Model establishment and pathological mechanism of portal vein thrombosis in rats with cirrhosis

Abstract

Abstract Background and Aims: Portal vein thrombosis (PVT) is a common complication of liver cirrhosis that can aggravate portal hypertension. However, there are features of both PVT and cirrhosis that are not recapitulated in most current animal models. In this study, we aimed to establish a stable animal model of PVT and cirrhosis, intervene with anticoagulants, and explore the related mechanism. Methods: First, 41 male SD rats were divided into 6 groups: the partial portal vein ligation (PPVL) group; week 4, 6, 8, and 10 model group; and the rivaroxaban-treated group. The rats were subjected to PPVL and were treated with or without carbon tetrachloride (CCl4) intoxication for different durations. Seven normal rats were used as controls. Serum alanine aminotransferase (ALT) and aspartate transferase (AST) levels and parameters for blood coagulation were all assayed with kits. Liver inflammation, collagen deposition and hydroxyproline (Hyp) levels were also evaluated. The extrahepatic macro-PVT was observed via portal vein HE staining, etc. The intrahepatic microthrombus was stained via fibrinogen immunohistochemistry. The portal blood flow velocity (PBFV) was detected via color Doppler ultrasound. Vascular endothelial injury was evaluated by von Willebrand Factor (vWF) immunofluorescence. Fibrinolytic activity was estimated by western blot analysis of fibrin and plasminogen activator inhibitor-1 (PAI-1). Results: After PPVL surgery and 10 weeks of CCl4 intoxication, a rat model that exhibited characteristics of both cirrhosis and extra and intrahepatic thrombus was established. In cirrhotic rats with PVT, the PBFV decreased, pro- and anticoagulation functions decreased, the PBFV tended to be easily embolized, and vascular endothelial injuried and fibrinolytic activity decreased. Rivaroxaban-treated rats had improved coagulation function, increased PBFV and fewer thrombi. This effect was related to the improvements in endothelial injury and fibrinolytic activity. Conclusions: The PPVL operation plus CCl4 intoxication can induce a rat model of PVT with cirrhosis that is consistent with clinical features. Rivaroxaban can attenuate PVT and has the effect against liver fibrosis. The mechanism is associated with endothelial cell dysfunction and fibrinolytic activity.