{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T10:32:10Z","timestamp":1794047530617,"version":"4.8.0"},"reference-count":0,"publisher":"Ferrata Storti Foundation (Haematologica)","license":[{"start":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T00:00:00Z","timestamp":1770854400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["haematol"],"abstract":"<jats:p>Background: Development of inhibitory antibodies (inhibitors) against FVIII is a significant complication of protein replacement therapy in hemophilia A (HA). Platelets, traditionally viewed as mediators of hemostasis, also modulate immune responses through cytokine release and interactions with immune cells. Harnessing these immunomodulatory properties may provide a novel strategy to prevent or suppress inhibitor formation. Objective: To investigate whether FVIII-engineered platelets and related platelet-based products modulate FVIII immune responses in HA mice. Methods: FVIII-containing platelets were isolated from 2bF8 transgenic mice. FVIII-deficient mice were infused with intact FVIII-containing platelets, desialylated FVIII-containing platelets (dPlts), or acidified platelet lysates in combination with or before recombinant human FVIII (rhF8) exposure. Anti-FVIII antibody titers were determined by the Bethesda assay and ELISA, and T cell responses were analyzed by flow cytometry and proliferation assays. Results: Co-infusion of FVIII platelets with rhF8 significantly reduced inhibitor titers compared with rhF8 alone. Acidified FVIII platelet lysates were potent, decreasing inhibitor titers by &gt;20-fold when co-infused with rhF8. In contrast, co-infusion of dPlts with rhF8 did not suppress immune responses. However, repeated pre-sensitization with dPlts alone promoted immune tolerance to FVIII, evidenced by reduced inhibitor titers upon rhF8 immunization and attenuated CD4\u00f4\u20ac\u20ac\u20ac T cell proliferation upon subsequent rhF8 exposure. These findings reveal a hierarchy of immune modulation, with intact platelets providing partial protection, lysates strongly suppressing immune responses, and dPlts inducing immune tolerance. Conclusions: FVIII-engineered platelets and platelet-derived products are potent immune modulators. These strategies offer novel and translatable approaches to both restore hemostasis and prevent or eradicate inhibitors in HA.<\/jats:p>","DOI":"10.3324\/haematol.2025.289331","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T10:11:17Z","timestamp":1770891077000},"source":"Crossref","is-referenced-by-count":0,"title":["FVIII-containing platelets modulate immune responses and attenuate inhibitor development in hemophilia A mice"],"prefix":"10.3324","author":[{"given":"Yingyu","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saurabh","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jocelyn A.","family":"Schroeder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiqing","family":"Jing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heyu","family":"Ni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qizhen","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1856","published-online":{"date-parts":[[2026,2,12]]},"container-title":["Haematologica"],"original-title":[],"link":[{"URL":"https:\/\/haematologica.org\/article\/download\/13158\/79481","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/haematologica.org\/article\/download\/13158\/79481","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T10:11:08Z","timestamp":1794046268000},"score":1,"resource":{"primary":{"URL":"https:\/\/haematologica.org\/article\/view\/13158"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,12]]},"references-count":0,"URL":"https:\/\/doi.org\/10.3324\/haematol.2025.289331","relation":{},"ISSN":["1592-8721","0390-6078"],"issn-type":[{"value":"1592-8721","type":"electronic"},{"value":"0390-6078","type":"print"}],"subject":[],"published":{"date-parts":[[2026,2,12]]}}}