A glycoprotein VI signaling defect in newly formed platelets generated in stress thrombopoiesis

Hyslop, SR; Corbin, J; Gangatirkar, P; Lebois, M; Au, AE; Moujalled, D; Pleines, I; Sutherland, KD; Andrews, RK; Gardiner, EE; Alexander, WS; Josefsson, EC

Author(s): Hyslop, SR; Corbin, J; Gangatirkar, P; Lebois, M; Au, AE; Moujalled, D; Pleines, I; Sutherland, KD; Andrews, RK; Gardiner, EE; Alexander, WS; Josefsson, EC;
Details: Publication Year 2025-06,Volume 23,Issue #6,Page 1996-2009
Journal Title: Journal of Thrombosis and Haemostasis
Abstract: BACKGROUND: 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.
Publisher: Elsevier
Keywords: Animals; *Platelet Membrane Glycoproteins/metabolism/genetics; *Blood Platelets/metabolism/drug effects; *Signal Transduction; *Thrombopoiesis; Platelet Aggregation; Syk Kinase; *Thrombocytopenia/blood/chemically induced/genetics; Disease Models, Animal; Mice; Mice, Inbred C57BL; Phosphorylation; Mice, Knockout; Protein-Tyrosine Kinases/metabolism/blood; Intracellular Signaling Peptides and Proteins/metabolism; Stress, Physiological; Crotalid Venoms/pharmacology; Flow Cytometry; Lectins, C-Type; Chemotherapy; immature blood platelets; platelet membrane glycoprotein VI; stress thrombopoiesis; thrombocytopenia
Research Division(s): Advanced Technology And Biology; Blood Cells and Blood Cancer; Cancer Biology and Stem Cells
PubMed ID: 40056985
Publisher's Version: https://doi.org/10.1016/j.jtha.2025.02.035
Open Access at Publisher's Site: https://doi.org/10.1016/j.jtha.2025.02.035
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-05-29 02:28:59

Last Modified: 2025-05-29 02:34:19