@article{3121233,
    title = "Pretransplant Genetic Susceptibility: Clinical Relevance in Transplant-Associated Thrombotic Microangiopathy",
    author = "Gavriilaki, E. and Touloumenidou, T. and Sakellari, I. and Batsis, I. and Mallouri, D. and Psomopoulos, F. and Tsagiopoulou, M. and Koutra, M. and Yannaki, E. and Papalexandri, A. and Taylor, P. and Nikolousis, E. and Stamouli, M. and Holbro, A. and Baltadakis, I. and Liga, M. and Spyridonidis, A. and Tsirigotis, P. and Charchalakis, N. and Tsakiris, D.A. and Brodsky, R.A. and Passweg, J. and Stamatopoulos, K. and Anagnostopoulos, A.",
    journal = "Thrombosis and Haemostasis",
    year = "2020",
    volume = "120",
    number = "4",
    pages = "638-646",
    publisher = "Georg Thieme Verlag",
    issn = "0340-6245",
    doi = "10.1055/s-0040-1702225",
    keywords = "ADAMTS13 gene;  adult;  allogeneic hematopoietic stem cell transplantation;  Article;  bioinformatics;  bone marrow transplantation;  CD46 gene;  CFH gene;  CFI gene;  clinical outcome;  controlled study;  enzyme linked immunosorbent assay;  follow up;  gene;  gene expression;  gene mutation;  gene sequence;  genetic analysis;  genetic association;  genetic susceptibility;  genotype;  graft versus host reaction;  hemolytic uremic syndrome;  human;  major clinical study;  male;  middle aged;  mortality;  overall survival;  phenotype;  plasma exchange;  priority journal;  single nucleotide polymorphism;  thrombotic thrombocytopenic purpura;  TMA gene;  untranslated region;  aged;  allotransplantation;  female;  genetic predisposition;  genetics;  genome;  genotype;  hematologic disease;  hematopoietic stem cell transplantation;  postoperative complication;  survival analysis;  thrombotic thrombocytopenic purpura;  young adult, ADAMTS13 protein, human;  von Willebrand factor cleaving proteinase, ADAMTS13 Protein;  Adult;  Aged;  Female;  Genetic Predisposition to Disease;  Genome;  Genotype;  Hematologic Neoplasms;  Hematopoietic Stem Cell Transplantation;  Humans;  Male;  Middle Aged;  Postoperative Complications;  Survival Analysis;  Thrombotic Microangiopathies;  Transplantation, Homologous;  Untranslated Regions;  Young Adult",
    abstract = "Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication of allogeneic hematopoietic cell transplantation (HCT). We hypothesized that pretransplant genetic susceptibility is evident in adult TA-TMA and further investigated the association of TMA-associated variants with clinical outcomes. We studied 40 patients with TA-TMA, donors of 18 patients and 40 control non-TMA HCT recipients, without significant differences in transplant characteristics. Genomic DNA from pretransplant peripheral blood was sequenced for TMA-associated genes. Donors presented significantly lower frequency of rare variants and variants in exonic/splicing/untranslated region (UTR) regions, compared with TA-TMA patients. Controls also showed a significantly lower frequency of rare variants in ADAMTS13, CD46, CFH, and CFI. The majority of TA-TMA patients (31/40) presented with pathogenic or likely pathogenic variants. Patients refractory to conventional treatment (62%) and patients that succumbed to transplant-related mortality (65%) were significantly enriched for variants in exonic/splicing/UTR regions. In conclusion, increased incidence of pathogenic, rare and variants in exonic/splicing/UTR regions of TA-TMA patients suggests genetic susceptibility not evident in controls or donors. Notably, variants in exonic/splicing/UTR regions were associated with poor response and survival. Therefore, pretransplant genomic screening may be useful to intensify monitoring and early intervention in patients at high risk for TA-TMA. © 2020 Georg Thieme Verlag. All rights reserved."
}