Molecular mechanisms regulating platelet clearance and thrombopoietin production

The human body produces and removes 1011 platelets daily to maintain a normal steady-state platelet count. Platelet production must be tightly regulated to avoid spontaneous bleeding if counts are low (thrombocytopenia) or arterial occlusion and organ damage if counts are high (thrombocytosis). Recent studies have highlighted the role of glycan modifications on platelet surface proteins in mediating platelet clearance. Platelets undergoing cold storage lose sialic acid and β-galactose. Following transfusion, cold-stored platelets are cleared via hepatic Ashwell–Morell receptor (AMR) and the macrophage (Kupffer cell) αMβ2 integrin lectin domain. New data point to the fact that platelets surface loses sialic acid during their circulatory lifetime, suggesting a novel platelet in vivo clearance mechanism via the AMR. Thrombopoietin (TPO) is the primary regulator of platelet production, supporting the survival, proliferation and differentiation of the platelet precursors, bone marrow megakaryocytes. Although it is clear that hepatocytes are the primary source of TPO, the mechanisms regulating circulating TPO levels have been subject to discussion for decades. Two major models for TPO regulation have been proposed. In one model, hepatic TPO production is constitutive and TPO serum levels are maintained solely by its uptake and metabolism by the TPO receptor c-Mpl on platelets and megakaryocytes. In another model, hepatic TPO production is regulated. However, the physiological ligand–receptor pair capable of regulating steady-state TPO production remains unclear. In this review, mechanisms of glycan–lectin-mediated platelet clearance and TPO production will be discussed.