The York Platelet Syndrome: A Third Case and New Findings

Abstract 2526

Studies published in 2003 described a mother and son with a mitochondrial myopathy and abnormal platelets containing giant electron opaque organelles and large, multilayered organelles resembling targets. The condition has remained a familial disorder until recently when a new patient, a four year old female, with the same myopathy and platelet ultrastructure was discovered. Now the disorder can be considered a syndrome named after the initial family, the York Platelet Syndrome (YPS). Whole mount preparations of unfixed, unstained YPS platelets revealed that the giant opaque organelles (OO) were as inherently electron dense as delta granules (dense bodies, DB) but several times larger. Analytical electron microscopy revealed both organelles were rich in phosphorous and calcium, suggesting they might have the same origin. However, measurements of serotonin and adenine nucleotides in YPS platelets revealed normal levels. Also, staining YPS platelets for acid phosphatase with cerium as the capture ion and using analytical electron microscopy to determine its location in whole mount preparations revealed the presence of cerium in the giant OO, but not in DB. The findings suggested the OO might be giant secretory organelles. However, exposure of YPS platelets to high dose thrombin caused complete secretion of α granules and DB, but OO and TO were not released through the open canalicular system or the surface membrane. Thus, OO and TO are not secretory organelles. Studies of YPS in the new patient have confirmed and extended these findings. Staining her cells with diaminobenzidine and H₂0₂ to detect platelet peroxidase has revealed enzyme reaction product in both OO and TO, as well as in channels of the dense tubular system. Thus, the giant OO and TO organelles contain proteins and elements usually separated into vesicles in the Golgi Complex and reassembled into alpha granules, dense bodies and lysosomes in megakaryocytes. Instead proteins and elements from the rough and smooth endoplasmic reticulum (SER) develop into giant OO and TO without passing through lamellae of the Golgi complex. Involvement of the SER and DTS in formation of the giant organelles is strongly supported by YPS platelets from the new patient. Large, flat sheets and coils of SER were a common finding in the new YPS patient platelets, and present, but less frequent in the original two YPS patients. The findings strongly support the concept that the YPS in a disorder of megakaryocyte endoplasmic reticulum allowing the formation OO and TO which continue to develop in the DTS of YPS circulating platelets. It is the first such disorder to be described in human megakaryocytes and platelets.