Pretransplant Genetic Susceptibility: Clinical Relevance in Transplant-Associated Thrombotic Microangiopathy.

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.

• Authors: Eleni Gavriilaki, Tasoula Touloumenidou, Ioanna Sakellari, Ioannis Batsis, Despina Mallouri, Fotis Psomopoulos, Maria Tsagiopoulou, Maria Koutra, Evangelia Yannaki, Apostolia Papalexandri, Pat Taylor, Emmanuel Nikolousis, Maria Stamouli, Andreas Holbro, Ioannis Baltadakis, Maria Liga, Alexandros Spyridonidis, Panagiotis Tsirigotis, Nikolaos Charchalakis, Dimitrios A Tsakiris, Robert A Brodsky, Jacob Passweg, Kostas Stamatopoulos, Achilles Anagnostopoulos
• Journal: Thrombosis and haemostasis (Thromb Haemost) Vol. 120 Issue 4 Pg. 638-646 (Apr 2020) ISSN: 2567-689X [Electronic] Germany
• PMID: 32131130 (Publication Type: Journal Article)
• Copyright: Georg Thieme Verlag KG Stuttgart · New York.

Chemical References

• Untranslated Regions
• ADAMTS13 Protein
• ADAMTS13 protein, human

Topics

• ADAMTS13 Protein (genetics)
• Adult
• Aged
• Female
• Genetic Predisposition to Disease
• Genome
• Genotype
• Hematologic Neoplasms (genetics, mortality, therapy)
• Hematopoietic Stem Cell Transplantation
• Humans
• Male
• Middle Aged
• Postoperative Complications (genetics)
• Survival Analysis
• Thrombotic Microangiopathies (etiology, genetics)
• Transplantation, Homologous
• Untranslated Regions (genetics)
• Young Adult