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Thrombin-activatable fibrinolysis inhibitor and its relation with inflammation in rheumatoid arthritis
  1. M J L Peters1,
  2. M T Nurmohamed1,2,
  3. I C van Eijk2,
  4. C J N Verkleij3,
  5. P F Marx3
  1. 1
    Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands
  2. 2
    Department of Rheumatology, Jan van Breemen Institute, Amsterdam, The Netherlands
  3. 3
    Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  1. P F Marx, Academic Medical Center, Department of Experimental Vascular Medicine, Meibergdreef 9, 1105 AZ (Room G1-145), Amsterdam, The Netherlands; p.f.marx{at}amc.uva.nl

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Rheumatoid arthritis (RA) is associated with an excessive risk of cardiovascular morbidity and mortality, and inflammation appears to be the missing link explaining this markedly elevated risk.1 Inflammation is a potent inducer of coagulation and fibrinolysis and may contribute to atherosclerotic and thrombotic components of cardiovascular events.2 Thrombin-activatable fibrinolysis inhibitor (TAFI), a procarboxypeptidase in plasma, is a regulatory protein of the coagulation/fibrinolysis balance as well as inflammation. TAFIa, the activated form of TAFI, acts by removing C-terminal arginine and lysine residues from substrates such as fibrin degradation products, bradykinin and the anaphylatoxins C3a and C5a. Elevated TAFI levels may reflect an enhanced risk of developing cardiovascular disease, although evidence for this is somewhat contradictory since the use of genotype-sensitive assays complicates interpretation of the data.35 Furthermore, TAFI levels associate with acute phase reactants in patients with cardiovascular disease and are elevated in patients with RA, as compared with non-RA controls.6 7 TAFI’s dual function in regulating haemostatic and inflammatory processes makes it an interesting protein to study in relation to RA. The objective of this study was to determine TAFI levels and its relation with inflammation in patients with RA.

In this study, the serum C-reactive protein (CRP) concentration was used to express the level of inflammation. A total of 21 patients with RA with normal CRP levels (low inflammatory state; <10 mg/litre) and 21 age-matched and sex-matched patients with RA with elevated CRP levels (high inflammatory state) were selected for evaluation of TAFI levels. All patients with RA attended the outpatient clinic at the Jan van Breemen Institute (Amsterdam, The Netherlands) where they were seen by a research doctor, and completed a questionnaire recording demographic data, medical and medication history (table 1). The local ethics committees approved the study protocol and all participants signed a written informed consent. TAFI levels were determined with a genotype-insensitive kinetic activity assay in which the zymogen is first quantitatively converted to TAFIa, as described previously.8 TAFI levels were expressed as the percentage of a plasma pool of 20 healthy volunteers.

Table 1 Characteristics from patients with rheumatoid arthritis (RA) in high versus low inflammatory state

TAFI levels were significantly higher in patients with RA with elevated CRP levels. These differences disappeared after adjustment for inflammation by means of erythrocyte sedimentation rate (ESR) or 28-joint Disease Activity Score (DAS28). Separate adjustments for potential other confounders (ie, age, gender, disease duration, IgM-rheumatoid factor (RF), the use of statins, aspirin, calcium suppletion, non-steroidal anti-inflammatory drugs (NSAIDs), prednisone or methotrexate) did not change these results. No differences in TAFI levels in this small population were found between patients with RA stratified for the TAFI polymorphisms 147 and 325.

In conclusion, we report that TAFI levels are significantly higher in the plasma of patients with RA with a high inflammatory state. This finding supports the need for prospective studies investigating the association between TAFI levels and cardiovascular disease as, on the one hand, high TAFI levels may facilitate the development of cardiovascular comorbidity by shifting the haemostatic balance to a more hypofibrinolytic state and, on the other hand, TAFI levels may relate to the body’s mechanisms dampening the excessive inflammatory reaction found in patients with RA.

REFERENCES

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Footnotes

  • Competing interests: None declared.

  • Ethics approval: The local ethics committees approved the study protocol and all participants provided written informed consent.

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