{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T13:55:30Z","timestamp":1792418130428,"version":"4.4.0"},"reference-count":25,"publisher":"American Society of Hematology","issue":"13","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,3,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Advances in genomic diagnostics hold promise for improved care of rare hematologic diseases. Here, we describe a novel targeted therapeutic approach for Ghosal hematodiaphyseal dysplasia, an autosomal recessive disease characterized by severe normocytic anemia and bone abnormalities due to loss-of-function mutations in thromboxane A synthase 1 (TBXAS1). TBXAS1 metabolizes prostaglandin H2 (PGH2), a cyclooxygenase (COX) product of arachidonic acid, into thromboxane A2. Loss-of-function mutations in TBXAS result in an increase in PGH2 availability for other PG synthases. The current treatment for Ghosal hematodiaphyseal dysplasia syndrome consists of corticosteroids. We hypothesize that nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit COX-1 and COX-2, could ameliorate the effects of TBXAS1 loss and improve hematologic function by reducing prostaglandin formation. We treated 2 patients with Ghosal hematodiaphyseal dysplasia syndrome, an adult and a child, with standard doses of NSAIDs (aspirin or ibuprofen). Both patients had rapid improvements concerning hematologic parameters and inflammatory markers without adverse events. Mass spectrometry analysis demonstrated that urinary PG metabolites were increased along with proinflammatory lipoxygenase (LOX) products 5-hydroxyeicosatetraenoic acid and leukotriene E4. Our data show that NSAIDs at standard doses surprisingly reduced both COX and LOX products, leading to the resolution of cytopenia, and should be considered for first-line treatment for Ghosal hematodiaphyseal dysplasia syndrome.<\/jats:p>","DOI":"10.1182\/blood.2022018667","type":"journal-article","created":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T17:36:03Z","timestamp":1672162563000},"page":"1553-1559","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":19,"title":["Nonsteroidal anti-inflammatory drugs as a targeted therapy for bone marrow failure in Ghosal hematodiaphyseal dysplasia"],"prefix":"10.1182","volume":"141","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4843-4639","authenticated-orcid":false,"given":"Timothy J.","family":"Brown","sequence":"first","affiliation":[{"name":"1Division of Hematology-Oncology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"Barrett","sequence":"additional","affiliation":[{"name":"2Paediatric Haematology, Children's Health Ireland at Temple Street\/Crumlin, Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2224-5431","authenticated-orcid":false,"given":"Hu","family":"Meng","sequence":"additional","affiliation":[{"name":"3Institute for Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela","family":"Ricciotti","sequence":"additional","affiliation":[{"name":"3Institute for Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA"},{"name":"4Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciara","family":"McDonnell","sequence":"additional","affiliation":[{"name":"5Paediatric Endocrinology, Children's Health Ireland at Temple Street\/Crumlin and Discipline of Paediatrics, University of Dublin Trinity College Dublin, Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Dancis","sequence":"additional","affiliation":[{"name":"1Division of Hematology-Oncology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julianne","family":"Qualtieri","sequence":"additional","affiliation":[{"name":"6Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garret A.","family":"FitzGerald","sequence":"additional","affiliation":[{"name":"3Institute for Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Cotter","sequence":"additional","affiliation":[{"name":"2Paediatric Haematology, Children's Health Ireland at Temple Street\/Crumlin, Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1745-0353","authenticated-orcid":false,"given":"Daria V.","family":"Babushok","sequence":"additional","affiliation":[{"name":"1Division of Hematology-Oncology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA"},{"name":"7Comprehensive Bone Marrow Failure Center, Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"1","key":"2023110216011504900_bib1","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S0022-3476(88)80527-4","article-title":"Diaphyseal dysplasia associated with anemia","volume":"113","author":"Ghosal","year":"1988","journal-title":"J\u00a0Pediatr"},{"issue":"3","key":"2023110216011504900_bib2","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1038\/ng.2007.66","article-title":"Thromboxane synthase mutations in an increased bone density disorder (Ghosal syndrome)","volume":"40","author":"Genevi\u00e8ve","year":"2008","journal-title":"Nat Genet"},{"issue":"3","key":"2023110216011504900_bib3","doi-asserted-by":"crossref","DOI":"10.1002\/mgg3.1494","article-title":"Novel compound heterozygous variants of TBXAS1 presenting with Ghosal hematodiaphyseal dysplasia treated with steroids","volume":"9","author":"Kim","year":"2021","journal-title":"Mol. Genet. Genomic Med"},{"issue":"2","key":"2023110216011504900_bib4","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1002\/ajmg.a.61961","article-title":"Ghosal hematodiaphyseal dysplasia and response to corticosteroid therapy","volume":"185","author":"Joy","year":"2021","journal-title":"Am J Med Genet"},{"issue":"3","key":"2023110216011504900_bib5","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1007\/s00256-014-1989-0","article-title":"Ghosal hematodiaphyseal dysplasia\u2014a concise review including an illustrative patient","volume":"44","author":"Arora","year":"2015","journal-title":"Skeletal Radiol"},{"issue":"4","key":"2023110216011504900_bib6","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.transci.2019.04.027","article-title":"Ghosal hematodiaphyseal dysplasia with autoimmune anemia in two adult siblings","volume":"58","author":"Ciftciler","year":"2019","journal-title":"Transfus Apher Sci"},{"issue":"4","key":"2023110216011504900_bib7","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1007\/s13312-016-0851-y","article-title":"Ghosal type hematodiaphyseal dysplasia","volume":"53","author":"Jeevan","year":"2016","journal-title":"Indian Pediatr"},{"issue":"1","key":"2023110216011504900_bib8","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/s12288-017-0818-8","article-title":"Ghosal hemato-diaphyseal dysplasia: a rare variety of hypoplastic anemia with good response to steroid therapy","volume":"34","author":"Kini","year":"2018","journal-title":"Indian J Hematol Blood Transfus"},{"key":"2023110216011504900_bib9","doi-asserted-by":"crossref","DOI":"10.18502\/ijhoscr.v14i2.2677","article-title":"Ghosal hematodiaphyseal dysplasia: a case report","author":"Shakiba","year":"2020","journal-title":"IJHOSCR"},{"issue":"24","key":"2023110216011504900_bib10","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1007\/BF02902979","article-title":"An unusual bone dysplasia","volume":"118","author":"Ghosal","year":"1957","journal-title":"Indian J Pediatr"},{"issue":"5","key":"2023110216011504900_bib11","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1016\/S0022-3476(89)80170-2","article-title":"High-dose intravenous methylprednisolone therapy for anemia associated with diaphyseal dysplasia","volume":"114","author":"\u00d6zsoyla","year":"1989","journal-title":"J\u00a0Pediatr"},{"issue":"1","key":"2023110216011504900_bib12","doi-asserted-by":"crossref","first-page":"e26777","DOI":"10.1002\/pbc.26777","article-title":"Chronic steroid-response pancytopenia and increased bone density due to thromboxane synthase deficiency","volume":"65","author":"Sharma","year":"2018","journal-title":"Pediatr Blood Cancer"},{"issue":"6","key":"2023110216011504900_bib13","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1161\/01.CIR.67.6.1174","article-title":"Analysis of prostacyclin and thromboxane biosynthesis in cardiovascular disease","volume":"67","author":"FitzGerald","year":"1983","journal-title":"Circulation"},{"issue":"4","key":"2023110216011504900_bib14","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1038\/ki.1989.251","article-title":"Prostaglandin-mediated suppression of in\u00a0vitro growth of erythroid progenitor cells","volume":"36","author":"Taniguchi","year":"1989","journal-title":"Kidney Int"},{"key":"2023110216011504900_bib15","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/0262-1746(84)90124-0","article-title":"A\u00a0clinical trial of prostaglandin E2 to increase erythropoiesis in anemia of end stage renal disease. A preliminary report","volume":"14","author":"Ortega","year":"1984","journal-title":"Prostaglandins Leukot Med"},{"issue":"6","key":"2023110216011504900_bib16","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1182\/blood.V71.6.1633.1633","article-title":"In\u00a0vivo modulation of myelopoiesis by prostaglandin E2. III. Induction of suppressor cells in marrow and spleen capable of mediating inhibition of CFU-GM proliferation","volume":"71","author":"Pelus","year":"1988","journal-title":"Blood"},{"issue":"6","key":"2023110216011504900_bib17","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1016\/j.cell.2009.01.015","article-title":"Genetic interaction of PGE2 and Wnt signaling regulates developmental specification of stem cells and regeneration","volume":"136","author":"Goessling","year":"2009","journal-title":"Cell"},{"issue":"2","key":"2023110216011504900_bib18","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.yexcr.2014.07.030","article-title":"Getting more for your marrow: boosting hematopoietic stem cell numbers with PGE2","volume":"329","author":"Hagedorn","year":"2014","journal-title":"Exp Cell Res"},{"issue":"6","key":"2023110216011504900_bib19","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1002\/pbc.22662","article-title":"Ghosal hematodiaphyseal dysplasia: a rare cause of a myelophthisic anemia: Ghosal Hematodiaphyseal Dysplasia","volume":"55","author":"Mazaheri","year":"2010","journal-title":"Pediatr Blood Cancer"},{"issue":"12","key":"2023110216011504900_bib20","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1007\/s12098-012-0872-z","article-title":"Ghosal hematodiaphyseal dysplasia with myelofibrosis","volume":"80","author":"Datta","year":"2013","journal-title":"Indian J Pediatr"},{"issue":"1","key":"2023110216011504900_bib21","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/ajh.10258","article-title":"Primary autoimmune myelofibrosis: definition of a distinct clinicopathologic syndrome","volume":"72","author":"Pullarkat","year":"2003","journal-title":"Am J Hematol"},{"issue":"01","key":"2023110216011504900_bib22","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1055\/s-0037-1612953","article-title":"Prostaglandin endoperoxides and thromboxane A2 activate the same receptor isoforms in human platelets","volume":"87","author":"Vezza","year":"2002","journal-title":"Thromb Haemost"},{"issue":"6","key":"2023110216011504900_bib23","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1161\/01.CIR.72.6.1194","article-title":"The biochemical pharmacology of thromboxane synthase inhibition in man","volume":"72","author":"FitzGerald","year":"1985","journal-title":"Circulation"},{"issue":"5","key":"2023110216011504900_bib24","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1016\/0006-2952(86)90243-1","article-title":"Effects on prostanoid formation and pharmacokinetics of dazmegrel (UK-38,485), a novel thromboxane synthase inhibitor, in man","volume":"35","author":"Lorenz","year":"1986","journal-title":"Biochem Pharmacol"},{"issue":"5","key":"2023110216011504900_bib25","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.1172\/JCI113784","article-title":"Prostaglandin endoperoxides modulate the response to thromboxane synthase inhibition during coronary thrombosis","volume":"82","author":"Fitzgerald","year":"1988","journal-title":"J\u00a0Clin Invest"}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/141\/13\/1553\/2087760\/blood_bld-2022-018667-main.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/141\/13\/1553\/2087760\/blood_bld-2022-018667-main.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,2]],"date-time":"2023-11-02T16:01:45Z","timestamp":1698940905000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/141\/13\/1553\/493891\/Nonsteroidal-anti-inflammatory-drugs-as-a-targeted"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,30]]},"references-count":25,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2023,3,30]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.2022018667","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,30]]}}}