Role of PAI-1 and TAFI in the aetiology of IBD and as prognostic marker or/and therapeutic target to prevent venous thromboembolism in IBD patients.

Inflammatory bowel diseases (IBD) are a group of chronic systemic diseases involving inflammation of the gastrointestinal tract of which ulcerative colitis can only affect the large bowel and Crohn’s disease can affect the entire gastrointestinal tract. The pathogenesis of IBDs is not well understood but it is known that the aetiology of the diseases involve predisposing genetic and environmental factors. Often resulting in higher morbidity, clinical research revealed a higher prevalence of thromboembolic events (TE) in IBD patients. This implicates a crucial bond between inflammation and fibrinolysis which is mainly regulated by Plasminogen Activator Inhibitor-1 (PAI-1) and Thrombin Activatable Fibrinolysis Inhibitor (TAFI). In conclusion, there is a high need to unravel the reason why IBD patients have a higher risk for thrombosis. In addition, less is known about the effect of IBD treatment on the risk for thrombosis, especially of the more recent biological therapies. Furthermore, a diagnostic or prognostic marker to identify IBD patients who are particularly at risk is desirable to stratify the patients who will benefit (balancing the bleeding risk and cost) from those who will not benefit from prophylaxis with anticoagulant therapy. Therefore the aim of this PhD thesis was to further unravel the role of fibrinolysis, in particular PAI-1 and TAFI, in the elevated risk for thrombosis observed in IBD patients. For that purpose, several studies were initiated:

In a first case-control study, we measured total PAI-1 antigen, active PAI-1, intact TAFI and the activation peptide of TAFI (AP-TAFI) in patients with a venous thrombosis and compared the concentrations to those in healthy controls. After correcting for different co-founding factors, we found that active PAI-1 is significantly associated with the occurrence of venous thrombosis. Also total PAI-1 antigen was associated, however to a lesser extent. Intact TAFI and AP-TAFI played a minor role in the presence of venous thrombosis.

In a second retrospective study, the clinical characteristics of IBD patients with a history of thrombosis are described. We had to deal with some limitations such as the lack of a specific disease activity score. Nonetheless, we believe that the detailed information on the type of thrombosis, the disease state at time of thrombosis, the IBD medication and the surgery history of this cohort can contribute to a better risk assessment for thrombosis in IBD. Furthermore, we confirmed many findings of other studies investigating the occurrence of thrombosis in IBD (association with disease activity, high risk of recurrence, greater occurrence of venous thrombosis …). Greater and completer knowledge would enable physicians to perform a better risk assessment for each individual patient and to decide which patient needs thromboprophylaxis and to optimize IBD medication in order to reduce the risk for a (recurrent) TE.

Third, we determined the clot lysis profile in a female IBD patient on IBD medication before and after she developed a deep vein thrombosis. We suggested that the clot lysis profile may be considered as a candidate test for prospective studies aimed at assessing the risk of thrombosis in IBD patients. Furthermore, we showed that the patient developed a thrombosis when she was treated with corticosteroids, not with infliximab therapy.

Fourth, in a case-control study, we found that, compared to healthy controls, the clot lysis profiles and PAI-1 concentrations were significantly increased in IBD patients. This latter included a real life cohort of patients with and without a history of thrombosis and patients with all different types of disease activity and disease medication. The results indicate that the haemostatic profile of IBD patients is indeed altered compared to general population, and that TAFI concentrations seem to play a minor role. In a second part - and to the best of our knowledge, the first study - we compared the clot lysis profiles and the fibrinolysis inhibitors of IBD patients with a history of thrombosis to those of IBD patients without a history of thrombosis. The clot lysis profiles were significantly altered in patients with a history of thrombosis. PAI-1 was as well different, but in a lesser extent than the clot lysis profiles, and TAFI played no significant role. Again, this study suggested that the clot lysis profile may be considered as a candidate test for prospective studies aimed at assessing the risk of thrombosis in IBD patients. Furthermore, we believe that the determining the clot lysis profile of IBD patients can substantially contribute to a risk assessment for thrombosis in IBD.

In a last prospective study, the effect of infliximab therapy on the fibrinolysis inhibitors was investigated and clot lysis profiles were measured before therapy and after induction therapy. Infliximab (Remicade®) is a biological drug targeting tumour necrosis factor-alpha, the central cytokine in IBD. Interestingly, some patients do not respond to this induction treatment and are called primary non-responders. This study showed that before start of therapy, patients are in a severe state of disease which was reflected in their clot lysis profile. The clot lysis profiles and PAI-1 concentrations were increased compared to healthy controls, indicating that the haemostatic profile is altered in favour of the coagulation. Upon effective treatment with infliximab - response is required - the clot lysis profiles normalised to the level of healthy controls, suggesting that effective infliximab treatment may reduce the risk for thrombosis in IBD patients.

To conclude, this thesis describes the role of PAI-1 and TAFI in the elevated risk for (venous) thrombosis in IBD. TAFI seems to play no role in the thrombotic tendency of IBD patients. PAI-1 concentrations are significantly higher in IBD patients, compared to the general population, but the clinical role is not fully elucidated. The clot lysis profiles are significantly altered in IBD patients compared to healthy controls, moreover they are significantly different between IBD patients with and without a history of thrombosis. In summary, the clot lysis profile of an IBD patient may be considered as a candidate test for prospective studies aimed at assessing the risk of thrombosis in IBD patients. Steroid treatment should be avoided in IBD patients at risk for thrombosis, anti-TNF therapy seem to be safe and therefore a better choice in IBD patients with prothrombotic tendencies.