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ORIGINAL ARTICLE
Association between portal vein thrombosis and risk of bleeding in liver cirrhosis: A systematic review of the literature Xingshun Qi a,b,∗, Chunping Su c, Weirong Ren b,d, Man Yang b,e, Jia Jia b,f, Junna Dai a, Wenda Xu a, Xiaozhong Guo a,∗ a
Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang 110840, China Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an 710032, China c Library of Fourth Military Medical University, Xi’an 710032, China d Department of Digestive Diseases, Sanmenxia Central Hospital, Henan University of Science and Technology, Xiaoshan Road, Sanmenxia 472000, China e Department of Gastroenterology, Songgang People’s Hospital, Shenzhen 518105, China f Department of Digestive Diseases, Shaanxi Provincial People’s Hospital, Xi’an 710068, China b
Summary Aims: A systematic review of the literature was conducted to explore the association of portal vein thrombosis (PVT) with the risk of bleeding in liver cirrhosis. Methods: PubMed, EMBASE, and Cochrane library databases were searched for all relevant papers, which compared the prevalence of bleeding at baseline and/or incidence of bleeding during follow-up between cirrhotic patients with and without PVT. Results: Eighteen papers were eligible for this systematic review. The heterogeneity among studies was marked with regards to the treatment modalities, sources of bleeding, lengths of follow-up, and ways of data expression. But most of their findings were homozygous and suggested that the cirrhotic patients with PVT were more likely to have previous histories of bleeding at their admission and to develop de novo bleeding and/or rebleeding during the short- and long-term follow-up. The association of PVT with the risk of bleeding might be weakened in the multivariate analyses. Additionally, as for the cirrhotic patients with gastric variceal bleeding treated with medical/endoscopic therapy, the association of PVT with the risk of rebleeding remained controversial in 2 studies; as for the cirrhotic patients undergoing transjugular intrahepatic portosystemic shunts for the management of variceal bleeding, a pre-existing PVT was not associated with the risk of rebleeding.
∗ Corresponding authors. Department of Gastroenterology, General Hospital of Shenyang Military Area, No. 83 Wenhua Road, Shenyang 110840 China. Tel.: +86 24 288 976 03; fax: +86 24 288 511 13. E-mail addresses: [email protected] (X. Qi), guo xiao [email protected] (X. Guo).
http://dx.doi.org/10.1016/j.clinre.2015.02.012 2210-7401/© 2015 Published by Elsevier Masson SAS.
Please cite this article in press as: Qi X, et al. Association between portal vein thrombosis and risk of bleeding in liver cirrhosis: A systematic review of the literature. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.02.012
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Conclusions: Based on a systematic review of the literature, there was a positive association between the presence of PVT and risk of bleeding in liver cirrhosis in most of clinical conditions. However, whether PVT aggravated the development of bleeding during follow-up needed to be further explored. © 2015 Published by Elsevier Masson SAS.
Introduction Gastroesophageal varices can be found in approximately 50% of cirrhotic patients at the time of diagnosis [1,2]. The development of varices is primarily attributed to an increased portal pressure caused by fibrosis and regenerative nodules (as the hepatic venous pressure gradient is more than 10 mmHg, varcies will develop [3]). Once the varices are ruptured, the mortality is up to 15—20% within 6 weeks and as high as 40% within 1 year [4,5]. The most common predictors for the first occurrence or recurrence of variceal bleeding include the diameter of varices, red signs on endoscopy, and Child-Pugh score [6]. Recently, the researchers also have cast more attention to the effect of portal vein thrombosis (PVT) on the development of variceal bleeding in liver cirrhosis [7,8], because it can further elevate the resistance to portal inflow. The important topic may influence the risk stratification of variceal bleeding, thereby improving the algorithm for the management of variceal bleeding in liver cirrhosis. Herein, we systematically review the relevant literature to clarify the association between PVT and risk of bleeding in liver cirrhosis.
Methods Search strategy and study selection As previously described, we retrieved all papers regarding PVT via the PubMed, EMBASE, and Cochrane library databases [9,10]. After this systematic search, more recently published publications were also hand-searched. Among the clinical studies with more than 10 patients, we further identified the studies that evaluated the association between PVT and risk of bleeding in liver cirrhosis. Exclusion criteria were as follows: • only malignancy was enrolled; • PVT developed after surgery, therapeutic endoscopy, or interventional treatments; • PVT developed in non-cirrhotic patients; • the control group (i.e., patients without PVT) was missing; • the association between PVT and risk of bleeding was not evaluated.
Data extraction We extracted the following characteristics of the included studies: first author, publication year, study design, enrolment period, target population, treatment modalities, total
number of observed patients, and number of patients with PVT. Additionally, we collected the data regarding the proportion of bleeding in cirrhotic patients with and without PVT. If the original data were not reported, we collected the odds or hazard ratios to express the difference in the proportion of bleeding between the two groups. Data were not synthesized, because they were expressed in different ways.
Grade of evidence The evidence was classified into high- and low-grade. The evidence was of high-grade, if any one of the 2 following points was met: • a multivariate analysis was performed to explore the statistically significant difference; • if only a univariate analysis was performed, the baseline Child-Pugh class or MELD score should be matched between patients with and without PVT. Otherwise, the evidence was of low-grade.
Results Characteristics of studies Initially, 10,936 papers regarding PVT were identified. Among them, 14 papers were eligible for this systematic review [11—24] (Fig. 1). Another 4 eligible papers, which were published after the systematic search, were also identified by hand searching [25—28]. Thus, 18 studies were finally included. The characteristics of included studies were summarized in Table 1. According to the regions, 5 studies were performed in China Taiwan, 5 studies in Italy, 3 studies in USA, 2 studies in France, 1 study in Canada, 1 study in Switzerland, and 1 study in France and Belgium. According to the enrolment periods, 3 studies were launched before 1990, 5 studies between 1990 and 2000, and 10 studies after 2000. According to the publication forms, 2 studies were published in abstracts, and 16 studies in full-texts. Hepatocellular carcinoma was excluded in 7 studies, but not in 9 studies. The information regarding the exclusion of hepatocellular carcinoma was not reported in 2 other studies. The prevalence of PVT in liver cirrhosis was 7—25%. Multivariate analyses were performed in 8 studies [11,13,14,17,18,23,24,28], and only univariate analyses were performed in 10 others. Of these studies without multivariate analyses, 5 had similar proportions of
Please cite this article in press as: Qi X, et al. Association between portal vein thrombosis and risk of bleeding in liver cirrhosis: A systematic review of the literature. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.02.012
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PVT and bleeding in liver cirrhosis
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Figure 1
Flowchart of study selection.
Child-Pugh classes between patients with and without PVT [12,15,20,25,27], 1 had similar MELD scores between the two groups [26], 3 had significantly different proportions of Child-Pugh classes between the two groups [16,19,21], and 1 did not clearly report any relevant information [22]. Thus, 14 studies were considered to have relatively high-grade evidence. The results regarding the association between PVT and the risk of bleeding were shown in Table 2.
Prior bleeding Three studies showed that the cirrhotic patients with PVT had a higher proportion of history of variceal bleeding than those without PVT [15,16,22]. First, Schmassmann et al. enrolled 60 cirrhotic patients with and without previous hemorrhage [22]. In the hemorrhage group, 10 of 30 patients had PVT; by contrast, in the non-hemorrhage group, only 3 of 30 patients had PVT. Second, Francoz et al. enrolled 251 cirrhotic patients listed for the first liver transplantation [16]. Of the patients with splanchnic vein thrombosis,
47% (18/38) had a previous history of variceal bleeding; by comparison, 23% (48/213) of the patients without splanchnic vein thrombosis had a previous history of variceal bleeding. Third, Doumit et al. also reported that significantly more cirrhotic patients with PVT had a history of variceal bleeding at admission (the detailed data were missing in the abstract) [15]. By contrast, one study by Amitrano et al., in which 387 patients presenting with esophageal variceal bleeding within recent 4 weeks were included, reported a similar proportion of previous bleeding between patients with and without PVT (10/67, 14.9% versus 60/316, 19.0%; P = 0.435) [25]. But the source of previous bleeding was not shown.
All bleeding (de novo or rebleeding) during the total follow-up Two studies reported a higher rate of bleeding in cirrhotic patients with PVT than in those without PVT. John et al. prospectively collected 290 cirrhotic patients evaluated for liver transplantation [26]. Among them, 47 patients were
Please cite this article in press as: Qi X, et al. Association between portal vein thrombosis and risk of bleeding in liver cirrhosis: A systematic review of the literature. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.02.012
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X. Qi et al. Table 1
Characteristics of included studies.
First author (year)
Country
Design
Period
Target population
Amitrano et al., 2012 [11] Amitrano et al., 2012 [25] Attili et al., 2012 [12]
Italy
Prospective cohort study (full-text) Cohort study (full-text)
January 2010— July 2011
185
32 (17%)
387
67 (17.3%)
February 2000— July 2005
129
25 (19%)
Chen et al., 2012 [13]
Taiwan
25 (25%)
Italy
291a
37 (13%)a
Dell’Era et al., 2014 [27]
Italy
Retrospective study (full-text)
February 1995— February 2009
214
44 (11%)
Doumit et al., 2009 [15]
Canada
NA (abstract)
2002
398
44 (11%)
Francoz et al., 2005 [16] Hung et al., 2012 [17]
France
NA (full-text) RCT (full-text)
Jan 1996— December 2001 April 2007— March 2011
251
38 (15%)
95
13 (14%)
John, et al. 2013 [26]
USA
Prospective cohort study (full-text) Retrospective study (full-text) Satellite study of a multicenter RCT (full-text)
July 2004— June 2009
LC with acute EVB treated with somatostatin, antibiotics, EVL LC with hematemesis and/or melena (treatments include vasoactive drugs, endoscopic therapy, combination of endoscopic and vasoactive therapy, balloon tamponade alone, or none) LC treated with EVL in the primary and secondary prophylaxis of variceal bleeding (advanced HCC was excluded) LC who underwent portal vein doppler US and who had no pre-existing HCC, TIPS or surgical shunt in-situ, or prior LT LC listed for a first LT with or without hemorrhage LC with acute GVB after primary hemostasis using gastric variceal obturation therapy (randomized to repeated gastric variceal obturation alone or in combination with non-selective -blockers) LC evaluated for LT (HCC was excluded, follow-up > 6 months) LC after the cessation of acute EVB
101
D’Amico et al., 2003 [14]
Prospective longitudinal study (abstract) Retrospective study (full-text) Multicenter, prospective, cohort study (full-text)
LC with acute EVB vasoactive therapy, antibiotics, and EVL LC and recent EVB treated by band ligation (HCC was excluded) LC without HCC
Italy
Italy
Taiwan
Lee et al., 2009 Taiwan [18] Nery, et al. 2015 [28]
France, Belgium
January 2001— December 2010
July 2005— December 2009 October 1997—January 1998a
Decemeber 2005— February 2008 June 2000— March 2006
LC without HCC
Total number of patients
290
No. PVT (%)
70b (24%)
97
19 (20%)
1243
118c (9%)
Please cite this article in press as: Qi X, et al. Association between portal vein thrombosis and risk of bleeding in liver cirrhosis: A systematic review of the literature. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.02.012
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PVT and bleeding in liver cirrhosis Table 1
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(Continued)
First author (year)
Country
Design
Period
Target population
Total number of patients
No. PVT (%)
Orloff et al., 1997 [19]
USA
Prospective cohort study (full-text)
1958—1991
1300
85 (7%)
Perarnau et al., France 2010 [20]
Retrospective study (full-text)
1990—2004
273
27 (10%)
Sarfeh, 1979 [21]
USA
Retrospective study (full-text)
1972—1978
86
18 (21%)
Schmassmann et al., 1993 [12] Wu et al., 2002 [23]
Switzerland
NA (full-text)
January 1989— Decemeber 1990
LC with acutely bleeding esophagogastric varices or a previous episode of bleeding esophagogastric varices treated with emergency or elective portacaval shunt LC undergoing TIPS for emergency bleeding hemostasis or rebleeding prevention Biopsy-proved LC treated with portal decompression surgery for active or previous variceal hemorrhage Biopsy-proved LC with or without hemorrhage
60
13 (22%)
Taiwan
Retrospective study (full-text)
November 1992— October 1998
83
15 (18%)
Yang et al., 2007 [24]
Taiwan
NA (full-text)
May 2002— October 2004
LC with acute GVB treated with endoscopic N-butyl-2-cyanoacrylate injection LC with esophageal varices treated with elective or emergent EVL
96
9 (9%)
EVB: esophageal variceal bleeding; EVL: endoscopic variceal ligation; GVB: gastric variceal bleeding; HCC: hepatocellular carcinoma; LC: liver cirrhosis; LT: liver transplantation; NA: not available; PVT: portal vein thrombosis; RCT: randomized controlled trial; TIPS: transjugular intrahepatic portosystemic shunt. a The data in the training set. b Forty-seven patients were diagnosed with PVT at baseline, and 23 patients developed PVT during follow-up. c One hundred and eighteen patients developed PVT during follow-up.
diagnosed with PVT at baseline, and another 23 patients developed PVT during the follow-up period. The incidence of upper gastrointestinal bleeding was 21.3% (10/47) in patients with PVT at baseline, 17.4% (4/23) in those who developed PVT, and 11.4% (25/220) in those without PVT. A trend toward a higher incidence of bleeding in patients with PVT was observed (14/70 versus 25/220, P = 0.065). Dell’Era et al. performed a retrospective analysis to explore the impact of PVT on the efficacy of endosopic variceal band ligation in 214 cirrhotic patients (22 with PVT and 192 without PVT) [27]. The rate of bleeding was higher in PVT patients than in non-PVT patients (2/22, 9.1% versus 15/192, 7.8%), but no significant difference was achieved. Notably, one bleeding episode in non-PVT patients was attributed to endoscopic treatment-related ulcer. In addition, a multicenter prospective study by Nevy et al. compared the risk of decompensation between patients who developed PVT during follow-up and those who did not [28]. Variceal bleeding was one of 4 features for decompensation. In the univariate analysis, the risk of decompensation was significantly associated with the development of PVT. However, the significance disappeared in the multivariate analysis.
De novo bleeding during the total follow-up Two follow-up studies reported a higher incidence of de novo bleeding in cirrhotic patients with PVT than in those without PVT [12,15]. Notably, the detailed treatment modalities were not reported. First, in a 5-year follow-up study of 398 cirrhotic patients, the incidence of de novo variceal bleeding was 39% and 20% in PVT (n = 44) and no PVT (n = 354) groups, respectively [15]. Second, Attili et al. also reported a significantly higher cumulative incidence of gastrointestinal bleeding in cirrhotic patients who developed PVT during the follow-up than in those who did not (P < 0.00001, by log-rank test) [12].
De novo bleeding within 14 days after endoscopic therapy One study by Yang et al. analyzed the risk factors associated with early bleeding in cirrhotic patients undergoing elective or emergent endoscopic variceal band ligation [24]. Early bleeding was defined as the bleeding episode or rebleeding within 14 days after endoscopic therapy. The proportion
Please cite this article in press as: Qi X, et al. Association between portal vein thrombosis and risk of bleeding in liver cirrhosis: A systematic review of the literature. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.02.012
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Results of included studies.
First author (year)
Outcomes observed
Comparative data (statistical significance)
Amitrano et al., 2012 [11] — AJG
Proportion of PVT in patients with and without 5-day failure after acute variceal bleeding Rebleeding at the 1-year follow-up in patients with and without PVT Rebleeding at the final follow-up in patients with and without PVT Gastrointestinal bleeding from any sources in patients with and without PVT PVT for predicting the 6-week rebleeding
8/31 versus 24/154 (P = 0.047)
Amitrano et al., 2012 [11] — EJGH
Attili et al., 2012 [12] Chen et al., 2012 [13]
D’Amico et al., 2003 [14]
PVT for predicting the 5-day failure after acute upper digestive bleeding
Dell’Era et al., 2014 [27]
Bleeding from esophageal varices in patients with and without PVT Percentage of variceal bleeding during follow-up in patients with and without PVT History of variceal bleed at baseline in patients with and without PVT History of variceal bleed in patients with and without PVT PVT for predicting the gastric variceal rebleeding
Doumit et al., 2009 [15] Francoz et al., 2005 [16]
Hung et al., 2012 [17]
John et al., 2013 [26] Lee et al., 2009 [18] Nery et al., 2014 [28]
Orloff et al., 1997 [19] Perarnau et al., 2010 [20] Sarfeh, 1979 [21] Schmassmann et al., 1993 [12] Wu et al., 2002 [22]
Yang et al., 2007 [23]
Upper gastrointestinal bleeding in patients with and without PVT Percentage of PVT in patients with and without rebleeding PVT for predicting the decompensation (including variceal bleeding)
Percentage of variceal rebleeding in patients with and without PVT Percentage of rebleeding in patients with and without rebleeding Proportion of rebleeding in PVT and non-PVT groups Proportion of PVT in hemorrhage and non-hemorrhage groups PVT for predicting the gastric variceal rebleeding
Proportion of PVT in bleeding and non-bleeding groups
8/67 versus 30/316 (P = 0.543) 14/67 versus 52/316 (P = 0.382) No detailed data were reported. (P < 0.00001 by log-rank test) Univariate: HR = 2.62, 95% CI: 1.18—5.79 (P = 0.018) Multivariate: HR = 2.734, 95% CI: 1.228—6.088 (P = 0.014) For any sources of bleeding: multivariate: OR = 3.19, 95% CI: 1.53—6.67 (P = 0.002) For variceal bleeding: multivariate: OR = 3.06, 95% CI: 1.39—6.68 (P = 0.005) 2/22 versus 15/192 (P = 0.761) 39% versus 20% (P < 0.05) Data were not reported (P = 0.05) 18/38 versus 48/165 (P = 0.001) Univariate: HR = 3.344, 95% CI: 1.613—6.897 (P = 0.001) Multivariate: HR = 4.049, 95% CI: 1.908—8.621 (P < 0.001) 14/70 versus 25/220 (P = 0.065) 5/14 versus 14/83 (P = 0.141) For partial PVT: univariate: HR = 1.77, 95% CI: 1.07—2.92 (P = 0.027) For partial PVT: multivariate: HR = 1.60, 95% CI: 0.69—3.74 (P = 0.28) For partial or complete PVT: univariate: HR = 1.61, 95% CI: 0.98—2.62 (P = 0.058) For partial or complete PVT: multivariate: HR = 1.37, 95% CI: 0.62—3.03 (P = 0.44) 5% versus 1% (emergency) or 0.3% (elective) 2/29 versus 18/402 (not significant) 8/18 versus 4/68 (P < 0.01) 10/30 versus 3/30 (not significant) Univariate: OR = 0.96, 95% CI: 0.24—8.89 (not significant) Multivariate: OR = 0.17, 95% CI: 0.02—1.69 (not significant) 4/19 versus 5/77 (not significant)
CI: confidence interval; HR: hazard ratio; OR: odds ratio; LC: liver cirrhosis; LT: liver transplantation; NA: not available; PVT: portal vein thrombosis.
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PVT and bleeding in liver cirrhosis of PVT was higher in bleeding group than in non-bleeding group (4/19, 21% versus 5/77, 7%), but the difference was not statistically significant.
Five-day failure after medical/endoscopic therapy Two prospective cohort studies demonstrated a higher rate of 5-day failure in cirrhotic patients with PVT than in those without PVT [11,14]. Five-day failure was defined as the failure to control bleeding, rebleeding, or death within 5 days. First, D’Amico et al. evaluated the short-term outcomes and prognostic indicators of cirrhotic patients with upper digestive bleeding [14]. In the training cohort, 37 of 251 cirrhotic patients had PVT. In the multivariate logistic regression analysis, the presence of PVT was the independent predictor for 5-day failure (for any sources of bleeding: odds ratio = 3.19, 95% confidence interval: 1.53—6.67, P = 0.002; for variceal bleeding: odds ratio = 3.06, 95% confidence interval: 1.39—6.68, P = 0.005). Second, Amitrano et al. collected the data from 185 cirrhotic patients with acute variceal bleeding [11]. In the univariate analysis, PVT was more prevalent in patients with 5-day failure than in those without (26%, 8/31 versus 16%, 24/154, P = 0.047). But only a trend was showed without any statistical significance in a multivariate logistic regression analysis (odds ratio = 2.942, 95% confidence interval: 0.884—9.790, P = 0.079).
Six-week rebleeding after medical/endoscopic therapy Two retrospective studies found a higher rate of 6-week rebleeding in cirrhotic patients with PVT than in those without PVT [13,18]. First, Chen et al. enrolled 101 cirrhotic patients with endoscopy-proven active esophageal variceal bleeding who underwent esophageal variceal ligation [13]. Among them, 25 patients were diagnosed with PVT. Univariate Cox regression analysis demonstrated a significant relationship between PVT and 6-week rebleeding (hazard ratio = 2.62, 95% confidence interval: 1.18—5.79, P = 0.018). The statistical significance was confirmed by a multivariate analysis (hazard ratio = 2.734, 95% confidence interval: 1.228—6.088, P = 0.014). Lee et al. also showed a higher proportion of PVT in patients who developed variceal rebleeding within 6 weeks after the cessation of initial esophageal variceal bleeding than in those who did not (5/14, 36% versus 14/83, 17%) [18]. But the difference between the two groups was not statistically significant.
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Gastric variceal rebleeding after medical/endoscopic therapy during the total follow-up In 2 studies, the findings regarding the association between gastric variceal rebleeding and PVT in liver cirrhosis were opposite [17,23]. First, Wu et al. retrospectively analyzed the risk factors of gastric variceal rebleeding in 83 patients undergoing endoscopic N-butyl-2-cyanoacrylate injection [23]. Fifteen of them had PVT. The odds ratios for PVT were 0.96 (95% confidence interval: 0.24—8.89) and 0.17 (95% confidence interval: 0.02—1.69) in univariate and multivariate logistic regression analyses, respectively. This suggested a similar incidence of gastric variceal rebleeding between cirrhotic patients with and without PVT. Second, a randomized controlled trial by Hung et al. evaluated the predictors for rebleeding in 95 cirrhotic patients with acute gastric variceal bleeding after gastric variceal obturation in combination with and without non-selective beta-blockers [17]. Cox regression analysis identified the presence of main portal vein thrombosis as a major predictor for rebleeding (univariate analysis: hazard ratio = 3.344, 95% confidence interval: 1.613—6.897, P = 0.001; multivariate analysis: hazard ratio = 4.049, 95% confidence interval: 1.908—8.621, P = 0.001).
Rebleeding after shunt surgery during the total follow-up Two studies demonstrated a higher rate of rebleeding after shunt surgery in cirrhotic patients with PVT than in those without [19,21]. First, in an early report, Sarfeh observed the probability of rebleeding in cirrhotic patients who had undergone portal decompression surgery for variceal hemorrhage [21]. Seven of 68 patients with the patent portal veins rebled from varices, whereas 9 of 18 patients with the thrombosed portal veins rebled (P < 0.01). Second, in a prospective cohort study, Orloff et al. enrolled 1300 cirrhotic patients who underwent emergency (n = 400) and elective (n = 900) portacaval shunt surgery [19]. The incidence of variceal rebleeding was 5% in 85 patients with PVT, 1% in 335 patients without PVT undergoing emergency surgery, and 0.3% in 880 patients without PVT undergoing elective surgery.
Rebleeding after transjugular intrahepatic portosystemic shunt during the total follow-up In a retrospective study by Perarnau et al., the incidence of rebleeding after transjugular intrahepatic portosystemic shunt was similar between cirrhotic patients with and without PVT (8% versus 7%) [20].
Rebleeding after medical/endoscopic therapy during the total follow-up
Discussion
One study by Amitrano et al. showed a higher incidence of rebleeding from varices in patients with PVT than in those without PVT at the 1-year follow-up (8/67, 11.9% versus 30/316, 9.5%; P = 0.543) and at the final follow-up (14/67, 20.9% versus 52/316, 16.5%; P = 0.382) [25].
This is the first systematic review of the literature to explore whether or not the presence of PVT can increase the risk of bleeding in liver cirrhosis. In this study, the relevant papers were identified from an extensive search strategy. Additionally, the reliability of their findings was assessed according
Please cite this article in press as: Qi X, et al. Association between portal vein thrombosis and risk of bleeding in liver cirrhosis: A systematic review of the literature. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.02.012
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to the pre-specified criteria. A majority of studies reported relatively high-grade evidence. Several positive correlations were summarized as follows: • at admission, a higher proportion of cirrhotic patients with PVT had experienced bleeding; • regardless of treatment modalities, previous histories of bleeding, or sources of bleeding, PVT increased the risk of de novo bleeding; • as for the cirrhotic patients with acute variceal bleeding treated with medical/endoscopic therapy, PVT increased the risk of 5-day failure and 6-week rebleeding; • as for the cirrhotic patients undergoing surgical shunts for the management of variceal bleeding, a pre-existing PVT increased the risk of rebleeding. Unexpectedly, as for the cirrhotic patients with gastric variceal bleeding treated with medical/endoscopic therapy, whether or not PVT would increase the risk of rebleeding remained controversial in 2 studies. This might be explained by the fact that gastric variceal bleeding was more likely to develop at a relatively low portal pressure than esophageal variceal bleeding [29,30]. In addition, as for the cirrhotic patients undergoing transjugular intrahepatic portosystemic shunts for the management of variceal bleeding, a preexisting PVT was not associated with the risk of rebleeding. However, it should be noticeable that a transjugular intrahepatic portosystemic shunt becomes technically complex in the setting of complete PVT and even impossible when an occluded portal vein progresses into fibrotic cord [31,32]. Generally, these findings suggested that PVT should increase the risk of bleeding in liver cirrhosis in nearly all clinical conditions but after transjugular intrahepatic portosystemic shunt. Given the detrimental effect of PVT on the risk of bleeding, the necessity of recanalizing the thrombosed portal vein in a timely fashion might be considered. Several case series have recently showed a relatively high rate of portal vein recanalization after anticoagulation in cirrhotic patients with PVT with or without gastroesophageal varices [16,33—35]. And few serious drug-related adverse events were reported [36]. On the other hand, the researchers have suggested the possibility of spontaneous portal vein recanalization in cirrhotic patients with partial PVT [26,37,38]. However, the probability of disease progression appeared to be higher in the absence of anticoagulation therapy [36]. More importantly, once PVT worsened, the prognosis of liver cirrhosis would be further deteriorated [38]. Unfortunately, no predictors for the thrombus extension in untreated patients are well established [39]. Thus, anticoagulation should be recommended to cirrhotic patients with PVT, if its contraindications are excluded [40]. A major limitation of this study was that the treatment modalities (medical/endoscopic therapy, shunt surgery, or transjugular intrahepatic portosystemic shunt), sources of bleeding (esophageal varices, gastric varices, or unknown), lengths of observation (short-term or total follow-up), and ways of data expression (number of events, hazard ratio, or odd ratios) were very heterogeneous among studies. Because only a few studies were eligible for every outcome, the meta-analyses might be inappropriate. Instead,
we just described the relevant outcomes from every individual study. Another limitation was that most of included studies (9/14) did not exclude the patients with hepatocellular carcinoma. Thus, we could not identify whether the nature of PVT should be attributed to malignancy or not. If PVT originated from the tumor invasion, the patients would be considered to have advanced HCC (BCLCC stage) with a very short survival time [41], which might preclude from the development of bleeding. Finally, the degree of PVT was not reported in any included studies. Therefore, we could not clarify the risk of bleeding in the subgroups with complete versus partial PVT [42,43]. In conclusions, based on the present systematic review of the literature, the presence of PVT should be positively associated with the risk of portal hypertension-related bleeding in liver cirrhosis. However, this issue regarding whether or not PVT aggravated the development of bleeding during follow-up needed to be further explored by well-designed observational studies. If the answer was ‘‘Yes’’, an early diagnosis and treatment of PVT would be further encouraged to minimize the risk of bleeding. Otherwise, a wait-and-see strategy would be considered.
Author contributions Xingshun Qi conceived and drafted the manuscript. Xingshun Qi, Chunping Su, Weirong Ren, Man Yang, Jia Jia, Junna Dai, and Wenda Xu performed the literature search and selection, and data extraction; Xiaozhong Guo gave critical comments and revised the manuscript. All authors have made an intellectual contribution to the manuscript and approved the submission.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
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9 [27] Dell’Era A, Iannuzzi F, Fabris FM, et al. Impact of portal vein thrombosis on the efficacy of endoscopic variceal band ligation. Dig Liver Dis 2014;46:152—6. [28] Nery F, Chevret S, Condat B, et al. Causes and consequences of portal vein thrombosis in 1243 patients with cirrhosis: results of a longitudinal study. Hepatology 2015;61:660—7. [29] Huang YH, Yeh HZ, Chen GH, et al. Endoscopic treatment of bleeding gastric varices by N-butyl-2-cyanoacrylate (Histoacryl) injection: long-term efficacy and safety. Gastrointest Endosc 2000;52:160—7. [30] Seewald S, Ang TL, Imazu H, et al. A standardized injection technique and regimen ensures success and safety of N-butyl-2-cyanoacrylate injection for the treatment of gastric fundal varices (with videos). Gastrointest Endosc 2008;68: 447—54. [31] Qi X, Han G, Yin Z, et al. Transjugular intrahepatic portosystemic shunt for portal cavernoma with symptomatic portal hypertension in non-cirrhotic patients. Dig Dis Sci 2012;57:1072—82. [32] Han G, Qi X, He C, et al. Transjugular intrahepatic portosystemic shunt for portal vein thrombosis with symptomatic portal hypertension in liver cirrhosis. J Hepatol 2011;54: 78—88. [33] Senzolo MT, Rossetto MSV, et al. Prospective evaluation of anticoagulation and transjugular intrahepatic portosystemic shunt for the management of portal vein thrombosis in cirrhosis. Liver Int 2012;32:919—27. [34] Delgado MG, Seijo S, Yepes I, et al. Efficacy and safety of anticoagulation on patients with cirrhosis and portal vein thrombosis. Clin Gastroenterol Hepatol 2012;10: 776—83. [35] Amitrano L, Guardascione MA, Menchise A, et al. Safety and efficacy of anticoagulation therapy with low molecular weight heparin for portal vein thrombosis in patients with liver cirrhosis. J Clin Gastroenterol 2010;44:448—51. [36] Qi X, De Stefano V, Li H, Dai J, Guo X, Fan D. Anticoagulation for the treatment of portal vein thrombosis in liver cirrhosis: a systematic review and meta-analysis of observational studies. Eur J Intern Med 2015;26:154—5. [37] 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 2013;108:568—74. [38] Luca A, Caruso S, Milazzo M, et al. Natural course of extrahepatic non-malignant partial portal vein thrombosis in patients with cirrhosis. Radiology 2012;265:124—32. [39] Qi X, Yang Z, Fan D. Spontaneous resolution of portal vein thrombosis in cirrhosis: where do we stand, and where will we go? Saudi J Gastroenterol 2014;20:265—6. [40] Qi X, Han G, Fan D. Management of portal vein thrombosis in liver cirrhosis. Nat Rev Gastroenterol Hepatol 2014;11:435—46. [41] EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012;56:908—43. [42] Qi X, Han G, Fan D. Degree of portal vein thrombosis might be associated with recanalization during anticoagulation. Clin Gastroenterol Hepatol 2012;10:820. [43] Qi X, Han G, Wang J, Wu K, Fan D. Degree of portal vein thrombosis. Hepatology 2010;51:1089—90.
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ORIGINAL ARTICLE
Association between portal vein thrombosis and risk of bleeding in liver cirrhosis: A systematic review of the literature Xingshun Qi a,b,∗, Chunping Su c, Weirong Ren b,d, Man Yang b,e, Jia Jia b,f, Junna Dai a, Wenda Xu a, Xiaozhong Guo a,∗ a
Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang 110840, China Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an 710032, China c Library of Fourth Military Medical University, Xi’an 710032, China d Department of Digestive Diseases, Sanmenxia Central Hospital, Henan University of Science and Technology, Xiaoshan Road, Sanmenxia 472000, China e Department of Gastroenterology, Songgang People’s Hospital, Shenzhen 518105, China f Department of Digestive Diseases, Shaanxi Provincial People’s Hospital, Xi’an 710068, China b
Summary Aims: A systematic review of the literature was conducted to explore the association of portal vein thrombosis (PVT) with the risk of bleeding in liver cirrhosis. Methods: PubMed, EMBASE, and Cochrane library databases were searched for all relevant papers, which compared the prevalence of bleeding at baseline and/or incidence of bleeding during follow-up between cirrhotic patients with and without PVT. Results: Eighteen papers were eligible for this systematic review. The heterogeneity among studies was marked with regards to the treatment modalities, sources of bleeding, lengths of follow-up, and ways of data expression. But most of their findings were homozygous and suggested that the cirrhotic patients with PVT were more likely to have previous histories of bleeding at their admission and to develop de novo bleeding and/or rebleeding during the short- and long-term follow-up. The association of PVT with the risk of bleeding might be weakened in the multivariate analyses. Additionally, as for the cirrhotic patients with gastric variceal bleeding treated with medical/endoscopic therapy, the association of PVT with the risk of rebleeding remained controversial in 2 studies; as for the cirrhotic patients undergoing transjugular intrahepatic portosystemic shunts for the management of variceal bleeding, a pre-existing PVT was not associated with the risk of rebleeding.
∗ Corresponding authors. Department of Gastroenterology, General Hospital of Shenyang Military Area, No. 83 Wenhua Road, Shenyang 110840 China. Tel.: +86 24 288 976 03; fax: +86 24 288 511 13. E-mail addresses: [email protected] (X. Qi), guo xiao [email protected] (X. Guo).
http://dx.doi.org/10.1016/j.clinre.2015.02.012 2210-7401/© 2015 Published by Elsevier Masson SAS.
Please cite this article in press as: Qi X, et al. Association between portal vein thrombosis and risk of bleeding in liver cirrhosis: A systematic review of the literature. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.02.012
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Conclusions: Based on a systematic review of the literature, there was a positive association between the presence of PVT and risk of bleeding in liver cirrhosis in most of clinical conditions. However, whether PVT aggravated the development of bleeding during follow-up needed to be further explored. © 2015 Published by Elsevier Masson SAS.
Introduction Gastroesophageal varices can be found in approximately 50% of cirrhotic patients at the time of diagnosis [1,2]. The development of varices is primarily attributed to an increased portal pressure caused by fibrosis and regenerative nodules (as the hepatic venous pressure gradient is more than 10 mmHg, varcies will develop [3]). Once the varices are ruptured, the mortality is up to 15—20% within 6 weeks and as high as 40% within 1 year [4,5]. The most common predictors for the first occurrence or recurrence of variceal bleeding include the diameter of varices, red signs on endoscopy, and Child-Pugh score [6]. Recently, the researchers also have cast more attention to the effect of portal vein thrombosis (PVT) on the development of variceal bleeding in liver cirrhosis [7,8], because it can further elevate the resistance to portal inflow. The important topic may influence the risk stratification of variceal bleeding, thereby improving the algorithm for the management of variceal bleeding in liver cirrhosis. Herein, we systematically review the relevant literature to clarify the association between PVT and risk of bleeding in liver cirrhosis.
Methods Search strategy and study selection As previously described, we retrieved all papers regarding PVT via the PubMed, EMBASE, and Cochrane library databases [9,10]. After this systematic search, more recently published publications were also hand-searched. Among the clinical studies with more than 10 patients, we further identified the studies that evaluated the association between PVT and risk of bleeding in liver cirrhosis. Exclusion criteria were as follows: • only malignancy was enrolled; • PVT developed after surgery, therapeutic endoscopy, or interventional treatments; • PVT developed in non-cirrhotic patients; • the control group (i.e., patients without PVT) was missing; • the association between PVT and risk of bleeding was not evaluated.
Data extraction We extracted the following characteristics of the included studies: first author, publication year, study design, enrolment period, target population, treatment modalities, total
number of observed patients, and number of patients with PVT. Additionally, we collected the data regarding the proportion of bleeding in cirrhotic patients with and without PVT. If the original data were not reported, we collected the odds or hazard ratios to express the difference in the proportion of bleeding between the two groups. Data were not synthesized, because they were expressed in different ways.
Grade of evidence The evidence was classified into high- and low-grade. The evidence was of high-grade, if any one of the 2 following points was met: • a multivariate analysis was performed to explore the statistically significant difference; • if only a univariate analysis was performed, the baseline Child-Pugh class or MELD score should be matched between patients with and without PVT. Otherwise, the evidence was of low-grade.
Results Characteristics of studies Initially, 10,936 papers regarding PVT were identified. Among them, 14 papers were eligible for this systematic review [11—24] (Fig. 1). Another 4 eligible papers, which were published after the systematic search, were also identified by hand searching [25—28]. Thus, 18 studies were finally included. The characteristics of included studies were summarized in Table 1. According to the regions, 5 studies were performed in China Taiwan, 5 studies in Italy, 3 studies in USA, 2 studies in France, 1 study in Canada, 1 study in Switzerland, and 1 study in France and Belgium. According to the enrolment periods, 3 studies were launched before 1990, 5 studies between 1990 and 2000, and 10 studies after 2000. According to the publication forms, 2 studies were published in abstracts, and 16 studies in full-texts. Hepatocellular carcinoma was excluded in 7 studies, but not in 9 studies. The information regarding the exclusion of hepatocellular carcinoma was not reported in 2 other studies. The prevalence of PVT in liver cirrhosis was 7—25%. Multivariate analyses were performed in 8 studies [11,13,14,17,18,23,24,28], and only univariate analyses were performed in 10 others. Of these studies without multivariate analyses, 5 had similar proportions of
Please cite this article in press as: Qi X, et al. Association between portal vein thrombosis and risk of bleeding in liver cirrhosis: A systematic review of the literature. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.02.012
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PVT and bleeding in liver cirrhosis
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Figure 1
Flowchart of study selection.
Child-Pugh classes between patients with and without PVT [12,15,20,25,27], 1 had similar MELD scores between the two groups [26], 3 had significantly different proportions of Child-Pugh classes between the two groups [16,19,21], and 1 did not clearly report any relevant information [22]. Thus, 14 studies were considered to have relatively high-grade evidence. The results regarding the association between PVT and the risk of bleeding were shown in Table 2.
Prior bleeding Three studies showed that the cirrhotic patients with PVT had a higher proportion of history of variceal bleeding than those without PVT [15,16,22]. First, Schmassmann et al. enrolled 60 cirrhotic patients with and without previous hemorrhage [22]. In the hemorrhage group, 10 of 30 patients had PVT; by contrast, in the non-hemorrhage group, only 3 of 30 patients had PVT. Second, Francoz et al. enrolled 251 cirrhotic patients listed for the first liver transplantation [16]. Of the patients with splanchnic vein thrombosis,
47% (18/38) had a previous history of variceal bleeding; by comparison, 23% (48/213) of the patients without splanchnic vein thrombosis had a previous history of variceal bleeding. Third, Doumit et al. also reported that significantly more cirrhotic patients with PVT had a history of variceal bleeding at admission (the detailed data were missing in the abstract) [15]. By contrast, one study by Amitrano et al., in which 387 patients presenting with esophageal variceal bleeding within recent 4 weeks were included, reported a similar proportion of previous bleeding between patients with and without PVT (10/67, 14.9% versus 60/316, 19.0%; P = 0.435) [25]. But the source of previous bleeding was not shown.
All bleeding (de novo or rebleeding) during the total follow-up Two studies reported a higher rate of bleeding in cirrhotic patients with PVT than in those without PVT. John et al. prospectively collected 290 cirrhotic patients evaluated for liver transplantation [26]. Among them, 47 patients were
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Characteristics of included studies.
First author (year)
Country
Design
Period
Target population
Amitrano et al., 2012 [11] Amitrano et al., 2012 [25] Attili et al., 2012 [12]
Italy
Prospective cohort study (full-text) Cohort study (full-text)
January 2010— July 2011
185
32 (17%)
387
67 (17.3%)
February 2000— July 2005
129
25 (19%)
Chen et al., 2012 [13]
Taiwan
25 (25%)
Italy
291a
37 (13%)a
Dell’Era et al., 2014 [27]
Italy
Retrospective study (full-text)
February 1995— February 2009
214
44 (11%)
Doumit et al., 2009 [15]
Canada
NA (abstract)
2002
398
44 (11%)
Francoz et al., 2005 [16] Hung et al., 2012 [17]
France
NA (full-text) RCT (full-text)
Jan 1996— December 2001 April 2007— March 2011
251
38 (15%)
95
13 (14%)
John, et al. 2013 [26]
USA
Prospective cohort study (full-text) Retrospective study (full-text) Satellite study of a multicenter RCT (full-text)
July 2004— June 2009
LC with acute EVB treated with somatostatin, antibiotics, EVL LC with hematemesis and/or melena (treatments include vasoactive drugs, endoscopic therapy, combination of endoscopic and vasoactive therapy, balloon tamponade alone, or none) LC treated with EVL in the primary and secondary prophylaxis of variceal bleeding (advanced HCC was excluded) LC who underwent portal vein doppler US and who had no pre-existing HCC, TIPS or surgical shunt in-situ, or prior LT LC listed for a first LT with or without hemorrhage LC with acute GVB after primary hemostasis using gastric variceal obturation therapy (randomized to repeated gastric variceal obturation alone or in combination with non-selective -blockers) LC evaluated for LT (HCC was excluded, follow-up > 6 months) LC after the cessation of acute EVB
101
D’Amico et al., 2003 [14]
Prospective longitudinal study (abstract) Retrospective study (full-text) Multicenter, prospective, cohort study (full-text)
LC with acute EVB vasoactive therapy, antibiotics, and EVL LC and recent EVB treated by band ligation (HCC was excluded) LC without HCC
Italy
Italy
Taiwan
Lee et al., 2009 Taiwan [18] Nery, et al. 2015 [28]
France, Belgium
January 2001— December 2010
July 2005— December 2009 October 1997—January 1998a
Decemeber 2005— February 2008 June 2000— March 2006
LC without HCC
Total number of patients
290
No. PVT (%)
70b (24%)
97
19 (20%)
1243
118c (9%)
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PVT and bleeding in liver cirrhosis Table 1
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(Continued)
First author (year)
Country
Design
Period
Target population
Total number of patients
No. PVT (%)
Orloff et al., 1997 [19]
USA
Prospective cohort study (full-text)
1958—1991
1300
85 (7%)
Perarnau et al., France 2010 [20]
Retrospective study (full-text)
1990—2004
273
27 (10%)
Sarfeh, 1979 [21]
USA
Retrospective study (full-text)
1972—1978
86
18 (21%)
Schmassmann et al., 1993 [12] Wu et al., 2002 [23]
Switzerland
NA (full-text)
January 1989— Decemeber 1990
LC with acutely bleeding esophagogastric varices or a previous episode of bleeding esophagogastric varices treated with emergency or elective portacaval shunt LC undergoing TIPS for emergency bleeding hemostasis or rebleeding prevention Biopsy-proved LC treated with portal decompression surgery for active or previous variceal hemorrhage Biopsy-proved LC with or without hemorrhage
60
13 (22%)
Taiwan
Retrospective study (full-text)
November 1992— October 1998
83
15 (18%)
Yang et al., 2007 [24]
Taiwan
NA (full-text)
May 2002— October 2004
LC with acute GVB treated with endoscopic N-butyl-2-cyanoacrylate injection LC with esophageal varices treated with elective or emergent EVL
96
9 (9%)
EVB: esophageal variceal bleeding; EVL: endoscopic variceal ligation; GVB: gastric variceal bleeding; HCC: hepatocellular carcinoma; LC: liver cirrhosis; LT: liver transplantation; NA: not available; PVT: portal vein thrombosis; RCT: randomized controlled trial; TIPS: transjugular intrahepatic portosystemic shunt. a The data in the training set. b Forty-seven patients were diagnosed with PVT at baseline, and 23 patients developed PVT during follow-up. c One hundred and eighteen patients developed PVT during follow-up.
diagnosed with PVT at baseline, and another 23 patients developed PVT during the follow-up period. The incidence of upper gastrointestinal bleeding was 21.3% (10/47) in patients with PVT at baseline, 17.4% (4/23) in those who developed PVT, and 11.4% (25/220) in those without PVT. A trend toward a higher incidence of bleeding in patients with PVT was observed (14/70 versus 25/220, P = 0.065). Dell’Era et al. performed a retrospective analysis to explore the impact of PVT on the efficacy of endosopic variceal band ligation in 214 cirrhotic patients (22 with PVT and 192 without PVT) [27]. The rate of bleeding was higher in PVT patients than in non-PVT patients (2/22, 9.1% versus 15/192, 7.8%), but no significant difference was achieved. Notably, one bleeding episode in non-PVT patients was attributed to endoscopic treatment-related ulcer. In addition, a multicenter prospective study by Nevy et al. compared the risk of decompensation between patients who developed PVT during follow-up and those who did not [28]. Variceal bleeding was one of 4 features for decompensation. In the univariate analysis, the risk of decompensation was significantly associated with the development of PVT. However, the significance disappeared in the multivariate analysis.
De novo bleeding during the total follow-up Two follow-up studies reported a higher incidence of de novo bleeding in cirrhotic patients with PVT than in those without PVT [12,15]. Notably, the detailed treatment modalities were not reported. First, in a 5-year follow-up study of 398 cirrhotic patients, the incidence of de novo variceal bleeding was 39% and 20% in PVT (n = 44) and no PVT (n = 354) groups, respectively [15]. Second, Attili et al. also reported a significantly higher cumulative incidence of gastrointestinal bleeding in cirrhotic patients who developed PVT during the follow-up than in those who did not (P < 0.00001, by log-rank test) [12].
De novo bleeding within 14 days after endoscopic therapy One study by Yang et al. analyzed the risk factors associated with early bleeding in cirrhotic patients undergoing elective or emergent endoscopic variceal band ligation [24]. Early bleeding was defined as the bleeding episode or rebleeding within 14 days after endoscopic therapy. The proportion
Please cite this article in press as: Qi X, et al. Association between portal vein thrombosis and risk of bleeding in liver cirrhosis: A systematic review of the literature. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.02.012
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Results of included studies.
First author (year)
Outcomes observed
Comparative data (statistical significance)
Amitrano et al., 2012 [11] — AJG
Proportion of PVT in patients with and without 5-day failure after acute variceal bleeding Rebleeding at the 1-year follow-up in patients with and without PVT Rebleeding at the final follow-up in patients with and without PVT Gastrointestinal bleeding from any sources in patients with and without PVT PVT for predicting the 6-week rebleeding
8/31 versus 24/154 (P = 0.047)
Amitrano et al., 2012 [11] — EJGH
Attili et al., 2012 [12] Chen et al., 2012 [13]
D’Amico et al., 2003 [14]
PVT for predicting the 5-day failure after acute upper digestive bleeding
Dell’Era et al., 2014 [27]
Bleeding from esophageal varices in patients with and without PVT Percentage of variceal bleeding during follow-up in patients with and without PVT History of variceal bleed at baseline in patients with and without PVT History of variceal bleed in patients with and without PVT PVT for predicting the gastric variceal rebleeding
Doumit et al., 2009 [15] Francoz et al., 2005 [16]
Hung et al., 2012 [17]
John et al., 2013 [26] Lee et al., 2009 [18] Nery et al., 2014 [28]
Orloff et al., 1997 [19] Perarnau et al., 2010 [20] Sarfeh, 1979 [21] Schmassmann et al., 1993 [12] Wu et al., 2002 [22]
Yang et al., 2007 [23]
Upper gastrointestinal bleeding in patients with and without PVT Percentage of PVT in patients with and without rebleeding PVT for predicting the decompensation (including variceal bleeding)
Percentage of variceal rebleeding in patients with and without PVT Percentage of rebleeding in patients with and without rebleeding Proportion of rebleeding in PVT and non-PVT groups Proportion of PVT in hemorrhage and non-hemorrhage groups PVT for predicting the gastric variceal rebleeding
Proportion of PVT in bleeding and non-bleeding groups
8/67 versus 30/316 (P = 0.543) 14/67 versus 52/316 (P = 0.382) No detailed data were reported. (P < 0.00001 by log-rank test) Univariate: HR = 2.62, 95% CI: 1.18—5.79 (P = 0.018) Multivariate: HR = 2.734, 95% CI: 1.228—6.088 (P = 0.014) For any sources of bleeding: multivariate: OR = 3.19, 95% CI: 1.53—6.67 (P = 0.002) For variceal bleeding: multivariate: OR = 3.06, 95% CI: 1.39—6.68 (P = 0.005) 2/22 versus 15/192 (P = 0.761) 39% versus 20% (P < 0.05) Data were not reported (P = 0.05) 18/38 versus 48/165 (P = 0.001) Univariate: HR = 3.344, 95% CI: 1.613—6.897 (P = 0.001) Multivariate: HR = 4.049, 95% CI: 1.908—8.621 (P < 0.001) 14/70 versus 25/220 (P = 0.065) 5/14 versus 14/83 (P = 0.141) For partial PVT: univariate: HR = 1.77, 95% CI: 1.07—2.92 (P = 0.027) For partial PVT: multivariate: HR = 1.60, 95% CI: 0.69—3.74 (P = 0.28) For partial or complete PVT: univariate: HR = 1.61, 95% CI: 0.98—2.62 (P = 0.058) For partial or complete PVT: multivariate: HR = 1.37, 95% CI: 0.62—3.03 (P = 0.44) 5% versus 1% (emergency) or 0.3% (elective) 2/29 versus 18/402 (not significant) 8/18 versus 4/68 (P < 0.01) 10/30 versus 3/30 (not significant) Univariate: OR = 0.96, 95% CI: 0.24—8.89 (not significant) Multivariate: OR = 0.17, 95% CI: 0.02—1.69 (not significant) 4/19 versus 5/77 (not significant)
CI: confidence interval; HR: hazard ratio; OR: odds ratio; LC: liver cirrhosis; LT: liver transplantation; NA: not available; PVT: portal vein thrombosis.
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PVT and bleeding in liver cirrhosis of PVT was higher in bleeding group than in non-bleeding group (4/19, 21% versus 5/77, 7%), but the difference was not statistically significant.
Five-day failure after medical/endoscopic therapy Two prospective cohort studies demonstrated a higher rate of 5-day failure in cirrhotic patients with PVT than in those without PVT [11,14]. Five-day failure was defined as the failure to control bleeding, rebleeding, or death within 5 days. First, D’Amico et al. evaluated the short-term outcomes and prognostic indicators of cirrhotic patients with upper digestive bleeding [14]. In the training cohort, 37 of 251 cirrhotic patients had PVT. In the multivariate logistic regression analysis, the presence of PVT was the independent predictor for 5-day failure (for any sources of bleeding: odds ratio = 3.19, 95% confidence interval: 1.53—6.67, P = 0.002; for variceal bleeding: odds ratio = 3.06, 95% confidence interval: 1.39—6.68, P = 0.005). Second, Amitrano et al. collected the data from 185 cirrhotic patients with acute variceal bleeding [11]. In the univariate analysis, PVT was more prevalent in patients with 5-day failure than in those without (26%, 8/31 versus 16%, 24/154, P = 0.047). But only a trend was showed without any statistical significance in a multivariate logistic regression analysis (odds ratio = 2.942, 95% confidence interval: 0.884—9.790, P = 0.079).
Six-week rebleeding after medical/endoscopic therapy Two retrospective studies found a higher rate of 6-week rebleeding in cirrhotic patients with PVT than in those without PVT [13,18]. First, Chen et al. enrolled 101 cirrhotic patients with endoscopy-proven active esophageal variceal bleeding who underwent esophageal variceal ligation [13]. Among them, 25 patients were diagnosed with PVT. Univariate Cox regression analysis demonstrated a significant relationship between PVT and 6-week rebleeding (hazard ratio = 2.62, 95% confidence interval: 1.18—5.79, P = 0.018). The statistical significance was confirmed by a multivariate analysis (hazard ratio = 2.734, 95% confidence interval: 1.228—6.088, P = 0.014). Lee et al. also showed a higher proportion of PVT in patients who developed variceal rebleeding within 6 weeks after the cessation of initial esophageal variceal bleeding than in those who did not (5/14, 36% versus 14/83, 17%) [18]. But the difference between the two groups was not statistically significant.
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Gastric variceal rebleeding after medical/endoscopic therapy during the total follow-up In 2 studies, the findings regarding the association between gastric variceal rebleeding and PVT in liver cirrhosis were opposite [17,23]. First, Wu et al. retrospectively analyzed the risk factors of gastric variceal rebleeding in 83 patients undergoing endoscopic N-butyl-2-cyanoacrylate injection [23]. Fifteen of them had PVT. The odds ratios for PVT were 0.96 (95% confidence interval: 0.24—8.89) and 0.17 (95% confidence interval: 0.02—1.69) in univariate and multivariate logistic regression analyses, respectively. This suggested a similar incidence of gastric variceal rebleeding between cirrhotic patients with and without PVT. Second, a randomized controlled trial by Hung et al. evaluated the predictors for rebleeding in 95 cirrhotic patients with acute gastric variceal bleeding after gastric variceal obturation in combination with and without non-selective beta-blockers [17]. Cox regression analysis identified the presence of main portal vein thrombosis as a major predictor for rebleeding (univariate analysis: hazard ratio = 3.344, 95% confidence interval: 1.613—6.897, P = 0.001; multivariate analysis: hazard ratio = 4.049, 95% confidence interval: 1.908—8.621, P = 0.001).
Rebleeding after shunt surgery during the total follow-up Two studies demonstrated a higher rate of rebleeding after shunt surgery in cirrhotic patients with PVT than in those without [19,21]. First, in an early report, Sarfeh observed the probability of rebleeding in cirrhotic patients who had undergone portal decompression surgery for variceal hemorrhage [21]. Seven of 68 patients with the patent portal veins rebled from varices, whereas 9 of 18 patients with the thrombosed portal veins rebled (P < 0.01). Second, in a prospective cohort study, Orloff et al. enrolled 1300 cirrhotic patients who underwent emergency (n = 400) and elective (n = 900) portacaval shunt surgery [19]. The incidence of variceal rebleeding was 5% in 85 patients with PVT, 1% in 335 patients without PVT undergoing emergency surgery, and 0.3% in 880 patients without PVT undergoing elective surgery.
Rebleeding after transjugular intrahepatic portosystemic shunt during the total follow-up In a retrospective study by Perarnau et al., the incidence of rebleeding after transjugular intrahepatic portosystemic shunt was similar between cirrhotic patients with and without PVT (8% versus 7%) [20].
Rebleeding after medical/endoscopic therapy during the total follow-up
Discussion
One study by Amitrano et al. showed a higher incidence of rebleeding from varices in patients with PVT than in those without PVT at the 1-year follow-up (8/67, 11.9% versus 30/316, 9.5%; P = 0.543) and at the final follow-up (14/67, 20.9% versus 52/316, 16.5%; P = 0.382) [25].
This is the first systematic review of the literature to explore whether or not the presence of PVT can increase the risk of bleeding in liver cirrhosis. In this study, the relevant papers were identified from an extensive search strategy. Additionally, the reliability of their findings was assessed according
Please cite this article in press as: Qi X, et al. Association between portal vein thrombosis and risk of bleeding in liver cirrhosis: A systematic review of the literature. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.02.012
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to the pre-specified criteria. A majority of studies reported relatively high-grade evidence. Several positive correlations were summarized as follows: • at admission, a higher proportion of cirrhotic patients with PVT had experienced bleeding; • regardless of treatment modalities, previous histories of bleeding, or sources of bleeding, PVT increased the risk of de novo bleeding; • as for the cirrhotic patients with acute variceal bleeding treated with medical/endoscopic therapy, PVT increased the risk of 5-day failure and 6-week rebleeding; • as for the cirrhotic patients undergoing surgical shunts for the management of variceal bleeding, a pre-existing PVT increased the risk of rebleeding. Unexpectedly, as for the cirrhotic patients with gastric variceal bleeding treated with medical/endoscopic therapy, whether or not PVT would increase the risk of rebleeding remained controversial in 2 studies. This might be explained by the fact that gastric variceal bleeding was more likely to develop at a relatively low portal pressure than esophageal variceal bleeding [29,30]. In addition, as for the cirrhotic patients undergoing transjugular intrahepatic portosystemic shunts for the management of variceal bleeding, a preexisting PVT was not associated with the risk of rebleeding. However, it should be noticeable that a transjugular intrahepatic portosystemic shunt becomes technically complex in the setting of complete PVT and even impossible when an occluded portal vein progresses into fibrotic cord [31,32]. Generally, these findings suggested that PVT should increase the risk of bleeding in liver cirrhosis in nearly all clinical conditions but after transjugular intrahepatic portosystemic shunt. Given the detrimental effect of PVT on the risk of bleeding, the necessity of recanalizing the thrombosed portal vein in a timely fashion might be considered. Several case series have recently showed a relatively high rate of portal vein recanalization after anticoagulation in cirrhotic patients with PVT with or without gastroesophageal varices [16,33—35]. And few serious drug-related adverse events were reported [36]. On the other hand, the researchers have suggested the possibility of spontaneous portal vein recanalization in cirrhotic patients with partial PVT [26,37,38]. However, the probability of disease progression appeared to be higher in the absence of anticoagulation therapy [36]. More importantly, once PVT worsened, the prognosis of liver cirrhosis would be further deteriorated [38]. Unfortunately, no predictors for the thrombus extension in untreated patients are well established [39]. Thus, anticoagulation should be recommended to cirrhotic patients with PVT, if its contraindications are excluded [40]. A major limitation of this study was that the treatment modalities (medical/endoscopic therapy, shunt surgery, or transjugular intrahepatic portosystemic shunt), sources of bleeding (esophageal varices, gastric varices, or unknown), lengths of observation (short-term or total follow-up), and ways of data expression (number of events, hazard ratio, or odd ratios) were very heterogeneous among studies. Because only a few studies were eligible for every outcome, the meta-analyses might be inappropriate. Instead,
we just described the relevant outcomes from every individual study. Another limitation was that most of included studies (9/14) did not exclude the patients with hepatocellular carcinoma. Thus, we could not identify whether the nature of PVT should be attributed to malignancy or not. If PVT originated from the tumor invasion, the patients would be considered to have advanced HCC (BCLCC stage) with a very short survival time [41], which might preclude from the development of bleeding. Finally, the degree of PVT was not reported in any included studies. Therefore, we could not clarify the risk of bleeding in the subgroups with complete versus partial PVT [42,43]. In conclusions, based on the present systematic review of the literature, the presence of PVT should be positively associated with the risk of portal hypertension-related bleeding in liver cirrhosis. However, this issue regarding whether or not PVT aggravated the development of bleeding during follow-up needed to be further explored by well-designed observational studies. If the answer was ‘‘Yes’’, an early diagnosis and treatment of PVT would be further encouraged to minimize the risk of bleeding. Otherwise, a wait-and-see strategy would be considered.
Author contributions Xingshun Qi conceived and drafted the manuscript. Xingshun Qi, Chunping Su, Weirong Ren, Man Yang, Jia Jia, Junna Dai, and Wenda Xu performed the literature search and selection, and data extraction; Xiaozhong Guo gave critical comments and revised the manuscript. All authors have made an intellectual contribution to the manuscript and approved the submission.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
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Please cite this article in press as: Qi X, et al. Association between portal vein thrombosis and risk of bleeding in liver cirrhosis: A systematic review of the literature. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.02.012