Thrombin generation in rheumatoid arthritis: Dependence on plasma factor composition

Anetta Undas; Matthew Gissel; Beata Kwasny-Krochin; Piotr Gluszko; Kenneth G. Mann; Kathleen E. Brummel-Ziedins

doi:10.1160/TH10-02-0091

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2010; 104(02): 224-230
DOI: 10.1160/TH10-02-0091

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Thrombin generation in rheumatoid arthritis: Dependence on plasma factor composition

Anetta Undas

¹Institute of Cardiology, Jagiellonian University School of Medicine, Krakow, Poland

,

Matthew Gissel

²Department of Biochemistry, University of Vermont, Burlington, Vermont

,

Beata Kwasny-Krochin

³Department of Rheumatology, Jagiellonian University School of Medicine, Krakow, Poland

,

Piotr Gluszko

³Department of Rheumatology, Jagiellonian University School of Medicine, Krakow, Poland

,

Kenneth G. Mann

²Department of Biochemistry, University of Vermont, Burlington, Vermont

,

Kathleen E. Brummel-Ziedins

²Department of Biochemistry, University of Vermont, Burlington, Vermont

› Author Affiliations

Abstract

PDF Download

Summary

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.

Keywords

Inflammation - plasma composition - prothrombotic phenotype - rheumatoid arthritis - thrombin generation

PDF (389 kb)

References

References
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.
3 Gabriel SE. Cardiovascular morbidity and mortality in rheumatoid arthritis. Am J Med 2008; 121: S9-14.
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.
8 Belch JJ, McArdle B, Madhok R. et al. Decreased plasma fibrinolysis in patients with rheumatoid arthritis. Ann Rheum Dis 1984; 43: 774-777.
9 Matta F, Singala R, Yaekoub AY. et al. Risk of venous thromboembolism with rheumatoid arthritis. Thromb Haemost 2009; 101: 134-138.
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.
14 Cawthern KM, van 't Veer C, Lock JB. et al. Blood coagulation in hemophilia A and hemophilia C. Blood 1998; 91: 4581-4592.
15 Higgins DL, Mann KG. The interaction of bovine factor V and factor V-derived peptides with phospholipid vesicles. J Biol Chem 1983; 258: 6503-6508.
16 Hockin MF, Jones KC, Everse SJ. et al. A model for the stoichiometric regulation of blood coagulation. J Biol Chem 2002; 277: 18322-18333.
17 Brummel-Ziedins KE, Vossen CY, Butenas S. et al. Thrombin generation profiles in deep venous thrombosis. J Thromb Haemost 2005; 03: 2497-2505.
18 Brummel-Ziedins K, Undas A, Orfeo T. et al. Thrombin generation in acute coronary syndrome and stable coronary artery disease: dependence on plasma factor composition. J Thromb Haemost 2008; 06: 104-110.
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.
20 Brummel-Ziedins K, Orfeo T, Jenny NS. et al. Blood coagulation and fibrinolysis. In: Wintrobe's Clinical Hematology. Philidelphia: Lippencott Williams & Wilkins 2003; 269: 677-774.
21 Martinelli I. von Willebrand factor and factor VIII as risk factors for arterial and venous thrombosis. Semin Hematol 2005; 42: 49-55.
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.
25 Foster W, Carruthers D, Lip GY. et al. Inflammation and Microvascular and Macrovascular Endothelial Dysfunction in Rheumatoid Arthritis: Effect of Treatment. J Rheumatol 2010; 37: 711-716.
26 Brummel-Ziedins KE, Pouliot RL, Mann KG. Thrombin generation: phenotypic quantitation. J Thromb Haemost 2004; 02: 281-288.