Abstract
Lipoprotein(a) (Lp(a)) is associated with atherothrombosis through several mechanisms, including putative antifibrinolytic properties. However, genetic association studies have not demonstrated an association between high plasma levels of Lp(a) and the risk of venous thromboembolism, and studies in patients with highly elevated Lp(a) levels have shown that Lp(a) lowering does not modify the clotting properties of plasma ex vivo. Lp(a) can interact with several platelet receptors, providing biological plausibility for a pro-aggregatory effect. Observational clinical studies suggest that elevated plasma Lp(a) concentrations are associated with worse long-term outcomes in patients undergoing revascularization. Furthermore, in these patients, those with elevated plasma Lp(a) levels derive more benefit from prolonged dual antiplatelet therapy than those with normal Lp(a) levels. The ASPREE trial in healthy older individuals treated with aspirin showed a reduction in ischaemic events in those who had a single-nucleotide polymorphism in LPA that is associated with elevated Lp(a) levels in plasma, without an increase in bleeding events. In this Review, we re-examine the role of Lp(a) in the regulation of platelet function and suggest areas of research to define further the clinical relevance to cardiovascular disease of the observed associations between Lp(a) and platelet function.
Key points
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Lipoprotein(a) (Lp(a)) independently contributes to atherothrombosis through several mechanisms, including putative antifibrinolytic properties.
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However, genetic association studies and experimental studies have not demonstrated an association between high Lp(a) levels in the plasma and the risk of venous thromboembolism or clot properties, respectively.
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Oxidized phospholipids present in Lp(a) can interact with several platelet receptors, including protease-activated receptor 1 and CD36, which provides biological plausibility for a pro-aggregatory effect of Lp(a).
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Observational studies suggest that elevated plasma Lp(a) concentrations are associated with worse long-term outcomes in patients undergoing revascularization and that prolonged dual antiplatelet therapy provides benefit to these patients.
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The ASPREE trial in healthy older individuals treated with aspirin demonstrated a reduction in ischaemic events in those with genetically elevated Lp(a) levels in plasma, without an increase in bleeding events.
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We propose a re-examination of the role of Lp(a) in regulating platelet function and suggest that future research should focus on defining the clinical relevance of the interaction between Lp(a) and platelets in cardiovascular disease.
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Acknowledgements
H.S.B. is partially supported by NIH grants 1K08HL166962, 1KL2TR001444 and 5T32HL079891. P.L. is supported by a National Heart Foundation Future Leader Fellowship (10260). S.T. is supported by NHLBI R01 HL159156 and R01 HL170224.
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H.S.B., G.L. and S.T. researched data for the article and wrote the manuscript. H.S.B., R.C.B., G.L. and S.T. provided substantial contribution to discussion of content. H.S.B., R.C.B., G.L., M.P., P.L., A.T. and J.N. reviewed and/or edited the manuscript before submission.
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H.S.B. has received consulting fees from Kaneka Medical and Novartis. R.C.B. is a member of the Data Safety Monitoring Board (DSMB) for Ionis and Novartis and is on the scientific advisory board for Basking Biosciences. A.T. has received honoraria for lectures or DSMB participation from Amgen, Boehringer-Ingelheim, Merck, The Medicines Company, Novartis and Pfizer. S.T. is a co-inventor and has received royalties from patents owned by the University of California San Diego, is a co-founder of and has an equity interest in Kleanthi Diagnostics and Oxitope and has a dual appointment at the University of California San Diego and Ionis Pharmaceuticals. The other authors declare no competing interests.
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Bhatia, H.S., Becker, R.C., Leibundgut, G. et al. Lipoprotein(a), platelet function and cardiovascular disease. Nat Rev Cardiol 21, 299–311 (2024). https://doi.org/10.1038/s41569-023-00947-2
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DOI: https://doi.org/10.1038/s41569-023-00947-2