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Established and new-generation antithrombotic drugs in patients with cirrhosis – Possibilities and caveats

  • Ton Lisman
    Correspondence
    Corresponding author. Address: University Medical Center Groningen, Department of Surgery, BA44, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. Tel.: +31 50 3619028; fax: +31 50 3632796.
    Affiliations
    Department of Surgery, Section of Hepatobiliairy Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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  • Pieter W. Kamphuisen
    Affiliations
    Department of Vascular Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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  • Patrick G. Northup
    Affiliations
    Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, VA, USA
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  • Robert J. Porte
    Affiliations
    Department of Surgery, Section of Hepatobiliairy Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Open AccessPublished:April 01, 2013DOI:https://doi.org/10.1016/j.jhep.2013.03.027

      Summary

      Until recently, it was widely accepted that patients with cirrhosis have a bleeding tendency related to the changes in the hemostatic system that occur as a consequence of the disease. However, it has now been well established that patients with cirrhosis are at risk for both bleeding and thrombotic complications. These thrombotic complications include portal vein thrombosis, deep vein thrombosis and pulmonary embolism, and coronary or cerebrovascular infarctions. Antithrombotic drugs to prevent or treat thrombotic complications in patients with cirrhosis have been used only minimally in the past due to the perceived bleeding risk. As the thrombotic complications and the necessity of antithrombotic treatment in these patients are increasingly recognized, the use of antithrombotic drugs in this population is likely increasing. Moreover, given the rising incidence of fatty liver disease and generally longer survival times of patients with chronic liver diseases, it would be reasonable to presume that some of these thrombotic complications may be increasing in incidence over time. In this review, we will outline the indications for antithrombotic treatment in patients with cirrhosis. Furthermore, we will discuss the available antithrombotic drugs and indicate possible applications, advantages, and caveats. Since for many of these drugs very little experience in patients with cirrhosis exists, these data are essential in the design of future clinical and laboratory studies on mechanisms, efficacy, and safety of the various antithrombotic strategies in these patients.

      Abbreviations:

      PT (prothrombin time), aPTT (activated partial thromboplastin time), PVT (portal vein thrombosis), LMWH (low molecular weight heparin), DVT (deep vein thrombosis), VKA (vitamin K antagonists), NAFLD (non-alcoholic fatty liver disease), NASH (non-alcoholic steatohepatitis), HIT (heparin-induced thrombocytopenia), GI (gastrointestinal), INR (international normalized ratio)

      Keywords

      Introduction

      Cirrhosis is frequently associated with complex changes in the hemostatic system. These changes include thrombocytopenia and platelet function defects, decreased levels of pro- and anticoagulant proteins, and alterations in the fibrinolytic system. The net result of these changes has long been thought to be a bleeding tendency. Indeed, routine diagnostic tests of hemostasis, such as the platelet count, and coagulation tests, such as the prothrombin time (PT) and activated partial thromboplastin time (aPTT), indicate a hypocoagulable state. Clinical experience in patients with liver disease combined with sophisticated laboratory studies of hemostasis has led to the conclusion that despite the major changes in the hemostatic system associated with cirrhosis, the net result is a system that remains in balance due to a commensurate decline in pro- and antihemostatic pathways. This ‘rebalanced’ hemostatic system in patients with cirrhosis, however, appears much more fragile compared to the hemostatic balance of healthy individuals (Fig. 1). This precarious hemostatic balance explains why patients with cirrhosis may experience bleeding complications as well as thrombotic episodes [
      • Lisman T.
      • Porte R.J.
      Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences.
      ,
      • Tripodi A.
      • Mannucci P.M.
      The coagulopathy of chronic liver disease.
      ].
      Figure thumbnail gr1
      Fig. 1The hemostatic balance in patients with liver disease as compared to that of healthy individuals. This cartoon depicts the stable hemostatic balance in healthy individuals and shows that although the hemostatic system in patients with liver disease is (re)balanced, the balance is fragile and may easily tip to either a hypo or hypercoagulable status.
      Until recent years, the common belief was that patients with cirrhosis were protected against thrombotic disease as they were ‘auto-anticoagulated’ as suggested by prolonged routine tests of hemostasis. Consequently, antithrombotic therapy to prevent or treat thrombotic disease was used minimally. Limited use of antithrombotic drugs is also explained by the perceived bleeding risk. Nowadays, there is increasing recognition of various thrombotic complications that may occur in patients with chronic liver diseases [
      • Tripodi A.
      • Anstee Q.M.
      • Sogaard K.K.
      • Primignani M.
      • Valla D.C.
      Hypercoagulability in cirrhosis: causes and consequences.
      ,
      • Northup P.G.
      • Sundaram V.
      • Fallon M.B.
      • Reddy K.R.
      • Balogun R.A.
      • Sanyal A.J.
      • et al.
      Hypercoagulation and thrombophilia in liver disease.
      ,
      • Lisman T.
      • Caldwell S.H.
      • Burroughs A.K.
      • Northup P.G.
      • Senzolo M.
      • Stravitz R.T.
      • et al.
      Hemostasis and thrombosis in patients with liver disease: the ups and downs.
      ]. With increasing rates of fatty liver disease and generally longer survival times in patients with chronic liver diseases, it would be reasonable to presume that some of these complications may be increasing in incidence over time. Prevention or treatment of these complications is complex due to many issues including dosing, monitoring, and safety of the available antithrombotic agents. In this review, we will discuss the thrombotic complications that may occur in patients with cirrhosis. Subsequently, we will discuss advantages and disadvantages of currently available antithrombotic drugs that potentially could be used to treat thrombotic complications of patients with liver disease. We would like to stress that there are no established guidelines for treatment or prevention of thrombotic disease in patients with liver disease. In addition, there is limited clinical data to support or refute the use of available antithrombotic drugs for the different potential indications. We aim at giving an overview of pros and cons of the available drugs with the aim to provide a rationale for future studies on safety and efficacy of potential antithrombotic strategies for the different indications. In our discussion of the possible antithrombotic drugs, we have limited ourselves to antithrombotic drugs that are recommended for venous and arterial events in the general population in the most current guidelines, and only discuss drugs that are generally available for clinical use.

      Thrombotic diseases in patients with cirrhosis

      Portal vein thrombosis

      A common complication of cirrhosis is development of portal vein thrombosis (PVT), which is associated with clinical deterioration [
      • Tsochatzis E.A.
      • Senzolo M.
      • Germani G.
      • Gatt A.
      • Burroughs A.K.
      Systematic review: portal vein thrombosis in cirrhosis.
      ]. Furthermore, PVT complicates liver transplant surgery, and may adversely affect outcome after liver transplantation [
      • Rodriguez-Castro K.I.
      • Porte R.J.
      • Nadal E.
      • Germani G.
      • Burra P.
      • Senzolo M.
      Management of nonneoplastic portal vein thrombosis in the setting of liver transplantation: a systematic review.
      ]. Although there are no established guidelines for treatment of PVT in a patient with cirrhosis, anticoagulant therapy with low molecular weight heparin (LMWH) or vitamin K antagonists (VKAs) results in recanalisation in a proportion of patients with established PVT [
      • Senzolo M.
      • M. Sartori T.
      • 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.
      ,
      • Delgado M.G.
      • Seijo S.
      • Yepes I.
      • Achecar L.
      • Catalina M.V.
      • Garcia-Criado A.
      • et al.
      Efficacy and safety of anticoagulation on patients with cirrhosis and portal vein thrombosis.
      ,
      • 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.
      ,
      • 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.
      ]. There are multiple reasons to assume that successful recanalisation improves clinical outcome. First, an untreated PVT may extend further into the mesenteric/splenic venous system, leading to venous infarction. Second, an untreated PVT may result in accelerated progression of disease as a result of accelerated ‘parenchymal extinction’ [
      • Anstee Q.M.
      • Wright M.
      • Goldin R.
      • Thursz M.R.
      Parenchymal extinction: coagulation and hepatic fibrogenesis.
      ]. There is, however, little clinical evidence as to whether recanalisation following anticoagulant therapy indeed improves clinical outcome.
      Currently, no strategies to prevent development of PVT are available. Nevertheless, a recent randomized trial demonstrated that a daily prophylactic administration of a prophylactic dose of LMWH prevents PVT in patients with compensated cirrhosis, and in addition appears to delay hepatic decompensation [
      • Villa E.
      • Camma C.
      • Marietta M.
      • Luongo M.
      • Critelli R.
      • Colopi S.
      • et al.
      Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis.
      ].
      Although PVT is generally regarded as a deep venous thrombosis, it has not yet been established whether the pathophysiology of the portal vein thrombus indeed resembles the classical venous thrombus (i.e., a fibrin-rich thrombus, as opposed to the platelet-rich thrombus that occurs in systemic arterial thrombosis such as myocardial infarction or stroke). The effect of anti-platelet drugs on PVT has not yet been explored in the non-liver transplant setting, which may be due to the bleeding risk associated with aspirin in patients with esophageal varices [
      • De Ledinghen V.
      • Heresbach D.
      • Fourdan O.
      • Bernard P.
      • Liebaert-Bories M.P.
      • Nousbaum J.B.
      • et al.
      Anti-inflammatory drugs and variceal bleeding: a case-control study.
      ].

      Venous thrombosis

      Multiple studies have demonstrated that patients with chronic liver disease are not protected against venous thrombosis (which includes deep vein thrombosis (DVT) and pulmonary embolism), even in the presence of mechanical or pharmacological thromboprophylaxis [
      • Sogaard K.K.
      • Horvath-Puho E.
      • Gronbaek H.
      • Jepsen P.
      • Vilstrup H.
      • Sorensen H.T.
      Risk of venous thromboembolism in patients with liver disease: a nationwide population-based case-control study.
      ,
      • 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.
      ,
      • Aldawood A.
      • Arabi Y.
      • Aljumah A.
      • Alsaadi A.
      • Rishu A.
      • Aldorzi H.
      • et al.
      The incidence of venous thromboembolism and practice of deep venous thrombosis prophylaxis in hospitalized cirrhotic patients.
      ,
      • Garcia-Fuster M.J.
      • Abdilla N.
      • Fabia M.J.
      • Fernandez C.
      • Oliver V.
      • Forner M.J.
      Venous thromboembolism and liver cirrhosis.
      ]. Some studies indicate that chronic liver disease is in fact a risk factor for venous thrombosis with a more than 2-fold increased risk [
      • Sogaard K.K.
      • Horvath-Puho E.
      • Gronbaek H.
      • Jepsen P.
      • Vilstrup H.
      • Sorensen H.T.
      Risk of venous thromboembolism in patients with liver disease: a nationwide population-based case-control study.
      ], although not all studies agree [
      • Heit J.A.
      • Silverstein M.D.
      • Mohr D.N.
      • Petterson T.M.
      • O’Fallon W.M.
      • Melton 3rd, L.J.
      Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study.
      ].
      Treatment of venous thrombosis in the general population during immobilization, hospitalization or following major surgery is typically achieved with LMWH followed by VKAs or by novel anticoagulant agents, including oral direct factor Xa and IIa inhibitors [
      • Guyatt G.H.
      • Akl E.A.
      • Crowther M.
      • Gutterman D.D.
      • Schuunemann H.J.
      • American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel
      Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines.
      ]. Primary prevention of venous thrombosis in the general population is achieved by LMWH, the heparin-derived synthetic pentasaccharide fondaparinux, low-dose unfractionated heparin, or by oral anti Xa or IIa inhibitors [
      • Guyatt G.H.
      • Akl E.A.
      • Crowther M.
      • Gutterman D.D.
      • Schuunemann H.J.
      • American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel
      Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines.
      ]. The oral Xa and IIa inhibitors Rivaroxaban and Dabigatran have been registered for primary prophylaxis after orthopedic surgery. There is mounting evidence that thromboprophylactic treatment is safe in patients with cirrhosis [
      • Intagliata N.M.
      • Henry Z.H.
      • Shah N.
      • Caldwell S.H.
      • Northup P.G.
      Prophylactic anticoagulation for deep venous thrombosis in hospitalized cirrhosis patients is safe and does not lead to increased bleeding events.
      ] and it would follow that prophylaxis should not be withheld from patients with liver disease even in the presence of abnormal routine tests of coagulation. Indications for thromboprophylaxis include hospitalization and immobilization, surgery, and perhaps also the presence of (hepatocellular) cancer, as cancer in general is a risk factor for venous thrombosis.

      Arterial thrombosis

      The incidence of arterial thrombotic events, including coronary and cerebrovascular infarctions, was traditionally believed to occur in a lower frequency in patients with cirrhosis as compared to the general population [
      • Melato M.
      • Mucli E.
      • Poldrugo F.
      • Valente M.
      • Zanconati F.
      • Okuda K.
      Stroke-cirrhosis relationship: an autopsy study in a heavy drinking population.
      ,
      • Howell W.L.
      • Manion W.C.
      The low incidence of myocardial infarction in patients with portal cirrhosis of the liver: a review of 639 cases of cirrhosis of the liver from 17,731 autopsies.
      ,
      • Marchesini G.
      • Ronchi M.
      • Forlani G.
      • Bugianesi E.
      • Bianchi G.
      • Fabbri A.
      • et al.
      Cardiovascular disease in cirrhosis – a point-prevalence study in relation to glucose tolerance.
      ]. Recent studies, however, have challenged these earlier findings [
      • Kalaitzakis E.
      • Rosengren A.
      • Skommevik T.
      • Bjornsson E.
      Coronary artery disease in patients with liver cirrhosis.
      ,
      • Patel S.
      • Kiefer T.L.
      • Ahmed A.
      • Ali Z.A.
      • Tremmel J.A.
      • Lee D.P.
      • et al.
      Comparison of the frequency of coronary artery disease in alcohol-related versus non-alcohol-related endstage liver disease.
      ,
      • McAvoy N.C.
      • Kochar N.
      • McKillop G.
      • Newby D.E.
      • Hayes P.C.
      Prevalence of coronary artery calcification in patients undergoing assessment for orthotopic liver transplantation.
      ]. Patients with non-alcoholic fatty liver disease (NAFLD) have been repeatedly shown to have an increased risk for arterial disease, which is in fact the leading cause of death in this group [
      • Argo C.K.
      • Caldwell S.H.
      Epidemiology and natural history of non-alcoholic steatohepatitis.
      ]. As the number of patients with NAFLD/non-alcoholic steatohepatitis (NASH) is increasing, the number of patients with both liver and cardiovascular disease will likely increase as well.
      For primary prevention of arterial disease in the general population >50 years of age, low dose aspirin therapy may be considered. Antithrombotic therapy and/or secondary prevention of cardiovascular events consist of antiplatelet monotherapy (aspirin or clopidogrel) for patients with established coronary artery disease and dual antiplatelet therapy (aspirin with a P2Y12 receptor blocker) following acute coronary syndromes with percutaneous coronary intervention and stent placement [
      • Guyatt G.H.
      • Akl E.A.
      • Crowther M.
      • Gutterman D.D.
      • Schuunemann H.J.
      • American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel
      Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines.
      ]. Secondary prevention of ischemic stroke consists of single anti-platelet therapy or oral anticoagulant therapy. Secondary prevention of arterial events should presumably not be withheld from patients with cirrhosis, but the risk of bleeding complications may be increased (see below).

      Thrombosis as a contributor to progression of disease

      Figure thumbnail fx2

      Pros and cons of different antithrombotic drugs in patients with cirrhosis

      Anti-platelet agents

      Unlike many anticoagulant drugs, anti-platelet agents do not require laboratory monitoring for dose adjustments, so many of the issues regarding monitoring that are present in the use of anticoagulants in patients with cirrhosis do not apply to anti-platelet agents. Nevertheless, functional tests are sometimes performed to assess anti-platelet drug efficacy, as some patients appear to be resistant against aspirin or Clopidogrel [
      • Cattaneo M.
      Resistance to anti-platelet agents.
      ]. Despite this, no tests are usually performed to avoid excessive inhibition of platelet function. Tests to detect anti-platelet-resistance in patients with cirrhosis may be complicated by thrombocytopenia and platelet function defects that are already present in the patient with cirrhosis [
      • Hugenholtz G.G.
      • Porte R.J.
      • Lisman T.
      The platelet and platelet function testing in liver disease.
      ]. As laboratory tests of platelet function are frequently abnormal in patients with cirrhosis, it may be challenging to detect efficacy of anti-platelet agents, but the clinical relevance of laboratory evidence of resistance against anti-platelet regimens is unclear.
      There is tremendous clinical evidence for the efficacy of aspirin in secondary prevention of arterial disease. The published study with aspirin in patients with cirrhosis, however, is limited. Cirrhosis has been listed as an absolute contraindication for aspirin use due to gastrointestinal (GI) bleeding risk [
      • De Ledinghen V.
      • Heresbach D.
      • Fourdan O.
      • Bernard P.
      • Liebaert-Bories M.P.
      • Nousbaum J.B.
      • et al.
      Anti-inflammatory drugs and variceal bleeding: a case-control study.
      ,
      • Miser W.F.
      Appropriate aspirin use for primary prevention of cardiovascular disease.
      ]. Furthermore, patients with ascites may suffer from acute renal failure, hyponatremia, and diuretic resistance in response to aspirin treatment [
      • European Association for the Study of the Liver
      EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis.
      ], although these complications are rare at the low doses used for antiplatelet therapies. Nevertheless, the number of patients with cirrhosis that require antiplatelet therapy for secondary prevention of arterial events (e.g., after coronary stenting) is likely increasing over time due to the increasing prevalence of NAFLD/NASH. The currently available evidence suggests that aspirin is relatively safe in terms of bleeding risk in patients with cirrhosis, but without significant varices, after coronary artery stenting [
      • Russo M.W.
      • Pierson J.
      • Narang T.
      • Montegudo A.
      • Eskind L.
      • Gulati S.
      Coronary artery stents and antiplatelet therapy in patients with cirrhosis.
      ]. On the other hand, use of aspirin has been associated with an increased risk of a first variceal bleeding in patients with established varices, and therefore, in these patients aspirin is likely contraindicated for primary, and perhaps also for secondary prevention [
      • De Ledinghen V.
      • Heresbach D.
      • Fourdan O.
      • Bernard P.
      • Liebaert-Bories M.P.
      • Nousbaum J.B.
      • et al.
      Anti-inflammatory drugs and variceal bleeding: a case-control study.
      ].
      Inhibitors of the P2Y12 receptor, which block ADP-induced platelet aggregation, have become an integral part of treatment and prevention of arterial thrombosis. The irreversible P2Y12 blockers Clopidogrel and Ticlopidine were the first clinically approved antiplatelet drugs in this class. Genetic variation and drug-interaction issues complicate the use of these drugs and result in variable responses to treatment [
      • Patrono C.
      • Andreotti F.
      • Arnesen H.
      • Badimon L.
      • Baigent C.
      • Collet J.P.
      • et al.
      Antiplatelet agents for the treatment and prevention of atherothrombosis.
      ]. The second generation irreversible P2Y12 inhibitor Prasugrel has the advantage of a more rapid onset of action and results in a more consistent inhibition of platelet function as compared to Clopidogrel [
      • Cattaneo M.
      New P2Y(12) inhibitors.
      ]. A major disadvantage of the irreversible P2Y12 inhibitors is that they require metabolic activation by the liver, which may result in unpredictable pharmacokinetics in patients with cirrhosis. The pharmacokinetics and pharmacodynamics of Clopidogrel are unaltered in patients with Child A or B cirrhosis [
      • Slugg P.H.
      • Much D.R.
      • Smith W.B.
      • Vargas R.
      • Nichola P.
      • Necciari J.
      Cirrhosis does not affect the pharmacokinetics and pharmacodynamics of clopidogrel.
      ], yet “significant liver impairment or cholestatic jaundice” is stated as contraindications in the package insert. No pharmacokinetic differences in patients with Child B cirrhosis were demonstrated for Prasugrel [
      • Small D.S.
      • Farid N.A.
      • Li Y.G.
      • Ernest 2nd, C.S.
      • Winters K.J.
      • Salazar D.E.
      • et al.
      Pharmacokinetics and pharmacodynamics of prasugrel in subjects with moderate liver disease.
      ], and chronic liver disease is not a contraindication according to the package insert, although caution is advised. The reversible P2Y12 inhibitor Ticagrelor does not require metabolic activation, but is cleared by the liver. Although it has been demonstrated that patients with Child A cirrhosis do not have impaired pharmacokinetic responses to Ticagrelor [
      • Butler K.
      • Teng R.
      Pharmacokinetics, pharmacodynamics, and safety of ticagrelor in volunteers with mild hepatic impairment.
      ], severe chronic liver disease is a contraindication for this drug according to the package insert. Since most of the P2Y12 blockers state (severe) liver disease as a contraindication, the role of these drugs in patients with cirrhosis is unclear. However, since the contraindication appears primarily based on the perceived bleeding risk, studies on safety of Clopidogrel in these patients appear justified. Anecdotal evidence is suggestive of an acceptable safety profile [
      • Russo M.W.
      • Pierson J.
      • Narang T.
      • Montegudo A.
      • Eskind L.
      • Gulati S.
      Coronary artery stents and antiplatelet therapy in patients with cirrhosis.
      ]. The use of P2Y12 inhibitors for prevention of arterial events in cirrhosis may be limited to those patients without varices, since the rate of variceal bleeding in patients receiving antiplatelet agents following stent placement was substantial (12.5%).
      Extended-release dipyridamole may be used for specific arterial indications. It is eliminated primarily by biliary excretion and undergoes enterohepatic recirculation. Although dipyridamole has potential beneficial side effects such as reducing progression of disease (shown in animal models) [
      • Wanless I.R.
      • Belgiorno J.
      • Huet P.M.
      Hepatic sinusoidal fibrosis induced by cholesterol and stilbestrol in the rabbit: 1. Morphology and inhibition of fibrogenesis by dipyridamole.
      ] and improvement of portal circulation [
      • Sansoe G.
      • Ferrari A.
      • D’Alimonte P.
      • Trenti T.
      • Zoboli P.
      • Romagnoli R.
      • et al.
      Beneficial hemodynamic effects of dipyridamole on portal circulation in cirrhosis.
      ], it does worsen renal function in patients with ascites and increased plasma renin activity [
      • Llach J.
      • Gines P.
      • Arroyo V.
      • Salmeron J.M.
      • Gines A.
      • Jimenez W.
      • et al.
      Effect of dipyridamole on kidney function in cirrhosis.
      ].

      Heparins

      Heparins may be considered for prevention or treatment of venous thrombosis, PVT, and as adjunct treatment in acute arterial thrombosis. Three classes of heparins are currently available; unfractionated heparin, LMWHs, and the synthetic pentasaccharide Fondaparinux. In the general population, the advantages of LMWH or pentasaccharide are mode of administration (s.c. vs. i.v.) and the fixed dose that does not require laboratory monitoring, except in patients with extreme obesity and patients with renal dysfunction. Unfractionated heparin is routinely monitored with the aPTT, whereas LMWH dosing can be monitored with anti-Xa assays in patients without severe liver dysfunction.
      The mode of administration of these agents (i.v. for unfractionated heparin, and s.c. for LMWH and fondaparinux) as well as the concern for heparin-induced thrombocytopenia (HIT), however, may limit long-term use. Nevertheless, patients with cirrhosis have been treated with daily s.c. injections of LMWHs for up to a year with the aim to either treat or prevent portal vein thrombosis [
      • Senzolo M.
      • M. Sartori T.
      • 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.
      ,
      • Villa E.
      • Camma C.
      • Marietta M.
      • Luongo M.
      • Critelli R.
      • Colopi S.
      • et al.
      Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis.
      ]. These prolonged daily s.c. injections are clearly inconvenient for the patient and may be associated with poor compliance. Furthermore, skin reactions, which are mainly type IV delayed hypersensitivity reactions, at the injection site may occur, which may require a switch to a different LMWH preparation or alternative anticoagulant therapy [
      • Schindewolf M.
      • Lindhoff-Last E.
      • Ludwig R.J.
      • Boehncke W.H.
      Heparin-induced skin lesions.
      ]. Although the incidence of delayed-type hypersensitivity reactions towards LMWH is estimated at 7.5% but may go up to 40% in specific populations (in particular in pregnant women), such problems have not been reported in the studies performed in patients with cirrhosis. Importantly, these adverse events are known to be under-reported in patients without liver disease, and future studies in patients with cirrhosis should thus carefully examine the incidence of skin reactions.
      Although the published experience in patients with cirrhosis is limited, LMWHs appear to have an excellent safety profile in patients with cirrhosis and venous thrombosis or PVT [
      • Senzolo M.
      • M. Sartori T.
      • 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.
      ,
      • Delgado M.G.
      • Seijo S.
      • Yepes I.
      • Achecar L.
      • Catalina M.V.
      • Garcia-Criado A.
      • et al.
      Efficacy and safety of anticoagulation on patients with cirrhosis and portal vein thrombosis.
      ,
      • 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.
      ,
      • Villa E.
      • Camma C.
      • Marietta M.
      • Luongo M.
      • Critelli R.
      • Colopi S.
      • et al.
      Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis.
      ,
      • Intagliata N.M.
      • Henry Z.H.
      • Shah N.
      • Caldwell S.H.
      • Northup P.G.
      Prophylactic anticoagulation for deep venous thrombosis in hospitalized cirrhosis patients is safe and does not lead to increased bleeding events.
      ,
      • Bechmann L.P.
      • Sichau M.
      • Wichert M.
      • Gerken G.
      • Kroger K.
      • Hilgard P.
      Low-molecular-weight heparin in patients with advanced cirrhosis.
      ]. Nevertheless, there are important caveats in using these agents in this patient population. First, LMWH accumulation is known to occur in patients with renal failure, and thus patients with cirrhosis and decreased renal function likely require dose-adjustments. Second, heparins possess anticoagulant activity by virtue of an enhancing effect of the endogenous anticoagulant antithrombin. Since antithrombin is synthesized in the liver, plasma levels are frequently decreased in patients with cirrhosis, which theoretically leads to an unpredictable anticoagulant effect. This is especially true in the context of the multiple other changes in the hemostatic system in patients with cirrhosis. Indeed, in vitro studies have demonstrated that LMWH has a more profound anticoagulant effect in plasma from patients with cirrhosis as compared to plasma from healthy controls [
      • Senzolo M.
      • Rodriguez-Castro K.I.
      • Rossetto V.
      • Radu C.
      • Gavasso S.
      • Carraro P.
      • et al.
      Increased anticoagulant response to low-molecular-weight heparin in plasma from patients with advanced cirrhosis.
      ]. In addition, it has been suggested in patients with cirrhosis that anti-Xa levels after a standard prophylactic or therapeutic dose of LMWH fall below the recommended ranges for optimal anticoagulant control [
      • Bechmann L.P.
      • Sichau M.
      • Wichert M.
      • Gerken G.
      • Kroger K.
      • Hilgard P.
      Low-molecular-weight heparin in patients with advanced cirrhosis.
      ]. However, the decreased anti-Xa levels in these patients appear to be a laboratory anomaly and not a true indication of anticoagulation effect. In vitro addition of LMWH to plasma from patients with cirrhosis has demonstrated that the anti-Xa level subsequently measured in these plasmas is substantially lower as compared to the levels that were actually added (recoveries as little as 32% have been reported), whereas the recovery in normal plasma is around 100% [
      • Senzolo M.
      • Rodriguez-Castro K.I.
      • Rossetto V.
      • Radu C.
      • Gavasso S.
      • Carraro P.
      • et al.
      Increased anticoagulant response to low-molecular-weight heparin in plasma from patients with advanced cirrhosis.
      ,
      • Lisman T.
      • Porte R.J.
      Towards a rational use of low-molecular-weight heparin in patients with cirrhosis.
      ]. Thus, in patients with cirrhosis who generally have an acquired antithrombin deficiency, the anti-Xa assay underestimates the true LMWH mass. This laboratory anomaly will cause a falsely low level of anti-Xa activity and may lead to incorrect and possibly dangerous dose escalations. On the other hand, the anticoagulant potency of LMWH appears increased in patients with cirrhosis, which points to a requirement for dose-reductions. Clinicians need to be aware of these caveats, and clinical studies on the risk/benefit of different dosing strategies of these agents are required in order to formulate liver-specific guidelines. A more reliable monitoring test would assist in these studies. The thrombin generation test might hold promise as such a test, but a major problem is that the test is relatively complex and not available in the routine clinical laboratory. Alternatively, point of care tests such as thromboelastography may be useful for LMWH monitoring, but studies assessing usefulness of this technique and to establish target ranges have not been published in the cirrhosis population.
      Whether similar monitoring problems also occur with unfractionated heparin or fondaparinux has not yet been assessed. An additional problem with monitoring of unfractionated heparin is that the aPTT, which is instrumental in dosing this agent, is already prolonged in many patients with cirrhosis, and therefore aPTT target ranges for these patients are unclear.

      Vitamin K antagonists

      VKAs are still the cornerstone of long-term anticoagulant treatment in the general medical population. The major issue with VKA use is the absolute requirement for regular monitoring of the anticoagulant intensity by the International Normalized Ratio (INR). INR target ranges for different indications have been established, and dose adjustments are made when a patient is out of range. It has been well established that an INR below the target range increases this risk of (re)thrombosis, whereas an INR above the target range increases bleeding risk.
      VKAs result in decreased functional levels of the vitamin K-dependent procoagulant proteins factor VII, IX, X, and II. In addition, VKAs reduce functional levels of the anticoagulant proteins C and S, but the net result of VKAs is a reduction of hemostatic potential.
      The major concern with the use of VKAs in patients with cirrhosis is that the target INR for patients with cirrhosis and an already prolonged INR is unclear. It is now well established that while a prolonged INR due to VKAs indicates a decreased hemostatic potential, a prolonged INR due to cirrhosis is unrelated to hemostatic capacity [
      • Lisman T.
      • Porte R.J.
      Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences.
      ,
      • Tripodi A.
      • Baglin T.
      • Robert A.
      • Kitchen S.
      • Lisman T.
      • Trotter J.F.
      • et al.
      Reporting prothrombin time results as international normalized ratios for patients with chronic liver disease.
      ]. Furthermore, it is difficult to interpret an INR that is elevated due to a combination of cirrhosis and VKAs since the impact of VKAs on coagulation is so different from the impact of the coagulation abnormalities of cirrhosis on the clotting system. Finally, it has been demonstrated by multiple independent groups that the between-laboratory variability of the INR in patients with cirrhosis is unacceptably high [
      • Porte R.J.
      • Lisman T.
      • Tripodi A.
      • Caldwell S.H.
      • Trotter J.F.
      • Coagulation in Liver Disease Study Group
      The international normalized ratio (INR) in the MELD score: problems and solutions.
      ,
      • Lisman T.
      • van Leeuwen Y.
      • Adelmeijer J.
      • Pereboom I.T.
      • Haagsma E.B.
      • van den Berg A.P.
      • et al.
      Interlaboratory variability in assessment of the model of end-stage liver disease score.
      ,
      • Tripodi A.
      • Chantarangkul V.
      • Primignani M.
      • Fabris F.
      • Dell’Era A.
      • Sei C.
      • et al.
      The international normalized ratio calibrated for cirrhosis (INR(liver)) normalizes prothrombin time results for model for end-stage liver disease calculation.
      ], which complicates VKA monitoring by the INR in patients with cirrhosis even further.
      The use of VKAs in patients with cirrhosis is thus likely associated with an unfavorable risk/benefit ratio, in particular in patients with high INRs prior to VKA initiation, as an optimal anticoagulant intensity will be difficult to achieve. Indeed, the use of VKAs in patients with cirrhosis has been associated with an increased risk of bleeding complications [
      • Garcia-Fuster M.J.
      • Abdilla N.
      • Fabia M.J.
      • Fernandez C.
      • Oliver V.
      • Forner M.J.
      Venous thromboembolism and liver cirrhosis.
      ,
      • Levi M.
      • Hovingh G.K.
      • Cannegieter S.C.
      • Vermeulen M.
      • Buller H.R.
      • Rosendaal F.R.
      Bleeding in patients receiving vitamin K antagonists who would have been excluded from trials on which the indication for anticoagulation was based.
      ]. There is a need for a more reliable monitoring test for intensity of VKA anticoagulation in the patient with cirrhosis. Thrombin generation tests or thromboelastography may have a better performance as compared to the INR, but studies examining this are still lacking. Another possible alternative towards monitoring of VKAs in patients with cirrhosis is measurements of activity levels of one of the vitamin K-dependent factors (for example FII), but the target FII level for optimal anticoagulant activity has not yet been established.

      New-generation oral anticoagulants

      Two novel oral anticoagulants have recently been approved for clinical use. Rivaroxaban is a direct factor Xa inhibitor, and Dabigatran is a direct factor IIa inhibitor [
      • Schulman S.
      • Crowther M.A.
      How I treat with anticoagulants in 2012: new and old anticoagulants, and when and how to switch.
      ]. Unlike VKAs, both agents inhibit a single coagulation protease, and unlike heparins, both agents are independent of antithrombin. Both agents do not require laboratory monitoring in the general population. Although this is considered as a major advantage of these drugs, it is at the same time also a disadvantage as it increases the risk for non-compliance, which is rapidly detected in patients using VKAs as a drop in the INR. Further advantages of these drugs are the mode of administration (oral) and lack of heparin-induced thrombocytopenia. These new drugs would potentially be applicable in both long- and short-term anticoagulant strategies including prevention or treatment of venous thrombosis, prevention or treatment of PVT and prevention of disease progression.
      Potential advantages of these drugs over VKAs are the wider therapeutic window. Nevertheless, monitoring of the new drugs may be required in patients with liver disease. Laboratory methodologies for monitoring these new drugs are still in development, and validation in patients with cirrhosis will be required. A major advantage of the new drugs over heparins is the mode of administration. In particular the long-term anticoagulant regimens that are currently applied to patients with PVT may be improved substantially by switching to oral agents.

      Rivaroxaban

      There are little published clinical studies with Rivaroxaban in patients with cirrhosis, as they were excluded from clinical trials. Nevertheless, there is a warning to avoid Rivaroxaban in patients with Child B and C cirrhosis according to the package insert, which is related to a (perceived) bleeding risk. Furthermore, significant increases in Rivaroxaban exposure are observed in patients with Child B cirrhosis [
      • Kubitza D.
      • Roth A.
      • Becka M.
      • Alatrach A.
      • Halabi A.
      • Hinrichsen H.
      • et al.
      Effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban – an oral, direct Factor Xa inhibitor.
      ]. In addition, Rivaroxaban was associated with a higher risk for GI bleeding compared to warfarin in patients with adequate liver function [
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • Pan G.
      • Singer D.E.
      • Hacke W.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      ]. Finally, Rivaroxaban is cleared primarily by the kidneys (66%) and liver (34%) [
      • Graff J.
      • Harder S.
      Anticoagulant therapy with the oral direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban and the thrombin inhibitor dabigatran etexilate in patients with hepatic impairment.
      ]. Patients with cirrhosis with or without concomitant renal failure, and in particular patients with the hepatorenal syndrome may thus not be ideal candidates for Rivaroxaban, and dose adjustments may be required.
      A major concern regarding the use of Rivaroxaban is the lack of established reversal agents. Given its half life of 5–13 hours, drug discontinuation is insufficient when an acute bleeding occurs. One study in healthy volunteers has demonstrated that a prothrombin complex concentrate reverses the anticoagulant effect of Rivaroxaban [
      • Eerenberg E.S.
      • Kamphuisen P.W.
      • Sijpkens M.K.
      • Meijers J.C.
      • Buller H.R.
      • Levi M.
      Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects.
      ]. A second study, in which reversal agents were added in vitro to plasma from healthy volunteers receiving Rivaroxaban, showed (partial) reversal of the anticoagulant effect by both (activated) prothrombin concentrates and recombinant factor VIIa [
      • Marlu R.
      • Hodaj E.
      • Paris A.
      • Albaladejo P.
      • Crackowski J.L.
      • Pernod G.
      Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban. A randomised crossover ex vivo study in healthy volunteers.
      ].

      Dabigatran

      There is also little clinical experience with Dabigatran in patients with cirrhosis, but contrary to Rivaroxaban, Dabigatran is not explicitly contraindicated for patients with cirrhosis. The pharmacokinetics of Dabigatran is not different between patients with Child B cirrhosis and healthy individuals [
      • Stangier J.
      • Stahle H.
      • Rathgen K.
      • Roth W.
      • Shakeri-Nejad K.
      Pharmacokinetics and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor, are not affected by moderate hepatic impairment.
      ]. Dabigatran is mainly (80%) eliminated via the kidneys, and in severe renal failure bioaccumulation occurs [
      • Stangier J.
      • Rathgen K.
      • Stahle H.
      • Mazur D.
      Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study.
      ]. Patients with cirrhosis and renal failure may thus not be ideal candidates for Dabigatran, and dose adjustments may be required.
      Similar to Rivaroxaban, the long half life of Dabigatran (12–14 hours) renders drug discontinuation alone insufficient in case of acute bleeding. Dabigatran may be neutralized soon after ingestion by gastric lavage or charcoal administration, and in severe cases acute hemodialysis may be considered [
      • van Ryn J.
      • Stangier J.
      • Haertter S.
      • Liesenfeld K.H.
      • Wienen W.
      • Feuring M.
      • et al.
      Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity.
      ]. A study in which reversal agents were added in vitro to plasma from healthy volunteers receiving Dabigatran showed (partial) reversal of the anticoagulant effect by both (activated) prothrombin concentrates and recombinant factor VIIa [
      • Marlu R.
      • Hodaj E.
      • Paris A.
      • Albaladejo P.
      • Crackowski J.L.
      • Pernod G.
      Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban. A randomised crossover ex vivo study in healthy volunteers.
      ].
      Figure thumbnail fx3

      A practical approach to prevention or treatment of thrombosis in patients with liver disease

      As outlined in the previous sections, we believe that there are multiple indications for antithrombotic treatment in patients with liver disease. Both prevention and treatment of thromboses may require antithrombotic therapy, but due to the lack of clinical data, the type of drug and dosing are in most instances unclear. A more rational approach to antithrombotic therapy requires extensive clinical and laboratory research, and fortunately many groups are currently embarking on such journeys. However, the practicing clinician is at present facing dilemmas on if and how to apply antithrombotic therapy in patients with liver disease. Here we will provide some guidance on how to approach prevention or treatment of the various types of thrombosis at present, but we need to stress that none of these approaches is evidenced-based.

      Portal vein thrombosis

      We believe that anticoagulant therapy with the aim of preventing PVT at present should only be considered in the context of clinical trials. Insufficient data on efficacy and safety of anticoagulation to avoid PVT is currently available to justify widespread use of this approach.
      Although it is uncertain whether treatment of PVT in patients with cirrhosis improves outcome, more and more clinicians will be inclined to start anticoagulant treatment. We believe LMWH is at present the anticoagulant of choice, as the available clinical data suggest LMWH to be effective and safe in patients with liver disease. We suggest conservative dosing, in particular in patients with advanced disease, and in those patients with risk factors for bleeding, such as renal failure and severe thrombocytopenia. Laboratory monitoring by anti-Xa assays is not recommended since these values likely underestimate the in vivo anticoagulant status. Given the high rates of bleeding and the lack of a suitable target INR, vitamin K antagonists are discouraged in the treatment of PVT.

      Venous thrombosis

      We believe that thromboprophylaxis to prevent venous thrombosis should not be withheld from patients with cirrhosis, even in the presence of profoundly prolonged INRs. Specifically, we recommend LMWH thromboprophylaxis in all situations (hospitalization, immobilization, and post-surgery) in which patients without liver disease would receive thromboprophylaxis. Dosing regimens may be adapted in patients with risk factors for bleeding such as renal failure or profound thrombocytopenia. In those patients with clear contraindications for anticoagulant treatment, mechanical thromboprophylaxis (for example using compression stockings or pneumatic compression devices) should be considered. Monitoring of LMWH prophylaxis should not be performed. If anti-Xa levels are absolutely required, for example in patients with severe renal failure, we recommend assessing anti-Xa levels only with a test kit in which the test plasma is supplemented with antithrombin to avoid falsely-low anti-Xa levels as a consequence of the patients’ low plasma antithrombin levels.
      Treatment of venous thrombosis should be initiated with LMWHs, and may be continued with VKAs or prolonged LMWH administration. Studies on optimal dosing regimens for VKAs are urgently required, and until these studies become available, we recommend conservative dosing. When prolonged LMWH administration instead of a switch to VKAs is chosen, this should be performed with great care. Reductions in LMWH or VKA dosages may be required in those patients with risk factors for bleeding, such as renal failure or severe thrombocytopenia.

      Arterial thrombosis

      Aspirin prophylaxis for primary or secondary prevention of arterial events and P2Y12 inhibitors for secondary prevention should not be withheld from all patients with cirrhosis, but there may be (low-risk) patients in whom the risk/benefit profile is unfavorable. Although data are largely lacking, the bleeding risk of primary and secondary prophylaxis is likely increased in patients with liver disease compared to the general population, in particular in those patients with varices. Nevertheless, the benefit of prophylaxis, particularly in high-risk patients, such as patients with NASH-related cirrhosis, likely justifies the bleeding risk.

      Antithrombotic therapy to delay disease progression

      Based on one study, anticoagulation using LMWH appears to delay progression of liver disease. Although these results suggest that antithrombotic therapy may be a fundamentally novel approach to treat patients with cirrhosis, such strategies should at present only be performed in the context of well-designed clinical trials.

      Conclusions

      Anticoagulant therapy in the patient with cirrhosis is a major challenge. As the hemostatic system in cirrhosis is frequently altered substantially, compared to healthy individuals, it is likely that anticoagulant drug regimens applied in the general population will result in unpredictable effects in the patient with cirrhosis. Moreover, monitoring of anticoagulant therapy is difficult as the available monitoring strategies are developed for use in individuals with a competent hemostatic system prior to initiation of anticoagulant therapy. For these reasons, it will be difficult to achieve an optimal intensity of the anticoagulant treatment which will increase the risks of thrombosis, recurrent thrombosis, or bleeding.
      For many of the available agents, little or no published experience in the patient with cirrhosis exists. Nevertheless, we believe it is relevant that the hepatology community is aware of the (theoretical) advantages and disadvantages of the available drugs, which we have described in this review and are summarized in Table 1. The awareness that patients with cirrhosis may be candidates for prophylactic or therapeutic anticoagulant intervention is increasing. Similarly, the proportion of patients requiring anticoagulant therapy is likely increasing (for example due to the increasing incidence of NASH). Clinical and laboratory studies on mechanisms, efficacy, and safety of the various antithrombotic strategies will be required in patients with cirrhosis. Such studies will assist in future management decisions as well in design of clinical trials assessing efficacy and safety of various antithrombotic regimens. For some of the newer drugs, including Rivaroxaban and Dabigatran, the theoretical disadvantages such as drug accumulation with a resulting bleeding risk may prohibit clinical trials in patients with advanced disease. Nevertheless, a potentially important new indication for antithrombotic therapy in patients with mild to moderate cirrhosis is prevention of progression of disease, and in such patients the new oral anticoagulants may be applicable. In these patients with compensated disease, the advantages of the new drugs may outweigh the drawbacks.
      Table 1Antithrombotic drugs that are registered for clinical use and recommended for prevention or treatment of venous or arterial events in the most current guidelines. Their mechanism of action, potential indications in patients with liver disease, and advantages or disadvantages are shown.

      Conflict of interest

      PWK has received research grants from LeoPharma en Sanquin and served on advisory boards of LeoPharma, Boehringer Ingelheim, and Pfizer. The other authors report no conflicts of interest.

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