Novel Aspects Targeting Platelets in Atherosclerotic Cardiovascular Disease-A Translational Perspective

Abstract

Platelets are important cellular targets in cardiovascular disease. Based on insights from basic science, translational approaches and clinical studies, a distinguished anti-platelet drug treatment regimen for cardiovascular patients could be established. Furthermore, platelets are increasingly considered as cells mediating effects "beyond thrombosis", including vascular inflammation, tissue remodeling and healing of vascular and tissue lesions. This review has its focus on the functions and interactions of platelets with potential translational and clinical relevance. The role of platelets for the development of atherosclerosis and therapeutic modalities for primary and secondary prevention of atherosclerotic disease are addressed. Furthermore, novel therapeutic options for inhibiting platelet function and the use of platelets in regenerative medicine are considered.

Keywords: atherosclerosis; coronary artery disease; ischemic stroke; myocardial infarction; neuroinflammation; neurovascular disease; platelets; thrombosis.

Figure 1

Platelet activation in atherosclerotic disease. Platelet endothelial and platelet monocyte interactions promote transendothelial migration. First, there is a binding between platelets and endothelial cells (CX3CR1 vs. CXCL1, PSGL1 vs. P-/E-selectin). Attached platelets bridge the connection of endothelial cells and monocytes (GPIba vs. LFA-1, GPIIbIIIa vs. MAX-1) and then both migrate between endothelial cells into the intima (mediated with endothelial P-Selectin, ICAM-1 and VCAM-1 receptors). In the intima, platelets release Platelet Factor 4 which recruit and mediate vascular smooth cells injury. Monocytes transform to macrophages and further to foam cells by picking up oxidized LDL particles.

Figure 2

Antiplatelet strategies. Platelet activation pathways and antiplatelet drug strategies. Initial platelet adhesion to damaged vessel walls is mediated by the binding of collagen to platelet GPVI receptor. Thrombin, generated by the coagulation cascade, is also a potent activator of human platelets through PAR1 und PAR4 receptors. P2Y1 and P2Y12 receptors are stimulated by ADP released from dense granules and the thromboxane prostanoid receptor is stimulated by thromboxane generated by COX-1 signaling pathway. Platelet to platelet aggregation is triggered by fibrinogen and von Willebrand factor binding to αIIbß3 receptor. Direct and indirect (via thrombin inhibition) antiplatelet agents and their targets are shown in the figure above [36,37,38].