Thrombin generation in rheumatoid arthritis: Dependence on plasma factor composition

Abstract

Summary Background Growing evidence indicates that rheumatoid arthritis (RA) is associated with an increased risk for thromboembolic cardiovascular events. Objectives We investigated thrombin generation profiles in RA patients and their dependence on plasma factor/inhibitor composition. Patients/Methods Plasma factor (F) compositions (FII, V, VII, VIII, IX, X), antithrombin and free tissue factor pathway inhibitor (TFPI) from 46 consecutive RA patients with no cardiovascular events (39F, 7M, 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. Patients on anticoagulant therapy were excluded. Using each individual’s plasma coagulation protein composition, tissue factor-initiated thrombin generation was assessed both computationally and empirically. Results 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. Conclusions 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.

In silico thrombin generation: Plasma composition imbalance and mortality in human immunodeficiency virus

“…To determine which factor(s) were responsible for differences between cases and controls, we used a previously described procedure39, 40 in which each of the individuals in the mortality group had one of the factor levels sequentially adjusted to the mean of the control group and the reaction rerun with a 5 pmol/L TF stimulus and in silico thrombin outputs recalculated. This process was repeated for each factor (and expanded to multiple factors simultaneously).…”

“…We believe that the sum of developmental, environmental, genetic, nutritional, and pharmacological influences are reflected in the protein levels at any given time that specifically alter the synthesis and/or presentation of the proteins and active enzymes. We have described changes in thrombin generation and related these changes to plasma coagulation factor composition in the following groups: genetic bleeding tendencies30, 31, 32, 33 and clotting tendencies34, 35; women undergoing in vitro fertilization36; chronic obstructive pulmonary disease37; stroke38; rheumatoid arthritis39; and cardiovascular disease 40. In all cases, thrombin generation was more pronounced in individuals with procoagulant vs bleeding tendencies 30, 31, 32.…”

“…Individuals with acute conditions appeared to have more pronounced thrombin generation than individuals with chronic conditions 38, 40. Individuals with inflammatory diseases displayed a wide range of thrombin generation 37, 39…”

Consenso 2012 da Sociedade Brasileira de Reumatologia sobre o manejo de comorbidades em pacientes com artrite reumatoide

“…[74][75][76] In general, the following fi ndings contribute to increase the risk of thromboembolism: lower mobility consequent to joint lesions; hospitalizations with prolonged bed confi nement; more advanced age of most arthritic patients; compression of the venous system adjacent to a joint with huge joint effusion; and obesity. 74 Patients with RA have changes in the coagulation parameters and in the fi brinolytic system, 77 the most common fi ndings being as follows: increased platelet count; increased platelet activation markers; and increased thrombin markers, such as thrombin-antithrombin complexes and prothrombin fragments. The increase in pro-infl ammatory cytokines in RA is associated with high levels of fi brinogen, von Willebrand factor, and D-dimer.…”

“…The increase in pro-infl ammatory cytokines in RA is associated with high levels of fi brinogen, von Willebrand factor, and D-dimer. 77,78 Although the studies on the prevalence of DVT and PTE in RA have shown discordant results, an important study has reported that RA is a risk factor for DVT and PTE. 75,79,80 That study has assessed the incidence of DVT and PTE in patients with RA hospitalized in the United States from 1979 to 2005.…”