medicina

Review
Oral Anticoagulation in Patients with Chronic Liver Disease
Raluca S. Costache 1, * , Andreea S. Dragomirică 2 , Bogdan E. Gheorghe 2 , Vasile D. Balaban 1 ,
Silviu M. Stanciu 1, *, Mariana Jinga 1 and Daniel O. Costache 3

1 Internal Medicine and Gastroenterology Discipline, Carol Davila University of Medicine and Pharmacy,
7000 Bucharest, Romania
2 Gastroenterology Department, Carol Davila University Central Emergency Military Hospital,
7000 Bucharest, Romania
3 Dermatology II Discipline, Carol Davila University of Medicine and Pharmacy, 7000 Bucharest, Romania
* Correspondence: raluca.costache@umfcd.ro (R.S.C.); silviu.stanciu@umfcd.ro (S.M.S.)

Abstract: The administration of an anticoagulant in patients with liver disease (nonalcoholic

steatohepatitis—NASH, nonalcoholic fatty liver disease—NAFLD, chronic hepatitis, or cirrhosis)
who have an indication (atrial fibrillation, venous thrombosis, or pulmonary embolism) is challenging
because there is an imbalance between thrombosis and bleeding. There is a need to focus our attention
on preventing risk factors because diabetes, obesity, dyslipidemia, smoking, and sedentary behavior
are risk factors for both NASH/NAFLD and AF, and these patients require anticoagulant treatment.
Patients with advanced liver disease (Child–Pugh C) were excluded from studies, so vitamin K
antagonists (VKAs) are still recommended. Currently, VKAs are recommended for other conditions
(antiphospholipid syndrome, mitral valve stenosis, and mechanical valve prosthesis). Amongst the
patients under chronic anticoagulant treatment, especially for the elderly, bleeding as a result of the
improper use of warfarin is one of the important causes of emergency admissions due to adverse
reactions. DOACs are considered to be efficient and safe, with apixaban offering superior protection
against stroke and a good safety profile as far as major bleeding is concerned compared to warfarin.
DOACs are safe in the Child–Pugh A and B classes (except rivaroxaban), and in the Child–Pugh C
class are contraindicated. Given that there are certain and reliable data for chronic kidney disease
regarding the recommendations, in liver function impairment more randomized studies must be
carried out, as the current data are still uncertain. In particular, DOACs have a simple administration,
minimal medication interactions, a high safety and effectiveness profile, and now a reversal agent is
Citation: Costache, R.S.; Dragomirică, available (for dabigatran and idarucizumab). Patients are also statistically more compliant and do
A.S.; Gheorghe, B.E.; Balaban, V.D.; not require INR monitoring.
Stanciu, S.M.; Jinga, M.; Costache,
D.O. Oral Anticoagulation in Patients Keywords: liver disease; VKAs; DOACs; atrial fibrillation; venous thrombosis
with Chronic Liver Disease. Medicina
2023, 59, 346. https://doi.org/
10.3390/medicina59020346

Received: 15 January 2023 1. Introduction

Revised: 8 February 2023 In the USA, thrombosis is a conductive factor in increased morbidity and mortality
Accepted: 10 February 2023 and it is involved in the etiology of important disorders, especially in ischemic stroke,
Published: 12 February 2023 venous and/or arterial thromboembolism (VTE), and cardiac arrest. For many years,
warfarin has been used for the management and prophylaxis of venous thrombosis and
ischemic stroke in patients with atrial fibrillation (AF), which is the most frequent cardiac
rhythm disorder [1]. After 50 years, warfarin continues to be one of the most common oral
Copyright: © 2023 by the authors.
anticoagulants (OAC) for VTE, stroke prevention in patients with AF, and for patients with
Licensee MDPI, Basel, Switzerland.
This article is an open access article
mechanical heart valves [2]. However, an observational study of more than three million
distributed under the terms and
patients with non-valvular atrial fibrillation concluded that VKA use had declined from
conditions of the Creative Commons 2010 to 2017, while DOAC use had significantly increased in those patients [3]. One of the
Attribution (CC BY) license (https:// major causes of liver function impairment is nonalcoholic fatty liver disease (NAFLD), often
creativecommons.org/licenses/by/ leading to cirrhosis and hepatocarcinoma and is an important risk factor for cardiovascular
4.0/). disease because it fits well among the cardiometabolic risk factors, such as smoking,

Medicina 2023, 59, 346. https://doi.org/10.3390/medicina59020346 https://www.mdpi.com/journal/medicina

Medicina 2023, 59, 346 2 of 13

obesity, dyslipidemia, and diabetes mellitus. The association between AF and NAFLD
(because they have the same risk factors) is common, but using OAC in liver pathology
is complicated because of the lack of evidence; most of them have been disqualified
from clinical trials. The number of patients with NAFLD or nonalcoholic steatohepatitis
(NASH) who require anticoagulation is steadily increasing, making them perfect subjects
for additional investigation examining the effects of long-term anticoagulation, particularly
direct oral anticoagulants (DOACs), on fibrogenesis and portal hypertension.
However, NAFLD is strongly associated with metabolic syndrome and it is a problem
distinguishing which of both entities independently contribute to a procoagulant state. It
seems that NASH, the necro-inflammatory form of NAFLD, contributes significantly and
independently to procoagulant and prothrombotic states. Therefore, this evidence shows
the benefits of the assessment of the prothrombotic and procoagulant risk factors in chronic
liver diseases, particularly in NAFLD [4].
Some studies have demonstrated the association between NAFLD and the risk of
stroke. It seems that the risk of stroke gradually increases with an increase in the fatty liver
index, which is why patients with NAFLD should be counseled and carefully monitored
for the risk of stroke [5]. Additionally, other studies have shown that NAFLD was inde-
pendently associated with a higher risk of incident AF, which is accentuated in individuals
with low and normal weight [6].
Papatheodoridis et al. demonstrated in their study that thrombotic risk factors are
frequently detected in patients with chronic viral hepatitis and more extensive fibrosis and
advanced stages are associated with at least one of the significant factors [7].
Regarding patients with cirrhosis, DOACs can be used safely except for in Child–
Pugh C cirrhosis. Portal vein thrombosis (PVT), one of several indicators of progressive
liver disease, is a common complication in cirrhosis that needs anticoagulation. Another
indication for anticoagulation therapy in these patients is the prevention or treatment of
liver fibrosis [8,9].
This review presents the safety and potency of DOACs in mild–moderate hepatic
impairment liver function. Even though the actual guidelines recommend DOACs in
chronic liver disease, there is not sufficient data, which is why more perspective and solid
reports are needed [10].

2. Indications for Oral Anticoagulation

The general evidence for prescribing OAC are the following: valvular and non-valvular
atrial fibrillation for the prevention of ischemic stroke and mechanical valve (indication for
using warfarin with an international normalized ratio (INR) target between 2–3, increased
in mechanical valves). For nonvalvular atrial fibrillation, deep vein thrombosis, pulmonary
embolism, and VTE prophylaxis in orthopedic surgery DOACs or warfarin are used [11].
Management of anticoagulated patients with liver disorders is difficult because of an
increased risk of bleeding (correlated with a reduction in synthetic liver functions in cases
of progressive liver disease, varicose lesions, and thrombocytopenia) and also a higher
ischemic risk. In recent research, patients with AF with liver cirrhosis had no improve-
ment in hemorrhagic events on using DOACs in contrast with VKAs. DOACs are not
recommended for patients with Child–Pugh cirrhosis, and rivaroxaban is contraindicated
for Child–Pugh B or C patients [12]. Apixaban and rivaroxaban have shown pharmacoki-
netic characteristics similar to non-hepatically unhealthy patients for individuals with
Child–Pugh Class A and B. Each DOAC has a different hepatic excretion rate (20 percent
for dabigatran, 65 percent for rivaroxaban, 50 percent for edoxaban, and 75 percent for
apixaban), but warfarin has a 100 percent hepatic excretion rate, implying more predictable
pharmacokinetics for DOACs in liver cirrhosis [10,13]. In addition, INR is a less accurate
monitoring indicator in hepatic dysfunction due to metabolic alterations in coagulation
factors synthesis. Despite being hypercoagulable, cirrhotic individuals have elevated serum
INRs, which could lead to a misleading identification of therapeutic warfarin anticoagula-
tion despite sub-therapeutic dosages. Even though these obstacles appear to favor DOACs,
Medicina 2023, 59, 346 3 of 13

anticoagulation with warfarin is still preferable in hepatic dysfunction due to its ability to
be managed and adjusted appropriately, in contrast to DOACs, which lack a defined and
proven to-measure criterion [10].

3. Warfarin in Liver Disease

Participants with hepatic disease had higher risks of ischemic stroke and deep venous
thrombosis than patients without liver disease, according to some observational studies
throughout the general population [14]. The presence of liver cirrhosis was independently
related to a greater risk of ischemic stroke in a retrospective study of 289,559 individuals
with AF from Taiwan’s National Health Insurance Research Database, compared to patients
without liver cirrhosis [15].
Furthermore, a meta-analysis of nine observational studies indicated that individuals
with liver disease have a 2.5-fold increased risk of ischemic stroke than those without liver
disease [16]. Ischemic stroke in individuals with liver function impairment is a predictor of
poor prognosis and is linked to a greater risk of mortality in the hospital.
Patients with chronic liver disease have an increased risk of portal vein thrombosis
(PVT) due to poor flow in the splanchnic veins, intra-abdominal infections, malignancy,
inflammation, and compression from secondary splenomegaly and ascites, concerning
the risk of deep vein thrombosis and pulmonary embolism. PVT is the most common
thrombotic presentation in individuals with liver damage, according to research, with a
frequency of 8% to 18% in patients with liver cirrhosis, and it is a sign of poor outcomes.
PVT developed in 11% of subjects after 5 years and was linked to the existence of advanced
liver disease symptoms such as esophageal varices and hepatic coagulopathy [17].
Even with its limited therapeutic range, warfarin is difficult to employ in regular med-
ical care, especially in patients with chronic liver disease. However, due to its metabolism
via the cytochrome P450 enzymes, warfarin is susceptible to severe drug–drug interactions,
resulting in supra-therapeutic or sub-therapeutic international normalized ratio (INR) lev-
els. This trait can be harmful in patients with hepatic dysfunction, who are at a higher risk
of bleeding and thrombosis.
When compared with individuals without liver diseases, patients with liver disease
had a shorter mean duration in the therapeutic range, which has been linked to a 2-fold
increase in the risk of bleeding. In individuals with liver illness, additional parameters such
as albumin and glomerular filtration rate may have a major impact on this incidence [18].
Warfarin was linked to a 24 percent decreased incidence of ischemic stroke when
compared to no antithrombotic medication in a statistical model study of 10,336 individuals
with liver fibrosis and a CHA2DS2-VASc score of 2 in Taiwan [15].
Early administration of warfarin was substantially linked to recanalization of the
portal vein in a case study of 55 individuals with cirrhosis and secondary PVT. On the
other hand, anticoagulation with warfarin was linked to gastrointestinal hemorrhage in
five individuals (9%) due to the larger varices [19].
Even though warfarin has been shown in randomized trials of patients with AF and
VTE to reduce the risk of thromboembolism in patients with impaired liver function, it
has several limitations in medical practice, including the need for frequent INR measure-
ment, interactions with food and prescription drugs, phenotypic variation in reaction, and
increased rates of intracerebral hemorrhage and death, especially in contrast to DOACs [10].
Even apart from patients with liver diseases, bleeding as a result of warfarin’s improper
use is one of the important causes of emergency admissions due to adverse reactions among
patients under chronic anticoagulant treatment, especially in the elderly [20,21].

4. DOACs in Liver Disease

Patients with hepatic function impairment may not be the optimal candidates for these
medicines since there is no good monitoring measure to check indicators for their safety.
The Child–Pugh grading system and selection criteria used in pivotal studies are used to
limit the use of DOACs in individuals with hepatic impairment. In patients with severe
Medicina 2023, 59, 346 4 of 13

hepatic disease, all DOACs are contraindicated, and warfarin is the only anticoagulant
approved for these patients [22]. In patients with modest hepatic impairment, dabigatran,
apixaban, and edoxaban are acceptable alternatives that do not require dosage changes.
Due to a lack of data, the best anticoagulation approach for these patients is unknown,
hence blood tests to assess liver function and coagulation parameters should be obtained
before starting and frequently following DOAC medication [23].

Recommendations for the DOACs Due to the Severity of Liver Disease

For Child–Pugh A, there is no dosage reduction for dabigatran, rivaroxaban, apixaban,
edoxaban, or betrixaban. Dabigatran, apixaban, edoxaban, and rivaroxaban should be
used with attention to usage for Child–Pugh B (betrixaban—not applicable (NA)), and
contraindication for all of these drugs is indicated in Child–Pugh C (score more than 9)
(rivaroxaban is contraindicated in Child–Pugh B) [23], according to the 2021 European
Heart Rhythm Association Practical Guide for DOACs (Table 1).

Table 1. Oral anticoagulant options related to Child–Pugh classes. Green: no dosage reduction
needed, yellow: careful usage, red: contraindication.

AVKs DOACs
Dabigatran, Rivaroxaban,
Child–Pugh A Warfarin Apixaban, Edoxaban,
Betrixaban
Dabigatran, Rivaroxaban,
Child–Pugh B Warfarin
Apixaban, Edoxaban
Dabigatran, Rivaroxaban,
Child–Pugh C Warfarin Apixaban, Edoxaban,
Betrixaban

Most DOACs are exposed to some extent of liver metabolism, particularly cytochrome
p450 enzymes in the case of some DOACs. As a result, compromised liver functions are
thought to increase drug levels and hemorrhage risks.
Patients with current or chronic liver illness were often excluded from large-scale
randomized controlled trials (RCTs). In landmark RCTs, anemia and thrombocytopenia,
both of which are likely to be present in CLD, were also ruled out.
In the ROCKET AF trial, for rivaroxaban, the exclusion criteria (indicators) were acute
or chronic hepatitis, liver cirrhosis, an ALT > 3x upper limit of normal (ULN), or a level of
hemoglobin < 10 g/dL [24].
In the ARISTOTLE trial, for apixaban, the exclusion criteria conditions were AST or ALT 2x
ULN or total bilirubin > 1.5x ULN, hemoglobin < 9 g/dL, or thrombocytopenia < 100.000/mm3 [25].
In the RE-LY trial, dabigatran was ruled out with persistently high levels of ALT or AST, the pres-
ence of hepatitis A, B, or C, anemia (hemoglobin < 10 g/dL), or thrombocytopenia < 100.000/mm3 [26].
In the ENGAGE AF-TIMI 48 trial, when ALT or AST > 2x UL or total bilirubin > 1.5 UL,
anemia (hemoglobin under 10 g/dL), or thrombocytopenia (100.000/m3 ), precaution is
recommended for edoxaban [27].

5. OACs Medication in Liver Disease

Before starting OACs, all patients with or at risk of liver disease might have their liver
function tests, platelet levels, serum creatinine, and coagulation profile evaluated, and the
results should be monitored during therapy. In the context of significant thrombocytopenia
(platelet count levels between 50,000 and 70,000/mm3 ), anticoagulation medication should
be postponed, based on the patient’s thrombotic risk [28].
Before administering OACs, all at-risk patients must be examined for varices and
high-risk abnormalities. Before starting OAC, all individuals with liver disease should
be evaluated for alcohol abuse and, if necessary, they should be provided with cessation
therapy [29].
Medicina 2023, 59, 346 5 of 13

Patients with a significant recent bleeding event, persistent coagulopathy, or clinically

significant hemorrhagic risk (including high-risk esophageal varices) should be given per-
sonalized anticoagulant therapy. Even though warfarin has generally been the therapeutic
option for most patients with hepatic impairment who need OACs, DOACs (without
dosage adjustment) might be a safe option in certain individuals with minimal hepatic
impairment (Child–Pugh A).
In patients with serious hepatic impairment, warfarin seems to be the only OAC
that is advised (Child–Pugh C). When warfarin is not an option, apixaban, dabigatran, or
edoxaban may be cautiously administered in individuals with mild hepatic impairment
(Child–Pugh B). Early collaboration between cardiologists and gastroenterologists should
assist in the optimal use of OACs in patients with chronic liver disease who are already at
high risk of bleeding and thrombosis at the same time [10].
Cirrhotic patients, irrespective of etiology balance between a hypercoagulable and
a hypercoagulable state, are often associated with conditions that require antithrombotic
treatment for prophylactic or therapeutic purposes. Therefore, the clinician often faces seri-
ous challenges in establishing if anticoagulant therapy would bring the patient benefits that
outweigh the bleeding risks. Practice guidelines developed by relevant scientific organiza-
tions try to facilitate the process. For example, the AGA suggests standard anticoagulation
prophylaxis in patients with cirrhosis and who otherwise meet standard guidelines for the
use of VTE prophylaxis over no anticoagulation [30].
Special concerns regarding anticoagulation have been introduced involving patients
with portal vein thrombosis (PVT) and concomitant liver disease [31]. The American
Gastroenterological Association Institute (AGA) suggests against PVT routine screening in
cirrhotic patients, except for candidates for liver transplantation [30].
Historically, research on this topic has been focused on unfractionated heparin, low
molecular weight heparin, and AVKs, but recently there has been increasing interest in
evaluating DOACs as well, thus generating greater complexity of choice between the
available pharmacological agents.
The findings are that the anticoagulated patients with cirrhosis have similar non-
variceal bleeding complication risk to the general population and their bleeding risk related
to portal-hypertensive complications remains unchanged [31]. However, decisions about
initiating anticoagulant therapy should be made in an individualized fashion. Screening
esophagogastroduodenoscopy (EGD) for the diagnosis of esophageal and gastric varices is
recommended when the diagnosis of cirrhosis is made (Class IIa, Level C), so that assess-
ment of high bleeding risk lesions related to portal hypertension is inherently made [29].
However, although recanalization of the portal axis has been observed to occur sponta-
neously in some patients with cirrhosis who develop PVT, there are studies that show anti-
coagulation improves the recanalization rate (42% of patients with anticoagulation therapy
alone and 13% of patients who did not receive anticoagulation or vascular intervention) [31].
Furthermore, the AGA suggests using anticoagulation over no anticoagu-lation for the
treatment of PVT, citing a lack of data supporting one anticoagulant over another [30].
A beneficial approach seems to be waiting a period of time to identify patients with
progressive or persistent PVT before starting anticoagulants. The optimal time for initiation
of therapy is described as being less than 6 months, but individuals may benefit from
earlier initiation as well. In patients with cirrhosis who have recent thrombosis of small
intrahepatic sub-branches of the PV or minimally occlusive (<50% obstruction of the
lumen) thrombosis of the main PV, observation with serial imaging every 3 months without
therapy is reasonable, while recent occlusion or partial occlusion (>50% of the lumen
occluded) requires treatment in order to avoid the progression of portal hypertension and
complicate future liver transplantation. Cavernous transformation of the portal vein with
the development of collaterals does not require anticoagulant. The duration of therapy
with traditional anticoagulation is unclear, and dosing is not standardized.
 occluded) requires treatment in order to avoid the progression of portal hypertension and
complicate future liver transplantation. Cavernous transformation of the portal vein with
occluded) requires treatment in order to avoid the progression of portal hypertension and
the development of collaterals does not require anticoagulant. The duration of therapy
complicate future liver transplantation. Cavernous transformation of the portal vein with
Medicina 2023, 59, 346 with traditional anticoagulation is unclear, and dosing is not standardized. 6 of 13
the development of collaterals does not require anticoagulant. The duration of therapy
Whenever candidates for liver transplantation are involved, anticoagulant therapy
with traditional anticoagulation is unclear, and dosing is not standardized.
may be initiated with the goal of recanalization as a patent main portal vein is associated
Whenever candidates for liver transplantation are involved, anticoagulant therapy
with an increased posttransplant survival rate [31,32].
may be Whenever candidates
initiated with the goalforofliver transplantation
recanalization are involved,
as a patent anticoagulant
main portal therapy
vein is associated
mayan
with beincreased
initiated with the goal ofsurvival
posttransplant recanalization
rate as a patent main portal vein is associated
[31,32].
6. Pharmacology of OACs in Liver Disease
with an increased posttransplant survival rate [31,32].
In the generalofsubset
6. Pharmacology OACsofinpatients with AF and VTE, DOACs have been demonstrated
Liver Disease
to6. decrease
Pharmacology stroke ofand thrombosis
OACs in Liversafely.
Disease Patients with liver impairment, on the other
In the general subset of patients with AF and VTE, DOACs have been demonstrated
hand,In have
the been mostly
general eliminated
subset of patients from
withrandomized
AF and VTE, clinical studies
haveof OACs for stroke
to decrease stroke and thrombosis safely. Patients with DOACs been
liver impairment, demonstrated
on the other
and venous
to decrease thromboembolism
stroke and thrombosis (VTE) prevention. Additionally, because all presently au-
hand, have been mostly eliminatedsafely.
from Patients
randomized with clinical
liver impairment,
studies of on OACsthe other hand,
for stroke
thorized DOACs require extensive hepatic metabolism, liver dysfunction
have been mostly eliminated from randomized clinical studies of OACs for stroke and may result in
and venous thromboembolism (VTE) prevention. Additionally, because all presently au-
higher drug levels, lower coagulation factor levels, and higher bleeding
venous thromboembolism (VTE) prevention. Additionally, because all presently authorized risks. Further-
thorized DOACs require extensive hepatic metabolism, liver dysfunction may result in
more,
DOACs the require
metabolism of several
extensive hepaticDOACs is dependent
metabolism, liveron cytochromemay
dysfunction P450result
enzymes [33],
in higher
higher drug levels, lower coagulation factor levels, and higher bleeding risks. Further-
and
drugthelevels,
activity of these
lower enzymes
coagulation may levels,
factor be altered
and or changed
higher in liver
bleeding disease.
risks. As a result,
Furthermore, the
more, the metabolism of several DOACs is dependent on cytochrome P450 enzymes [33],
the best anticoagulation
metabolism approach
of several DOACs for individuals
is dependent with AF and
on cytochrome VTEenzymes
P450 who also[33],have
andliver
the
and the activity of these enzymes may be altered or changed in liver disease. As a result,
function
activity impairment is complicated
of these enzymes and poorly
may be altered characterized
or changed [10].
in liver disease. As a result, the best
the best anticoagulation approach for individuals with AF and VTE who also have liver
The vitamin K-dependent production of coagulation
anticoagulation approach for individuals with AF and VTE who also have factors II, VII, IX, liver
and Xfunction
in the
function impairment is complicated and poorly characterized [10].
liver is inhibited
impairment by warfarinand
is complicated (Figures
poorly 1 and 2).
characterized [10].
The vitamin K-dependent production of coagulation factors II, VII, IX, and X in the
The vitamin K-dependent production of coagulation factors II, VII, IX, and X in the
liver is inhibited by warfarin (Figures 1 and 2).
liver is inhibited by warfarin (Figures 1 and 2).

Figure 1. Warfarin mechanism of action .

Figure 1. Warfarin mechanism of action.
Figure 1. Warfarin mechanism of action .

Figure 2. DOAC’s mechanism of action.

Figure 2. Warfarin mechanism of action.
Antithrombotic proteins, such as proteins C and S, are also reduced. It has a near-
Figure 2. Warfarin
Antithrombotic
complete mechanism of action.
proteins,
oral bioavailability such
and aasmaximum
proteins C and S,concentration
plasma are also reduced. It has
of 2 to 6 h. aItnear-
has a
complete oralvolume
rather small bioavailability and a(0.14
of distribution maximum
L/kg), plasma concentration
yet it binds of 2 to in
to plasma proteins 6 h. It has a
substantial
Antithrombotic
amounts proteins, such
(99 percent). has aashalf-life
proteins C and 60S,h.areisalso reduced. It has a near-
rather small volume Warfarin
of distribution of 20
(0.14 L/kg), toyet it Itbinds
mostly removed
to plasma by the
proteins liver,
in
complete oral bioavailability and a maximum plasma concentration of 2 to
where it is changed to an inactive metabolite via a cytochrome P450-dependent metabolism 6 h. It has a
rather
and is small volume of
not eliminated by distribution (0.14INR
the kidneys. An L/kg),
of 2.0yet it binds
to 3.0 to plasma
is considered proteins
optimum in
for the
protection of thromboembolic events in the general population, according to AF and VTE
recommendations. Unfortunately, there are no particular guidelines for the use of warfarin
in individuals with liver disease.
Medicina 2023, 59, 346 7 of 13

Patients with liver function impairment had a shorter mean duration in the therapeutic
window, which has been linked to a two-fold increased risk of major bleeding events [33].
Other variables, such as albumin and glomerular filtration rate, may impact this risk.
Warfarin’s safety and effectiveness in preventing thrombotic events have never been studied
in a prospective clinical study [10]. In patients with hepatic disease, warfarin may be
useful in the treatment of portal vein thrombosis (PVT). Anticoagulant medication with
warfarin was found to be effective in a retrospective observational analysis of 28 individuals
with PVT. Keeping the INR between 2.0 and 3.0 resulted in higher rates of portal vein
revascularization and a lower incidence of recurrent thrombosis.
Even though warfarin has been shown in observational studies of patients with AF
and VTE to reduce the risk of thromboembolism in patients with impaired liver function,
it has several drawbacks in medical care, including the need for regular INR checking,
interactions with nutrition and treatments, phenotypic variation in response, and increasing
rates of intracerebral hemorrhage and fatality in comparison with DOACs [10].
Patients with acute liver disease are removed from RCTs, even though DOACs have
become the first-choice medication in the treatment and prevention of stroke-systemic
thromboembolism and VTE. DOACs have a shorter half-life and are less dependent on hep-
atic elimination versus warfarin. These pharmacodynamic features make them appealing
for use in individuals with liver disease as well.
Apixaban and rivaroxaban are mostly removed by the liver (75 and 65 percent, respec-
tively), with edoxaban (50 percent) and dabigatran (20 percent) following closely behind.
These pharmacokinetic qualities can all be influenced to variable degrees by liver disease
illness, so they should be used with caution in patients with impaired hepatic function.
While liver albumin production is altered, several DOACs have a high plasma protein
binding capacity, which can be linked to elevated free drug fraction levels. Apixaban and
rivaroxaban are metabolized primarily by cytochrome P450 enzymes, whose activity is
lowered by liver disease, whereas dabigatran and edoxaban are processed by cytochrome
P450 enzymes to a lesser extent (Table 2). Liver illness reduces the excretion of all DOACs
in the bile. Finally, when liver illness is accompanied by hepatorenal syndrome or other
kidney disorders coexist, renal clearance of DOACs may be compromised [34].

Table 2. Oral anticoagulants and their metabolism pathways.

Hepatic Metabolization (%) Renal Excretion (%)

Warfarin 100% 0
Apixaban 75% 25%
Rivaroxaban 65% 35%
Edoxaban 50% 50%
Dabigatran 20% 80%

Anticoagulant therapy should not be used in patients with Child–Pugh Class C, which
has a 1-year survival rate of less than 50% without a liver transplant. Patients with portal
hypertension, esophageal varices, portal-hypertensive gastropathy, thrombocytopenia,
coagulopathy, bleeding risk, decreased drug metabolism, and reduced glomerular filtration
rate should be investigated [10].

7. The Imbalance between Thrombosis and Bleeding in Liver Disease

Reduced intrinsic anticoagulants and elevated amounts of circulating procoagulants
are linked to a higher risk of thrombosis in patients with hepatic disease. In individuals
with liver function impairment, a reduction in protein C level and antithrombin synthesis
seems to be the main reason for the thrombotic risk. Patients with liver disease are often
more likely to experience thrombosis as a result of increased platelet aggregation caused by
high von Willebrand (vWF) factor activity and low rates of ADAMTS13 (a disintegrin and
metalloprotease with thrombospondin type 1 motif 13), a variable of von Willebrand factor
action [35]. They have a greater affinity for both glycoproteins Ib and collagen; therefore,
Medicina 2023, 59, 346 8 of 13

high-molecular-weight multimers are more effective in promoting hemostasis. Other

proteases, including plasmin or elastase, can also break down vWF in liver disease. vWF’s
multimeric composition is partly influenced by the vWF enzyme that breaks down protease
ADAMTS13 [36]. An INR greater than 2.0 was previously thought to protect against VTE;
however, more recent observations have disproved this theory. This assertion dates back
since studies have shown that even in healthy people, there is a substantial chance risk of
developing VTE. It only evaluates the activity of several procoagulant components (FI, FII,
FV, FVII, and FX), and not the activity of anticoagulant proteins C and S; therefore, INR
does not appear to be a viable tool for monitoring hemostasis in cirrhotic patients.
Specific clotting tests (such as thrombo-elastography) may be able to circumvent and
overcome INR’s diagnostic limitations, but they lack proven target values and are thus not
commonly employed. Using a PTT test to monitor unfractionated heparin (UFH) treatment
presents similar issues to using an INR test to monitor VKAs [22]. All coagulation factors
(apart from factor VIII and von Willebrand factor) are generated in the liver; therefore,
their plasmatic levels are reduced in liver disease, linked to an increased risk of bleeding.
Reduced levels of fibrinogen and factors II, V, VII, and X are reflected in a longer PT, whereas
the lower activity of coagulation factors II, V, IX, X, XI, and XII is reflected in a long-activated
partial thromboplastin time. Increased fibrinolysis has also been linked to liver disease due
to higher levels of tissue plasminogen activator and lower levels of plasmin inhibitor and
thrombin-activated fibrinolysis inhibitor [37]. In a compensated cirrhotic patient, the mix
of these pro-and anti-coagulant elements creates a delicate equilibrium that can be easily
disrupted by any precipitating causes (hepatic decompensation, sepsis, volume status,
renal failure, or invasive procedures) and result in thrombosis or bleeding [38,39].

8. DOACs—Safety, Efficiency, and Risk of Liver Injury, Gastrointestinal Tolerability

The earliest evidence came through retrospective case studies or small cohort studies
that showed DOACs had a lower or equivalent hemorrhagic risk to warfarin in cirrhotic
individuals using anticoagulants for various reasons. The confidence interval of these
investigations, however, did not always provide a sufficient comparison of thrombotic
effects [40]. The American Gastroenterological Association Institute (AGA) suggests using
anticoagulation over no anticoagulation in individuals with cirrhosis and atrial fibrillation
who have a justification for it. Patients with severe cirrhosis (Child–Pugh class C) and/or
low CHA2DS2-VASC scores who place a higher emphasis on avoiding bleeding risk while
taking anticoagulants and a lower value on stroke prevention might opt not to take an-
ticoagulation. There was a decrease in mortality in individuals with cirrhosis and atrial
fibrillation who were given anticoagulation compared to those who were not (RR, 0.72;
95 percent CI, 0.55–0.94). Patients on DOACs had a decreased risk of nonfatal cerebrovas-
cular accident than those taking warfarin (RR, 0.81; 95 percent CI, 0.73–0.91). Patients who
were anticoagulated compared to untreated controls had a greater risk of bleeding (RR,
1.91; 95 percent CI, 1.85–2.26), while the risk was decreased in patients receiving DOACs
compared to VKAs (RR, 0.62; 95 percent CI, 0.45–0.85). Similar trends were observed when
comparing the incidence of intracranial hemorrhage in patients receiving VKAs to the con-
trol group (RR, 3.5; 95 percent confidence interval, 3.30–4.0) with a reduced rate in patients
treated with DOACs versus VKAs (RR 0.7; 95 percent confidence interval, 0.58–0.84). In
patients with liver cirrhosis and atrial fibrillation with a CHA2DS2-VASC score of 2, the
overall advantages of anticoagulation seem to exceed the risk of hemorrhage [30].
In a recent study called “Direct Oral Anticoagulants in Patients with Atrial Fibril-
lation and Liver Disease”, published by Elsevier in the Journal of the American College of
Cardiology in 2019, DOACs were compared with warfarin in patients with non-valvular
atrial fibrillation and liver disease. The patients were treated with oral anticoagulants
(12,778 with warfarin and 24,575 with DOACs), and the outcomes were studied. Ischemic
stroke, cerebral and gastrointestinal bleeding, severe bleeding, all-cause fatality, and the
composite are all conditions in this situation that can result in death. In patients with AF
and significant liver function impairment, DOACs were linked to a decreased incidence
Medicina 2023, 59, 346 9 of 13

of ischemic stroke, intracerebral bleeding, gastrointestinal bleeding, major bleeding, and

all-cause mortality when compared to warfarin. In general, DOACs outperformed warfarin
in terms of the composite outcome for patients with hepatic diseases, including those with
substantial active liver disease. DOAC efficacy and safety were consistently observed in
diverse high-risk populations, depending on type and dosing regimen [41].
Concerns regarding DOACs causing liver injury originated from ximelagatran, an oral
direct thrombin inhibitor that was widely explored for thromboembolism prophylaxis but
was revealed to cause significant liver harm, and it was never approved in the United States.
In studies of VTE and stroke protection in AF, there was no difference in the frequency of
liver injury comparing warfarin and other DOAC medications. DOAC hepatic safety has
been continuously monitored and reported in clinical practice since its approval by the FDA.
Elevations of liver enzymes have been linked to all DOACs. During a median follow-up of
14 months, there were seven admissions for liver damage per 1000 person-years in a study
of 113,717 patients with AF who were using OACs (50 percent warfarin and 50 percent
DOACs). The risk of liver damage was lower in DOAC users than in warfarin users (nine
vs. five per thousand person-years).
Dabigatran had the smallest relative risk of liver damage of all the DOACs studied. A
meta-analysis of 29 randomized studies comparing DOACs to conventional anticoagulation
medication or placebo found that DOACs did not generate liver-related events [10,42].
Many case studies have revealed potentially fatal liver injuries in people taking ri-
varoxaban or dabigatran. In clinical investigations, the frequency ranged between 0.1 and
1%, and it tended to be lower than enoxaparin or warfarin. The majority of those afflicted
were symptomatic, with hepatocellular or mixed liver damage being the most common.
This liver injury appears to be associated with all currently available DOACs. Patients
should be warned about probable potential symptoms, and these medicines should be
stopped if they have significant liver damage [43].

9. Management of Bleeding in Patients Who Are Taking DOACs.

Therapeutic Methods
The management of bleeding in patients with liver disease who are taking OACs
depends on many factors such as the indication for anticoagulation therapy, the underlying
thrombotic risk, and the severity of bleeding [10]. There are no differences between the
management of bleeding in patients with or without liver disease [44]. Patients with major
bleeding events, such as intracranial hemorrhage, gastrointestinal bleeding, muscle bleeds,
and extensive hematomas, should be admitted for further evaluation and treatment in an
emergency department [45].
According to the 2017 American College of Cardiology expert consensus recommenda-
tions, the reversal of anticoagulation may be lifesaving in individuals with life-threatening
bleeding despite standard measures. Having said that, life-threatening bleeding in patients
with an INR > 2 should be managed with unactivated 4-factor prothrombin complex con-
centrate (PCC) and intravenous vitamin K [46]. As a result of the similar effectiveness and
reduced frequency of side effects, PCC is favored over fresh frozen plasma. Further PCC or
vitamin K needs should be determined based on subsequent INR levels and the patient’s
clinical state [46].
Specific coagulation tests may aid in determining the amount of anticoagulation in
individuals using DOACs. The impact of dabigatran could be measured using thrombin
time and ecarin clotting time, whereas the activity of apixaban, rivaroxaban, and edoxaban
can be measured using a calibrated anti-factor Xa chromogenic test. These tests, however,
are not commonly available and are not always indicated before using reversal drugs [10].
If a patient with liver disease (similar to those without liver disease) experiences major
bleeding within 2 h of ingesting an anticoagulant, they should be treated with activated
charcoal [10]. Idarucizumab (Praxbind), a completely humanized monoclonal antibody
fragment developed to selectively reverse the anticoagulant action of dabigatran, has been
approved by the FDA and EMA as a reversal medication for dabigatran, based on the
Medicina 2023, 59, 346 10 of 13

findings of a phase III trial. Antidotes to DOACs, such as andexanet alfa (a factor Xa mimic)
and ciraparantag (a neutral small molecule that reverses either factor IIa or Xa inhibitors)
are now being investigated as reversal medicines for rivaroxaban and apixaban [2,10]. In
clinical studies, PER977 (Perosphere) is being evaluated as a reversal drug for edoxaban,
with encouraging preliminary findings [2]. In certain persistently bleeding cases of severe
thrombocytopenia, platelet transfusion may be recommended. Proton-pump inhibitors can
be used at the same time with a somatostatin analog such as octreotide to reduce portal
venous pressure. Additionally, antibiotics should be administered as prophylaxis against
spontaneous bacterial peritonitis because it has been shown that administering short-term
prophylactic antibiotics in patients with cirrhosis and gastrointestinal hemorrhage increases
survival and decreases the rate of bacterial infections [47,48]. The recommended antibiotic
is norfloxacin administered orally because it has poor absorption and it is Gram-negative
bacteria selective [44]. To enhance platelet function, desmopressin (an endothelial stimulant
that raises factor VIII and the von Willebrand factor) can be used especially in patients with
liver disease complicated by a hepatorenal syndrome that leads to uremia [10].
Before initiating OACs, all at-risk patients should be checked for esophageal varices
and high-risk lesions, according to the American Association for the Study of Liver Diseases’
recommendations [40]. In a study called “Prevention and Management of Gastroesophageal
Varices and Variceal Hemorrhage in Cirrhosis”, published by the American Journal of Gas-
troenterology in 2007, there were some recommendations for the management of an acute
episode of variceal hemorrhage in patients with cirrhosis. Caution should be taken when
resuscitating the blood volume and the goal is maintaining hemodynamic stability and
a hemoglobin level of approximately 8 g/dL. Vigorous resuscitation should be avoided
with saline solution because this can precipitate the accumulation of fluid at extravascular
sites [44]. A meta-analysis of 15 trials comparing emergency sclerotherapy and pharma-
cological treatment suggested that the first-line treatment of variceal bleeding should be
pharmacological because it has a similar efficacy as sclerotherapy [49].
Before commencing OAC therapy, all patients with liver function impairment should
be evaluated for alcohol abuse issues and given cessation therapy. Patients should be
educated about the potential hazards and advantages of OACs and should be involved in
joint decision-making about their usage and selection. Although warfarin has traditionally
been the drug of choice for most patients with hepatic conditions needing OACs, DOACs
(without dosage modification) might be a safe option for certain individuals with moderate
hepatic function impairment (Child–Pugh A). In cirrhotic patients, warfarin is the only
OAC advised (Child–Pugh C). When warfarin is not an option, apixaban, dabigatran, or
edoxaban may be taken with care in individuals with mild hepatic function impairment
(Child–Pugh B) [40].
Although VKAs are frequently thought to be cheaper compared to DOACs, the total
cost of VKA treatment must account for expenses linked to therapy management in general.
These are examples of routine coagulation monitoring, negative clinical events during
medication (such as hemorrhage and thromboembolic events), and non-adherence [50]. The
estimated mean number of inpatient days, outpatient visits, and AF-related hospitalizations
linked to rivaroxaban are lower in clinical practice than those related to warfarin [51].

10. Conclusions and Future Perspectives

According to the available data, NAFLD and NASH are linked to both AF and VTE,
showing that these individuals are in a procoagulant condition. Cirrhosis, regardless of
the cause, has an unstable hemostatic equilibrium, making anticoagulant therapy diffi-
cult [34]. Finally, real-world evidence suggests that DOACs may be administered safely in
Child–Pugh A cirrhotic patients and carefully in Child–Pugh B patients, with comparable
effectiveness and potentially greater safety than warfarin. Interestingly, rivaroxaban and
edoxaban have been used in Child–Pugh B cirrhotic patients without substantial adverse
effects in several trials, even though they are contraindicated in these patients by the EMA
(European Medicines Agency) and FDA (Food and Drug Administration) [13]. DOACs are
Medicina 2023, 59, 346 11 of 13

a promising alternative for the treatment of AF and VTE in individuals with liver disease,
based on growing real-world evidence demonstrating at least equivalent effectiveness and
improved protection compared to warfarin. Specific reversal medications for all DOACs
are now available for the treatment of bleeding in individuals with liver disease. There is
no evidence that a specific DOAC with a superior efficacy/safety profile should be admin-
istered more frequently in cirrhotic individuals. RCTs on the use of DOACs in cirrhotic
patients are needed [10,31,34]. The CIRROXABAN trial is looking at how rivaroxaban
can help patients with liver disease and portal hypertension prevent thrombotic events.
There is an unmet need for evidence-based and practical data for guiding anticoagulant
therapy [3]. In addition to treatment efficacy and safety, cost-effectiveness is another factor
that healthcare professionals evaluate when making treatment decisions.
Although VKAs are frequently thought to have cheaper costs, while the medicine itself
is less expensive when compared to DOACs, the total cost of VKA treatment must account
for expenses linked to therapy management in general. Routine coagulation monitoring,
negative clinical events during medication (such as hemorrhages and thromboembolic
events), and non-adherence are all examples. The estimated mean number of inpatient
days, outpatient visits, and AF-related hospitalizations linked to rivaroxaban are lower in
clinical practice than those related to warfarin [51].

Author Contributions: Conceptualization, R.S.C. and A.S.D.; methodology, S.M.S. and M.J.; vali-
dation, R.S.C., S.M.S. and D.O.C.; investigation, A.S.D., V.D.B. and B.E.G.; resources, R.S.C., M.J.
and A.S.D.; writing—original draft preparation, A.S.D.; writing—review and editing, R.S.C., S.M.S.,
D.O.C. and B.E.G.; supervision, R.S.C. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations
vitamin K antagonists (VKAs), non-vitamin K antagonists (DOACs), direct oral anticoagu-
lants (DOACs), oral anticoagulants (OACs) nonalcoholic fatty liver disease (NAFLD), nonalco-
holic steatohepatitis (NASH), atrial fibrillation (AF), venous thromboembolism (VTE), antiphospho-
lipid syndrome (APS), mitral stenosis (MS), systemic embolism (SE), American College of Cardiol-
ogy/American Heart Association (ACC/AHA), hazard ratio (HR), gastrointestinal bleeding (GIB),
portal vein thrombosis (PVT), international normalized ratio (INR), alanine transaminase (ALT),
aspartate transaminase (AST), randomized controlled trials (RCTs), the upper limit of normal (ULN),
von Willebrand factor (VWF), unfractionated heparin (UFH), American Gastroenterological Associa-
tion Institute (AGA), European Medicines Agency (EMA), Food and Drug Administration (FDA).

References
1. Milling, T.J.; Frontera, J.A. Exploring Indications for the Use of Direct Oral Anticoagulants. Am. J. Manag. Care 2017, 23 (Suppl. S4),
S67–S80.
2. Zirlik, A.; Bode, C. Vitamin K antagonists: Relative strengths and weaknesses vs. direct oral anticoagulants for stroke prevention
in patients. J. Thromb. Thrombolysis 2017, 43, 365–379. [CrossRef] [PubMed]
3. Vora, P.; Stewart, H.M.; Russell, B.; Asiimwe, A.; Brobert, G. Time Trends and Treatment Pathways in Prescribing Individual Oral
Anticoagulants in Patients with Nonvalvular Atrial Fibrillation: An Observational Study of More than Three Million Patients
from Europe and the United States. Int. J. Clin. Pract. 2022, 2022, 6707985. [CrossRef]
4. Virović-Jukić, L.; Stojsavljević-Shapeski, S.; Forgač, J.; Kukla, M.; Mikolašević, I. Non-alcoholic fatty liver disease—A procoagulant
condition? Croat. Med. J. 2021, 62, 25–33. [CrossRef]
5. Yang, Y.J.; Jung, M.H.; Jeong, S.H.; Hong, Y.P.; Kim, Y.I.; An, S.J. The Association between Nonalcoholic Fatty Liver Disease and Stroke:
Results from the Korean Genome and Epidemiology Study (KoGES). Int. J. Environ. Res. Public Health 2020, 17, 9568. [CrossRef] [PubMed]
Medicina 2023, 59, 346 12 of 13

6. Lee, S.-R.; Han, K.-D.; Choi, E.-K.; Oh, S.; Lip, G.Y.H. Nonalcoholic fatty liver disease and the risk of atrial fibrillation stratified by
body mass index: A nationwide population-based study. Sci. Rep. 2021, 11, 3737. [CrossRef]
7. Papatheodoridis, G.V.; Papakonstantinou, E.; Andrioti, E.; Cholongitas, E.; Petraki, K.; Kontopoulou, I.; Hadziyannis, S.J.
Thrombotic risk factors and extent of liver fibrosis in chronic viral hepatitis. Gut 2003, 52, 404–409. [CrossRef] [PubMed]
8. Turco, L.; de Raucourt, E.; Valla, D.C.; Villa, E. Anticoagulation in the cirrhotic patient. JHEP Rep. 2019, 1, 227–239. [CrossRef]
9. Di Nisio, M.; Valeriani, E.; Riva, N.; Schulman, S.; Beyer-Westendorf, J.; Ageno, W. Anticoagulant therapy for splanchnic vein
thrombosis: ISTH SSC Subcommittee Control of Anticoagulation. J. Thromb. Haemost. 2020, 18, 1562–1568. [CrossRef] [PubMed]
10. Qamar, A.; Vaduganathan, M.; Greenberger, N.J.; Giugliano, R.P. Oral Anticoagulation in Patients with Liver Disease. J. Am. Coll.
Cardiol 2018, 71, 2162–2175. [CrossRef]
11. Oral Anticoagulants. Available online: https://www.amboss.com/us/knowledge/Oral_anticoagulants (accessed on 21 November 2022).
12. Hindricks, G.; Potpara, T.; Dagres, N.; Arbelo, E.; Bax, J.J.; Blomström-Lundqvist, C.; Boriani, G.; Castella, M.; Dan, G.-A.;
Dilaveris, P.E.; et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with
the European Association for Cardio-Thoracic Surgery (EACTS). Eur. Heart J. 2021, 42, 373–498. [CrossRef] [PubMed]
13. Steuber, T.D.; Howard, M.L.; Nisly, S.A. Direct oral anticoagulants in chronic liver disease. Ann. Pharmacother. 2019, 53, 1042–1049.
[CrossRef] [PubMed]
14. Mahfood, H.T.; Hamdeh, S.; Kanmanthareddy, A.; Alla, V.M. Nonalcoholic fatty liver disease and the risk of clinical cardiovascular
events: A systematic review and meta-analysis. Diabetes Metab. Syndr. 2017, 11 (Suppl. S1), S209–S216. [CrossRef] [PubMed]
15. Kuo, L.; Chao, T.; Liu, C.; Lin, Y.; Chang, S.; Lo, L.; Hu, Y.; Tuan, T.; Liao, J.; Chung, F.; et al. Liver Cirrhosis in Patients With Atrial
Fibrillation: Would Oral Anticoagulation Have a Net Clinical Benefit for Stroke Prevention? J. Am. Heart Assoc. 2017, 6, e005307.
[CrossRef] [PubMed]
16. Hu, J.; Xu, Y.; He, Z.; Zhang, H.; Lian, X.; Zhu, T.; Liang, C.; Li, J. Increased risk of cerebrovascular accident related to non-alcoholic
fatty liver disease: A meta-analysis. Oncotarget 2017, 9, 2752–2760. [CrossRef]
17. Nery, F.; Chevret, S.; Condat, B.; de Raucourt, E.; Boudaoud, L.; Rautou, P.-E.; Plessier, A.; Roulot, D.; Chaffaut, C.; Bourcier,
V.; et al. Groupe d’Etude et de Traitement du Carcinome Hépatocellulaire. Causes and consequences of portal vein thrombosis in
1,243 patients with cirrhosis: Results of a longitudinal study. Hepatology 2015, 61, 660–667. [CrossRef]
18. Efird, L.M.; Mishkin, D.S.; Berlowitz, D.R.; Ash, A.S.; Hylek, E.M.; Ozonoff, A.; Reisman, J.I.; Zhao, S.; Jasuja, G.K.; Rose, A.J.
Stratifying the risks of oral anticoagulation in patients with liver disease. Circ. Cardiovasc. Qual. Outcomes 2014, 7, 461–467.
[CrossRef] [PubMed]
19. Delgado, M.G.; Seijo, S.; Yepes, I.; Achécar, L.; Catalina, M.V.; García-Criado, Á.; Abraldes, J.G.; de la Peña, J.; Bañares, R.; Albillos,
A.; et al. Efficacy and safety of anticoagulation on patients with cirrhosis and portal vein thrombosis. Clin. Gastroenterol. Hepatol.
2012, 10, 776–783. [CrossRef]
20. Ozturk, M.; Ipekci, A.; Kiyak, S.K.; Akdeniz, Y.S.; Aydin, Y.; Ikizceli, I.; Sogut, O. Bleeding Complications in Warfarin-Treated
Patients Admitted to the Emergency Department. J. Clin. Med. Res. 2019, 11, 106–113. [CrossRef]
21. Lau, W.C.Y.; Li, X.; Wong, I.C.K.; Man, K.K.C.; Lip, G.Y.H.; Leung, W.K.; Siu, C.W.; Chan, E.W. Bleeding-related hospital
admissions and 30-day readmissions in patients with non-valvular atrial fibrillation treated with dabigatran versus warfarin.
J. Thromb. Haemost. 2017, 15, 1923–1933. [CrossRef]
22. De Pietri, L.; Bianchini, M.; Montalti, R.; De Maria, N.; Di Maira, T.; Begliomini, B.; Gerunda, G.E.; di Benedetto, F.; Garcia-Tsao,
G.; Villa, E. Thrombelastography-guided blood product use before invasive procedures in cirrhosis with severe coagulopathy: A
randomized, controlled trial. Hepatology 2016, 63, 566–573. [CrossRef] [PubMed]
23. Steffel, J.; Verhamme, P.; Potpara, T.S.; Albaladejo, P.; Antz, M.; Desteghe, L.; Haeusler, K.G.; Oldgren, J.; Reinecke, H.; Roldan-Schilling,
V.; et al. ESC Scientific Document Group. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K
antagonist oral anticoagulants in patients with atrial fibrillation. Eur. Heart J. 2018, 39, 1330–1393. [CrossRef] [PubMed]
24. Bansilal, S.; Bloomgarden, Z.; Halperin, J.L.; Hellkamp, A.S.; Lokhnygina, Y.; Patel, M.R.; Becker, R.C.; Breithardt, G.; Hacke,
W.; Hankey, G.J.; et al. ROCKET AF Steering Committee and Investigators. Efficacy and safety of rivaroxaban in patients with
diabetes and nonvalvular atrial fibrillation: The Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibition Compared with
Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF Trial). Am. Heart J. 2015,
170, 675–682.e8. [CrossRef]
25. Lopes, R.D.; Alexander, J.H.; Al-Khatib, S.M.; Ansell, J.; Diaz, R.; Easton, J.D.; Gersh, B.J.; Granger, C.B.; Hanna, M.; Horowitz,
J.; et al. ARISTOTLE Investigators. Apixaban for reduction in stroke and other ThromboemboLic events in atrial fibrillation
(ARISTOTLE) trial: Design and rationale. Am. Heart J. 2010, 159, 331–339. [CrossRef]
26. Ezekowitz, M.D.; Connolly, S.; Parekh, A.; Reilly, P.A.; Varrone, J.; Wang, S.; Oldgren, J.; Themeles, E.; Wallentin, L.; Yusuf, S.
Rationale and design of RE-LY: Randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran.
Am. Heart J. 2009, 157, 805–810.e2. [CrossRef]
27. Ruff, C.T.; Giugliano, R.P.; Antman, E.M.; Crugnale, S.E.; Bocanegra, T.; Mercuri, M.; Hanyok, J.; Patel, I.; Shi, M.; Salazar, D.; et al.
Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: Design and
rationale for the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis In Myocardial
Infarction study 48 (ENGAGE AF-TIMI 48). Am. Heart J. 2010, 160, 635–641. [CrossRef]
Medicina 2023, 59, 346 13 of 13

28. Kearon, C.; Akl, E.A.; Ornelas, J.; Blaivas, A.; Jimenez, D.; Bounameaux, H.; Huisman, M.; King, C.S.; Morris, T.A.; Sood, N.; et al.
Antithrombotic therapy for VTE disease: CHEST guideline and Expert Panel Report. Chest 2016, 149, 315–352. [CrossRef] [PubMed]
29. Garcia-Tsao, G.; Abraldes, J.G.; Berzigotti, A.; Bosch, J. Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and
management: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology 2017, 65, 310–335. [CrossRef]
30. O’Shea, R.S.; Davitkov, P.; Ko, C.W.; Rajasekhar, A.; Su, G.L. AGA Clinical Practice Guideline on the Management of Coagulation
Disorders in Patients With Cirrhosis. Gastroenterology 2021, 161, 1615–1627.e1. [CrossRef] [PubMed]
31. Northup, P.G.; Garcia-Pagan, J.C.; Garcia-Tsao, G.; Intagliata, N.M.; Superina, R.A.; Roberts, L.N.; Lisman, T.; Valla, D.C. Vascular
Liver Disorders, Portal Vein Thrombosis, and Procedural Bleeding in Patients With Liver Disease: 2020 Practice Guidance by the
American Association for the Study of Liver Diseases. Hepatology 2020, 73, 366–413. [CrossRef] [PubMed]
32. Chang, S.-H.; Chou, I.-J.; Yeh, Y.-H.; Chiou, M.-J.; Wen, M.-S.; Kuo, C.-T.; See, L.-C.; Kuo, C.-F. Association Between Use of
Non–Vitamin K Oral Anticoagulants With and Without Concurrent Medications and Risk of Major Bleeding in Nonvalvular
Atrial Fibrillation. JAMA 2017, 318, 1250–1259. [CrossRef]
33. Chung, J.W.; Kim, G.H.; Lee, J.H.; Ok, K.S.; Jang, E.S.; Jeong, S.-H.; Kim, J.-W. Safety, efficacy, and response predictors of
anticoagulation for the treatment of nonmalignant portal-vein thrombosis in patients with cirrhosis: A propensity score matching
analysis. Clin. Mol. Hepatol. 2014, 20, 384–391. [CrossRef] [PubMed]
34. Ballestri, S.; Capitelli, M.; Fontana, M.C.; Arioli, D.; Romagnoli, E.; Graziosi, C.; Lonardo, A.; Marietta, M.; Dentali, F.; Cioni, G.
Direct Oral Anticoagulants in Patients with Liver Disease in the Era of Non-Alcoholic Fatty Liver Disease Global Epidemic: A
Narrative Review. Adv. Ther. 2020, 37, 1910–1932. [CrossRef] [PubMed]
35. Lisman, T.; Bongers, T.N.; Adelmeijer, J.; Janssen, H.L.; de Maat, M.P.; de Groot, P.G.; Leebeek, F.W. Elevated levels of von
Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology 2006, 44, 53–61. [CrossRef]
36. Federici, A.B.; Berkowitz, S.D.; Lattuada, A.; Mannucci, P.M. Degradation of von Willebrand factor in patients with acquired
clinical conditions in which there is heightened proteolysis. Blood 1993, 81, 720–725. [CrossRef]
37. Caldwell, S.H.; Hoffman, M.; Lisman, T.; Macik, B.G.; Northup, P.G.; Reddy, K.R.; Tripodi, A.; Sanyal, A.J.; Coagulation in Liver
Disease Group. Coagulation disorders and hemostasis in liver disease: Pathophysiology and critical assessment of current
management. Hepatology 2006, 44, 1039–1046. [CrossRef]
38. O’Leary, J.G.; Greenberg, C.S.; Patton, H.M.; Caldwell, S.H. AGA clinical practice update: Coagulation in cirrhosis. Gastroenterology
2019, 157, 34–43.e1. [CrossRef]
39. Simonetto, D.A.; Singal, A.K.; Garcia-Tsao, G.; Caldwell, S.H.; Ahn, J.; Kamath, P.S. ACG Clinical Guideline: Disorders of the
Hepatic and Mesenteric Circulation. Am. J. Gastroenterol. 2020, 115, 18–40. [CrossRef]
40. Hoolwerf, E.W.; Kraaijpoel, N.; Buller, H.R.; van Es, N. Direct oral anticoagulants in patients with liver cirrhosis: A systematic
review. Thromb. Res. 2018, 170, 102–108. [CrossRef] [PubMed]
41. Lee, S.-R.; Lee, H.-J.; Choi, E.-K.; Han, K.-D.; Jung, J.-H.; Cha, M.-J.; Oh, S.; Lip, G.Y. Direct Oral Anticoagulants in Patients with
Atrial Fibrillation and Liver Disease. J. Am. Coll. Cardiol. 2019, 73, 3295–3308. [CrossRef] [PubMed]
42. Caldeira, D.; Barra, M.; Santos, A.T.; de Abreu, D.; Pinto, F.J.; Ferreira, J.J.; Costa, J. Risk of drug-induced liver injury with the new
oral anticoagulants: Systematic review and meta-analysis. Heart 2014, 100, 550–556. [CrossRef] [PubMed]
43. Liakoni, E.; Rätz Bravo, A.E.; Krähenbühl, S. Hepatotoxicity of New Oral Anticoagulants (NOACs). Drug Saf. 2015, 38, 711–720.
[CrossRef] [PubMed]
44. Garcia-Tsao, G.; Sanyal, A.J.; Grace, N.D.; Carey, W.; Practice Guidelines Committee of the American Association for the Study
of Liver Diseases; Practice Parameters Committee of the American College of Gastroenterology. Prevention and management of
gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007, 46, 922–938, Erratum in Hepatology 2007, 46, 2052.
[CrossRef]
45. Gish, R.G.; Flamm, S.L. Anticoagulation in Patients With Chronic Liver Disease. Gastroenterol. Hepatol. 2021, 17 (Suppl. S1), 10–15.
46. Goldstein, J.N.; Refaai, M.A.; Milling, T.J.; Lewis, B.; Goldberg-Alberts, R.; Hug, B.A.; Sarode, R. Four-factor prothrombin complex
concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions:
A phase 3b, open-label, non-inferiority, randomized trial. Lancet 2015, 385, 2077–2087. [CrossRef] [PubMed]
47. Bernard, B.; Grange, J.D.; Khac, E.N.; Amiot, X.; Opolon, P.; Poynard, T. Antibiotic prophylaxis for the prevention of bacterial
infections in cirrhotic patients with gastrointestinal bleeding: A meta-analysis. Hepatology 1999, 29, 1655–1661. [CrossRef]
48. Soares-Weiser, K.; Brezis, M.; Tur-Kaspa, R.; Leibovici, L. Antibiotic prophylaxis for cirrhotic patients with gastrointestinal
bleeding. Cochrane Database Syst. Rev. 2002, 2, CD002907, Update in: Cochrane Database Syst. Rev. 2010, 9, CD002907. [CrossRef]
49. D’Amico, G.; Pietrosi, G.; Tarantino, I.; Pagliaro, L. Emergency sclerotherapy versus vasoactive drugs for variceal bleeding in
cirrhosis: A Cochrane meta-analysis. Gastroenterology 2003, 124, 1277–1291. [CrossRef]
50. Leonardi, F.; De Maria, N.; Villa, E. Anticoagulation in cirrhosis: A new paradigm? Clin. Mol. Hepatol. 2017, 23, 13–21. [CrossRef]
51. Laliberté, F.; Cloutier, M.; Crivera, C.; Nelson, W.W.; Olson, W.H.; Schein, J.; Vanderpoel, J.; Germain, G.; Lefebvre, P. Effect of
rivaroxaban versus warfarin on health care costs among nonvalvular atrial fibrillation patients: Observations from rivaroxaban
users and matched warfarin users. Adv. Ther. 2015, 32, 216–227, Erratum in Adv. Ther. 2015, 32, 387. [CrossRef]

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual
author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to
people or property resulting from any ideas, methods, instructions or products referred to in the content.