Efficacy And Safety Of Anticoagulation Therapy For Pyrrolizidine Alkaloids-induced Hepatic Sinusoidal Obstruction Syndrome

Background & Aims:Hepatic sinusoidal obstruction syndrome(HSOS)is a kind of hepatic vascular disease characterized by liver injury and acute sinus portal hypertension,which is caused by the stenosis or occlusion of the lumen caused by the injury of hepatic blood sinus,central vein of hepatic lobule and/or interlobular vein endothelial cells.In China,HSOS were caused mainly by ingestion of herbal containing pyrrolizidine alkaloids,the cases have still markedly increased with a high mortality rate.There is no effective treatment method supported by high intensity evidence at present and the fundamental reason is that the specific pathogenesis is still unclear.The current unified view of the pathogenesis is that PAs may eventually lead to bleeding in hepatic sinuses,shedding of endothelial cells and microthrombus formation through direct injury to hepatic sinuses and central venous endothelial cells or bone marrow progenitor cells,leading to the occurrence and development of PA-HSOS.Based on this view,scholars had proposed the possibility of anticoagulation therapy.In 2017,thescheme of anticoagulation therapy as soon as possible after excluded the contraindications has been proposed by the Committee of Hepatobiliary Disease of Chinese Society of Gastroenterology for the treatment of PA-HSOS in early stage.However,the present evidences in support of anticoagulation therapy have been graded as low quality,and it stressed the need for higher quality clinical studies.The aim of this study was to evaluate the efficacy and safety of anticoagulation therapy for the patients with PA-HSOS andalso to explore the possible predictors for anticoagulation efficacy.Methods:Clinical data on a total of 249 PA-HSOS patients from January 2012 to December 2017 at 4 tertiary care hospitals(Department of Gastroenterology,Nanjing Drum Tower Hospital,the Affiliated Hospital of Nanjing University Medical School;Department of Hepatology,Changzhou Third People's Hospital;Department of Gastroenterology,the Northern Jiangsu People's Hospital;Division of Gastroenterology,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology.)in China were retrospectively analyzed.All the patients were divided into the anticoagulant group and the symptomatic treatment group.All patients received symptomatic support therapy,and the anticoagulant group received warfarin or LMWH or both combined anticoagulant therapy on the basis of symptomatic support therapy.Among these patients,151 received anticoagulation therapy plus symptomatic treatment,the other 98 patients received symptomatic treatment.The primary outcome of this study was complete response in both groups,and the secondary outcome was allcause mortality in both groups.The safety index was the occurrence of major bleeding events and clinically related non-major bleeding events in the two groups.Clinical data were analyzed using Fine and Grey competing risk analysis method and Cox regression model to explore the efficacy and safety outcomes of anticogulation therapy and the possible factors for complete response to anticoagulation therapy in PA-HSOS patients.Results:The cumulative complete response rate was higher in the anticoagulation group than in the symptomatic group(60.9% vs36.7%,adjusted HR,4.51;p<0.0001).The cumulative mortality was 12.6% in the anticoagulation group compared with 43.9% in the symptomatic group(adjusted HR,0.07;p<0.0001).In subgroup analysis,for mild,moderate,severe,and very severe groups,the adjusted HRs(95% CI)for complete response rates were 7.05(3.00-16.59),5.26(2.31-12.42),2.59(0.85-7.87),and 2.05(0.61-6.92),respectively;and the adjusted HRs(95% CI)for mortalities were 0.02(0.01-0.09),0.04(0.01-0.14),0.19(0.01-3.98),and 0.07(0.02-1.27),respectively(p<0.0001 for the interaction test).There was no significant difference between both groups in the incidence of bleeding events(6.6% in the anticoagulation group vs 2.0% in the symptomatic group,p=0.674).Lower total bilirubin level(HR 0.98)and longer treatment duration(HR 1.27)predicted higher complete response rates of anticoagulation therapy.Conclusions: Anticoagulation therapy improves clinical remission and the survival in selected patients with mild or moderate PA-HSOS.Anticoagulation therapy has a similar safety profile to supportive therapy.