Elevated plasma levels of plasminogen activator inhibitor‐1 are associated with risk of future incident venous thromboembolism

Background Plasminogen activator inhibitor‐1 (PAI‐1), the main inhibitor of fibrinolysis, is frequently elevated in obesity and could potentially mediate the risk of venous thromboembolism (VTE) in obese subjects. However, whether PAI‐1 is associated with VTE remains uncertain. Objective To investigate the association between plasma PAI‐1 levels and risk of future incident VTE and whether PAI‐1 could mediate the VTE risk in obesity. Methods A population‐based nested case‐control study, comprising 383 VTE cases and 782 age‐ and sex‐matched controls, was derived from the Tromsø Study cohort. PAI‐1 antigen levels were measured in samples collected at cohort inclusion. Logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for VTE across PAI‐1 tertiles. Results The VTE risk increased dose‐dependently across PAI‐1 tertiles ( P for trend <.001) in the age‐ and sex‐adjusted model. The OR of VTE for the highest versus lowest tertile was 1.73 (95% CI 1.27–2.35), and risk estimates were only slightly attenuated with additional stepwise adjustment for body mass index (BMI; OR 1.59, 95% CI 1.16–2.17) and C‐reactive protein (CRP; OR 1.54, 95% CI 1.13–2.11). Similar results were obtained for provoked/unprovoked events, deep vein thrombosis, and pulmonary embolism. In obese subjects (BMI of ≥30 kg/m 2 vs. <25 kg/m 2 ), PAI‐1 mediated 14.9% (95% CI 4.1%‐49.4%) of the VTE risk in analysis adjusted for age, sex, and CRP. Conclusion Our findings indicate that plasma PAI‐1 is associated with increased risk of future incident VTE and has the potential to partially mediate the VTE risk in obesity.