Orchestration of Primary Hemostasis Megakaryocyte-derived platelets and endothelial cells store their hemostatic cargo in α- and δ-granules and Weibel-Palade bodies, respectively. These storage granules belong to the lysosome-related organelles (LROs), a heterogeneous group of organelles that are rapidly released following agonist-induced triggering of intracellular signaling pathways. Following vascular injury, endothelial Weibel-Palade bodies release their content into the vascular lumen and promote the formation of long VWF (von Willebrand factor) strings that form an adhesive platform for platelets. Binding to VWF strings as well as exposed subendothelial collagen activates platelets resulting in the release of α- and δ-granules, which are crucial events in formation of a primary hemostatic plug. Biogenesis and secretion of these LROs are pivotal for the maintenance of proper hemostasis. Several bleeding disorders have been linked to abnormal generation of LROs in megakaryocytes and endothelial cells. Recent reviews have emphasized common pathways in the biogenesis and biological properties of LROs, focusing mainly on melanosomes. Despite many similarities, LROs in platelet and endothelial cells clearly possess distinct properties that allow them to provide a highly coordinated and synergistic contribution to primary hemostasis by sequentially releasing hemostatic cargo. In this brief review, we discuss in depth the known regulators of α- and δ-granules in megakaryocytes/platelets and Weibel-Palade bodies in endothelial cells, starting from transcription factors that have been associated with granule formation to protein complexes that promote granule maturation. In addition, we provide a detailed view on the interplay between platelet and endothelial LROs in controlling hemostasis as well as their dysfunction in LRO related bleeding disorders.To get more news about Hemostatic granules, you can visit rusunmedical.com official website. Lysosome-related organelles (LROs) are specialized storage compartments that include melanosomes in skin and eye melanocytes, lytic granules of cytotoxic T cells and natural killer cells, alpha (α) and dense (δ) granules in platelets, as well as Weibel-Palade bodies (WPB) in endothelial cells.1 Originally evolving from lysosomes, they have critically adapted to a highly specialized physiological role in the storage, clustering and regulated on demand release of bioactive components.1 In line with their evolutionary origin LROs, or as recently proposed endo-lysome related organelles,1 share common features with endosomes.2 In this review, we focus on the biogenesis, morphological features, and physiological role of LROs present in platelets and endothelial cells which are released in a coordinated fashion during primary hemostasis. Megakaryocytes and platelets contain 2 types of LROs, the α-, and δ-granules, whereas endothelial cells contain only one, the WPBs. Each type of LRO can be considered as the adaptation of the cell’s endosomes into functional secretory organelles that have evolved to specific physiological needs related to on demand cargo delivery.1 Although LROs are similar enough to be placed in the same category, they differ in their stored cargoes, which is highly cell specific. In megakaryocytes, α-granules contain hemostatic proteins like VWF (von Willebrand factor) and Fbg (fibrinogen), whereas δ-granules store small molecules like ATP, Ca2 and serotonin as well as the tetraspanin CD63.3 Similar to α-granules, WPBs primarily store VWF, along with a diverse cocktail of proinflammatory and angiogenic proteins, but also CD63.4 Because of their absence or dysfunction in specific bleeding disorders, both platelet granules and WPBs have been positioned as master orchestrators of primary hemostasis. At the site of vascular damage, endothelial cell activation drives the bulk expulsion of highly condensed VWF from WPBs and their conversion into adhesive strings, that serve as a landing platform for platelets.5 Platelets are arrested from the circulation by GPIb-V-IX/VWF interaction, which is the predominant receptor-ligand interaction supporting platelet recruitment (Figure 1A).6,7 Subsequently, adhered platelets interact with exposed subendothelial collagen which initiates an intracellular cascade leading to platelet activation (Figure 1B), which, in turn, results in the α- and δ-granules release and their respective cargoes (Figure 1C).9 In more detail, ADP released from δ-granules binds to the P2Y12 receptor which strongly potentiates collagen and thromboxane A2–mediated platelet activation, shape changes and aggregation.10,11 In addition, polyphosphate, whose trafficking mechanisms to δ-granules are still unclear, is released and may promote secondary hemostasis by accelerating the generation of FXIa by thrombin.12 Release of stored Fbg and VWF from α-granules during platelet activation is likely to contribute to cross-linking of the activation-dependent open conformation of integrin αIIbβ3 (glycoprotein IIb/IIIa), thereby promoting formation of a stable platelet plug.13 Apart from Fbg and VWF, multiple growth factors like PDGFB (platelet-derived growth factor subunit B) and VEGF (vascular endothelial growth factor) as well as chemokines like PF4 (platelet factor 4) and RANTES are present in α-granules, suggesting that α-granule release also contributes to restoration of vascular integrity following injury.14,15 Besides active α- and δ-granules exocytosis, platelets also release their lysosomal content16; however, this is beyond the scope of this review.