The Challenge of Anticoagulation in Liver Cirrhosis

Background: Advanced liver diseases are characterized by a number of changes in the hemostatic system. Due to the occurrence of bleeding events in patients with liver cirrhosis, there seems to be a hesitance to the administration of anticoagulant medications. This review summarizes challenges, recommendations, and current developments of anticoagulation in the cirrhotic patient. Summary: The risk of thrombotic events in patients with liver cirrhosis is at least as high as in patients with healthy liver function if not even higher. Standard laboratory markers do not truly reflect the complexity of changes that take place in the coagulative system and therefore cannot be used as a reference for risk of thrombosis or hemorrhage. Potential options for anticoagulant therapy are heparins, vitamin K antagonists, and direct-acting oral anticoagulants which come with differences in safety, application, possible side effects, and data availability for the patient cohort. Key Message: The administration of anticoagulation can be beneficial in patients with liver disease if the indication is present and bleeding prophylaxis has been established. Direct-acting oral anticoagulants appear to be a promising new approach with many improvements compared to conventional substances. Nevertheless, there is a need for further data and prospective trials on the use in patients with liver cirrhosis.


Introduction
In clinical practice, end-stage liver disease is generally linked with cirrhosis-associated coagulopathy and, therefore, an increased risk for bleeding events.However, complex changes in the coagulative cascade lead to uncertainty of how to handle both the management of hemorrhage as well as thrombosis.As a consequence, the use of anticoagulant agents in hospitalized patients with liver cirrhosis presents a common challenge.Under physiologic circumstances, procoagulant and anticoagulant components, which are mainly synthesized by hepatic parenchymal cells, form a balance in the hemostatic system [1].In this state, protein levels well above the required quantity are reached, as only 20-50% of the physiological plasma levels are needed for stable hemostasis [2].Hepatic insufficiency leads to a reduced production of these proteins and, therefore, to lower levels of clotting factors such as factor II, V, VII, IX, X, and XI [3].Notable exceptions are von Willebrand factor and factor VIII, whose plasma levels typically increase in chronic liver diseases [4].Historically, this led to a one-sided focus on liver cirrhosis, considering bleeding complications as the predominant issue in affected patients.Nevertheless, one should note that simultaneously, a reduction of anticoagulant factors such as antithrombin and protein C takes place [5].The parallel decrease of procoagulant and anticoagulant factors resulted in the new concept of "rebalanced coagulation" with an increased risk of bleeding episodes and thrombotic events, depending on the circumstantial risk factors [4].This idea is underlined by studies showing evidence that liver diseases may even be associated with a substantially increased risk of venous thromboembolisms [6].An important conclusion drawn from these findings was that patients with end stage liver diseases do not own an "auto-anticoagulation" [4] and are, despite their coagulopathy, not protected from thrombotic episodes [7,8].Challenges in clinical practice are aggravated by the fact that typical laboratory parameters such as INR (international normalized ratio) and aPTT (activated partial thromboplastin time) only reflect one part of the hemostatic alterations: both represent pathways of the coagulation cascade; the reduced levels of the anticoagulants protein C and S are not included into the daily used clotting tests [2,9].Thus, traditional laboratory tests cannot be considered suitable predictors of bleeding or thrombotic complications in this patient collective [9]. Figure 1 illustrates the process of rebalanced hemostasis by showing examples of anti-and prohemostatic factors with decreased levels in liver cirrhosis.

The Risk of Thrombotic Events in Advanced Liver Diseases
Taking into account that patients with compensated liver cirrhosis present a nearly normal coagulative balance [10], other mechanisms than hypocoagulability were identified as risk factors for bleeding events: There is sufficient evidence that endothelial dysfunction, renal failure, bacterial infections, and hemodynamic alterations due to portal hypertension could act as potential factors to impair the hemostatic state [11][12][13].Therefore, the importance of clinical signs and symptoms as risk factors for hemorrhage in cirrhotic patients should not be underestimated.Overall, the coagulation system in cirrhotic patients, in particular in the decompensated state, seems more fragile than in healthy subjects as its ability to tolerate impairments is decreased; hemorrhage and thrombosis are the results of this deficiency [4].The European Association for the Study of the Liver (EASL) estimates the risk of deep vein thrombosis and pulmonary embolism in patients with liver cirrhosis to be at least as high as in the general population [14].In fact, a number of studies and reviews showed an increased risk of venous thromboembolism in patients with liver cirrhosis [6,15,16].Within the cirrhotic cohort, patients with nonalcoholic steatohepatitis (NASH) as an underlying etiology of tissue remodeling seem to be at particularly high risk, as the disease is a hypercoagulable state and was identified as an independent risk factor for venous thromboembolisms [17].Considering the rising prevalence of NASH worldwide [18], management of thromboembolic complications might become an even more significant matter in the future treatment of end-stage liver diseases.In the following, we want to shed light on different anticoagulant substances in liver cirrhosis and therapeutic options for cirrhotic patients in common clinical indications.

Anticoagulant Therapeutics
Low Molecular Weight Heparin and Unfractionated Heparin Low molecular weight heparin (LMWH) acts by binding antithrombin (AT), leading to an inhibition of factor X and, therefore, a suppressed conversion of factor II to its activated version, factor IIa [19].It is administered subcutaneously once or twice a day, for thromboprophylaxis in a fixed dose and for therapeutic purposes in a weight-adjusted dose.There is plenty of clinical experience with heparins as a prophylactic treatment; dosing regimens are clearly defined, and previous studies confirmed the safety in patients with advanced liver diseases [20].However, in comparison to other anticoagulants, decreased levels of antithrombin in liver cirrhosis may lead to a reduced efficacy of the substance in these patients [21].In addition, LMWH is considerably more expensive than other anticoagulant medications [22].In a long-term perspective, its parenteral application might also have an impact on patients' compliance and outcome.A recurrent comorbidity of advanced liver diseases is impaired renal function [23].In patients with renal diseases, a dosage reduction adjusted to the glomerular filtration rate or a replacement of LMWH with unfractionated heparin (UFH) should be evaluated.In contrast to the use of LMWH, where monitoring is only recommended in patients with obesity, pregnancy, or renal insufficiency, the use of UFH always requires regular laboratory monitoring with partial thromboplastin time (PTT) and/or anti-Xa activity [24].Other disadvantages that one should take into consideration are potential side effects of UFH such as osteoporosis and the risk of heparin-induced thrombocytopenia (HIT) [25].A directive that should be applied in every cirrhotic patient with any form of planned anticoagulation is that bleeding risk should be diligently checked and a prophylaxis for gastrointestinal bleeding should be established; beta-blockers as well as endoscopic band ligation are reasonable options for this purpose [25].

Vitamin K Antagonists
The anticoagulant effect of vitamin K antagonists (VKA) is based on an inhibition of vitamin K epoxide reductase complex subunit 1 (VKCOR1), which results in lower plasma levels of vitamin K required for vitamin-Kdependent clotting factors in coagulation [26].This leads to the advantageous consequence that VKA activity can be antagonized by administration of vitamin K [27].Before the introduction of direct oral anticoagulants (DOAC), VKA as warfarin and phenprocoumon were considered the standard for oral anticoagulation.However, they are associated with a number of major disadvantages: first, frequent laboratory monitoring of INR with a target value of 2-3 is necessary during admission of VKA [28].Adjusted to the INR result, the dosage of warfarin or phenprocoumon is adapted to reach the relatively narrow therapeutic range of the substances.As patients with advanced liver diseases often present an elevated INR at baseline, finding the correct dosage can be challenging [21].Moreover, the INR scale is, by defini-tion, only valid for patients receiving VKA without an additional coagulation disorder [29].The result of suboptimal dosing of VKA is an elevated risk for thrombotic events in this patient group.Besides challenges in laboratory surveillance during VKA therapy, numerous drug-and food-interactions between VKA and other substances have been identified [30,31].

Direct Oral Anticoagulants
Over the past few years, direct oral anticoagulants (DOACs) have been introduced into clinics.The group contains the direct thrombin inhibitor dabigatran and three factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) blocking the active site of their respective target enzyme [32].DOACs are administered orally in a fixed dose, and unlike VKA, they do not require consistent coagulation monitoring as they provide a wider therapeutic window [33].Therefore, the questionable validity of INR in patients with liver diseases should have a lower impact on therapeutic effectiveness.Moreover, no bridging period with heparin is necessary [33], and drugs from the DOAC group show a rapid mode of action [34].Another advantage is that the use of DOAC is associated with a lower risk of drugdrug interaction [33].In addition, neutralizing agents are available as potential countermeasures in bleeding episodes [35].Antagonizing dabigatran is possible with the antibody fragment idarucizumab; the effect of DOAC targeting factor Xa can be reversed with prothrombin complex concentrate or (partly) with andexanet alpha [36].Given the named advantages, the use of direct oral anticoagulants is recommended as a first-line treatment in the management of atrial fibrillation, deep vein thrombosis, and pulmonary embolism [37,38].Unfortunately, patients with liver cirrhosis were not sufficiently represented in the decisive randomized controlled trials, leading to limited evidence for this collective [37].So far, the few available studies have demonstrated the use of DOAC in prophylaxis and therapy of thrombotic events to be safe and efficient in patients with liver cirrhosis [39,40].Nevertheless, one should note that all substances in the DOAC group undergo hepatic metabolism to a varying extent [41].In case of impaired liver function, consecutive alterations in drug levels and associated bleeding risk should be taken into consideration.Therefore, international guidelines regarding DOAC in cirrhotic patients are based on the Child Pugh scoring system predicting mortality in cirrhotic patients based on liver impairment [42].A generally accepted principle for the majority of DOAC substances including apixaban, dabigatran, and edoxaban is that they can be administered in patients with a Child Pugh A and B cirrhosis, whereas the use in Child C cirrhosis is not recommended [14,21].There are more constraints regarding the use of rivaroxaban, as the substance should be generally avoided in Child Pugh class B and C [21].Besides, rivaroxaban showed higher rates of hepatotoxicity than other DOAC [43].This leads to the assumption that, within DOAC, rivaroxaban could be the least reasonable choice for cirrhotic patients [44].Apixaban owns a more favorable substance profile because its risk of drug-induced liver injury (DILI) is lower [45] and there is less impact of hepatic injury on its pharmacodynamics [44].More prospective studies are necessary to facilitate the administration of DOAC in this vulnerable patient cohort.A brief comparison of the described anticoagulant classes with advantages and disadvantages in liver cirrhosis can be found in Figure 2.

Deep Vein Thrombosis
Deep vein thrombosis and pulmonary embolism are common conditions in hospitalized patients and lead to a substantial global disease burden [46].According to the guidelines of the European Association for the Study of the Liver (EASL), the risk of developing thrombotic events in patients with liver cirrhosis is estimated to be at least as high as in the general population [14].In fact, case-controlled studies indicated that peripheral venous thromboembolisms also occur in hospitalized patients with cirrhosis and that traditional laboratory markers such as INR did not act as useful predictive markers for these events [7,47].Although these findings emphasize the relevance of thromboprophylaxis, the administration of prophylactic anticoagulation in hospitalized cirrhotic patients has been assessed as suboptimal [48].The generally recommended substances for prophylactic anticoagulation by the American Society of Hematology are parenteral anticoagulants such as LMWH, UFH, and fondaparinux with a preference to LMWH in critically ill patients [49].For the acute phase treatment of deep vein thrombosis, LMWH, UFH, fondaparinux, and DOAC are available options [50].According to EASL, thromboprophylaxis with LMWH in patients with liver cirrhosis can be recommended as the substance shows an adequate safety profile without an increased risk for gastrointestinal bleeding [14].The administration of DOAC in thromboprophylaxis can be recommended in patients with Child Pugh class A and B, whereas the use of the substances is not recommended in Child Pugh C cirrhosis [14].Those limitations are based on the fact that several steps in DOAC pharmacokinetics (e.g., plasma protein binding and cytochrome-mediated metabolism) could be influenced by impaired liver function [41].For the treatment of deep vein thrombosis, similar suggestions can be found: due to the monitoring issues with the INR values mentioned above, VKA should be used with caution in the treatment of venous thrombosis; their administration is only reasonable in Child Pugh class A [14].As stated by the EASL, therapeutic administration of DOAC can be considered safe in patients with compensated cirrhosis in Child Pugh stage A [14].However, they should be used with caution in Child Pugh class B patients with impaired liver function and should rather be avoided in patients with severe liver dysfunction (Child Pugh C patients) [21].

Portal Vein Thrombosis
Portal vein thrombosis is a frequently occurring event in patients with liver cirrhosis [51].It is often asymptomatic but can favor a tendency towards decompensation events such as variceal bleeding [52].In this group of high-risk patients, the presence of portal vein thrombosis seems to be associated with a higher risk of endoscopic bleeding control failure [53].Besides, studies indicated that occlusive thrombosis of the portal vein leads to increased mortality both in patients with liver cirrhosis and in patients with liver cirrhosis in the follow-up phase after liver transplantation [54,55].To this regard, recanalization of the portal vein should be an objective to improve the prospect of liver transplantation and the general clinical outcome in these patients.According to international consensus, anticoagulation should be established in patients with liver cirrhosis and a recently (<6 months) diagnosed portal vein thrombosis with complete or partial occlusion of the portal vein trunk, in any case with a symptomatic portal vein thrombosis, and in patients who are potential candidates for liver transplantation [56].In cirrhotic patients with minimally occlusive thrombosis (<50% of the lumen), the administration of anticoagulant substances should be taken into consideration if the thrombosis either shows progress within 1-3 months or if the thrombus is spreading in the superior mesenteric vein [56].Recommendations on anticoagulation in portal vein thrombosis by the Baveno VII consensus are summarized in Figure 3. Anticoagulation should be maintained for at least 6 months in a therapeutic dose [25], as recurrence of the thrombosis was reported in cases where the administration was discontinued too early [57].Lifelong anticoagulation should be taken into account in patients with superior mesenteric vein thrombosis, with intestinal ischemia in their medical history and in liver transplant candidates [25].Regarding the optional substances, initiation of anticoagulation should be performed with LMWH, whereas VKA, LMWH, or DOAC are recommended for maintaining the anticoagulant therapy [56].A recent meta-analysis analyzed in total 500 patients with liver cirrhosis and portal vein thrombosis who were anticoagulated with LMWH or VKA and reported that anticoagulation reduced the allcause mortality in that patient cohort [58].In cases of insufficient responses to anticoagulation, the placement of a transjugular intrahepatic portosystemic shunt (TIPS) should additionally be considered as a treatment option in liver transplantation candidates [25].The necessity of anticoagulation or antiplatelet therapy after TIPS procedure remains controversial.There are studies which could demonstrate a beneficial effect of the administration of aspirin in terms of post-TIPS survival [59].Nevertheless, with the occurrence of polytetrafluoroethylene (PTFE)-covered stents, the general rate of shunt dysfunction was observed to be lower [60,61].At present, a general clinical recommendation regarding Fig. 3. Baveno VII consensus on anticoagulation in portal vein thrombosis [56].
anticoagulation or antiplatelet therapy after TIPS implantation cannot be provided yet [62].As shown by Villa et al. [63] in 2012, improvement of outcome in cirrhotic patients can also be achieved by prevention of portal vein thrombosis.In their study, the use of enoxaparin reduced the risk of portal vein thrombosis and liver decompensation and led to an increase in liver function and overall survival.Hence, survival benefit of portal recanalization and prevention of portal vein thrombosis could be confirmed by previous studies.

Atrial Fibrillation
Atrial fibrillation is the most common cardiac arrhythmia in adult patients [64].Initiation of an anticoagulation regime in liver cirrhosis is perceived as a challenging task because presence of an advanced liver disease is one of the main risk factors for bleeding [65,66].An example for the impact of hepatic function on therapeutic decisions is the HAS-BLED score, which includes advanced liver disease as an independent risk factor for bleeding in atrial fibrillation and which should be calculated before establishing oral anticoagulation [66].After calculating the CHA2DS2-VASc-Score and the HAS-BLED-Score to select suitable candidates for anticoagulation, DOACs are recommended as first-line treatment for stroke prevention [37].Patients with mechanic heart valves or a moderate to severe mitral stenosis form an exception to this standard because, in those cases, VKA are recommended in preference to DOAC [37].Although again, data are only sparse for patients with liver cirrhosis, observational data [40] and recent cohort studies [39,67,68] reported that DOAC are a safe and effective option in patients with liver cirrhosis and atrial fibrillation.A nationwide retrospective cohort study could confirm that the use of DOAC in cirrhotic patients showed a comparable risk of stroke and intracranial hemorrhage but a lower risk of gastrointestinal bleeding compared to warfarin [39].This leads to the assumption that cirrhotic patients with atrial fibrillation also benefit from oral anticoagulation and that a decrease in stroke risk outweighs a possible bleeding risk [37].

Management in Variceal Bleeding
A clinical constellation that could potentially be complicated by the use of anticoagulant agents is acute variceal bleeding.In studies which evaluated this issue, comparing patient cohorts with and without anticoagulant therapy, there was no difference in the risk for postprocedural bleeding after endoscopic band ligation [69][70][71].In the analyzed patient cohorts, this could be shown for the use of LMWH and VKA.Another important finding was that the use of anticoagulation did not have an impact on the risk for treatment failure [70].
Nevertheless, whenever anticoagulant therapy is planned to be initiated in cirrhotic patients with vascular diseases, screening for esophageal varices and implementing a bleeding prophylaxis are important steps [25].Both endoscopic band ligation and beta-blocker treatment are appropriate options for bleeding prophylaxis [25].This leads to the general question of how to deal with anticoagulant and antiplatelet medication in cirrhotic patients undergoing invasive procedures: The EASL recommends to follow the same approach as in normal patients, regardless of the presence of liver disease [14].In that respect, multiple factors such as bleeding risk, thrombotic risk, and the underlying disease should be included in the pursuing procedures.

Conclusion
Patients with advanced liver diseases appear to be a challenging subgroup in the management of hemorrhage and thrombosis.Standard laboratory parameters did not turn out to be reliable markers, neither for the patients' coagulative status nor for the risk of thrombotic events.In fact, common laboratory diagnostics might even lead to the misjudgment of underestimating the increased risk of thrombotic events in liver cirrhosis.Clinical symptoms, current risk factors, and medical history should play the leading role in evaluating the risk for bleeding events or thrombosis.In contrast to the former perception, patients with advanced liver diseases are not "auto-anticoagulated" and should receive suitable anticoagulant therapy if the indication is present.Anticoagulation can preferably be performed with DOAC or LWMH, although the available data are not extensive and further randomized trials are needed, especially on the administration of DOAC.Despite their increasing application in anticoagulant therapy, it should be noted that in Child B cirrhosis, DOAC should only be used with caution and that they should be avoided in patients with severe impairments of hepatic function.After establishing a bleeding prophylaxis, the implementation of antithrombotic therapies can be a reasonable procedure.Recanalization of portal vein thrombosis can be cited as an example for the gained clinical benefit of anticoagulation.As in all patients with chronic progressive diseases, for the final decision-making regarding the preferential treatment multiple factors including hepatic and renal function, data on efficiency, safety profile, and clinical experience should be considered.consultant for AbbVie, Aligos Therapeutics, Altimmune, Astra Zeneca, Biotest AG, Bristol-Myers-Squibb, BTG Pharmaceuticals, Dicerna Pharmaceuticals, Eisai, Enanta Pharmaceuticals, Dr. Falk Pharma, Falk Foundation, Gilead, Intercept Pharmaceuticals, Janssen, Merck KGaA, MSD Sharp & Dohme GmbH, MYR GmbH, Norgine, Pfizer Pharma GmbH, Roche, and Vir Biotechnology.H.W. receives research grants from AbbVie, Biotest AG, and Gilead.B.M. serves as a consultant and speaker for MSD, Falk, AbbVie, Astellas, Fortbildungskolleg, Medical Tribune, Luvos, Roche, Norgine, Gilead, and Fujirebio and receives research funds from Fujirebio, Altona Diagnostics, Roche, and EWIMED.No other potential conflict of interest relevant to this article was reported.

Fig. 1 .
Fig. 1.Examples of anti-and prohemostatic factors with decreased levels in advanced liver diseases.Created with BioRender.com.

Fig. 2 .
Fig. 2. Advantages and disadvantages of common anticoagulant substances in liver cirrhosis.