Pathogenesis And Management Of Thrombosis Complications After Hematopoietic Stem Cell Transplantation

Background and ObjectiveHematopoietic stem cell transplantation(HSCT)is currently the only curative option for most hematological malignancies,but a wide spectrum of post-transplant complications considerably affect patients' prognosis,especially thrombotic complications,including transplant-associated thrombotic microangiopathy(TA-TMA),hepatic veno-occlusive disease/sinusoidal obstruction syndrome(VOD/SOS),etc.The pathogenesis of both is associated with endothelial injury.The pathogenesis of TA-TMA remains ambiguous,and recent studies indicate the role of complement activation in endothelial injury,while sinusoidal endothelial cells and hepatocytes are damaged by a host of factors(chemotherapy,radiotherapy and cytokines released).Current treatment options for TA-TMA are limited.Eculizumab,a monoclonal antibody against C5,inhibits the formation of complement terminal complex C5b-9,while the efficacy of plasma exchange remains unclear.Defibrotide is the only drug approved for the treatment of VOD.However,available data on efficacy and safety for its use in VOD are contrasting.This study was designed to detect complement activation for post-transplant thrombotic complications in vitro and clinical data,the distribution of vWF multimers in TA-TMA plasma and the role of N-acetylcysteine(NAC)in both situations,and the efficacy and safety of defibrotide for the treatment of VOD.Methods1.Twenty TA-TMA patients,fourteen VOD patients,and twenty patients with no complications post-HSCT were diagnosed at the First Affiliated Hospital of Soochow University from January 2012 through October 2019 in our study.Plasma levels of C3b and sC5b-9 were detected by ELISA.2.TA-TMA plasma was used to coculture with human dermal microvascular endothelium(HMEC-1)to serve as a TA-TMA vitro model to detect the deposition levels of C3 and C5b-9 on endothelial cells with the absence or presence of NAC by flow cytometry,western blot,and immunofluorescence assay.3.The vWF multimers were detected by electrophoresis,NAC was added into the reaction system to detect its function.4.Meta-analysis was performed to evaluate the efficacy and safety of defibrotide in the treatment of VOD post-HSCT.Results1.Plasma levels of C3b and sC5b-9 were significantly elevated in TA-TMA patients compared with those in post-HSCT patients with no complications(454.5 ± 223.8 vs.153.5±88.44ng/ml,P<0.0001;1058 ± 276.4 vs:639.8 ± 155.0ng/ml,P<0.0001).Nevertheless,no statistical significance of complement levels was detected between VOD patients and patients without complications.2.Complement C3 and C5b-9 deposits on HMEC-1 with TA-TMA plasma were significantly higher than normal human plasma(2.75 ± 0.09 vs.1.00 ± 0.12,P<0.0001;2.99± 0.07 vs.1.00 ± 0.08,P<0.0001).Moreover,N-acetylcysteine(NAC),a drug against oxidation,degraded the deposition of C3 and C5b-9 on HMEC-1(1.60 ± 0.03 vs.2.75 ±0.09,P<0.0001;1.26 ± 0.07 vs.2.99 ± 0.07,P<0.0001).3.VWF multimers,especially ultra-large vWF multimers in TA-TMA plasma were significantly elevated compared with those in normal human plasma.Furthermore,NAC reduced the size of vWF multimers.4.Pooled estimates for overall survival rate at day+100 post-HSCT(D+100 SR)as well as rate of complete response(CR),serious adverse events(SAEs)in VOD patients post-HSCT were 58%(95%CI:54-62%),57%(95%Cl:45-68%),53%(95%CI:51-55%),respectively,and were 44%(95%CI:39-48%),39%(95%CI:28-50%),58%(95%CI:52-64%),respectively,in severe VOD(sVOD)patients.Conclusions1.Plasma levels of C3b and sC5b-9 were significantly elevated in TA-TMA patients,while the plasma levels of complement were not considerably changed in VOD patients compared with patients without complications after HSCT.2.TA-TMA in vitro model was successfully constructed by TA-TMA plasma incubation of HMEC-1.3.NAC degraded the deposition of C3 and C5b-9 on HMEC-1 induced by TA-TMA plasma.4.VWF multimers,especially ultra-large vWF multimers,were elevated in TA-TMA plasma.Our study indicated the interplay between complement activation,vWF multimers and endothelial injury in TA-TMA.5.The present systematic review and meta-analysis indicated that defibrotide improved the D+100 SR and CR in VOD/sVOD patients following HSCT.Hemorrhage and hypotension were the most common adverse events.