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Haemostatic alterations and management of haemostasis in patients with cirrhosis

  • Ton Lisman
    Correspondence
    Corresponding author. Address: University Medical Center Groningen, Department of Surgery, BA33, 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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  • Stephen H. Caldwell
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Medicine, Center for Coagulation in Liver Disease, University of Virginia Medical Center, Charlottesville VA, United States
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  • Nicolas M. Intagliata
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Medicine, Center for Coagulation in Liver Disease, University of Virginia Medical Center, Charlottesville VA, United States
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      Summary

      Patients with cirrhosis frequently acquire complex changes in their haemostatic system including a decreased platelet count and decreased levels of various haemostatic proteins. Although historically patients with cirrhosis were thought to have a haemostasis-related bleeding tendency, it is now widely accepted that the haemostatic system of patients with cirrhosis remains in balance as a result of simultaneous changes in pro- and anti-haemostatic systems. The concept of rebalanced haemostasis has led to changes in clinical management, although firm evidence from well-designed clinical studies is largely lacking. For example, many invasive procedures in patients with cirrhosis and a prolonged prothrombin time are now performed without prophylaxis with fresh frozen plasma. Conversely, clinicians have become more aware of the need for anti-thrombotic therapy, even in those patients with abnormal routine coagulation tests. This paper will outline recent advances in pathogenesis, prevention and treatment of both bleeding and thrombotic complications in patients with cirrhosis. Among other topics, we will discuss the haemostatic status of acutely ill patients with cirrhosis, the various causes of bleeding in patients with cirrhosis, and how best to prevent or treat bleeding. In addition, we will discuss the hypercoagulable features of patients with cirrhosis, new insights into the pathogenesis of portal vein thrombosis, and how best to prevent or treat thromboses.

      Keywords

      Linked Article

      Introduction

      Patients with liver disease may acquire complex alterations in their haemostatic system as the liver is the site of synthesis of many haemostatic proteins.
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      The coagulopathy of chronic liver disease.
      These haemostatic changes include thrombocytopenia and alterations in platelet function, low plasma levels of coagulation proteins and inhibitors of coagulation, and low levels of fibrinolytic proteins. In addition, plasma levels of proteins that are synthesised by endothelial cells, rather than hepatocytes, are frequently elevated. As both pro- and anti-haemostatic pathways change simultaneously, the net effect of the haemostatic changes in patients with cirrhosis is relatively neutral
      • Lisman T.
      • Porte R.J.
      Rebalanced haemostasis in patients with liver disease: evidence and clinical consequences.
      (Fig. 1).
      Figure thumbnail gr1
      Fig. 1Haemostatic balance in patients with liver disease.
      Concomitant changes in both pro- and anti-haemostatic pathways result in a ‘rebalanced’ haemostatic state in patients with liver disease. (A) shows the haemostatic balance in healthy individuals; (B) shows the haemostatic balance in patients with liver disease together with the individual changes in the haemostatic system. The new haemostatic balance in patients with liver disease is much less stable than the balance in healthy individuals, as there is much less weight on each end of the haemostatic scale. Simultaneous changes promoting bleeding and promoting thrombosis occur in primary and secondary haemostasis, and fibrinolysis. Modified from Curr Opin Organ Transplant 2008; 13: 298–9 with permission from Wolters Kluwer Health.
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      The two tales of coagulation in liver transplantation.
      ADAMTS-13, A disintegrin and metalloprotease with thrombospondin-1 domain; APTT, activated partial thromboplastin time; FVIII, factor VIII; PT, prothrombin time; TAFI, thrombin activatable fibrinolysis inhibitor; VWF, von Willebrand factor.
      The concept of ‘rebalanced haemostasis’ in patients with cirrhosis is embraced by both the hepatology and haematology communities.
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      Vascular liver disorders, portal vein thrombosis, and procedural bleeding in patients with liver disease: 2020 practice guidance by the American association for the study of liver diseases.
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      • Lisman T.
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      The concept of rebalanced haemostasis in patients with liver disease: communication from the ISTH SSC working group on haemostatic management of patients with liver disease.
      Although patients with cirrhosis remain in haemostatic balance, this balance is much less stable than in individuals with a healthy liver. In addition, the haemostatic profile of patients with cirrhosis has notable hypo- and hypercoagulable features which may predispose to bleeding or thrombosis.
      Indeed, patients with cirrhosis may experience both bleeding and thrombotic complications, although not all of these complications are a consequence of the haemostatic alterations of cirrhosis. Some bleeding and thrombotic complications are common in patients with cirrhosis and advanced portal hypertension, including variceal bleeding and portal vein thrombosis (PVT). Deep vein thrombosis (DVT), pulmonary embolism (PE), and procedure-associated bleeding occur less commonly, but have important clinical consequences.
      Unfortunately, the best strategies for prevention and treatment of bleeding and thrombosis are not fully established as we lack firm clinical data. Despite few randomised trials on haemostasis in patients with cirrhosis, there is increasing consensus on therapeutic strategies that are summarised in recent guidance documents.
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      ,
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      AGA clinical practice update: coagulation in cirrhosis.
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      ACG clinical guideline: disorders of the hepatic and mesenteric circulation.
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      • et al.
      Periprocedural management of abnormal coagulation parameters and thrombocytopenia in patients with cirrhosis: guidance from the SSC of the ISTH.
      For example, there is broad consensus on the futility of using fresh frozen plasma (FFP) with the aim to prevent spontaneous or procedure-related bleeding in patients with cirrhosis and a prolonged international normalised ratio (INR), and there is increasing utilisation of anticoagulant therapy to prevent venous thrombosis.
      This review will outline recent advances in the pathogenesis and management of bleeding and thrombotic complications in patients with cirrhosis. We will specifically focus on recent breakthroughs and do not intend to give a complete overview of the field which is covered elsewhere.
      • Lisman T.
      • Porte R.J.
      Pathogenesis, prevention, and management of bleeding and thrombosis in patients with liver diseases.
      • Lebreton A.
      • Sinegre T.
      • Lecompte T.
      • Talon L.
      • Abergel A.
      • Lisman T.
      Thrombin generation and cirrhosis: state of the art and perspectives.
      • Intagliata N.M.
      • Caldwell S.H.
      • Tripodi A.
      Diagnosis, development, and treatment of portal vein thrombosis in patients with and without cirrhosis.
      • Stotts M.J.
      • Lisman T.
      • Intagliata N.M.
      The spectrum of disease severity in cirrhosis and its implications for haemostasis.
      • Schepis F.
      • Turco L.
      • Bianchini M.
      • Villa E.
      Prevention and management of bleeding risk related to invasive procedures in cirrhosis.
      • Turco L.
      • de Raucourt E.
      • Valla D.C.
      • Villa E.
      Anticoagulation in the cirrhotic patient.

      Pathogenesis of bleeding

      The clinical observation that patients frequently bleed, either spontaneously or during major invasive procedures, has fuelled the dogma of liver disease as an acquired bleeding disorder. Although the concept of rebalanced haemostasis is broadly accepted, it remains difficult to reconcile with severe clinical bleeding complications.
      This paper reviews recent developments in pathogenesis, prevention, and treatment of bleeding and thrombosis in patients with cirrhosis.
      The recent guidance document from the American Association for the Study of Liver Disease (AASLD) has defined 3 causes of bleeding in patients with cirrhosis
      • Northup P.G.
      • Garcia-Pagan J.C.
      • Garcia-Tsao G.
      • Intagliata N.M.
      • Superina R.A.
      • Roberts L.N.
      • et al.
      Vascular liver disorders, portal vein thrombosis, and procedural bleeding in patients with liver disease: 2020 practice guidance by the American association for the study of liver diseases.
      (Fig. 2). First, portal hypertension-related bleeding complications, such as variceal bleeding, which appear to be unrelated to haemostatic failure (based on substantial evidence). For example, it has been demonstrated that patients with acute variceal bleeding do not have a worse outcome when they are using anticoagulant drugs at the time of the bleed
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      • et al.
      Impact of anticoagulation on upper-gastrointestinal bleeding in cirrhosis. A retrospective multicenter study.
      ; moreover, pro-haemostatic drugs have little effect in stopping a variceal bleed.
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      • Massard J.
      • et al.
      Recombinant factor VIIa for variceal bleeding in patients with advanced cirrhosis: a randomfd, controlled trial.
      ,
      • Roberts I.
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      • Afolabi A.
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      • Arribas M.
      • Brenner A.
      • et al.
      Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial.
      These collective data suggest that haemostatic failure is not the primary driver of induction or propagation of a variceal bleed. Second, provoked bleeds may occur during procedures as a result of mechanical injury to vessels. Again, such bleeds are not caused by haemostatic failure per se, and therefore it is unlikely that prophylactic procoagulant therapy will prevent this. Third, spontaneous or unprovoked bleeds that may be related to haemostatic failure include bruising, mucosal bleeding, and oozing from puncture sites. These bleeding events are difficult to predict and are thought to be driven by underlying systemic processes. It has been proposed that pro-haemostatic therapy is not a first-line therapeutic strategy in many common bleeding scenarios in patients with cirrhosis as these bleeds can be better managed by other strategies depending on the circumstances.
      • Northup P.G.
      • Lisman T.
      • Roberts L.
      Treatment of bleeding in patients with liver disease.
      Figure thumbnail gr2
      Fig. 2Common sources of bleeding in patients with cirrhosis.
      Many bleeding events are due to spontaneous mechanical sources such as ruptured oesophageal varices while others are related to trauma to blood vessels and tissues, often caused by medical interventions. The minority of bleeding events are purely due to the haemostatic failure of end-stage liver disease. Figure adapted from Northup, et al. used with permission.
      • Northup P.G.
      • Garcia-Pagan J.C.
      • Garcia-Tsao G.
      • Intagliata N.M.
      • Superina R.A.
      • Roberts L.N.
      • et al.
      Vascular liver disorders, portal vein thrombosis, and procedural bleeding in patients with liver disease: 2020 practice guidance by the American association for the study of liver diseases.

      The haemostatic status of critically ill patients with cirrhosis

      Historically, cirrhosis was classified as an acquired bleeding disorder. The combination of abnormal conventional laboratory parameters (thrombocytopenia, prolonged INR) and pervasive clinical bleeding fuelled the notion that the haemostatic changes in cirrhosis were responsible for bleeding. Variceal bleeding and bleeding during liver transplantation are common and can be dramatic. Although bleeding during liver transplantation was uniformly severe in the early days of liver transplantation,
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      Blood use in liver transplantation.
      even patients with profound haemostatic abnormalities can now undergo transplantation without the need for blood transfusions.
      • Massicotte L.
      • Thibeault L.
      • Roy A.
      Classical notions of coagulation revisited in relation with blood losses, transfusion rate for 700 consecutive liver transplantations.
      Variceal bleeding is primarily driven by portal pressure and not related to failure of the haemostatic system. These observations have contributed to the development of the ‘rebalanced haemostasis’ concept. Laboratory studies have demonstrated that acquired defects in pro-haemostatic pathways are accompanied by acquired changes in anti-haemostatic pathways leading to a ‘biochemical’ reset in the haemostatic balance. Specifically, defects in platelet number are balanced by elevated levels of the platelet adhesive protein von Willebrand factor (VWF),
      • Lisman T.
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      • Adelmeijer J.
      • Janssen H.L.A.
      • De Maat M.P.M.
      • De Groot P.G.
      • et al.
      Elevated levels of von Willebrand factor in cirrhosis support platelet adhesion despite reduced functional capacity.
      and decreases in procoagulant and antifibrinolytic proteins are balanced by concomitant decreases in anticoagulant and profibrinolytic proteins.
      • Lisman T.
      • Leebeek F.W.G.
      • Mosnier L.O.
      • Bouma B.N.
      • Meijers J.C.M.
      • Janssen H.L.A.
      • et al.
      Thrombin-activatable fibrinolysis inhibitor deficiency in cirrhosis is not associated with increased plasma fibrinolysis.
      ,
      • Tripodi A.
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      • 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.
      Perhaps the most notable breakthrough in the biochemical characterisation of haemostasis in patients with cirrhosis has been the use of thrombin generation assays that have been modified to include activators of the anticoagulant protein C pathway.
      • Tripodi A.
      • Salerno F.
      • Chantarangkul V.
      • Clerici M.
      • Cazzaniga M.
      • Primignani M.
      • et al.
      Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests.
      Such thrombin generation assays show normal to enhanced thrombin-generating capacity in plasma from patients with cirrhosis, despite clearly abnormal conventional coagulation tests such as the INR.
      • Lebreton A.
      • Sinegre T.
      • Lecompte T.
      • Talon L.
      • Abergel A.
      • Lisman T.
      Thrombin generation and cirrhosis: state of the art and perspectives.
      However, most studies have been performed in patients in a relatively stable clinical condition. Only recently have studies begun to address the haemostatic status in critically ill patients with cirrhosis (i.e., those with acutely decompensated cirrhosis [AD] and acute-on-chronic liver failure [ACLF]).
      • Stotts M.J.
      • Lisman T.
      • Intagliata N.M.
      The spectrum of disease severity in cirrhosis and its implications for haemostasis.
      Bleeding in patients with cirrhosis may be related to portal hypertension, to mechanical injury to vessels, or to haemostatic failure.
      Fisher and coworkers provided initial evidence that the haemostatic balance in patients with AD and ACLF remains in equilibrium, despite progressive deterioration in routine haemostatic tests (platelets, INR) and levels of individual haemostatic proteins.
      • 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.
      The same group subsequently confirmed and extended these findings.
      • Lisman T.
      • Kleiss S.
      • Patel V.C.V.C.
      • Fisher C.
      • Adelmeijer J.
      • Bos S.
      • et al.
      In vitro efficacy of pro- and anticoagulant strategies in compensated and acutely ill patients with cirrhosis.
      • Lisman T.
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      • Adelmeijer J.
      • Zamalloa A.
      • Corcoran E.
      • Smith J.G.
      • et al.
      Global haemostatic status in patients with acute-on-chronic liver failure and septics without underlying liver disease.
      • Blasi A.
      • Patel V.C.
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      • Azarian S.
      • Hernandez Tejero M.
      • Calvo A.
      • et al.
      Mixed fibrinolytic phenotypes in decompensated cirrhosis and acute-on-chronic liver failure with hypofibrinolysis in those with complications and poor survival.
      • von Meijenfeldt F.A.
      • van den Boom B.P.
      • Adelmeijer J.
      • Roberts L.N.
      • Lisman T.
      • Bernal W.
      Prophylactic fresh frozen plasma and platelet transfusion have a prothrombotic effect in patients with liver disease.
      Collectively, these studies confirmed that the haemostatic system remains functional even in severely ill patients. It was demonstrated that patients with AD and ACLF have highly elevated levels of the platelet adhesive protein VWF and decreased levels of the VWF-regulating protein ADAMTS13.
      • 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.
      ,
      • Lisman T.
      • Arefaine B.
      • Adelmeijer J.
      • Zamalloa A.
      • Corcoran E.
      • Smith J.G.
      • et al.
      Global haemostatic status in patients with acute-on-chronic liver failure and septics without underlying liver disease.
      The VWF/ADAMTS13 imbalance is prothrombotic and may compensate for the decrease in platelet count, as has been demonstrated in patients with stable cirrhosis and patients with acute liver failure.
      • Lisman T.
      • Bongers T.N.
      • Adelmeijer J.
      • Janssen H.L.A.
      • De Maat M.P.M.
      • De Groot P.G.
      • et al.
      Elevated levels of von Willebrand factor in cirrhosis support platelet adhesion despite reduced functional capacity.
      ,
      • Hugenholtz G.C.G.
      • Adelmeijer J.
      • Meijers J.C.M.
      • Porte R.J.
      • Stravitz R.T.
      • Lisman T.
      An unbalance between von Willebrand factor and ADAMTS13 in acute liver failure: implications for haemostasis and clinical outcome.
      In addition, multiple studies have demonstrated preserved to enhanced thrombin-generating potential using plasma-based calibrated automated thrombinography.
      • 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.
      • Lisman T.
      • Kleiss S.
      • Patel V.C.V.C.
      • Fisher C.
      • Adelmeijer J.
      • Bos S.
      • et al.
      In vitro efficacy of pro- and anticoagulant strategies in compensated and acutely ill patients with cirrhosis.
      • Lisman T.
      • Arefaine B.
      • Adelmeijer J.
      • Zamalloa A.
      • Corcoran E.
      • Smith J.G.
      • et al.
      Global haemostatic status in patients with acute-on-chronic liver failure and septics without underlying liver disease.
      ,
      • Campello E.
      • Zanetto A.
      • Bulato C.
      • Maggiolo S.
      • Spiezia L.
      • Russo F.P.
      • et al.
      Coagulopathy is not predictive of bleeding in patients with acute decompensation of cirrhosis and acute-on-chronic liver failure.
      Also, despite decreased fibrinogen plasma levels, the quality of fibrin clots in patients with AD and ACLF appears preserved as estimated by fluid permeation experiments.
      • Lisman T.
      • Kleiss S.
      • Patel V.C.V.C.
      • Fisher C.
      • Adelmeijer J.
      • Bos S.
      • et al.
      In vitro efficacy of pro- and anticoagulant strategies in compensated and acutely ill patients with cirrhosis.
      ,
      • Lisman T.
      • Arefaine B.
      • Adelmeijer J.
      • Zamalloa A.
      • Corcoran E.
      • Smith J.G.
      • et al.
      Global haemostatic status in patients with acute-on-chronic liver failure and septics without underlying liver disease.
      Finally, complex changes in plasma fibrinolytic potential were shown with a hyperfibrinolytic state dominating in patients with AD, but a hypofibrinolytic state in patients with ACLF, particularly in those with sepsis.
      • Blasi A.
      • Patel V.C.
      • Adelmeijer J.
      • Azarian S.
      • Hernandez Tejero M.
      • Calvo A.
      • et al.
      Mixed fibrinolytic phenotypes in decompensated cirrhosis and acute-on-chronic liver failure with hypofibrinolysis in those with complications and poor survival.
      The hyperfibrinolytic state in AD may be related to the fibrinolytic activity of ascites,
      • Thaler J.
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      • Quehenberger P.
      • Hell L.
      • Schwabl P.
      • Scheiner B.
      • et al.
      Intraperitoneal activation of coagulation and fibrinolysis in patients with cirrhosis and ascites.
      whereas in ACLF the hypofibrinolytic status may primarily be related to critical illness rather than to liver disease given the well-established hypofibrinolytic status in patients with sepsis but without underlying liver disease.
      • Semeraro N.
      • Ammollo C.T.
      • Semeraro F.
      • Colucci M.
      Coagulopathy of acute sepsis.
      One study has compared the haemostatic profile between patients with ACLF and patients with sepsis without underlying liver disease.
      • Lisman T.
      • Arefaine B.
      • Adelmeijer J.
      • Zamalloa A.
      • Corcoran E.
      • Smith J.G.
      • et al.
      Global haemostatic status in patients with acute-on-chronic liver failure and septics without underlying liver disease.
      This study showed important overlap between the haemostatic profile of patients with ACLF and patients with sepsis without underlying liver disease, suggesting that the haemostatic changes occurring in ACLF are at least partly unrelated to liver function but are rather a consequence of infection and sepsis.
      Studies using whole blood viscoelastic tests performed by multiple groups came to a different conclusion and provided evidence for a hypocoagulable state in patients with ACLF.
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      • et al.
      Coagulation failure in patients with acute-on-chronic liver failure and decompensated cirrhosis: beyond the international normalized ratio.
      • Premkumar M.
      • Saxena P.
      • Rangegowda D.
      • Baweja S.
      • Mirza R.
      • Jain P.
      • et al.
      Coagulation failure is associated with bleeding events and clinical outcome during systemic inflammatory response and sepsis in acute-on-chronic liver failure: an observational cohort study.
      • Bihari C.
      • Patil A.
      • Shasthry S.M.
      • Baweja S.
      • Kumar G.
      • Sarin S.K.
      Viscoelastic test-based bleeding risk score reliably predicts coagulopathic bleeding in decompensated cirrhosis and ACLF patients.
      Using 3 different technologies (thromboelastography, rotational thromboelastometry, and sonoclot), defective whole blood clot formation (also referred to as ‘coagulation failure’) was demonstrated. However, as opposed to thrombin generation tests,
      • Lebreton A.
      • Sinegre T.
      • Lecompte T.
      • Talon L.
      • Abergel A.
      • Lisman T.
      Thrombin generation and cirrhosis: state of the art and perspectives.
      viscoelastic tests do not take the anticoagulant protein C system into account. In addition, whole blood viscoelastic tests are insensitive to the elevated levels of VWF. Both these factors would lead to an underestimation of haemostatic capacity and may explain differences with studies using other technologies.
      • Lisman T.
      Interpreting haemostatic profiles assessed with viscoelastic tests in patients with cirrhosis.
      Haemostatic balance in patients with cirrhosis is maintained in those with critical illness, although specific hypo- and hypercoagulable features are present.
      Recent studies have demonstrated a deterioration in haemostatic profile in hospitalised patients with decompensated cirrhosis who develop acute kidney injury (AKI).
      • Zanetto A.
      • Rinder H.M.
      • Campello E.
      • Saggiorato G.
      • Deng Y.
      • Ciarleglio M.
      • et al.
      Acute kidney injury in decompensated cirrhosis is associated with both hypo-coagulable and hyper-coagulable features.
      ,
      • Intagliata N.M.
      • Davis J.P.E.
      • Lafond J.
      • Erdbruegger U.
      • Greenberg C.S.
      • Northup P.G.
      • et al.
      Acute kidney injury is associated with low factor XIII in decompensated cirrhosis.
      Patients who develop AKI have decreased platelet function and hyperfibrinolysis, possible related to decreased plasma levels of factor XIII. Conversely, patients with AKI had an increase in thrombin-generating capacity. Importantly, haemostatic parameters largely improved when AKI resolved.

      Prevention of bleeding

      Most experienced clinicians carry the indelible image of a profusely bleeding liver disease patient and may recall the rapid transition of a relatively minor procedure into a bloody debacle. These associations often prompt clinicians to intervene with prophylactic measures when caring for patients with cirrhosis. Indeed, in the intensive care unit, significantly more bleeding was demonstrated among 211 patients with cirrhosis compared to 1,493 without cirrhosis.
      • Drolz A.
      • Horvatits T.
      • Roedl K.
      • Rutter K.
      • Staufer K.
      • Kneidinger N.
      • et al.
      Coagulation parameters and major bleeding in critically ill patients with cirrhosis.
      Bleeding risk was related to a disseminated intravascular coagulation score according to the definition of the International Society on Thrombosis and Haemostasis. Bleeding was particularly related to decreased fibrinogen and platelet counts. Notably, both spontaneous and procedure-related bleeding were significantly increased in critically ill patients with cirrhosis. However, many of the spontaneous bleeds were related to portal hypertension, and therefore these bleeds may have not been prevented by pro-haemostatic therapy. Notably, it is conceivable that bleeding risk may be enhanced by worsening underlying liver disease and that lower platelet counts or fibrinogen plasma levels are merely a marker of hepatic decompensation.
      Strategies for prevention of bleeding or re-bleeding in cirrhosis should take the 3 potential causes of bleeding (related to portal hypertension, provoked, and related to haemostatic failure) into account. Importantly, haemostatic pathways have limited involvement in portal hypertensive bleeding. Procedure-related risk is likely to be partly independent of haemostasis, but it has not been established whether prophylactic pro-haemostatic therapy reduces bleeding risk. Studies comparing prophylaxis based on viscoelastic tests vs. traditional coagulation testing indicate that using conventional parameters leads to significant overuse of prophylaxis without a clear reduction in bleeding.
      • De Pietri L.
      • Bianchini M.
      • Montalti R.
      • De Maria N.
      • Di Maira T.
      • Begliomini B.
      • et al.
      Thrombelastography-guided blood product use before invasive procedures in cirrhosis with severe coagulopathy: a randomized, controlled trial.
      ,
      • Rout G.
      • Shalimar
      • Gunjan D.
      • Mahapatra S.J.
      • Kedia S.
      • Garg P.K.
      • et al.
      Thromboelastography-guided blood product transfusion in cirrhosis patients with variceal bleeding: a randomized controlled trial.
      Overall bleeding is rare and studies have been underpowered and lacked restrictive arms to understand the true baseline risk of bleeding.
      • Intagliata N.M.
      • Caldwell S.H.
      • Porte R.J.
      • Lisman T.
      Prediction of bleeding in cirrhosis patients: is the forecast any clearer?.
      Risk assessment of a procedure is complex, but some guidance is emerging and a multicentre prospective study assessing risk and risk factors for post-procedural bleeding in patients with cirrhosis (ProcBleed) is in progress (clinicaltrials.gov NCT04076605). Notably, common procedures like paracentesis, thoracentesis and variceal ligation are associated with a low bleeding risk and, in such cases, prophylactic procoagulant measures are unlikely to confer a benefit, as outlined in recent guidance documents.
      • Northup P.G.
      • Garcia-Pagan J.C.
      • Garcia-Tsao G.
      • Intagliata N.M.
      • Superina R.A.
      • Roberts L.N.
      • et al.
      Vascular liver disorders, portal vein thrombosis, and procedural bleeding in patients with liver disease: 2020 practice guidance by the American association for the study of liver diseases.
      ,
      • Roberts L.N.
      • Lisman T.
      • Stanworth S.
      • Hernandez-Gea V.
      • Magnusson M.
      • Tripodi A.
      • et al.
      Periprocedural management of abnormal coagulation parameters and thrombocytopenia in patients with cirrhosis: guidance from the SSC of the ISTH.
      ,
      • Schepis F.
      • Turco L.
      • Bianchini M.
      • Villa E.
      Prevention and management of bleeding risk related to invasive procedures in cirrhosis.
      Importantly, operator experience is a determinant of bleeding risk, as documented in studies on liver biopsy,
      • Gilmore I.T.
      • Burroughs A.
      • Murray-Lyon I.M.
      • Williams R.
      • Jenkins D.
      • Hopkins A.
      Indications, methods, and outcomes of percutaneous liver biopsy in England and Wales: an audit by the British society of Gastroenterology and the royal college of physicians of london.
      as is the use of image guidance (e.g. during catheter placement).
      • Tercan F.
      • Ozkan U.
      • Oguzkurt L.
      US-guided placement of central vein catheters in patients with disorders of haemostasis.
      Of note, even if pro-haemostatic measures would reduce bleeding risk in certain settings, the number needed to treat would likely be substantial, even for high-risk procedures.
      In clinical practice, standard laboratory tests are still frequently used to assess procedural bleeding risk in patients with cirrhosis. Whether laboratory testing has any use in this context remains controversial, and there is wide variation in the laboratory tests used to estimate bleeding risk. A solid consensus has emerged around the need to avoid using the INR and its ‘correction’ with FFP,
      • Bernal W.
      • Caldwell S.H.
      • Lisman T.
      Nails in the coffin of fresh frozen plasma to prevent or treat bleeding in cirrhosis?.
      ,
      • Kovalic A.J.
      • Majeed C.N.
      • Samji N.S.
      • Thuluvath P.J.
      • Satapathy S.K.
      Systematic review with meta-analysis: abnormalities in the international normalised ratio do not correlate with periprocedural bleeding events among patients with cirrhosis.
      as this does not seem to increase pro-haemostatic capacity
      • von Meijenfeldt F.A.
      • van den Boom B.P.
      • Adelmeijer J.
      • Roberts L.N.
      • Lisman T.
      • Bernal W.
      Prophylactic fresh frozen plasma and platelet transfusion have a prothrombotic effect in patients with liver disease.
      ,
      • Tripodi A.
      • Chantarangkul V.
      • Primignani M.
      • Clerici M.
      • Dell’Era A.
      • Aghaemo A.
      • et al.
      Thrombin generation in plasma from patients with cirrhosis supplemented with normal plasma: considerations on the efficacy of treatment with fresh-frozen plasma.
      ,
      • Rassi A.B.
      • d’Amico E.A.
      • Tripodi A.
      • da Rocha T.R.F.
      • Migita B.Y.
      • Ferreira C.M.
      • et al.
      Fresh frozen plasma transfusion in patients with cirrhosis and coagulopathy: effect on conventional coagulation tests and thrombomodulin-modified thrombin generation.
      and volume expansion in this setting can exacerbate portal hypertension.
      • Giannini E.G.
      • Stravitz R.T.
      • Caldwell S.H.
      Correction of haemostatic abnormalities and portal pressure variations in patients with cirrhosis.
      Importantly, administration of FFP can have various other detrimental effects.
      • Pandey S.
      • Vyas G.N.
      Adverse effects of plasma transfusion.
      Prophylactic administration of blood products with the aim of preventing procedural bleeding in patients with cirrhosis should not be performed routinely.
      Whether platelet counts or fibrinogen levels need to be corrected prior to procedures is more controversial. According to a recent meta-analysis, pre-procedural correction of platelet count by thrombopoietin receptor agonists may reduce bleeding risk, although the effect was modest.
      • Lindquist I.
      • Olson S.R.
      • Li A.
      • Al-Samkari H.
      • Jou J.H.
      • McCarty O.J.T.
      • et al.
      The efficacy and safety of thrombopoietin receptor agonists in patients with chronic liver disease undergoing elective procedures: a systematic review and meta-analysis.
      Another study concluded that the benefits of thrombopoietin receptor agonists in this setting was low and these drugs are not cost effective.
      • Armstrong N.
      • Büyükkaramikli N.
      • Penton H.
      • Riemsma R.
      • Wetzelaer P.
      • Carrera V.H.
      • et al.
      Avatrombopag and lusutrombopag for thrombocytopenia in people with chronic liver disease needing an elective procedure: a systematic review and cost-effectiveness analysis.
      Indeed, the recent AASLD guidance document argues against correction of the platelet count for both low- and high-risk procedures based on a lack of evidence to define a specific cut-off.
      • Northup P.G.
      • Garcia-Pagan J.C.
      • Garcia-Tsao G.
      • Intagliata N.M.
      • Superina R.A.
      • Roberts L.N.
      • et al.
      Vascular liver disorders, portal vein thrombosis, and procedural bleeding in patients with liver disease: 2020 practice guidance by the American association for the study of liver diseases.
      A recent retrospective study has suggested that increasing fibrinogen levels using cryoprecipitate does not reduce bleeding risk in critically ill patients with cirrhosis.
      • Budnick I.M.
      • Davis J.P.E.
      • Sundararaghavan A.
      • Konkol S.B.
      • Lau C.E.
      • Alsobrooks J.P.
      • et al.
      Transfusion with cryoprecipitate for very low fibrinogen levels does not affect bleeding or survival in critically ill cirrhosis patients.
      Nevertheless, we acknowledge that the haemostatic system may require support in cases of severe deficiency and that current data are not conclusive on the relationships of bleeding risk with conventional markers, such as fibrinogen and platelet count. Indeed, correction may be indicated in patients with exceptionally low levels of platelets or fibrinogen, and individualised decisions should be taken on whether to undertake restrictive or proactive pro-haemostatic management in patients with profound haemostatic abnormalities.
      The procedural bleeding risks of patients with cirrhosis are genuine but the limitations of various prophylactic strategies, the relative infrequency of (severe) problems, and uncertainty around the role of haemostatic failure in some bleeding complications has led to a proposed ‘rescue’ approach which has emerged informally from past consensus meetings.
      • Intagliata N.M.
      • Argo C.K.
      • Stine J.G.
      • Lisman T.
      • Caldwell S.H.
      • Violi F.
      Concepts and controversies in haemostasis and thrombosis associated with liver disease: proceedings of the 7th international coagulation in liver disease conference.
      • Stine J.G.
      • Intagliata N.M.
      • Shah N.L.
      • Lisman T.
      • Violi F.
      • Caldwell S.H.
      • et al.
      Clinical cirrhosis dilemmas: survey of practice from the 7th international coagulation in liver disease conference.
      • Caldwell S.
      • Intagliata N.
      • Gatt A.
      • Reuben A.
      • Farias A.
      • Lackner C.
      • et al.
      A summary of the 6th international conference on coagulation in liver disease: discussion, debate, deliberations.
      • Lisman T.
      • Caldwell S.H.
      • Burroughs A.K.
      • Northup P.G.
      • Senzolo M.
      • Stravitz R.T.
      • et al.
      Haemostasis and thrombosis in patients with liver disease: the ups and downs.
      This has generally involved recommendations to optimise renal and volume status and control infection prior to procedures and to use pro-haemostatic treatment if bleeding occurs. My own bias (SC) remains to ‘optimise’ platelet counts to ≥50,000/ul and fibrinogen to 1.2 g/L prior to procedures associated with a higher bleeding risk.
      As bleeding can be catastrophic if provoked, multidisciplinary approaches to each individual case require specific plans depending on multiple factors. Limiting unnecessary transfusions, focusing on optimising risk factors prior to procedures – such as infection, AKI, anaemia, and metabolic acidosis – and developing a plan for rescue bleeding is imperative. Future studies in this field will benefit from the more restrictive use of pre-procedure prophylaxis, which will help delineate the overall need in each particular situation. Box 1 outlines a proposed approach for prevention of procedural bleeding risk.
      Considerations for periprocedural management of haemostasis in patients with cirrhosis.

      Treatment of bleeding

      Provoked and unprovoked bleeding

      Many bleeds in patients with cirrhosis are not directly related to haemostatic failure, and haemostatic capacity is maintained, even in severely ill patients. Therefore, management of active non-variceal bleeds does not always require pro-haemostatic therapy. In patients with cirrhosis who are actively bleeding from a provoked source after a procedure, first focusing on local measures and/or interventional radiology procedures is essential. In patients with continuous oozing in whom local measures fail to stop the bleeding, addressing contributing factors (renal failure, infection or sepsis, and anaemia) may reduce bleeding while correction of haemostatic abnormalities can be considered on a case-by-case basis.
      • Northup P.G.
      • Lisman T.
      • Roberts L.
      Treatment of bleeding in patients with liver disease.
      Thus, pro-haemostatic therapy is not always a first-line treatment for active bleeding. Best practices for those cases in which pro-haemostatic therapy is deemed necessary are unknown. In patients with unprovoked bleeding, such as oozing from mucosal surfaces, careful assessment of the underlying aetiology is essential. Cases with severe coagulation protein or platelet deficiency may benefit from replacement therapy and point-of-care tools such as viscoelastic tests may assist in assessment, acknowledging the aforementioned limitations. Antifibrinolytics may also have a role in certain circumstances, although they have not been studied extensively in patients with cirrhosis outside the context of liver transplantation.
      Pro-haemostatic therapy is not always the first-line treatment for bleeding in patients with cirrhosis.

      Variceal bleeding

      It has been well-established that acute massive variceal bleeding should be managed by endoscopic and pharmacologic therapies and with restrictive red blood cell transfusion.
      • Garcia-Tsao G.
      • Abraldes J.G.
      • Berzigotti A.
      • Bosch J.
      Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases.
      ,
      • Villanueva C.
      • Colomo A.
      • Bosch A.
      • Concepción M.
      • Hernandez-Gea V.
      • Aracil C.
      • et al.
      Transfusion strategies for acute upper gastrointestinal bleeding.
      Notably, transfusions of blood components, such as FFP, exacerbate portal hypertension and thus worsen bleeding. Indeed, a recent retrospective study showed that transfusion of FFP during acute variceal bleeding is ineffective and may do harm.
      • Mohanty A.
      • Kapuria D.
      • Canakis A.
      • Lin H.
      • Amat M.J.
      • Rangel Paniz G.
      • et al.
      Fresh frozen plasma transfusion in acute variceal haemorrhage: results from a multicenter cohort study.
      ,
      • Lisman T.
      • Procopet B.
      Fresh frozen plasma in treating acute variceal bleeding: not effective and likely harmful.
      Specifically, in multivariable analysis, FFP transfusion was associated with an increased risk of failure to control bleeding at 5 days and with mortality at 42 days. It is tempting to speculate that FFP-induced exacerbation of portal hypertension contributed to the increased risk of failure to control bleeding in this study, whereas the combination of failure to control bleeding and potential side effects of FFP transfusion relate to increased mortality.
      Tranexamic acid (TXA) is an antifibrinolytic drug that reduces mortality in bleeding patients with trauma and post-partum bleeding.
      • Shakur H.
      • Roberts I.
      • Fawole B.
      • Chaudhri R.
      • El-Sheikh M.
      • Akintan A.
      • et al.
      Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial.
      ,
      • Olldashi F.
      • Kerçi M.
      • Zhurda T.
      • Ruçi K.
      • Banushi A.
      • Traverso M.S.
      • et al.
      Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial.
      The HALT-IT trial was a placebo-controlled, randomised trial of TXA in patients with gastrointestinal bleeding.
      • Roberts I.
      • Shakur-Still H.
      • Afolabi A.
      • Akere A.
      • Arribas M.
      • Brenner A.
      • et al.
      Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial.
      A significant proportion of patients had underlying liver disease and many of the bleeds in these patients were likely variceal bleeds. This study showed that TXA did not reduce death due to bleeding but was associated with an increased risk of thromboembolic events. Similarly, recombinant factor VIIa did not confer a benefit in this setting, reinforcing the notion that pro-haemostatic therapy does not help in controlling variceal bleeding.
      • Bosch J.
      • Thabut D.
      • Albillos A.
      • Carbonell N.
      • Spicak J.
      • Massard J.
      • et al.
      Recombinant factor VIIa for variceal bleeding in patients with advanced cirrhosis: a randomfd, controlled trial.
      ,
      • Sozio M.S.
      • Chalasani N.
      Activated recombinant factor VIIa should not be used in patients with refractory variceal bleeding: it is mostly ineffective, is expensive, and may rarely cause serious adverse events.
      The standard approach to control of variceal haemorrhage is focused on endoscopic or pharmacological measures to reduce portal hypertension.
      • Garcia-Tsao G.
      • Abraldes J.G.
      • Berzigotti A.
      • Bosch J.
      Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases.
      ,
      • de Franchis R.
      • Faculty B.V.
      Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
      ,
      • Angeli P.
      • Bernardi M.
      • Villanueva C.
      • Francoz C.
      • Mookerjee R.P.
      • Trebicka J.
      • et al.
      EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.
      Therefore, transfusions or medications aimed to improve coagulation indices or support the haemostatic system do not improve outcomes and may make the situation worse.
      Post banding ulcerative bleeding is an uncommon but serious complication of band ligation for oesophageal ulcers. Studies do not demonstrate a relationship between risk of bleeding and pre-endoscopic coagulation testing.
      • Vieira da Rocha E.C.
      • D’Amico E.A.
      • Caldwell S.H.
      • Flores da Rocha T.R.
      • Soares E.
      • Silva C.S.S.
      • et al.
      A prospective study of conventional and expanded coagulation indices in predicting ulcer bleeding after variceal band ligation.
      • Vanbiervliet G.
      • Giudicelli-Bornard S.
      • Piche T.
      • Berthier F.
      • Gelsi E.
      • Filippi J.
      • et al.
      Predictive factors of bleeding related to post-banding ulcer following endoscopic variceal ligation in cirrhotic patients: a case-control study.
      • Dueñas E.
      • Cachero A.
      • Amador A.
      • Rota R.
      • Salord S.
      • Gornals J.
      • et al.
      Ulcer bleeding after band ligation of esophageal varices: risk factors and prognosis.
      • Blasi A.
      • Machlab S.
      • Risco R.
      • Costa-Freixas J.P.
      • Hernández-Cely G.
      • Horta D.
      • et al.
      A multicenter analysis of the role of prophylactic transfusion of blood products in patients with cirrhosis and esophageal varices undergoing endoscopic band ligation.
      Rather, markers of disease severity and portal hypertension (model for end-stage liver disease and Child-Pugh score) may be more predictive of risk. Management is typically based on direct endoscopic measures for control and in some indications TIPS (transjugular intrahepatic portosystemic shunt). A recent multicentre study demonstrated that administering platelets or FFP prior to endoscopic band ligation did not reduce bleeding.
      • Blasi A.
      • Machlab S.
      • Risco R.
      • Costa-Freixas J.P.
      • Hernández-Cely G.
      • Horta D.
      • et al.
      A multicenter analysis of the role of prophylactic transfusion of blood products in patients with cirrhosis and esophageal varices undergoing endoscopic band ligation.
      The role of measures to support the haemostatic system in active severe bleeding remain unstudied and empirical individualised approaches are recommended.

      Pathogenesis of thrombosis

      It has been well-established that the haemostatic system in patients with cirrhosis has distinct hypercoagulable features, which may contribute to the risk of thrombotic complications. Specifically, a VWF/ADAMTS13 imbalance,
      • Lisman T.
      • Bongers T.N.
      • Adelmeijer J.
      • Janssen H.L.A.
      • De Maat M.P.M.
      • De Groot P.G.
      • et al.
      Elevated levels of von Willebrand factor in cirrhosis support platelet adhesion despite reduced functional capacity.
      ,
      • Uemura M.
      • Fujimura Y.
      • Matsumoto M.
      • Ishizashi H.
      • Kato S.
      • Matsuyama T.
      • et al.
      Comprehensive analysis of ADAMTS13 in patients with liver cirrhosis.
      enhanced thrombin-generating capacity,
      • Lebreton A.
      • Sinegre T.
      • Lecompte T.
      • Talon L.
      • Abergel A.
      • Lisman T.
      Thrombin generation and cirrhosis: state of the art and perspectives.
      and a hypofibrinolytic status
      • Blasi A.
      • Patel V.C.
      • Adelmeijer J.
      • Azarian S.
      • Hernandez Tejero M.
      • Calvo A.
      • et al.
      Mixed fibrinolytic phenotypes in decompensated cirrhosis and acute-on-chronic liver failure with hypofibrinolysis in those with complications and poor survival.
      are present in some patients with cirrhosis. Importantly, these haemostatic changes are known to enhance thrombotic risk in the general population.
      • Bongers T.N.
      • de Bruijne E.L.E.
      • Dippel D.W.J.
      • de Jong A.J.
      • Deckers J.W.
      • Poldermans D.
      • et al.
      Lower levels of ADAMTS13 are associated with cardiovascular disease in young patients.
      • Mancini I.
      • Baronciani L.
      • Artoni A.
      • Colpani P.
      • Biganzoli M.
      • Cozzi G.
      • et al.
      The ADAMTS13-von Willebrand factor axis in COVID-19 patients.
      • Donkel S.J.
      • Pater K.
      • Leebeek F.W.G.
      • Dippel D.W.J.
      • ten Cate H.
      • de Maat M.P.M.
      Thrombin generation is associated with ischemic stroke at a young age.
      • van Hylckama Vlieg A.
      • Baglin C.A.
      • Luddington R.
      • Macdonald S.
      • Rosendaal F.R.
      • Baglin T.P.
      The risk of a first and a recurrent venous thrombosis associated with an elevated D-dimer level and an elevated thrombin potential: results of the THE-VTE study.
      • Lisman T.
      Decreased plasma fibrinolytic potential as a risk for venous and arterial thrombosis.
      Recent advances in this field include confirmation of a thrombotic phenotype of the fibrin clot,
      • Becatti M.
      • Mannucci A.
      • Argento F.R.
      • Gitto S.
      • Vizzutti F.
      • Marra F.
      • et al.
      Super-resolution microscopy reveals an altered fibrin network in cirrhosis: the key role of oxidative stress in fibrinogen structural modifications.
      ,
      • Hugenholtz G.C.G.
      • Macrae F.
      • Adelmeijer J.
      • Dulfer S.
      • Porte R.J.
      • Lisman T.
      • et al.
      Procoagulant changes in fibrin clot structure in patients with cirrhosis are associated with oxidative modifications of fibrinogen.
      and conformation of enhanced thrombin-generating capacity in patients with cirrhosis as detected with better standardised thrombin generation assays (using the Genesia device).
      • Zermatten M.G.
      • Fraga M.
      • Calderara D.B.
      • Aliotta A.
      • Moradpour D.
      • Alberio L.
      Biomarkers of liver dysfunction correlate with a prothrombotic and not with a prohaemorrhagic profile in patients with cirrhosis.
      ,
      • Talon L.
      • Sinegre T.
      • Lecompte T.
      • Pereira B.
      • Massoulié S.
      • Abergel A.
      • et al.
      Hypercoagulability (thrombin generation) in patients with cirrhosis is detected with ST-Genesia.
      Animal models have suggested a role for neutrophil extracellular traps (NETs) in the hypercoagulability of cirrhosis.
      • Hilscher M.B.
      • Sehrawat T.
      • Arab J.P.
      • Zeng Z.
      • Gao J.
      • Liu M.
      • et al.
      Mechanical stretch increases expression of CXCL1 in liver sinusoidal endothelial cells to recruit neutrophils, generate sinusoidal microthombi, and promote portal hypertension.
      ,
      • Meijenfeldt F.A.V.
      • Jenne C.N.
      Netting liver disease: neutrophil extracellular traps in the initiation and exacerbation of liver pathology.
      It has been demonstrated that NETs mediate development of portal hypertension via thrombus formation, although the role of NETs in humans with cirrhosis has not been firmly established.
      • Blasi A.
      • Patel V.C.
      • Adelmeijer J.
      • Azarian S.
      • Aziz F.
      • Fernández J.
      • et al.
      Plasma levels of circulating DNA are associated with outcome, but not with activation of coagulation in decompensated cirrhosis and ACLF.
      Cirrhotic portal vein ‘thrombosis’ often consists of a thickened portal vein wall intima, and a fibrin-rich thrombus is frequently not present.

      Advances in our understanding of the pathogenesis of portal vein thrombosis

      Very little is known about the pathogenesis of PVT and current treatment strategies are extrapolated from venous thrombosis treatment strategies.
      • Senzolo M.
      • Garcia-Tsao G.
      • García-Pagán J.C.
      Current knowledge and management of portal vein thrombosis in cirrhosis.
      Importantly, the portal venous system is not directly comparable to deep venous systems as the portal vein does not drain blood to the heart, but to hepatic sinusoids in the liver, and perhaps more importantly, the portal vein does not have venous valves,
      • Okudaira M.
      Anatomy of the portal vein system and hepatic vasculature.
      which are important in the development of DVT.
      • Karino T.
      • Motomiya M.
      Flow through a venous valve and its implication for thrombus formation.
      Some studies have suggested that a hypercoagulable state (for example factor V leiden) increases the risk of PVT development in patients with cirrhosis,
      • Ma S.D.
      • Wang J.
      • Bezinover D.
      • Kadry Z.
      • Northup P.G.
      • Stine J.G.
      Inherited thrombophilia and portal vein thrombosis in cirrhosis: a systematic review and meta-analysis.
      whereas other studies have indicated that reduced portal flow and severity of disease are important risk factors.
      • Turon F.
      • Driever E.G.
      • Baiges A.
      • Cerda E.
      • García-Criado Á.
      • Gilabert R.
      • et al.
      Predicting portal thrombosis in cirrhosis: a prospective study of clinical, ultrasonographic and haemostatic factors.
      • Stine J.G.
      • Wang J.
      • Shah P.M.
      • Argo C.K.
      • Intagliata N.
      • Uflacker A.
      • et al.
      Decreased portal vein velocity is predictive of the development of portal vein thrombosis: a matched case-control study.
      • 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.
      A recent large prospective study extensively evaluated clinical factors, the haemostatic profile, and inflammatory parameters in relation to the risk of PVT development.
      • Turon F.
      • Driever E.G.
      • Baiges A.
      • Cerda E.
      • García-Criado Á.
      • Gilabert R.
      • et al.
      Predicting portal thrombosis in cirrhosis: a prospective study of clinical, ultrasonographic and haemostatic factors.
      This study showed that factors related to the severity of portal hypertension including portal flow are associated with PVT development. In contrast, inherited or acquired hypercoagulable factors and inflammatory markers did not predict PVT development. This study thus questions whether haemostatic changes have a central role in PVT development.
      In line with this study, it was recently demonstrated that portal vein thrombi obtained during liver transplant surgery frequently do not contain haemostatic components such as fibrin or platelets.
      • 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.
      All portal vein thrombi examined consisted of collagenised material that presents as intimal hyperplasia of the portal vein. In some patients, a true clot consisting of fibrin and platelets was present on top of this thickened intima (Fig. 3). Interestingly the fibrin-rich parts of these clots have red blood cells captured within the fibrin mesh, but these red blood cells did not have the polyhedral structure that is characteristic of red blood cells in venous and arterial thrombi. The absence of polyhedral erythrocytes within PVT clots reinforces that they are a unique entity. It was also demonstrated that portal vein intimal hyperplasia was already present in a much milder form in patients with cirrhosis without PVT, but not in healthy livers or livers from patients with acute liver failure. These results suggest that intimal thickening (and not clot formation) leads to the development of PVT (Fig. 4) and that strategies to prevent the progression of intimal thickening may be relevant for the prevention or treatment of PVT. Interestingly, activation of coagulation has an important role in intima hyperplasia in other vascular beds. Thus, although hypercoagulability and clot formation may not be central in PVT development, the activation of coagulation may play an important secondary role.
      Figure thumbnail gr3
      Fig. 3Martius scarlet blue-stained sections of extrahepatic portal vein samples removed during liver transplant surgery.
      (A) A portal vein thrombus consisting of a focally thickened intimal layer of the vessel wall with some haemorrhage but without a fibrin-rich thrombus. (B) A portal vein thrombus consisting of a circumferential thickened intimal layer of the vessel wall with a fibrin-rich thrombus on top. Figure adapted from Driever et al.
      • 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.
      Figure thumbnail gr4
      Fig. 4Schematic overview of the role of intima hyperplasia of the portal vein in the development of cirrhotic portal vein thrombosis.
      The portal vein of a healthy liver lacks a detectable intima. In patients with cirrhosis, thickening of the portal vein wall is observed with an intima thickness in the order of magnitude of 200-400 um. A cirrhotic portal vein thrombus consists of a profoundly enlarged intima with a thickness of around 2 mm with or without a fibrin thrombus on top. Whether development of intimal thickening in the cirrhotic portal vein is a result of changes in blood flow (as is seen in intimal hyperplasia occurring after coronary artery bypass surgery using veins or synthetic grafts) or a result of initial clot formation with subsequent re-endothelialisation (a phenomenon previously observed in experimental venous thrombosis) requires further study.
      As a PVT primarily consists of intimal thickening, the term ‘portal vein thrombosis’ may be a misnomer, and ‘portal vein stenosis’ or ‘non-malignant portal vein occlusion’ may be more appropriate. These results may also explain why anticoagulant therapy frequently fails to lead to complete recanalisation, as only those portal vein thrombi with fibrin-rich sections may be susceptible to anticoagulant therapy.
      There is increasing awareness of the requirement of thromboprophylaxis in patients with cirrhosis.

      Prevention of thrombosis

      For many years patients with cirrhosis were felt to be “auto-anticoagulated”, however, a seminal study in 2006 challenged this myth by clearly demonstrating that patients with cirrhosis develop venous thromboembolism (VTE).
      • Northup P.G.
      • McMahon M.M.
      • Ruhl A.P.
      • Altschuler S.E.
      • Volk-Bednarz A.
      • Caldwell S.H.
      • et al.
      Coagulopathy does not fully protect hospitalized cirrhosis patients from peripheral venous thromboembolism.
      Since this time numerous larger cohort studies have corroborated this finding and we now recognise that patients with cirrhosis are likely at increased risk of developing VTE.
      • Ambrosino P.
      • Tarantino L.
      • Di Minno G.
      • Paternoster M.
      • Graziano V.
      • Petitto M.
      • et al.
      The risk of venous thromboembolism in patients with cirrhosis: a systematic review and meta-analysis.
      As the development of VTE in patients with cirrhosis is associated with increased morbidity and mortality, prevention is highly desired.
      • Jepsen P.
      • Tapper E.B.
      • Deleuran T.
      • Kazankov K.
      • Askgaard G.
      • Sørensen H.T.
      • et al.
      Risk and outcome of venous and arterial thrombosis in patients with cirrhosis: a Danish nationwide cohort study.
      ,
      • Søgaard K.K.
      • Horváth-Puhó E.
      • Montomoli J.
      • Vilstrup H.
      • Sørensen H.T.
      Cirrhosis is associated with an increased 30-day mortality after venous thromboembolism.
      PVT is closely associated with cirrhosis and portal hypertension. While studies have demonstrated that prevention of PVT is possible with anticoagulation, data remain sparse regarding the practice of PVT prevention. Nevertheless, anticoagulation appears to prevent the development of PVT in patients with cirrhosis
      • 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.
      and is an effective therapy to promote recanalisation in recent PVT.
      • 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.
      Atrial fibrillation is a known risk factor for the development of ischaemic stroke. Patients with cirrhosis are at risk of developing atrial fibrillation and recent data in large cohorts has provided insights into the safety of direct oral anticoagulants (DOACs) in this unique population.
      • Violi F.
      • Vestri A.
      • Menichelli D.
      • Di Rocco A.
      • Pastori D.
      • Pignatelli P.
      Direct oral anticoagulants in patients with atrial fibrillation and advanced liver disease: an exploratory meta-analysis.
      In hospitalised patients at increased risk of thrombosis, anticoagulation is indicated to prevent the development of VTE.
      • Kahn S.R.
      • Lim W.
      • Dunn A.S.
      • Cushman M.
      • Dentali F.
      • Akl E.A.
      • et al.
      Prevention of VTE in nonsurgical patients. Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines.
      Our understanding of the role of anticoagulation in the prevention of VTE in patients with cirrhosis remains limited, as patients with liver disease are historically excluded from clinical trials. Moreover, clinicians are often hesitant to prescribe anticoagulation to patients with liver disease owing to concerns around bleeding.
      • Yang L.S.
      • Alukaidey S.
      • Croucher K.
      • Dowling D.
      Suboptimal use of pharmacological venous thromboembolism prophylaxis in cirrhotic patients.
      However in 2014, a study showed that patients with cirrhosis treated prophylactically to prevent VTE had low rates of gastrointestinal bleeding.
      • Intagliata N.M.
      • Henry Z.H.
      • Shah N.
      • Lisman T.
      • Caldwell S.H.
      • Northup P.G.
      Prophylactic anticoagulation for venous thromboembolism in hospitalized cirrhosis patients is not associated with high rates of gastrointestinal bleeding.
      Subsequently, the use of prophylactic anticoagulation was not associated with a significant risk of bleeding in a larger cohort study.
      • Shatzel J.
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      • Harbin D.
      • Cheung H.
      • Reid T.N.
      • Kim J.
      • et al.
      Safety and efficacy of pharmacological thromboprophylaxis for hospitalized patients with cirrhosis: a single-center retrospective cohort study.
      To date, no study clearly demonstrates the efficacy of anticoagulation to prevent VTE and clinicians are reliant on extrapolation from medical studies in general populations.
      • Intagliata N.M.
      • Davitkov P.
      • Allen A.M.
      • Falck-Ytter Y.T.
      • Stine J.G.
      AGA technical review on coagulation in cirrhosis.
      Based on data from the general medical population and recent studies specific to patients with cirrhosis, current societal guidelines support the use of thromboprophylaxis in patients with cirrhosis.
      • Northup P.G.
      • Garcia-Pagan J.C.
      • Garcia-Tsao G.
      • Intagliata N.M.
      • Superina R.A.
      • Roberts L.N.
      • et al.
      Vascular liver disorders, portal vein thrombosis, and procedural bleeding in patients with liver disease: 2020 practice guidance by the American association for the study of liver diseases.
      ,
      • O’Shea R.S.
      • Davitkov P.
      • Ko C.W.
      • Rajasekhar A.
      • Su G.L.
      • Sultan S.
      • et al.
      AGA clinical practice guideline on the management of coagulation disorders in patients with cirrhosis.
      PVT occurs more frequently in patients with cirrhosis compared to the general population.
      • Senzolo M.
      • Garcia-Tsao G.
      • García-Pagán J.C.
      Current knowledge and management of portal vein thrombosis in cirrhosis.
      The most significant risk factor for the development of PVT is advanced portal hypertension and reduced portal vein velocity.
      • Turon F.
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      • Baiges A.
      • Cerda E.
      • García-Criado Á.
      • Gilabert R.
      • et al.
      Predicting portal thrombosis in cirrhosis: a prospective study of clinical, ultrasonographic and haemostatic factors.
      ,
      • Stine J.G.
      • Wang J.
      • Shah P.M.
      • Argo C.K.
      • Intagliata N.
      • Uflacker A.
      • et al.
      Decreased portal vein velocity is predictive of the development of portal vein thrombosis: a matched case-control study.
      Other risk factors may include abdominal surgery, malignancy, portosystemic shunts, and aetiology of liver disease.
      • Intagliata N.M.
      • Caldwell S.H.
      • Tripodi A.
      Diagnosis, development, and treatment of portal vein thrombosis in patients with and without cirrhosis.
      Controversy remains regarding the putative association of PVT with the development of worsening hepatic decompensation and poor outcomes.
      • 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.
      Nevertheless, a considerable amount of research has accumulated on the treatment of PVT and prevention of extension or recurrence (see below). However, less is known about preventing the development of PVT in patients with cirrhosis. A seminal study was published in 2012 examining the safety and efficacy of prophylactic enoxaparin, compared to no treatment, for the prevention of PVT in patients with cirrhosis.
      • 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.
      In the group who received low molecular weight heparin (LMWH) no patients developed a PVT compared to 16.6% in the group who did not receive anticoagulation. Beyond prevention of PVT, the enoxaparin group had decreased hepatic decompensation and improved survival. Current studies now seek to further evaluate the role of anticoagulation in prevention of PVT in cirrhosis (CIRROXABAN trial, clinicaltrials.gov NCT02643212). In other cohorts, such as patients with cirrhosis undergoing splenectomy, prophylactic anticoagulation reduces the incidence of PVT.
      • Ding H.
      • Zhang Y.
      • Zhao L.
      • Wu S.
      • Liu J.
      • Wang C.
      • et al.
      What intervention regimen is most effective prevention for Portal venous system thrombosis after splenectomy in cirrhotics patients with Portal hypertension? Systematic review and network meta-analysis.
      Given our lack of understanding of the role of screening for PVT and the unclear clinical significance of PVT, more data are needed to clarify the role, if any, of anticoagulation to prevent the development of PVT in patients with cirrhosis.
      Direct oral anticoagulants may have advantages over traditional anticoagulants in prevention or treatment of thrombosis in patients with cirrhosis.
      Atrial fibrillation may result in the development of ischaemic stroke in high-risk patients and anticoagulation is recommended to prevent VTE.
      • Lip G.Y.H.
      • Banerjee A.
      • Boriani G.
      • Chiang C en
      • Fargo R.
      • Freedman B.
      • et al.
      Antithrombotic therapy for atrial fibrillation: CHEST guideline and expert panel report.
      Several recent studies examined the role of warfarin and DOACs in patients with well-compensated cirrhosis.
      • Goriacko P.
      • Veltri K.T.
      Safety of direct oral anticoagulants vs warfarin in patients with chronic liver disease and atrial fibrillation.
      • Lee S.J.
      • Sung J.H.
      • Kim J.B.
      • Ahn M.S.
      • Lee H.Y.
      • Uhm J.S.
      • et al.
      The safety and efficacy of Vitamin K antagonist in atrial fibrillation patients with previous ulcer bleeding Long-term results from a multicenter study.
      • Lee S.R.
      • Lee H.J.
      • Choi E.K.
      • Han K Do
      • Jung J.H.
      • Cha M.J.
      • et al.
      Direct oral anticoagulants in patients with atrial fibrillation and liver disease.
      • Pastori D.
      • Lip G.Y.H.
      • Farcomeni A.
      • Del Sole F.
      • Sciacqua A.
      • Perticone F.
      • et al.
      Incidence of bleeding in patients with atrial fibrillation and advanced liver fibrosis on treatment with vitamin K or non-vitamin K antagonist oral anticoagulants.
      • Serper M.
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      • Cohen J.B.
      • Reese P.P.
      • Taddei T.H.
      • Kaplan D.E.
      Mortality and hepatic decompensation in patients with cirrhosis and atrial fibrillation treated with anticoagulation.
      • Wang C.L.
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      • Kuo C.F.
      • Chu P.H.
      • Tseng H.J.
      • Wen M.S.
      • et al.
      Efficacy and safety of non–vitamin K antagonist oral anticoagulants in atrial fibrillation patients with impaired liver function: a retrospective cohort study.
      Overall, anticoagulation appears safe and effective to prevent stroke in patients with well-compensated cirrhosis and DOACs may be safer.
      • Intagliata N.M.
      • Davitkov P.
      • Allen A.M.
      • Falck-Ytter Y.T.
      • Stine J.G.
      AGA technical review on coagulation in cirrhosis.
      As randomised controlled data are lacking, further evidence is needed in patients with more advanced cirrhosis to better understand the safety of anticoagulation to prevent stroke in this population.

      Treatment of thrombosis

      Over recent years, the medical treatment options for thrombosis have grown tremendously with the advent of DOACs. Comprehensive knowledge of the risks and benefits of traditional anticoagulation (LMWH and vitamin K antagonists [VKA]) and DOACs can now be used to guide treatment for VTE in most patients. However, patients with liver disease are routinely excluded from clinical trials studying anticoagulation; therefore, our understanding of the safety and efficacy of these treatments in patients with cirrhosis remains limited. Nevertheless, patients with cirrhosis often develop venous thrombosis including DVT, PE, and PVT. Treatment requires a thorough understanding of the unique aspects of the haemostatic system described above and each drug has risks and benefits particular to patients with cirrhosis (Table 1). As the liver and kidneys play key roles in drug metabolism, the pharmacokinetics of anticoagulants may be different, particularly in advanced liver disease. In addition, data from in vitro studies have identified important alterations in the anticoagulant capacity of commonly used drugs.
      • Bos S.
      • Potze W.
      • Siddiqui M.S.
      • Boyett S.L.
      • Adelmeijer J.
      • Daita K.
      • et al.
      Changes of in vitro potency of anticoagulant drugs are similar between patients with cirrhosis due to alcohol or non-alcoholic fatty liver disease.
      • Potze W.
      • Arshad F.
      • Adelmeijer J.
      • Blokzijl H.
      • van den Berg A.P.
      • Porte R.J.
      • et al.
      Routine coagulation assays underestimate levels of antithrombin-dependent drugs but not of direct anticoagulant drugs in plasma from patients with cirrhosis.
      • Potze W.
      • Adelmeijer J.
      • Lisman T.
      Decreased in vitro anticoagulant potency of Rivaroxaban and Apixaban in plasma from patients with cirrhosis.
      • Potze W.
      • Arshad F.
      • Adelmeijer J.
      • Blokzijl H.
      • Van Den Berg A.P.
      • Meijers J.C.M.
      • et al.
      Differential in vitro inhibition of thrombin generation by anticoagulant drugs in plasma from patients with cirrhosis.
      In these important studies, investigators used thrombin generation assays to measure the anticoagulation potency of traditional anticoagulation and DOACs. In one study, the potency of anticoagulation differed significantly between drugs and depending on degree of hepatic decompensation.
      • Potze W.
      • Arshad F.
      • Adelmeijer J.
      • Blokzijl H.
      • Van Den Berg A.P.
      • Meijers J.C.M.
      • et al.
      Differential in vitro inhibition of thrombin generation by anticoagulant drugs in plasma from patients with cirrhosis.
      Dabigatran demonstrated significantly increased potency in more advanced cirrhosis whereas rivaroxaban had decreased potency. The first detailed pharmacokinetic study in patients with cirrhosis analysed the plasma after repeated doses of edoxaban.
      • Bos S.
      • Schreuder T.
      • Blokzijl H.
      • Adelmeijer J.
      • Lisman T.
      • Kamphuisen P.W.
      Anticoagulant activity of edoxaban in patients with cirrhosis.
      Compared to healthy controls, drug levels were similar in patients with cirrhosis, however the anticoagulant effect was reduced, as measured by ex vivo thrombin generation tests and reduction in d-dimer level.
      Table 1Characteristics of anticoagulant drugs and their use in patients with cirrhosis.
      AnticoagulantMechanismDosing recommendation in cirrhosis
      Based on FDA package inserts.
      ExcretionIn vitro studies in cirrhosis assessing potency
      115–117
      Clinical studies in cirrhosis
      Unfractionated heparinBinds to AT indirectly inhibits Xa and IIaNot specifiedReticulo-endothelial systems, Urine (dose-dependent mechanisms of excretion)No significant change potency according to Child-PughCase series

      Cohort studies
      Low molecular weight heparinsBinds to AT indirectly inhibits Xa“Caution advised in hepatic impairment”Urine 40%No significant change potency according to Child-PughCase reports/series

      Cohort studies

      Randomised controlled trial
      WarfarinInhibits vitamin K dependent coagulation factorsWarning in “moderate to severe hepatic impairment”Urine 92%NoneCase reports/series

      Cohort studies
      DabigatranInhibits factor IIaChild-Pugh A- Not specified

      Child-Pugh B- Not specified

      Child-Pugh C- Not specified
      Urine primarilyIncreased potency in Child-Pugh A/B/C cirrhosisCase reports/series

      Cohort studies
      Rivaroxaban

      Apixaban

      Edoxaban
      Inhibit factor XaChild-Pugh A- No adjustment

      Child-Pugh B- Caution/Avoid

      Child-Pugh C- Avoid
      Urine 66%/faeces 28%

      Urine 27%/faeces 73%

      Urine 50%/faeces 50%
      Decreased potency in Child-Pugh A/B/C cirrhosisCase reports/series

      Cohort studies

      Randomised controlled trial
      Studies assessing PVT in patients with cirrhosis.
      AT, antithrombin; PVT, portal vein thrombosis.
      1
      • Potze W.
      • Adelmeijer J.
      • Lisman T.
      Decreased in vitro anticoagulant potency of Rivaroxaban and Apixaban in plasma from patients with cirrhosis.
      • Potze W.
      • Arshad F.
      • Adelmeijer J.
      • Blokzijl H.
      • Van Den Berg A.P.
      • Meijers J.C.M.
      • et al.
      Differential in vitro inhibition of thrombin generation by anticoagulant drugs in plasma from patients with cirrhosis.
      • Bos S.
      • Schreuder T.
      • Blokzijl H.
      • Adelmeijer J.
      • Lisman T.
      • Kamphuisen P.W.
      Anticoagulant activity of edoxaban in patients with cirrhosis.
      Studies assessing PVT in patients with cirrhosis.
      ˆ Based on FDA package inserts.
      Much of our understanding of the safety and efficacy of anticoagulation for venous thrombosis in patients with cirrhosis has arisen from studies in patients with PVT. Two early studies examined treatment of PVT using VKA
      • Francoz C.
      • Belghiti J.
      • Vilgrain V.
      • Sommacale D.
      • Paradis V.
      • Condat B.
      • et al.
      Splanchnic vein thrombosis in candidates for liver transplantation: usefulness of screening and anticoagulation.
      and LMWH
      • Amitrano L.
      • Guardascione M.A.
      • Menchise A.
      • Martino R.
      • Scaglione M.
      • Giovine S.
      • et al.
      Safety and efficacy of anticoagulation therapy with low molecular weight heparin for portal vein thrombosis in patients with liver cirrhosis.
      in patients with cirrhosis and showed substantial rates of portal vein recanalisation and low risk of bleeding. Subsequently a seminal study was published in 2012 which examined the effect of anticoagulation (LMWH or VKA) in 55 patients.
      • Delgado M.G.
      • Seijo S.
      • Yepes I.
      • Achécar L.
      • Catalina M.V.
      • García-Criado Á.
      • et al.
      Efficacy and safety of anticoagulation on patients with cirrhosis and portal vein thrombosis.
      In this cohort a complete or partial response to therapy was achieved in 60% of patients with low rates of bleeding due to anticoagulation. Now these findings have been reproduced in a wide variety of cohorts.
      • Werner K.T.
      • Sando S.
      • Carey E.J.
      • Vargas H.E.
      • Byrne T.J.
      • Douglas D.D.
      • et al.
      Portal vein thrombosis in patients with end stage liver disease awaiting liver transplantation: outcome of anticoagulation.
      • Chung JW.h.
      • Kim GH. yu.
      • Lee JH.o.
      • Ok KS.a.
      • Jang ES.u.
      • Jeong S.H.
      • et al.
      Safety, efficacy, and response predictors of anticoagulation for the treatment of nonmalignant portal-vein thrombosis in patients with cirrhosis: a propensity score matching analysis.
      • Chen H.
      • Turon F.
      • Hernández-Gea V.
      • Fuster J.
      • Garcia-Criado A.
      • Barrufet M.
      • et al.
      Nontumoral portal vein thrombosis in patients awaiting liver transplantation.
      • Noronha Ferreira C.
      • Seijo S.
      • Plessier A.
      • Silva-Junior G.
      • Turon F.
      • Rautou P.E.
      • et al.
      Natural history and management of esophagogastric varices in chronic noncirrhotic, nontumoral portal vein thrombosis.
      • Rodriguez-Castro K.I.
      • Vitale A.
      • Fadin M.
      • Shalaby S.
      • Zerbinati P.
      • Sartori M.T.
      • et al.
      A prediction model for successful anticoagulation in cirrhotic portal vein thrombosis.
      • Scheiner B.
      • Stammet P.R.
      • Pokorny S.
      • Bucsics T.
      • Schwabl P.
      • Brichta A.
      • et al.
      Anticoagulation in non-malignant portal vein thrombosis is safe and improves hepatic function.
      • Pettinari I.
      • Vukotic R.
      • Stefanescu H.
      • Pecorelli A.
      • Morelli M.
      • Grigoras C.
      • et al.
      Clinical impact and safety of anticoagulants for portal vein thrombosis in cirrhosis.
      • Senzolo M.
      • Sartori T.M.
      • Rossetto V.
      • Burra P.
      • Cillo U.
      • Boccagni P.
      • et al.
      Prospective evaluation of anticoagulation and transjugular intrahepatic portosistemic shunt for the management of portal vein thrombosis in cirrhosis.
      A recent systematic review found that 64% of patients treated with anticoagulation (LMWH or VKA) undergo recanalisation compared to 21% who do not receive anticoagulation, with similar rates of overall bleeding between groups.
      • Intagliata N.M.
      • Davitkov P.
      • Allen A.M.
      • Falck-Ytter Y.T.
      • Stine J.G.
      AGA technical review on coagulation in cirrhosis.
      However, these studies are limited by their retrospective (non-randomised) designs, and variations in outcome definitions and durations of treatment. Current guideline recommendations support the use of anticoagulation for treatment in patients with cirrhosis and acute or recent PVT without contraindications.
      • Northup P.G.
      • Garcia-Pagan J.C.
      • Garcia-Tsao G.
      • Intagliata N.M.
      • Superina R.A.
      • Roberts L.N.
      • et al.
      Vascular liver disorders, portal vein thrombosis, and procedural bleeding in patients with liver disease: 2020 practice guidance by the American association for the study of liver diseases.
      Beyond medical therapy for PVT, TIPS is emerging as a very effective treatment for both recent PVT and in certain circumstances chronic PVT.
      • Thornburg B.
      • Desai K.
      • Hickey R.
      • Hohlastos E.
      • Kulik L.
      • Ganger D.
      • et al.
      Pretransplantation portal vein recanalization and transjugular intrahepatic portosystemic shunt creation for chronic portal vein thrombosis: final analysis of a 61-patient cohort.
      • Salem R.
      • Vouche M.
      • Baker T.
      • Herrero J.I.
      • Caicedo J.C.
      • Fryer J.
      • et al.
      Pretransplant portal vein recanalization-transjugular intrahepatic portosystemic shunt in patients with complete obliterative portal vein thrombosis.
      • Luca A.
      • Miraglia R.
      • Caruso S.
      • Milazzo M.
      • Sapere C.
      • Maruzzelli L.
      • et al.
      Short- and long-term effects of the transjugular intrahepatic portosystemic shunt on portal vein thrombosis in patients with cirrhosis.
      There is a clear need for well-designed prospective clinical trials to obtain high-quality evidence for best management practices to prevent or treat bleeding and thrombosis in patients with cirrhosis.
      The use of DOACs has proliferated in recent years owing to many attractive features including ease of use, oral administration, and there being no requirement for monitoring or dietary adjustments (see Table 1). However, clinical data in patients with cirrhosis, particularly advanced cirrhosis, was initially lacking. Manufacturers do not recommend the use of most DOACs in patients with Child-Pugh B or C cirrhosis. An initial series of patients with cirrhosis treated with DOACs for a variety of indications was reported in 2016.
      • Intagliata N.M.
      • Henry Z.H.
      • Maitland H.
      • Shah N.L.
      • Argo C.K.
      • Northup P.G.
      • et al.
      Direct oral anticoagulants in cirrhosis patients pose similar risks of bleeding when compared to traditional anticoagulation.
      When comparing patients treated with DOACs to a similar cohort treated with traditional agents, there were similar rates of bleeding events. Subsequent studies corroborated these findings.
      • Hum J.
      • Shatzel J.J.
      • Jou J.H.
      • Deloughery T.G.
      The efficacy and safety of direct oral anticoagulants vs traditional anticoagulants in cirrhosis.
      ,
      • De Gottardi A.
      • Trebicka J.
      • Klinger C.
      • Plessier A.
      • Seijo S.
      • Terziroli B.
      • et al.
      Antithrombotic treatment with direct-acting oral anticoagulants in patients with splanchnic vein thrombosis and cirrhosis.
      A recent systematic review of 7 studies including 683 patients found no significant difference in major bleeding rates between patients who received DOACs or traditional anticoagulants.
      • Nisly S.A.
      • Mihm A.E.
      • Gillette C.
      • Davis K.A.
      • Tillett J.
      Safety of direct oral anticoagulants in patients with mild to moderate cirrhosis: a systematic review and meta-analysis.
      However, more recently, experience with DOAC use in patients with Child-Pugh B/C cirrhosis reveals increased bleeding rates in patients with advanced cirrhosis.
      • Mort J.F.
      • Davis J.P.E.
      • Mahoro G.
      • Stotts M.J.
      • Intagliata N.M.
      • Northup P.G.
      Rates of bleeding and discontinuation of direct oral anticoagulants in patients with decompensated cirrhosis.
      ,
      • Semmler G.
      • Pomej K.
      • Bauer D.J.M.
      • Balcar L.
      • Simbrunner B.
      • Binter T.
      • et al.
      Safety of direct oral anticoagulants in patients with advanced liver disease.
      Therefore, caution is required when using DOACs in patients with cirrhosis and further studies are needed.
      As the paradigm of the rebalanced haemostatic system in cirrhosis is now established, our understanding of the role of anticoagulation has advanced significantly. Through studies of anticoagulation in PVT we are beginning to more clearly understand safety and efficacy profiles which may be extrapolated for use in other indications. Future research is needed to define safety profile, proper dose adjustment, and efficacy more clearly for all anticoagulants in this unique patient population.

      Conclusion

      We have learned a great deal on the consequences of haemostatic changes in patients with cirrhosis in the last 20 years. Although high-quality clinical evidence is largely lacking, we have moved to a much more rational approach to management of bleeding and thrombotic complications in these patients. Herein, we have described recent advances in pathogenesis, prevention, and treatment of bleeding and thrombosis in patients with cirrhosis. Although there have been exciting advances in this field, large, well-designed, prospective trials are urgently needed to provide the high-quality evidence required to define best practices.

      Abbreviations

      AASLD, American Association for the Study of Liver Disease; ACLF, acute-on-chronic liver failure; AD, acute decompensation of cirrhosis; AKI, acute kidney injury, DIC, disseminated intravascular coagulation; DOAC, direct oral anticoagulant; DVT, deep vein thrombosis; FFP, fresh frozen plasma; INR, international normalised ratio; LMWH, low molecular weight heparin; NET, neutrophil extracellular trap; PVT, portal vein thrombosis; TIPS, transjugular intrahepatic portosystemic shunt; TXA, tranexamic acid; VKA, vitamin K antagonist; VTE, venous thromboembolism; VWF, von Willebrand factor.

      Financial support

      The authors received no financial support for this paper.

      Authors’ contributions

      TL, SHC, and NMI drafted individual sections of the manuscript and all authors revised each other’s sections.

      Conflict of interest

      TL has no conflicts of interest to report. NMI reports education grant support from Dova. SHC reports research sponsored trials (NASH, PBC, PSC) from Gilead, Madrigal, BMS, GenFit, Zydus, Galectin, Akero, Galmed, and Inventiva; Royalty for device from Avanos; Honoraria for Lectures from Houston Methodist, University Washington, Thomas Jefferson University; Grant support for Coagulation in Liver Disease meeting from Shionogi and Dova.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following is the supplementary data to this article:

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