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Early Elevation of Complement Factor Ba Is a Predictive Biomarker for Transplant-Associated Thrombotic Microangiopathy

Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Previous reports suggest that TA-TMA is caused by complement activation by complement-related genetic variants; however, this needs to be verified,...

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Autores principales: Okamura, Hiroshi, Nakamae, Hirohisa, Shindo, Takero, Ohtani, Katsuki, Hidaka, Yoshihiko, Ohtsuka, Yasufumi, Makuuchi, Yosuke, Kuno, Masatomo, Takakuwa, Teruhito, Harada, Naonori, Nishimoto, Mitsutaka, Nakashima, Yasuhiro, Koh, Hideo, Hirose, Asao, Nakamae, Mika, Wakamiya, Nobutaka, Hino, Masayuki, Inoue, Norimitsu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315095/
https://www.ncbi.nlm.nih.gov/pubmed/34326846
http://dx.doi.org/10.3389/fimmu.2021.695037
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author Okamura, Hiroshi
Nakamae, Hirohisa
Shindo, Takero
Ohtani, Katsuki
Hidaka, Yoshihiko
Ohtsuka, Yasufumi
Makuuchi, Yosuke
Kuno, Masatomo
Takakuwa, Teruhito
Harada, Naonori
Nishimoto, Mitsutaka
Nakashima, Yasuhiro
Koh, Hideo
Hirose, Asao
Nakamae, Mika
Wakamiya, Nobutaka
Hino, Masayuki
Inoue, Norimitsu
author_facet Okamura, Hiroshi
Nakamae, Hirohisa
Shindo, Takero
Ohtani, Katsuki
Hidaka, Yoshihiko
Ohtsuka, Yasufumi
Makuuchi, Yosuke
Kuno, Masatomo
Takakuwa, Teruhito
Harada, Naonori
Nishimoto, Mitsutaka
Nakashima, Yasuhiro
Koh, Hideo
Hirose, Asao
Nakamae, Mika
Wakamiya, Nobutaka
Hino, Masayuki
Inoue, Norimitsu
author_sort Okamura, Hiroshi
collection PubMed
description Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Previous reports suggest that TA-TMA is caused by complement activation by complement-related genetic variants; however, this needs to be verified, especially in adults. Here, we performed a nested case-control study of allo-HSCT-treated adults at a single center. Fifteen TA-TMA patients and 15 non-TA-TMA patients, matched according to the propensity score, were enrolled. Based on a previous report showing an association between complement-related genes and development of TA-TMA, we first sequenced these 17 genes. Both cohorts harbored several genetic variants with rare allele frequencies; however, there was no difference in the percentage of patients in the TA-TMA and non-TA-TMA groups with the rare variants, or in the average number of rare variants per patient. Second, we measured plasma concentrations of complement proteins. Notably, levels of Ba protein on Day 7 following allo-HSCT were abnormally and significantly higher in TA-TMA than in non-TA-TMA cases, suggesting that complement activation via the alternative pathway contributes to TA-TMA. All other parameters, including soluble C5b-9, on Day 7 were similar between the groups. The levels of C3, C4, CH50, and complement factors H and I in the TA-TMA group after Day 28 were significantly lower than those in the non-TA-TMA group. Complement-related genetic variants did not predict TA-TMA development. By contrast, abnormally high levels of Ba on Day 7 did predict development of TA-TMA and non-relapse mortality. Thus, Ba levels on Day 7 after allo-HSCT are a sensitive and prognostic biomarker of TA-TMA.
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spelling pubmed-83150952021-07-28 Early Elevation of Complement Factor Ba Is a Predictive Biomarker for Transplant-Associated Thrombotic Microangiopathy Okamura, Hiroshi Nakamae, Hirohisa Shindo, Takero Ohtani, Katsuki Hidaka, Yoshihiko Ohtsuka, Yasufumi Makuuchi, Yosuke Kuno, Masatomo Takakuwa, Teruhito Harada, Naonori Nishimoto, Mitsutaka Nakashima, Yasuhiro Koh, Hideo Hirose, Asao Nakamae, Mika Wakamiya, Nobutaka Hino, Masayuki Inoue, Norimitsu Front Immunol Immunology Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Previous reports suggest that TA-TMA is caused by complement activation by complement-related genetic variants; however, this needs to be verified, especially in adults. Here, we performed a nested case-control study of allo-HSCT-treated adults at a single center. Fifteen TA-TMA patients and 15 non-TA-TMA patients, matched according to the propensity score, were enrolled. Based on a previous report showing an association between complement-related genes and development of TA-TMA, we first sequenced these 17 genes. Both cohorts harbored several genetic variants with rare allele frequencies; however, there was no difference in the percentage of patients in the TA-TMA and non-TA-TMA groups with the rare variants, or in the average number of rare variants per patient. Second, we measured plasma concentrations of complement proteins. Notably, levels of Ba protein on Day 7 following allo-HSCT were abnormally and significantly higher in TA-TMA than in non-TA-TMA cases, suggesting that complement activation via the alternative pathway contributes to TA-TMA. All other parameters, including soluble C5b-9, on Day 7 were similar between the groups. The levels of C3, C4, CH50, and complement factors H and I in the TA-TMA group after Day 28 were significantly lower than those in the non-TA-TMA group. Complement-related genetic variants did not predict TA-TMA development. By contrast, abnormally high levels of Ba on Day 7 did predict development of TA-TMA and non-relapse mortality. Thus, Ba levels on Day 7 after allo-HSCT are a sensitive and prognostic biomarker of TA-TMA. Frontiers Media S.A. 2021-07-13 /pmc/articles/PMC8315095/ /pubmed/34326846 http://dx.doi.org/10.3389/fimmu.2021.695037 Text en Copyright © 2021 Okamura, Nakamae, Shindo, Ohtani, Hidaka, Ohtsuka, Makuuchi, Kuno, Takakuwa, Harada, Nishimoto, Nakashima, Koh, Hirose, Nakamae, Wakamiya, Hino and Inoue https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Okamura, Hiroshi
Nakamae, Hirohisa
Shindo, Takero
Ohtani, Katsuki
Hidaka, Yoshihiko
Ohtsuka, Yasufumi
Makuuchi, Yosuke
Kuno, Masatomo
Takakuwa, Teruhito
Harada, Naonori
Nishimoto, Mitsutaka
Nakashima, Yasuhiro
Koh, Hideo
Hirose, Asao
Nakamae, Mika
Wakamiya, Nobutaka
Hino, Masayuki
Inoue, Norimitsu
Early Elevation of Complement Factor Ba Is a Predictive Biomarker for Transplant-Associated Thrombotic Microangiopathy
title Early Elevation of Complement Factor Ba Is a Predictive Biomarker for Transplant-Associated Thrombotic Microangiopathy
title_full Early Elevation of Complement Factor Ba Is a Predictive Biomarker for Transplant-Associated Thrombotic Microangiopathy
title_fullStr Early Elevation of Complement Factor Ba Is a Predictive Biomarker for Transplant-Associated Thrombotic Microangiopathy
title_full_unstemmed Early Elevation of Complement Factor Ba Is a Predictive Biomarker for Transplant-Associated Thrombotic Microangiopathy
title_short Early Elevation of Complement Factor Ba Is a Predictive Biomarker for Transplant-Associated Thrombotic Microangiopathy
title_sort early elevation of complement factor ba is a predictive biomarker for transplant-associated thrombotic microangiopathy
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315095/
https://www.ncbi.nlm.nih.gov/pubmed/34326846
http://dx.doi.org/10.3389/fimmu.2021.695037
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