title: Thrombin generation in rheumatoid arthritis: dependence on plasma factor composition.
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.
authors.affiliation: Institute of Cardiology, Jagiellonian University School of Medicine, Krakow, Poland.
authors.forename: Anetta
authors.initials: A
authors.lastname: Undas
authors.forename: Matthew
authors.initials: M
authors.lastname: Gissel
authors.forename: Beata
authors.initials: B
authors.lastname: Kwasny-Krochin
authors.forename: Piotr
authors.initials: P
authors.lastname: Gluszko
authors.forename: Kenneth G
authors.initials: KG
authors.lastname: Mann
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Brummel-Ziedins
mesh_terms: D000328:Adult; D000368:Aged; D000991:Antithrombins / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000150:complications / Q000175:diagnosis; D015415:Biomarkers / Q000097:blood; D001777:Blood Coagulation; D001779:Blood Coagulation Factors / Q000378:metabolism*; D001780:Blood Coagulation Tests; D003198:Computer Simulation; D005260:Female; D006801:Humans; D007700:Kinetics; D008074:Lipoproteins / Q000097:blood; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D020379:Risk Adjustment; D012720:Severity of Illness Index; D013917:Thrombin / Q000378:metabolism*; D013923:Thromboembolism / Q000097:blood / Q000209:etiology*; D055815:Young Adult
chemical_list: D000991:Antithrombins; D015415:Biomarkers; D001779:Blood Coagulation Factors; D008074:Lipoproteins; C051928:lipoprotein-associated coagulation inhibitor; D013917:Thrombin