Publication:
TNF-α-driven inflammation and mitochondrial dysfunction define the platelet hyperreactivity of aging.

Simple item page
dc.contributor.authorDavizon-Castillo, Pavel
dc.contributor.authorMcMahon, Brandon
dc.contributor.authorÁguila Martínez, Sonia
dc.contributor.authorBark, David
dc.contributor.authorAshworth, Katrina
dc.contributor.authorAllawzi, Ayed
dc.contributor.authorCampbell, Robert A.
dc.contributor.authorMontenont, Emilie
dc.contributor.authorNemkov, Travis
dc.contributor.authorD’Alessandro, Angelo
dc.contributor.authorClendenen, Nathan
dc.contributor.authorShih, Lauren
dc.contributor.authorSanders, Natalie A.
dc.contributor.authorHiga, Kelly
dc.contributor.authorCox, Allaura
dc.contributor.authorPadilla-Romo, Zavelia
dc.contributor.authorHernandez, Giovanni
dc.contributor.authorWartchow, Eric
dc.contributor.authorTrahan, George D.
dc.contributor.authorNozik-Grayck, Eva
dc.contributor.authorJones, Kenneth
dc.contributor.authorPietras, Eric M.
dc.contributor.authorDeGregori, James
dc.contributor.authorRondina, Matthew T.
dc.contributor.authorDi Paola, Jorge
dc.contributor.departmentMedicina Interna
dc.date.accessioned2026-02-16T08:56:38Z
dc.date.available2026-02-16T08:56:38Z
dc.date.copyright© 2019 by The American Society of Hematology
dc.date.issued2019-08-29
dc.description.abstractAging and chronic inflammation are independent risk factors for the development of atherothrombosis and cardiovascular disease. We hypothesized that aging- associated inflammation promotes the development of platelet hyperreactivity and increases thrombotic risk during aging. Functional platelet studies in aged-frail adults and old mice demonstrated that their platelets are hyperreactive and form larger thrombi.Weidentified tumor necrosis factor a (TNF-a) as the key aging-associated proinflammatory cytokine responsible for platelet hyperreactivity. We further showed that platelet hyperreactivity is neutralized by abrogating signaling through TNF-a receptors in vivo in a mouse model of aging. Analysis of the bone marrow compartments showed significant platelet-biased hematopoiesis in old mice reflected by increased megakaryocyte-committed progenitor cells, megakaryocyte ploidy status, and thrombocytosis. Single-cell RNA-sequencing analysis of native mouse megakaryocytes showed significant reprogramming of inflammatory, metabolic, and mitochondrial gene pathways in old mice that appeared to play a significant role in determining platelet hyperreactivity. Platelets from old mice (where TNF-a was endogenously increased) and from young mice exposed to exogenous TNF-a exhibited significant mitochondrial changes characterized by elevated mitochondrial mass and increased oxygen consumption during activation. These mitochondrial changes were mitigated upon TNF-a blockade. Similar increases in platelet mitochondrial mass were seen in platelets from patients with myeloproliferative neoplasms, where TNF-a levels are also increased. Furthermore, metabolomics studies of platelets from young and old mice demonstrated agedependent metabolic profiles that may differentially poise platelets for activation. Altogether, we present previously unrecognized evidence that TNF-a critically regulates megakaryocytes resident in the bone marrow niche and agingassociated platelet hyperreactivity and thrombosis. (Blood. 2019;134(9):727-740)
dc.formatapplication/pdf
dc.format.extent14
dc.identifier.citationBlood® 29 August 2019 | Volume 134, Number 9, 727-740
dc.identifier.doihttps://doi.org/10.1182/blood.2019000200
dc.identifier.eissn1528-0020
dc.identifier.issn0006-4971
dc.identifier.urihttp://hdl.handle.net/10201/205301
dc.languageeng
dc.publisherAmerican Society of Hematology (ASH Publications)
dc.relationThis work was supported by: the Pediatric Scientist Development Program of the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development, grant K12HD00050 (P.D.-C.); the 2018 American Society of Hematology Research Training Award for Fellows (P.D.-C.); National Heart, Lung, and Blood Institute grants R01HL120728 (J.D.P.), HL142804 (M.T.R.), HL112311, and HL126547; grant H30MC24049 of the Mountain States Hemophilia Network (J.D.P.); the Postle Chair of Pediatric Cancer and Blood Disorders (J.D.P.); National Cancer Institute grants R01CA180175 (J.D.) and F30CA210383-01 (K.H.); National Institute on Aging grant AG04802 (M.T.R.); National Heart, Lung, and Blood Institute grants 1R35HL139726-01 (E.N.-G.) and T32 HL007171 (A.A.); and American Heart Association grant 19POST34380396 (A.A.). Additional support was received by the National Center for Research Resources of the National Institutes of Health under award number 1S10RR026802-01, the Flow Cytometry Core at the University of Utah, and the Cancer Center Shared Resources at the University of Colorado (National Cancer Institute grant 2-P30-CA46934).
dc.relation.publisherversionhttps://ashpublications.org/blood/article/134/9/727/260784/TNF-driven-inflammation-and-mitochondrial
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subject.odsObjetivo 3: Salud
dc.titleTNF-α-driven inflammation and mitochondrial dysfunction define the platelet hyperreactivity of aging.
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublicationes
relation.isAuthorOfPublication49779dfb-f4b4-4013-9b03-2ad7e3c247b7
relation.isAuthorOfPublication.latestForDiscovery49779dfb-f4b4-4013-9b03-2ad7e3c247b7
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
bloodbld2019000200.pdf
Size:
2.33 MB
Format:
Adobe Portable Document Format
Description:
Download
License bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
license.txt
Size:
1.37 KB
Format:
Item-specific license agreed upon to submission
Description:
Download
Collections
Artículos