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

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

doi:10.1055/s-0040-1702225

Thrombosis and Haemostasis, Table of Contents

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

¹Hematology Department–BMT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece

,

Tasoula Touloumenidou

¹Hematology Department–BMT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece

,

Ioanna Sakellari

¹Hematology Department–BMT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece

,

Ioannis Batsis

¹Hematology Department–BMT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece

,

Despina Mallouri

¹Hematology Department–BMT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece

,

Fotis Psomopoulos

²Department of Hematology, Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece

,

Maria Tsagiopoulou

²Department of Hematology, Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece

,

Maria Koutra

¹Hematology Department–BMT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece

,

Evangelia Yannaki

¹Hematology Department–BMT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece

,

Apostolia Papalexandri

¹Hematology Department–BMT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece

,

Pat Taylor

³Department of Haematology, University Hospitals Birmingham, Birmingham, United Kingdom

,

Emmanuel Nikolousis

³Department of Haematology, University Hospitals Birmingham, Birmingham, United Kingdom

,

Maria Stamouli

⁴Division of Hematology, Second Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece

,

Andreas Holbro

⁵Division of Hematology, Department of Medicine, University Hospital Basel, Basel, Switzerland

,

Ioannis Baltadakis

⁶Department of Hematology, Bone Marrow Transplantation Unit, Evangelismos Hospital, Athens, Greece

,

Maria Liga

⁷Department of Hematology, BMT Unit, University Hospital of Patras, Patras, Greece

,

Alexandros Spyridonidis

⁷Department of Hematology, BMT Unit, University Hospital of Patras, Patras, Greece

,

Panagiotis Tsirigotis

⁴Division of Hematology, Second Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece

,

Nikolaos Charchalakis

⁶Department of Hematology, Bone Marrow Transplantation Unit, Evangelismos Hospital, Athens, Greece

,

Dimitrios A. Tsakiris

⁵Division of Hematology, Department of Medicine, University Hospital Basel, Basel, Switzerland

,

Robert A. Brodsky

⁸Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States

,

Jacob Passweg

⁵Division of Hematology, Department of Medicine, University Hospital Basel, Basel, Switzerland

,

Kostas Stamatopoulos

²Department of Hematology, Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece

,

Achilles Anagnostopoulos

¹Hematology Department–BMT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece

› Author Affiliations

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

Full Text

References

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