{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T16:09:09Z","timestamp":1789834149510,"version":"4.0.1"},"reference-count":34,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2022,11,12]],"date-time":"2022-11-12T00:00:00Z","timestamp":1668211200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Israeli Society of Hematology"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Bleeding tendency, a prominent feature of patients with Gaucher disease (GD), is associated with abnormal platelet function. Brain-derived neurotrophic factor (BDNF) is a protein with neuroprotective potential stored in alpha granules of circulating platelets. Here we studied BDNF levels in 50 patients with type I GD (GD1) and their correlation with platelet activity and bleeding tendency. Flow cytometry was used to test unstimulated and stimulated measurement of platelet surface-activated expression of \u03b1IIb\u03b23 integrin, P-selectin and lysosomal-associated membrane protein (LAMP3\/CD63). Serum and plasma BDNF levels were quantified using ELISA. The bleeding history was recorded by a bleeding questionnaire. Serum BDNF levels were positively correlated with platelet count and moderately correlated with unstimulated and stimulated platelet P-selectin expression. Patients with more than one bleeding manifestation were shown to have lower serum BDNF levels, albeit similar platelet count. Plasma BDNF levels were significantly elevated in splenectomized patients and showed a moderate positive correlation with stimulated platelet CD63 expression. These observations demonstrate the first association between BDNF levels in the peripheral blood with platelet dysfunction and increased bleeding manifestation. The role of measuring serum BDNF for assessing platelet alpha degranulation defects and bleeding risk in patients with GD and the general population needs further study.<\/jats:p>","DOI":"10.3390\/ijms232213982","type":"journal-article","created":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T02:29:32Z","timestamp":1668392972000},"page":"13982","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Brain-Derived Neurotrophic Factor (BDNF) Is Associated with Platelet Activity and Bleeding Tendency in Patients with Gaucher Disease"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3451-5737","authenticated-orcid":false,"given":"David","family":"Azoulay","sequence":"first","affiliation":[{"name":"Hematology Unit and Laboratories, Galilee Medical Center, Nahariya 22100, Israel"},{"name":"Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mira","family":"Naamad","sequence":"additional","affiliation":[{"name":"Flow Cytometry Unit, Shaare Zedek Medical Center, Jerusalem 9103102, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dafna","family":"Frydman","sequence":"additional","affiliation":[{"name":"Gaucher Unit, Shaare Zedek Medical Center, Jerusalem 9103102, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Broide","sequence":"additional","affiliation":[{"name":"Flow Cytometry Unit, Shaare Zedek Medical Center, Jerusalem 9103102, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0077-8608","authenticated-orcid":false,"given":"Ari","family":"Zimran","sequence":"additional","affiliation":[{"name":"Gaucher Unit, Shaare Zedek Medical Center, Jerusalem 9103102, Israel"},{"name":"Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112002, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galia","family":"Stemer","sequence":"additional","affiliation":[{"name":"Hematology Unit and Laboratories, Galilee Medical Center, Nahariya 22100, Israel"},{"name":"Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9151-0337","authenticated-orcid":false,"given":"Shoshana","family":"Revel-Vilk","sequence":"additional","affiliation":[{"name":"Gaucher Unit, Shaare Zedek Medical Center, Jerusalem 9103102, Israel"},{"name":"Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112002, Israel"},{"name":"Pediatric Hematology\/Oncology Unit, Shaare Zedek Medical Center, Jerusalem 9103102, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,12]]},"reference":[{"key":"ref_1","unstructured":"Kaushansky, K., Lichtman, M., Prchal, J., Levi, M., Press, O., Burns, L., and Caligiuri, M. (2021). Gaucher disease and related lysosomal storage diseases. Williams Hematology, McGraw-Hill. [10th ed.]."},{"key":"ref_2","unstructured":"(2022, October 19). Patient Centered Guidelines for the Laboratory Diagnosis of Gaucher Disease (GD) Type 1. Available online: https:\/\/www.ewggd.com\/wp-content\/uploads\/2022\/09\/Laboratory-diagnosis-of-Gaucher-disease-GD-type-1-.pdf."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"121","DOI":"10.14740\/jh543","article-title":"Coagulation Parameters in Adult Patients With Type-1 Gaucher Disease","volume":"8","author":"Serratrice","year":"2019","journal-title":"J. Hematol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1080\/17474086.2021.1908120","article-title":"Hematological manifestations and complications of Gaucher disease","volume":"14","author":"Szer","year":"2021","journal-title":"Expert Rev. Hematol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1160\/TH10-07-0503","article-title":"Impaired platelet function and peripartum bleeding in women with Gaucher disease","volume":"105","author":"Simchen","year":"2011","journal-title":"Thromb. Haemost."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1111\/j.1365-2141.2011.08613.x","article-title":"Platelet adhesion defect in type I Gaucher Disease is associated with a risk of mucosal bleeding","volume":"153","author":"Spectre","year":"2011","journal-title":"Br. J. Haematol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1111\/j.1538-7836.2006.02037.x","article-title":"Platelet function and coagulation abnormalities in type 1 Gaucher disease patients: Effects of enzyme replacement therapy (ERT)","volume":"4","author":"Giona","year":"2006","journal-title":"J. Thromb. Haemost."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1055\/s-0035-1570082","article-title":"Platelet Function Determined by Flow Cytometry: New Perspectives?","volume":"42","author":"Ramstrom","year":"2016","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1002\/rth2.12193","article-title":"Platelet function testing at low platelet counts: When can you trust your analysis?","volume":"3","author":"Boknas","year":"2019","journal-title":"Res. Pract. Thromb. Haemost."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1055\/a-1642-4206","article-title":"Platelet Activation and Reactivity in a Large Cohort of Patients with Gaucher Disease","volume":"122","author":"Naamad","year":"2022","journal-title":"Thromb. Haemost."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-1-61779-536-7_1","article-title":"The neurotrophin family of neurotrophic factors: An overview","volume":"846","author":"Skaper","year":"2012","journal-title":"Methods Mol. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1055\/s-0037-1613072","article-title":"Brain-derived neurotrophic factor is stored in human platelets and released by agonist stimulation","volume":"87","author":"Fujimura","year":"2002","journal-title":"Thromb. Haemost."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.jneuroim.2005.07.001","article-title":"Lower brain-derived neurotrophic factor in serum of relapsing remitting MS: Reversal by glatiramer acetate","volume":"167","author":"Azoulay","year":"2005","journal-title":"J. Neuroimmunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.jneuroim.2008.01.010","article-title":"Low and dysregulated BDNF secretion from immune cells of MS patients is related to reduced neuroprotection","volume":"195","author":"Azoulay","year":"2008","journal-title":"J. Neuroimmunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1084\/jem.189.5.865","article-title":"Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: A neuroprotective role of inflammation?","volume":"189","author":"Kerschensteiner","year":"1999","journal-title":"J. Exp. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"9655","DOI":"10.1038\/s41598-019-45976-5","article-title":"Associations between serum and plasma brain-derived neurotrophic factor and influence of storage time and centrifugation strategy","volume":"9","author":"Gejl","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Nettiksimmons, J., Simonsick, E.M., Harris, T., Satterfield, S., Rosano, C., Yaffe, K., and Health, A.B.C.S. (2014). The associations between serum brain-derived neurotrophic factor, potential confounders, and cognitive decline: A longitudinal study. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0091339"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"100871","DOI":"10.1016\/j.blre.2021.100871","article-title":"Brain-derived neurotrophic factor in hematological malignancies: From detrimental to potentially beneficial","volume":"51","author":"Azoulay","year":"2022","journal-title":"Blood Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"84","DOI":"10.5498\/wjp.v6.i1.84","article-title":"Are the changes in the peripheral brain-derived neurotrophic factor levels due to platelet activation?","volume":"6","year":"2016","journal-title":"World J. Psychiatry"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.clinbiochem.2016.11.014","article-title":"The modulation of inflammatory parameters, Brain-derived neurotrophic factor levels and global histone H4 acetylation status in peripheral blood of patients with Gaucher disease type 1","volume":"50","author":"Reinaldo","year":"2017","journal-title":"Clin. Biochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.jneuroim.2014.11.005","article-title":"Brain-derived neurotrophic factor expression increases after enzyme replacement therapy in Gaucher disease","volume":"278","author":"Vairo","year":"2015","journal-title":"J. Neuroimmunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/s41598-018-37117-1","article-title":"Patho- physiological role of BDNF in fibrin clotting","volume":"9","author":"Amadio","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4265","DOI":"10.1182\/blood-2010-11-321489","article-title":"CD63 is an essential cofactor to leukocyte recruitment by endothelial P-selectin","volume":"118","author":"Doyle","year":"2011","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"20300","DOI":"10.1038\/s41598-021-99777-w","article-title":"Exosomal CD63 in critically ill patients with sepsis","volume":"11","author":"Im","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1160\/TH04-08-0503","article-title":"CD63 modulates spreading and tyrosine phosphorylation of platelets on immobilized fibrinogen","volume":"93","author":"Israels","year":"2005","journal-title":"Thromb. Haemost."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1189\/jlb.3A1015-480R","article-title":"CD63 is tightly associated with intracellular, secretory events chaperoning piecemeal degranulation and compound exocytosis in human eosinophils","volume":"100","author":"Carmo","year":"2016","journal-title":"J. Leukoc. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"114402","DOI":"10.1016\/j.addr.2022.114402","article-title":"Lysosomal functions and dysfunctions: Molecular and cellular mechanisms underlying Gaucher disease and its association with Parkinson disease","volume":"187","author":"Horowitz","year":"2022","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"167","DOI":"10.3892\/br.2012.48","article-title":"The neuroprotective roles of BDNF in hypoxic ischemic brain injury","volume":"1","author":"Chen","year":"2013","journal-title":"Biomed. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1038\/sj.cdd.4401662","article-title":"Neuroprotection by BDNF against glutamate-induced apoptotic cell death is mediated by ERK and PI3-kinase pathways","volume":"12","author":"Almeida","year":"2005","journal-title":"Cell Death Differ."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.pnpbp.2018.07.010","article-title":"Serum level of brain-derived neurotrophic factor in Parkinson\u2019s disease: A meta-analysis","volume":"88","author":"Jiang","year":"2019","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"747","DOI":"10.3389\/fimmu.2020.00747","article-title":"Platelets in Neurodegenerative Conditions-Friend or Foe?","volume":"11","author":"Leiter","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.1097\/01.HS9.0000849388.86217.d1","article-title":"P1633: Low serum BDNF levels are associated with lower platelet CD62P reactivity and increased bleeding tendency in patients with Gaucher disease","volume":"6","author":"Azoulay","year":"2022","journal-title":"Hemasphere"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.1111\/j.1538-7836.2010.03975.x","article-title":"ISTH\/SSC bleeding assessment tool: A standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders","volume":"8","author":"Rodeghiero","year":"2010","journal-title":"J. Thromb. Haemost."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Rolfs, A., Giese, A.K., Grittner, U., Mascher, D., Elstein, D., Zimran, A., Bottcher, T., Lukas, J., Hubner, R., and Golnitz, U. (2013). Glucosylsphingosine is a highly sensitive and specific biomarker for primary diagnostic and follow-up monitoring in Gaucher disease in a non-Jewish, Caucasian cohort of Gaucher disease patients. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0079732"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/13982\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:17:08Z","timestamp":1760145428000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/13982"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,12]]},"references-count":34,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["ijms232213982"],"URL":"https:\/\/doi.org\/10.3390\/ijms232213982","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,12]]}}}