Elsevier

Blood Reviews

Volume 23, Issue 4, July 2009, Pages 177-189
Blood Reviews

REVIEW
Platelet α-granules: Basic biology and clinical correlates

https://doi.org/10.1016/j.blre.2009.04.001Get rights and content

Summary

α-Granules are essential to normal platelet activity. These unusual secretory granules derive their cargo from both regulated secretory and endocytotic pathways in megakaryocytes. Rare, inheritable defects of α-granule formation in mice and man have enabled identification of proteins that mediate cargo trafficking and α-granule formation. In platelets, α-granules fuse with the plasma membrane upon activation, releasing their cargo and increasing platelet surface area. The mechanisms that control α-granule membrane fusion have begun to be elucidated at the molecular level. SNAREs and SNARE accessory proteins that control α-granule secretion have been identified. Proteomic studies demonstrate that hundreds of bioactive proteins are released from α-granules. This breadth of proteins implies a versatile functionality. While initially known primarily for their participation in thrombosis and hemostasis, the role of α-granules in inflammation, atherosclerosis, antimicrobial host defense, wound healing, angiogenesis, and malignancy has become increasingly appreciated as the function of platelets in the pathophysiology of these processes has been defined. This review will consider the formation, release, and physiologic roles of α-granules with special emphasis on work performed over the last decade.

Section snippets

Overview of platelet α-granules

Platelets are anucleate, discoid shaped blood cells that serve a critical function in hemostasis and other aspects of host defense. These cells are replete with secretory granules, which are critical to normal platelet function. Among the three types of platelet secretory granules – α-granules, dense granules, and lysosomes – the α-granule is the most abundant. There are approximately 50–80 α-granules per platelet, ranging in size from 200 to 500 nm.1 They comprise roughly 10% of the platelet

Vesicle trafficking

The development of α-granules begins in the megakaryocyte, but continues in the circulating platelet. In the megakaryocyte, α-granules are derived in part from budding of small vesicles containing α-granule cargo from the trans-Golgi network (Fig. 1).[6], [7] In other cell models, an orchestrated assemblage of coat proteins (e.g., clathrin, COPII), adaptor proteins (e.g., AP-1, AP-2, AP-3), fusion machinery (e.g., soluble NSF attachment protein receptors [SNAREs]), and monomeric GTPases (e.g.,

Molecular mechanisms of α-granule release

α-Granule contents must be released from their intracellular repository in order to achieve their physiologic function. α-Granule contents are release when the α-granule membrane fuses with surface-connected membranes of the OCS or the plasma membrane.69 SNAREs represent the core of the fusion machinery. They are membrane-associated proteins that are oriented to the cytosol (Fig. 4). SNAREs associated with granules are termed vesicular SNAREs (vSNAREs), while those associated with target

Platelet α-granules content

α-Granule function derives from their contents. The content of α-granules includes both membrane bound proteins that become expressed on the platelet surface and soluble proteins that are released into the extracellular space. Most membrane bound proteins are also present on the resting plasma membrane92 These proteins include integrins (e.g., αIIb, α6, β3), immunoglobulin family receptors (e.g., GPVI, Fc receptors, PECAM), leucine-rich repeat family receptors (e.g., GPIb-IX-V complex),

Coagulation

Platelets secrete many mediators of blood coagulation. Whereas platelet dense granules contain high concentrations of low molecular weight compounds that potentiate platelet activation (e.g., ADP, serotonin, and calcium), α-granules concentrate large polypeptides that contribute to both primary and secondary hemostasis. α-Granules secrete fibrinogen and von Willebrand factor (vWf), adhesive proteins which mediate platelet–platelet and platelet–endothelial interactions. α-Granular vWf

Conflict of interest statement

The authors have no conflicts of interest to declare.

Acknowledgements

This work was supported by NIH HL87203 (R.F.) and T32 HL07917 (P.B.) and an Established Investigator Award from the American Heart Association (R.F.).

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