Molecular basis of platelet granule defects.

Abstract

Platelets are small, discoid, anucleate blood cells that play key roles in clotting and other functions involved in health and disease. Platelets are derived from bone marrow-resident megakaryocytes, which undergo a complex developmental process where they increase dramatically in size and produce an abundance of organelles destined for platelets. These organelles include mitochondria, lysosomes, peroxisomes and two unique types of secretory organelle: α and dense (δ) granules. Dense granules contain small molecules including ATP, ADP and serotonin, and ions such as Ca²⁺ and Zn²⁺. α-granules contain a variety of cargo proteins, which when secreted by activated platelets are involved in processes such as hemostasis (e.g. fibrinogen and Von Willebrand factor), angiogenesis, inflammation and wound healing. Investigations of patients with inherited conditions resulting in decreased/abnormal platelet secretory granules have led to the identification of proteins, protein complexes and cellular processes involved in their production by megakaryocytes. Notably, studies of ARPC1B deficiency, Hermansky-Pudlak and Chediak-Higashi syndromes have linked several genes/proteins to dense granule biogenesis. Studies of multisystemic ARC syndrome revealed the requirement of two proteins, VPS33B and VPS16B in α-granule formation. Identification of the genetic cause of gray platelet syndrome established that NBEAL2 is an additional protein needed for α-granule cargo retention. These discoveries enabled studies using animal models, cell culture and molecular analysis to gain insights regarding the roles of proteins and cellular processes involved in platelet secretory granule production, which are discussed in this review.