Lipoprotein(a), platelet function and cardiovascular disease

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.

Fig. 1 |. Main platelet-activating ligands, platelet receptors and antiplatelet drugs.

Schema of a platelet showing the main ligands, receptors and intracellular molecules involved in platelet activation and the main available antiplatelet drugs (shown in blue). The stimuli (in yellow) and receptors that are most relevant to lipoprotein(a) include thrombin–proteinase-activated receptor 1 (PAR1), oxidized phospholipids (OxPLs)–CD36, platelet-activating factor (PAF)–PAF receptor (PAFR) and fibrinogen–αIIbβ3 integrin (also known as GPIIb/IIIa). Other stimuli are shown in red. Ac, adenylyl cyclase; CD40L, CD40 ligand; COX1, cyclooxygenase 1; GP, glycoprotein; LysoPC, lysophosphatidylcholine; MDA, malondialdehyde; PAFAH, platelet-activating factor acetylhydrolase; PLA₂, phospholipase A₂; PSGL1, P-selectin glycoprotein ligand 1; SFLLRN, thrombin receptor-activating peptide; TRAP, thrombin receptor-activating peptide; TXA₂, thromboxane A₂; TXA₂R, thromboxane A₂ receptor; VASP, vasodilator-stimulated phosphoprotein; vWF, von Willebrand factor.

Fig. 2 |. Potential lipoprotein(a) interactions with platelets and the coagulation system.

Lipoprotein(a) (Lp(a)) can prolong fibrinolysis by inhibiting tissue plasminogen activator (tPA)-mediated activation of plasminogen and conversion to plasmin. Lp(a) also binds to several platelet receptors that can influence platelet activity. The apolipoprotein(a) (apo(a)) component of Lp(a) can bind to proteinase-activated receptor 1 (PAR1) and oxidized phospholipids (OxPLs) on Lp(a) might theoretically bind to CD36 receptors, both of which activate platelets and have pro-aggregatory effects. OxPLs released from platelets promote platelet–neutrophil interactions and neutrophil extracellular trap (NET) formation. By contrast, Lp(a) might prevent the activation of platelets by inhibiting the binding of fibrinogen to αIIbβ3 integrin (also known as GPIIb/IIIa) and by preventing the generation of platelet-activating factor (PAF) by PAF acetylhydrolase (PAFAH). ApoB, apolipoprotein B; FC, free cholesterol; KIV, Kringle IV; KV, Kringle V; LysoPC, lysophosphatidylcholine; PAFR, PAF receptor; PL, phospholipid.

Fig. 3 |. Balance of pro-aggregatory and anti-aggregatory platelet effects of lipoprotein(a).

The main stimuli that potentiate lipoprotein(a) (Lp(a)) binding to platelets and promote platelet activity include thrombin and thrombin agonists, oxidized phospholipids and arachidonic acid. The relevant platelet receptors that interact with Lp(a) are proteinase-activated receptor 1 (PAR1) and potentially CD36 through the oxidized phospholipid content of Lp(a). By contrast, collagen and platelet-activating factor (PAF) mediate anti-aggregatory effects of Lp(a) on platelets, and Lp(a) might interfere with fibrinogen–αIIbβ3 integrin (also known as GPIIb/IIIa) interactions, thereby preventing platelet aggregation. The net effect of Lp(a) seems to be pro-aggregatory on the basis of the preponderance and quality of the available evidence, but this conclusion needs to be confirmed with studies of the global platelet function. PAFAH, platelet-activating factor acetylhydrolase; PAFR, platelet-activating factor receptor.

Fig. 4 |. Aspirin therapy, LPA genotype and primary prevention of cardiovascular disease.

The ASPREE trial included 12,815 participants with no history of cardiovascular disease who were genotyped for LPA (which encodes apolipoprotein(a)). The trial demonstrated that aspirin therapy reduced the number of major adverse cardiovascular events (MACEs) by 1.7 events per 1,000 person-years and increased clinically significant bleeding by 1.7 events per 1,000 person-years (indicating no net benefit of aspirin) compared with placebo. However, in the group of participants who carried the rs3798220-C LPA variant and in those who were in the highest quintile of the lipoprotein(a) genomic risk score (LPA-GRS) distribution, aspirin reduced MACE by 11.4 and 3.3 events, respectively, indicating a shift towards a net benefit of aspirin therapy in these patients.

Fig. 5 |. Oxidized phospholipids, lipoprotein(a) and acute coronary syndrome.

Oxidized phospholipids (OxPLs) from lipoprotein(a) (Lp(a)) are released during percutaneous coronary intervention (PCI) and are present in chronic total occlusions, ruptured atherosclerotic plaques and emboli captured in distal protection devices. a, Lp(a) particle and its content of OxPLs present in the lipid phase and covalently bound to apolipoprotein(a) (apo(a)). b,c, Serial changes in plasma concentrations of Lp(a) (panel b) and OxPL–apolipoprotein B (apoB) (panel c) after uncomplicated PCI. d,e, Histology images of a chronic total occlusion in a right coronary artery from an individual aged 49 years with sudden death, showing the presence of Lp(a) (panel d) and OxPLs (panel e). f,g, Histology images of a ruptured atheroma in the left anterior descending coronary artery from an individual with sudden cardiac death, showing the presence of Lp(a) (panel f) and OxPLs (panel g). h,i, Immunostaining of an embolized atheroma captured by a distal protection device used in a saphenous vein graft intervention, showing the presence of OxPL epitopes detected by staining with the mouse monoclonal antibody E06 (panel h). The presence of the specific OxPL 1-palmitoyl-2-(5′-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC) extracted from the atheroma and detected by liquid chromatography–tandem mass spectrometry (panel i). FC, free cholesterol; KIV, Kringle IV; KV, Kringle V; PL, phospholipid. Panels b and c adapted with permission from ref. , Wolters Kluwer. Panels d and e adapted with permission from ref. , Elsevier. Panels f,g and i adapted with permission from ref. , Elsevier. Panel h adapted with permission from ref. , Elsevier.

Fig. 6 |. Design of clinical trials of interventions targeting lipoprotein(a)-mediated cardiovascular risk.

Schematic of potential designs of two clinical trials to assess therapeutic effects on lipoprotein(a) (Lp(a))-mediated risk of cardiovascular events in patients undergoing first-time percutaneous coronary intervention (PCI). a, The ACS DAPT-Lp(a) trial has a prospective, randomized, registry-based design and would include patients with acute coronary syndrome (ACS) and plasma Lp(a) levels >75 nmol/l (>30 mg/dl) who are randomly assigned 1:1 to receive dual antiplatelet therapy (DAPT) for 1 year or 2 years. b, The NIRS/IVUS/OCT-Lp(a) trial is designed to assess the effect of Lp(a) lowering on lipid core burden index and plaque cap thickness with the use of intravascular imaging, including near-infrared spectroscopy (NIRS), intravascular ultrasonography (IVUS) and optical coherence tomography (OCT). Adapted with permission from ref. , Elsevier.