ROS-driven structural and functional fibrinogen modifications are reverted by interleukin-6 inhibition in Giant Cell Arteritis

Alessandra Bettiol; Flavia Rita Argento; Eleonora Fini; Federica Bello; Gerardo Di Scala; Niccolò Taddei; Giacomo Emmi; Domenico Prisco; Matteo Becatti; Claudia Fiorillo

doi:10.1016/j.thromres.2023.08.011

ROS-driven structural and functional fibrinogen modifications are reverted by interleukin-6 inhibition in Giant Cell Arteritis

Thromb Res. 2023 Oct:230:1-10. doi: 10.1016/j.thromres.2023.08.011. Epub 2023 Aug 15.

Affiliations

¹ Department of Experimental and Clinical Medicine, University of Firenze, Largo Brambilla 3, 50134, Firenze, Italy.
² Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Firenze; viale Pieraccini, 6 - 50139 Firenze, Italy.
³ Department of Experimental and Clinical Medicine, University of Firenze, Largo Brambilla 3, 50134, Firenze, Italy; Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Melbourne, Australia.
⁴ Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Firenze; viale Pieraccini, 6 - 50139 Firenze, Italy. Electronic address: matteo.becatti@unifi.it.

PMID: 37598635
DOI: 10.1016/j.thromres.2023.08.011

Abstract

Background: Cranial and extra-cranial vascular events are among the major determinants of morbidity and mortality in Giant Cell Arteritis (GCA). Vascular events seem mostly of inflammatory nature, although the precise pathogenetic mechanisms are still unclear. We investigated the role of oxidation-induced structural and functional fibrinogen modifications in GCA. The effects of the anti-IL6R tocilizumab in counteracting these mechanisms were also assessed.

Materials and methods: A cross-sectional study was conducted on 65 GCA patients and 65 matched controls. Leucocyte reactive oxygen species (ROS) production, redox state, and fibrinogen structural and functional features were compared between patients and controls. In 19 patients receiving tocilizumab, pre vs post treatment variations were assessed.

Results: GCA patients displayed enhanced blood lymphocyte, monocyte and neutrophil ROS production compared to controls, with an increased plasma lipid peroxidation and a reduced total antioxidant capacity. This oxidative impairment resulted in a sustained fibrinogen oxidation (i.e. dityrosine content 320 (204-410) vs 136 (120-176) Relative Fluorescence Units (RFU), p < 0.0001), with marked alterations in fibrinogen secondary and tertiary structure [intrinsic fluorescence: 134 (101-227) vs 400 (366-433) RFU, p < 0.001]. Structural alterations paralleled a remarkable fibrinogen functional impairment, with a reduced ability to polymerize into fibrin and a lower fibrin susceptibility to plasmin-induced lysis. In patients receiving tocilizumab, a significant improvement in redox status was observed, accompanied by a significant improvement in fibrinogen structural and functional features (p < 0.001).

Conclusions: An impaired redox status accounts for structural and functional fibrinogen modifications in GCA, suggesting a potential role of tocilizumab for cardiovascular prevention in GCA.

Keywords: Fibrinogen; Giant cell arteritis; Reactive oxygen species; Thrombosis; Vasculitis.

MeSH terms

Cross-Sectional Studies
Fibrin
Fibrinogen / chemistry
Giant Cell Arteritis* / drug therapy
Hemostatics*
Humans
Interleukin-6
Reactive Oxygen Species

Substances

Interleukin-6
Reactive Oxygen Species
Fibrinogen
Hemostatics
Fibrin