Should any genetic defect affecting α‐granules in platelets be classified as gray platelet syndrome?

Abstract

There is much current interest in the role of the platelet storage pool of α‐granule proteins both in hemostasis and non‐hemostatic events. As well as in the arrest of bleeding, the secreted proteins participate in wound healing, inflammation, and innate immunity while in pathology they may be actors in arterial thrombosis and atherosclerosis as well as cancer and metastasis. For a long time, gray platelet syndrome (GPS) has been regarded as the classic inherited platelet disorder caused by an absence of α‐granules and their contents. While NBEAL2 is the major source of mutations in GPS, other gene variants may give rise to significant α‐granule deficiencies in platelets. These include GATA1, VPS33B, or VIPAS39 in the arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome and now GFI1B. Nevertheless, many phenotypic differences are associated with mutations in these genes. This critical review was aimed to assess genotype/phenotype variability in disorders of platelet α‐granule biogenesis and to urge caution in grouping all genetic defects of α‐granules as GPS. Am. J. Hematol. 91:714–718, 2016. © 2016 Wiley Periodicals, Inc.

Defective Zn2+ homeostasis in mouse and human platelets with α- and δ-storage pool diseases

“…α-, δ- Storage pool disease (SPD) is characterized by deficiency of either α- or δ-granules or both types of granules in platelets. The Gray Platelet Syndrome in mouse 11,12 and human 13–15 is associated with an abolished gene function of Nbeal2 (NBEAL2) , where primarily α-granule formation is severely impaired 14,15 . Mice lacking the Unc13d gene have an abolished δ-granule secretion and also partially defective exocytosis of α-granules and lysosomes 16 .…”

Acquired Gray Platelet Syndrome Associated with Primary Myelofibrosis

“…GPS is an inherited platelet dysfunction disorder characterized by levels of platelet α-granules which are less than 15% of normal (19)(20)(21). Mutations in the genes encoding several proteins, such as NBEAL2, GATA1, and VPS33B/ VIPS39, in arthrogryposis, renal dysfunction, and cholestasis syndrome, respectively, and GFI1B were reported to be responsible for GPS, although the mutation sites are heterogeneous (22,23). The LTA pattern of GPS is reported to be heterogenous, although a decreased aggregation response to collagen and the loss of the second wave by ADP are typical (18,19,24,25).…”

Dominant negative Gfi1b mutations cause moderate thrombocytopenia and an impaired stress thrombopoiesis associated with mild erythropoietic abnormalities in mice

“… 14 Although these two forms of thrombocytopenia share a variety of features such as enlarged platelets with reduced α-granule content and abnormal megakaryocytes (MK), 6 , 14 , 15 they also exhibit significant differences, such as a higher variability in α- granule deficiency in GFI1B-RT, differences in platelet aggregation function, autosomal recessive ( NBEAL2 ) versus autosomal dominant ( GFI1B ) transmission and GFI1B specific red blood cell (RBC) defects. 6 , 7 , 16 , 17 …”