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On coagulation in advanced chronic liver disease and the origin of freshwater eels

  • Mattias Mandorfer
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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  • Bernhard Scheiner
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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  • Ton Lisman
    Correspondence
    Corresponding author. Address: Surgical Research Laboratory and Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, BA44, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands; Tel.: +31-50-3619028, fax: +31-50-3632796.
    Affiliations
    Surgical Research Laboratory and Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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      Linked Article

      • Cirrhosis: What are all those factor VIII and protein C for?
        Journal of HepatologyVol. 77Issue 3
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          Over the last decades our understanding of cirrhotic coagulopathy has undergone considerable changes. Clinical, experimental, and pathophysiological observations helped us to view cirrhosis not as the epitome of acquired bleeding disorders, but as a disease characterized by rebalanced hemostasis and possibly even the increased risk of thrombosis.1 Scheiner et al. recently published an interesting paper on this topic.2 Based on retrospective evaluation of coagulation biomarkers and clinical observations, the authors conclude that the factor (F)VIII/protein C(PC) ratio in cirrhosis is independently associated with liver-related events/death.
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      • Factor VIII/protein C ratio independently predicts liver-related events but does not indicate a hypercoagulable state in ACLD
        Journal of HepatologyVol. 76Issue 5
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          It has been suggested that the ratio of procoagulant factor VIII to anticoagulant protein C (FVIII/PC) reflects the hemostatic equilibrium. Moreover, FVIII/PC predicted decompensation/death in a small study not accounting for portal hypertension severity. We investigated (i) the prognostic value of FVIII/PC (outcome-cohort) and (ii) whether FVIII/PC reflects the hypercoagulable state (assessed by thrombomodulin-modified thrombin generation assay [TM-TGA]) or the risk of bleeding/thrombotic events in patients undergoing hepatic venous pressure gradient (HVPG) measurement during follow-up.
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        Open Access
      To the Editor:
      We would like to thank Dr. Tripodi for his interest in our work.
      • Scheiner B.
      • Balcar L.
      • Nussbaumer R.J.
      • Weinzierl J.
      • Paternostro R.
      • Simbrunner B.
      • et al.
      Factor VIII/protein C ratio independently predicts liver-related events but does not indicate a hypercoagulable state in ACLD.
      The conundrum of haemostatic balance in patients with advanced chronic liver disease (ACLD) shares several similarities with the mystery of the freshwater eel. Reports on the presumed origin of the European eel go back to Aristotle who, due to the absence of reproductive organs at the yellow eel stage, considered them a spontaneous generation, e.g. derived from mud. It was not until 1922 that Johannes Schmidt located the origin of all European eel (Anguilla anguilla) to the Saragossa Sea (Atlantic Ocean) by capturing the smallest eel larvae. Nonetheless, the spawning of the European eel has never been observed in the wild, and thus, key aspects of its biology remain obscure. Notably, Aristotle also recognized the capability of blood to clot, which – in the context of ACLD – remains enigmatic in 2022. Although our knowledge on mechanisms leading to bleeding and thrombosis in patients with ACLD is steadily increasing, bleeding and clot formation are hard to study ‘in the wild’, limiting the available evidence mostly to experimental, genetic, and blood-/plasma-based laboratory investigations.
      In this regard, different stages of ACLD have been extensively characterized by quantifying levels of coagulation factors and proteins involved in fibrinolysis,
      • Fisher C.
      • Patel V.C.
      • Stoy S.H.
      • Singanayagam A.
      • Adelmeijer J.
      • Wendon J.
      • et al.
      Balanced haemostasis with both hypo- and hyper-coagulable features in critically ill patients with acute-on-chronic-liver failure.
      ,
      • Tripodi A.
      • Primignani M.
      • Chantarangkul V.
      • Dell'Era A.
      • Clerici M.
      • de Franchis R.
      • et al.
      An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis.
      with studies indicating profound differences throughout the course of ACLD. Functional assays such as thromboelastography
      • Stravitz R.T.
      Potential applications of thromboelastography in patients with acute and chronic liver disease.
      and rotational thromboelastometry have reinforced the clinical observation of a capable haemostatic system in the vast majority of patients with ACLD,
      • Raeven P.
      • Baron-Stefaniak J.
      • Simbrunner B.
      • Stadlmann A.
      • Schwabl P.
      • Scheiner B.
      • et al.
      Thromboelastometry in patients with advanced chronic liver disease stratified by severity of portal hypertension.
      although readouts of the latter method may be suggestive of hypocoagulability.
      • Kleinegris M.C.
      • Bos M.H.
      • Roest M.
      • Henskens Y.
      • Ten Cate-Hoek A.
      • Van Deursen C.
      • et al.
      Cirrhosis patients have a coagulopathy that is associated with decreased clot formation capacity.
      Furthermore, seminal work by Tripodi et al.
      • Fisher C.
      • Patel V.C.
      • Stoy S.H.
      • Singanayagam A.
      • Adelmeijer J.
      • Wendon J.
      • et al.
      Balanced haemostasis with both hypo- and hyper-coagulable features in critically ill patients with acute-on-chronic-liver failure.
      and other groups
      • Lebreton A.
      • Sinegre T.
      • Lecompte T.
      • Talon L.
      • Abergel A.
      • Lisman T.
      Thrombin generation and cirrhosis: state of the art and perspectives.
      revealed laboratory evidence supporting a hypercoagulable state at advanced stages, as identified by increased endogenous thrombin potential in thrombomodulin-modified thrombin generation assays (TM-TGA). It has been hypothesized that this presumed hypercoagulable state promotes further deterioration via the development portal vein thrombosis (PVT) or even liver disease progression due to parenchymal extinction via a ‘congestive escalator’.
      • Wanless I.R.
      The role of vascular injury and congestion in the pathogenesis of cirrhosis: the congestive escalator and the parenchymal extinction sequence.
      However, TM-TGA are poorly standardized and require considerable expertise, and thus, the ratio of factor VIII/protein C (FVIII/PC) has been applied in several studies attempting to link the presumed ‘hypercoagulable state’ to clinically meaningful endpoints. Intriguingly, this simplification led to positive results that were well-perceived by the community. However, the Achilles’ heel of all laboratory-based ‘coagulation’ tests is that they cannot be considered as surrogates for haemostasis in ACLD, as they are largely unrelated to clinical endpoints. This even applies to TM-TGA (which is considered as the most capable test for detecting the presumed ‘hypercoagulable state’), as it failed to predict thrombotic events including PVT in our
      • Scheiner B.
      • Balcar L.
      • Nussbaumer R.J.
      • Weinzierl J.
      • Paternostro R.
      • Simbrunner B.
      • et al.
      Factor VIII/protein C ratio independently predicts liver-related events but does not indicate a hypercoagulable state in ACLD.
      and another well-conducted longitudinal study.
      • Turon F.
      • Driever E.G.
      • Baiges A.
      • Cerda E.
      • Garcia-Criado A.
      • Gilabert R.
      • et al.
      Predicting portal thrombosis in cirrhosis: a prospective study of clinical, ultrasonographic and hemostatic factors.
      This could be explained by considerable variations in ex vivo thrombin generation capacity over time (an aspect that seems understudied), which may compromise the predictive ability of baseline values that have been acquired (long) before the occurrence of the clinical outcome. While this emphasizes the need for further studies on the clinical significance of TM-TGA results, the findings of our studies may have put the final nails in the coffin of the (mis)use of FVIII/PC as a surrogate for the presumed ‘hypercoagulable state’. First, its association with TM-TGA results is confounded by liver disease severity. Second, it is unrelated to bleeding and thrombotic events. Third, its link with clinical endpoints is much better explained by associated well-established disease-driving mechanisms that are not directly related to coagulation.
      Accordingly, we very much agree with Dr. Tripodi when he refers to ‘laboratory biomarkers’ or ‘biochemical hypercoagulability’ and underlines the potentially overwhelming contribution of circumstantial risk factors to bleeding and thrombosis in ACLD, which – apart from the contribution of portal hypertension to gastrointestinal bleeding events – seems poorly defined.
      Finally, accumulating evidence suggests that plasma-based studies only scratch the surface of the pathophysiology of thrombosis in ACLD. Recent observations regarding the composition of portal vein ‘thrombi’
      • Driever E.G.
      • von Meijenfeldt F.A.
      • Adelmeijer J.
      • de Haas R.J.
      • van den Heuvel M.C.
      • Nagasami C.
      • et al.
      Nonmalignant portal vein thrombi in patients with cirrhosis consist of intimal fibrosis with or without a fibrin-rich thrombus.
      question current paradigms, as intimal hyperplasia rather than fibrin-rich thrombi seemed to be their main constituent. As a heretical thought, one may even conclude that very limited histological data
      • Wanless I.R.
      The role of vascular injury and congestion in the pathogenesis of cirrhosis: the congestive escalator and the parenchymal extinction sequence.
      has provided more insights into the potential role of thrombosis in liver disease progression than a multitude of conventional coagulation studies. Accordingly, it may be hypothesized that one has to delve into the thrombotic crime scene (i.e., the tissues of the portal and intrahepatic vasculature) and the Saragossa Sea to gain further insights into ‘thrombus’ formation and the spawning of the European/American eel, respectively.
      We would like to conclude that our study failed to substantiate the link between the haemostatic balance and haemostasis-related clinical outcomes. However, it shifted another unknown unknown to the long list of known unknowns in our field: We have learned that FVIII/PC should not be used as an indicator of the presumed ‘hypercoagulable state’ – surrogate markers for bleeding and thrombosis in ACLD have yet to be established.

      Financial support

      No funding specific to this work was received.

      Authors’ contributions

      Drafting of the manuscript (M.M.) and revision for important intellectual content as well as approval of the final manuscript (all authors).

      Conflict of interest

      M.M. served as a speaker and/or consultant and/or advisory board member for AbbVie, Gilead, Collective Acumen, and W. L. Gore & Associates and received travel support from AbbVie and Gilead. Be.Sc. received travel support from AbbVie, Ipsen, and Gilead. T.L. has nothing to disclose.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the supplementary data to this article:

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