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Severity of systemic inflammation is the main predictor of ACLF and bleeding in individuals with acutely decompensated cirrhosis

  • Alberto Zanetto
    Affiliations
    Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale - Università Padova, Padova, Italy

    Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
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  • Filippo Pelizzaro
    Affiliations
    Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale - Università Padova, Padova, Italy

    Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
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  • Elena Campello
    Affiliations
    General Internal Medicine and Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, Padova University Hospital, Padova, Italy
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  • Cristiana Bulato
    Affiliations
    General Internal Medicine and Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, Padova University Hospital, Padova, Italy
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  • Lorenz Balcar
    Affiliations
    Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
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  • Wenyi Gu
    Affiliations
    Department of Internal Medicine I, Goethe University, Frankfurt, Germany

    Department of Internal Medicine B, University Clinic Münster and Westfalen Wilhelms University, Münster, Germany
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  • Sabrina Gavasso
    Affiliations
    General Internal Medicine and Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, Padova University Hospital, Padova, Italy
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  • Graziella Saggiorato
    Affiliations
    General Internal Medicine and Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, Padova University Hospital, Padova, Italy
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  • Stefan Zeuzem
    Affiliations
    Department of Internal Medicine I, Goethe University, Frankfurt, Germany
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  • Francesco Paolo Russo
    Affiliations
    Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale - Università Padova, Padova, Italy

    Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
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  • Mattias Mandorfer
    Affiliations
    Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
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  • Thomas Reiberger
    Affiliations
    Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
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  • Jonel Trebicka
    Affiliations
    Department of Internal Medicine I, Goethe University, Frankfurt, Germany

    Department of Internal Medicine B, University Clinic Münster and Westfalen Wilhelms University, Münster, Germany

    European Foundation for Study of Chronic Liver Failure (EF-Clif), Barcelona, Spain
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  • Patrizia Burra
    Affiliations
    Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale - Università Padova, Padova, Italy

    Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
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  • Author Footnotes
    † These authors contributed equally.
    Paolo Simioni
    Correspondence
    General Internal Medicine and Thrombotic and Hemorrhagic Diseases Unit, Padova University Hospital, Padova, Italy. Tel.: +39-49-8212667.
    Footnotes
    † These authors contributed equally.
    Affiliations
    General Internal Medicine and Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, Padova University Hospital, Padova, Italy
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  • Author Footnotes
    † These authors contributed equally.
    Marco Senzolo
    Correspondence
    Corresponding authors. Addresses: Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale - Università Padova, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy. Tel.: +39-49-8218726.
    Footnotes
    † These authors contributed equally.
    Affiliations
    Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale - Università Padova, Padova, Italy

    Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
    Search for articles by this author
  • Author Footnotes
    † These authors contributed equally.
Published:September 20, 2022DOI:https://doi.org/10.1016/j.jhep.2022.09.005

      Highlights

      • Alterations in hypercoagulability and fibrinolysis are not associated with ACLF development in individuals with AD.
      • CRP, CLIF-C AD score, and Child-Pugh stage were independent predictors of ACLF.
      • We developed and validated the Padua predictive score, which accurately identified individuals with AD at risk of ACLF.
      • CRP and progression to ACLF, but not coagulopathy, were associated with development of bleeding unrelated to portal hypertension.
      • CRP and antifibrinolytic factor PAI-1 >50 ng/ml were associated with development of venous thrombosis.

      Background & Aims

      Hypercoagulability and hypofibrinolysis in acutely decompensated cirrhosis (AD) may be implicated in disease progression and haemostatic complications. We conducted a prospective study to: (1) characterise haemostatic alterations in AD; (2) evaluate whether such alterations can predict acute-on-chronic liver failure (ACLF) and bleeding/thrombosis.

      Methods

      Hospitalised individuals with AD were prospectively recruited and underwent an extensive haemostatic profiling including coagulation factors, thrombomodulin-modified thrombin generation assay with evaluation of endogenous thrombin potential (ETP; marker for plasmatic hypercoagulability), fibrinolytic factors, and plasmin–antiplasmin complex (fibrinolysis activation marker). Inflammation severity was assessed by C-reactive protein (CRP). In part 1 of the study, we compared haemostasis in AD vs. controls (stable decompensated and compensated cirrhosis). In part 2 of the study, we prospectively followed individuals with AD for 1 year and investigated predictors of ACLF and bleeding/thrombosis.

      Results

      A total of 169 individuals with AD were recruited (median model for end-stage liver disease score 20; CLIF-C AD 54). Compared with controls, AD was associated with more pronounced hypercoagulability (ETP: 871 vs. 750 vs. 605 nmol/L per min; p <0.0001), without differences in fibrinolysis activation. During follow-up, 55 individuals developed ACLF. CLIF-C AD, CRP, and Child-Pugh were independently associated with ACLF. A predictive model combining these variables (Padua model) accurately identified individuals at higher risk of ACLF (AUROC 0.857; 95% CI 0.798–0.915; sensitivity 74.5%, specificity 83.3%). Notably, CRP and progression to ACLF, but not baseline coagulopathy, were associated with bleeding (n = 11); CRP and antifibrinolytic factor PAI-1 >50 ng/ml were associated with thrombosis (n = 14). The prognostic value of the Padua model was validated in an independent, bicentric European cohort (N = 301).

      Conclusions

      Inflammation severity, and not coagulopathy, is the most important predictor of ACLF and bleeding in AD. The Padua model can be used to identify individuals with AD at risk of ACLF.

      Impact and implications

      A better understanding of haemostasis in individuals with acutely decompensated cirrhosis may help to identify those at higher risk of progression and complications. In this prospective study, we found no significant association between alterations of haemostasis and cirrhosis progression, indicating that the assessment of haemostatic alterations is not useful to identify those at risk. However, we found that C-reactive protein (a simple blood test that reflects severity of inflammation) and severity of chronic liver disease itself (as assessed by specific scores) were associated with cirrhosis progression and development of bleeding complications. Therefore, we developed a simple predictive model – based on C-reactive protein and liver disease scores – that, if validated by independent studies, could be used in clinical practice to assist physicians in identifying individuals with decompensated cirrhosis at higher risk of disease progression and death (i.e. in whom to consider an expedited evaluation for liver transplantation).

      Graphical abstract

      Keywords

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