Portal vein surgical treatment on non-tumoral portal vein thrombosis in liver transplantation: Systematic Review and Meta-Analysis

Non-tumoral portal vein thrombosis (PVT) is associated with higher morbidity and mortality in liver transplantation (LT). In this study, we aimed to evaluate the impact of PVT in LT outcomes and analyze the types of surgical techniques used for dealing with PVT during LT. A systematic review was conducted in Cochrane, MEDLINE, and EMBASE databases, selecting articles from January 1990 to December 2019. The MESH-terms used were (“Portal Vein”[Mesh] AND “Thrombosis”[Mesh] NOT “Neoplasms”[Mesh]) AND (“Liver Transplantation”[Mesh]). The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) recommendation was used, and meta-analysis was performed with Review Manager Version 5.3 software. A total of 1,638 articles were initially found: 488 in PubMed, 289 in Cochrane Library, and 861 in EMBASE, from which 27 were eventually selected for the meta-analysis. Surgery time of LT in patients with PVT was longer than in patients without LT (p<0.0001). Intraoperative red blood cell (p<0.00001), fresh frozen plasma (p=0.01), and platelets (p=0.03) transfusions during LT were higher in patients with PVT. One-year (odds ratio [OR] 1.17; p=0.002) and 5-year (OR 1.12; p=0.01) patient survival after LT was worse in the PVT group. Total occlusive PVT presented higher mortality (OR 3.70; p=0.00009) and rethrombosis rates (OR 3.47 [1.18-10.21]; p=0.02). PVT Yerdel III/IV classification exhibited worse 1-year [2.04 (1.21-3.42); p=0.007] and 5-year [0.98 (0.59-1.62); p=0.93] patient survival. Thrombectomy with primary anastomosis was associated with better outcomes. LT in patients with non-tumoral PVT demands more surgical time, needs more intraoperative transfusion, and presents worse 1- and 5-year patient survival. Total occlusive PVT and Yerdel III/IV PVT classification were associated with higher mortality. (PROSPERO, registration number: CRD42020132915).


' INTRODUCTION
Non-tumoral portal vein thrombosis (PVT) is a relevant condition in liver cirrhosis evolution, with an estimated incidence rate of 0.7 per 100,000 and prevalence ranging from 0.6-28% in cirrhotic patients (1)(2)(3). It is well-established that patients with severe cirrhosis (Child-Pugh C Classification) have a high incidence of PVT (4).
PVT is defined as partial or complete obstruction of blood flow that occurs secondary to a thrombus in the portal vein, which results in the occlusion of the vessel lumen (1)(2)(3). Despite this, the decreased portal flow velocity and the increased flow volume are considered independent risk factors in developing PVT (4). There are many classifications regarding the extent of involvement of the portal venous system, with the Yerdel classification being the most used one (5). It is paramount to promptly diagnose PVT, as this may lead to better outcomes and survival.
In the past, PVT in cirrhotic patients was considered a contraindication for liver transplantation (LT). Nevertheless, with the development of better diagnostic tools, medical therapy, and surgical techniques in the last decades, LT became a feasible therapeutic option even for patients with PVT (6). Based on the grade of PVT and severity of the cirrhosis, the decision to perform LT in these patients remains controversial.
Despite the modern advances in with the management of PVT, the outcome of LT in patients with PVT is still under debate, especially in the current era of organ shortage associated with a high model of end-stage liver disease (MELD) score of patients. The main objective of this study was to compare the outcomes of LT in patients with PVT and those without, focusing on the types of PVT surgical treatment, which include thrombectomy with primary anastomosis, interposition vein graft (physiological reconstruction), superior mesenteric vein (SMV) jump graft, interposition vein graft from a collateral vein (non-physiological reconstruction), renoportal anastomosis and cavoportal hemitransposition (CPH).
The present data may help validate whether the different types of portal vein (PV) reconstructions influence transplant outcomes in terms of survival and complications. The terms and MESH-terms for PubMed database search were developed based on the PICO (patient, intervention, comparison, or control, outcome) structure. The results of the search terms forming the ''P'' (patients) group were merged with the results of the ''I'' (intervention) group with an ''AND.'' To exclude terms, they were merged with ''NOT.''

Study identification and selection
The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist were followed throughout this study (7,8).
Two independent researchers (LSN and LYZ) evaluated the quality and selection of the studies. In the case of disagreement, the researchers held a consensus meeting to reach a final decision.

Inclusion and exclusion criteria
Within the research question of the PICO structure, the comparison of patients with non-tumoral PVT who underwent LT was defined as inclusion criteria. Only randomized controlled trials, nonrandomized controlled trials, or comparative clinical studies were included. All studies evaluated were written in English. Case series with less than six patients and studies reporting on tumoral thrombosis or Budd-Chiari syndrome were excluded.

Data synthesis and statistical analysis
Data were extracted from text, tables, and figures of the original published articles. The measures of effectiveness for each treatment were expressed in absolute numbers and respective frequencies, i.e., the absolute risk. For the metaanalysis, the data were synthesized using Review Manager Version 5.4 software provided by the Cochrane Collaboration (RevMan; The Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen, Denmark). The results from the included papers were compared with the differences observed in absolute risks. Continuous data were expressed as mean difference and 95% confidence intervals (CI).

Heterogeneity and sensitivity analysis in the studies
Heterogeneity was evaluated with I 2 statistics, in which I 2 values of 70% or more represented an indicator of substantial heterogeneity. In the absence of this heterogeneity, we pooled data with a fixed-effect model (I 2 o50%); otherwise, we used a random-effects model (I 2 450%). Results were considered statistically significant at po0.05.

Data analysis and critical evaluation
Study quality assessment included study design, level of evidence, and the New Castle score (Ottawa Quality Assessment Cohort Studies) (accessed July 2019) for nonrandomized clinical trials (9).

Study selection
Using the search strategy mentioned above, we identified 1688 articles, of which 488 articles were from PubMed/ MEDLINE, 861 from EMBASE, and 289 from Cochrane Library. After applying the previously defined inclusion and exclusion criteria, 73 articles were selected in the PICO structure, and 27 were eventually included in the metaanalysis, as shown in Figure 1.
The New Castle-Ottawa Scale (NOS) qualification of the studies for non-tumoral PVT in LT and the overall demographics data of selected studies are depicted in Tables 1 and 2, respectively. Table 2 also shows the extent of thrombosis in the portal system according to the Yerdel classification and the types of surgical techniques employed. Thrombectomy was performed in 932 patients, SMV jump graft in 95, interposition vein graft in 23, collateral anastomosis in 32, renoportal anastomosis in 27, and CPH in 50 (Table 2).

Patient Survival according to Yerdel classification.
Data from three studies (5,23,24)  ' DISCUSSION PVT may either be a cause or consequence of cirrhosis decompensation. It is asymptomatic in 50% of cirrhotic patients; however, it may lead to severe complications if symptomatic. Early identification and treatment may lead to a better prognosis of these complex patients. The present systematic review and meta-analysis demonstrated that LT in patients with non-tumoral PVT is associated with higher surgery time, higher intraoperative transfusions, and worse 1-and 5-year patient survival. Occlusive PVT, rethrombosis, and Yerdel III/IV also present worse prognosis. Gao et al. (23), retrospectively analyzing a large casuistic of more than 1800 PVT patients, showed that the overall surgery time of LT was longer in cases with PVT compared to those without it (23). Our meta-analysis, with more than 2,126 PVT patients, confirmed these results.
PVT is considered a very unfavorable prognostic marker in advanced liver disease. Extensive PVT is positively associated with higher mortality during LT (30). One study particularly found that patients with PVT undergoing LT had longer operation time, increased need for transfusions, and lower survival rate than those without PVT (35). Another study revealed similar results, showing that patients with PVT had higher post-transplant mortality than those without PVT. Interestingly, PVT was not associated with increased mortality among patients on the transplant waiting list (15).
Other retrospective studies demonstrated higher intraoperative use of FFP and RBC in PVT cases (10,12,22,29,31). Similar results were found in this meta-analysis. Intraoperative RBC transfusion was evaluated in a total of 4,551 patients (499 with PVT and 4,052 patients without PVT), and a mean difference was 0.80 packs [0.61-0.90] (po0.0001) was found. Furthermore, intraoperative transfusion of FFP (p=0.01) and platelets (p=0.03) were also higher, comparing 111 patients with PVT to 559 without PVT.
Another meta-analysis by Zanetto et al. (37) identified lower 1-year survival and higher 30 days postoperative mortality in patients with PVT undergoing LT. The survival in partial PVT was better than in the total PVT group (37). We also found lower 1-and 5-year patient survival in the PVT group and lower survival for patients with total occlusive PVT.
Different preoperative strategies have been reported to treat PVT, including anticoagulants and interventional radiology techniques, which may reduce intraoperative technical difficulties and improve outcomes (38)(39)(40) and portal vein thrombosis in the living donor (41). In our metaanalysis, thrombectomy with primary anastomosis was associated with better outcomes. Total occlusive PVT presented higher mortality and rethrombosis rates. Accordingly, PVT Yerdel III/IV classification demonstrated worse 1-year and 5-year patient survival.
One limitation of this study is that we found only nonrandomized clinical trials and comparative studies, both prospective and retrospective (Table 1). Therefore, more randomized controlled trials are needed to define more

' CONCLUSION
In conclusion, LT in patients with non-tumoral PVT demands more surgical time, needs more intraoperative transfusion, and presents worse 1-and 5-year patient survival. In addition to this, total occlusive PVT presents higher mortality and rethrombosis rates, and PVT Yerdel III/ IV classification is associated with worse survival. When feasible, thrombectomy with primary anastomosis is associated with better outcomes.

' AUTHOR CONTRIBUTIONS
All authors have approved the final draft of the manuscript submitted. Nacif LS was responsible for the study conception and design, data collection, analysis and interpretation, manuscript writing, and literature search. Zanini LY, Waisberg DR, Pinheiro RS were responsible for the study conception and design, data collection, analysis and interpretation, manuscript critical review. Rocha-Santos V was responsible for the study conception, interpretation and critical revision. Andraus W, Carrilho FJ and Carneiro-D'Albuquerque L were responsible for the study conception, interpretation, and critical review.