PT  - JOURNAL ARTICLE
AU  - Johannes A. Bezuidenhout
AU  - Chantelle Venter
AU  - Timothy Roberts
AU  - Gareth Tarr
AU  - Douglas B. Kell
AU  - Etheresia Pretorius
TI  - The Atypical Fibrin Fibre Network in Rheumatoid Arthritis and its Relation to Autoimmunity, Inflammation and Thrombosis
AID  - 10.1101/2020.05.28.121301
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.05.28.121301
4099  - http://biorxiv.org/content/early/2020/05/30/2020.05.28.121301.short
4100  - http://biorxiv.org/content/early/2020/05/30/2020.05.28.121301.full
AB  - 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 StatementThe authors have declared no competing interest.