Elevated Levels of IL-6 and IL-8 Are Associated with An Increased Risk of Venous Thromboembolism – a Case Control Study.

high levels of some cytokines have been associated with an increased risk of venous thromboembolism (VTE) in some case-control studies, but not in prospective studies. However, data regarding the impact of cytokines levels on the risk of VTE are still limited. The aim of this study was to investigate the association between the risk of VTE and plasma levels of interleukin (IL)-1β, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-αa and monocyte chemotactic protein (MCP)-1.

we studied 122 patients (96 women, 79%), with a first objectively confirmed episode of VTE and with a median age of 39.5 years (range: 21-60). Exclusion criteria were malignancy, autoimmune diseases, antiphospholipid syndrome, chronic renal or liver disease and arterial thrombosis. Patients were seen at least 1 month after the discontinuation of the anticoagulant treatment and > 7 months after the event of VTE. Control group was comprised of 131 healthy subjects (105 women, 80%), with median age of 38 years (range: 18-66), recruited via the patients from the same geographic region and ethnic background. Controls were matched for age and sex. Plasma levels of cytokines were measured by commercial ELISA and a highly sensitive assay was used to measure IL-1β, IL-6 and IL-10 levels. Since a high percentage of samples of IL-1β (73%), IL-10 (62%) and TNF-αa (97%) was below the lower limit of detection (LLD) of the assay, levels of these cytokines were categorized as detectable (> LLD) and not detectable (< LLD). Elevated levels of IL-6 (> 2.15pg/mL), IL-8 (> 10.11pg/mL) and MCP-1 (> 84.11pg/mL) were defined by plasma concentration of these cytokines exceeding the 90th percentile of the distribution of the control population.

elevated levels of IL-6 were detected in 27% of the patients with VTE in comparison with 10% (by definition) of the controls [odds ratios (OR) = 3.4, 95% Confidence Interval (CI) 1.6 - 7.6]. Elevated levels of IL-8 were detected in 21% of the patients in comparison with 10% of the controls (OR = 2.5, 95%CI 1.1 - 5.6). The risk remained significant for IL-6 (OR = 2.8, 95%CI 1.2 - 6.5) and IL-8 (OR = 2.6, 95%CI 1.1 - 6.7) after adjustment for putative confounders (sex, age, body mass index, smoking and high levels of homocysteine and C-reactive protein). On the other hand, we found no significant association between VTE and elevated levels of MCP-1 (OR = 0.8, 95%CI 0.3 - 1.9) as well as detectable levels of IL-1β (OR = 0.9, 95%CI 0.5-1.6), IL-10 (OR = 1.3, 95%CI 0.8 - 2.2) and TNF-αa (OR = 6.7, 95%CI 0.8 - 56.7). In our study, patients were included at different time intervals after the VTE episode [median: 36 months (range: 7-87)]. No correlation was found between the time since the event of VTE and levels of IL-6 (r_s = 0.06, P = 0.54) and IL-8 (r_s= 0.07; P = 0.48).

this study shows a significant impact of elevated levels of IL-6 and IL-8 on the risk of VTE in a relatively young population of patients. Interestingly, no association was found between the time since the event and the level of these cytokines. Taking into account the importance of the relationship between inflammation and VTE, more epidemiological data including prospective studies are required to elucidate the role of inflammation on the risk of VTE.

This study was supported by FAPESP (2005/56799-0).

No relevant conflicts of interest to declare.