Blood clotting in arthritis patients may explain their increased risk for heart attack, and stroke
New research into rheumatoid arthritis has provided a better understanding of potential links between this condition and increased cardiovascular disease risk.
Rheumatoid arthritis (RA) is a painful and debilitating autoimmune condition, associated with inflammation in the joints and throughout the body. For some time now, scientists have known that sufferers of the disease also have a 50% higher risk of cardiovascular disease (CVD) outcomes – like strokes or heart attacks. A key factor in that risk is the effect inflammation has on the blood clotting process.
In this study, researchers investigated this relationship, to find out exactly why RA heightens CVD risk. More specifically, the researchers examined the effects of inflammation and structural changes on specific proteins associated with blood-clotting, called fibrins. These proteins occur as long chains that form the basic “mesh-work” for blood clots, so any changes to the fibrins themselves could have knock-on effects for the clotting process overall.
Researchers compared blood samples of RA patients to samples from healthy individuals. In each case, the researchers were looking for “markers” in the blood that indicate inflammation, as well as for any unusual differences in the normal clotting process that could heighten CVD risk. The clots themselves were also analysed microscopically, to identify any changes to the structure of their fibrin proteins.
The researchers noticed that clots from RA patients formed faster than those in healthy individuals, and that the protein strands they were made of were also significantly thicker than normal fibrins. There were also changes to the amino acids that make up the fibrin proteins, which caused them to trigger the body’s immune response, leading to further inflammation.
Other researchers have noticed changes to the amino acid structure of fibrins in the joints of RA patients before, but this is the first time researchers have seen the same effect in blood. Combined with the other changes seen in the blood clots, the findings may help scientists develop a deeper understanding of the relationship between RA and CVD, and how to detect early signs of these diseases.
Though these initial results are promising, it’s worth noting that the sample size for the study was comparatively small. The researchers also mentioned that the method they used to detect amino acid changes in the proteins could also have picked up results from unrelated substances, meaning that more specific tests targeting fibrins would be needed to confirm the result in future.
In the long run, understanding the complex links between RA and increased CVD risk may improve outcomes for RA patients as we learn to identify and treat these diseases more effectively. Researchers from South Africa, Denmark and the United Kingdom were involved in this study, which was funded by the South African Medical Research Council.
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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.
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.
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).
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.
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