Background: Newly produced platelets are thought to be more functional than their older counterparts. However, recent work suggests that murine platelets formed following immune thrombocytopenia possess a transient glycoprotein VI (GPVI) signalling defect.
Objectives: In this study we explored if 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 two 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- or immune-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: Here, we report a functional defect in platelet GPVI signalling 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.
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