Département d’hématologie, hôpital Lariboisière et Institut Cochin de génétique moléculaire, INSERM U. 474, Maternité Port-Royal, 5e étage, 123, boulevard de Port-Royal, 75014 Paris.
The gray platelet syndrome (GPS) is a rare congenital disease which associates thrombocytopenia and platelet abnormalities : indeed the appear grey on Romanowsky stained smears and this is due to the lack of normal a-granules. This disorder has become a paradigm, firstly to evaluate the role of a-granules in platelet function : this role which seems secondary since GPS patients only have mild hemorrhagic symptoms ; secondly, it offers a model of cell biology in order to understand the mechanisms of granule formation and secretion. The present review recalls the dual origin of platelet a-granule proteins in the megakaryocyte, endogenous synthesis and endocytosis from the circulating plasma proteins. The literature on intracellular trafficking and packaging of secretory proteins is then summarised. The clinical and biological symptoms of this congenital disorder are presented and its possible modes of transmission are discussed. As far as cellular abnormalities of the disease are concerned, it has been shown that platelet a-granules are not absent since their limiting membrane proteic components are quasi-normally detected, but these secretion granules are virtually empty, deprived of normal content, the endocytosed proteins being less decreased though than the endogenously synthesised ones. The ultrastructural study of culture megakaryocytes from the patient peripheral blood has allowed to recognize that megakaryocytes are undergoing active biosynthesis but that the routing of the a-granule soluble proteins was massively diverted towards the extracellular space. The relationship of the megakaryocyte abnormalities and myelofibrosis, which is a common finding in the patients, is discussed. Finally, several research directions are followed to understand the primum movens of this abnormal trafficking of a-granule proteins in megakaryocytes from GPS, and possible physiopathological hypothesis are discussed.