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P343. Role of plasminogen activator inhibitor and thrombin activatable fibrinolysis inhibitor in the elevated thromboembolic risk seen in inflammatory bowel disease patients

N. Vande Casteele1, W. Van Moerkercke2, V. Ballet2, P.J. Declerck1, P. Rutgeerts2, S. Vermeire2, A. Gils1

1KULeuven, Leuven, Belgium; 2University Hospitals Leuven, Leuven, Belgium

Introduction: Plasminogen Activator Inhibitor (PAI-1) and Thrombin Activatable Fibrinolysis Inhibitor (TAFI), both inhibitory proteins of the fibrinolytic system, attenuate the formation of plasmin from its precursor plasminogen. Elevated levels of PAI-1 and TAFI give rise to a prothrombotic state and have been associated with venous thromboembolism amongst other cardiovascular diseases. Inflammatory Bowel Disease (IBD) patients have a higher risk of developing a VTE not only during active disease (hazard ratio 8.4, 95% CI 5.5–12.8) but also during remission (hazard ratio 3.4, 95% CI 2.7–4.3) in comparison to healthy controls. This elevated risk could be caused by a hypofibrinolytic state.

Objective: To analyse and compare PAI-1 and TAFI levels in plasma of IBD patients and controls.

Methods: Samples from 148 IBD patients and 74 healthy controls (HC) were analysed for PAI-1, active PAI-1, endogenous PAI-1/t-PA complex, intact TAFI and TAFI activation peptide levels. The IBD group consists of 97/148 (66%) Crohn's disease (CD) and 50/148 (34%) ulcerative colitis (UC) patients. PAI-1 and TAFI levels were determined in plasma using two-side ELISA with specific in-house developed monoclonal antibodies (MA). Total PAI-1 antigen levels were determined with MA-31C9/MA-55F4C12-HRP. PAI-1/t-PA complex was detected with MA-21F7C4/MA-51H8-HRP and active PAI-1 could be detected after incubating the plasma samples with an excess of t-PA and measuring the complex present after incubation, taking into account the detected endogenous complex. Intact TAFI antigen level was determined with MA-T12D11/MA-T30E5A2-HRP and the TAFI activation peptide level – indicative for the degree of TAFI activation – was determined with MA-T12D11/MA-T18A8-HRP.

Results: PAI-1, active PAI-1, endogenous PAI-1/t-PA complex and TAFI activation peptide levels were elevated in the plasma of IBD patients vs. controls whereas intact TAFI levels were not (Table 1). PAI-1 and TAFI levels did not differ between UC vs. CD patients, except for TAFI activation peptide levels which were significantly elevated in the UC compared to CD group.

Table 1: PAI-1, active PAI-1, endogenous PAI-1/t-PA complex, intact TAFI and TAFI activation peptide levels in healthy controls (HC) vs. IBD patients and in Crohn's disease (CD) vs. ulcerative colitis (UC) patientsa
 PAI-1 (ng/ml)active PAI-1 (ng/ml)endogenous PAI-1/t-PA complex (ng/ml)TAFI (μg/ml)TAFI activation peptide (ng/ml)
HC25.3 (18.5–36.7)3.6 (2.4–6.5)2.7 (1.8–3.7)6.4 (5.0–7.7)36.6 (25.6–51.0)
IBD 43.4* (31.0–64.8)5.2* (3.1–8.5)3.9* (2.9–5.6)6.2 (4.9–7.5)42.9* (28.6–58.0)
CD42.9 (30.3–62.6)4.9 (3.1–7.5)3.8 (2.8–5.6)5.9 (4.7–7.3)38.5 (27.9–54.2)
UC46.0 (32.3–67.0)6.2 (3.3–12.8)4.0 (2.9–6.2)6.8 (5.8–7.6)50.8** (35.2–72.2)
Values are Median (IQR).
*p-value <0.05 vs. HC, **p-value <0.05 vs. CD.

Conclusion: The increased PAI-1 levels measured in IBD patients could play a possible role in the elevated thromboembolic risk seen in these patients. Elevated TAFI activation peptide levels in UC patients could indicate that an increased TAFI activation is the underlying basis for the increased number of VTE in UC patients compared to CD patients.