Cholestasis enhances liver ischemia/reperfusion-induced coagulation activation in rats

Aim: Cholestasis is associated with increased morbidity and mortality in patients undergoing major liver surgery. An additional risk is induced when vascular inflow occlusion is applied giving rise to liver ischemia/reperfusion (I/R) injury. The role of the coagulation system in this type of injury is elusive. The aim of the current study was to assess activation of coagulation following hepatic I/R injury in cholestatic rats. Methods: Male Wistar rats were randomized into two groups and subjected to bile duct ligation (BDL) or sham laparotomy. After 7 days, both groups underwent 30 min partial liver ischemia. Animals were sacrificed before ischemia or after 6 h, 24 h, and 48 h reperfusion. Results: Plasma AST and ALT levels were higher after I/R in cholestatic rats (P <0.05). Hepatic necrosis, liver wet/dry ratio and neutrophil influx were increased in the BDL group up to 48 h reperfusion (P <0.05). Liver synthetic function was decreased in the BDL group as reflected by prolonged prothrombin time after 6 h and 24 h reperfusion (P <0.05). I/R in cholestatic rats resulted in a 12-fold vs. 7-fold (P <0.01) increase in markers for thrombin generation and a 6-fold vs. 2-fold (P <0.01) increase in fibrin degradation products (BDL vs. control, respectively). In addition, the cholestatic rats exhibited significantly decreased levels of antithrombin (AT) III and increased levels of the fibrinolytic inhibitor plasminogen activator inhibitor (PAI-1) during reperfusion. Conclusions: Cholestasis significantly enhances I/R-induced hepatic damage and inflammation that concurs with an increased activation of coagulation and fibrinolysis