Abstract
AimsThe risk of cardiovascular events in patients with Rheumatoid Arthritis (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 parameter association with disease presence.MethodsBlood samples were collected from 30 RA patients and 30 age- and gender-matched healthy volunteers. Levels of serum amyloid A (SAA), c-reactive protein (CRP), soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1) was measured using a sandwich immunoassay. Whole blood coagulation was assessed using Thromboelastography (TEG®). Fibrin clot networks and fiber structure was investigated using Scanning Electron Microscopy. The detection and quantification of citrullination in formed fibrin clots was performed using a fluorescently labeled Citrulline monoclonal antibody with Fluorescence Wide Field Microscopy.ResultsConcentrations of SAA, CRP and ICAM-1 were significantly elevated in RA patients compared to controls. TEG parameters relating to coagulation initiation, rate of fibrin cross-linking, and time to reach maximum thrombus generation were attenuated in RA patients. Microscopic analysis revealed denser networks of thicker fibrin fibers in RA patients compared to controls and multiple citrullinated regions within fibrin clot structures in RA patients were present.ConclusionOur findings provide novel evidence for the citrullination of fibrin within vasculature is more prominent in RA plasma compared to control plasma and plasma is more accessible than synovial fluid. Citrullinated fibrinogen could play a role as a determinant of thrombotic risk in RA patients.
Highlights
Rheumatoid Arthritis (RA) is a chronic, systemic autoimmune disease characterized by both peripheral joint and extra-articular site inflammation, with an increased predisposition to a higher incidence of cardiovascular disease (CVD) [1]
This circumstance holds true for RA, with elevated levels of both pro-inflammatory and prothrombotic markers (e.g. D-dimer Fibrinogen Tissue Factor (TF) and von Willebrand factor), which is associated with one another and with the risk of future cardiovascular complications [6]
The majority of RA patients presented with positive titers for anti-cyclic citrullinated peptide (CCP) (77%) and rheumatoid factor (97%) autoantibodies
Summary
Rheumatoid Arthritis (RA) is a chronic, systemic autoimmune disease characterized by both peripheral joint and extra-articular site inflammation, with an increased predisposition to a higher incidence of cardiovascular disease (CVD) [1]. Disruption of the tightly regulated homeostatic control of immune and hemostatic systems could result in a rapid progression towards a prothrombotic tendency, a central cause of ischemic stroke and myocardial infarction [5]. This circumstance holds true for RA, with elevated levels of both pro-inflammatory and prothrombotic markers (e.g. D-dimer Fibrinogen Tissue Factor (TF) and von Willebrand factor (vWF)), which is associated with one another and with the risk of future cardiovascular complications [6]
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