Abstract
Patients with liver cirrhosis are known to have increased risk
bleeding particularly from gastrointestinal tract. However,
recent literature has shown that patients with liver cirrhosis are also
at increased risk of developing deep venous thrombosis and
pulmonary embolism. Therefore, it is important to consider prophylactic
and therapeutic anticoagulation in cirrhotic patients. In
this article, we have reviewed the available literature on the safety
and efficacy of the utilization of prophylactic and therapeutic
anticoagulation in cirrhotic patients.
Abbreviations: INR: International Normalized Ratio, VTE: Venous Thromboembolism, DVT: Deep Venous Thrombosis, PE:
Pulmonary Embolism, PTT: Partial Thromboplastin Time, LMWH: Low-Molecular-Weight Heparin, UFH: Unfractionated Heparin,
CLD: Chronic Liver Disease
Introduction
Liver plays central physiologic role in hemostasis as it
synthesizes the majority of the procoagulant and anticoagulant
factors. The levels of these factors are markedly affected by
decrease function of liver associated with cirrhosis resulting in
abnormal hemostatic mechanism. Generally, the impression in the
clinical world is that liver cirrhosis is associated with decrease
synthesis of procoagulant factors resulting in increased risk of
bleeding. This phenomenon is known as auto-anticoagulation and
is supported by elevated international normalized ratio (INR) and
low platelet count usually observed in cirrhotic patients. In this
regard, gastrointestinal bleeding and more specifically variceal
bleed are of major concern since they contribute significantly to the
mortality of patients with liver cirrhosis. At least, 30% mortality
has been reported at the first episode with a 70% recurrence rate
in this patient population and a 1year survival estimate ranging
from 32% to 80% [1]. However, decrease function of cirrhotic
liver also results in reduce level of anticoagulant factors including
antithrombin III, protein S, and C which may result in increased
tendency to form clots. Interestingly, recent data has also noted
cases of venous thromboembolism (VTE) including both deep
venous thrombosis (DVT) and pulmonary embolism (PE) in
cirrhotic patients ranging between 0.5% to 6.3% [2-10]. Dabbagh
et al. [4] found that even an elevated INR > 2.2 was not protective
against VTE in this patient population. Gulley D et al. [10] noted that
hospitalized cirrhotic patients without predisposing co-morbidities
(e.g. neoplasm, congestive heart disease and chronic renal failure)
had similar risks for VTE as compared to noncirrhotic patients [10].
Thus, the myth of auto-anticoagulation seems to be only partially
true. Therefore, the abnormal routine blood tests (like elevated
INR, Partial Thromboplastin Time [PTT], high MELD score and
low platelet count) may indicate increased hemorrhage risk in this
patient population but may not be necessarily completely true as
these tests do not accurately reflect the activity of aforementioned
anticoagulant factors in the serum. The purpose of this article is
to review the epidemiological data available on the utilization
of traditional VTE prophylaxis and treatment on the increased
bleeding risk in patients with liver cirrhosis.
Methods
An electronic Medline search was conducted using the key
terms anticoagulation, low-molecular-weight heparin (LMWH), unfractionated heparin (UFH), oral anticoagulant, deep venous
thrombosis, pulmonary embolism, venous thromboembolism, liver
cirrhosis, chronic liver disease, and decompensated liver disease.
Studies written in the English from January 2000 to March 2018
were considered for this review article. All search results were
reviewed.
Results
Intagliata N et al. [11] studied the complication rates associated
with administration of thromboprophylaxis in 235 hospitalized
cirrhosis patients admitted to the University of Virginia between
2007 and 2010 accounting for 355 discrete hospitalizations.
They noticed only nine gastrointestinal bleeding events (2.5%
of admissions) and concluded that VTE prophylaxis was not
associated with increased risk of bleeding or death in their patient
population [11]. Vivarelli M et al. [12] conducted a retrospective
study in Italy on 229 consecutive cirrhotic patients with HCC
who underwent hepatic resection. They assess the safety and
effectiveness of prophylaxis for VTE in terms of thrombotic or
hemorrhagic complications between those who received and
those who did not receive prophylaxis with low-molecular weight
heparin. They divided the patients into two groups i.e. Group A
included 68.5% of patients and Group B included 31.5 % patients.
Group B patients had higher Child-Pugh and MELD scores, lower
platelet counts, a higher prevalence of esophageal varices and
higher requirements for intraoperative transfusion of FFP. Group
A received VTE prophylaxis with LMWH while Group B did not
receive VTE prophylaxis. The cases of VTE were higher in group
B (1.38%) as compared to the group A (0.63%) but the difference
was not statistically significant (P = 0.530). On the other hand, the
prevalence of hemorrhagic complications was higher in group A as
compared to group B but again the difference was not statistically
significant (P = 0.380). Moreover, only the presence of varices
was associated with increased risk of bleeding (P=0.05) among
other studied risk factors including age, CTP class and Model for
End-stage Liver disease scores, platelet count and intraoperative
transfusion requirements [12].
Bechmann L et al. [13] conducted a retrospective study in
Germany to evaluate the safety of LMWH utilization for either
prophylactic or therapeutic indications anticoagulation among 84
patients with cirrhosis. Only seven patients developed variceal
bleeding at a rate comparable with the baseline rate in patients
with advanced cirrhosis. The hemorrhagic complications were
either secondary to bleeding esophageal varices or 2whypertensive
gastropathy with no mortality. They concluded that a prophylactic
use of LMWH in patients with cirrhosis appears to be safe [13].
Smith C et al. [14] also conducted a retrospective chart review
of 410 chronic liver disease (CLD) patients admitted to a tertiary
care academic medical center in US from August 2009 through July
2011. 225 (55%) patients received thromboprophylaxis including
mechanical (154), pharmacologic (49), and combined (22). They
noticed a significant decrease in overall thromboprophylaxis use
and pharmacologic prophylaxis use for patients with INR >2.0 as
compared to those with INR 1.4 to 2.0 (P = 0.013 and P < 0.001,
respectively). 0.7% of patients developed VTE (DVT) and fifteen
(3.7 %) patients had bleeding event. Out of fifteen patients who
developed bleeding, nine were on mechanical prophylaxis, 1 on
pharmacologic, 3 on combination, and 2 with no prophylaxis.
Majority of patients experiencing a bleeding event had an INR
>2.0 (P = 0.001). They concluded that use of VTE pharmacologic
prophylaxis does not appear to increase bleeding risk in CLD
patients with INR ≤2.0 [14].
Barclay S et al. [15] conducted another retrospective study
to determine whether pharmacologic prophylaxis for VTE was
associated with a decrease in the incidence of VTE or an increased
incidence of bleeding in patients with CLD. The study sample
consisted of a total of 1581 CLD patients hospitalized over a
3-year period and divided into two groups based on receipt of
pharmacologic VTE prophylaxis. 392 (24.7%) patients received
pharmacologic VTE prophylaxis. Decrease risk of VTE (0.5% vs
1.8%, p=0.05) and bleeding (2.0% vs 10.3%, p<0.001) were noted
in the prophylaxis group as compared to the nonprophylaxis group
[15].
In a multicenter retrospective study conducted in 5 hospitals,
Reichert J et al, studied the pharmacologic VTE prophylaxis
on risk of hemorrhage while hospitalized in patients with CLD
and concurrent coagulopathy. They utilized the ICD-9 codes to
identify subjects with CLD admitted from January 1, 2012, until
December 31, 2012. 256 patients met criteria for analysis, with 80
received pharmacologic VTE prophylaxis and 176 did not receive
pharmacologic VTE prophylaxis. They found that pharmacologic
thromboprophylaxis was associated with increased number of
hemorrhagic events among cirrhotic patients who received it as
compared to those who did not (17.5% vs 7.4%, p=0.02). However,
it was noted that difference in rate of overall hemorrhage was
driven primarily by a difference in minor hemorrhage [16].
Conclusion
The use of anticoagulation for VTE prophylaxis and treatment in
cirrhosis remains underutilized and it is still not a universal practice
to provide hospitalized cirrhotic patients with such prophylaxis
and treatment due to the concerns of increased bleeding risk. Also,
the literature on the safety and efficacy of anticoagulation in liver
cirrhosis is in initial stages and is based mainly on retrospective
studies. Six studies have investigated the use of VTE prophylaxis.
Two studies have shown that DVT prophylaxis does decrease the
risk VTE in cirrhotic patients [12,15]. However, the results of one of
the study did not reached the statistical significance which could be
due to low power of the study because of the small sample size [12].
On the other hand, only one study have shown that pharmacologic
thromboprophylaxis was associated with increased number of
hemorrhagic events among cirrhotic patients which they attributed to increased incidence of minor hemorrhage [16]. Another study
noticed higher prevalence of hemorrhagic complication in VTE
prophylaxis group as compared to cirrhotic patients who did not
received VTE prophylaxis, but their result did not achieve statistical
significance [12]. Moreover, only the presence of varices was
associated with increased risk of bleeding.
It is possible that risk of hemorrhage is underestimated in these
studies because of retrospective nature of studies with possibility
of underreporting of bleeding events and underutilization of
thromboprophylaxis of VTE in patients at higher risk of bleeding
such as those with high INR, low platelets and presence of
esophageal varices. Only one study investigated the use of VTE
treatment in cirrhotic patients and they found no increased
bleeding risk with it [13]. However, it was a small sampled study
and there was no control group utilized to compare [13]. In general,
recent data suggest that utilization of VTE prophylaxis in cirrhotic
patients is safe and should be considered. Underutilization of both
chemical and mechanical VTE prophylaxis in hospitalized cirrhotic
patients has been noted ranging to as high as 75% [8,17]. In another
study, only 9% of hospitalized patients with CLD were treated
with pharmacological VTE prophylaxis, while only 16% received
mechanical VTE prophylaxis [2]. The major concern regarding the
use of anticoagulation in this population is the gastrointestinal
bleed and specifically esophageal variceal bleed. However, VTE
prophylaxis appears relatively safe in cirrhotic patients and should
be considered in all hospitalized cirrhotic patients with minimal
varices, no evidence of clinical bleeding and with an appropriate
clinical indication.
Infact, the safety of prophylactic or therapeutic anticoagulation
in carefully selected patients with cirrhosis without the presence of
high-risk esophageal varices appears to be comparable to general
medical patients. Also, in patients with esophageal varices, primary
or secondary prophylaxis with either endoscopic variceal ligation or
use of non-selective beta-blockers is suggested prior to initiation of
anticoagulation and after discussing about the risks and benefits of
anticoagulation with the patients. Periodical screening endoscopy
should be considered to assess varices and the risk of bleeding in
these patients. Various classes of heparin are currently available for
prophylactic or therapeutic purposes including UFH, LMWH and
fondaparinux. LMWH seems to be the treatment of choice for both
the prevention and treatment of VTE in cirrhotic patients. UFH is an
alternative in cirrhotic patients for shorter-term use and in cases
of severe renal dysfunction and/or hemodynamic instability. The
possible role for the new antithrombotic drugs with direct action
on factor Xa or thrombin has yet to be evaluated.
Clinical tools to evaluate the risk of VTE in cirrhotic patient
population also need to be developed to target the cirrhotic patient
who will benefit most from the anticoagulation. Bogari H et al. [18]
conducted a retrospective cohort study to evaluate the utilization
of the Padua Predictor Score (PPS) as a risk-stratification tool for
the development of VTE in 163 patients with liver cirrhosis [18,19].
They categorized the patients into two groups based on whether
they developed a VTE (11%) or not (89%). Patients were further
risk stratified into high-risk (score ≥4) and low-risk (score <4)
using the PPS. Patients in the VTE group had significantly greater
mean PPS than in the non-VTE group (5.8 ± 2.0 versus 3.0 ± 2.1,
respectively; p<0.001). Also, High-risk patients were more likely
to have VTE (OR 12.7, 95% CI 2.8 to 57.4, p=0.001) as compared
to low risk. Based on their findings, Bogari H et al. [18] concluded
that PPS is an effective risk assessment tool for development of VTE
in patients hospitalized with chronic liver disease. Various other
factors like low serum albumin and decompensated liver cirrhosis
have also shown to be associated with increased risk of VTE in
patients with liver cirrhosis. In two retrospective studies conducted
by Northup et al. [2], Garcia Fuster et al. [3] low serum albumin
was found to be associated with increased risk of developing VTE
independent from elevated INR or low platelet count [2,3]. Certain
other factors like INR > 2 and low platelet count may lower the risk
of developing VTE. It will be prudent to develop tools including
such factors to help accurately characterizing cirrhotic patients at
higher risk of developing VTE. This will help provide clinicians with
more confident to start anticoagulation in cirrhotic patients at high
risk of bleeding secondary to esophageal varices.
Further studies are needed to determine the utility of novel
methods to monitor the anticoagulation therapy in cirrhotic
patients. LMWH is conventionally monitored by anti-Xa assay,
while UFH can be monitored by activated PTT (aPTT) assay in the
general population. However, monitoring of LMWH anticoagulation
with anti-Xa levels for dose adjustment is challenging in cirrhotic
patients since the levels of anti-Xa factor have been found to be
lower in cirrhotic patients compared to normal controls after
administration of prophylactic or therapeutic dose of LMWH [13].
For example, Bechmann et al. [13] studied the pharmacokinetics of
LMWH in patients with cirrhosis and confirmed that standard doses
of enoxaparin failed to achieve target anti Xa levels recommended
for prophylactic or therapeutic use against VTE [13]. However, in
vitro studies evaluating the effect of LMWH on thrombin generation
found that despite reduced antithrombin and anti-Xa activity levels,
cirrhotic patients had an increased response to LMWH [20]. They
concluded that the likely explanation of low anti-Xa levels could be
a laboratory artifact while the efficacy of LMWH is preserved [20].
Thus, targeting its levels for the prophylaxis and treatment of VTE
in noncirrhotic patients might underestimate the true degree of
anticoagulation which could lead to incorrect dosing and subsequent
increase morbidity and mortality secondary to bleeding. The role
of thrombin generation in monitoring the response to LMWH in
cirrhotic patients has been investigated by Lisman T et al. [21] and
they found it to be a useful tool and an alternative to anti-Xa levels
[21]. On the other hand, UFH is monitored with aPTT in general
population. But again, aPTT levels are also known to be prolonged
in patients with liver cirrhosis thus making it difficult to predict the
dose accuracy of UFH in this patient population.
In the end, the treatment and prophylaxis for VTE should
be utilized in patients with liver cirrhosis who are at low risk
of bleeding i.e. does not have esophageal varices. Moreover,
randomized prospective studies needs to be performed to confirm
the efficacy of VTE prophylaxis in cirrhotic patients, to determine
the safety of therapeutic anticoagulation against VTE in cirrhotic
patients, to figure out accurate markers for monitoring the use
anticoagulation in cirrhotic patients, and to better understand the
role of coumadin and newer oral anticoagulants in VTE prophylaxis
and treatment in cirrhotic patients.
Read More About Lupine Publishers Current Trends in Gastroenterology and Hepatology (CTGH) Please Click on Below Link: https://currenttrendsingastroenterology.blogspot.com/
