Hyslop, Stephanie R.Corbin, JasonGangatirkar, PradnyaLebois, MarionAu, Amanda E.Moujalled, DianePleines, IrinaSutherland, Kate D.Andrews, Robert K.Gardiner, Elizabeth E.Alexander, Warren S.Josefsson, Emma C.2025-05-232025-05-231538-7933PubMed:40056985ORCID:/0000-0001-9453-9688/work/184100853http://www.scopus.com/inward/record.url?scp=105001799063&partnerID=8YFLogxKhttps://hdl.handle.net/1885/733753081Background: Newly produced platelets are thought to be more functional than their older counterparts. However, recent work suggests that murine platelets formed following immune-mediated thrombocytopenia possess a transient glycoprotein (GP) VI signaling defect. Objectives: In this study, we explored whether other models of stress thrombopoiesis would generate platelets that display a functional defect. Methods: Platelet function was assessed by light transmission aggregometry and/or flow cytometry in genetic and disease models of thrombocytopenia and after chemotherapy-induced thrombocytopenia. Results: We evaluated platelet function in mice bearing a point mutation in Bcl-x and in 2 cancer models, all presenting with thrombocytopenia and a high proportion of reticulated platelets. Flow cytometric analysis of platelet degranulation and integrin activation revealed a significantly diminished response to the GPVI agonist convulxin in all models, but not thrombin. Likewise, platelet aggregation and Syk phosphorylation downstream of GPVI, in response to convulxin, was significantly reduced. Furthermore, a rebound from carboplatin-induced or immune-mediated thrombocytopenia caused a transient GPVI defect. The Mpl−/− model of thrombocytopenia (with a normal proportion of reticulated platelets) was included as a negative control. In response to convulxin, Mpl−/− platelets exhibited normal degranulation and integrin activation. Conclusion: In this study, we report a functional defect in platelet GPVI signaling present in multiple models of thrombocytopenia that are accompanied by an increased proportion of rapidly generated young platelets. These results indicate that during stress thrombopoiesis, the GPVI receptor becomes entirely functional only after spending some time in circulation.Funding information National Health and Medical Research Council of Australia Project and Program Grants, Grant/Award Numbers: 1079250 (to E.C.J.) and 1113577 (to W.S.A.); Fellowship, Grant/Award Number: 1058344 (to W.S.A); Investigator, Grant/Award Number: 1173342 (to W.S.A.); Independent Research Institutes Infrastructure Support Scheme Grant, Grant/Award Number: 9000587; and Victorian State Government Operational Infrastructure Support Grant. E.C.J. is the recipient of a fellowship from the Lorenzo and Pamela Galli Charitable Trust Australia. S.R.H. is the recipient of an Australian Postgraduate Award from the University of Melbourne.14en© 2025 The AuthorsChemotherapyimmature blood plateletsplatelet membrane glycoprotein VIstress thrombopoiesisthrombocytopenia202510.1016/j.jtha.2025.02.035105001799063