Anticoagulation to prevent disease progression in patients with cirrhosis

Anticoagulation improves survival in patients with cirrhosis and portal vein thrombosis: The IMPORTAL competing-risk meta-analysisJournal of HepatologyVol. 79Issue 1PreviewPrevious meta-analyses demonstrated the safety and efficacy of anticoagulation in the recanalization of portal vein thrombosis in patients with cirrhosis. Whether this benefit translates into improved survival is unknown. We conducted an individual patient data (IPD) meta-analysis to assess the effect of anticoagulation on all-cause mortality in patients with cirrhosis and portal vein thrombosis. Full-Text PDF Reply to: "Anticoagulation to prevent disease progression in patients with cirrhosis"Journal of HepatologyVol. 79Issue 3PreviewWe thank Dr. Lisman and colleagues for their interest and their gratifying comments regarding our article.1 We agree with Lisman et al. that our results could represent a breakthrough in the clinical management of cirrhosis that should be added to the accumulating evidence supporting the favorable impact of anticoagulation on cirrhosis progression. Full-Text PDF We read the individual patient data meta-analysis on anticoagulation for cirrhotic non-tumoral portal vein thrombosis (PVT) in relation to survival by Guerrero and coworkers with interest.[1]Guerrero A. Campo L del Piscaglia F. Scheiner B. Han G. Violi F. et al.Anticoagulation improves survival in patients with cirrhosis and portal vein thrombosis: the IMPORTAL competing-risk meta-analysis.J Hepatol. 2023; 79: 69-78https://doi.org/10.1016/j.jhep.2023.02.023Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar This study may be a game-changer in the clinical management of PVT, as it suggests that anticoagulation substantially improves survival independently of portal vein recanalisation with an acceptable bleeding risk. Interestingly, and in line with other meta-analyses,[2]Loffredo L. Pastori D. Farcomeni A. Violi F. Effects of anticoagulants in patients with cirrhosis and portal vein thrombosis: a systematic review and meta-analysis.Gastroenterology. 2017; 153: 480-487.e1https://doi.org/10.1053/j.gastro.2017.04.042Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar the effect of anticoagulation on portal vein recanalisation is not very impressive, with 58% of patients recanalising with anticoagulation, while 33% of patients recanalise without anticoagulation. The modest effect of anticoagulation on recanalisation may be explained by recent observations showing that portal vein thrombi frequently do not universally consist of a true thrombus, but rather are related to thickening of the portal vein wall intima.[3]Driever E.G. von Meijenfeldt F.A. Adelmeijer J. de Haas R.J. van den Heuvel M.C. Nagasami C. et al.Non-malignant portal vein thrombi in patients with cirrhosis consist of intimal fibrosis with or without a fibrin-rich thrombus.Hepatol. 2022; 75: 898-911https://doi.org/10.1002/HEP.32169Crossref PubMed Scopus (0) Google Scholar Portal vein intimal fibrosis may not be susceptible to anticoagulant therapy, which targets the coagulation system. Despite a relatively modest effect of anticoagulation on portal vein recanalisation, all-cause mortality was strikingly reduced in patients on anticoagulation (25% vs. 39%, a relative risk reduction of 36%). Importantly, the effect of anticoagulation was independent of PVT severity or recanalisation, but was proportional to duration of anticoagulant treatment. As previous studies have demonstrated that PVT per se does not affect progression of disease,[4]Nery F. Chevret S. Condat B. de Raucourt E. Boudaoud L. Rautou P.E. et al.Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis: results of a longitudinal study.Hepatology. 2015; 61: 660-667https://doi.org/10.1002/hep.27546Crossref PubMed Scopus (349) Google Scholar these data strongly suggest that anticoagulation has a PVT-independent effect on outcome. Thus, this study suggests that portal vein recanalization should not be considered as a primary goal of anticoagulant treatment in patients with cirrhosis and PVT. The authors mention that the survival benefit of anticoagulation may be related to prevention of macro- and microvascular thrombosis. The beneficial effect of anticoagulation in the absence of PVT recanalization emphasizes the likely role of the hemostatic system in pathogenesis and progression of liver diseases. Indeed, evidence from experimental settings suggests multiple mechanisms coupling components of the hemostatic system, including coagulation proteases, to the progression of chronic liver disease. Protease activated receptor (PAR)-1 and -2 have been shown to drive hepatic fibrosis, with most studies focusing on direct activation of hepatic stellate cells to a myofibroblast phenotype. In addition, both PAR-1 and PAR-2 have been shown to amplify hepatic steatosis and inflammation in a variety of models. The impact of PAR signaling on intrahepatic blood flow, perhaps related to construction of sinusoidal blood flow by stellate cells, may be of equal importance. The activation of coagulation may exaggerate the formation or persistence of microthrombi in the sinusoids across the liver lobule, negatively affecting tissue perfusion, exacerbating injury, and impeding access to leukocytes essential for repair. These concepts have been reviewed elsewhere.[5]Pant A. Kopec A.K. Luyendyk J.P. Role of the blood coagulation cascade in hepatic fibrosis.Am J Physiology-Gastrointestinal Liver Physiol. 2018; 315: G171-G176https://doi.org/10.1152/ajpgi.00402.2017Crossref PubMed Scopus (39) Google Scholar Pathologic roles of VWF and platelets have been noted in multiple experimental settings, and fibrin may also contribute, although its role is less well defined.[6]Luyendyk J.P. Schoenecker J.G. Flick M.J. The multifaceted role of fibrinogen in tissue injury and inflammation.Blood. 2019; 133: 511-520https://doi.org/10.1182/blood-2018-07-818211Crossref PubMed Scopus (255) Google Scholar,[7]Groeneveld D.J. Poole L.G. Luyendyk J.P. Targeting von Willebrand factor in liver diseases: a novel therapeutic strategy?.J Thromb Haemost. 2021; 19: 1390-1408https://doi.org/10.1111/jth.15312Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar The findings of Guerrero and coworkers emphasize the need to further define these mechanistic connections and pathologic consequences of increased coagulation within the liver microvasculature. Indeed, the dominant therapeutic action of heparin in this patient population may extend well beyond correction of PV occlusion. The authors conclude that 'PVT may identify a group of patients with cirrhosis that benefit from long-term anticoagulation'. This conclusion is perhaps too narrow. Both preclinical studies and clinical observations suggest a survival benefit of anticoagulant therapy in patients with cirrhosis without PVT.[8]Villa E. Cammà C. Marietta M. Luongo M. Critelli R. Colopi S. et al.Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis.Gastroenterology. 2012; 143https://doi.org/10.1053/j.gastro.2012.07.018Abstract Full Text Full Text PDF PubMed Scopus (562) Google Scholar,[9]Kopec A.K. Joshi N. Luyendyk J.P. Role of hemostatic factors in hepatic injury and disease: animal models de-liver.J Thromb Haemost. 2016; 14: 1337-1349https://doi.org/10.1111/jth.13327Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar We thus feel that it is not the PVT per se that will identify patients who may benefit from long-term anticoagulation. We encourage studies to identify those subgroups of patients with advanced disease in whom outcome of disease is likely to be impacted by anticoagulant therapy. We propose that in those patients in whom a potential survival benefit justifies an increased bleeding risk, long-term anticoagulation requires consideration, preferably in the context of well-designed clinical trials. Unfortunately, studies aimed at testing the effect of anticoagulation on progression of chronic liver disease have proven difficult: one randomized-controlled trial assessing low molecular weight heparin in France (Childbenox) was prematurely discontinued because of a low rate of enrollment, and one randomized-controlled trial in Spain (clinicaltrials.gov NCT02643212) has recently been completed without reaching the planned number of inclusions. Hopefully, the encouraging results of the current study by Guerrero and coworkers will set the stage for additional randomized studies, preferably with direct oral anticoagulants, which have a good safety profile in patients with Child-Pugh A and B cirrhosis and are more suitable for long-term use than low molecular weight heparin. Of note, the concept of clinical anticoagulation to improve survival in patients with cirrhosis was already suggested over a decade ago. In a provocative paper, it was argued that a combination of drugs, specifically an anticoagulant, a beta blocker, a statin, and an antibiotic, may delay decompensation and improve survival.[10]Tsochatzis E.A. Bosch J. Burroughs A.K. New therapeutic paradigm for patients with cirrhosis.Hepatology. 2012; 56: 1983-1992https://doi.org/10.1002/hep.25915Crossref PubMed Scopus (99) Google Scholar Whereas such a polypill approach may still be a bridge too far, we feel the time has come to extensively trial anticoagulant drugs for this purpose. The authors received no financial support to produce this manuscript. The authors have no conflict of interest to report. Please refer to the accompanying ICMJE disclosure forms for further details. TL and JPL drafted the letter, TL WB and JPL revised the initial draft and approved the final version. The following are the supplementary data to this article: Download .pdf (.22 MB) Help with pdf files Multimedia component 1