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).


OBJECTIVE
To evaluate anti-t-PA antibodies in patients with IBD, considering clinical, biochemical and functional characteristics.


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.
Saibeni
S
S
Gastroenterology and Gastrointestinal Endoscopy Service, IRCCS Fondazione Ospedale Policlinico, Mangiagalli and Regina Elena, University of Milan, Via Pace 9, 20122 Milan, Italy.
Ciscato
C
C
Vecchi
M
M
Boscolo Anzoletti
M
M
Kaczmarek
E
E
Caccia
S
S
de Franchis
R
R
Cugno
M
M
D000328:Adult; D001323:Autoantibodies / Q000097:blood*; D016022:Case-Control Studies; D020134:Catalytic Domain / Q000276:immunology; D000939:Epitopes; D005260:Female; D006801:Humans; D007074:Immunoglobulin G; D015212:Inflammatory Bowel Diseases / Q000453:epidemiology / Q000209:etiology / Q000276:immunology*; D018082:Kringles / Q000276:immunology; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D017434:Protein Structure, Tertiary; D013927:Thrombosis / Q000209:etiology / Q000276:immunology*; D010959:Tissue Plasminogen Activator / Q000276:immunology*
D001323:Autoantibodies; D000939:Epitopes; D007074:Immunoglobulin G; D010959:Tissue Plasminogen Activator