{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T16:38:46Z","timestamp":1785515926664,"version":"3.56.0"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T00:00:00Z","timestamp":1626134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["17K09017, JP17H04108"],"award-info":[{"award-number":["17K09017, JP17H04108"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004330","name":"Smoking Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004330","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>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 <jats:italic>via<\/jats:italic> 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.<\/jats:p>","DOI":"10.3389\/fimmu.2021.695037","type":"journal-article","created":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T14:27:28Z","timestamp":1626186448000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":31,"title":["Early Elevation of Complement Factor Ba Is a Predictive Biomarker for Transplant-Associated Thrombotic Microangiopathy"],"prefix":"10.3389","volume":"12","author":[{"given":"Hiroshi","family":"Okamura","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirohisa","family":"Nakamae","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takero","family":"Shindo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsuki","family":"Ohtani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiko","family":"Hidaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasufumi","family":"Ohtsuka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosuke","family":"Makuuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masatomo","family":"Kuno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teruhito","family":"Takakuwa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naonori","family":"Harada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsutaka","family":"Nishimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Nakashima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideo","family":"Koh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asao","family":"Hirose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mika","family":"Nakamae","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobutaka","family":"Wakamiya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayuki","family":"Hino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norimitsu","family":"Inoue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,7,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.20648","article-title":"Risk Factor Analysis for Thrombotic Microangiopathy After Reduced-Intensity or Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation","volume":"81","author":"Nakamae","year":"2006","journal-title":"Am J Hematol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41409-018-0374-3","article-title":"Clinical and Morphological Practices in the Diagnosis of Transplant-Associated Microangiopathy: A Study on Behalf of Transplant Complications Working Party of the EBMT","volume":"54","author":"Moiseev","year":"2019","journal-title":"Bone Marrow Transplant"},{"key":"B3","doi-asserted-by":"publisher","first-page":"e13371","DOI":"10.1111\/ctr.13371","article-title":"Transplant-Associated Thrombotic Microangiopathy: Incidence, Prognostic Factors, Morbidity, and Mortality in Allogeneic Hematopoietic Cell Transplantation","volume":"32","author":"Gavriilaki","year":"2018","journal-title":"Clin Transplant"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/bmt.2017.119","article-title":"Transplant-Associated Thrombotic Microangiopathy Is an Endothelial Complication Associated With Refractoriness of Acute GvHD","volume":"52","author":"Zeisbrich","year":"2017","journal-title":"Bone Marrow Transplant"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.2147\/JBM.S102235","article-title":"Hematopoietic Cell Transplantation-Associated Thrombotic Microangiopathy: A Review of Pathophysiology, Diagnosis, and Treatment","volume":"7","author":"Rosenthal","year":"2016","journal-title":"J Blood Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2018.10.015","article-title":"Transplant-Associated Thrombotic Microangiopathy Is a Multifactorial Disease Unresponsive to Immunosuppressant Withdrawal","volume":"25","author":"Li","year":"2019","journal-title":"Biol Blood Marrow 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