Crosstalk between Inflammation and Coagulation in Acute Pancreatitis - Experimental and Clinical Studies.

Abstract: In various inflammatory conditions a close interplay between inflammation and coagulation is known to exist, where coagulation factor VII (FVII) and tissue factor (TF) are considered to be pivotal players. In this thesis the crosstalk between inflammation and coagulation in acute pancreatitis (AP) has been investigated. The results from the first paper, where active site inactivated FVII (FVIIai) is given as pre-treatment in a rat model of severe AP, show a decreased inflammatory response in the FVIIai pre-treated animals. In the second paper the activation of nuclear factor kappa B (NFκB) is studied in the rat model of severe AP. NFκB is a pivotal transcription factor, involved in the regulation of expression of multiple inflammatory mediators. The results show a decreased activation of NFκB in remote organs in FVIIai pre-treated rats with severe AP. In the third paper the effect of FVIIai administered after the induction of severe AP in the rat model is studied. The results show some anti-inflammatory effects though less evident than in the pre-treatment study. In the fourth paper the incidence, management and outcome of major haemorrhagic complications in AP is studied in a retrospective study. 1356 patients were included. Severe haemorrhagic complications turned out to be very rare. Only 14 patients with severe bleeding were identified. Despite the rareness of this condition, it is a clinical challenge to manage these patients, as severe bleeding complications are associated with a very high mortality. In the fifth paper plasma levels of TF are studied in 49 patients with predicted severe AP. TF at admission was higher in the group of patients that actually developed severe AP, compared to those with a mild form of the disease. The results may indicate a role of tissue factor in the development of severe disease. We conclude that - FVIIai exerts powerful anti-inflammatory effects in experimental severe AP, at least in part by reducing activation of NFκB, - Severe haemorrhagic complications in AP are rare, but associated with a high risk of mortality. - Levels of TF rise early in the course of AP and higher levels of TF early in the course of the disease may be associated with development of severe AP.