Abstract Number: OC 26.1
Meeting: ISTH 2022 Congress
Theme: Platelets and Megakaryocytes » Platelet Function and Interactions
Background: While anti-platelet drugs are commonly used to prevent ischemic stroke, they are incompletely effective. Preclinical studies identified platelet-neutrophil interactions as important mediators of stroke. One subpopulation of platelets that preferentially interacts with neutrophils are procoagulant platelets.
Aims: To study the role of procoagulant platelets in ischemic stroke pathophysiology.
Methods: Stroke patient brain tissue and blood was analyzed for the presence of platelet-neutrophil aggregates (PNAs) and procoagulant platelets. RNAseq was performed on platelets isolated from stroke patients and healthy donors. Mechanistic studies were performed in mice subjected to transient middle cerebral artery occlusion.
Results: Occlusive platelet-neutrophil microthrombi were observed in stroke patient brain tissue. Stroke patients had increased PNAs and procoagulant platelets in the circulation compared to healthy donors. A strong correlation was observed between circulating procoagulant platelets and PNAs. RNAseq from platelets isolated from stroke patients uncovered several genes (ANO6, CAPN2 and MCUR1) associated with procoagulant platelet formation that were significantly increased compared to matched controls.
Two distinct pathways regulate procoagulant platelet formation: platelet apoptosis, mediated by BAK and BAX; and platelet necrosis mediated, in part, by mitochondrial calcium uniporter (MCU). To analyze which pathway contributes to stroke outcomes, we subjected mice whose platelets were unable to undergo apoptosis (BAK KO/BAXfl/fl-PF4-cre) or necrosis (MCUfl/fl-PF4-cre) to stroke. After stroke, BAK KO/BAXfl/fl-PF4-cre mice had similar levels of procoagulant platelets and PNAs, and stroke outcomes were comparable to littermate controls. In contrast, MCUfl/fl-PF4-cre mice had reduced levels of procoagulant platelets and PNAs circulating after stroke, and were protected from ischemic stroke brain injury. This protection was attributed to decreased PNAs in the cerebral microvasculature, resulting in improved blood flow and reduced neuronal apoptosis.
Conclusion(s): Ischemic stroke patients have an increased potential to form procoagulant platelets, leading to detrimental platelet-neutrophil interactions. Prevention of procoagulant platelet formation through inhibition of platelet MCU conferred protection from stroke in mice.
To cite this abstract in AMA style:
Denorme F, Portier I, Kosaka Y, Ajanel A, Cody M, Kile B, Rondina M, Majersik J, Campbell R. Procoagulant Platelet – Neutrophil Interactions Exacerbate Ischemic Stroke [abstract]. https://abstracts.isth.org/abstract/procoagulant-platelet-neutrophil-interactions-exacerbate-ischemic-stroke/. Accessed March 21, 2024.« Back to ISTH 2022 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/procoagulant-platelet-neutrophil-interactions-exacerbate-ischemic-stroke/