The traditionally attributed role of platelets is to assure hemostasis. Platelets become rapidly activated and adhere tightly to other platelets and to the wall vessel as soon as damage is found. Briefly, platelets bind to von Willebrand factor (vWF), which forms a bridge with exposed collagen on the injury and glycoprotein Ib (GPIb)/V/IX receptor complex on the platelet membrane. The exposed collagen also binds directly to platelet GPIa/IIa and GPVI receptors to induce platelet activation in a positive feedback loop. Platelets then release mediators such as ADP and serotonin that activate platelet G protein-coupled receptors. This process results in increased levels of cytosolic calcium and activates signaling pathways leading to platelet shape change and activation of integrins, enhancing the adhesion of platelets to the endothelial wall. Furthermore, ADP acts on platelet P2Y1 and P2Y12 G-protein-coupled receptors to sustain platelet activation ^[1][2][7,8]. Finally, the activation of the GPIIb/IIIa receptor results in the cross-linking of fibrinogen or vWF with their receptors (integrin aIIbβ3) leading to platelet aggregation. This promotes the recruitment of additional platelets to the site of vascular injury allowing the formation of the thrombus ^[3][4][9,10].

Platelets also participate in biological processes such as vascular integrity, tissue regeneration and angiogenesis, and lymphatic vessel development ^{[5][6][7][8][9][10][11][12]}[11,12,13,14,15,16,17,18].

Platelets count with several organelles such as mitochondria, lysosomes and peroxisomes, and a plethora of intracellular immune mediators stored in granules and vesicles ^[13][19]. Moreover, platelets express a high number of membrane receptors and contain cytoplasmic mRNA, which can synthetize a limited number of proteins and miRNA ^[14][3][4,9]. These receptors and proteins allow them to interact with leukocytes and endothelial cells, both by contact-dependent mechanisms and through secreted immune mediators. Thus, platelets can modulate immune responses at the sites of platelet activation systemically ^[15][20].

Platelet receptors and the molecules stored in platelet granules govern platelet functions. These molecules are listed in Table 1. There are three types of platelet granules: α-granules, dense granules and lysosomal granules. Additionally, a potential new type of granule termed a T-granule has been described ^[16][21]. α-granules are the most numerous (50–60 per platelet) and largest (200–400 nm) granules. They contain a large variety of proteins, close to 300, including a diverse range of chemokines, such as CXCL1, platelet factor 4 (PF4), CXCL5, CXCL7, CXCL12, macrophage inflammatory protein (MIP)-1α and regulated on activation normal T expressed and secreted (RANTES) ^[17][22]. Dense granules are smaller (~150 nm), less abundant (3–8 per platelet) and store small molecules, such as ADP, ATP, inorganic polyphosphate, pyrophosphate, histamine, serotonin, and calcium. Finally, lysosomal granules are sparse and contain proteases and glycosidases ^[4][18][10,23]. Upon platelet stimulation, granules undergo regulated exocytosis and release their content into the extracellular environment. In addition, molecules found on the inner granule membrane become surface-expressed. Many of these granule-derived molecules are immune mediators.

This is the case of P-selectin, which is one of the most bioactive molecules contained in α-granules and involved in inflammation. It promotes platelet aggregation and platelet-endothelial and platelet-leukocyte interactions ^[19][24]. Other α-granule constituents such as PF4 or RANTES are immune mediators that recruit and activate immune cells or induce endothelial cell inflammation ^[20][21][25,26]. The inflammatory roles of most α-granule-derived chemokines, cytokines and adhesion molecules are well described. However, the direct contribution of dense granule constituents to immune responses is still largely unexplored. It is nevertheless known that serotonin, contained in dense granules, increases monocyte differentiation into dendritic cells (DCs) ^[22][27] and early naïve T-cell activation ^[23][28]. Moreover, platelets can recruit and activate DCs via integrin alphaMbeta2 (Mac-1) ^[24][29]. In addition, DC expression of T-cell co-stimulatory molecules CD80 and CD86 is increased by activated platelets in a contact-independent manner leading to a stronger and more rapid T-cell response ^[25][30]. In turn, T cells may activate platelets through a T-cell CD40L/platelet CD40 interaction leading to platelet release of RANTES and further T-cell recruitment ^[26][31]. Platelets are also the major source of soluble CD40L, which induces B-cell production of immunoglobulin (Ig)G, by activating DCs and promoting B-cell isotype switching ^[19][24]. It has also been suggested that platelets enhance signals needed for adaptive humoral immunity and germinal center formation ^[27][32].

Activated platelets also release interleukin-1β (IL-1β), which is not granule-stored but produced upon platelet stimulation ^[28][33]. Typical markers of platelet activation (granule exocytosis and integrin expression) are increased rapidly after platelet stimulation (seconds to minutes), but the release of IL-1β from stimulated platelets occurs over hours ^[29][34].

Platelets affect all phases of immune responses. Their interactions with immune cells likely mediate beneficial outcomes in limiting infection and maintaining hemostasis ^[30][35]. However, continued platelet interactions with leukocytes or endothelial cells can also lead to adverse effects from excessive immune stimulation and inflammatory insult ^[14][4].

Despite being small and lacking a nucleus, platelets possess extraordinary metabolic machinery. The metabolism of platelets is not fully known yet; however, it has been estimated that at their basal metabolic state, ATP is generated by both mitochondrial oxidative phosphorylation (OXPHOS) (35%) and glycolysis (65%) ^[31][36]. During platelet activation, fatty acid oxidation and glutaminolysis is promoted to meet the energetic needs for aggregation ^[31][36]. Fatty acids and L-glutamine are required for OXPHOS, and if necessary, platelets can uptake extracellular fatty acids ^[31][36]. Interestingly, platelets proved to have metabolic plasticity, which allows them to compensate the energetic demand driven by activation and aggregation switching from one to another metabolic route ^[31][36]. These two important ATP-generating pathways have become relevant in translational research, where it has been observed that severe phenotypes of allergic and respiratory diseases show a bioenergetic dysfunction in platelets and leukocytes ^[32][37]. As an example of dysfunction, decreased glycolytic function in platelets from asthmatic patients has shown to be compensated by increased tricarboxylic acid (TCA) cycle activity leading to a re-direction of their metabolism towards mitochondrial metabolism, which might increase oxidative injury in asthma ^[33][38].