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In their interesting review, Dixon W.G. and Symmons D.P.M (1) discuss the role of TNF alpha and other factors, which may contribute to the increased cardiovascular morbidity in patients with rheumatoid arthritis (RA). The Authors support a hypothesis that TNF alpha blockade may reduce development of atherosclerosis in RA.
There is also a growing body of evidence that TNF alpha and other inflammatory...
There is also a growing body of evidence that TNF alpha and other inflammatory mediators up-regulate proteins involved in haemostasis leading to a pro-thrombotic state in RA (2,3). To evaluate the effects ofanti-TNF treatment on thrombin formation and function of fibrinolytic system in blood, we performed a study in a group of 20 patients with active disease (DAS 28 >3.0) who met the ACR criteria for RA (15 women, 5 men, aged 24 -68 years). Patients with a history of thrombosis, cardiovascular diseases or treated with anticoagulants were excluded from the study. All patients were treated with a fixed dose of methotrexate and received Infliximab (Remicade, Schering-Plough, USA) i.v. at a dose of 3mg/kg on days 0, 14, 42 and then every 8 weeks.
Blood samples were drawn before the initiation of treatment (day 0) and on days 3, 14, 16,42 and 44. The study was approved by the Ethics Committee.
In our licensed laboratory, using commercially available assays we measured plasma concentrations of thrombin – antithrombin III complexes (TAT), plasmin- antiplasmin complexes (PAP), tissue-type plasminogen activator antigen (t-PA) and its inhibitor PAI-1, plasma
fibrinogen, D-dimers, serum levels of IL6 and C –reactive protein (CRP). Platelet count, WBC and ESR were evaluated by routine methods.
Before introduction of an anti –TNF treatment (day 0) (Table 1) we observed an increased thrombin formation (elevated TAT complexes in plasma above normal levels) and elevated levels of PAP complexes and D-dimers.
17 patients completed the 44 day study protocol and continued therapy. 3 patients were withdrawn from the study due to adverse events. In majority of our patients anti-TNF treatment led to a quick clinical improvement of
RA and marked decrease of acute phase markers (IL6, CRP, ESR, fibrinogen, platelet counts). We found a significant (p< 0,02) correlation between CRP and TAT (r=0,54), PAP (r=0,51) and D –dimers (r=0,62) levels.
Correlations with IL6 and ESR gave similar results (data not shown). On days 3, 14, 16, 42 there was almost a parallel decrease (Fig.1, Tab.1) in plasma concentrations of TAT and PAP complexes, and plasma levels of D-
dimers showed even more stable reduction (Tab.1) indicating down regulation of both, thrombin formation and fibrinolysis.
Plasma levels of t-PA did not changed significantly throughout the study, however, we observed a significant fall in PAI-1 antigen level on day 14 (p< 0.05) with partial recovery by days 42 and 44 (data not shown).
Results of our study indicate that down regulation of systemic inflammatory process during the initial period of anti-TNF treatment is associated with a simultaneous decrease of procoagulant and fibrinolytic activity in blood. Complex links between inflammatory factors,
haemostasis and cardiovascular morbidity in RA need further elucidation (4, 5). We could only speculate that TNF alpha blockade might be associated with a decreased risk of thrombophilia in patients with RA.
anti-TNF alpha treatment on acute phase markers and thrombotic variables in
patients with RA
48,72 ± 48,17
21,05 ± 19,25*
8,75 ± 13,63*
9,38 ± 13,5*
19,6 ± 33,38*
14,19 ± 29,33*
99,69 ± 114,42
7,34 ± 6,32*
13,72 ± 19,67*
10,23 ± 10,8*
38,36 ± 75,77*
14,32 ± 29,88*
15,44 ± 16,9
12,32 ± 20,56
6,92 ± 7,02*
7,11 ± 9,38*
7,7 ± 11,15
8,52 ± 16,38
706,05 ± 444,06
592,27 ± 307,3*
398,84 ± 173,85*
492,82 ± 363,49*
469,99 ± 447,84*
458,27 ± 358,98*
1360,08 ± 257,37
1275,34 ± 285,14*
1010,37 ± 388,55*
1044,51 ± 398,82*
964,44 ± 525,97*
963,37 ± 440,15*
The PAP and TAT complexes levels in plasma during anti-TNF alpha therapy
(mean values +/- SEM)
1. Dixon WG, Symmons DPM. What effects might anti-TNF alpha; treatment be expected to have on cardiovascular morbidity and mortality in rheumatoid arthritis? A review of the role of TNF alpha in cardiovascular athophysiology. Ann Rheum Dis 2007;66:1132-1136.
2. Kamper EF, Kopeikina LT, Trontzas P, Potamianou A, Tsiroglou E, Stavridis JC. The effect of disease activity related cytokines on the fibrinolytic potential and c ICAM-1 expression in rheumatoid arthritis. J Rheumatol 2000;27: 2545-2550.
3. So A, Varisco PA, Kemkes-Matthes B, Herkenne-Morard C, Chobaz-Peclat V, Gerster JC, Busso N. Arthritis is linked to local and systemic activation of coagulation and fibrynolysis pathways. J Thromb Hemost 2003;12:2510-2515.
4. Wållberg-Jonsson S, Cvetkovic JT, Sundqvist KG, Lefvert AK, Rantapää-Dahlqvist S. Activation of the immune system and inflammatory activity in relation to markers of atherothrombotic disease and atherosclerosis in rheumatoid arthritis. J. Rheumatol 2002;5:875-882.
5. McEntergart A, Capell HA, Creran A, Rumley A, Woodward M, Lowe GD. Cardiovascular risk factors, including thrombotic variables in a population with rheumatoid arthritis. Rheumatology. 2001;40:640-644.