Enoxaparin does not ameliorate liver fibrosis or portal hypertension in rats with advanced cirrhosis

Liver Int. 2018 Jan;38(1):102-112. doi: 10.1111/liv.13510. Epub 2017 Sep 30.


Background & aims: Recent studies suggest that heparins reduce liver fibrosis and the risk of decompensation of liver disease. Here, we evaluated the effects of enoxaparin in several experimental models of advanced cirrhosis.

Methods: Cirrhosis was induced in male Sprague-Dawley (SD) rats by: (i) Oral gavage with carbon tetrachloride (CCl4ORAL ), (ii) Bile duct ligation (BDL) and (iii) CCl4 inhalation (CCl4INH ). Rats received saline or enoxaparin s.c. (40 IU/Kg/d or 180 IU/Kg/d) following various protocols. Blood biochemical parameters, liver fibrosis, endothelium- and fibrosis-related genes, portal pressure, splenomegaly, bacterial translocation, systemic inflammation and survival were evaluated. Endothelial dysfunction was assessed by in situ bivascular liver perfusions.

Results: Enoxaparin did not ameliorate liver function, liver fibrosis, profibrogenic gene expression, portal hypertension, splenomegaly, ascites development and infection, serum IL-6 levels or survival in rats with CCl4ORAL or BDL-induced cirrhosis. Contrarily, enoxaparin worsened portal pressure in BDL rats and decreased survival in CCl4ORAL rats. In CCl4INH rats, enoxaparin had no effects on hepatic endothelial dysfunction, except for correcting the hepatic arterial dysfunction when enoxaparin was started with the CCl4 exposure. In these rats, however, enoxaparin increased liver fibrosis and the absolute values of portal venous and sinusoidal resistance.

Conclusions: Our results do not support a role of enoxaparin for improving liver fibrosis, portal hypertension or endothelial dysfunction in active disease at advanced stages of cirrhosis. These disease-related factors and the possibility of a limited therapeutic window should be considered in future studies evaluating the use of anticoagulants in cirrhosis.

Keywords: anticoagulation; liver fibrosis; portal hypertension; rat.

MeSH terms

  • Animals
  • Anticoagulants / pharmacology*
  • Anticoagulants / toxicity
  • Bacterial Translocation / drug effects
  • Biomarkers / blood
  • Blood Coagulation / drug effects
  • Chemical and Drug Induced Liver Injury / blood
  • Chemical and Drug Induced Liver Injury / pathology
  • Chemical and Drug Induced Liver Injury / physiopathology
  • Chemical and Drug Induced Liver Injury / prevention & control*
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Enoxaparin / pharmacology*
  • Enoxaparin / toxicity
  • Hypertension, Portal / blood
  • Hypertension, Portal / pathology
  • Hypertension, Portal / physiopathology
  • Hypertension, Portal / prevention & control*
  • Inflammation Mediators / blood
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Liver Circulation / drug effects
  • Liver Cirrhosis, Experimental / blood
  • Liver Cirrhosis, Experimental / pathology
  • Liver Cirrhosis, Experimental / physiopathology
  • Liver Cirrhosis, Experimental / prevention & control*
  • Male
  • Microcirculation / drug effects
  • Portal Pressure / drug effects*
  • Rats, Sprague-Dawley


  • Anticoagulants
  • Biomarkers
  • Enoxaparin
  • Inflammation Mediators