Portal Vein Thrombosis in the Setting of Cirrhosis: A Comprehensive Review

Abstract

Portal vein thrombosis constitutes the most common thrombotic event in patients with cirrhosis, with increased rates in the setting of advanced liver disease. Despite being a well-known complication of cirrhosis, the contribution of portal vein thrombosis to hepatic decompensation and overall mortality is still a matter of debate. The incorporation of direct oral anticoagulants and new radiological techniques for portal vein recanalization have expanded our therapeutic arsenal. However, the lack of large prospective observational studies and randomized trials explain the heterogenous diagnostic and therapeutic recommendations of current guidelines. This article seeks to make a comprehensive review of the pathophysiology, clinical features, diagnosis, and treatment of portal vein thrombosis in patients with cirrhosis.

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Citation: Odriozola, A.; Puente, Á.;
Cuadrado, A.; Rivas, C.; Anton, Á.;
González, F.J.; Pellón, R.; Fábrega, E.;
Crespo, J.; Fortea, J.I. Portal Vein
Thrombosis in the Setting of
Cirrhosis: A Comprehensive Review.
J. Clin. Med. 2022,11, 6435. https://
doi.org/10.3390/jcm11216435
Academic Editor: Antonio
M Caballero-Mateos
Received: 8 October 2022
Accepted: 28 October 2022
Published: 30 October 2022
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Journal of
Clinical Medicine
Review
Portal Vein Thrombosis in the Setting of Cirrhosis:
A Comprehensive Review
Aitor Odriozola 1,Ángela Puente 1, Antonio Cuadrado 1, Coral Rivas 1,Ángela Anton 1,
Francisco JoséGonzález 2, Raúl Pellón2, Emilio Fábrega 1, Javier Crespo 1and JoséIgnacio Fortea 1, *
1Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases,
Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla University Hospital, 39008 Santander, Spain
2Radiology Department, Marqués de Valdecilla University Hospital, 39008 Santander, Spain
*Correspondence: joseignacio.fortea@scsalud.es; Tel.: +34-942202520 (ext. 72929)
Abstract:
Portal vein thrombosis constitutes the most common thrombotic event in patients with
cirrhosis, with increased rates in the setting of advanced liver disease. Despite being a well-known
complication of cirrhosis, the contribution of portal vein thrombosis to hepatic decompensation
and overall mortality is still a matter of debate. The incorporation of direct oral anticoagulants and
new radiological techniques for portal vein recanalization have expanded our therapeutic arsenal.
However, the lack of large prospective observational studies and randomized trials explain the
heterogenous diagnostic and therapeutic recommendations of current guidelines. This article seeks
to make a comprehensive review of the pathophysiology, clinical features, diagnosis, and treatment
of portal vein thrombosis in patients with cirrhosis.
Keywords:
portal hypertension; cirrhosis; portal vein thrombosis; anticoagulation; transjugular
intrahepatic portosystemic shunt
1. Introduction
Portal vein obstruction can occur due to a malignant tumor (frequently but improperly
referred to as malignant thrombosis), in which the obstruction is secondary to portal vein
narrowing, and/or direct invasion of the portal vein by the neoplasm, or due to non-
malignant portal vein thrombosis (PVT). The latter is defined as a thrombus that develops
within the portal vein trunk and intrahepatic portal branches, which may also involve
the splenic (SV) or superior mesenteric veins (SMV). In the absence of recanalization,
the portal venous lumen is obliterated, and porto-portal collaterals develop, resulting
in portal cavernoma. Non-malignant PVT can arise in two settings depending on the
presence/absence of cirrhosis. This differentiation is critical since etiology, manifestations,
natural history, and therapeutic options differ [
1
–
4
]. Previous early literature combined
patients in these two settings and this should be accounted for to better interpret the
results [5–8].
This article seeks to make a comprehensive review of the pathophysiology, clinical
features, diagnosis, and treatment of PVT in patients with cirrhosis. It constitutes the
most common thrombotic event in this population, with increased rates in the setting
of advanced liver disease. Despite being a well-known complication of cirrhosis, the
contribution of PVT to hepatic decompensation and overall mortality is still a matter of
debate. There is consequently no consensus on its optimal management, and no definitive
recommendations were reported in clinical guidelines or consensus conferences [
1
–
4
,
9
–
12
].
2. Anatomy of the Venous Portal System
The liver is a highly vascular organ that receives up to 25% of the total cardiac output
from a dual blood supply. The hepatic artery delivers well-oxygenated blood and comprises
J. Clin. Med. 2022,11, 6435. https://doi.org/10.3390/jcm11216435 https://www.mdpi.com/journal/jcm

J. Clin. Med. 2022,11, 6435 2 of 26
approximately 25% of total hepatic blood flow, whereas the remaining 75% is deoxygenated
blood supplied by the portal vein [
13
]. These two afferent vascular systems drain into
the modified capillary network of the liver, composed of fenestrated sinusoids. From the
sinusoids, blood flows into the central veins that drain in the hepatic veins and then in the
inferior vena cava [2].
The hepatic portal system is the most known portal venous system in the body, hence
its name. The latter is defined as a circulatory system in which veins connect two capillary
beds without first carrying blood to the heart. In the case of the hepatic portal venous
system, capillary blood from the entire gastrointestinal tract (except for the upper esophagus
and distal rectum), pancreas, gallbladder, and spleen is carried to the hepatic sinusoids.
The portal vein is an 8-cm, valveless conduit originating from the confluence of the SMV
and SV posterior to the neck of the pancreas [
2
]. The inferior mesenteric vein (IMV) is a
tributary vessel that usually drains in the SV (up to 40% of the cases). However, there are
many variants in the drainage of this vein [
14
]. In the other two most frequent variants, the
IMV enters into the angle of the confluence of the SV and the SMV (30%) or the SMV (20%).
Other lesser frequent variants (10%) consist of accessory mesenteric veins entering the SV
or SMV.
The portal vein develops during the second and third month of gestation from two
vitelline veins, which drain the yolk sac. These veins form few anastomoses between
each other which result in the formation of the portal vein. Deviations from the normal
process of these anastomosis result in variations in the branching pattern of the portal
vein. Its distribution within the liver is segmental and closely follows the hepatic artery.
Cheng Y et al. classified these intrahepatic portal vein variations into five different types
(Figure 1) [15].
J. Clin. Med. 2022, 11, x FOR PEER REVIEW 2 of 26
2. Anatomy of the Venous Portal System
The liver is a highly vascular organ that receives up to 25% of the total cardiac output
from a dual blood supply. The hepatic artery delivers well-oxygenated blood and com-
prises approximately 25% of total hepatic blood flow, whereas the remaining 75% is de-
oxygenated blood supplied by the portal vein [13]. These two afferent vascular systems
drain into the modified capillary network of the liver, composed of fenestrated sinusoids.
From the sinusoids, blood flows into the central veins that drain in the hepatic veins and
then in the inferior vena cava [2].
The hepatic portal system is the most known portal venous system in the body, hence
its name. The latter is defined as a circulatory system in which veins connect two capillary
beds without first carrying blood to the heart. In the case of the hepatic portal venous
system, capillary blood from the entire gastrointestinal tract (except for the upper esoph-
agus and distal rectum), pancreas, gallbladder, and spleen is carried to the hepatic sinus-
oids. The portal vein is an 8-cm, valveless conduit originating from the confluence of the
SMV and SV posterior to the neck of the pancreas [2]. The inferior mesenteric vein (IMV)
is a tributary vessel that usually drains in the SV (up to 40% of the cases). However, there
are many variants in the drainage of this vein [14]. In the other two most frequent variants,
the IMV enters into the angle of the confluence of the SV and the SMV (30%) or the SMV
(20%). Other lesser frequent variants (10%) consist of accessory mesenteric veins entering
the SV or SMV.
The portal vein develops during the second and third month of gestation from two
vitelline veins, which drain the yolk sac. These veins form few anastomoses between each
other which result in the formation of the portal vein. Deviations from the normal process
of these anastomosis result in variations in the branching pattern of the portal vein. Its
distribution within the liver is segmental and closely follows the hepatic artery. Cheng Y
et al. classified these intrahepatic portal vein variations into five different types (Figure 1)
[15].
Figure 1. The intrahepatic portal vein has a segmental distribution and it closely follows the hepatic
artery. Cheng Y [15] et al. classified intrahepatic portal vein variations into five different types. (A).
Type 1 (65–80%): after its entry through the hilium, the main portal vein (MPV) divides into a larger
right portal vein (RPV) and a smaller left portal vein (LPV). RPV is divided into an anterior branch
(supplying segments V and VIII) and a posterior branch (supplying segments VI and VII). LVP runs
horizontally to the left and then turns medially (supplying segments I, II, III, and IV). (B). Type II
(10–15%): trifurcation of MVP, dividing into the right anterior and posterior branches and the LPV.
(C). Type III (0.3–7%): the right posterior portal branch arises directly from the MPV as its first
Figure 1.
The intrahepatic portal vein has a segmental distribution and it closely follows the hepatic
artery. Cheng Y [
15
] et al. classified intrahepatic portal vein variations into five different types.
(A) Type
1 (65–80%): after its entry through the hilium, the main portal vein (MPV) divides into a
larger right portal vein (RPV) and a smaller left portal vein (LPV). RPV is divided into an anterior
branch (supplying segments V and VIII) and a posterior branch (supplying segments VI and VII).
LVP runs horizontally to the left and then turns medially (supplying segments I, II, III, and IV).
(B) Type
II (10–15%): trifurcation of MVP, dividing into the right anterior and posterior branches and
the LPV. (
C
) Type III (0.3–7%): the right posterior portal branch arises directly from the MPV as its
first branch and the LPV is the terminal branch, arising after the origin of the right anterior portal
vein. (
D
) Type IV (0.6–2.7%): trifurcation of the RPV, in which the branch of segment VII is the first
branch of the RPV. (
E
) Type V (1.3–2.4%): trifurcation of the RPV, in which the branch of segment
VI arises early as a separate branch of the RPV. (
F
) Different variants in the drainage of the inferior
mesenteric vein (IMV). I: drainage into the splenic vein (SV). II: drainage into the confluence of the
superior mesenteric vein (SMV) and SV. III: drainage into the SMV.

J. Clin. Med. 2022,11, 6435 3 of 26
3. Classification
Terminology and classification systems of PVT vary extensively in the literature, with
most developed exclusively in the liver transplant (LT) population [
3
]. Four of the major
published PVT classification systems are presented in Table 1[
16
–
19
]. More recently, the
latest guidelines of the American Association for the Study of the Liver (AASLD) on
vascular disorders and the Baveno VII workshop have promoted the establishment of a
standardized terminology in describing PVT to allow comparison and external validation
of future studies. They proposed a systematic documentation of initial site, extent/degree
of luminal obstruction, and chronicity of PVT to enable subsequent evaluation of the
spontaneous course and/or response to treatment (Figure 2) [3,4].
Table 1. Classification of portal vein thrombosis according several authors.
Classification Description Categories Strengths vs. Weaknesses
Yerdel et al.,
2000 [16]
Post-transplant survival
(i) Involvement of MPV, SMV
and SV
(ii) Degree of occlusion
Grade 1: <50% occlusion
Grade 2: >50% occlusion
Grade 3: Complete PV or SV
occlusionGrade 4: Complete PV
occlusion with SMV extension
- Well-defined long-term
post-transplant survival
- Only for LT candidates
- Most widely used classification
to date
Bauer et al.,
2006 [17]
PVT response to TIPS
placement in patients listed
for LT
(i) Involvement of MPV, SMV
and SV
(ii) Degree of occlusion
(iii) Stratification by location
of clot and cavernous
transformation
Grade 1: <25% occlusion of PV
Grade 2: 26–50% occlusion
Grade 3: 51–75% occlusion
Grade 4: 76–100% occlusion
- Available data not only in LT
recipients but also in non-LT
patients and patients with
cavernous transformation
- Better characterization of the
location and degree of occlusion
than other classifications
- Only for patients who
underwent TIPS placement.
Validated in 9 patients. No
long-term outcome data.
Sarin et al.,
2016 [18]
Based on revision of previous
PVT classifications
(i) Involvement of MPV, SMV,
and SV
(ii) Degree of occlusion
(iii) Underlying liver disease
Site of PVT (Type 1, 2a, 2b, 3)
* Type 1: only trunk
* Type II: only branches (a: one, b:
both branches)
* Type 3: trunk and branches
Degree of occlusion
* Occlusive
* Non-occlusive
Duration and presentation
* Recent or chronic
* Symptomatic or asymptomatic
Extension
* SV, SMV, or both
Underlying liver disease
- “Anatomical-functional”
classification
- Complex
- No correlation with outcomes
Bhangui et al.,
2019 [19]
(i) Involvement of MPV, SMV
and SV
(ii) LT surgery choices based
on collaterals
Complex
- SYerdel grade 4 and Jamieson
and Charco grades 3/4
- Non-complex
- Yerdel grade 1–3
- Simplifies anatomical
considerations for PV
management.
- Mainly focused on LT surgical
techniques not in outcomes.
Abbreviations: LT: liver transplant; MPV: main portal vein; PH: portal hypertension; PV: portal vein;
PVT: portal
vein thrombosis; SMV: superior mesenteric vein; SV: splenic vein; TIPS: transjugular intrahepatic
portosystemic shunt.

J. Clin. Med. 2022,11, 6435 4 of 26
J. Clin. Med. 2022, 11, x FOR PEER REVIEW 3 of 26
branch and the LPV is the terminal branch, arising after the origin of the right anterior portal vein.
(D). Type IV (0.6–2.7%): trifurcation of the RPV, in which the branch of segment VII is the first
branch of the RPV. (E). Type V (1.3–2.4%): trifurcation of the RPV, in which the branch of segment
VI arises early as a separate branch of the RPV. (F). Different variants in the drainage of the inferior
mesenteric vein (IMV). I: drainage into the splenic vein (SV). II: drainage into the confluence of the
superior mesenteric vein (SMV) and SV. III: drainage into the SMV.
3. Classification
Terminology and classification systems of PVT vary extensively in the literature, with
most developed exclusively in the liver transplant (LT) population [3]. Four of the major
published PVT classification systems are presented in Table 1 [16–19]. More recently, the
latest guidelines of the American Association for the Study of the Liver (AASLD) on vas-
cular disorders and the Baveno VII workshop have promoted the establishment of a stand-
ardized terminology in describing PVT to allow comparison and external validation of
future studies. They proposed a systematic documentation of initial site, extent/degree of
luminal obstruction, and chronicity of PVT to enable subsequent evaluation of the spon-
taneous course and/or response to treatment (Figure 2) [3,4].
Figure 2. Classification of portal vein thrombosis. (A). It is crucial to characterize the extension of
the portal vein thrombosis and its relationship with the main portal vein (MPV). The involvement
of the superior mesenteric vein (SMV) and splenic vein (SV) should be properly characterized due
to its implication in prognosis and treatment. (B). Cavernous transformation of the portal vein. At-
rophy of the MPV (marked in red) secondary to chronic PVT causes hypertrophy in the vasa vaso-
rum of the portal vein with the apparition of porto-portal shunts.
Table 1. Classification of portal vein thrombosis according several authors.
Classification
Description
Categories
Strengths vs. Weaknesses
Yerdel et al.,
2000 [16]
Post-transplant survival
(i) Involvement of MPV,
SMV and SV
(ii) Degree of occlusion
Grade 1: <50% occlusion
Grade 2: >50% occlusion
Grade 3: Complete PV or SV
occlusion
Grade 4: Complete PV occlusion
with SMV extension
- Well-defined long-term post-
transplant survival
- Only for LT candidates
- Most widely used classification to
date
Figure 2.
Classification of portal vein thrombosis. (
A
) It is crucial to characterize the extension of the
portal vein thrombosis and its relationship with the main portal vein (MPV). The involvement of the
superior mesenteric vein (SMV) and splenic vein (SV) should be properly characterized due to its
implication in prognosis and treatment. (
B
) Cavernous transformation of the portal vein. Atrophy of
the MPV (marked in red) secondary to chronic PVT causes hypertrophy in the vasa vasorum of the
portal vein with the apparition of porto-portal shunts.
In line with the above, the initial description of PVT must detail the location and
extension of the thrombosis, specifying whether it involves the intrahepatic branches, main
portal vein, SV, and/or SMV. The percent of lumen occluded in each of these locations is
graded as completely occlusive (no persistent lumen), partially occlusive (clot obstructing
>50% of original vessel lumen), or minimally occlusive (clot
obstructing <50%
of original
vessel lumen). If present, cavernous transformation (i.e., gross porto-portal collaterals
without original portal vein seen) must be reported. This documentation is not only
important for therapeutic decisions and evaluating response to treatment but also for
establishing a correlation between the site of thrombosis and the clinical presentation of
PVT. Indeed, the involvement of SMV may cause intestinal ischemia and development of
ectopic varices, whereas SV thrombosis could lead to the appearance of fundic varices [
3
,
4
].
As far as the time course of thrombosis is concerned, PVT is classified as recent if PVT
is presumed to be present for less than 6 months and as chronic if PVT persists longer than
this time frame. The term recent is preferred over acute because the latter implies clinical
symptoms and PVT is often asymptomatic and incidentally diagnosed. That is why precise
dating is impossible in a significant proportion of patients. The 6-month threshold was
chosen based on data from a prospective study of 102 patients with recent non-cirrhotic PVT.
In this study, failure to recanalize within 6 months of PVT diagnosis led to development of
cavernous transformation in most patients despite continued anticoagulation [
20
]. Similar
results were observed in the setting of liver cirrhosis [
21
,
22
]. When chronic obstruction
persists and cavernous transformation occurs, the latter term is preferred. However,
cavernous transformation is not synonymous with chronic PVT since this finding can be
demonstrated within 1–3 weeks after PVT onset [23].
Finally, depending on the spontaneous course and/or response to treatment, PVT
is classified as progressive (thrombus increases in size or becomes completely occlusive),
stable (no changes in size nor occlusion) or regressive (thrombus decreases in size or degree
of occlusion) [3,4].

J. Clin. Med. 2022,11, 6435 5 of 26
4. Pathophysiology and Risk Factors
As with any other thrombus, the pathogenesis of PVT is generally multifactorial
and it is believed to be primarily determined by the interplay of the three physiological
factors of Virchow’s triad: slow blood flow, hypercoagulability, and endothelial damage.
Nevertheless, the exact contribution of each of these factors to PVT development was not
fully elucidated [24].
4.1. Reduced Blood Flow
A reduced portal flow velocity secondary to a “steal effect” produced by porto-
collateral circulation, combined with the increase in portal vein diameter commonly seen in
patients with clinically significant portal hypertension (CSPH) seems to be the most impor-
tant factor for PVT development in patients with cirrhosis. Specifically, a 15 cm/s threshold
was proposed to identify patients at higher risk of developing PVT. This was first reported
by Zocco et al. in a prospective study of 100 cirrhotic patients followed up for one year [
25
].
Since then, other retrospective and prospective studies have confirmed this finding [
26
–
28
].
However, a large satellite study of a prospective trial of ultrasound screening for hepa-
tocellular carcinoma (HCC) did not and raised concerns regarding the reproducibility of
portal vein blood flow velocity measurements, thus, making uncertain the generalization of
specific thresholds [
29
]. Further indirect data in this regard comes from studies identifying a
higher portal vein diameter and the presence of large porto-collateral vessels as risk factors
for developing PVT [
26
,
30
,
31
]. The efficacy of a transjugular intrahepatic portosystemic
shunt (TIPS) in restoring PVT patency by presumably increasing portal flow also supports
this major role of altered portal hemodynamics in PVT development [32].
As nonselective
β
-blockers (NSBB) may reduce portal venous flow by decreasing
cardiac output and by inducing splanchnic arterial vasoconstriction, it was suggested that
they might increase the risk of PVT [
33
,
34
]. This is of great importance since indications
of NSBB have recently widened, and they are now recommended not only for primary or
secondary prevention of variceal bleeding but also to prevent decompensation in patients
with compensated advanced chronic liver disease and CSPH [
4
]. A recent systemic review
and meta-analysis of mostly retrospective studies showed an increased risk of PVT in
subjects on NSSBs treatment (OR 4.62, 95% CI 2.50–8.53; p< 0.00001) [35]. However, there
was high heterogeneity in relation to sample size, definition of PVT and stage of liver
disease and most of the studies did not evaluate the potential role of confounding factors.
Indeed, in two large prospective studies, NSBB were not associated with an increased risk
of PVT after adjustment for variables related to the severity of portal hypertension [
28
,
29
].
Therefore, the use of NSBB should not be limited based on this concern, even more so
considering their larger benefits in patients with cirrhosis [24].
4.2. Alterations in Coagulation
Cirrhosis has long been perceived as an acquired bleeding disorder as a consequence
of thrombocytopenia and abnormal routine coagulation tests. However, unlike hereditary
coagulopathies, cirrhosis affects the whole spectrum of the coagulation cascade (i.e., both
procoagulant and anticoagulant factors) and is associated with both platelet hyperactiv-
ity and increased levels of von Willebrand factor, all of which results in a “rebalanced
hemostasis”. This new equilibrium is fragile and can easily be tipped towards either a
prohemorrhagic or a prothrombotic phenotype. Furthermore, it was suggested that this
potential prothrombotic state is intimately involved in the progression of liver disease and
could also be involved in PVT development [3,24,36,37].
Several studies have evaluated whether the hemostatic alterations associated with
cirrhosis increase the risk of PVT and were extensively reviewed elsewhere [
24
]. Traditional
coagulation tests (e.g., prothrombin time or partial thromboplastin time) do not adequately
reflect this new hemostatic balance since they do not take into account the inhibition of
thrombin by anticoagulant factors [
3
,
36
]. The ratio between FVIII and protein C has long
been suggested to reflect this increase in coagulation potential [
38
], although recent data

J. Clin. Med. 2022,11, 6435 6 of 26
have challenged this assumption showing that despite predicting the development of com-
plications of cirrhosis, it is unrelated to the coagulation status of patients with cirrhosis [
39
].
Regarding its role in PVT, contradictory results were published [
28
,
40
,
41
]. Similar findings
were observed with other cirrhosis-related hemostatic alterations, such as the ratio of fac-
tor II to protein C, levels of coagulation factors, thrombomodulin resistance, fibrinolysis
markers, plasminogen activator inhibitor-1 levels [
42
], or viscoelastic parameters [
24
]. Of
note, the aforementioned studies evaluated coagulation factors in systemic blood with
few studies evaluating whether the portal vein may represent a hypercoagulable vascular
bed. Although initial studies described the existence of a relative hypercoagulability in
this territory [
43
,
44
], a more recent study failed to replicate this finding in cirrhotic patients
who underwent TIPS placement [
45
]. Its hypothetical contribution in PVT development
was not tested as none of these studies evaluated patients with PVT.
There are fewer data on the role of platelet aggregation in PVT development. In
opposition to previous studies suggesting platelet dysfunction in patients with cirrhosis,
recent studies show that platelets are hyperfunctional in these patients, particularly in the
decompensated stage and in the portal vein [
46
–
48
]. Moreover, this increased platelet aggre-
gatory potential was associated with a higher risk of further decompensation, death, and
PVT [
47
,
49
]. In line with these findings, a recent study showed that the ADAMTS-13/von
Willebrand factor ratio was predictive of PVT [
50
]. These results establish a rational basis
for evaluating the use of antiplatelet agents to prevent PVT and halt disease progression.
Other factors that may induce blood hypercoagulability in patients with cirrhosis are
systemic inflammation, a well-recognized feature of decompensated cirrhosis [
51
], and
HCC [
52
]. The former is scarcely studied with contradictory results [
24
,
28
]. A recent
paper observed that serum albumin was inversely associated with PVT and suggested
albumin as a modulator of the hemostatic system by reducing platelet activation through its
inhibitory effects on oxidative stress. According to the authors, these findings established
a rationale for randomized interventional studies to investigate the beneficial effects of
albumin to prevent PVT in cirrhosis [
53
]. No information in this matter was provided in
the long-term albumin administration trials [
54
,
55
]. As far as HCC is concerned, there
is growing evidence suggesting that it is associated with pro-thrombotic alterations (i.e.,
increased platelet activation and function, enhanced thrombin generation, hypo-fibrinolysis,
and elevated levels of prothrombotic microvesicles) that may synergistically contribute to
hypercoagulability and thrombosis [52].
Regarding the role of inherited and other acquired prothrombotic disorders in PVT
development, current data are conflicting. The limited number of studies available are
mostly case-control studies with small sample sizes. Their study design, target popu-
lation (diverse ethnicities and geographical locations), diagnostic criteria for PVT, and
assessment of thrombophilic conditions vary widely and contribute to the inconsistent
results [21,29,56–77].
Moreover, none of these studies have properly evaluated whether
the presence of thrombophilia impacts the progression rate or response to treatment [
77
].
Among the different thrombophilic genetic defects, Factor V Leiden and prothrombin
G20210A mutations are the most frequently studied. Three meta-analyses concluded that
they increased the risk of PVT in patients with cirrhosis [
78
–
80
], although in one of them,
this association was not shown for the prothrombin mutation [
79
], and all of them were
biased by the quality of the studies included. Inherited protein C, protein S, or antithrombin
III deficiencies are difficult to detect due to co-existent liver synthetic dysfunction [
36
].
Their levels, however, do not seem to be associated with PVT development [
81
]. The
methylene tetrahydrofolate reductase C677T and plasminogen activator inhibitor—type 1
4G–4G mutations were also described as independent predictors of PVT [
63
,
82
], although
these polymorphisms are not conclusively associated with increased thrombotic risk [
82
].
The role of other acquired prothrombotic disorders was less evaluated in patients with
liver cirrhosis and PVT. In contrast to non-cirrhotic PVT, the relevance of myeloprolifer-
ative disorders and antiphospholipid syndrome is, so far, inconclusive [
83
]. Due to the
conflicting data, current guidelines make no strong recommendations regarding testing for

J. Clin. Med. 2022,11, 6435 7 of 26
these conditions in either a screening capacity before PVT diagnosis or confirmatory once
thrombosis has developed [1–4,10].
In summary, there is no solid evidence that hypercoagulability due to cirrhosis-related
hemostatic alterations or to inherited and other acquired prothrombotic disorders plays a
major role in the pathophysiology of PVT.
4.3. Endothelial Damage
Of the three components of Virchow’s triad, the hypothetical role of endothelial
dysfunction in PVT generation is the least studied, partially due to the inaccessibility of the
splanchnic territory (for review see [
24
]). Therefore, more studies are needed that compare
endothelial-specific markers in blood from the portal area between cirrhotic patients with
or without PVT.
Endothelial injury due to sclerotherapy, previous abdominal surgery, splenectomy,
and portosystemic shunt surgery were also identified as risk factors for PVT, although
altered portal venous blood flow due to some of these procedures also promotes thrombus
formation [84].
5. Epidemiology
PVT constitutes the most common thrombotic event in the setting of cirrhosis. Defining
its incidence and prevalence is difficult due to the heterogeneity of studies regarding the
population included (LT candidates are the most studied), the definition of PVT, and the
tests used for its diagnosis [
3
]. The few prospective studies have reported incidence rates in
the range from 1.6% to 4.6% at 1 year [
28
,
29
,
85
,
86
]. A recent meta-analysis showed 1-year
and 3-year cumulative incidences of 4.8% and 9.3%, respectively [
87
]. This incidence varies
among compensated and decompensated patients. In the latter meta-analysis, the pool
incidence of PVT was 9.9% in Child–Pugh class A and 18.3% in Child–Pugh class B–C.
Higher rates were described in the presence of HCC (up to 40%) [
84
,
88
]. Incidence rates
also vary by disease etiology with evidence that PVT is more frequently associated with
nonalcoholic fatty liver disease [89].
6. Clinical Manifestations and Prognostic Impact
Diagnosis of PVT is most often asymptomatic and commonly discovered by routine
imaging tests [
1
]. Symptoms ascribed to PVT are non-specific and include nausea, vomiting,
mild abdominal pain, diarrhea, and loss of appetite. Rarely, mesenteric ischemia due
to the extension of PVT to the SMV can occur [
2
]. Patients with more advanced liver
cirrhosis are more protected than non-cirrhotic patients from this complication due to the
decompression achieved through the frequent presence of porto-systemic collaterals [
3
]. It
is, thus, important to establish a correlation between PVT features (time course, degree of
occlusion, and stage of liver disease) and the clinical presentation [
84
]. For example, in the
setting of acute abdominal pain, the finding of a partially occlusive PVT on ultrasound (US)
should not defer the performance of a contrast-enhanced computed tomography (CT) or
magnetic resonance (MR) scan to rule out other causes of abdominal pain (e.g., pileflebitis
or malignant infiltration into the portal vein) and to better characterize the true extension
of PVT.
In other instances, PVT is diagnosed in coincidence with a liver decompensation,
and again, the temporal relationship should not be directly interpreted as evidence of
causality. Indeed, the impact of PVT on the natural history and prognosis of cirrhosis is
controversial, and whether PVT is merely a manifestation of progressive disease, or an
actual cause of disease progression remains to be elucidated [
3
]. Discrepancies among
studies regarding patient selection criteria (compensated vs. decompensated), degree and
extent of thrombosis (occlusive vs. nonocclusive), treatment strategies (anticoagulation vs.
no anticoagulation), sample size, and time of follow-up have led to conflicting data [
90
].
Hence, several prospective [
29
,
85
,
91
,
92
] and retrospective studies [
30
,
93
] have shown that
PVT is not responsible for disease progression or increased mortality, whereas a randomized

J. Clin. Med. 2022,11, 6435 8 of 26
study by Villa et al. indirectly suggested the opposite. In this small, controlled trial, a
12-month
course of 4000 IU/day enoxaparin in patients with Child B–C (7–10 points)
cirrhosis not only prevented PVT but also improved survival and decompensation [
94
].
Moreover, PVT was shown to be independently associated with a higher risk of variceal
bleeding and failure of endoscopic control of bleeding and rebleeding [95–97].
In LT recipients, the impact of PVT on survival after LT seems to depend on the size
and extent of PVT at the time of surgery [
98
]. Two large transplant database analyses
showed PVT as a strong independent predictive variable of posttransplant survival but
did not stratify this risk according to the grade of PVT [
99
,
100
]. Other studies [
16
,
101
,
102
]
and a meta-analysis [
103
] have shown that only a completely occlusive PVT increases
post-transplant mortality. The threshold of PVT extension at which outcomes are worse
is unknown but is probably related to the need for non-anatomical PV reconstructions
(renoportal anastomosis, cavoportal hemitransposition, or portal vein arterialization). These
cases have worse outcomes by adding technical difficulties and increasing graft ischemic
times [
19
]. Unfortunately, there are no randomized controlled trials showing that PVT
therapy improves post-transplant survival. Due to these discrepant results and lack of
randomized controlled trials, guidelines differ on their recommendations. Hence, the
AASLD guideline on vascular disorders states that there are insufficient data to recommend
pretransplant treatment of PVT with the goal of improving posttransplant outcomes [
3
],
while the Baveno VII consensus recommends anticoagulation in potential LT candidates
independently of the degree of occlusion and extension with the goal of preventing re-
thrombosis or progression of thrombosis to facilitate adequate portal anastomosis in LT
and reduce post-transplant morbidity and mortality [
4
]. Similarly, some guidelines only
recommend screening for PVT in potential LT candidates at the time of screening for HCC
(1, 4, 10), while others do not make any specific recommendations [3].
7. Natural History
PVT is a heterogeneous condition also with respect to its natural history, and this
heterogeneity makes PVT a unique entity among venous thromboses [
24
]. On the one hand,
the spontaneous recanalization of PVT is extensively described [
21
,
29
,
30
,
92
,
93
,
102
,
104
].
A recent meta-analysis comparing anticoagulated vs. non-anticoagulated patients with
cirrhotic PVT showed a rate of spontaneous portal vein recanalization of 42% [
105
]. The
probability of this event is higher in compensated cirrhosis or with partial PVT (up to
70%) [
29
] and much lower in patients with decompensated cirrhosis and those listed
for LT [
21
,
98
,
102
,
106
]. The different imaging techniques used to stage the extent of the
thrombus also contribute to the heterogeneous rates of spontaneous recanalization or
of progression reported. In addition to these factors, no other predictors of spontaneous
improvement or progression are known, which makes it difficult to evaluate the real efficacy
of the different treatments used for PVT. It must be noted that although spontaneous
resolution of PVT may occur, especially if non-occlusive and in compensated cirrhosis, PVT
progression occurs in 33% of untreated patients [105].
On the other hand, the rates of portal vein recanalization after anticoagulation are
substantially lower than in other thromboses, especially in an aged thrombus [
24
]. Driever
et al. recently proposed an explanation for this finding [
107
]. In their study, they described
the composition and structure of nonmalignant cirrhotic PVT that were collected during
LT in 79 patients. They observed that all PVT consisted of tunica intima thickening of the
portal vein vessel wall in an appearance resembling intimal fibrosis, with only one-third of
the thrombi containing an additional fibrin-rich thrombus. Based on these findings, they
suggested changing the name PVT to portal vein stenosis and that the absence of fibrin in
most patients may explain the low rates of recanalization with anticoagulant therapy.
8. Diagnosis
The initial diagnosis of PVT is often made with Doppler US and this diagnostic
technique is the screening method of choice for PVT [
2
,
4
]. Doppler US may demonstrate

J. Clin. Med. 2022,11, 6435 9 of 26
hyperechoic material within the vessel lumen, dilatation of the portal vein, and diminished
portal venous flow [
108
–
110
]. US has a sensitivity ranging from 73–93%, specificity of 99%,
and positive predictive value of 87–96% compared with angiogram [
16
] and CT scan [
108
].
Advantages of US Doppler over other diagnostic tests include lower cost, wider availability,
and lack of radiation exposure. Despite being an excellent initial screening test, US Doppler
is an operator-dependent exploration and has lower reliability in the presence of bowel
gas, obesity, partially occlusive PVT, and in delimiting the extension of the thrombi to SV
and SMV. Furthermore, it may be difficult to differentiate bland thrombi from malignant
portal vein invasion. For all these reasons, current guidelines recommend performing a
contrast-enhanced imaging study following PVT diagnosis with US [
1
–
4
,
10
]. Both CT and
MR scans are excellent techniques for diagnosing PVT and portal cavernoma [
108
]. In
comparison to CT, MR scan has the advantages of less radiation and a better safety profile,
but it is limited by motion and flow artifacts, lower availability, higher cost, and technical
difficulties in patients with implanted metallic devices or surgical clips [
2
]. Another less
studied technique in this setting is endoscopic US. In a small cohort of patients with
and without cirrhosis it had a sensitivity of 81% and a specificity of 93% for diagnosing
PVT [
111
]. However, given its moderately invasive nature and inability to definitively
assess for HCC or mesenteric infarction, it is not routinely recommended in the diagnostic
algorithm of PVT.
The exclusion of tumoral invasion of the portal vein is essential to both decisions
regarding further management of HCC and determination of LT candidacy [
84
]. It may
occur in up to 12% to 20% of the patients with HCC [
112
,
113
]. Findings that support this
malignant invasion include enlarged portal vein diameter, enhancement of the throm-
bus in the arterial phase of contrast injection, neovascularity, distance from tumor to
thrombus lower than 2 cm, and tumor size > 5 cm [
114
,
115
]. The recently proposed A-
VENA criteria incorporates all these findings, except for tumor size, and also includes
alfa-fetoprotein > 1000 ng/dL.
In patients with
≥
3 of these criteria, the diagnosis of ma-
lignant invasion could be accurately made (100% sensibility, 94% specificity, 80% positive
predictive value and 100% negative predictive value) [116].
In regard to the “age” of PVT, features of recent PVT include hypoechogenic and
hypodense thrombus, increased attenuation in the portal vein on an unenhanced CT scan,
and increased attenuation in the portal vein and a central lucency on a contrast-enhanced
CT scan. Associated hepatic perfusion changes can also be seen in the form of increased
hepatic parenchymal enhancement in the arterial phase and reduced enhancement during
the portal phase. In contrast, calcification within the wall of a thrombus and presence of
cavernoma suggest chronicity [
2
,
84
] (Figure 3). It must be pointed out that the former can
only be detected using US or CT but not MR and that cavernous transformation can occur
within 1–3 weeks after PVT onset [23] (Figure 4).

J. Clin. Med. 2022,11, 6435 10 of 26
J. Clin. Med. 2022, 11, x FOR PEER REVIEW 10 of 26
Figure 3. Different presentations of portal vein thrombosis through contrast-enhanced CT scan. (A)
Axial plane showing a partially occlusive portal vein thrombosis of the main portal trunk without
collaterals or other indirect signs of portal hypertension. (B) Apparition of collateral circulation with
umbilical vein repermeabilization and enlarged spleen in the context of portal vein thrombosis. (C)
Oblique plane showing a partially occlusive portal vein thrombosis of the main portal trunk with
hepatic perfusion defects on the lower segments of the right lobe. (D) Chronic portal vein throm-
bosis in patient with cirrhosis. Note the calcification of the portal vein as an indirect sign of chronic-
ity. Atrophic liver with splenomegaly, collaterals, and ascites are found in the context of cirrhosis.
Figure 4. Cavernous transformation of the portal vein. (A) Axial plane showing the substitution of
the main portal vein trunk by porto-portal collaterals originated from the vasa vasorum of the portal
vein. (B) Coronal plane of the portal vein and its cavernous transformation with the entanglement
of the new vessels composing the porto-portal collaterals.
Figure 3.
Different presentations of portal vein thrombosis through contrast-enhanced CT scan.
(A) Axial
plane showing a partially occlusive portal vein thrombosis of the main portal trunk without
collaterals or other indirect signs of portal hypertension. (
B
) Apparition of collateral circulation
with umbilical vein repermeabilization and enlarged spleen in the context of portal vein thrombosis.
(C) Oblique
plane showing a partially occlusive portal vein thrombosis of the main portal trunk with
hepatic perfusion defects on the lower segments of the right lobe. (
D
) Chronic portal vein thrombosis
in patient with cirrhosis. Note the calcification of the portal vein as an indirect sign of chronicity.
Atrophic liver with splenomegaly, collaterals, and ascites are found in the context of cirrhosis.
J. Clin. Med. 2022, 11, x FOR PEER REVIEW 10 of 26
Figure 3. Different presentations of portal vein thrombosis through contrast-enhanced CT scan. (A)
Axial plane showing a partially occlusive portal vein thrombosis of the main portal trunk without
collaterals or other indirect signs of portal hypertension. (B) Apparition of collateral circulation with
umbilical vein repermeabilization and enlarged spleen in the context of portal vein thrombosis. (C)
Oblique plane showing a partially occlusive portal vein thrombosis of the main portal trunk with
hepatic perfusion defects on the lower segments of the right lobe. (D) Chronic portal vein throm-
bosis in patient with cirrhosis. Note the calcification of the portal vein as an indirect sign of chronic-
ity. Atrophic liver with splenomegaly, collaterals, and ascites are found in the context of cirrhosis.
Figure 4. Cavernous transformation of the portal vein. (A) Axial plane showing the substitution of
the main portal vein trunk by porto-portal collaterals originated from the vasa vasorum of the portal
vein. (B) Coronal plane of the portal vein and its cavernous transformation with the entanglement
of the new vessels composing the porto-portal collaterals.
Figure 4.
Cavernous transformation of the portal vein. (
A
) Axial plane showing the substitution of
the main portal vein trunk by porto-portal collaterals originated from the vasa vasorum of the portal
vein. (
B
) Coronal plane of the portal vein and its cavernous transformation with the entanglement of
the new vessels composing the porto-portal collaterals.

J. Clin. Med. 2022,11, 6435 11 of 26
9. Prophylaxis
There is only one trial assessing the use of anticoagulation for preventing PVT. In
this study by Villa et al., 70 patients with cirrhosis (Child B7-C10) were randomized to
receive enoxaparin at prophylactic doses (4000 IU/day for 48 weeks) vs. no treatment.
Patients receiving enoxaparin had lower incidence of PVT and a sustained decrease in
decompensation events that exceeded the expected from the reduction in PVT. The au-
thors hinted at an enoxaparin-induced improvement of intestinal barrier function and
reduced bacterial translocation as a potential mechanism [
94
]. It was also postulated that
these beneficial effects could also be related to the antifibrotic effects of anticoagulation.
Indeed, increasing evidence suggests that the potential prothrombotic state associated
with cirrhosis leads to liver fibrosis development and progression in liver disease pre-
sumably by generating thrombi in the hepatic microcirculation that cause parenchymal
extinction and by activating hepatic stellate cells through thrombin and Factor Xa via
protease-activated receptors [
37
,
117
]. Results from a confirmatory study using ribaroxaban
instead of enoxaparin are eagerly awaited (ClinicalTrials.gov Identifier: NCT02643212).
10. Treatment
The decision to treat a PVT in the setting of cirrhosis is determined by the age and
extent of thrombus, the presence of symptoms, and the patient’s transplant status [
84
].
In patients with concern for intestinal ischemia, early initiation of anticoagulation and
immediate consultation with surgery, critical care, interventional radiology, and hematology
is advised [
3
]. In the patient without ischemic symptoms, the weak existing evidence on
the beneficial effects of therapy and the uncertain impact of PVT on the natural history of
cirrhosis explain the heterogenous recommendations of current guidelines. In this scenario,
the aim of treatment is to prevent clot extension that could potentially lead to progression
of portal hypertension, hinder a future LT, or preclude a conventional end-to-end portal
vein anastomosis, thus, reducing post-transplant morbidity and mortality [
3
,
4
]. Overall,
and especially in non-LT candidates, treatment should be considered on a case-by-case
basis. Table 2shows the recommendations of the different guidelines regarding treatment
indications and other issues.
10.1. No Treatment
A conservative approach is generally considered in asymptomatic non-LT candidates
in whom the uncertainties of the survival benefit of anticoagulation are greater. In this
scenario, recent guidelines suggest a conservative approach in thrombosis of small in-
trahepatic sub-branches of the portal vein or minimally occlusive (<50% obstruction of
the lumen) PVT. In case of progression at serial imaging, anticoagulation should then be
considered [3,4].
The latter strategy can be also applied to patients with chronic complete occlusion
of PVT or cavernous transformation of the portal vein with established collaterals in
whom there is no established benefit for anticoagulant therapy [
3
]. The main objective of
anticoagulation in these patients is to prevent recurrent thrombosis and, to a lesser extent,
recanalization. The decision-making process in this setting should be based on bleeding
risk, SMV involvement, presence of a thrombophilic condition, LT candidacy, and patient
preferences. Thus, the guideline on disorders of the hepatic and mesenteric circulation of
the American College of Gastroenterology suggests anticoagulation in patients with chronic
PVT only if there is (i) evidence of inherited thrombophilia, (ii) progression of thrombus,
(iii) history of bowel ischemia due to thrombus extension into the mesenteric veins, or (iv)
PVT in a patient awaiting LT [2].

J. Clin. Med. 2022,11, 6435 12 of 26
Table 2. Current guidelines recommendations for management of portal vein thrombosis in cirrhosis.
Baveno VII 2022 AASLD 2021 ACG 2020 ICLDC 2018 EASL 2015
Screening
for PVT
Listed or potential candidates for
LT at the time of HCC screening -
(i) new diagnosis of cirrhosis
(ii) onset of PH
(iii) decompensation.
US every 6 months in
(i) patients with cirrhosis and PH, or
(ii) Listed or potential candidates for LT
Listed or potential
candidates for LT
Imaging
test
- Screening: US
- Diagnosis: CT scan or MRI - Diagnosis: CT scan or MRI
- Screening: US
- Diagnosis: CT scan or
MRI
- Screening: US
- Diagnosis: CT scan or MRI
- Diagnosis: CT scan or
MRI
Screening
for throm-
bophilia
-(i) family history of MPN
(ii) suggestive laboratory findings
(i) previous thrombosis
(ii) thrombosis at unusual sites
(iii) family history
“Consider on an individual basis” “Consider screening”
Indications
for
treatment
- Recommended:
(i) recent (<6 m) PVT completely
or partially occlusive of the PV
trunk
(ii) symptomatic PVT
(iii) potential candidates for LT
- Considered:
(iv) minimally occlusive that
progresses (v) compromise of
SMV
(i) Recent (<6 m) completely or
partially occlusive of the main PV
or SMV
(ii) Ischemic symptoms
(i) evidence of thrombophilia,
(ii) progression into the
mesenteric veins, or
(iii) current or previous
evidence of bowel ischemia
(i) LT candidates with occlusive main
PVT with or without extension to SMV
(ii) Yerdel Grade ≥2 PVT considered on
an individual basis
(i) SMV thrombosis, with a
past history suggestive of
intestinal ischemia or
(ii) liver transplant
candidates
Medical
therapies
Initial agent: preferably LWMH
Maintenance:
- LWMH, VKAs, DOACs LWMH, VKAs or DOACs
Initial agent: UH or LWMH
Maintenance:
- LWMH, VKAs - -
TIPS
(i) PVT of the main PV without
recanalization on AC, especially
in patients listed for LT
(i) PVT that hinders a
physiological anastomosis
between the graft and recipient
(ii) refractary PH complications
-
(i) acute and chronic PVT in patients
with cirrhosis requiring treatment for
significant PH
(i) LT candidates not
responding to AC
Abbreviations: AASLD: American Association for the Study of Liver Diseases; AC: anticoagulant; ACG: American College of Gastroenterology; DOACs: direct oral anticoagulants;
EASL: European Association for the Study of the Liver; HCC: hepatocellular carcinoma; ICLDC: International Coagulation in Liver Diseases Conference; LT: liver transplant; LWMH: low
weight molecular heparin; MPN: myeloproliferative neoplasm; MRI: magnetic resonance imaging; SMV: superior mesenteric vein; SV: splenic vein; TIPS: transjugular intrahepatic
portosystemic shunt; PH: portal hypertension; PV: portal vein; PVT: portal vein thrombosis; UH: unfractionated heparin; US: ultrasound; VKAs: vitamin K antagonists.

J. Clin. Med. 2022,11, 6435 13 of 26
10.2. Anticoagulation
Anticoagulation is the mainstay of PVT treatment. The majority of studies assessing the
safety and effectiveness of anticoagulants in patients with cirrhosis are small retrospective
studies that differ in inclusion criteria, magnitude of PVT (predominancy of partially occlusive
PVT), timing and type of anticoagulation, and in the assessment of outcomes. Moreover, anti-
coagulation decisions were based on provider’s judgment and were not based on predefined
protocols [
2
]. With these limitations, data from these
studies [21,22,68,73,77,102,104,118–126]
and from aggregate-data meta-analyses [
105
,
127
–
129
] have shown that anticoagulation is
safe and effective in achieving portal vein recanalization, but its effect on survival is
still uncertain.
In regard to effectiveness, the latter meta-analyses have shown rates of recanaliza-
tion ranging between 66.6% and 71.5% for any degree of recanalization and between
40.8% and 53% for complete portal vein recanalization. In contrast, rates of thrombus
progression despite anticoagulation range between 5.7 and 9%. Early administration of
anticoagulation (<14 days in one study [
119
] or <6 months in others [
21
,
120
,
130
]) is of
utmost importance for treatment success with the mean time of recanalization ranging
from 5.5 to 8 months. However, delayed responses even after 1 year of treatment were
reported [
68
]. Other factors that are associated with a good response are less advanced
disease, less extensive thrombosis [
119
,
126
], degree of SMV occlusion less than 50%, lower
platelet count, absence of previous PHT-related bleeding, and lower spleen thickness at
baseline [
129
,
131
]. Importantly, when anticoagulation is stopped, PVT relapses in 30–40%
of the patients [
118
,
119
,
132
]. The time elapsed between discontinuation of anticoagulation
therapy and recurrence of thrombosis ranges between 2 and 5 months [119,132]. All these
findings explain the recommendations from current guidelines to anticoagulate for at
least 6 months and to maintain anticoagulation until LT (Table 2). The lack of evidence
to recommend a specific timing or type of imaging study regardless of the decision to
initiate anticoagulation or not is also of note. The AASLD suggests serial imaging every
2 to 3 months
to assess treatment response and every 3 months if a conservative approach
is chosen, but anticoagulation is considered in case of PVT progression.
The former recanalization rates in patients treated with anticoagulants are significantly
higher than those seen in untreated patients (25–42% for overall recanalization with odds
ratio ranging between 2.61 and 4.8 and 33% for complete portal vein recanalization with
odds ratio ranging between 2.14 and 3.4). Similarly, PVT progression is more likely in
untreated patients (33% with odds ratio ranging between 0.06 and 0.26) [
105
,
127
–
129
].
The impact of these higher rates of recanalization under anticoagulation therapy is still
uncertain, with two meta-analyses showing a decreased risk of variceal bleeding [
105
,
128
]
and another an improvement in overall survival [
129
]. An unpublished individual patient
data meta-analysis also showed an increased overall survival and found that the beneficial
effect of anticoagulation largely depended on portal vein recanalization [133].
Whatever the impact, anticoagulant treatment was shown to be safe, with similar
major and minor bleedings rates when compared to untreated patients (10.3–11%) [
105
,
129
].
Moreover, anticoagulation was not associated with an increase in 5-day treatment failure
or 6-week mortality in patients with cirrhosis having an episode of upper gastrointestinal
bleeding [
134
]. A platelet count below 50
×
109/L was identified as a risk factor for
bleeding from any site in patients with cirrhosis and PVT receiving anticoagulation [
119
].
These patients are also at higher risk of PVT, and consequently, management should be
assessed on a case-by-case basis [4].
Current options for anticoagulation include vitamin K antagonists (VKAs), unfrac-
tionated heparin, low-molecular-weight heparin (LMWH), fondaparinux, and direct oral
anticoagulants (DOACs). Table 3shows the main characteristics of each therapeutic option.
Most of the published studies have used VKAs and LMWH, and both seem to have similar
effectiveness [105].

J. Clin. Med. 2022,11, 6435 14 of 26
Table 3. Characteristics of the different anticoagulation therapies for the treatment of portal vein thrombosis.
Unfractionated Heparin Low-Weight Molecular Heparin Vitamin-K Antagonists Direct Oral Anticoagulants
Administration Endovenous Subcutaneous Oral Oral
Posology Daily infusion qd/bid Qd Apixaban/dabigatran: bid
Edoxaban: qd
Rivaroxaban: bd for 3 weeks, qd thereafter
Half-life Minutes to 1–2 h 4–12 h 10–24 h 6–18 h
Absorption and
bioavailability Caution if hypoalbuminemia BA 85–95%, caution if hypoalbuminemia Affected from bowel edema in PH
and diet Affected from bowel edema in PH
Monitoring antiXa factor or aPTT Not needed, but
caution if GFR < 15 mL/min/m2, obesity, and
female sex PT and INR (2–3) Not needed, especially if GFR > 15 mL/min/m2,
non-obese, and male sex
Renal function Dose change not necessary but monitor
with antiXa and aPTT
Contraindicated if severe renal failure or
dialysis, caution in mild/moderate renal
failure
Contraindicated if severe renal
failure or dialysis, caution in
mild/moderate renal failure
- No dose change needed
- Not indicated if GFR < 15 mL/min/m2
Side Effects
- Hemorrhage/hematoma
- Heparin-induced thrombopenia
(+++)
- Hyperkalemia
- Hemorrhage/hematoma
- Heparin-induced thrombopenia (++)
- Altered LFT Hemorrhage/hematoma - Hemorrhage/hematoma
- Altered LFT
Bleeding risk ++ ++ ++ Apixaban: +
Dabigatran/Edoxaban: ++
Rivaroxaban: +++
Antidote Protamine sulfate Protamine sulfate * Vitamin-K AntiX: andexanet alpha **
Dabigatran: idarucizumab **
Pros in cirrhosis - Allowed in renal failure
- Short half-life
- Subcutaneous administration
- Easy interruption before invasive
procedures Oral administration
- Oral administration
- Predictable effect
- Fewer interactions than VKAs
Cons in cirrhosis Not suitable for maintainance therapy
Fluctuating levels of ATIII
- Renal function lability
- Not well monitored through antiXa - INR not reliable in cirrhosis Not recommended in Child C
Caution in Child B
Higher costs
Abbreviations; AC: anticoagulation; antiX: apixaban, edoxaban, and rivaroxaban; aPPT: activated-partial thromboplastin clotting time; ATIII: antithrombin III; BA: bioavailability;
DOACs: direct oral anticoagulants; GFR: glomerular filtration rate; LFT: liver function test; LWMH: low-weight molecular heparin; PH: portal hypertension; PT: prothrombin time; INR:
international normalized ratio; UH: unfractionated heparin; VKAs: vitamin-K antagonists. * Less effective in LWMH than unfractionated heparin. ** Available only in selected centers.

J. Clin. Med. 2022,11, 6435 15 of 26
10.2.1. Unfractionated Heparin
Treatment of PVT with unfractionated heparin may be used as the initial agent in
the presence of renal insufficiency and/or in patients with concern for intestinal ischemia
due to the possibility of rapid reversal of anticoagulation [
2
]. However, its intravenous
administration precludes its use as a long-term treatment.
10.2.2. Low Molecular Weight Heparin (LMWH)
LMWH is traditionally considered the initial treatment of choice for PVT. Due to its
parenteral administration, patient compliance and quality of life can be compromised.
Therefore, it is generally used as a “bridge” therapy in patients that will ultimately receive
VKAs or DOACs. The duration of this “bridge” therapy varies greatly among centers, with
some initiating LMWH and VKAs simultaneously (with discontinuation of LMWH once
the INR reaches therapeutic range of 2–3) and others (similar to our center) postponing
oral anticoagulation for a month. However, in some specific patients, LMWH may be
more suitable than VKAs, such as in patients with refractory ascites requiring periodic
paracentesis or patients with prolonged INR.
In terms of dose, a small study showed that enoxaparin 1 mg/kg twice daily had
similar efficacy with fewer complications than 1.5 mg/kg daily [
121
]. Whether a reduction
in dose is necessary in patients with high bleeding risk (e.g., severe thrombocytopenia) is
unknown, with one small study showing that a reduced dose was not associated with a
decrease in efficacy [
130
]. Measuring anti–Factor Xa activity to monitor the anticoagulant
effect of LMWH may lead to therapeutic overdose due to the low levels of antithrombin III
(the substrate to which LMWH binds) in patients with advanced disease. Thus, anti-Xa
levels were found to be significantly lower in patients with cirrhosis despite an adequate
anticoagulation effect [
135
,
136
]. Despite this limitation, we still use anti-Xa levels to help
us adjust the dose in patients with bleeding complications on LMWH therapy, more so in
the presence of renal dysfunction and morbid obesity.
10.2.3. Fondaparinux
Fondaparinux constitutes a molecule that inhibits activated factor X through selective
high-affinity binding to antithrombin III [
137
]. Unlike heparin, fondaparinux does not
inhibit thrombin directly or platelet factor IV. For this reason, risk of heparin-induced throm-
bocytopenia is much lower [
138
]. Its once-daily administration makes it more convenient
than most LMWH.
Regarding its efficacy and safety, fondaparinux was compared to LMWH in one
retrospective study including 124 patients with cirrhosis and PVT. Fondaparinux showed
higher probability of resolution of PVT at 36 months (77% vs. 51%; p= 0.001) but also
higher bleeding rates (27% vs. 13%; p= 0.06) [
139
]. Further prospective studies are required
before making a formal recommendation.
10.2.4. Vitamin K Antagonists
The use of VKAs with the aforementioned “bridge” strategy was shown to be safe
and effective in both waitlist and non-waitlist cohorts [
102
,
126
]. Recanalization rates
and adverse effects seem to be similar when compared to LMWH [
104
,
120
]. The main
limitations of VKA are their narrow therapeutic window and the risk of underdosing due
to the baseline elevation of INR observed in patients with advanced cirrhosis.
10.2.5. Direct Oral Anticoagulants
DOACs, including direct thrombin inhibitor (dabigatran) and factor Xa inhibitors
(rivaroxaban, apixaban, and edoxaban) were recently added to the PVT therapeutic ar-
mamentarium. Their main advantages are their oral administration in fixed doses and
poor interaction with other drugs. Current available data suggest that there are no major
safety concerns regarding the use of DOACs in patients with Child–Pugh A and that
they should be used with caution in patients with Child–Pugh B (some authors do not

J. Clin. Med. 2022,11, 6435 16 of 26
recommend rivaroxaban in these patients because of increased plasma concentrations
and pharmacodynamic effects [
140
]). In patients with Child–Pugh C, DOACs are not
recommended [4]
In regard to their pharmacokinetics in cirrhosis, very little is known.
In vitro
studies
using plasma of decompensated cirrhosis have shown differences in anticoagulation po-
tency when measured by thrombin generation assays [
141
,
142
]. Defects in various steps
of drug metabolism such as plasma protein binding, cytochrome p450 function, biliary
excretion, and renal clearance due to the underlying cirrhosis may partially explain these
results, although larger in vivo studies are needed [3,84].
Several retrospective studies [
143
–
147
] and meta-analyses [
148
,
149
] have observed a
similar or better safety profile in terms of bleeding complications of DOACs compared to
VKAs in cirrhotic patients affected by atrial fibrillation, venous thromboembolism, or PVT.
Bleeding definitions differed among these studies, and to control for this bias, Nisly et al.
conducted a systematic review and meta-analysis considering only studies in which the
primary safety outcome was major bleeding according to the definition of the International
Society on Thrombosis and Haemostasis. They found no major differences in this regard
between DOACS and traditional anticoagulants [
148
]. It must be noted, however, that
the bleeding risk increased in patients with advanced cirrhosis. In a retrospective study,
Semmler et al. observed a significant association of spontaneous bleedings with liver
disease severity [147].
There is even less evidence in relation to the effectiveness of DOACs in patients with
cirrhosis and PVT. In the only randomized, controlled trial, Hanafy et al. showed that
rivaroxaban was more effective than warfarin in terms of recanalization rates, recurrence
of PVT, and safety in patients with HCV-related cirrhosis and PVT [
150
]. Similar findings
were found in a retrospective study comparing edoxaban with warfarin [
151
] and in a
prospective study comparing ribaroxaban and dabigatran with no treatment [152].
Due to this increasing evidence, their much easier administration, and the existence
of reversal agents (idarucizumab for dabigatran and andexanet alfa for rivaroxaban and
apixaban), these agents are increasingly utilized. Current barriers, beyond safety issues in
patients with advanced liver disease, are their high cost and limited availability.
10.3. Transjugular Intrahepatic Porto-Systemic Shunt
PVT was previously considered a contraindication to TIPS creation. However, the
introduction of new interventional radiological techniques has improved the rates of
technical success up to 86.7–95%. It must be highlighted that most of the available data
come from small, non-controlled, and retrospective cohorts that differ in inclusion criteria
and treatment applied. Moreover, complications of portal hypertension refractory to
conventional therapy, and not PVT itself, were the most common indications for TIPS
placement in patients with cirrhosis and PVT [153–155].
Two meta-analyses have shown recanalization rates after TIPS of 81–84.4% and of 73%
for complete recanalization. The rates of major complications were 10% [
156
,
157
]. When
compared to anticoagulation, TIPS has a higher effectiveness in terms of portal vein recanal-
ization [
158
,
159
]. Regarding portal-hypertension-related complications, two randomized
controlled trials have evaluated the effectiveness of TIPS in comparison to standard therapy
(endoscopic band ligation + propranolol + anticoagulation) for the prevention of variceal
rebleeding in cirrhotic patients with PVT. Both studies showed that TIPS was more effective
in preventing rebleeding and in recanalizing PVT without increasing the risk of hepatic
encephalopathy and adverse effects. These beneficial effects, however, did not translate into
improved survival [
160
,
161
]. Both of these trials used anticoagulation after TIPS placement,
although indications of anticoagulation after TIPS placement are not clear. In fact, current
evidence does not support its use for further improving recanalization rates, although it
might be considered in cases of PVT extension to the SMV [32,156,158,162].
Patients with portal cavernoma or with no identifiable intrahepatic portal trunk or
branches are the most challenging. For these patients, a modified transplenic or transhepatic

J. Clin. Med. 2022,11, 6435 17 of 26
approach, known as portal vein recanalization-TIPS, was shown to improve technical
success to over 90% in the most recent series (range 75–100%) [
163
–
166
]. In these procedures,
portal vein recanalization is performed by angioplasty/stenting with subsequent TIPS
insertion to ensure the outflow of the system. TIPS failure may be due to lack of a landing
zone at the distal end of the portal vein or at the spleno-mesenteric confluence [167].
In line with the above, current guidelines recommend considering TIPS for the follow-
ing indications in patients with cirrhosis and PVT: (1) inadequate response to or contraindi-
cation of anticoagulation; (2) chronic PVT/portal cavernoma with portal-hypertension-
related complications refractory to medical treatment; and (3) chronic PVT that hinders a
physiological anastomosis between the graft and recipient portal vein [
1
–
4
,
168
]. Figure 5
shows the therapeutic algorithm according to the latest Baveno VII consensus [4].
J. Clin. Med. 2022, 11, x FOR PEER REVIEW 17 of 26
Figure 5. The algorithm for the management of portal vein thrombosis in patients with cirrhosis
according to the Baveno VII consensus recommendations.
10.4. Thrombolysis
Local or systemic thrombolysis was proposed as an adjunct to anticoagulation for the
treatment of recent PVT. Small case series have reported similar efficacy rates to those
achieved with anticoagulation alone but with a high risk of procedure-related morbidity
and mortality [169–171]. Based on these preliminary observations, current guidelines only
recommend thrombolitic therapy in specialized centers for very selected patients in whom
intestinal ischemia persists despite anticoagulation [3,12].
10.5. Other Considerations
The management of complications of portal hypertension should not differ from
those of other patients with cirrhosis. Anticoagulation must be started always after imple-
menting an adequate prophylaxis for gastrointestinal bleeding [1]. Therefore, decompen-
sated patients not receiving NSBB should undergo screening endoscopy while patients
with compensated advanced chronic liver disease with unequivocal signs of clinically sig-
nificant portal hypertension may be started directly on NSBB. Otherwise, an upper endos-
copy should be performed in patients not fulfilling the Baveno VI criteria [4]. If these cri-
teria are met, this decision should be individualized depending on the age and extent of
PVT and on whether anticoagulant therapy is to be initiated. Importantly, recent data sug-
gest that anticoagulation should not be delayed until variceal eradication or complete β-
blockade is achieved [3]. This recommendation also applies to the setting of secondary
prophylaxis. Indeed, the continuation of LMWH through prophylactic endoscopic vari-
ceal ligation did not increase the risk of bleeding in patients with cirrhosis [172], with
similar findings in patients with non-cirrhotic PVT [173]. Further data in this regard are
needed.
Figure 5.
The algorithm for the management of portal vein thrombosis in patients with cirrhosis
according to the Baveno VII consensus recommendations.
10.4. Thrombolysis
Local or systemic thrombolysis was proposed as an adjunct to anticoagulation for
the treatment of recent PVT. Small case series have reported similar efficacy rates to those
achieved with anticoagulation alone but with a high risk of procedure-related morbidity
and mortality [
169
–
171
]. Based on these preliminary observations, current guidelines only
recommend thrombolitic therapy in specialized centers for very selected patients in whom
intestinal ischemia persists despite anticoagulation [3,12].
10.5. Other Considerations
The management of complications of portal hypertension should not differ from those
of other patients with cirrhosis. Anticoagulation must be started always after implementing
an adequate prophylaxis for gastrointestinal bleeding [
1
]. Therefore, decompensated
patients not receiving NSBB should undergo screening endoscopy while patients with
compensated advanced chronic liver disease with unequivocal signs of clinically significant
portal hypertension may be started directly on NSBB. Otherwise, an upper endoscopy

J. Clin. Med. 2022,11, 6435 18 of 26
should be performed in patients not fulfilling the Baveno VI criteria [
4
]. If these criteria are
met, this decision should be individualized depending on the age and extent of PVT and
on whether anticoagulant therapy is to be initiated. Importantly, recent data suggest that
anticoagulation should not be delayed until variceal eradication or complete
β
-blockade is
achieved [
3
]. This recommendation also applies to the setting of secondary prophylaxis.
Indeed, the continuation of LMWH through prophylactic endoscopic variceal ligation did
not increase the risk of bleeding in patients with cirrhosis [
172
], with similar findings in
patients with non-cirrhotic PVT [173]. Further data in this regard are needed.
Patients with HCC invasion of the portal vein do not benefit from anticoagulation [
2
].
However, in some rare cases, the initial “malignant” thrombus induces a stagnant flow that
can lead to clot formation and symptomatic PVT (e.g., intestinal ischemia). In this infrequent
scenario, anticoagulation may be considered after weighing the risk and benefits. In regard
to cancer-associated symptomatic recent (non-cirrhotic) splanchnic vein thrombosis, the
International Society on Thrombosis and Haemostasis recommends LMWH or DOACs.
They suggest LMWH in patients with luminal gastrointestinal cancer, active gastrointestinal
mucosal abnormalities, genitourinary cancer at high risk of bleeding, or receiving current
systemic therapy with potentially relevant drug–drug interactions with DOACs [12].
Finally, we have a few words regarding the prevention of PVT after LT. Pre-LT PVT
is a risk factor for PVT recurrence, with a greater risk if a non-anatomical anastomosis is
performed or if pre-LT PVT was of a great degree and extension [
98
]. In the recent consensus
of the Spanish Society of Liver Transplantation and the Spanish Society of Thrombosis and
Hemostasis, therapeutic LMWH (i.e., 1 mg/kg) started within the first 24 h after surgery is
recommended in patients with risk factors of PVT in the absence of coagulopathy, liver graft
dysfunction, or low platelet count (<30,000–50,000/
µ
L). Risk factors include pre-LT PVT,
slow portal flow (after reperfusion) defined as <1300 mL/min or <65 mL/min/100 g, partial
thrombectomy or vein intimal layer lesion during thrombectomy, nonphysiologically portal
vein inflow reconstruction, and thrombophilic disorders in the recipient. In the absence of
complications, therapy should be prolonged at least 2 months after LT and individualized
thereafter [174].
11. Conclusions
Portal vein thrombosis constitutes the most common thrombotic event in patients with
cirrhosis. The recent incorporation of DOACs and of new radiological techniques for portal
vein recanalization are major breakthroughs in the treatment of this complication. However,
the lack of large prospective observational studies and randomized trials explain the
uncertainties regarding its impact on the natural history of cirrhosis and the heterogenous
diagnostic and therapeutic recommendations of current guidelines. Thus, future research
to fill current gaps of knowledge is needed and will likely require multicenter collaboration.
Author Contributions:
A.O.: investigation, resources, data curation, writing—original draft prepara-
tion, writing—review and editing. J.I.F.: investigation, resources, data curation, writing—original
draft preparation, writing—review and editing, supervision, project administration. Á.P., A.C., C.R.,
Á.A., R.P., F.J.G., E.F. and J.C.: visualization and supervision. All authors have read and agreed to the
published version of the manuscript.
Funding:
JoséIgnacio Fortea was supported by grants from the Carlos III Health Institute (PI20/01258)
and the Spanish Association for Study of the Liver (AEEH, Juan Cordoba grant).
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
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