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The Atypical Fibrin Fibre Network in Rheumatoid Arthritis and its Relation to Autoimmunity, Inflammation and Thrombosis

Johannes A. Bezuidenhout, Chantelle Venter, Timothy Roberts, Gareth Tarr, View ORCID ProfileDouglas B. Kell, View ORCID ProfileEtheresia Pretorius
doi: https://doi.org/10.1101/2020.05.28.121301
Johannes A. Bezuidenhout
1Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, Private Bag X1 Matieland, 7602, South Africa
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Chantelle Venter
1Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, Private Bag X1 Matieland, 7602, South Africa
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Timothy Roberts
1Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, Private Bag X1 Matieland, 7602, South Africa
3Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Crown St, Liverpool L69 7ZB, UK
5University College London Hospital NHS Foundation Trust, 250 Euston Road, London, NW1 2PB.
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Gareth Tarr
2Division of Rheumatology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241 Cape Town, 8000, South Africa
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Douglas B. Kell
1Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, Private Bag X1 Matieland, 7602, South Africa
3Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Crown St, Liverpool L69 7ZB, UK
4The Novo Nordisk Foundation Centre for Biosustainability, Building 220, Chemitorvet 200, Technical University of Denmark, 2800 Kongens Lyngby, Denmark
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  • For correspondence: resiap@sun.ac.za dbk@liv.ac.uk
Etheresia Pretorius
1Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, Private Bag X1 Matieland, 7602, South Africa
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  • ORCID record for Etheresia Pretorius
  • For correspondence: resiap@sun.ac.za dbk@liv.ac.uk
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Abstract

Objective The risk of cardiovascular events in patients with RA is disproportionately heightened as a result of systemic inflammation. The relative effect of autoimmune-associated citrullination on the structure and thrombotic potential of fibrin(ogen) remains unknown. We therefore compared indices of vascular function, inflammation, coagulation and fibrin clot composition in RA patients with healthy controls and evaluated inter-parameter relationships.

Methods Blood samples were collected from 30 RA patients and 25 age- and gender-matched healthy volunteers. Levels of SAA, CRP, ICAM-1 and VCAM-1 was measured using a sandwich immunoassay. Whole blood coagulation was assessed using Thromboelastography. Fibrin clot networks and fiber structure was investigated using Scanning Electron Microscopy. The detection and quantification of citrullination in formed fibrin clots were performed using a fluorescently labeled Citrulline monoclonal antibody with Confocal Microscopy.

Results Concentrations of SAA, CRP and ICAM-1 were significantly elevated in RA patients compared to controls. TEG parameters relating to coagulation initiation (R and K), rate of fibrin cross-linking (α-Angle), and time to reach maximum thrombus generation (TMRTG) were attenuated in RA patients. Parameters relating to clot strength (MA, MRTG, TGG) did not statistically differ between RA and controls. Logistic regression modelling revealed stronger association between acute phase reactants (CRP, SAA) with TEG parameters than endothelial function markers. Microscopic analysis revealed denser networks of thicker fibrin fibers in RA patients compared to controls [median (interquartile range) 214 (170-285) vs 120 (100-144) nm respectively, p<0.0001, Odds ratio=22.7). Detection of multiple citrullinated regions within fibrin clot structures in RA patients, which was less prevalent in control samples (p<0.05, OR=2.2).

Conclusion Patients with active RA display a coagulation profile that is dissimilar to general findings associated with other inflammatory conditions. The alteration of protein structures by autoimmune linked citrullination could play a role in determining the structure of fibrin and the potential of conferring a heightened thrombotic risk in RA patients.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted May 30, 2020.
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The Atypical Fibrin Fibre Network in Rheumatoid Arthritis and its Relation to Autoimmunity, Inflammation and Thrombosis
Johannes A. Bezuidenhout, Chantelle Venter, Timothy Roberts, Gareth Tarr, Douglas B. Kell, Etheresia Pretorius
bioRxiv 2020.05.28.121301; doi: https://doi.org/10.1101/2020.05.28.121301
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The Atypical Fibrin Fibre Network in Rheumatoid Arthritis and its Relation to Autoimmunity, Inflammation and Thrombosis
Johannes A. Bezuidenhout, Chantelle Venter, Timothy Roberts, Gareth Tarr, Douglas B. Kell, Etheresia Pretorius
bioRxiv 2020.05.28.121301; doi: https://doi.org/10.1101/2020.05.28.121301

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