Supplementary table 1 | Common risk factors for portal vein thrombosis in patients with liver cirrhosis
Risk factors for PVT
Results of univariate
analysis
Sources of evidence
Multivariate
analysis
performed?
Results of
multivariate analysis
Interpretation of results
Type of analysis
Study design
Patients
( n)
Relevant papers
Characteristics of portal flow
Decreased portal flow
velocity (cut-off:
15 cm/s)
P <0.001
Yes
OR = 44.9 (95% CI
5.3–382.7, P <0.001)
Significant in both
univariate and multivariate
analyses
Chi-square test,
logistic regression
analysis
Prospective
cohort study
73
Zocco et al.
(2009)S1
Lower mean portal vein
flow velocity
P <0.001
Yes
OR = 4.5 (95% CI
3.7–8.2, P <0.001)
Significant in both
univariate and multivariate
analyses
Chi-square test,
logistic regression
analysis
Retrospective
study
56
Pellicelli et al.
(2011)S2
Portal trunk vessel
diameter
NS
Uncertain
N/A
NS in univariate analysis
Portal trunk flow velocity
NS
Uncertain
N/A
NS in univariate analysis
Student’s t-test
Retrospective
study
150
Maruyama et al.
(2013)S3
Lower portal trunk flow
volume
P = 0.016
Uncertain
N/A
Significant in univariate
analysis
Yes
N/A
Yes
N/A
Cox regression
analysis
Retrospective
study
150
Maruyama et al.
(2013)S3
Yes
HR = 3.992 (95% CI
3.697–4.415,
P <0.0001)
Significant in univariate,
but not in multivariate
analysis
Significant in univariate,
but not in multivariate
analysis
Significant in both
univariate and multivariate
analyses
P = 0.78
No
N/A
NS in univariate analysis
Chi-square test
Retrospective
study
63
Amitrano et al.
(2000)S4
P <0.05
No
N/A
Significant in univariate
analysis
Chi-square test
Retrospective
study
64
Erkan et al.
(2005)S5
NS
No
N/A
NS in univariate analysis
Chi-square test
Retrospective
study
219
Mangia et al.
(2005)S6
Characteristics of largest collateral vessel
Larger vessel diameter
Higher flow velocity
(cut-off: 10.2 cm/s)
Higher flow volume (cutoff: 398 ml/min)
HR = 1.422 (95%
CI 1.210–1.732,
P = 0.0103)
HR = 2.876 (95%
CI 2.691–3.170,
P <0.0001)
HR = 3.894 (95%
CI 3.189–4.798,
P <0.0001)
Characteristics of coagulation abnormalities
Factor V Leiden
mutation
1
Prothrombin G20210A
mutation
MTHFR C667T mutation
OR = 1.52 (95% CI
0.64–3.60, NS)
No
N/A
NS
Meta-analysis
Meta-analysis
5 studies
Dentali et al.
(2008)S7
P = 0.002
No
N/A
Significant in univariate
analysis
Chi-square test
Retrospective
study
63
Amitrano et al.
(2000)S4
P <0.01
No
N/A
Significant in univariate
analysis
Chi-square test
Retrospective
study
64
Erkan et al.
(2005)S5
NS
No
N/A
NS in univariate analysis
Chi-square test
Retrospective
study
219
Mangia et al.
(2005)S6
OR = 3.68 (95% CI
1.58–8.57)
No
N/A
Significant in univariate
analysis
Meta-analysis
Meta-analysis
3 studies
Dentali et al.
(2008)S7
P <0.001
No
N/A
Significant in univariate
analysis
Chi-square test
Retrospective
study
63
Amitrano et al.
(2000)S4
NS
No
N/A
NS
Chi-square test
Retrospective
study
64
Erkan et al.
(2005)S5
NS (homozygous)
No
N/A
NS in univariate analysis
Chi-square test
Retrospective
study
219
Mangia et al.
(2005)S6
No
N/A
Significant
Chi-square test
Retrospective
study
76
Gabr et al. (2010)S8
Yes
OR = 4.1 (95% CI
3.2–7.3, P <0.001)
Significant in both
univariate and multivariate
analyses
Chi-square test,
logistic regression
analysis
Retrospective
study
56
Pellicelli et al.
(2011)S2
No
N/A
Significant in univariate
analysis
Chi-square test
Retrospective
study
73
Violi et al. (1994)S9
P = 0.037
(homozygous)
P <0.001
(homozygous)
Positive anticardiolipin
antibodies
Positive lupus
anticoagulant
P = 0.015
P = 0.0008
No
N/A
Significant in univariate
analysis
2
Hypofibrinolysis
TAFI: P = 0.001;
activated TAFI:
P = 0.037; PAI-1:
P = 0.004
No
N/A
Significant in univariate
analysis
PAI-1: P = 0.947;
t-PA: P = 0.205
No
N/A
NS in univariate analysis
P <0.001
Yes
OR = 15.57 (95% CI
4.09–59.14, P <0.01)
Significant in univariate
and multivariate analysis
P <0.01
No
N/A
Significant in univariate
analysis
NS
No
N/A
NS
No
NS
Retrospective
study
66
Rossetto et al.
(2013)S10
Retrospective
study
116
Zhang et al.
(2010)S11
Retrospective
study
116
Zhang et al.
(2010)S11
Mann-Whitney
U-test
Retrospective
study
188
Zhang et al.
(2013)S12
NS in univariate analysis
Student’s t--test
Retrospective
study
63
Amitrano et al.
(2000)S4
N/A
NS in univariate analysis
Student’s t--test
Retrospective
study
64
Erkan et al.
(2005)S5
No
N/A
NS in univariate analysis
Student’s t--test
Retrospective
study
76
Gabr et al. (2010)S8
AT: P = 0.119; PS:
P = 0.028; PC:
P = 0.007
Yes
PS: NS; Increased PC:
OR = 0.48 (95% CI
0.24–0.95, P = 0.036)
PC and PS were significant
in univariate analysis, but
only PC was significant in
multivariate analysis
Student’s t-test &
logistic regression
analysis
Retrospective
study
116
Zhang et al.
(2010)S11
AT: P = 0.24; PS:
P = 0.006; PC:
P = 0.16
No
N/A
Only PS was significant in
univariate analysis
Meta-analysis
Meta-analysis
9 studies
Qi et al. (2013)S13
AT: P = 0.53; PS:
P = 0.125; PC:
P = 0.058
No
N/A
NS in univariate analysis
Student’s t--test
Retrospective
study
60
Chen et al.
(2013)S14
Increased levels of
D-dimer
Decreased levels of AT,
PC and PS
Nonparametric
Mann-Whitney U
test
3
Mann-Whitney
U-test & student’s
t-test
Mann-Whitney
U-test & student’s
t-test
Abbreviations: AT, antithrombin; HR, hazard ratio; N/A, not available; NS, not significant; OR, odds ratio; PC, protein C; PS, protein S; PVT, portal vein thrombosis; PAI-1, plasminogen activator
inhibitor; TAFI, thrombin activatable fibrinolysis inhibitor; t-PA, tissue-type plasminogen activator.
S1. Zocco, M. A. et al. Thrombotic risk factors in patients with liver cirrhosis: correlation with MELD scoring system and portal vein thrombosis development. J. Hepatol 51, 682–689
(2009).
S2. Pellicelli, A. M. et al. Clinical and genetic factors associated to development of portal vein thrombosis in cirrhotic patients without hepatocellular carcinoma. J. Hepatol. 54, S77
(2011).
S3. Maruyama, H., Okugawa, H., Takahashi, M. & Yokosuka, O. De novo portal vein thrombosis in virus-related cirrhosis: predictive factors and long-term outcomes. Am. J.
Gastroenterol. 108, 568–574 (2013).
S4. Amitrano, L. et al. Inherited coagulation disorders in cirrhotic patients with portal vein thrombosis. Hepatology 31, 345–348 (2000).
S5. Erkan, O. et al. Thrombophilic gene mutations in cirrhotic patients with portal vein thrombosis. Eur. J. Gastroenterol. Hepatol. 17, 339–343 (2005).
S6. Mangia, A. et al. Causes of portal venous thrombosis in cirrhotic patients: the role of genetic and acquired factors. Eur. J. Gastroenterol. Hepatol. 17, 745–751 (2005).
S7. Dentali, F., Galli, M., Gianni, M. & Ageno, W. Inherited thrombophilic abnormalities and risk of portal vein thrombosis. A meta-analysis. Thromb. Haemost 99, 675–682 (2008).
S8. Gabr, M. A., Bessa, S. S. & El-Zamarani, E. A. Portal vein thrombosis in Egyptian patients with liver cirrhosis: Role of methylenetetrahydrofolate reductase C677T gene mutation.
Hepatol. Res. 40, 486–493 (2010).
S9. Violi, F. et al. Relation between lupus anticoagulant and splanchnic venous thrombosis in cirrhosis of the liver. BMJ 309, 239–240 (1994).
S10.
Rossetto, V. et al. Does decreased fibrinolysis have a role to play in the development of non-neoplastic portal vein thrombosis in patients with hepatic cirrhosis? Intern.
Emerg. Med. http://dx.doi.org/10.1007/s11739-013-0929-7
S11.
Zhang, D., Hao, J. & Yang, N. Protein C and D-dimer are related to portal vein thrombosis in patients with liver cirrhosis. J. Gastroenterol. Hepatol 25, 116–121 (2010).
S12.
Zhang, D. L., Hao, J. Y. & Yang, N. Value of D-dimer and protein S for diagnosis of portal vein thrombosis in patients with liver cirrhosis. J. Int. Med. Res. 41, 664–672
(2013).
S13.
Qi, X., Chen, H. & Han, G. Effect of antithrombin, protein C and protein S on portal vein thrombosis in liver cirrhosis: a meta-analysis. Am. J. Med. Sci 346, 38–44 (2013).
S14.
Chen, H. et al. Coagulation imbalance may not contribute to the development of portal vein thrombosis in patients with cirrhosis. Thromb. Res 131, 173–177 (2013).
4
Supplementary table 2 | Effect of portal vein thrombosis on the prognosis of cirrhotic patients with bleeding
Effect of PVT on
prognosis
Results of
univariate analysis
Multivariate
analysis
performed?
Results of multivariate
analysis
Interpretation of
results
Sources of evidence
Type of
analysis
Study design
Target
population
Patients
( n)
Relevant
papers
5-day failure (failure to control bleeding, rebleeding, or death within 5 days of admission)
P <0.05
Yes
OR = 3.19 (95% CI
1.53–6.67,
P = 0.002)*
OR = 3.06 (95% CI
1.39-6.68,
P = 0.005)#
P = 0.047
Yes
OR = 2.942 (95% CI
0.884–9.790,
P = 0.079)
Significant in
univariate, but not in
multivariate analysis
Logistic
regressio
n analysis
Prospective
study
LC with EVB
185
Amitrano et
al. (2012)S16
OR = 7.54 (95% CI
3.25–17.50,
P <0.01)
No
N/A
Significant in
univariate analysis
Logistic
regressio
n analysis
Retrospective
study
LC with
acute EVB
342
Xu et al.
(2011)S17
HR = 2.62 (95% CI
1.18–5.79,
P = 0.018)
Yes
HR = 2.734 (95% CI
1.228–6.088,
P = 0.014)
Significant in both
univariate and
multivariate analyses
Cox
regressio
n analysis
Cohort study
LC with
active EVB
101
Chen et al.
(2012)S18
P = 0.141
No
N/A
NS in univariate
analysis
Fisher’s
exact test
Retrospective
study
LC with EVB
97
Lee et al.
(2009)S19
P = 0.543
No
N/A
NS in univariate
analysis
Prospective
study
LC with
recent EVB
383
Amitrano et
al. (2012)S20
P = 0.382
No
N/A
NS in univariate
analysis
Prospective
study
LC with
recent EVB
83
Amitrano et
al. (2012)S20
HR = 3.344 (95%
CI 1.613–6.897,
P = 0.001)
Yes
HR = 4.049 (95% CI
1.908–8.621,
P <0.001)
Significant in both
univariate and
multivariate analyses
Randomized
controlled trial
LC with
acute GVB
95
Hung et al.
(2012)S21
Increased 5-day
failure
Significant in both
univariate and
multivariate analyses
Logistic
regressio
n analysis
Multi-center,
prospective
cohort study
LC with
hematemesis
and/or
melena
291*
207#
D’Amico et al.
(2003)S15
Bleeding
Increased 2-week
rebleeding
Increased 6-week
rebleeding
Increased 1-year
rebleeding
Increased
rebleeding during
final follow-up
5
Chisquare
test
Chisquare
test
Cox
regressio
n analysis
NS
Yes
OR = 0.17 (95% CI
0.02–1.69, NS)
NS in both univariate
and multivariate
analyses
Logistic
regressio
n analysis
Retrospective
study
LC with
acute GVB
83
Wu et al.
(2002)S22
HR = 3.19 (95% CI
1.59–6.41,
P = 0.001)
Yes
N/A
Significant in
univariate, but not in
multivariate analysis
Cox
regressio
n analysis
Cohort study
LC with
active EVB
101
Chen et al.
(2012)S18
Retrospective
study
LC with EVB
97
Lee et al.
(2010)S23
Prospectively
built cohort
LC with
acute EVB
164
Augustin et
al. (2009)S24
Prospective
study
LC with
recent EVB
383
Amitrano et
al. (2012)S20
Prospective
study
LC with
recent EVB
383
Amitrano et
al. (2012)S20
Mortality
Increased 6-week
mortality
Increased
mortality during
1-year follow-up
Increased
mortality during
final follow-up
P = 0.102
No
N/A
NS in univariate
analysis
Univariate
(Cox
regressio
n
analysis)
P = 0.01
No (PVT was not
included in
multivariate
analysis)
N/A
Significant in
univariate analysis
Logistic
regressio
n analysis
P = 0.382
No
N/A
NS in univariate
analysis
P = 0.040
No
N/A
Significant in
univariate analysis
HR = 6.024 (95%
CI: 2.770–13.158,
P <0.001)
Yes
HR = 3.390 (95% CI
1.499–7.692,
P = 0.003)
Significant in both
univariate and
multivariate analyses
Cox
regressio
n analysis
Randomized
controlled trial
LC with
acute GVB
95
Hung et al.
(2012)S21
HR = 12.6 (95% CI
5.93–26.72,
P <0.01)
Yes
HR = 6.99 (95% CI
2.42–20.16, P <0.01)
Significant in both
univariate and
multivariate analyses
Cox
regressio
n analysis
Retrospective
study
LC with
acute GVB
83
Wu et al.
(2002)S22
Notes: * data in patients independent of source of bleeding;
#
Chisquare
test
Chisquare
test
data in patients with bleeding from varices.
Abbreviations: EVB, esophageal variceal bleeding; GV, gastric variceal bleeding; HR, hazard ratio; LC, liver cirrhosis; N/A, not available; NS, not significant; OR, odds ratio; PVT, portal
vein thrombosis.
S15.
D’Amico, G. & De Franchis, R. Upper digestive bleeding in cirrhosis. Post-therapeutic outcome and prognostic indicators. Hepatology 38, 599–612 (2003).
S16.
Amitrano, L. et al. The effectiveness of current acute variceal bleed treatments in unselected cirrhotic patients: refining short-term prognosis and risk factors. Am. J.
6
Gastroenterol 107, 1872–1878 (2012).
S17.
Xu, L., Ji, F., Xu, Q. W. & Zhang, M. Q. Risk factors for predicting early variceal rebleeding after endoscopic variceal ligation. World J. Gastroenterol. 17, 3347–3352 (2011).
S18.
Chen, P. H. et al. Delayed endoscopy increases re-bleeding and mortality in patients with hematemesis and active esophageal variceal bleeding: a cohort study. J. Hepatol.
57, 1207–1213 (2012).
S19.
Lee, S. W., Lee, T. Y. & Chang, C. S. Independent factors associated with recurrent bleeding in cirrhotic patients with esophageal variceal hemorrhage. Dig. Dis. Sci. 54,
1128–1134 (2009).
S20.
Amitrano, L. et al. Splanchnic vein thrombosis and variceal rebleeding in patients with cirrhosis. Eur. J. Gastroenterol. Hepatol. 24, 1381–1385 (2012).
S21.
Hung., H. H. et al. Efficacy of non-selective beta-blockers as adjunct to endoscopic prophylactic treatment for gastric variceal bleeding: a randomized controlled trial. J.
Hepatol. 56, 1025–1032 (2012).
S22.
Wu, C. Y., Yeh, H. Z. & Chen, G. H. Pharmacologic efficacy in gastric variceal rebleeding and survival: including multivariate analysis. J. Clin. Gastroenterol. 35, 127–132
(2002).
S23.
Lee, S. W. et al. Independent factors associated with early outcome in Chinese cirrhotic patients after cessation of initial esophageal variceal hemorrhage. J. Clin.
Gastroenterol. 44, e123–e127 (2010).
S24.
Augustin, S. et al. Predicting early mortality after acute variceal hemorrhage based on classification and regression tree analysis. Clin. Gastroenterol. Hepatol. 7, 1347–1354
(2009).
7
Supplementary Table 3 | Incidence and type of TIPS procedure-related complications
Study
Enrollment
period
Target
population
Pati
ents
( n)
Gaba et al.
2013,
USAS25
June 2010—
January 2012
LT candidates
with LC and
partial PVT
4
Luca et al.
2011,
ItalyS26
January
2003—
February 2010
Han et al.
2011,
ChinaS27
December
2001—
September
2008
Perarnau et
al. 2010,
FranceS28
1990— 2004
Van Ha et
al. 2006,
USAS29
December
1995—
December
2003
LC with PVT
LC with PVT
LC with PVT
LC with PVT
70
57
Characteristics of PVT
Success
rate of
TIPS
Incidence of
procedurerelated
complications
Type of procedurerelated complications
HE
Shunt dysfunction
Degree: partial PVT (n = 4)
4/4
(100%)
0/4 (0%)
N/A
Rate of HE:
1/4 (25%)
N/A
Migration of the stent in
the MPV (n = 1)
Rate of HE at
12 and
24 months:
27% and
32%
Rate of dysfunction at
12 and 24 months:
38% and 85% (bare
stent);
21% and 29%
(covered stent)
1- and 2-year
cumulative
rate:
25% and
27%
1- and 2-year
cumulative rate:
21% and 32% (bare
stent)
Acute and
chronic HE:
4/27
(14.8%);
2/27 (7.4%)
Long-term stenosis:
8/27 (29.7%)
Rate of early
HE:
1/13 (7.7%)
Shunt revision:
1/13 (7.7%)
Degree: stenosis<50%
(n = 31); >50% (n = 39);
CTPV (n = 0) Extension: MPV
(n = 67); SMV (n = 55); SV
(n = 18); one vessel (n = 18);
2 vessels (n = 34); 3 vessels
(n = 18)
Degree: stenosis>50%
(n = 35); complete occlusion
(n = 14); fibrotic cord (n = 8);
CTPV (n = 30) Extension: MPV
(n = 57); SMV (n = 43); SV
(n = 45)
70/70
(100%)
43/57
(75%)
34
Degree: complete PVT
(n = 34); CTPV (n = 19)
27/34
(79%)
15
Degree: partially or acute PVT
(n = 11); chronic PVT with
CTPV (n = 4) Extension: MPV
(n = 15); SMV (n = 2)
13/15
(87%)
8
1/70 (1.4%)
4/57 (7%)
6/34 (17.6%)
1/15 (6.7%)
Hepatic capsule
perforation (n = 2);
caudate-lobe hematoma
(n = 1);
the bile duct was
punctured (n = 1)
Early thrombosis
(n = 3); haemobilia
(n = 1);
digestive bleeding
(n = 1);
death from intravascular
disseminated
coagulopathy (n = 1)
An access site
hematoma in the neck
due to inadvertent
carotid puncture (n = 1)
Bauer et al.
2006,
USAS30
1999— 2005
LT candidates
with end-stage
liver disease and
PVT
Blum et al.
1995,
GermanyS31
January
1990—March
1994
LC with noncavernomatous
PVT
9
Degree: stenosis >50%
(n = 7); <50% (n = 2); CTPV
(n = 4) Extension: PV alone
(n = 1); PV+SMV (n = 4);
PV+SV (n = 2); PV+SMV+SV
(n = 2);
9/9
(100%)
7
Degree: complete PVT (n = 7);
CTPV (n = 0)
7/7
(100%)
0/9 (0%)
N/A
N/A
Shunt occlusion:
1/9 (11.1%)
0/7 (0%)
No major TIPS-related
complications such as
intraperitioneal bleeding
or PE
N/A
Shunt insufficiency:
1/7 (14%)
Abbreviations: CTPV, cavernous transformation of the portal vein; HE, hepatic encephalopathy; LC, liver cirrhosis; LT, liver transplantation; MPV, main portal vein trunk; N/A, not available;
PE, pulmonary embolism; PV, portal vein; PVT, portal vein thrombosis; SMV, superior mesenteric vein; SV, splenic vein.
S25.
Gaba, R. C. & Parvinian, A. Transjugular intrahepatic portosystemic shunt for maintenance of portal venous patency in liver transplant candidates. J. Clin. Imaging Sci. 3, 28
(2013).
S26.
Luca, A. et al. Short- and long-term effects of the transjugular intrahepatic portosystemic shunt on portal vein thrombosis in patients with cirrhosis. Gut..60,846-52 (2011).
S27.
Han, G. et al. Transjugular intrahepatic portosystemic shunt for portal vein thrombosis with symptomatic portal hypertension in liver cirrhosis. J. Hepatol. 54, 78–88 (2011).
S28.
Perarnau, J. M., Baju, A., D’Alteroche, L., Viguier, J. & Ayoub, J. Feasibility and long-term evolution of TIPS in cirrhotic patients with portal thrombosis. Eur. J. Gastroenterol.
Hepatol. 22, 1093–1098 (2010).
S29.
Van Ha, T. G. et al. Transjugular intrahepatic portosystemic shunt placement in patients with cirrhosis and concomitant portal vein thrombosis. Cardiovasc. Intervent.
Radiol. 29, 785–790 (2006).
S30.
Bauer, J. et al. The role of TIPS for portal vein patency in liver transplant patients with portal vein thrombosis. Liver Transpl. 12, 1544–1551 (2006).
S31.
Blum, U. et al. Noncavernomatous portal vein thrombosis in hepatic cirrhosis: treatment with transjugular intrahepatic portosystemic shunt and local thrombolysis.
Radiology 195, 153–157 (1995).
9