CD154 is a universal contributor to platelet functions. Activated platelets display CD154 at their membrane and release a soluble form (sCD154). Platelet CD154, directly or indirectly, is a molecular driver of inflammation, coagulation, tissue remodeling, and host defense, processes that intersect at multiple levels. Endothelium is a primary target. Platelet CD154 induces tissue factor (TF) expression and activity, thereby contributing to thrombin generation and upregulates urokinase plasminogen activator receptor which is at the interface between fibrinolysis/inflammation/tissue remodeling. MMP-9 and MT1-MMP induction contribute to regulate endothelium proteolytic activity . Platelet CD154 also induces pro-inflammatory and chemotactic (dotted semicircles) molecule expression, and adhesion molecule expression (CD62e, CD54, CD106,…), leading to leukocyte recruitment and activation. Once activated, target cells recruit and activate other cells through multiple inputs; several amplification loops are thus generated including platelet activation by sCD154 itself (blue arrow). Platelet CD154 also activates cellular effectors of the innate and adaptative immune responses, polymorphonuclear cells (PMN), monocytes (MNC), macrophages (MΦ), dendritic cells (DC); how platelet CD154 contributes to host defense is schematized in Figure 3. CD154-expressing platelet microparticles (PMPs) share most of these functions. Depicted molecules do not comprehensively represent the range of platelet-derived mediators that are controlled by platelet CD154, and other interfaces, such as with endothelin-1, continue to be identified. Magenta arrows depict interaction with CD40. Dotted line for thrombomodulin (ThMod) represents inhibition; full line for others represents stimulation. Dotted semicircles symbolize chemotaxis. Abbreviations: Ly, lymphocytes; MMP, matrix metalloproteinases.