Effect Of Portal Vein Thrombosis And Anticoagulation Therapy Early On Cirrhotic Patients With Acute Variceal Bleeding After Ligation

BackgroundAcute variceal bleeding(AVB)is a serious complication of liver cirrhosis,with a high risk of rebleeding and mortality.Ligation is recommended for acute oesophageal variceal bleeding(AEVB),and tissue adhesive is recommended for patients with gastric fundus variceal bleeding.Portal vein thrombosis(PVT)is a critical and frequent complication of liver cirrhosis.The prevalence of nonmalignant PVT increases with the degree of liver failure,usually ranging from 0.6%to 23%.The effect of PVT on prognosis of AVB after ligation is unclear and controversial.Treatments of PVT include anticoagulation therapy,thrombolytic therapy,portal vein angioplasty and transjugular intrahepatic portosystemic shunt(TIPS)etc.Studies have shown that initiation anticoagulant therapy early can significantly improve the recanalization rate of PVT and anticougulation therapy was safe on cirrhotic patients if varices were managed carefully before.Due to high risk of rebleeding in patients with cirrhotic AVB,research on the safety of anticoagulation therapy after ligation in this population is still lacking.This paper was divided into two parts.In the first part,218 cirrhotic patients with AVB treated with oesophageal variceal ligation(EVL)were analyzed retrospectively,including 109 patients in PVT group and 109 patients in cirrhotic control group(CCG)group.We analyzed the effect of PVT on rebleeding and survival after EVL.In the second part,86 cirrhotic patients having AVB and PVT were randomly divided into anticoagulation group and control group.6-month bleeding events and rates of PVT recanalization in the two groups were compared to evaluate the safety and efficacy of anticoagulation early in this population,so as to provide evidence for the application of anticoagulant therapy in this population.Part 1 The Influence of Portal Vein Thrombosis on Prognosis of Acute Variceal Bleeding Patients with CirrhosisAimsThis retrospective study aimed to analyze the influence of portal vein thrombosis on rebleeding and survival within 1 year after EVL in patients with liver cirrhosis.MethodsCollected data of consecutive patients with cirrhotic AVB treated at Qilu Hospital of Shandong University,Chinese People’s Liberation Army No.960 Hospital and Liaocheng People’s Hospital between January 2016 and December 2019.Eligible criteria were:age between 18 and 80 years,endoscopy-proven oesophageal variceal bleeding and treatment with EVL,having contrast-enhanced computed tomography scanning or magnetic resonance angiography before EVL and completion of at least 6 weeks of follow-up.Patients were divided into PVT group or non-PVT group.When one patient with PVT was included,one cirrhotic patient admitted and comparable for age(±5 years),sex,and Child-Pugh class was chosen as control.The primary endpoint was rebleeding after the first EVL,containing 5-day failure,14-day,6-week,and 1-year rebleeding.The secondary endpoint was all-cause mortality,containing 14-day,6-week,and 1-year morbidity.Additionally,we explored the risk factors for rebleeding and death in these patients.Results1.A total of 632 patients met the eligible criteria with 109 ones in PVT group and 523 ones in non-PVT group.Later 109 patients in non-PVT group were allocated to the CCG based on admission time,age,sex,and Child-Pugh class.2.Comparing with CCG,a history of splenectomy or partial splenic embolisis was significantly more common in patients with PVT(36.70%vs.15.60%;P=0.000).On comparing the endoscopic features at admission,we noted that the PVT group had significantly more Ls varices(55.05%vs.33.94%;P=0.002)and number of bands(11.41±3.29 vs.9.84±3.73;P=0.001).However,no significant differences were observed in the AVB history(P=0.169),incidence of ascites(P=0.775),platelet count(P=0.140),haemoglobin levels(P=0.560),international normalized ratio(P=0.732),prothrombin time(P=0.496),serum bilirubin levels(P=0.660),serum albumin levels(P=0.656),form of esophageal varices(P=0.406),rates of active bleeding under endoscope(P=0.524),rates of patients combined with gastric varices(P=0.465)between the groups.3.Comparing with CCG,patients with PVT had a higher rate of 14-day rebleeding(8.26%vs.1.83%,P=0.030).Child-Pugh class(P=0.022),PVT(P=0.050),albumin<30 g/L(P=0.023),and number of bands(P=0.010)were identified as the predictors for 14-day rebleeding by univariate analysis.Multivariate analysis revealed the number of bands(P=0.009)as an independent factor.4.Comparing with CCG,patients with PVT had a higher rate of 6-week rebleeding(11.92%vs 1.83%,P=0.003).PVT(P=0.012)and albumin<30 g/L(P=0.027)were identified as predictors for 6-week rebleeding,whereas PVT(P=0.015)was found to be an independent factor in the multivariate analysis.Further analyse found that SMV thrombosis.was the only factor predicting 6-week rebleeding in patients with PVT in the univariate Cox regression analysis(P=0.029)as well as in the multivariate Cox regression analysis(P=0.032).5.There were no significant differences in the rates of 5-day failure(3.67%vs 0.92%,P=0.175)and 1-year rebleeding(21.10%vs.20.18%,P=0.867)between PVT group and CCG;14-day,6-week,and 1-year mortality(14-day:3.67%vs.0.92%,P=0.175;6-week:3.67%vs.0.92%,P=0.175;1-year:3.67%vs.1.83%,P=0.408)were similar between the groups.Conclusion1.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-weekrebleeding risk.PVT was not associated with 5-day failure.2.PVT was not responsible for mortality after EVL during the 1-year follow-up.Part 2 Safety And Efficacy of Initiation Anticoagulation Therapy early In Cirrhotic Patients Having Portal Vein Thrombosis and Acute Variceal BleedingAimsWe aimed to establish the safety and efficacy of nadroparin calcium warfarin sequential(NWS)anticoagulation therapy within 48-hour after esophageal variceal band ligation in PVT patients having cirrhosis and AVB.MethodsAll AVB patients were immediately resuscitated and administered prophylactic antibiotics,vasoactive drugs meanwhile.Red blood cells were infused if necessary.When hemodynamic stability was achieved,patients underwent contrast-enhanced CT or MRI and then underwent esophagogastroduodenoscopy within twelve hours.Physicians above attending level and with more than three years experience in endoscopic treatment of esophageal varices performed the operation.Close loop ligatures were recommended for AVB,while tissue adhesives were recommended for acute bleeding due to gastric varices.Eligible cirrhotic patients were aged 18-75 years with abdominal contrast-enhanced computed tomography(CT)or contrast-enhanced magnetic resonance angiography(MRI)proven PVT,endoscopy-proven esophageal variceal bleeding(EVB)and treated by EVL with or without gastric variceal obstruction were randomly allocated(1:1)to either the NWS therapy group(one-month nadroparin calcium by subcutaneous injection followed by five-month warfarin through oral administration)or the control group(without any anticoagulation therapy).EVL was performed every 28 days until eradication,evidence of varices not suitable for banding,death,or conversion treatment.The primary safety outcome was major bleeding,containing variceal rebleeding(five-day failure,14-day,four-week,six-week and six-month rebleeding rates after EVL).The primary efficacy outcome was the overall recanalization rate of PVT among the two groups at six months.Results1.A total of 86 patients were eligible and randomly divided into the NWS group and the control group,with 43 patients in either group.Rates of Child-Pugh A,Child-Pugh B and Child-Pugh C were 34.9%,60.5%and 4.7%in NWS group,34.9%,62.8%and 2.3%in the control group.Baseline characteristics were comparable between the two groups.2.Safety.No patients experienced maj or bleeding except for variceal rebleeding and all ones survived at the end of sixth month.No patients rebled within five-day and 14-day after EVL in both groups.There were no significant differences in the rates of four-week(2.3%vs.4.7%,P=1.000),six-week(4.7%vs.9.3%,P=0.672)and six-month rebleeding(18.6%vs.20.9%,P=0.787)between the NWS group and control group.The 6-month cumulative risk of rebleeding were also similar between groups(P by Log-rank test=0.787;HR=0.878,95%CI=(0.339-2.275),P=0.789).3.Efficacy.The overall recanalization(complete and partial)rate in the NWS therapy group was significantly higher than in the control group(67.4%vs.39.5%,P=0.009).Low Child-Pugh score(P=0.039),D-dimer<2.00 ug/mL(P=0.030),and NWS anticoagulation therapy(P=0.002)were the predictors of PVT recanalization through univariate analysis of binary logistic regression.NWS anticoagulation therapy(P=0.003)was the independent factor of recanalization through multivariate analysis.4.Impact on liver function.Comparing with zeroth month,the Child-Pugh score(7[6-8]vs.6[5-7],P=0.003)and the albumin level(33.93±5.30 vs,37.28±4.32,P=0.002)were significantly improved in the NWS group.However,the difference was not significant in the control group,with the Child-Pugh score(7[6-8]vs.7[6-8],P=0.267)and the albumin level(34.27±4.61 vs.35.57±4.48,P=0.199).Conclusions1.Initiation of NWS anticoagulation therapy within 48-hour after EVL was safe.2.NWS anticoagulation therapy can promote PVT recanalization.Low Child-Pugh score,D-dimer and NWS anticoagulation therapy were associated with PVT recanalization.NWS anticoagulation therapy was the independent factor of recanalization.3.NWS anticoagulation therapy can also improve liver function.