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

Fortea, José Ignacio; Zipprich, Alexander; Fernández-Mena, Carolina; Puerto, Marta; Bosoi, Cristina R.; Almagro, Jorge; Hollenbach, Marcus; Bañares, Juan; Rodríguez‐Sánchez, Belén; Cercenado, Emilia; Clement, M.G.; Rose, Christopher F.; Bañares, Rafael; Ripoll, Cristina

doi:10.1111/liv.13510

Cited by 21 publications

(26 citation statements)

References 25 publications

(59 reference statements)

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“…In particular, the administration of CCl4 by oral gavage requires low quantities of CCl4 and ensures its direct delivery to the liver through the portal vein, diminishing the extrahepatic effects due to the selective accumulation of CCl4 in the liver 20 . The inhalational route is also frequently used 21 , 22 , but it exposes extra-hepatic organs to CCl4 and is more expensive due to the need of large amounts of CCl4 and specific facilities to perform the administration (fume-hoods, filters). Importantly, CCl4 causes liver toxicity in humans and was reasonably anticipated to be a human carcinogen in the 12 th Report on Carcinogens 23 .…”

Section: Discussionmentioning

confidence: 99%

Comparison of Two Protocols of Carbon Tetrachloride-Induced Cirrhosis in Rats – Improving Yield and Reproducibility

Fortea

Fernández-Mena

Puerto

et al. 2018

Sci Rep

Self Cite

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Despite being a cardinal experimental model, the induction of cirrhosis in rats by repeated exposure to carbon tetrachloride (CCl4) has low reproducibility. Here, we compared two models of cirrhosis induced by orogastric administration of CCl4 once (CCl4-1xWk) or twice a week (CCl4-2xWk) for 12 weeks in male Sprague-Dawley rats. Control rats received water instead of CCl4. Both CCl4 protocols similarly attenuated body weight gain (p < 0.01 vs. Control). Although both CCl4 protocols increased hepatic fibrosis, portal hypertension and splenomegaly, the magnitude of these alterations was higher and more consistent in CCl4-2xWk rats. Importantly, two CCl4-1xWk rats did not develop cirrhosis versus a 100% yield of cirrhosis in CCl4-2xWk rats. The CCl4-2xWk protocol consistently induced liver atrophy together with hematological, biochemical and coagulation abnormalities characteristic of advanced cirrhosis that were absent in CCl4-1xWk rats. Ascites occurred in 20% and 80% of rats in theCCl4-1xWk and CCl4-2xWk groups (p < 0.01). All rats showed normal renal function, arterial blood gases and stable systemic hemodynamics. The total dose of CCl4 and mortality rate were similar in both protocols. The CCl4-2xWk protocol, therefore, was highly reproducible and effective for the induction of experimental cirrhosis within a confined time, representing a valuable advance for liver research.

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Section: Discussionmentioning

confidence: 99%

Comparison of Two Protocols of Carbon Tetrachloride-Induced Cirrhosis in Rats – Improving Yield and Reproducibility

Fortea

Fernández-Mena

Puerto

et al. 2018

Sci Rep

Self Cite

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“…Hence, several experimental studies have shown that anticoagulant therapy improves liver fibrosis and reduces portal hypertension [62][63][64][65][66][67][68][69][70][71][72][73], and a clinical trial demonstrated that anticoagulation led to a reduction in portal thrombosis and other complications of liver disease and to increase in survival [74]. New clinical trials are needed in order to confirm these preliminary results and to establish whether the stage of liver disease may influence its efficacy [75].…”

Section: Pathophysiologymentioning

confidence: 99%

Cardiac Hepatopathy

Fortea¹,

Puente²,

Cuadrado³

et al. 2021

Liver Pathology

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Liver disease resulting from heart disease has generally been referred as "cardiac hepatopathy." The two main forms of cardiac hepatopathy are acute cardiogenic liver injury (ACLI) and congestive hepatopathy (CH). ACLI most commonly occurs in the setting of acute cardiocirculatory failure, whereas CH results from passive venous congestion in the setting of chronic right-sided heart failure (HF). Both conditions often coexist and potentiate the deleterious effects of each other on the liver. In CH, the chronic passive congestion leads to sinusoidal hypertension, centrilobular fibrosis, and ultimately, cirrhosis ("cardiac cirrhosis") and hepatocellular carcinoma. The differentiation between congestion and fibrosis currently represents an unmet need and a growing research area. Although cardiac cirrhosis may only arise after several decades of ongoing injury, the long-term survival of cardiac patients due to advances in medical and surgical treatments is responsible for the increased number of liver complications in this setting. Eventually, the liver disease could become as clinically relevant as the cardiac disease and further complicate its management.

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“…36,37 There are conflicting data on the effects of LMWH and DOACs on portal hypertension in cirrhosis rat models. [38][39][40] One group has demonstrated that both enoxaparin and rivaroxaban decreased portal hypertension and fibrosis in the rat cirrhosis model. It was hypothesized that these effects are mediated through deactivation of HSCs, as desmin and α-smooth muscle actin were both decreased in the rats treated with a factor Xa inhibitor.…”

Section: Mechanism Of Thrombosis and Role Of Doacs As Antifibrotic Agmentioning

confidence: 99%

“…40 However, another study demonstrated no improvements in portal hypertension in cirrhotic rats treated with enoxaparin. 39 Like thrombin, inhibition of factor Xa has also been linked to decreased fibrosis formation in the skin, but at the cost of decreased wound healing. 41 While most factors in the coagulation cascade are reduced in end-stage liver disease, von Willebrand factor (VWF) is increased.…”

Section: Mechanism Of Thrombosis and Role Of Doacs As Antifibrotic Agmentioning

confidence: 99%

Direct-Acting Oral Anticoagulants (DOACs) in Cirrhosis and Cirrhosis-Associated Portal Vein Thrombosis

2019

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Direct-acting oral anticoagulants (DOACs) have provided benefit in patients requiring anticoagulation for certain diseases by decreasing the burden of subcutaneous injections and the requirement for frequent monitoring through regular blood tests, to ensure adequacy of the therapeutic doses. Studies have demonstrated DOACs to be as safe, and in some instance safer, compared with traditional anticoagulants in the general population. However, the studies evaluating DOACs excluded patients with cirrhosis, a condition associated with an increased risk of developing portal vein thrombosis (PVT). Warfarin or low-molecular weight heparin are the standard-of-care treatment for acute PVT in cirrhosis, although there is enthusiasm in a paradigm shift switching to DOACs for the treatment of acute PVT in cirrhosis, particularly since the release of DOAC antidotes. This article reviews the current Food and Drug Administration-approved DOACs, hepatic metabolism of DOACs, pharmacokinetics of DOACs in patients with cirrhosis, safety of DOACs (including bleeding, hepatotoxicity, and pregnancy), current treatment guidelines for PVT in cirrhosis, and studies evaluating the use of DOACs in cirrhosis and for the treatment of PVT in cirrhosis. The potential use of DOACs for PVT primary prophylaxis in at-risk patients with cirrhosis and the possible antifibrotic effects of DOACs are also discussed.

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

Cited by 21 publications

References 25 publications

Comparison of Two Protocols of Carbon Tetrachloride-Induced Cirrhosis in Rats – Improving Yield and Reproducibility

Comparison of Two Protocols of Carbon Tetrachloride-Induced Cirrhosis in Rats – Improving Yield and Reproducibility

Cardiac Hepatopathy

Direct-Acting Oral Anticoagulants (DOACs) in Cirrhosis and Cirrhosis-Associated Portal Vein Thrombosis

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