Orchestration of Primary Hemostasis by Platelet and Endothelial Lysosome-Related Organelles

Abstract

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.

Inherited platelet diseases with normal platelet count: phenotypes, genotypes and diagnostic strategy

“…Identification of pathogenic variants for HPS involves ten subtypes (HPS1-10) and ten genes: AP3B1, AP3D1, BLOC1S3 encoding for BLOS-3, BLOC1S6 encoding for pallidin, DTNBP1 encoding for dysbindin, HPS1, HPS3-6. [69][70][71] All of the genes encode subunits organized in four multi-subunit protein complexes, named biogenesis of lysosome-related organelles complex (BLOC)-1, -2 and -3 and the adaptor protein-3 complex (AP-3). [67][68][69][70][71] The HPS phenotype is related to the BLOC complex affected (Figure 4).…”

“…[69][70][71] All of the genes encode subunits organized in four multi-subunit protein complexes, named biogenesis of lysosome-related organelles complex (BLOC)-1, -2 and -3 and the adaptor protein-3 complex (AP-3). [67][68][69][70][71] The HPS phenotype is related to the BLOC complex affected (Figure 4). BLOC-1 consists of eight subunits of which dysbindin (HPS7), BLOS-3 (HPS8) and pallidin (HPS9) are mutated in rare patients with a mild or absent bleeding diathesis and variable hypopigmentation.…”

“…AP-3 is important for dense granule biogenesis and protein delivery to the forming granule (e.g., the serotonin transporter, VMAT2). [69][70][71][72] Variants of AP3B1 are said to cause HPS type II. Interestingly, Enders et al detected a homozygous nonsense mutation in AP3B1 together with a heterozygous bystander RAB27A mutation in a child with bleeding, albinism, developmental delay and a susceptibility to infections; HPS type II was diagnosed rather than Griscelli syndrome as would indicate a RAB27A mutation.…”

“…67,69 LYST is a member of the BEACH protein family and is required for sorting resident endosomal proteins into late multivesicular endosomes ( Figure 4B). 71,74 Other defects involving platelet granules…”

“…As well as the above disorders, qualitative defects can lead to decreased dense granule content, inability to secrete their contents or combined dense-and α-granule deficiency. 71,75,76 An absent second wave of aggregation in response to ADP and collagen is characteristic. This can be secondary to mutations of genes for membrane receptors: P2RY12, GP6, TBXA2R, EPHB2, G6b-B; or genetic defects often accompanied by thrombocytopenia (Online Supplementary Table S1).…”