Clinical Characteristics Of Thrombotic Microangiopathy Associated With Allogeneic Hematopoietic Stem Cell Transplantation And Its Relationship With Complement Gene Polymorphisms

Part ⅠClinical Characteristics,Risk Factors,and Prognosis Analysis of Transplantation-Associated Thrombotic Microangiopathy after Allogeneic Hematopoietic Stem Cell TransplantationObjective:This study aims to investigate the clinical characteristics,risk factors,and prognosis analysis of transplantation-associated thrombotic microangiopathy(TATMA)after allogeneic hematopoietic stem cell transplantation(allo-HSCT).Methods:We conducted a retrospective analysis of the clinical data of 1370 patients who underwent allo-HSCT at the First Affiliated Hospital of Soochow University and Suzhou Hongci Hematology Hospital between April 1,2020,and April 1,2022.Results:By the end of the follow-up on December 1,2022,a total of 25 patients(incidence rate:1.82%)were diagnosed with TA-TMA.The median age of these patients was 40 years(IQR:33-50 years),and the median time of diagnosis was 50 days(range:15-217 days).The most common clinical manifestations observed in TA-TMA patients included anemia and thrombocytopenia(100%),followed by hypertension(80%),central nervous system abnormalities(48%).abdominal pain and bloody stools(40%),and the presence of multiple serous chamber liquid(28%).During the same period,75 patients with undiagnosed TA-TMA were randomly selected from the entire transplantation cohort at a 1:3 ratio to serve as the control group.The Cox proportional hazards model results revealed that female gender,concomitant grade Ⅲ-Ⅳ acute graft-versus-host disease(aGVHD),hepatic dysfunction,and severe infection were identified as independent risk factors for the occurrence of transplant-associated thrombotic microangiopathy(TATMA).The median survival time of patients in the TA-TMA group was 5.9 months,significantly shorter than that of the non-TA-TMA group(5.9 months vs.19.8 months,P<0.001).The 2-year overall survival rate(OS)was also significantly lower in the TATMA group compared to the non-TA-TMA group(32%vs.80%,P<0.001).Additionally,Cox regression analysis demonstrated that the presence of TA-TMA after transplantation was an independent risk factor associated with increased mortality in allo-HSCT patients.Conclusion:TA-TMA is a severe complication following allo-HSCT that significantly reduces overall patient survival.As TA-TMA lacks typical clinical manifestations,special attention should be given to patients with grade Ⅲ-Ⅳ aGVHD and severe infection after allo-HSCT,while remaining cautious about the possibility of TA-TMA.Part Ⅱ:The relationship between thrombotic microangiopathy associated with allogeneic hematopoietic stem cell transplantation and complement gene polymorphisms.Objective:The objective of this study is to explore the potential role of genetic susceptibility in complement-related genes in thrombotic microangiopathy associated with allogeneic hematopoietic stem cell transplantation.Methods:Peripheral blood samples were collected from 12 patients with TA-TMA and 12 patients without TA-TMA before transplantation.Genomic DNA from the two groups was extracted for whole-genome sequencing(WGS).The number and frequency of variants in 17 complement-related genes were analyzed across different regions of the genome,including all regions,exonic/splicing/untranslated regions,rare variants,and known pathogenic variants in ClinVar or software-predicted pathogenic variants.Results:A total of 26,200 variants were detected in the 24 samples,with 13,487 variants in the TA-TMA group and 12,713 variants in the non-TA-TMA group.The total number of gene variants across all regions of the genome in the TA-TMA group was higher than that in the non-TA-TMA group(1123.92±65.96 vs.1059.42±93.19,P=0.063).Furthermore,the TA-TMA group exhibited a significantly higher number of THBD gene variants across all regions of the genome,exonic/splicing/untranslated regions,and rare variants compared to the non-TA-TMA group.Additionally,the number of variants in the CFH gene across all regions of the genome and the number of rare variants in the CD55 gene were also significantly higher in the TA-TMA group than in the non-TA-TMA group.Conclusion:Complement-related gene variants in patients with TA-TMA following allo-HSCT may be associated with the development of TA-TMA,with the THBD gene showing a close relationship.