Potential effects of activated CD40L⁺ platelets in promoting atherosclerotic plaque growth. The endothelial cell surface can dynamically shift between pro- versus anti-inflammatory states. Under the influence of plaque-specific chemokine gradients (eg, CCL2), activated CD40L⁺ platelets tip the balance toward persistent proinflammation via a “pro-inflammatory cell coating” at the luminal side of the intimal endothelial cells, by increasing (1) endothelial translocation of circulating myeloid cells without augmenting their activation; (2) formation of circulating aggregates (platelet-leukocyte aggregates [PLAs]) between platelets and myeloid cells (left side of panel); and (3) their own endothelial translocation (right side of panel). Concomitantly, activated CD40L⁺ platelets reduce the circulating numbers of lymphoid immunosuppressive cells (right side of panel) via humoral, subcellular, and/or heterotypic cell-cell interactions. Unidentified potential underlying mechanisms might include CD40 activation and/or TRAF2/3/5 signaling, resulting in impaired T_reg formation via suppression of FoxP3/CD25 signaling and accelerated T_reg apoptosis and/or clearance via CD40L-induced overstimulation. In addition, activated CD40L⁺ platelets could cross-activate the endothelium (center of the panel) and affect plaque infiltration of inflammatory cells and smooth muscle cells (SMCs), but these effects might be less pronounced. This proinflammatory balance, caused by activated CD40L⁺ platelets, might progressively promote further plaque growth by enhanced neovascularization and capillary rarefaction, likely via CD40 signaling. After plaque rupture, activated CD40L⁺ platelets stimulate collagen/VWF-dependent thrombus formation and stability, likely via integrin-dependent and CD40-independent pathways. (Professional illustration by Kenneth X. Probst.)