Platelet alpha granule deficiency associated with decreased P-selectin and selective impairment of thrombin-induced activation in a new patient with gray platelet syndrome (α-storage pool deficiency)

We report studies on a new patient with gray platelet syndrome (GPS, α-storage pool deficiency). Her lifelong bleeding history is associated with platelet abnormalities characteristic of GPS including mild to moderate thrombocytopenia, a population of abnormally large platelets, and specific deficiencies of α-granule constituents and morphologically typical α-granules. Platelet function studies showed normal aggregation responses to adenosine diphosphate, epinephrine, collagen, arachidonate, and ristocetin but impaired activation responses to thrombin and a thrombin receptor-activating peptide (T1 peptide). These impaired responses included T1 peptide-induced aggregation, thrombin-induced adenine nucleotide secretion, and thrombin-induced (Ca 2+) i increases. The impairment of the thrombin-induced (Ca 2+) i increase was observed as a substantially slower initial rise in (Ca 2+) i levels and a smaller maximum (Ca 2+) i increase compared with the responses obtained in normal platelets and are thus similar to those reported previously in another patients with GPS. Flow cytometric measurements of the binding of two distinct monoclonal antibodies against the functional thrombin receptor indicated the presence of a normal number of receptors and normal receptor cleavage by thrombin in the GPS platelets, providing additional support for the hypothesis presented in previous studies that the thrombin activation defect in GPS platelets occurs subsequent to the interaction of thrombin with its receptor. The α-granule deficiency in this patient was associated with an approximately 50% decrease in the content and surface expression of the α-granule membrane-specific protein P-selectin in contrast to a previous report of normal amounts of P-selectin in the platelets of two related patients with GPS. This finding raises the possibility that the a-granule deficiency in GPS may be expressed in different phenotypes characterized by differences in the amount or constitution of residual a-granule membranes present in GPS platelets.