Growing evidence supports the view that statins, ezetimibe, PCSK9 inhibitors, inclisiran, and icosapent ethyl also act as antithrombotics. The main effect of antidyslipidemic agents is mainly related to the reduction in low-density lipoprotein (LDL) levels (which are causally related to atherosclerosis) and triglycerides. Some studies suggested a potential role of these drugs also on platelet function. In particular, by interacting with specific platelet receptors, they reduce adhesion, aggregation, degranulation, in-flammation, vasoconstriction, and oxidative stress.
1. Introduction
Atherosclerosis is the primary cause of cardiovascular deaths, regardless of gender
[1]. It involves the gradual development of fatty streaks in arterial walls, which transform into atheroma and eventually into vulnerable plaques. These atherosclerotic plaques consist of a fibrous cap and a lipid core, primarily composed of oxidized low-density lipoprotein (Ox-LDL). The plaque’s stability relies mainly on the fibrous cap’s thickness (FCT), as the exposure of the core material to the blood can trigger platelet activation. A vulnerable plaque is defined as having an FCT of ≤65 μm. Plaque rupture and subsequent formation of an intraluminal thrombus are the most common causes of acute coronary syndromes
[2].
It has been established that nonpharmacological and pharmacological interventions aimed at lowering cholesterol levels impact cardiovascular morbidity and mortality substantially. The history of hypercholesterolemic therapy starts in 1950 with the description of the cholesterol synthesis pathway. The evolution of hypolipidemic therapy has made it possible to achieve ambitious therapeutic targets in a short time.
The direct effect of the drugs currently available is related to lowering LDL-C. Several studies have shown an average cardiovascular risk decrease of 22–23% per 1.0 mmol/L LDL-C reduction
[3]. Statins inhibit HMG-CoA reductase, causing the reduction in endogenous cholesterol synthesis in the liver. Ezetimibe inhibits the absorption of dietary and biliary cholesterol by inhibiting the Niemann–Pick C1-like 1 (NPC1L1) protein expressed in intestinal cells and hepatocytes. PCSK9 is a hepatic protease that binds to the LDLR receptor on the surface of the liver and causes its degradation. PCSK9 inhibitors are monoclonal antibodies that reduce the expression of this protease, leading to increased LDL-C uptake. Inclisiran is a small interfering RNA (siRNA) that penetrates hepatocytes and blocks the translation of PCSK9 mRNA. Bempedoic acid acts similarly to statins by blocking cholesterol synthesis through the inhibition of adenosine triphosphate citrate lyase (ACLY). The rationale for the use of hypolipidemic drugs is mainly related to the stabilizing effect of atheromatous plaque, the decrease in the amount of the lipid core, and the increase in the thickness of the fibrous cap (
Figure 1)
[4].
Figure 1. Plaque stability. A vulnerable plaque is defined as having an FCT of ≤65 μm with a pronounced lipid core. The anticholesterolemic drugs work through a reduction in lipid core and an increase in FCT. The severity of the lesion usually does not impact the transition from stable to unstable plaque.
As a result, the latest international lipid guidelines now strongly advocate for lipid-lowering therapy as a crucial component of primary and secondary prevention in patients with atherosclerotic cardiovascular disease (ASCVD). In addition to diet and maximum tolerated statin or ezetimibe therapy, several additional lipid-lowering medications are available, including two fully human monoclonal antibodies (mAbs) anti-proprotein convertase subtilisin/kexin type 9 (PCSK9), alirocumab and evolocumab, a small interfering RNA (siRNA) that prevents the hepatic synthesis of PCSK9, inclisiran, and a further novel nonstatin drug bempedoic acid, are recently approved as agents available for use in adult hypercholesterolemia who do not achieve target LDL-C
[5].
2. Interaction between Atherosclerotic Plaque and Platelet Activity
In vivo and in vitro studies have shown that platelets adhere to the intact endothelium without proaggregating factors
[6]. Endothelium-expressed P-selectin (CD62P) contacts the platelet receptor PSGL-1 (P-selectin glycoprotein ligand-1) and mediates reversible adhesion and rolling. Stable adhesion is mediated by integrins, a family of CAMs (cell adhesion molecules). Stable binding to the endothelium activates the formation of an inflammatory environment that predisposes the development of atherosclerotic lesions. Platelets firmly attached to the endothelium increase the release of CD40L on the platelet surface, which then releases soluble CD40L. Activated platelets also express P-selectin. CD40L binding on the surface of platelets and endothelium increases adhesion molecules such as E-selectin, VCAM-1, ICAM-1, and proinflammatory cytokines such as interleukin-8 (IL-8), interleukin (IL)-6, RANTES (regulated on activation normal T cells expressed and secreted), monocyte endothelial chemotactic protein-1 (MCP-1), and metalloproteinase (MMP). MMPs are involved in the remodeling and degradation of the extracellular matrix. In addition, platelets release IL-1β, which increases MCP-1 secretion. MCP-1 protein promotes the recruitment of monocytes, which adhere to the endothelium through the platelet chemotactic factor RANTES and binding P-selectins and, subsequently the integrins VCAM (vascular cell adhesion molecule)
[7]. Activated platelets on the endothelial surface release alpha-granules and secrete PF4 (platelet factor 4), among other proteins. PF4 is involved in the differentiation of monocytes into macrophages. Furthermore, it was observed that PF4 and Ox-LDL were colocalized at atherosclerotic lesions. PF4 prevents LDL from binding to the macrophage receptor LDL-R. In this way, LDL is not degraded but remains trapped in the vascular space and is oxidized
[8][9]. Ox-LDL then binds class A scavenger receptors (SR-A, typical of activated macrophages and smooth muscle cells), class B scavenger receptors (CD36, expressed on macrophages and cells in the liver, brain, and heart), and a third class typically expressed by lysosomes (CD68, expressed on cells associated with the immune system and bone marrow such as monocytes, macrophages, dendritic cells, and osteoclasts). These binding favors endocytosis and the formation of foam cells that promote plaque formation and growth
[10]. In turn, Ox-LDL increases the local production of chemokines that attract monocytes and the production of oxidized LDL lectin-like receptor-1 (LOX-1). LOX-1 is expressed on endothelial cells and allows Ox-LDL accumulation (
Figure 2)
[11].
Figure 2. Interaction between atherosclerotic plaque and platelet activity. The figure shows the mechanism of platelet activation at the endothelial level. Based on in vitro and in vivo studies, platelets play a key role in the genesis of atherosclerotic plaque. PSGL-1, P-selectin glycoprotein ligand-1; PF4, platelet factor 4; MCP-1, endothelial monocyte chemotactic protein-1; MMPs, metalloproteinases; LOX-1, lectin-like receptor-1.
Several factors play a role in modulating the platelet response. It has been shown that inflammatory diseases can lead to alterations in platelet function
[12]. Indeed, platelets play a major role in the pathogenesis of acute coronary syndromes. The most frequent cause of acute coronary syndrome (ACS) is plaque rupture (60%). The second mechanism of ACS is the erosion of fibrous plaques. In both cases, exposure of the lipid core to the blood is the initial mechanism of platelet aggregation and intracoronary thrombus formation (
Figure 3).
Figure 3. Underlying causes of acute coronary syndromes. The most frequent cause of acute coronary syndrome (ACS) is plaque rupture (60%). The second mechanism of ACS is the erosion of fibrous caps. In both cases, the exposure of the lipid core to the blood is the initial mechanism of platelet aggregation and intracoronary thrombus formation.
Exposure to collagen and von Willebrand factor (vWF) results in platelet activation. Platelets adhere to the endothelium-expressed P-selectin via the platelet glycoprotein (GP) GPIbα and PSGL-1. Subsequently, stable adhesion is mediated by integrins to collagen. The attached platelets release ADP and thromboxane A2. The injured endothelium exposes tissue factors that trigger the coagulation cascade and thrombin activation. Platelet aggregation and thrombus formation are the results of the activation of three signal pathways on the surface of platelets: thrombin protease-activated receptor-1, TxA2-thromboxane receptor, and ADP-P2Y12 receptor pathways. In this way, numerous platelets are drawn to the site of injury, promoting thrombus formation
[13][14][15].
3. The Effect of Statins on Platelet Function
The protective effect of statins on cardiovascular events is well-known. Statins, or HMG-CoA reductase inhibitors, have as their main mechanism of action the reduction in endogenous cholesterol synthesis in the liver. The mechanism underlying the beneficial effect is mainly related to reducing the lipid core and increasing the fibrous cap (
Figure 1). However, several studies have shown that the protective effect of statins does not depend entirely on LDL-C reduction but is associated with a pleiotropic action. At high doses, statins have been shown in experimental studies performed to reduce neointimal proliferation after vascular injury and left ventricular hypertrophy (LVH) in a pressure overload model
[16][17][18]. Restenosis is one of the main mechanisms associated with percutaneous coronary intervention (PCI) failure of bare metal stents (BMS). Coronary stent placement triggers an inflammatory reaction and the differentiation of vascular smooth muscle cells (VSMCs), which migrate and form neointima. Intimal hyperplasia is associated with activation of the ras pathway. Ras protein is responsible for RAF and MAPKK activation (mitogen-activated protein kinase).
In addition, statins are involved in modulating platelet activation. A 2003 study showed that discontinuation of statin therapy was associated with an increase in cardiovascular events with an increase in Ox-LDL, P-selectin, and platelet aggregation observed 14 days after discontinuation
[19].
Another mechanism underlying the antiplatelet effect of statins is iteration with different signal transduction pathways. Statins, in particular simvastatin, atorvastatin, and rosuvastatin, play an important role in the inhibition to activation of several pathways (Table 1).
Table 1. Statin interaction in platelet function. The table summarizes the main interactions between platelet activity and the mechanism of action of statins. Inhibitory pathways are indicated in the red box. Activating mechanisms are indicated in the green box.
Inhibition Pathway |
P-selectin |
Reduction in platelet stable adhesion |
PAR-1 |
Reduction in platelet aggregation, release of proinflammatory particles, and production of adhesion molecules |
TF |
Reduction in extrinsic coagulation pathway and cMP release |
CD40L |
Reduction in serum inhibits platelet aggregation |
NOX2/NADPH |
Antioxidant effect |
Activation Pathway |
PPARα/PPARƴ |
Inhibition of platelet degranulation and aggregation by the suppression of PKCα pathway |
Increase in cAMP and decrease in Ca2+ level |
eNOS |
NO has vasoprotective, vasodilating effects, and reduced platelet aggregation |
PLA2 |
Reduction in TxA2 |
This entry is adapted from the peer-reviewed paper 10.3390/ijms241411739