{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T11:29:43Z","timestamp":1787052583518,"version":"build-2736575974"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Alexion Pharma GK"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Int J Hematol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, potentially life-threatening hematologic disease, often misdiagnosed because of its non-specific symptoms. PNH is characterized by terminal complement activity and intravascular hemolysis, potentially leading to thrombosis, kidney failure, and premature mortality. Early identification remains challenging, necessitating improved diagnostic strategies. In this retrospective JMDC Claims Database analysis, we evaluated the PNH patient journey, including the time from PNH-related symptom onset to first diagnosis and the association of this interval with outcomes. Overall, 160 patients were definitively diagnosed with PNH between July 2010 and April 2022. Flow cytometry (diagnostic standard to detect PNH-type blood cells) was performed in 99 of 160 patients. Ninety-two of 160 patients (57.5%) had PNH-related symptoms before first diagnosis. The median time from PNH-related symptom onset to diagnosis was 26.5 (range, 1\u2013146) months. The incidence of PNH-related complications (kidney failure, thrombosis [including venous thromboembolism]) per 1000 patient-years increased with time from symptom onset to diagnosis. Considerable time elapsed between symptom onset and definitive PNH diagnosis. Longer intervals from symptom onset to diagnosis were descriptively associated with higher rates of complications, including kidney failure and thrombosis, highlighting the potential importance of improved awareness and earlier diagnostic testing for improving PNH outcomes.<\/jats:p>","DOI":"10.1007\/s12185-026-04260-9","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T11:15:44Z","timestamp":1787051744000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Diagnostic delay and clinical outcomes of paroxysmal nocturnal hemoglobinuria: a retrospective cohort study using Japanese claims data"],"prefix":"10.1007","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1562-1013","authenticated-orcid":false,"given":"Yasutaka","family":"Ueda","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuya","family":"Kawaguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Ikezoe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiko","family":"Shimono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideo","family":"Hayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michihiro","family":"Uchiyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-ichi","family":"Nishimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaichi","family":"Nishiwaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"4260_CR1","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/S0065-2776(08)60584-2","volume":"60","author":"T Kinoshita","year":"1995","unstructured":"Kinoshita T, Inoue N, Takeda J. Defective glycosyl phosphatidylinositol anchor synthesis and paroxysmal nocturnal hemoglobinuria. Adv Immunol. 1995;60:57\u2013103.","journal-title":"Adv Immunol"},{"key":"4260_CR2","first-page":"49","volume-title":"Paroxysmal nocturnal hemoglobinuria and the glycosylphosphatidylinositol-linked proteins","author":"CJ Parker","year":"2000","unstructured":"Parker CJ. Hemolysis in PNH. In: Young NS, Moss J, editors. Paroxysmal nocturnal hemoglobinuria and the glycosylphosphatidylinositol-linked proteins. San Diego (CA): Academic Press; 2000. p. 49\u2013100."},{"key":"4260_CR3","volume-title":"Paroxysmal nocturnal hemoglobinuria","author":"N Shah","year":"2023","unstructured":"Shah N, Bhatt H. Paroxysmal nocturnal hemoglobinuria. Treasure Island (FL): StatPearls Publishing; 2023."},{"key":"4260_CR4","doi-asserted-by":"publisher","first-page":"1253","DOI":"10.1056\/NEJM199511093331904","volume":"333","author":"P Hillmen","year":"1995","unstructured":"Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med. 1995;333:1253\u20138.","journal-title":"N Engl J Med"},{"key":"4260_CR5","doi-asserted-by":"publisher","first-page":"3099","DOI":"10.1182\/blood-2008-01-133918","volume":"112","author":"RP de Latour","year":"2008","unstructured":"de Latour RP, Mary JY, Salanoubat C, Terriou L, Etienne G, Mohty M, et al. Paroxysmal nocturnal hemoglobinuria: Natural history of disease subcategories. Blood. 2008;112:3099\u2013106.","journal-title":"Blood"},{"key":"4260_CR6","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1111\/j.1365-2141.2004.04992.x","volume":"126","author":"VM Moyo","year":"2004","unstructured":"Moyo VM, Mukhina GL, Garrett ES, Brodsky RA. Natural history of paroxysmal nocturnal hemoglobinuria using modern diagnostic assays. Br J Haematol. 2004;126:133\u20138.","journal-title":"Br J Haematol"},{"key":"4260_CR7","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1097\/01.md.0000126763.68170.46","volume":"83","author":"JI Nishimura","year":"2004","unstructured":"Nishimura JI, Kanakura Y, Ware RE, Shichishima T, Nakakuma H, Ninomiya H, et al. Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan. Medicine (Baltimore). 2004;83:193\u2013207.","journal-title":"Medicine (Baltimore)"},{"key":"4260_CR8","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1002\/ajh.21757","volume":"85","author":"P Hillmen","year":"2010","unstructured":"Hillmen P, Elebute M, Kelly R, Urbano-Ispizua A, Hill A, Rother RP, et al. Long-term effect of the complement inhibitor eculizumab on kidney function in patients with paroxysmal nocturnal hemoglobinuria. Am J Hematol. 2010;85:553\u20139.","journal-title":"Am J Hematol"},{"key":"4260_CR9","doi-asserted-by":"publisher","first-page":"922","DOI":"10.3324\/haematol.2013.093161","volume":"99","author":"H Schrezenmeier","year":"2014","unstructured":"Schrezenmeier H, Muus P, Soci\u00e9 G, Szer J, Urbano-Ispizua A, Maciejewski JP, et al. Baseline characteristics and disease burden in patients in the international paroxysmal nocturnal hemoglobinuria registry. Haematologica. 2014;99:922\u20139.","journal-title":"Haematologica"},{"key":"4260_CR10","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1007\/s12185-022-03287-y","volume":"115","author":"T Ikezoe","year":"2022","unstructured":"Ikezoe T, Noji H, Ueda Y, Kanda Y, Okamoto S, Usuki K, et al. Long-term follow-up of patients with paroxysmal nocturnal hemoglobinuria treated with eculizumab: post-marketing surveillance in Japan. Int J Hematol. 2022;115:470\u201380.","journal-title":"Int J Hematol"},{"key":"4260_CR11","first-page":"100224","volume":"14","author":"K Sakai","year":"2020","unstructured":"Sakai K. Even mild hemolysis in paroxysmal nocturnal hemoglobinuria could severely compromise the quality of life due to long-term sustained intolerant fatigue. Leuk Res Rep. 2020;14:100224.","journal-title":"Leuk Res Rep"},{"key":"4260_CR12","doi-asserted-by":"publisher","first-page":"1505","DOI":"10.1007\/s00277-020-04052-z","volume":"99","author":"H Schrezenmeier","year":"2020","unstructured":"Schrezenmeier H, R\u00f6th A, Araten DJ, Kanakura Y, Larratt L, Shammo JM, et al. Baseline clinical characteristics and disease burden in patients with paroxysmal nocturnal hemoglobinuria (PNH): updated analysis from the international PNH registry. Ann Hematol. 2020;99:1505\u201314.","journal-title":"Ann Hematol"},{"key":"4260_CR13","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1111\/ejh.13176","volume":"102","author":"CJ Patriquin","year":"2019","unstructured":"Patriquin CJ, Kiss T, Caplan S, Chin-Yee I, Grewal K, Grossman J, et al. How we treat paroxysmal nocturnal hemoglobinuria: a consensus statement of the Canadian PNH network and review of the national registry. Eur J Haematol. 2019;102:36\u201352.","journal-title":"Eur J Haematol"},{"key":"4260_CR14","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1182\/asheducation-2016.1.208","volume":"2016","author":"CJ Parker","year":"2016","unstructured":"Parker CJ. Update on the diagnosis and management of paroxysmal nocturnal hemoglobinuria. Hematology Am Soc Hematol Educ Program. 2016;2016:208\u201316.","journal-title":"Hematology Am Soc Hematol Educ Program"},{"key":"4260_CR15","first-page":"S8","volume":"26","author":"M Bektas","year":"2020","unstructured":"Bektas M, Copley-Merriman C, Khan S, Sarda SP, Shammo JM. Paroxysmal nocturnal hemoglobinuria: patient journey and burden of disease. J Manag Care Spec Pharm. 2020;26:S8-14.","journal-title":"J Manag Care Spec Pharm"},{"key":"4260_CR16","first-page":"1001","volume":"1","author":"R Mitchell","year":"2017","unstructured":"Mitchell R, Salkeld E, Chisolm S, Clark M, Shammo JM. Path to diagnosis of paroxysmal nocturnal hemoglobinuria: the results of an exploratory study conducted by the Aplastic Anemia and MDS international Foundation and the National Organization for Rare Disorders utilizing an internet-based survey. SM Clin Med Oncol. 2017;1:1001.","journal-title":"SM Clin Med Oncol"},{"key":"4260_CR17","unstructured":"JMDC Claims Database. Available at: https:\/\/www.jmdc.co.jp\/en\/jmdc-claims-database\/. Accessed 7 Mar 2025."},{"key":"4260_CR18","unstructured":"Ministry of Health, Labour and Welfare (Research group on idiopathic hematopoietic disorders). Reference guide for the treatment of paroxysmal nocturnal hemoglobinuria. 2023. Available at: http:\/\/zoketsushogaihan.umin.jp\/file\/2022\/Paroxysmal_nocturnal_hemoglobinuria.pdf. Accessed 7 Mar 2025. [In Japanese]."},{"key":"4260_CR19","unstructured":"Japan Intractable Diseases Information Center. Paroxysmal nocturnal hemoglobinuria (designated intractable disease 62). 2024. Available at: https:\/\/www.nanbyou.or.jp\/entry\/3783. Accessed 6 Jan 2025. [In Japanese]."},{"key":"4260_CR20","doi-asserted-by":"publisher","first-page":"1157","DOI":"10.1182\/blood.2023021762","volume":"143","author":"RJ Kelly","year":"2024","unstructured":"Kelly RJ, Holt M, Vidler J, Arnold LM, Large J, Forrest B, et al. Treatment outcomes of complement protein C5 inhibition in 509 UK patients with paroxysmal nocturnal hemoglobinuria. Blood. 2024;143:1157\u201366.","journal-title":"Blood"},{"key":"4260_CR21","doi-asserted-by":"publisher","first-page":"204062071987472","DOI":"10.1177\/2040620719874728","volume":"10","author":"RM Stern","year":"2019","unstructured":"Stern RM, Connell NT. Ravulizumab: a novel C5 inhibitor for the treatment of paroxysmal nocturnal hemoglobinuria. 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Blood. 2011;117:6786\u201392.","journal-title":"Blood"},{"key":"4260_CR26","unstructured":"Nagalla S, Kelly RJ, Yu J, Campolo B, Fattizzo B, Szer J, et al. Assessment of long-term renal function in patients with paroxysmal nocturnal hemoglobinuria treated with ravulizumab in a phase 3 open-label study. EHA Library. 2025; 4161878."},{"key":"4260_CR27","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1182\/hematology.2021000245","volume":"2021","author":"DV Babushok","year":"2021","unstructured":"Babushok DV. When does a PNH clone have clinical significance? Hematol Am Soc Hematol Educ Program. 2021;2021:143\u201352.","journal-title":"Hematol Am Soc Hematol Educ Program"}],"container-title":["International Journal of Hematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12185-026-04260-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12185-026-04260-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12185-026-04260-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T11:15:46Z","timestamp":1787051746000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12185-026-04260-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,18]]},"references-count":27,"alternative-id":["4260"],"URL":"https:\/\/doi.org\/10.1007\/s12185-026-04260-9","relation":{},"ISSN":["0925-5710","1865-3774"],"issn-type":[{"value":"0925-5710","type":"print"},{"value":"1865-3774","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,18]]},"assertion":[{"value":"4 March 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 July 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 July 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 August 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Y. U. has received grants or contracts from Alexion Pharma GK. and Chugai Pharmaceutical Co., Ltd. (to institution); consulting fees and payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Alexion Pharma GK., Asahi Kasei Pharma Corp., Chugai Pharmaceutical Co., Ltd., Novartis Pharmaceuticals Corp., and Sobi Japan; and support for attending meetings and\/or travel from Chugai Pharmaceutical Co., Ltd., and Novartis Pharmaceuticals Corp.; participates on a Data Safety Monitoring Board or Advisory Board for Alexion Pharma GK. and Novartis Pharmaceuticals Corp.; and is an Editor of\n                      International Journal of Hematology\n                      . T. K. has received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Alexion Pharma GK., Chugai Pharmaceutical Co., Ltd., Sobi Japan, and Novartis Pharmaceuticals Corp. T. I. has received consulting fees, payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events, and support for attending meetings and\/or travel from Alexion Pharma GK., Chugai Pharmaceutical Co., Ltd., Novartis Pharmaceuticals Corp., and Asahi Kasei Pharma Corp.; and is the Director of the Japanese Society of Thrombosis and Hemostasis and Japanese Society of Hematology. A. S. and H. H. hold stock or stock options and are employees of Alexion Pharma GK. M. U. has no potential conflicts of interest to declare. J. N. has received consulting fees and payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Alexion Pharma GK., Chugai Pharmaceutical Co., Ltd., Roche Ltd., Novartis Pharmaceuticals Corp., Sobi Japan, and Asahi Kasei Pharma Corp. K. N. has received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Alexion Pharma GK., Pfizer Inc., and Argenx. All authors received funding from Alexion Pharma GK. for the analysis and medical writing support.","order":1,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}}]}}