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.

Number of words: 470

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. 

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