Novel Glycan Dependent Platelet Clearance Mechanisms

Abstract

Platelet numbers are intricately regulated to avoid spontaneous bleeding or arterial occlusion and organ damage. The growth factor thrombopoietin (TPO) promotes platelet biogenesis by controlling megakaryocyte maturation and differentiation. Recently, we identified a feedback mechanism by which clearance of aged, desialylated platelets stimulates TPO synthesis by hepatocytes in mice. The Ashwell-Morell receptor (AMR) of hepatocytes, originally termed the hepatic asialoglycoprotein receptor, was the first cellular receptor to be identified and isolated and the first lectin (carbohydrate-binding) to be detected in mammals. Our work showed that the AMR recognizes and removes senescent, sialic acid-depleted platelets (desialylated) under steady state conditions. Desialylated platelets and the AMR are the physiological ligand-receptor pair regulating hepatic TPO mRNA production. The AMR-mediated removal of desialylated platelets regulates hepatic TPO synthesis by recruiting JAK2 and STAT3 to increase thrombopoiesis. Recent genetics studies have revealed that AMR haplodeficiency provides protection from atherosclerosis by regulating plasma glycolipids and platelets. The potential interactions of AMR with LDL receptor may regulate the rate of LDL uptake and as a result may lower plasma non-HDL cholesterol. Taken together, the AMR appears to be a multifaceted receptor, specializing in the clearance of desialylated platelets and plasma glycolipids. Thus, platelet clearance, its biogenesis via TPO, and vascular integrity appear to be regulated by intricately interwoven mechanisms dependent on the AMR. Disclosures Hoffmeister: Amgen: Consultancy.