Supramaximal calcium signaling triggers procoagulant platelet formation.
Millington-Burgess, Sarah L
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Abbasian, N., Millington-Burgess, S. L., Chabra, S., Malcor, J., & Harper, M. (2020). Supramaximal calcium signaling triggers procoagulant platelet formation.. Blood advances, 4 (1), 154-164. https://doi.org/10.1182/bloodadvances.2019000182
Procoagulant platelets promote thrombin generation during thrombosis. Platelets become procoagulant in an all-or-nothing manner. We investigated how distinct Ca2+ signalling between platelet subpopulations commits some platelets to become procoagulant, using the high affinity Ca2+ indicator, Fluo-4, which may become saturated during platelet stimulation, or low affinity Fluo-5N, which reports only very high cytosolic Ca2+ concentrations. All activated platelets had high Fluo-4 fluorescence. However, in Fluo-5N-loaded platelets, only the procoagulant platelets had high fluorescence, indicating very high cytosolic Ca2+. This demonstrates a novel, ‘supramaximal’ Ca2+ signal in procoagulant platelets (i.e. much higher than normally considered maximal). Supramaximal Ca2+ signalling and the percentage of procoagulant platelets were inhibited by cyclosporine A, a mitochondrial permeability transition pore blocker, and Ru360, an inhibitor of the mitochondrial Ca2+ uniporter, without effect on Fluo-4 fluorescence. In contrast, Synta-66, an Orai1 blocker, reduced Fluo-4 fluorescence but did not directly inhibit generation of the supramaximal Ca2+ signal, Our findings demonstrate a distinct pattern of Ca2+ signalling in procoagulant platelets and provides a new framework to interpret the role of platelet signalling pathways in procoagulant platelets. This requires re-assessment of the role of different Ca2+ channels and may provide new targets to prevent procoagulant platelets formation and limit thrombosis.
British Heart Foundation (SP/15/7/31561)
British Heart Foundation (PG/17/45/33071)
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External DOI: https://doi.org/10.1182/bloodadvances.2019000182
This record's URL: https://www.repository.cam.ac.uk/handle/1810/299890
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