{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T15:57:52Z","timestamp":1790438272685,"version":"4.1.0"},"reference-count":17,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T00:00:00Z","timestamp":1790380800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T00:00:00Z","timestamp":1790380800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P01HL167668"],"award-info":[{"award-number":["P01HL167668"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL169144"],"award-info":[{"award-number":["R01HL169144"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Transfusion"],"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n Fetal\/neonatal alloimmune thrombocytopenia (FNAIT) is caused by maternal alloantibodies directed against fetal platelet antigens, most commonly human platelet antigen\u20101a (HPA\u20101a). These antibodies mediate platelet destruction and can lead to fetal and neonatal thrombocytopenia severe enough to cause life\u2010threatening organ bleeds. Antibody titer and isotype do not reliably predict disease severity, suggesting additional heterogeneity among anti\u2010HPA\u20101a antibodies.<\/jats:p>\n <\/jats:sec>\n \n Study Design and Methods<\/jats:title>\n We evaluated the effects of five previously characterized HPA\u20101a\u2010specific monoclonal antibodies (mAbs) on platelet activation, platelet aggregation, and induction of intracellular signaling. The involvement of Fc\u03b3RIIa was examined using Fc\u03b3RIIa\u2010blocking antibody IV.3, protein tyrosine kinase inhibitors, and selected monoclonal antibody Fab fragments.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n At saturating concentrations, all five mAbs inhibited thrombin\u2010induced aggregation. At sub\u2010saturating concentrations, however, mAb M\u2010204 uniquely induced spontaneous aggregation and \u03b1\u2010granule secretion in HPA\u20101a\u2010positive human, but not mouse, platelets, which lack Fc\u03b3RIIa. M\u2010204\u2010induced aggregation was abolished by mAb IV.3 and inhibitors of Src\u2010 and Syk\u2010family kinases and was absent using M\u2010204 Fab fragments. M\u2010204 induced tyrosine phosphorylation of Syk and PLC\u03b32 in an Fc\u03b3RIIa\u2010dependent manner. Finally, despite persistent platelet activation induced by M\u2010204, saturating concentrations of this antibody blocked the binding of the fibrinogen mimetic antibody, PAC\u20101, to HPA\u20101a homozygous, but not HPA\u20101a\/1b heterozygous, platelets, consistent with the known ability of HPA\u20101a\u2010specific antibodies to sterically interfere with ligand binding to HPA\u20101a\u2010positive \u03b1IIb\u03b23.<\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n These findings identify a previously unrecognized, functionally distinct subset of HPA\u20101a antibodies capable of activating platelets via Fc\u03b3RIIa, suggesting a potential mechanism contributing to variability in disease severity in FNAIT.<\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/trf.70411","type":"journal-article","created":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T15:00:33Z","timestamp":1790434833000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A functionally distinct\n HPA<\/scp>\n \u20101a\u2010specific alloantibody associated with fetal\/neonatal alloimmune thrombocytopenia that activates platelets via\n Fc\u03b3RIIa<\/scp>"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0041-3740","authenticated-orcid":false,"given":"Huiying","family":"Zhi","sequence":"first","affiliation":[{"name":"Versiti Blood Research Institute Versiti Blood Center of Wisconsin Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathy","family":"Paddock","sequence":"additional","affiliation":[{"name":"Versiti Blood Research Institute Versiti Blood Center of Wisconsin Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Villalobos\u2010Garcia","sequence":"additional","affiliation":[{"name":"Versiti Blood Research Institute Versiti Blood Center of Wisconsin Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6749-2594","authenticated-orcid":false,"given":"Janita","family":"Oosterhoff","sequence":"additional","affiliation":[{"name":"Department Research Sanquin Blood Supply Foundation Amsterdam The Netherlands"},{"name":"Department of Biomolecular Mass Spectrometry and Proteomics, Utrecht Institute for Pharmaceutical Sciences and Bijvoet Center for Biomolecular Research Utrecht University Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6580-2464","authenticated-orcid":false,"given":"Heng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Versiti Blood Research Institute Versiti Blood Center of Wisconsin Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5621-003X","authenticated-orcid":false,"given":"Gestur","family":"Vidarsson","sequence":"additional","affiliation":[{"name":"Department Research Sanquin Blood Supply Foundation Amsterdam The Netherlands"},{"name":"Department of Biomolecular Mass Spectrometry and Proteomics, Utrecht Institute for Pharmaceutical Sciences and Bijvoet Center for Biomolecular Research Utrecht University Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renren","family":"Wen","sequence":"additional","affiliation":[{"name":"Versiti Blood Research Institute Versiti Blood Center of Wisconsin Milwaukee Wisconsin USA"},{"name":"Department of Microbiology and Immunology Medical College of Wisconsin Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4508-4263","authenticated-orcid":false,"given":"Jieqing","family":"Zhu","sequence":"additional","affiliation":[{"name":"Versiti Blood Research Institute Versiti Blood Center of Wisconsin Milwaukee Wisconsin USA"},{"name":"Department of Biochemistry Medical College of Wisconsin Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9674-0801","authenticated-orcid":false,"given":"Debra","family":"Newman","sequence":"additional","affiliation":[{"name":"Versiti Blood Research Institute Versiti Blood Center of Wisconsin Milwaukee Wisconsin USA"},{"name":"Department of Pharmacology and Toxicology Medical College of Wisconsin Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8853-7707","authenticated-orcid":false,"given":"Peter J","family":"Newman","sequence":"additional","affiliation":[{"name":"Versiti Blood Research Institute Versiti Blood Center of Wisconsin Milwaukee Wisconsin USA"},{"name":"Department of Pharmacology and Toxicology Medical College of Wisconsin Milwaukee Wisconsin USA"},{"name":"Department of Cell Biology, Neurobiology, and Anatomy Medical College of Wisconsin Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,26]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1111\/bjh.13639","article-title":"Recent progress in understanding the pathogenesis of fetal and neonatal alloimmune thrombocytopenia","volume":"171","author":"Curtis BR","year":"2015","journal-title":"Br J Haematol"},{"key":"e_1_2_9_3_1","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1111\/j.1537-2995.2007.01273.x","article-title":"HPA\u20101a antibody potency and bioactivity do not predict severity of fetomaternal alloimmune thrombocytopenia","volume":"47","author":"Ghevaert C","year":"2007","journal-title":"Transfusion"},{"key":"e_1_2_9_4_1","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.1172\/JCI114082","article-title":"The human platelet alloantigens, PlA1 and PlA2, are associated with a leucine33\/proline33 amino acid polymorphism in membrane glycoprotein IIIa, and are distinguishable by DNA typing","volume":"83","author":"Newman PJ","year":"1989","journal-title":"J Clin Invest"},{"key":"e_1_2_9_5_1","doi-asserted-by":"crossref","first-page":"3028","DOI":"10.1182\/blood.V85.11.3028.bloodjournal85113028","article-title":"Involvement of the cysteine\u2010rich domain of glycoprotein IIIa in the expression of the human platelet alloantigen, PlA1: evidence for heterogeneity in the humoral response","volume":"85","author":"Valentin N","year":"1995","journal-title":"Blood"},{"key":"e_1_2_9_6_1","doi-asserted-by":"crossref","first-page":"3001","DOI":"10.1182\/bloodadvances.2018023341","article-title":"High\u2010resolution mapping of the polyclonal immune response to the human platelet alloantigen HPA\u20101a (PlA1)","volume":"2","author":"Zhi H","year":"2018","journal-title":"Blood Adv"},{"key":"e_1_2_9_7_1","doi-asserted-by":"crossref","first-page":"2569","DOI":"10.1182\/blood.2025032546","article-title":"Structural basis of HPA\u20101a alloimmunization in FNAIT and allosteric regulation of integrin conformation","volume":"147","author":"Zhang H","year":"2026","journal-title":"Blood"},{"key":"e_1_2_9_8_1","doi-asserted-by":"crossref","first-page":"2189","DOI":"10.1182\/blood.2025029618","article-title":"HPA\u20101a antibodies in FNAIT do not distinguish \u03b1v\u03b23 from \u03b1IIb\u03b23, and bind inactive integrins more strongly than active integrins","volume":"146","author":"Oosterhoff JJ","year":"2025","journal-title":"Blood"},{"key":"e_1_2_9_9_1","doi-asserted-by":"crossref","first-page":"2150","DOI":"10.1182\/blood.2025030524","article-title":"In pursuit of FNAIT biomarkers: \u03b1V\u03b23 specificity falls short","volume":"146","author":"Newman PJ","year":"2025","journal-title":"Blood"},{"key":"e_1_2_9_10_1","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1160\/TH05-03-0159","article-title":"Functional heterogeneity of alloantibodies against the human platelet antigen (HPA)\u20101a","volume":"94","author":"Kroll H","year":"2005","journal-title":"Thromb Haemost"},{"key":"e_1_2_9_11_1","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1111\/trf.17758","article-title":"Generation of human antibodies targeting human platelet antigen (HPA)\u20101a","volume":"64","author":"Oosterhoff JJ","year":"2024","journal-title":"Transfusion"},{"key":"e_1_2_9_12_1","doi-asserted-by":"crossref","first-page":"e70","DOI":"10.1182\/blood-2012-06-437723","article-title":"A novel flow cytometry\u2010based platelet aggregation assay","volume":"121","author":"De Cuyper IM","year":"2013","journal-title":"Blood"},{"key":"e_1_2_9_13_1","first-page":"280","article-title":"Effect of the binding of anti\u2010Zwa antibodies on platelet function","volume":"47","author":"Leeuwen EF","year":"1984","journal-title":"Vox Sang"},{"key":"e_1_2_9_14_1","doi-asserted-by":"crossref","first-page":"4311","DOI":"10.4049\/jimmunol.162.7.4311","article-title":"The role of the human fc receptor Fc\u03b3RIIA in the immune clearance of platelets: a transgenic mouse model","volume":"162","author":"McKenzie SE","year":"1999","journal-title":"J Immunol"},{"key":"e_1_2_9_15_1","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1182\/blood.V88.3.907.907","article-title":"Analysis of GPIIb\/IIIa receptor number by quantification of 7E3 binding to human platelets","volume":"88","author":"Wagner CL","year":"1996","journal-title":"Blood"},{"key":"e_1_2_9_16_1","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1111\/imr.12370","article-title":"The platelet fc receptor, Fc\u03b3RIIa","volume":"268","author":"Qiao J","year":"2015","journal-title":"Immunol Rev"},{"key":"e_1_2_9_17_1","doi-asserted-by":"crossref","first-page":"3518","DOI":"10.1182\/bloodadvances.2024015368","article-title":"An \u03b1IIb\u03b23 ligand\u2010mimetic murine monoclonal antibody that produces platelet activation by engaging the Fc\u03b3IIa receptor","volume":"9","author":"Wang J","year":"2025","journal-title":"Blood Adv"},{"key":"e_1_2_9_18_1","doi-asserted-by":"crossref","first-page":"1858","DOI":"10.1182\/blood-2012-07-443325","article-title":"Cooperative integrin\/ITAM signaling in platelets enhances thrombus formation in vitro and in vivo","volume":"121","author":"Zhi H","year":"2013","journal-title":"Blood"}],"container-title":["Transfusion"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/trf.70411","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/trf.70411","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/trf.70411","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T15:00:35Z","timestamp":1790434835000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/trf.70411"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,26]]},"references-count":17,"alternative-id":["10.1111\/trf.70411"],"URL":"https:\/\/doi.org\/10.1111\/trf.70411","archive":["Portico"],"relation":{},"ISSN":["0041-1132","1537-2995"],"issn-type":[{"value":"0041-1132","type":"print"},{"value":"1537-2995","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,26]]},"assertion":[{"value":"2026-05-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-16","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"trf.70411"}}