Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH
Thrombin generation in rheumatoid arthritis: Dependence on plasma factor composition
Anetta Undas
1
Institute of Cardiology, Jagiellonian University School of Medicine, Krakow, Poland
,
Matthew Gissel
2
Department of Biochemistry, University of Vermont, Burlington, Vermont
,
Beata Kwasny-Krochin
3
Department of Rheumatology, Jagiellonian University School of Medicine, Krakow, Poland
,
Piotr Gluszko
3
Department of Rheumatology, Jagiellonian University School of Medicine, Krakow, Poland
,
Kenneth G. Mann
2
Department of Biochemistry, University of Vermont, Burlington, Vermont
,
Kathleen E. Brummel-Ziedins
2
Department of Biochemistry, University of Vermont, Burlington, Vermont
› Author AffiliationsFinancial support: This research was supported by a grant from the Jagiellonian University School of Medicine (no K/ZDS/000565, to A.U.) and an NIH grant HL46703 (Project 5).
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-reac- tive 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.
1
Wolfe F,
Michaud K.
The risk of myocardial infarction and pharmacologic and nonpharmacologic myocardial infarction predictors in rheumatoid arthritis: A cohort and nested case-control analysis. Arthritis Rheum 2008; 58: 2612-2621.
2
Nadareishvili Z,
Michaud K,
Hallenbeck JM.
et al. Cardiovascular, rheumatologic, and pharmacologic predictors of stroke in patients with rheumatoid arthritis: a nested, case-control study. Arthritis Rheum 2008; 59: 1090-1096.
4
Sattar N,
McCarey DW,
Capell H.
et al. Explaining how „high-grade“ systemic inflammation accelerates vascular risk in rheumatoid arthritis. Circulation 2003; 108: 2957-2963.
5
Pamuk GE,
Vural O,
Turgut B.
et al. Increased platelet activation markers in rheumatoid arthritis: are they related with subclinical atherosclerosis?. Platelets 2008; 19: 146-154.
6
So AK,
Varisco PA,
Kemkes-Matthes B.
et al. Arthritis is linked to local and systemic activation of coagulation and fibrinolysis pathways. J Thromb Haemost 2003; 01: 2510-2515.
7
McEntegart A,
Capell HA,
Creran D.
et al. Cardiovascular risk factors, including thrombotic variables, in a population with rheumatoid arthritis. Rheumatology 2001; 40: 640-644.
10
Bajaj SP,
Rapaport I S,
Prodanos C.
A simplified procedure for purification of human prothrombin, factor IX and factor X. Prep Biochem 1981; 11: 397-412.
11
van 't Veer C,
Golden NJ,
Kalafatis M.
et al. Inhibitory mechanism of the protein C pathway on tissue factor-induced thrombin generation. Synergistic effect in combination with tissue factor pathway inhibitor. J Biol Chem 1997; 272: 7983-7994.
12
Katzmann JA,
Nesheim ME,
Hibbard LS.
et al. Isolation of functional human coagulation factor V by using a hybridoma antibody. Proc Natl Acad Sci USA 1981; 78: 162-166.
13
Griffith MJ,
Noyes CM,
Church FC.
Reactive site peptide structural similarity between heparin cofactor II and antithrombin III. J Biol Chem 1985; 260: 2218-2225.
19
Lawson JH,
Kalafatis M,
Stram S.
et al. A model for the tissue factor pathway to thrombin. I. An empirical study. J Biol Chem 1994; 269: 23357-23366.
22
Mackman N,
Tilley RE,
Key NS.
Role of the extrinsic pathway of blood coagulation in hemostasis and thrombosis. Arterioscler Thromb Vasc Biol 2007; 27: 1687-1693.
23
Bank I,
Libourel EJ,
Middeldorp S.
et al. Elevated levels of FVIII: C within families are associated with an increased risk for venous and arterial thrombosis. J Thromb Haemost 2005; 03: 79-84.
24
Morange PE,
Bickel C,
Nicaud V.
et al. Haemostatic factors and the risk of cardiovascular death in patients with coronary artery disease: the AtheroGene study. Arterioscler Thromb Vasc Biol 2006; 26: 2793-2799.
