Non-neoplastic PVT is a common complication of liver cirrhosis. A study reported that 17.3% of patients with AVB have PVT[16],which is in line with our results (17.25%). In our study, non-occlusive thrombosis was present in 89.91% (98/109) patients with PVT. Moreover, PVT had mostly occurred recently, and 90.83% of PVTs had occurred in the portal vein trunk alone or both in the trunk and branches.
For the first time, we comprehensively analysed the effect of PVT on rebleeding and mortality in patients with AVB after EVL. We found that PVT is associated with high 14-day and 6-week rebleeding after EVL. SMV thrombosis was found to be the only risk factor for 6-week rebleeding in patients with PVT.
Only a few studies have reported that the 5-day failure and 14-day and 6-week rebleeding rates are higher in cirrhotic patients with PVT than in those without PVT[12, 14, 16, 24]. However, those studies did not exclude patients with hepatocellular carcinoma, and the number of patients with PVT was small. In this multicentre study, we enrolled 109 cirrhotic AVB patients with PVT and excluded patients with hepatocellular carcinoma or those with a treatment history of EVL + NSBBs. Our results also revealed higher rates of 5-day failure and 14-day, 6-week, and 1-year rebleeding in patients with PVT, although only the 14-day and 6-week rebleeding rates were found to be significantly higher.
VB is a clinical emergency requiring immediate and intensive intervention. The first 5 days is considered the most crucial period for prognosis because most adverse events occur during this time[24]. All unfavourable outcomes (i.e. death, FTCB, and rebleeding within 5 days) were included in a complex variable defined as the 5-day failure. Amitrano et al. found that PVT is an independent predictor for the 5-day failure[16]. Although we observed a higher rate of 5-day failure in the PVT group, the difference was not significant because of a few events. This finding indicated that the combination treatment with endoscopy and pharmacologic agents is effective for AVB with PVT and helps achieve control of initial bleeding in 96.33% patients.
Baveno VI Consensus Workshop recommends 6-week mortality as the primary endpoint for AVB studies. Lee et al. found that[12]70% of the patients died 6 weeks after initial EV bleeding because of rebleeding and that most instances (71.43%) of rebleeding occurred within 14 days of EV bleeding cessation. This result is similar to those of other studies[15-16]. In our study, 73% (11/15) rebleeding occurred within 14 days of 6 weeks after the initial bleeding cessation. Rebleeding after EVL was mostly due to post-ligation ulcer (7/11), which occurred within 3–10 days of EVL. The incidence of PBUB was 3.21% in total, which is in line with a previously reported incidence rate of 2.6%–7.3%[25]. Despite the low incidence, PBUB was difficult to manage and resulted in high mortality (42.86% in our study). Of the 7 patients with PBUB, 2 patients received a second EVL, and 1 patient was transferred to the ICU for further treatment; all of these patients survived. Furthermore, of the 4 patients who were administered antibiotics, vasoactive drugs, and PPIs, 3 patients died. These results indicate that a second EVL and intensive care may be effective.
The Child-Pugh score, albumin < 30 g/L, PVT, and number of bands were associated with 14-day rebleeding, and the number of bands was the only risk factor predicting 14-day rebleeding (p = 0.009). This finding is in accordance with previous studies that have revealed a greater risk of early rebleeding in patients with a greater number of bands[12, 26] and can be ascribed to two reasons: first, placing more bands involves more surface area of mucosal injury and postbanding ulcers, causing a high risk of early rebleeding; second but more importantly, a greater number of bands indicates more extensive varices, with signs of bleeding and red plug, which indirectly reflects higher PH and risk of rebleeding in the future.
The most important and clinically relevant findings of this study were that PVT and albumin < 30 g/L were predictors for 6-week rebleeding and that PVT was an independent predictor. Published studies have reported that the serum bilirubin levels[27], size of varices[27], haemoglobin[17], PVT[16-17, 28], and Child-Pugh class C[15-16] are the predictors significantly associated with rebleeding after EVL. However, in our study, no significant differences were observed between rebleeding and no rebleeding in terms of the aforementioned risk factors, except PVT. Additionally, other parameters such as aetiology, ascites, and serum creatinine had no significant effect on the incidence of rebleeding.
Importantly, in our study, a significantly higher rate of splenectomy or PSE history was observed in the PVT group (p = 0.000), whereas the history of AVB was similar between the groups. Previously, AVB was treated with a combination of endoscopy and pharmacological agents. Patients with splenomegaly and associated hypersplenism with a Child-Pugh A/B classification are typically treated with splenectomy or PSE later[29]. The enhanced rate of splenectomy or PSE history in the PVT group suggested higher PH, with splenomegaly and the associated hypersplenism as the characteristic features[30]. Both static portal blood flow from advancing PH and splenectomy can increase the risk of PVT development in patients with cirrhosis[6-7].
Interestingly, we found that albumin < 30 g/L was a rebleeding predictor, although hypoalbuminemia was corrected to an extent. Hypoalbuminemia was assumed to be an indicator of the severity of liver dysfunction[24]. It indicated that 6-week rebleeding after EVL is related more to the liver disease than to the bleeding severity. Albumin is predominantly synthesised in the liver. Treatment with albumin has been widely used in liver cirrhosis due to its oncotic properties to prevent circulatory dysfunction. Albumin has other important functions, such as binding capacity and antioxidant and anti-inflammatory properties. It also regulates haemostasis, vasodilatation, and acid–base homeostasis[31]. In our study, albumin appeared to protect against 6-week rebleeding risk after EVL. Bacterial infection is a critical determinant of rebleeding in cirrhosis as it increases the portal pressure through vasoactive substances[32]. The effect of albumin on systemic inflammation can help reduce bleeding by preventing bacterial infection. Recently, Wang et al.[32] found that albumin infusion is associated with a low risk of rebleeding and in-hospital deaths in cirrhosis with acute gastrointestinal bleeding; however, more studies are required to confirm this finding.
On further analysis, we found that the absence of SMV thrombosis is the only independent predictor for 6-week rebleeding in patients with PVT. To the best of our knowledge, this study is the first to describe the prevalence of SMV thrombosis and its association with 6-week rebleeding in patients with AVB after EVL. This may be because obstruction of portal venous inflow was only partial in most of our patients (89.91%). The development of extensive portosystemic collaterals may limit PH exacerbation and reduce liver blood perfusion. However, in the setting of SMV thrombosis, the blood flow into the liver is reduced, which induces intestinal oedema, bacterial translocation, and liver dysfunction, ultimately leading to an increased rebleeding rate after EVL. Even TIPSS also had a high failure and shunt dysfunction in this population[33]. Anticoagulation therapy is the preferred first-line therapy. Importantly, occlusive PVT did not increase the risk of rebleeding in our study (p = 0.760), possibly because of the presence of a cavernoma and/or venous collateralisation. However, more studies are required to validate this finding.
The synthesis of most factors involved in coagulation and fibrinolysis process is known to be impaired in patients with cirrhosis due to reduced liver function and platelet count secondary to PH in these patients. The typical markers of hepatic coagulopathy, including reduced platelet count (and function) and elevated INR, were found to have no influence on early rebleeding in the studies by Lee and Drolz[12, 27]. These findings are in line with our results and imply that the coagulopathy status may play a minor role in early rebleeding. However, most clinicians are unsure whether the anticoagulation therapy is safe for patients with cirrhosis. A series of studies were conducted recently, and most of these studies found that the anticoagulation therapy in patients with cirrhosis is safe as well as effective (i.e. 62.5%–70% of patients reach partial or complete recanalisation, the incidence of PH complications and rate of thrombosis progression are reduced, liver function is improved, and survival is prolonged), if VB prophylaxis is performed well[34-38]. Data regarding the role of anticoagulant therapy and EVL-associated bleeding complications are unavailable to date. Therefore, a consensus regarding the efficacy of anticoagulation therapy for AVB combined with PVT is lacking, and more studies on this aspect are warranted.
Studies have reported that PVT is not associated with long-term (1-year) rebleeding[13] or increased mortality[7, 17, 39] among patients with cirrhosis. In this study, we found no significant difference in 1-year rebleeding between the groups, and the finding could be attributed to several factors. First, obstruction of portal venous inflow is only partial in most patients, and its impact on exacerbating PH and reducing liver blood perfusion requires a precise assessment. Second, approximately 30%–50% of patients with PVT can achieve spontaneous recanalisation, as revealed in a series of studies[35, 40-41], and the actual impact of PVT on clinical outcome in the long term remains unclear. The mortality rates were similar between the groups in our study. According to a systematic review by Qi et al.[42] liver dysfunction plays a crucial role in the prediction of survival in cirrhotic patients with PVT.
In our study, the rates of rebleeding and mortality at 6 weeks were lower than those reported in previous studies[4, 17]. This finding could be attributed to the following reasons: first, new medications and techniques have been developed recently to effectively decrease PH and prevent rebleeding; second and more importantly, it was the first EVL for our patients; more than half of our patients had never had a bleeding before and 90% of the patients were having a Child-Pugh class A or B; third, patients with hepatocellular carcinoma, which has been reported to be associated with the prognosis of patients who have experienced an episode of variceal bleeding[26, 43-45]were excluded from our study. Rebleeding occurred in 21.10% and 20.18% of patients with PVT and CCG, respectively, at 1 year. These rates are higher than those (11.9% vs. 9.5%) reported by Amitrano et al.[13]. The higher rate could be because of the following reasons: our study included a small number of patients with FTCB; NSBBs were not used in patients because it could increase the risk of PVT in cirrhotic patients; and anticoagulant therapy was not administered to patients with PVT as it could elevate the risk of bleeding. According to a systematic review and meta-analysis, the use of NSBBs increases the PVT risk by 4.62 folds in patients with cirrhosis[46].
Our study has several strengths. In this multicentre study, we enrolled 109 cirrhotic AVB patients with PVT and excluded those with a history of EVL + NSBBs or hepatocellular carcinoma. To clarify whether PVT is associated with poor outcomes independent of the severity of liver disease, the control group patients were matched to the study group patients in terms of Child-Pugh class, age, and sex. Subsequently, the baseline values of bilirubin, albumin, Child-Pugh score and MELD score, which are the possible independent predictors for poor outcomes,[42] were similar between the groups. Therefore, our result indicating the association of PVT with a high rate of 6-week rebleeding after EVL appears convincing. Moreover, we identified the prevalence and characteristics of AVB patients with PVT and discovered SMV thrombosis as an independent risk factor for 6-week rebleeding in the PVT group. Furthermore, albumin appeared to serve as a protective factor for the 6-week rebleeding risk. Albumin infusion may improve the prognosis of patients with AVB after EVL.
This study has certain limitations. First, the retrospective study design, which has its inherent disadvantages. However, our study comprised a large number of patients and procedures from 3 teaching hospitals. All data were documented in the patient data management systems in a prospective manner and extracted later for the analysis. Second, although the ‘control’ group was selected on the basis of admission time, comparable age, sex, and Child-Pugh class, we cannot completely rule out the selection bias. However, the inclusion of a larger number of CCG patients would increase the complexity of the study. Third, the incidence of rebleeding and death was low, which could have reduced the statistical power. Therefore, more multicentre, prospective studies are warranted for further analysis. Finally, the determining factor of VB was PH. It is a dynamic pathology regulated by complex interactions among the injured hepatocytes, sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells, which impact the sinusoidal calibre. Inflammation may be a key mediator[47]. However, we did not study the effect of inflammation on rebleeding because of the low infection rate in the patients possibly due to the use of antibiotics.
In conclusion, PVT was associated with a high rate of 14-day and 6-week rebleeding in patients after EVL. SMV thrombosis was the only risk factor for 6-week rebleeding in patients with PVT. High albumin levels possibly served as a protective factor for the 14-day and 6-week rebleeding risk. PVT was not responsible for mortality after EVL during the 1-year follow-up. Further studies are warranted to investigate the role of anticoagulant therapy and EVL-associated bleeding complications and the benefit of albumin infusion in reducing rebleeding risk in patients with AVB after EVL.