSH Terms: | Arthritis, Rheumatoid*/blood ; Arthritis, Rheumatoid*/complications ; Thrombosis*/blood ; Thrombosis*/etiology ; Phospholipids*/blood; Thrombin/metabolism ; Phosphatidylserines/blood ; Blood Platelets/metabolism ; Extracellular Vesicles/metabolism ; Humans ; Female ; Male ; Middle Aged ; Aged ; Adult |
| Abstract: | Patients with rheumatoid arthritis (RA) are at elevated risk of thrombotic events, yet the underlying mechanisms remain unknown. The contribution of the procoagulant membrane surface provided by aminophospholipids (aPLs) in driving thrombotic risk in RA has not been investigated. Specifically, neither the type of aPL exposed on circulating blood cell membranes in patients is characterized nor is their ability to support thrombin generation is known. Here, lipidomics was used to characterize the external-facing and total levels of aPL molecular species in RA, specifically phosphatidylserine and phosphatidylethanolamine on extracellular vesicles (EVs), platelets, and white blood cells (WBCs). The ability of the cells and EVs to support thrombin generation from patients and healthy controls was compared using an in vitro prothrombinase assay. RA patient plasma had significantly higher levels of thrombin-antithrombin and d-dimers, indicating increased thrombotic activity in vivo. Higher EV and platelet counts were seen in RA, but WBC counts were not elevated. EVs from RA patients supported higher levels of thrombin generation compared with healthy controls, whereas for platelets and WBC, thrombin generation was similar for both groups. EVs from RA patients also showed elevated external-facing phosphatidylserine molecular species, with total aPL also increased. For platelets and WBC, total and external-facing aPL levels were similar. Thrombin-antithrombin (TAT) complexes significantly correlated with EV particle counts, indicating that their circulating numbers are directly related to coagulation in vivo. Overall, our data suggest that elevated plasma EV levels in RA are a major source of procoagulant membranes, contributing to thrombotic risk in RA.; (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.) |
| Competing Interests: | Conflict of interest E. C. has received research grants and honoraria from Abbvie, Alfasigma, Bio-Cancer, Biocon, Biogen, Chugai Pharma, Eli Lilly, Fresenius Kai, Galapagos, Gedeon Richter, Gilead, Inmedix, Janssen, Pfizer, Sanofi, UCB, and Viatris. S. A. J. has received funding support from Hoffman-La Roche, GlaxoSmithKline, Ferring Pharmaceuticals, Meastag Therapeutics, and NovImmune. S. A. J. has acted as an advisory consultant for Roche, Chugai Pharmaceuticals, NovImmune SA, Genentech, Sanofi Regeneron, Johnson & Johnson, Janssen Pharmaceuticals, Eleven Biotherapeutics, and Mab Design. V. O. D. is a consultant for Metasight. |
| Contributed Indexing: | Keywords: aminophospholipids; extracellular vesicles; lipidomics; rheumatoid arthritis; thrombosis |
| Substance Nomenclature: | EC 3.4.21.5 (Thrombin); 0 (Phosphatidylserines); 0 (Phospholipids) |
| Entry Date(s): | Date Created: 20250616 Date Completed: 20250729 Latest Revision: 20250729 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC12273563 |
| DOI: | 10.1016/j.jlr.2025.100842 |
| PMID: | 40523622 |
| Database: | MEDLINE |
Journal Article