Available online at www.sciencedirect.
com Current Opinion in
ScienceDirect
When and how to use direct oral anticoagulants in
patients with advanced chronic liver disease?
Costanza De Maria1, Antonio Galante1, Alberto Fasoli1 and
Andrea De Gottardi1,2
Abstract
Direct oral anticoagulants (DOACs) emerged as effective and
safe alternatives to traditional anticoagulants for the prevention
and treatment of venous thromboembolic disease and the
prevention of stroke in non-valvular atrial fibrillation. Patients
with advanced chronic liver disease (ACLD) have a higher risk
of thromboembolism and bleeding than patients with normal
liver function. Therefore, anticoagulation and, in particular,
direct oral anticoagulants play a central role. Portal vein
thrombosis is a relatively frequent complication in patients with
ACLD, but its treatment remains challenging. DOACs have
been introduced in clinical practice and demonstrated similar
efficacy and safety profiles compared with vitamin K antagonist
and heparins. However, further data about the use of DOACs
in patients suffering from ACLD are needed. This review
summarizes current knowledge in terms of anticoagulation in
patients with ACLD and focuses on the available data about
the use of DOACs in this population.
Addresses
1
Gastroenterology and Hepatology, Ente Ospedaliero Cantonale,
Switzerland
2
Facoltà di Scienze Biomediche, Università Della Svizzera Italiana,
Lugano, Switzerland
Corresponding author: De Gottardi, Andrea (andrea.degottardi@usi.ch)
Current Opinion in Pharmacology 2021, 60:111–116
This review comes from a themed issue on Gastrointestinal
Edited by Jef Verbeek and Emmanouil Tsochatzis
For a complete overview see the Issue and the Editorial
https://doi.org/10.1016/j.coph.2021.07.006
1471-4892/© 2021 Elsevier Ltd. All rights reserved.
Keywords
Direct oral anticoagulants, Chronic liver disease, Bleeding, Thrombo-
embolism, Rebalanced hemostasis.
Introduction
For a long time, advanced chronic liver disease (ACLD)
has been considered a paradigm for acquired bleeding
disorders due to defects in the synthesis of procoagulant
factors and thrombocytopenia. Indeed, it is now well
established that individuals suffering from ACLD
www.sciencedirect.com
Pharmacology
present with various hemostatic abnormalities associ-
ated with both procoagulant and anticoagulant effects
[1,2]. These changes can affect all stages of the hemo-
static process, such as primary hemostasis, coagulation,
and fibrinolysis.
In ACLD, all procoagulant factors decreased except for
factor VIII and von Willebrand factor. However, these
changes are accompanied by a decrease in natural anti-
coagulants such as antithrombin, protein C and S [1] with
altered fibrinolytic mechanisms. Accordingly, recent evi-
dence shows that patients with ACLD are in a state of
hemostatic rebalanced situation, and most of these pa-
tients remain in a precarious state of hemostasis.
A major challenge for health-care providers is to properly
assess laboratory tests for these patients because they
mainly reflect decreased procoagulant proteins. Patients
with ACLD often present with an increased interna-
tional normalized ratio (INR), a prolonged PT and also
thrombocytopenia [3,4].
Therefore, many patients with impaired liver function
due to ACLD are at high risk of thrombosis or have an
indication for anticoagulation, which makes the thera-
peutic decision for the clinician more complex.
This article summarizes currently available knowledge
regarding the use of anticoagulants in patients with
ACLD, with a focus on direct oral anticoagulants
(DOACs).
Hemostatic alterations in patients with
ACLD
Hepatocytes are responsible for the synthesis of the
majority of coagulation factors, including fibrinogen
(factor I), thrombin (factor II), and upstream factors V,
VII, IX, X, and XI. Remarkable exceptions include factor
VIII, produced in endothelial cells, and factor XIII, a-
subunit, produced in megakaryocytes [5].
Platelets (PLTs) contribute to hemostasis in two
different ways. First, they adhere to the walls of the
damaged vessel through interaction with von Willebrand
factor, promoting aggregation and formation of the pri-
mary hemostatic plug. Second, they support thrombin
Current Opinion in Pharmacology 2021, 60:111–116
112 Gastrointestinal
generation through the assembly of activated coagulation
factors on their surfaces. Thrombocytopenia in patients
with ACLD is a common finding that occurs in up to 76%
of patients. It may be due to impaired PLT production,
decreased hepatic synthesis of thrombopoietin, bone
marrow suppression, hepatitis C virus infection, alcohol
use or increased PLT sequestration in the spleen [6].
There is not a strong correlation between thrombocyto-
penia and bleeding risk in ACLD patients, especially for
those patients with PLT counts >50 G/L [7].
The fibrinolytic system is responsible for the dissolution
of the fibrin clot as it converts the proenzyme plas-
minogen to the active enzyme plasmin. This process is
usually regulated by activators such as tissue plasmin-
ogen activator (t-PA), urokinase plasminogen activator,
and activated factor XII. These are opposed to inhibitors
such as t-PA inhibitors, plasmin inhibitor, and thrombin-
activatable fibrinolysis inhibitor. Disruption of this bal-
ance can lead to hyperfibrinolysis or hypofibrinolysis,
respectively, with an increased risk of hemorrhage or
thrombosis, both of which can occur in ACLD [8].
Recent evidence suggests that in patients with ACLD,
the hemostatic imbalance may be shifted
toward prothrombotic changes due to the decrease in
natural inhibitors such as protein S, protein C, anti-
thrombin, and fibrinolytic factors [9]. However, increases
in acute phase reactants, such as plasminogen activator
inhibitor 1 and decreased levels of the VWF-cleaving
protease ADAMTS13, as well as proinflammatory
changes in endothelial cells, may further promote
thrombosis [10].
Anticoagulants and ACLD
Clinical observations indicate that in patients with
cirrhosis, the risk of developing venous thromboembo-
lism is at least as high as in the general population. In
some patients with ACLD, the risk of deep vein
thrombosis and pulmonary embolism (PE) can be even
higher than in the general population. In particular,
portal vein thrombosis (PVT) is a common complication
in patients with cirrhosis, and its prevalence is higher
when the underlying liver disease is advanced [11,12].
Heparins (unfractioned and low-molecular-weight) and
vitamin K antagonists (VKAs) are recommended for
the treatment of deep vein thrombosis (DVT) and
PE in non-cirrhotic patients [13], whereas their use in
patients with ACLD is still a matter of debate. More-
over, the therapeutic approach of PVT in patients with
cirrhosis is usually individualized, and the decision to
treat is taken following a benefit-risk evaluation.
Therefore, it becomes essential to define which
patients with ACLD should undergo anticoagulant
therapy, although this decision remains highly
challenging.
Current Opinion in Pharmacology 2021, 60:111–116
Low-molecular-weight heparins (LMWHs), such as
dalteparin and enoxaparin, are generally preferred to
unfractioned heparins (requiring endovenous adminis-
tration and frequent monitoring) and are commonly
used in the prophylaxis of venous thromboembolic dis-
ease (VTE) in medium and high-risk groups (surgical,
orthopedic, and medical patients), in the treatment of
deep vein thromboses (DVT) and PE [14,15]. They
inhibit the final common pathway of the coagulation
cascade by activating antithrombin III, which binds to
and inhibits factor Xa, preventing the conversion of
fibrinogen into fibrin for clot formation.
In addition to their approved indications in the general
population, heparins are generally selected for the initial
anticoagulation regimen in patients with ACLD and
recent PVT. Available data suggest that in this indica-
tion, they represent a safe and effective treatment
option [16e18]. Indeed, no increased risk of bleeding
was found in patients with ACLD treated with LMWHs
[19,20], with LMWHs being safer than unfractioned
heparins [21]. In addition, Villa et al. [20] demonstrated
that patients with advanced cirrhosis, defined as Child-
Pugh-Turcotte class B7 to C10, treated with enoxaparin,
had a significantly lower incidence of PVT. Noteworthy,
patients treated with enoxaparin had lower rates of liver
decompensation (11.7 vs 59.4%, p < 0.0001) and lower
mortality (8/34 vs 13/36), without significantly increased
risk of bleeding, which suggests that enoxaparin may
delay hepatic decompensation and improve survival.
VKAs, including warfarin, acenocoumarol and phenpro-
coumon, have been used in clinical practice since the
50s and act by interfering with the vitamin Ke
dependent, post-translational modification of coagula-
tion factors II, VII, IX, and X, thus inducing an anti-
coagulated state. These drugs have similar indications to
LMWHs, to which prosthetic heart valves are added.
VKAs have a long half-life, a delayed onset of action, and
are reversible with the use of vitamin K. That is why
these compounds have been the drugs of choice for
chronic therapy for many years, by avoiding the need to
use the subcutaneous route of administration of
LMWHs. However, the management of patients under
treatment with AVKs is demanding because of frequent
dose adjustments after INR monitoring and possible
interactions with food and other drugs [22].
Anticoagulation with VKAs in patients with ACLD is
subject to some limitations, basically due to the diffi-
culty of providing reliable INR monitoring in these pa-
tients [18,23]. Nevertheless, in the long-term setting,
they were a frequently chosen therapeutic option for
anticoagulation due to their low cost and oral adminis-
tration. In this context, the use of VKAs in cirrhotic
patients with non-splanchnic VTE or thrombosis of the
spleno-porto-mesenteric axis [17] was associated with
more bleeding complications with respect to the general
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 DOACs in cirrhosis De Maria et al. 113

Table 1

Advantages and drawbacks of available oral anticoagulants (vitamin K anticoagulants versus direct oral anticoagulants).

Features Vitamin K antagonists Direct oral anticoagulants

Experience Long Limited

Safety profile Favorable Favorable (no data in Child-Pugh C)
Renal function Less relevant Caution in renal impairment
Action Prolonged Short
Reversibility Good Good
Monitoring (INR) Needed No monitoring needed
Costs Not expensive Rather expensive
Interactions Antimicrobials, NSAIDS, food NSBB, CNIs, statins

NSAIDs, nonsteroidal anti-inflammatory drugs; NSBB, nonselective beta-blockers; CNIs, calcineurin inhibitors.

population. Therefore, additional data mainly on safety
are needed.
Direct oral anticoagulants
DOACs have been adopted in the last decade as an
alternative to VKAs because of their clinical advantages,
especially their oral administration, which is exempt
from routine INR monitoring (Table 1), and their effi-
cacy in treating thrombosis [24]. These drugs act by
directly inhibiting factor IIa (thrombin), such as dabi-
gatran (Pradaxa) or factor Xa, such as apixaban (Eliquis),
rivaroxaban (Xarelto), and edoxaban (Lixiana). These
medications were approved for the prevention of
thromboembolic events in atrial fibrillation, prevention
of DVT in patients undergoing hip or knee replacement
and in patients hospitalized for acute illness, and finally
as a treatment of VTE or PE and prevention of
recurrence of VTE or PE [25e30]. Notably, in each of
the registration trials, patients with abnormal hepatic
biochemical tests and active or chronic liver disease
were systematically excluded, and in phase III trials for
apixaban, dabigatran, and edoxaban, patients with PLT
count less than 100 G/L were excluded [31].
Data regarding the use of DOACs in patients without
underlying liver disease have confirmed their efficacy and
safety compared with traditional anticoagulants such as
LMWHs or VKAs [32]. However, their use was associated
with a higher incidence of major gastrointestinal bleeding
in various clinical scenarios, highlighting a less favorable
safety profile for rivaroxaban and dabigatran [33,34].
Only a few studies assessed the efficacy and safety of
DOACs in patients with CLD presenting with an

Figure 1

Indication for DOAC therapy

Child Pugh A Child Pugh B Child Pugh C

No dose reduction Dabigatran Rivaroxaban

Apixaban Do not use any DOACs
for any DOACs
Edoxaban

Use with caution Not recommended

Current Opinion in Pharmacology

Recommended monitoring and usage of direct oral anticoagulants (DOACs) in advanced liver disease.

www.sciencedirect.com Current Opinion in Pharmacology 2021, 60:111–116

114 Gastrointestinal
Figure 2
No controindications
Patients with cirrhosis
Child Pugh A
Patients with
GFR > 50 ml/min
A three-color schematic based on liver and renal function to consult before the introduction of direct oral anticoagulants (DOACs).
indication for anticoagulant therapy, including
PVT [35e39]. However, these observational studies
included a low number of patients, had a retrospective
design, and did not involve a control group.
DOACs showed similar efficacy and safety profiles with
similar rates of bleeding complications, as traditional an-
ticoagulants in patients with ACLD with indications for
anticoagulation, including atrial fibrillation, VTE, and
PVT [35e37,39]. Compared with patients receiving
warfarin, cirrhotic patients treated with edoxaban for PVT
achieved complete thrombosis resolution and significantly
impacted thrombosis progression [40]. Similarly, anti-
coagulation with rivaroxaban in acute HCV-related non-
neoplastic PVT was found to be more effective than
warfarin, with an improved short-term survival rate [41].
Although the implementation of DOACs in patients
with cirrhosis is an appealing perspective, these medi-
cations, in addition of being more expensive, require
caution in patients with severe kidney disease and
impaired liver function (Figures 1 and 2). Indeed, the
elimination of DOACs partially depends on renal clear-
ance, and, although data suggest their efficient and safe
use in mild and moderate chronic kidney disease [42],
their dose should be reduced in patients with creatinine
clearance < 30 ml/min. Moreover, their use is not
recommended in Child-Pugh C patients. Indeed, there
is a substantial lack of data from this group of patients, as
they were excluded from clinical trials, because of the
presence of coagulopathy. In addition, the scarcity of
data on hepatic clearance of DOACs in Child-Pugh C
patients, resulting in the risk of drug accumulation and
the possible development of drug-induced liver injury,
makes the use of DOACs in this group of patients haz-
ardous [43].
Thus, current experience with DOACs in patients with
cirrhosis remains scant and is limited to patients with a
Current Opinion in Pharmacology 2021, 60:111–116
Prescribe with caution Not recommended
Patients with Patients with cirrhosis
cirrhosis Child Pugh C
Child Pugh B
*Rivaroxaban:
Patients with patients with
GFR < 30 ml/min Child Pugh B-C
*Dabigatran: Patients with
patients with GFR < 15 ml/min
GFR < 50 ml/min or on dialysis
Current Opinion in Pharmacology
compensated disease with cirrhosis stage Child-Pugh A
or B. In this group of patients, DOACs are increasingly
used in clinical practice [43], although the efficacy and
safety of these anticoagulants may be reduced [44].
However, studies are currently underway and may pro-
vide valuable data regarding the safety of these drugs
and their effect on portal hypertension complications in
patients with ACLD [45].
Furthermore, the risk of bleeding during therapy with
DOACs seems similar to the risk during therapy with
VKAs, except for gastrointestinal bleeding, which is
higher in patients treated with DOACs [46]. Bleeding
complications can be controlled by stopping DOACs in
case of minor bleedings. Nevertheless, in case of an
urgent need for reversal strategies, such as in life-
threatening bleedings or when urgent invasive proced-
ures are required, antidotes to DOACs are available and
effective. In this regard, idarucizumab, andexanet alfa,
and ciraparantag were developed as reversal agents for
the DOACs. To date, idarucizumab, a specific antidote
for dabigatran, and andexanet alfa, a reversal agent for
the factor Xa inhibitors, have been approved [47e49].
Still, postmarketing surveillance will be needed to
better determine their clinical utility, even considering
the cost of these therapies and the lack of data in cat-
egories of patients with altered coagulation balance,
such as in patients with ACLD.
Conclusions
Currently available data from observational studies
suggest that DOACs may be an effective and safe
alternative to traditional anticoagulation for patients
with ACLD. The choice of the type of anticoagulation in
this population remains challenging. The use of DOACs,
particularly in more advanced stages of the disease,
should result from an individualized evaluation focused
on appropriate assessment of both thromboembolic and
bleeding risk and renal function. While additional
www.sciencedirect.com

prospective studies are needed to better assess the ef-
ficacy and safety of DOACs in patients with ACLD,
their use should be limited to patients with moderate
impairment of the liver (Child-Pugh stage A-B) and
renal function (creatinine clearance > 30 mL/min).
Credit author statement
Costanza De Maria: Conceptualization; Data curation;
Methodology; Visualization; Writing e original draft;
Writing e review & editing.
Antonio Galante: Conceptualization; Data curation;
Methodology; Visualization; Writing e original draft;
Writing e review & editing.
Alberto Fasoli: Data curation; Project administration;
Supervision; Validation; Writing e review & editing.
Andrea De Gottardi: Conceptualization; Resources;
Supervision; Visualization; Roles/Writing e original
draft; Writing e review & editing.
Conflict of interest statement
Nothing declared.
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