Abstract Number: PB0845
Meeting: ISTH 2022 Congress
Theme: Platelets and Megakaryocytes » Platelet Function and Interactions
Background: Dyslipidemia and lipoprotein accumulation in the vasculature drive atherogenesis and cardiovascular disease and are risk factors for clinically significant atherothrombotic events, such as myocardial infarction, stroke, and sudden death. In these contexts, oxidized low density lipoprotein (oxLDL) contributes to atherosclerosis through interactions with peripheral blood cells, in particular platelets. However, the mechanisms by which oxLDL affects platelet activation and function, and how to best therapeutically target and safely prevent such responses remains to be elucidated.
Aims: The aim of this study is to investigate how oxLDL upregulates glycoprotein VI (GPVI) mediated platelet hemostatic and procoagulant responses, and how traditional and emerging antiplatelet therapies affect oxLDL-enhanced platelet activity ex vivo.
Methods: Human platelets were isolated and treated with oxLDL alone and in combination with GPVI specific agonist, crosslinked collage-related peptide (CRP-XL) and assayed for hemostatic and procoagulant responses in the presence of inhibitors of purinergic receptors (P2Y; ticagrelor, AR-C 66096, MRS2179), cyclooxygenase (COX; aspirin, indomethacin), Bruton’s tyrosine kinase (BTK; ibrutinib), and spleen tyrosine kinase (Syk; fostamatinib/R406).
Results: Ex vivo, oxLDL enhanced GPVI-mediated platelet dense granule secretion, alpha granule secretion, integrin activation, thromboxane generation, and platelet aggregation, as well as platelet procoagulant phosphatidylserine exposure and fibrin generation. Our study further demonstrates that CD36 signaling from oxLDL activation overlaps with the GPVI signaling pathway, in such that the phosphorylation of proteins along the Syk-BTK-PI3K/Akt axis is enhanced. P2Y antagonists (e.g., ticagrelor), BTK inhibitors (e.g., ibrutinib), and Syk inhibitors (e.g. fostamatinib) reduced oxLDL-mediated platelet responses and procoagulant activity, whereas COX inhibitors (e.g., aspirin) had no significant effect.
Conclusion(s): Altogether, our results demonstrate that oxLDL enhances ex vivo platelet responses and procoagulant activity downstream of GPVI signaling in a manner that may be reduced by P2Y antagonists (ticagrelor) and tyrosine kinase inhibitors (ibrutinib and fostamatinib), but not significantly affected by COX inhibitors (aspirin).
To cite this abstract in AMA style:
Zheng T, Kohs T, Pang J, Reitsma S, Parra-Izquierdo I, Melrose A, Larson M, Williams C, Hinds M, McCarty O, Aslan J. P2Y receptor antagonists and tyrosine kinase inhibitors reduce oxLDL-mediated procoagulant platelet activity [abstract]. https://abstracts.isth.org/abstract/p2y-receptor-antagonists-and-tyrosine-kinase-inhibitors-reduce-oxldl-mediated-procoagulant-platelet-activity/. Accessed March 22, 2024.« Back to ISTH 2022 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/p2y-receptor-antagonists-and-tyrosine-kinase-inhibitors-reduce-oxldl-mediated-procoagulant-platelet-activity/