Antibodies to tissue-type plasminogen activator (t-PA) in patients with inflammatory bowel disease: high prevalence, interactions with functional domains of t-PA and possible implications in thrombosis

Background: Patients with inflammatory bowel disease (IBD) have an increased prevalence of thromboembolic events. The pathogenetic mechanisms of these events include reduced fibrinolysis, which may be caused by antibodies to tissue-type plasminogen activator (t-PA). Objectives: To evaluate anti-t-PA antibodies in patients with IBD, considering clinical, biochemical and functional characteristics. Patients and methods: We immunoenzymatically measured anti-t-PA antibodies in plasma from 97 consecutive IBD patients and 97 age- and sex-matched healthy controls. We also assessed the antibody interactions with different epitopes of t-PA, the antibody inhibition on t-PA activity and the correlations with clinical features and other serum antibodies. Results: IBD patients had higher median anti-t-PA antibody levels (5.4 U mL(-1) vs. 4.0 U mL(-1); P < 0.0001): 18 patients were above the 95th percentile of the controls (OR 5.3; 95% CI 1.7-16.3; P < 0.003), and the six with a history of thrombosis tended to have high levels (6.9 U mL(-1)). Anti-t-PA antibody levels did not correlate with IBD type, activity, location or treatment, or with age, sex, acute-phase reactants or other antibodies. The anti-t-PA antibodies were frequently IgG1 and bound t-PA in fluid phase; they recognized the catalytic domain in 10 patients and the kringle-2 domain in six. The IgG fraction from the three patients with the highest anti-t-PA levels slightly reduced t-PA activity in vitro. Conclusions: The prevalence of anti-t-PA antibodies is high in IBD patients. By binding the catalytic or kringle-2 domains of t-PA, these antibodies could lead to hypofibrinolysis and contribute to the prothrombotic state of IBD.