Effects of melagatran, an inhibitor of thrombin, on fibrin deposits, haemodynamics, and platelet count in endotoxaemic pigs.

Abstract

Thrombin plays a pivotal role in the development of septic shock. Porcine endotoxaemia can replicate this condition. We wanted to evaluate whether melagatran, a novel inhibitor of thrombin, would counteract some of the endotoxin-induced changes in this model. Fifteen pigs were anaesthetised, monitored (circulatory and respiratory variables) and subjected to an infusion of E. coli endotoxin at 10 microg x kg(-1) x h(-1). Six pigs were given melagatran during the first 3 h of the 6-h endotoxaemic period. Nine controls were given the corresponding volume of saline instead of melagatran. Specimens from the liver and the left lung were taken for light microscopy post mortem. The endotoxin-induced increase in pulmonary capillary wedge pressure and drop in platelet count were significantly less pronounced in the melagatran-treated pigs. Deposits of pulmonary fibrin were significantly reduced in the melagatran group, without improving oxygenation. Light microscopy revealed no hepatic fibrin in the pigs treated with melagatran in contrast to the endotoxaemic controls. Hepatic neutrophil accumulation was reduced in the melagatran group as compared to controls. Hepatocellular degeneration and plasma levels of tumour necrosis factor alpha (TNF alpha) and bilirubin were of the same magnitude in both groups. Melagatran reduced pulmonary capillary wedge pressure, a retrograde reflection of the left ventricular end-diastolic filling pressure, and also pulmonary stasis in pigs subjected to endotoxaemic challenge. Pulmonary and hepatic fibrin depositions were reduced, but PaO2 levels or liver function markers were not affected by melagatran during the early phase of endotoxaemia. Obstruction of the intrahepatic bile ducts, by fibrin depositions, is not responsible for reduced excretion of conjugated bilirubin during endotoxaemia. The beneficial effects of melagatran during endotoxaemia were not due to any reduction of plasma TNF alpha.