{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:05:10Z","timestamp":1792789510321,"version":"4.5.0"},"reference-count":29,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2022,9,7]],"date-time":"2022-09-07T00:00:00Z","timestamp":1662508800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"AMRO foundation (Association Maladie de Rendu-Osler)","award":["446002501"],"award-info":[{"award-number":["446002501"]}]},{"name":"Kees Westermann Fund","award":["446002501"],"award-info":[{"award-number":["446002501"]}]},{"DOI":"10.13039\/501100001826","name":"Netherlands Organization for Health Research and Development (ZonMw)","doi-asserted-by":"publisher","award":["446002501"],"award-info":[{"award-number":["446002501"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Haploinsufficiency for Endoglin (ENG) and activin A receptor type II-like I (ACVRL1\/ALK1) lead to the formation of weak and abnormal vessels in hereditary hemorrhagic telangiectasia (HHT). These cause epistaxis (nosebleeds) and\/or gastrointestinal blood loss. In vitro in cultured endothelial cells, tacrolimus has been shown to increase ENG and ALK1 expression. It is, therefore, a potential treatment option. We report here a proof-of-concept study in patients with HHT and severe epistaxis and\/or gastrointestinal bleeding who were treated daily with orally-administered tacrolimus for twenty weeks. Twenty-five patients with HHT (11 females (44%)) and median age of 59 years were enrolled. Five patients (20%) stopped the trial prematurely-four due to (serious) adverse events ((S)AE). Twenty patients were included in further analyses. Hemoglobin levels increased during tacrolimus treatment from 6.1 (IQR 5.2\u20136.9) mmol\/L at baseline (9.8 g\/dL) to 6.7 (6.5\u20137.1) mmol\/L (10.8 g\/dL), p = 0.003. The number of blood transfusions over the twenty weeks decreased from a mean of 5.0 (\u00b19.2) to 1.9 (\u00b13.5), p = 0.04. In 64% of the patients, at least one AE occurred. Oral tacrolimus, thus, significantly increased hemoglobin levels and decreased blood transfusion needs, epistaxis and\/or gastrointestinal bleeding in patients with HHT. However, side-effects were common. Further investigation of the potential therapeutic benefit is justified by the outcome of the study.<\/jats:p>","DOI":"10.3390\/jcm11185280","type":"journal-article","created":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T01:40:13Z","timestamp":1662601213000},"page":"5280","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Efficacy and Safety of Tacrolimus as Treatment for Bleeding Caused by Hereditary Hemorrhagic Telangiectasia: An Open-Label, Pilot Study"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9001-9893","authenticated-orcid":false,"given":"Josefien","family":"Hessels","sequence":"first","affiliation":[{"name":"Department of Pulmonology, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1098-5555","authenticated-orcid":false,"given":"Steven","family":"Kroon","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanne","family":"Boerman","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rik C.","family":"Nelissen","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan C.","family":"Grutters","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands"},{"name":"Department of Pulmonology, University Medical Center Utrecht, Heidelberglaan 100, 3484 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Repke J.","family":"Snijder","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1650-6757","authenticated-orcid":false,"given":"Franck","family":"Lebrin","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco C.","family":"Post","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Medical Center Utrecht, Heidelberglaan 100, 3484 CX Utrecht, The Netherlands"},{"name":"Department of Cardiology, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine L.","family":"Mummery","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Embryology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes-Jurgen","family":"Mager","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/ng1294-345","article-title":"Endoglin, a TGF-\u03b2 binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1","volume":"8","author":"McAllister","year":"1994","journal-title":"Nat. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1038\/ng0696-189","article-title":"Mutations in the activin receptor\u2013like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2","volume":"13","author":"Johnson","year":"1996","journal-title":"Nat. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fgene.2015.00001","article-title":"Hereditary hemorrhagic telangiectasia: Genetics and molecular diagnostics in a new era","volume":"6","author":"McDonald","year":"2015","journal-title":"Front Genet."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Albi\u00f1ana, V., Cuesta, A.M., De Rojas-P, I., Gallardo-Vara, E., Recio-Poveda, L., Bernab\u00e9u, C., and Botella, L.M. (2020). Review of Pharmacological Strategies with Repurposed Drugs for Hereditary Hemorrhagic Telangiectasia Related Bleeding. J. Clin. Med., 9.","DOI":"10.3390\/jcm9061766"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s12955-017-0586-z","article-title":"Quality of life in patients with hereditary haemorrhagic telangiectasia (HHT)","volume":"15","author":"Zarrabeitia","year":"2017","journal-title":"Health Qual. Life Outcomes"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"226","DOI":"10.7326\/0003-4819-144-3-200602070-00030","article-title":"Regression of cutaneous and gastrointestinal telangiectasia with sirolimus and aspirin in a patient with hereditary hemorrhagic telangiectasia","volume":"144","author":"Skaro","year":"2006","journal-title":"Ann. Intern. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1124\/mol.110.067447","article-title":"Immunosuppressor FK506 Increases Endoglin and Activin Receptor-Like Kinase 1 Expression and Modulates Transforming Growth Factor-\u03b21 Signaling in Endothelial Cells","volume":"79","author":"Bernabeu","year":"2011","journal-title":"Mol. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4786","DOI":"10.1093\/hmg\/ddx358","article-title":"Tacrolimus rescues the signaling and gene expression signature of endothelial ALK1 loss-of-function and improves HHT vascular pathology","volume":"26","author":"Ruiz","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2045894018805406","DOI":"10.1177\/2045894018805406","article-title":"Treatment with low-dose tacrolimus inhibits bleeding complications in a patient with hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension","volume":"9","author":"Sommer","year":"2019","journal-title":"Pulm. Circ."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e133","DOI":"10.1097\/PG9.0000000000000133","article-title":"Tacrolimus in Gastrointestinal Bleeding in a Young Boy With Hereditary Hemorrhagic Telangiectasia","volume":"2","author":"Pruijsen","year":"2021","journal-title":"JPGN Rep."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Dupuis-Girod, S., Fargeton, A.-E., Grobost, V., Rivi\u00e8re, S., Beaudoin, M., Decullier, E., Bernard, L., Br\u00e9ant, V., Colombet, B., and Philouze, P. (2020). Efficacy and Safety of a 0.1% Tacrolimus Nasal Ointment as a Treatment for Epistaxis in Hereditary Hemorrhagic Telangiectasia: A Double-Blind, Randomized, Placebo-Controlled, Multicenter Trial. J. Clin. Med., 9.","DOI":"10.3390\/jcm9051262"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1002\/(SICI)1096-8628(20000306)91:1<66::AID-AJMG12>3.0.CO;2-P","article-title":"Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome)","volume":"91","author":"Shovlin","year":"2000","journal-title":"Am. J. Med. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1002\/lary.20818","article-title":"An epistaxis severity score for hereditary hemorrhagic telangiectasia","volume":"120","author":"Hoag","year":"2010","journal-title":"Laryngoscope"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1097\/00005650-199206000-00002","article-title":"The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection","volume":"30","author":"Ware","year":"1992","journal-title":"Med. Care"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/0022-3999(94)00125-O","article-title":"The multidimensional fatigue inventory (MFI) psychometric qualities of an instrument to assess fatigue","volume":"39","author":"Smets","year":"1995","journal-title":"J. Psychosom. Res."},{"key":"ref_16","first-page":"25","article-title":"Mouse models of hereditary hemorrhagic telangiectasia: Recent advances and future challenges","volume":"6","author":"Oh","year":"2015","journal-title":"Front. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Geisthoff, U., Nguyen, H.-L., Lefering, R., Maune, S., Thangavelu, K., and Droege, F. (2020). Trauma Can Induce Telangiectases in Hereditary Hemorrhagic Telangiectasia. J. Clin. Med., 9.","DOI":"10.3390\/jcm9051507"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1097\/00007691-199512000-00007","article-title":"Mode of Action of Tacrolimus (FK506): Molecular and Cellular Mechanisms","volume":"17","author":"Thomson","year":"1995","journal-title":"Ther. Drug Monit."},{"key":"ref_19","first-page":"818","article-title":"Patients with hereditary hemorrhagic telangiectasia have increased plasma levels of vascular endothelial growth factor and transforming growth factor-\u03b21 as well as high ALK1 tissue expression","volume":"90","author":"Sadick","year":"2005","journal-title":"Haematologica"},{"key":"ref_20","first-page":"948","article-title":"Bevacizumab in Patients With Hereditary Hemorrhagic Telangiectasia and Severe Hepatic Vascular Malformations and High Cardiac Output","volume":"307","author":"Ginon","year":"2012","journal-title":"JAMA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"34","DOI":"10.3109\/02713683.2010.516620","article-title":"The Impact of Tacrolimus on Vascular Endothelial Growth Factor in Experimental Corneal Neovascularization","volume":"36","author":"Turgut","year":"2011","journal-title":"Curr. Eye Res."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Siamakpour-Reihani, S., Caster, J., Nepal, D.B., Courtwright, A., Hilliard, E., Usary, J., Ketelsen, D., Darr, D., Shen, X.J., and Patterson, C. (2011). The Role of Calcineurin\/NFAT in SFRP2 Induced Angiogenesis\u2014A Rationale for Breast Cancer Treatment with the Calcineurin Inhibitor Tacrolimus. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0020412"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1007\/s10456-020-09758-2","article-title":"Oral itraconazole for epistaxis in hereditary hemorrhagic telangiectasia: A proof of concept study","volume":"24","author":"Kroon","year":"2021","journal-title":"Angiogenesis"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"E247","DOI":"10.1002\/ajh.25563","article-title":"Octreotide for gastrointestinal bleeding in hereditary hemorrhagic telangiectasia: A prospective case series","volume":"94","author":"Kroon","year":"2019","journal-title":"Am. J. Hematol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1177\/1526924817699960","article-title":"Insomnia and Relationship With Immunosuppressant Therapy After Lung Transplantation","volume":"27","author":"Rohde","year":"2017","journal-title":"Prog. Transplant."},{"key":"ref_26","first-page":"1039","article-title":"Immunosuppression in lung transplantation","volume":"6","author":"Scheffert","year":"2014","journal-title":"J. Thorac. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Hwang, Y.H., Kim, H., Min, K., and Yang, J. (2021). Tacrolimus trough levels in kidney transplant recipients. BMC Nephrol., 22.","DOI":"10.1186\/s12882-021-02622-5"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1038\/nrn3475","article-title":"Power failure: Why small sample size undermines the reliability of neuroscience","volume":"14","author":"Button","year":"2013","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1136\/bmj.311.7003.485","article-title":"Absence of evidence is not evidence of absence","volume":"311","author":"Altman","year":"1995","journal-title":"BMJ"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/18\/5280\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:25:00Z","timestamp":1760142300000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/18\/5280"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,7]]},"references-count":29,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["jcm11185280"],"URL":"https:\/\/doi.org\/10.3390\/jcm11185280","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,7]]}}}