Platelets and the Atherosclerotic Process: An Overview of New Markers of Platelet Activation and Reactivity, and Their Implications in Primary and Secondary Prevention

Abstract

The key role played by platelets in the atherosclerosis physiopathology, especially in the acute setting, is ascertained: they are the main actors during thrombus formation and, thus, one of the major investigated elements related to atherothrombotic process involving coronary arteries. Platelets have been studied from different points of view, according with the technology advances and the improvement in the hemostasis knowledge achieved in the last years. Morphology and reactivity constitute the first aspects investigated related to platelets with a significant body of evidence published linking a number of their values and markers to coronary artery disease and cardiovascular events. Recently, the impact of genetics on platelet activation has been explored with promising findings as additional instrument for patient risk stratification; however, this deserves further confirmations. Moreover, the interplay between immune system and platelets has been partially elucidated in the last years, providing intriguing elements that will be basic components for future research to better understand platelet regulation and improve cardiovascular outcome of patients.

Keywords: atherosclerosis; genetics; immunity; platelet function test; platelet reactivity; platelets; prevention.

Figure 1

Platelet activation pathways. The figure displays the intricate relationship between different stimuli and platelet activation. Created with BioRender.com. AC = adenylate cyclase; ADP = adenosine diphosphate; cAMP = cyclic adenosine monophosphate; DAG = diacylglycerol; IP3 = inositol triphosphate; MLKC = myosin light chain kinase; PAR-1 = protease activated receptor-1; PAR-4 = protease activated receptor-4; PIP2 = phosphatidylinositol bisphosphate; PKC = protein kinase C; PLC = phospholipase C; TP = thromboxane receptor; TXA2 = thromboxane A2; vWF = von Willebrand factor.

Figure 2

Activated platelet interplay between immune and cardiovascular systems. The figure shows complex interplays involving activated platelets between immune and cardiovascular system: on the left side, crosstalk between platelet and immune system is shown, reporting principal signaling pathways. On the right side, the main cardiovascular actions played by activated platelets are reported. The lines with arrows indicate promotion/activation, while the lines with final bar indicate blockage/inhibition. Created with BioRender.com. CAD = coronary artery disease; CXCL7 = chemokine (C-X-C motif) ligand 7; HMGB1 = high mobility group box 1; I-CAM = Intercellular adhesion molecule; NET = neutrophil extracellular trap; PF-4 = platelet factor-4; TGF-β1 = transforming growth factor-β1; V-CAM = Vascular adhesion molecule.

Figure 3

Genetic and miRNAs. The figure depicts essential but crucial steps in pharmacokinetic of routinely used P2Y₁₂ inhibitors, coupled with the potential target of the most studied miRNAs. The lines with arrows indicate promotion/activation, while the lines with final bar indicate blockage/inhibition. Created with BioRender.com. GPs = glycoproteins; ENT-1 = equilibrative nucleoside transporter-1; HRPR = high residual platelet reactivity; miRNAs = micro-RNAs; SNP = single nucleotide polymorphism; ? = hypothesized action.