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ABSTRACT: Growing evidence indicates that rheumatoid arthritis (RA) is associated with an increased risk for thromboembolic cardiovascular events. We investigated thrombin generation profiles in RA patients and their dependence on plasma factor/inhibitor composition. Plasma factor (F) compositions (II, V, VII, VIII, IX, X), antithrombin and free tissue factor pathway inhibitor (TFPI) from 46 consecutive RA patients with no cardiovascular events (39 female, 7 male, aged 57 [range, 23-75] years; DAS28 [Disease Activity Score] 5.2 +/- 1.1) were compared with those obtained in age- and sex-matched apparently healthy controls. Using each individual's plasma coagulation protein composition, tissue factor-initiated thrombin generation was assessed both computationally and empirically. RA patients had higher fibrinogen (4.18 [IQR 1.09] vs. 2.56 [0.41] g/l, p<0.0001), FVIII (226 +/- 40 vs. 113 +/- 15%, p<0.001), PC (107 [16] vs. 100 [14]%, p<0.001), and free TFPI levels (22.3 [2.2] vs. 14.7 [2.1] ng/ml, p<0.001). DAS28, but not age, RA duration, or C-reactive protein, was associated with FV, FVIII, FIX, FX, antithrombin, and free TFPI (r from 0.27 to 0.48, p<0.05). Intergroup comparison of computational thrombin generation profiles showed that in RA patients, maximum thrombin levels (p=0.01) and the rate of thrombin formation (p<0.0001) were higher, whereas the initiation phase of thrombin generation (p<0.0001) and the time to maximum thrombin levels (p<0.0001) were longer. Empirical reconstructions of the populations reproduced the thrombin generation profiles generated by the computational model. Simulations of thrombin formation suggest that blood plasma composition, i.e. a marked increase in FVIII, somewhat counterbalanced by free TFPI, contributes to the prothrombotic phenotype in RA patients.
Thrombosis and Haemostasis 08/2010; 104(2):224-30. · 5.04 Impact Factor
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ABSTRACT: Altered fibrin clot properties have been reported in cardiovascular diseases (CVD) and inflammatory states. Given increased prevalence of CVD in patients with rheumatoid arthritis (RA), we investigated whether fibrin characteristics are also altered in RA patients.
We studied 46 consecutive RA patients versus 50 controls matched for age and gender. Ex vivo plasma clot permeability, turbidity, tissue-type plasminogen activator (tPA)-induced fibrinolysis, and scanning electron microscopy (SEM) images of clots were evaluated.
Patients with RA had lower clot permeability, faster clot formation, higher maximum clot absorbency indicating thicker fibrin fibers, maximum clot mass and prolonged fibrinolysis time than controls. Maximum rates of clot lysis were similar in both groups. SEM images showed formation of dense clots with many projections on fibrin fibers. Clot permeability inversely correlated with fibrinogen, tPA, plasminogen activator inhibitor-1 (PAI-1), CRP, platelet count, disease activity score (DAS28) and a marker of oxidative stress, 8-iso-prostaglandin F2alpha (r from -0.44 to -0.79; all, p<0.0001). Similar positive associations were found for clot lysis time (r 0.44 to 0.69; all, p<0.01). Multiple regression analysis showed that fibrinogen was the only independent predictor of clot permeability (R2=0.87, p<0.0001) and lysis time (R2=0.80, p<0.003) in RA. Maximum D-dimer levels released from clots, maximum clot turbidity and the time of clot formation were predicted by PAI-1 (all, p<0.05).
We showed unfavorably altered plasma fibrin clot structure and function in RA, which might contribute to an increased risk of thrombotic events in this disease.
Thrombosis Research 07/2010; 126(1):e11-6. · 2.44 Impact Factor
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Clinical Chemistry and Laboratory Medicine 03/2010; 48(3):423-5. · 2.15 Impact Factor
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ABSTRACT: We have recently demonstrated elevated plasma levels of an endogenous nitric oxide synthase inhibitor, asymmetric dimethyl-L-arginine (ADMA), and its association with carotid atherosclerosis in rheumatoid arthritis (RA). Both an elevated risk of myocardial infarction and increased levels of anticitrullinated protein antibodies (ACPAs), specific for RA, had been shown to precede the onset of clinical RA symptoms. Therefore, our aim was to verify the hypothesis that ADMA accumulation might accompany raised ACPAs titers in RA of short duration (< or = 3 years). Twenty patients (16 women, 4 men; mean age, 45 +/- 12 years; mean disease duration, 2.3 +/- 0.5 years) with active RA despite chronic disease-modifying antirheumatic medication, free of cardiovascular disease or atherosclerotic risk factors, were studied. Plasma levels of ADMA and its stereoisomer, symmetric dimethyl-L-arginine (SDMA), were assayed by liquid chromatography/tandem mass spectrometry. The ACPAs were measured by a second-generation enzyme-linked immunosorbent assay. In addition to routine biochemical assays, plasma concentrations of tumor necrosis factor alpha, monocyte chemoattractant protein-1, and vascular cell adhesion molecule-1 soluble form were analyzed with respective enzyme-linked immunosorbent assays. A significant positive correlation between levels of ACPAs and ADMA (r = .60, P = .005), but not SDMA (r = -.02, P = .9), was found. Neither ADMA nor SDMA was correlated to any of the clinical or biochemical parameters reflecting disease activity and inflammatory activation. Thus, excessive ADMA accumulation accompanies elevated ACPAs levels in patients with RA of short duration free of cardiovascular disease or risk factors.
Metabolism: clinical and experimental 03/2009; 58(3):316-8. · 2.59 Impact Factor
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ABSTRACT: For more than 30 years statins have been successfully used in patients with hypercholesterolemia and cardiovascular diseases. Recently, there is a growing body of evidence, that statins exert effects by much exceeding the effect of cholesterol level decrease. Inhibition of earlier stages of cholesterol biosynthesis pathway (not influencing the very cholesterol level) results in blocking the intermediate metabolite synthesis; isoprenoids (farnesyl phosphate and geranyl phosphate), which play a regulatory function in cells. Statins have antiatherosclerotic, antiinflammatory, antioxidant, immunomodulatory and antithrombotic effects. It applies equally to diseases of chronic inflammation type, as to those, where bone metabolism is disturbed. It is well known that statins decrease bone fracture risk; through bone formation intensification, and inhibition of bone tissue resorption. Slowing down the atherosclerosis progression is a very important effect, considering that in rheumatoid arthritis (RA) and in systemic lupus erythematosus (SLE) we are dealing with premature and rapid progression of atherosclerotic lesions. In this paper statins pathways of action in rheumatic diseases (including pleiotropic effects), and their potential use in rheumatology have been discussed. Though there is lack of reliable data enabling statins introduction to standard complementary therapy in rheumatic diseases, the results however of completed studies allow concluding of their utility. The statins that were most frequently evaluated in clinical studies were simvastatin and atorvastatin. Studies on statins have been performed in RA, SLE, osteoporosis and systemic vasculotos.
Polskie archiwum medycyny wewnȩtrznej 10/2007; 117(9):420-5. · 1.37 Impact Factor
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Thrombosis and Haemostasis 06/2007; 97(5):868-70. · 5.04 Impact Factor
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JCR Journal of Clinical Rheumatology 01/2003; 8(6):359-60. · 1.36 Impact Factor
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ABSTRACT: Recombinant human gamma interferon was used to treat 10 atopic dermatitis patients. Recombinant gamma interferon was administered weekly for three consecutive days at 50 μg/M2 SQ for four weeks. All patients’ dermatitis improved with recombinant gamma interferon therapy and plasma tumor necrosis factor-α levels rose with treatment. Recombinant gamma interferon treatment positively correlated with reduced total plasma fibrinolysis as measured by the fibrin lysis plate, plasmin-α2antiplasmin complexes, and tissue type plasminogen activator levels. Accordingly, plasminogen activator inhibitor levels increased. Treatment also was associated with a transient increase in thrombin-antithrombin III complexes. Recombinant gamma interferon resulted in a significant increase in C1 inhibitor antigen but not activity. Plasma prekallikrein, high molecular weight kininogen, and factor XII levels were not decreased. However, 5 of the 10 atopic dermatitis patients before therapy had circulating cleaved plasma high molecular weight kininogen detected on immunoblot, indicating prior kallikrein formation. The cleaved, circulating plasma high molecular weight kininogen disappeared in four out of the five original patients who were reexamined at one year after treatment. These combined data indicated that recombinant gamma interferon treatment reduced total plasma fibrinolysis. In untreated atopic dermatitis, circulating cleaved high molecular weight kininogen also may be a presenting manifestation.
Thrombosis Research.
