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Traumatic brain injury (TBI) is the primary driver of mortality and morbidity among individuals aged 1\u201344 years worldwide, with intracranial hemorrhage (ICH) being the major contributor to acute mortality post-TBI. Based on prior studies, we hypothesized that lyophilized platelet-derived extracellular vesicles (LPEVs) would reduce ICH and preserve blood-brain barrier (BBB) integrity after TBI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>LPEVs were characterized by flow cytometry, scanning electron microscopy, and Nanosight. LPEVs were evaluated in vitro in human brain endothelial cell monolayers for barrier integrity. Utilizing a murine TBI model of controlled cortical impact, LPEVs were transfused 40\u00a0min after injury. The degree of BBB permeability was quantitated by 10kD infrared-tagged dye that leakage into the brain. ICH was quantitated by RBCs using Ter-119 antibody. Murine tail snip and cremaster muscle vascular injury models and thromboelastography analysis of healthy donor or trauma patient blood were used to assess hemostatic ability of LPEVs. Proteomic content was analyzed by mass spectrometry and mRNA and miRNA content by next-generation sequencing. Light transmission aggregometry using fresh apheresis platelets or generated dysfunctional platelets supported the mechanistic pathway assessment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>LPEVs were predominantly in the exosome range, expressed platelet and microvesicle markers and generated thrombin. In vitro, LPEVs attenuated thrombin-induced paracellular permeability and reduced intercellular gaps in human brain microvascular endothelial cells. In vivo, LPEVs exhibited potent hemostatic activity in a murine tail-transection and cremaster vascular injury models. Following experimental TBI in mice, acute administration of LPEVs significantly reduced ICH without impacting BBB permeability. Multi-omics analyses revealed that LPEVs retained platelet-derived hemostatic cargo, but lacked the vasculoprotective factors, typically present in intact platelets. LPEVs accelerated clot formation in blood from healthy donors, trauma patients, and dysfunctional platelet preparations. Mechanistically, LPEVs promote hemostasis in part through GPIIb\/IIIa-dependent platelet aggregation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These data demonstrate the therapeutic and hemostatic efficacy of LPEVs in reducing ICH following TBI without affecting BBB permeability or neuroinflammation. The multi-omics and GPIIB\/IIIA driven data can potentially explain the decoupled effects of LPEVs on hemostasis and vascular permeability in our experimental TBI model.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12967-026-08638-5","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T02:42:59Z","timestamp":1784515379000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lyophilized platelet derived extracellular vesicles promote hemostasis and attenuate intracranial hemorrhage following traumatic brain injury"],"prefix":"10.1186","volume":"24","author":[{"given":"Alpa","family":"Trivedi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byron","family":"Miyazawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander T.","family":"Fields","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Matthews","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsay","family":"Vivona","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Callie","family":"Keane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Potter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huimin","family":"Geng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoqian","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Taenaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena S.","family":"Kwek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly","family":"Herrera-Rodriguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda","family":"Nunez-Garcia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika Marques","family":"de Menezes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Barry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Nair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Kuhn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip J.","family":"Norris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence","family":"Fong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael M.","family":"Fitzpatrick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Schreiber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy Z.","family":"Kornblith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shibani","family":"Pati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"issue":"S2","key":"8638_CR1","doi-asserted-by":"publisher","first-page":"1423","DOI":"10.1111\/trf.15161","volume":"59","author":"BJ Eastridge","year":"2019","unstructured":"Eastridge BJ, Holcomb JB, Shackelford S. 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The experiments were conducted in compliance with the National Institutes of Health guidelines on the use of laboratory animals and the Department of Defense Animal Care and Use Review Office. All human participant study procedures were approved by the University of California, San Francisco Institutional Review Board and the Department of Defense Human Research Protection Office. Under an IRB-approved waiver of consent (IRB 19-29291), all whole-blood LPEV functional assays were performed in real time immediately after blood collection in the Emergency Department (ED). For injured patients, blood samples were collected under an IRB-approved waiver of informed consent because samples were obtained during emergency trauma resuscitation, the research posed minimal risk, and participants were frequently unable to provide consent at the time of enrollment. Injured patients or their legally authorized representatives were subsequently informed of study participation and given the opportunity to consent to continued clinical data collection when feasible. Written informed consent was obtained from all healthy volunteer control participants prior to participation.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"MF is Chief Scientific Officer at Cellphire Therapeutics. BK and MM are employees of Cellphire.","order":3,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"1308"}}