Abstract Number: PB1642
Meeting: ISTH 2020 Congress
Background: It is the current consensus that younger platelets are more functional than their older counterparts, however, recent work suggests otherwise. In Bcl-xPLT20/PLT20 mice, which have thrombocytopenia and an increased proportion of immature platelets, we detected a prolonged bleeding time following 3-mm tail amputation. This phenotype was not solely attributable to the moderate thrombocytopenia present in these mice, therefore, we hypothesised these mice also possess a platelet function defect.
Aims: We evaluated platelets from mice with thrombocytopenia and a high proportion of reticulated platelets to determine if function was affected.
Methods: The Bcl-xPLT20/PLT20 mouse model was used as a genetic model of thrombocytopenia. Additionally, two disease models exhibiting moderate to severe thrombocytopenia at high disease burden following intravenous transplant of a small-cell lung cancer (SCLC) cell line or an Eµ-Myc lymphoma cell line, were used. Platelet function was evaluated by light-transmission aggregometry and platelet integrin activation and degranulation by flow cytometry, in response to thrombin and convulxin.
Results: In all models, a high percentage of thiazole orange positive platelets was present, indicating an increased proportion of immature platelets. FACS analysis of platelet activation revealed a significantly diminished response to the GPVI agonist convulxin, but not thrombin. Likewise, platelet aggregation and Syk phosphorylation downstream of GPVI in response to convulxin was significantly reduced in all models. Surface expression of GPVI as assessed by FACS was unchanged in platelets from the Bcl-xPLT20/PLT20 and SCLC transplanted mice, compared to WT or non-transplanted mice, but was slightly reduced in platelets from Eµ-Myc transplanted mice. Assessing GPVI cleavage by western blot revealed no cleaved GPVI in any model.
Conclusions: Here, we report a functional defect in GPVI signalling present in three models of thrombocytopenia, possibly attributable to an increased proportion of young platelets. These results challenge the view that young platelets are more functional than older platelets.
To cite this abstract in AMA style:Hyslop SR, Lebois M, Corbin J, Gangatirkar P, Sutherland KD, Andrews RK, Gardiner EE, Alexander WS, Josefsson EC. Reduced GPVI Signalling in Genetic and Disease Models of Thrombocytopenia [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/reduced-gpvi-signalling-in-genetic-and-disease-models-of-thrombocytopenia/. Accessed October 1, 2023.
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