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

Abstract

Objective. The risk of cardiovascular events in patients with RA is disproportionately heightened as a result of systemic inflammation. The relative effect of autoimmuneassociated 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.

Deimination, Intermediate Filaments and Associated Proteins

“…Such a mechanism of regulating proteolysis via the deimination of the peptidase inhibitors or peptidase substrates involved therefore seems particularly interesting and should be better deciphered in the future in physiological and pathological contexts. microscopy approach, using fibrin isolated from blood plasma [109]. In this study, the amount of deiminated fibrin was significantly higher in patients than in healthy controls, but this observation was not disease-specific, as already published [79].…”

“…This may participate in pro-inflammatory processes in rheumatoid arthritis [ 107 , 108 ]. An atypical organization of the fibrin network in patients with rheumatoid arthritis has recently been characterized by a scanning electron microscopy approach, using fibrin isolated from blood plasma [ 109 ]. In this study, the amount of deiminated fibrin was significantly higher in patients than in healthy controls, but this observation was not disease-specific, as already published [ 79 ].…”

Covid-19: The Rollercoaster of Fibrin(Ogen), D-Dimer, Von Willebrand Factor, P-Selectin and Their Interactions with Endothelial Cells, Platelets and Erythrocytes

“…However, during hyperfibrinogenaemia, fibrinogen contributes to endothelial dysfunction, proliferation and angiogenesis [ 66 , 70 , 71 , 72 , 73 , 74 , 75 , 100 ]. Endothelial dysfunction also increases the risk of thrombus formation [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ...…”

“…In short, the morphology of D-dimer is characterized by the cross-linked, cleaved, identical monomers which each serve as D-dimer domains (see Figure 3). We also recognize the widespread prevalence in infection-related disease of an abnormal pathway of blood clotting to create an amyloid form of fibrin that is highly resistant to degradation [49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64]. Assessing this in COVID-19 patients would seem to be an important direction.…”

COVID-19: The Rollercoaster of Fibrin(ogen), D-dimer, von Willebrand Factor, P-selectin and Their Interactions with Endothelial Cells, Platelets and Erythrocytes

“…We also recognise the widespread prevalence in infection-related disease of an abnormal pathway of blood clotting to create an amyloid form of fibrin that is highly resistant to degradation [47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62].…”