Interruption of platelets and thrombin function as a new approach against liver fibrosis induced experimentally in rats

Research Abstract

AIM: Liver fibrosis is a serious health problem which is a critical cause of morbidity and mortality worldwide. It is the main complication of untreated chronic inflammatory liver diseases which can progress to liver cirrhosis, hepatocellular carcinoma, and finally death. Coagulation cascade plays a mechanistic role in the pathogenesis of different chronic inflammatory disease including atherosclerosis, stroke, and tissue fibrosis. The current study was designed to investigate the effect of inhibition of coagulation cascade on carbon tetrachloride (CCl4)-induced liver fibrosis in rats. MATERIAL AND METHODS: The study was conducted in rats. Rats were treated with CCl4 subcutaneously for 6 consecutive weeks to determine the onset of coagulation system activation in relation to development of fibrosis. To investigate the effects of coagulation system inhibition in CCl4-induced liver fibrosis, the anticoagulants drugs dabigatran and clopidogrel were administrated orally concurrently with CCl4 treatment. KEY FINDINGS: The results of our study revealed that during the first week, there were significant elevations of fibrin, tissue factor expressions, and prothrombin time (PT) coupled with neutropenia without significant changes in liver fibrosis markers such as TGF-β, α-SMA and collagen deposition. Starting from the second week, tissue injury markers including the oxidative, inflammatory and fibrosis markers as well as histopathological changes became evident progressively. Intriguingly, dabigatran and clopidogrel significantly normalized the biochemical and pathological changes. SIGNIFICANCE: In conclusion, activation of coagulation cascade is a triggering stimulus in the initiation of CCl4-induced liver fibrosis and the anticoagulant drugs may exert promising anti-fibrotic effect.

Research Keywords

Clopidogrel; Dabigatran; Fibrin; Liver fibrosis; Tissue factor; Transforming growth factor