The Beneficial Effect of Aspirin and Enoxaparin on Fibrosis Progression and Regenerative Activity in a Rat Model of Cirrhosis

Abstract

The aim of this study was to examine the effect of the antithrombotic drugs aspirin and enoxaparin on fibrosis progression and regenerative activity in a rat model of liver cirrhosis and to determine if these two drugs are beneficial in animals with advanced fibrosis or with established cirrhosis undergoing partial hepatectomy. Thioacetamide-induced cirrhotic rats received saline (N=10), aspirin (N=7), or enoxaparin (N=11) for a 5-week treatment period. Hepatic fibrosis was assessed according to METAVIR score. Liver regeneration was monitored using PCNA immunostaining. Compared to untreated cirrhotic controls, a significant improvement in fibrosis grade was observed in the aspirin (43%; chi(2)=54, P<0.001) and enoxaparin (36%; chi(2)=43, P<0.001) treated groups. Postoperatively, total serum bilirubin levels were lower in the aspirin (1.4+/-0.18 mg/dl; P<0.01) and enoxaparin (1.8+/-0.35 mg/dl; P<0.05)-treated groups compared to untreated cirrhotic controls (3.2+/-0.6 mg/dl). Hepatic regenerative activity was significantly improved in the aspirin group (57.3%+/-6.8%, versus 34.2%+/-7.2% in untreated cirrhotic controls; P<0.01) but unchanged in the enoxaparin group. We conclude that aspirin and enoxaparin hold promise as a useful therapy for patients with extensive fibrosis.

Is there a rationale for treatment of chronic liver disease with antithrombotic therapy?

“…This is certainly an appealing hypothesis, especially in relation to multiple epidemiological studies showing a positive correlation between congenital and acquired thrombophilia and liver disease progression, and on the other hand a milder course in female patients and patients with hemophilia [90][91][92][93][94][95][96][97]. In fact, these studies have been complemented using experimental animal models of liver disease, in which was it was demonstrated that thrombophilic gene mutations promote the fibrotic process in the parenchyma, but progression could be attenuated by antithrombotic treatment both in animals carrying the mutations and in wild-type counterparts [98][99][100]. Finally, in vitro studies demonstrated that the interplay between thrombin and members of the protease-activated cell surface receptors (PAR)-family facilitates the activation and transition of the hepatic stellate cell towards a pro-fibrotic phenotype.…”

Thrombotic risk factors and liver histologic lesions in non-alcoholic fatty liver disease

“…Dipyridamole suppressed fibrogenesis in a rabbit model, probably through inhibition of sinusoidal release of plateletderived factors that activate the hepatic stellate cells [22], while anticoagulation slowed fibrogenesis in a mouse model of chronic toxic liver injury [23]. Finally, the use of antithrombotic agents such as aspirin and enoxaparin was demonstrated to have beneficial effects on fibrosis progression and hepatic regeneration in a rat model of cirrhosis [24].…”

Coagulation and fibrosis in chronic liver disease

“…Assy et al 37 evaluated the effects of aspirin and the low molecular weight heparin (LMWH) enoxaparin on fibrosis progression and regenerative activity in a rat model of liver cirrhosis. Pharmacological doses of aspirin (300 mg/kg) prevented both the progression of fibrosis and stimulated liver regeneration.…”