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Thromb Haemost 2020; 120(04): 638-646
DOI: 10.1055/s-0040-1702225
Cellular Haemostasis and Platelets
Georg Thieme Verlag KG Stuttgart · New York

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

Eleni Gavriilaki
1   Hematology Department–BMT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece
,
Tasoula Touloumenidou
1   Hematology Department–BMT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece
,
Ioanna Sakellari
1   Hematology Department–BMT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece
,
Ioannis Batsis
1   Hematology Department–BMT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece
,
Despina Mallouri
1   Hematology Department–BMT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece
,
Fotis Psomopoulos
2   Department of Hematology, Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece
,
Maria Tsagiopoulou
2   Department of Hematology, Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece
,
Maria Koutra
1   Hematology Department–BMT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece
,
Evangelia Yannaki
1   Hematology Department–BMT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece
,
Apostolia Papalexandri
1   Hematology Department–BMT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece
,
Pat Taylor
3   Department of Haematology, University Hospitals Birmingham, Birmingham, United Kingdom
,
Emmanuel Nikolousis
3   Department of Haematology, University Hospitals Birmingham, Birmingham, United Kingdom
,
Maria Stamouli
4   Division of Hematology, Second Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
,
Andreas Holbro
5   Division of Hematology, Department of Medicine, University Hospital Basel, Basel, Switzerland
,
Ioannis Baltadakis
6   Department of Hematology, Bone Marrow Transplantation Unit, Evangelismos Hospital, Athens, Greece
,
Maria Liga
7   Department of Hematology, BMT Unit, University Hospital of Patras, Patras, Greece
,
Alexandros Spyridonidis
7   Department of Hematology, BMT Unit, University Hospital of Patras, Patras, Greece
,
Panagiotis Tsirigotis
4   Division of Hematology, Second Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
,
Nikolaos Charchalakis
6   Department of Hematology, Bone Marrow Transplantation Unit, Evangelismos Hospital, Athens, Greece
,
Dimitrios A. Tsakiris
5   Division of Hematology, Department of Medicine, University Hospital Basel, Basel, Switzerland
,
Robert A. Brodsky
8   Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
,
Jacob Passweg
5   Division of Hematology, Department of Medicine, University Hospital Basel, Basel, Switzerland
,
Kostas Stamatopoulos
2   Department of Hematology, Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece
,
Achilles Anagnostopoulos
1   Hematology Department–BMT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece
› Author Affiliations Funding This research was supported by the European Hematology Association “Clinical Research Grant 2016.”
Further Information

Publication History

17 October 2019

09 January 2020

Publication Date:
04 March 2020 (online)

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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.

Keywords

transplant-associated thrombotic microangiopathy - complement - genetic susceptibility - eculizumab

Authors' Contributions

E.G. and I.S. designed research. E.G., T.T., I.S., I.B., D.M., M.K., E.Y., A.P., P.T., E.N., M.S., A.H., I.B., M.L., A.S., and N.C. performed research. E.G., T.T., F.P, and M.T. analyzed data and wrote the paper. D.T, R.A.B., J.P., K.S., and A.A. contributed in research design, edited, and approved the paper.


Supplementary Material

 

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