PLATELET ALPHA-GRANULE DEFICIENCY ASSOCIATED WITH DECREASED P-SELECTIN AND SELECTIVE IMPAIRMENT OF THROMBIN-INDUCED ACTIVATION IN A NEW PATIENT WITH GRAY PLATELET SYNDROME (ALPHA-STORAGE POOL DEFICIENCY)

We report studies on a new patient with gray platelet syndrome (GPS, a lpha-storage pool deficiency). Her lifelong bleeding history is associ ated with platelet abnormalities characteristic of GPS including mild to moderate thrombocytopenia, a population of abnormally large platele ts, and specific deficiencies of alpha-granule constituents and morpho logically typical alpha-granules. Platelet function studies showed nor mal aggregation responses to adenosine diphosphate, epinephrine, colla gen, arachidonate, and ristocetin but impaired activation responses to thrombin and a thrombin receptor-activating peptide (T1 peptide). The se impaired responses included T1 peptide-induced aggregation, thrombi n-induced adenine nucleotide secretion, and thrombin-induced (Ca2+)(i) increases. The impairment of the thrombin-induced (Ca2+)(i) increase was observed as a substantially slower initial rise in (Ca2+)(i) level s and a smaller maximum (Ca2+)(i) increase compared with the responses obtained in normal platelets and are thus similar to those reported p reviously in another patients with GPS. Flow cytometric measurements o f the binding of two distinct monoclonal antibodies against the functi onal thrombin receptor indicated the presence of a normal number of re ceptors 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 s ubsequent to the interaction of thrombin with its receptor. The alpha- granule deficiency in this patient was associated with an approximatel y 50% decrease in the content and surface expression of the alpha-gran ule membrane-specific protein P-selectin in contrast to a previous rep ort of normal amounts of P-selectin in the platelets of two related pa tients with GPS. This finding raises the possibility that the alpha-gr anule deficiency in GPS may be expressed in different phenotypes chara cterized by differences in the amount or constitution of residual alph a-granule membranes present in GPS platelets.