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PAI-1 and TAFI in inflammatory bowel disease: the yin and yang of the fibrinolytic system

Danese, Silvioa; Papa, Alfredob

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European Journal of Gastroenterology & Hepatology: September 2008 - Volume 20 - Issue 9 - p 826-828
doi: 10.1097/MEG.0b013e3282faa769
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Abstract

Inflammatory bowel disease and alterations of fibrinolysis

Inflammation and coagulation play crucial roles in the pathogenesis of multiple chronic inflammatory disorders including Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel disease (IBD). A growing amount of data highlights a tight mutual network in which inflammation, coagulation, and fibrinolysis play closely related roles. In both forms of IBD, a hypercoagulable state and a prothrombotic condition exist, whereas coagulation abnormalities are an intimate part of the IBD clinical picture [1]. Indeed, IBD patients frequently suffer from thromboembolic events (TEs), which represent an important cause of morbidity and mortality [2,3]. Recently, a population-based study has found that IBD patients have a three-fold increased risk of developing deep venous thrombosis and pulmonary embolism than the general population [4]. This finding has been reinforced by another study, which demonstrated that TEs are a specific feature of IBD, as neither rheumatoid arthritis (another chronic inflammatory disease) nor celiac disease (another chronic bowel disease) displays an increased risk of TEs compared with controls [5].

It appears that both the arterial and venous systems may be involved. TEs occur more often in the deep vein of the leg and in pulmonary circulation, but they have been described to occur less frequently in other sites, such as the cerebrovascular system, portal vein, mesenteric veins, and retinal vein [6–11]. Arterial TEs occur less frequently in patients with IBD than venous TEs, and the majority occur after surgery. Arterial TEs may also affect several vascular districts [12–15].

The reasons for the increased occurrence of TEs in IBD are not completely understood. Several qualitative and quantitative abnormalities in hemostatic parameters in IBD patients have been reported [16–20] (Table 1), but no consistent unifying etiology has been identified to explain TEs in IBD patients. It has been suggested that in the majority of thrombotic IBD patients, at least one prothrombotic risk factor can be detected [21,22], but other authors [3] have indicated that approximately half of IBD patients develop TEs without any identifiable reason, reinforcing the hypothesis that IBD represents a risk factor per se for thrombosis.

T1-3
Table 1:
Abnormalities of hemostatic parameters observed in inflammatory bowel disease patients

Also, the fibrinolytic system has been widely investigated in IBD as a prothrombotic condition may also result from reduced fibrinolytic activity (Fig. 1). Under physiological conditions, both coagulation and fibrinolysis are precisely regulated by multiple factors that, acting in a coordinated way, ensure blood fluidity while preventing blood loss, in particular in response to vascular injury. Briefly, adhesion, activation, and aggregation of platelets are the first steps of hemostasis, which are followed by activation of coagulation (clot formation) and finally by the fibrinolytic process (clot dissolution). An essential component of the fibrinolytic system is the zymogen plasminogen, which is converted to plasmin by tissue plasminogen activator (tPA) as well as by urokinase plasminogen activator (uPA); it is inhibited by plasminogen activator inhibitor-1 and plasminogen activator inhibitor-2 (PAI-1, PAI-2) and α2-antiplasmin (Fig. 1). Once formed, plasmin cleaves fibrin, generating soluble degradation products. Recently, thrombin-activatable fibrinolysis inhibitor (TAFI) has been characterized and its active form (TAFIa) is a potent attenuator of fibrinolysis, working by inhibiting plasmin generation, stabilizing fibrin thrombi, and establishing a regulatory connection between coagulation and fibrinolysis [23].

F1-3
Fig. 1:
The fibrinolytic process (boxed molecules are inhibitors). FDP, fibrin degradation products; FgDP, fibrinogen degradation products: PAI, plasminogen activator inhibitor; TAFI, thrombin activatable fibrinolysis inhibitor; tPA, tissue-type plasminogen activator; uPA, urokinase plasminogen activator.

In this issue of the European Journal of Gastroenterology & Hepatology, Koutroubakis et al. [24] found, in a Greek population of IBD patients, increased PAI-1 plasma levels, but decreased TAFI plasma levels, compared with healthy controls. They concluded that an imbalance of fibrinolysis occurs in IBD. The literature data are in agreement with the findings of Koutroubakis et al. regarding the increased PAI-1 levels, whereas the only other study that has evaluated the levels of TAFI in IBD reports opposite conclusions, showing increased levels of TAFI [25]. Moreover, a fair amount of evidence demonstrates that PAI-1 and TAFI are acute-phase reactants with a linear correlation with other markers of inflammation. However, data obtained in IBD patients and in other chronic inflammatory disorders, such as Behçet's disease, are not conclusive [24–26]. It is important to keep in mind that the interpretation of the studies regarding hemostatic variables, such as PAI-1 or TAFI, are problematic because of the intra-assay and inter-assay variability of the different tests, pretest circumstances (i.e. modalities of sampling), and laboratory handling that may influence the results. In IBD, the comparisons of the different studies are further complicated by additional factors, such as differences in the clinical and demographic features of the patients studied and the disease activity evaluation. Moreover, some polymorphisms throughout the TAFI gene were recently identified and some of them may predispose some more than others to thrombosis development, although this point is still controversial [27]. In conclusion, data obtained by Koutroubakis et al. reinforce the notion that IBD is a prothrombotic disease, and the intricate relationship among coagulation, fibrinolysis, and inflammation. Future studies are needed to better elucidate the role of fibrinolysis abnormalities in the pathogenesis of thrombotic events in IBD patients.

Acknowledgement

Conflict of interest: none declared.

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Keywords:

fibrinolysis; inflammatory bowel disease; plasminogen activator inhibitor-1; thrombin-activatable fibrinolysis inhibitor

© 2008 Lippincott Williams & Wilkins, Inc.