Systemic inflammation and disorders of hemostasis in the AD-ACLF syndrome

With great interest we read the recent paper by Arroyo and coworkers in Journal of Hepatology, which they propose that systemic inflammation plays a central role transition from compensated to decompensated cirrhosis, development acute decompensation acute-on-chronic liver failure (ACLF)[1]Arroyo V. Angeli P. Moreau R. Jalan Claria J. Trebicka et al.The hypothesis: towards new paradigm multiorgan cirrhosis.J Hepatol. 2021; 74: 670-685Abstract Full Text PDF PubMed Scopus (22) Google Scholar We fully concur with authors this intriguing hypothesis will create research perspectives, would like one such theme, not directly addressed authors. It has been well established inflammatory responses are accompanied activation coagulation, vice versa.[2]Foley J.H. Conway E.M. Cross talk pathways between coagulation inflammation.Circ Res. 2016; 118: 1392-1408Crossref (190) Thus, if drive clinical deterioration patients disease, there is likely exaggeration decompensating patients. number potential consequences an inflammation-induced disease. First, intrahepatic hemostasis deposition platelets fibrin demonstrated animal models disease.[3]Kopec A.K. Joshi N. Luyendyk J.P. Role hemostatic factors hepatic injury disease: de-liver.J Thromb Haemost. 14: 1337-1349Crossref (18) This was propagate disease progression 1) inducing local ischemia, 2) cells proteases, 3) effects on modulating cellular responses.[3]Kopec Scholar,[4]Luyendyk Schoenecker J.G. Flick M.J. The multifaceted fibrinogen tissue inflammation.Blood. 2019; 133: 511-520Crossref (80) aggravation worsen way hasten injury. Second, lead hemostasis, may result extrahepatic tissues, leading other organs as seen ACLF. Disseminated intravascular (DIC) multiple organ thrombotic mechanism.[5]Levi M. Sivapalaratnam S. coagulation: update pathogenesis diagnosis.Expert Rev Hematol. 2018; 11: 663-672Crossref (29) long debated whether cirrhosis develop DIC, but suggest (low-grade) DIC patient, consistent concept inflammation-mediated could contribute In without underlying thought upregulation impairment natural anticoagulant mechanisms, downregulation fibrinolysis.[2]Foley these changes already apparent, inflammation-affiliated mechanisms aggravate changes, potentially more phenotype. prothrombotic state promote intraorgan microthrombosis failure.[6]Jackson S.P. Darbousset Schoenwaelder S.M. Thromboinflammation: challenges therapeutically targeting host defense mechanisms.Blood. 906-918Crossref (175) addition, precipitate macrovascular events venous thrombosis portal vein thrombosis. Third, or consumption factors. way, further decline hepatocyte-derived proteins consumption, perhaps addition decrease factor synthesis. form basis progressing patients.[7]Fisher C. Patel V.C. Stoy S.H. Singanayagam A. Adelmeijer Wendon al.Balanced haemostasis both hypo- hyper-coagulable features critically ill acute-on-chronic-liver failure.J Crit Care. 43: 54-60Crossref (44) Forth, although fibrinolysis hallmark picture complicated cirrhosis.[8]Blasi Azarian Hernandez Tejero Calvo al.Mixed fibrinolytic phenotypes hypofibrinolysis those complications poor survival.Hepatology. 2020; 71: 1381-1390Crossref (25) Mixed patterns observed ACLF, acutely particular sepsis. system uniformly downregulated.[9]Lisman T. Arefaine B. Zamalloa Corcoran E. Smith al.Global status septics disease.J (in press. Available from:)https://pubmed.ncbi.nlm.nih.gov/33006808/Google There indeed be divergent system, additional study required response overrules profibrinolytic Fifth, concomitant activate processes organs. Such include generation neutrophil extracellular traps formed complement also known communicate system.[2]Foley Scholar,[10]von Meijenfeldt F.A. Jenne C.N. Netting initiation exacerbation pathology.Semin Hemost. 46: 724-734Crossref (2) Both have roles their connection should overlooked. Overall, reciprocal connections through enhancement micro- thromboses. considerable investigate anti-inflammatory antithrombotic strategies (or combination thereof) halt deterioration. Indeed, therapy reduced risk small randomized controlled trial,[11]Villa Cammà Marietta Luongo Critelli Colopi al.Enoxaparin prevents advanced cirrhosis.Gastroenterology. 2012; 143: 1253-1260Abstract (439) data require validation before can clinically applied. As final remark, need for precise definitions context. Classifying elevated circulating markers true measure challenging, readout massive inflammation. critical seek understand switch cause consequence possible proportion genuine studies PREDICT unintentionally overestimated. because many measured cleared liver,[12]Andus Bauer Gerok W. Effects cytokines liver.Hepatology. 1991; 13: 364-375Crossref (379) creating scenario dysfunction indirectly elevates biomarkers. received no financial support produce manuscript. TL JPL jointly wrote conflicts declare. Please refer accompanying ICMJE disclosure forms details. following is/are supplementary article: Download .pdf (.15 MB) Help pdf files Multimedia component 1 Towards cirrhosisJournal HepatologyVol. 74Issue 3PreviewAcute (AD) defined ascites, encephalopathy and/or variceal bleeding. Ascites traditionally attributed splanchnic arterial vasodilation left ventricular dysfunction, hyperammonaemia, haemorrhage hypertension. Recent large-scale European observational shown AD. Here present working hypothesis, suggesting functions major systems common theme act synergistically traditional involved Full-Text Open AccessReply to: “Systemic disorders AD-ACLF syndrome”Journal 5PreviewWe grateful Drs. Lisman our proposing mechanism cirrhosis.1 core consists variety induced (immunopathology, metabolic dysregulation immunosuppression) which, operating synergy organ-specific (hyperammonemia, sinusoidal hypertension cardiocirculatory dysfunction), complex pathophysiological network explains nature decompensation-acute-on-chronic (AD-ACLF) syndrome.