A Novel Type of Macrothrombocytopenia Associated with a Defect in α2,3-Sialylation

We describe a novel type of human thrombocytopenia characterized by the appearance of giant platelets and variable neutropenia. Searching for the molecular defect, we found that neutrophils had strongly reduced sialyl-Lewis X and increased Lewis X surface expression, pointing to a deficiency in sialylation. We show that the glycosylation defect is restricted to alpha 2,3-sialylation and can be detected in platelets, neutrophils, and monocytes. Platelets exhibited a distorted structure of the open canalicular system, indicating defective platelet generation. Importantly, patient platelets, but not normal platelets, bound to the asialoglycoprotein receptor (ASGP-R), a liver cell-surface protein that removes desialylated thrombocytes from the circulation in mice. Taken together, this is the first type of human thrombocytopenia in which a specific defect of alpha 2,3-sialylation and an induction of platelet binding to the liver ASGP-R could be detected. (Am J Pathol 2011, 179:1969-1977; DOI: 10.1016/j.ajpath.2011.06.012)