Clinical impact of glycans in platelet and megakaryocyte biology

Abstract

Humans produce and remove 1011 platelets daily to maintain a steady-state platelet count. The tight regulation of platelet production and removal from the blood circulation prevents anomalies in both processes from resulting in reduced or increased platelet count, often associated with the risk of bleeding or overt thrombus formation, respectively. This review focuses on the role of glycans, also known as carbohydrates or oligosaccharides, including N- and O-glycans, proteoglycans, and glycosaminoglycans, in human and mouse platelet and megakaryocyte physiology. Based on recent clinical observations and mouse models, we focused on the pathologic aspects of glycan biosynthesis and degradation and their effects on platelet numbers and megakaryocyte function.

Graphical abstract

Figure 1.

Glycan diversity. Schematic figures of glycans and genes that regulate platelet production and clearance. (A) N-glycans are bound to glycoproteins through an N-glycosidic bond to asparagine (Asn). Depending on how their core is branched out, they can be classified as oligomannose, complex, or hybrid. (B) O-glycans are bound through an O-glycosidic bond to serine (Ser) or threonine (Thr). (C) Proteoglycans consist of a protein core (orange) and ≥1 covalently attached GAG chains. GAGs consist of repeating disaccharide units composed of an N-acetylated or N-sulfated hexosamine and either a uronic acid (GlcA or IdoA) or galactose. LacNAc, N-acetyllactosamine; TF, Thomsen-Friedenreich.

Figure 2.

Glycosylation changes affect platelet production directly and indirectly. (A) Deficit in the sialyltransferase ST3Gal1 (St3gal1^MK−/−) causes exposure of the cryptic TF antigen that is recognized by a plasmocytoid dendritic-like cell inducing the release of type 1 interferon dampening platelet production. Increased immunoglobulin G antibodies against the TF antigen are observed in pediatric patients with immune thrombocytopenia (ITP). (B) β4GalT1 regulates platelet production. Megakaryocytes derived from B4galt1^−/− mice have an underdeveloped demarcation membrane system, β1 integrin hyperactivity, and impaired platelet production, causing thrombocytopenia. Increased expression and activity of β4GalT1 is observed in megakaryocytes isolated from patients with myeloproliferative neoplasms (MPNs) with high allele burden. Highly galactosylated platelets in MPNs may promote increased hepatic TPO synthesis that sustains the aberrant megakaryopoiesis. IL-6, interleukin 6.

Figure 3.

Platelet and liver TPO production feedback loop. (A) At steady state, completely sialylated platelets (purple circles) circulate through the hepatic sinusoids. Aged platelets with heightened terminal Gal and GalNAc residues (yellow circles) are cleared in the liver, initiating hepatic TPO production. (B) The hepatic AMR directly recognizes desialylated platelets, activating the JAK2-STAT3 pathway to elicit TPO production. Various lectins on liver macrophages (Kupffer cells), including the integrin αMβ2, the macrophage Gal lectin (MGL), and Clec4f bind desialylated platelets. Platelet binding to macrophage lectins could trigger cytokine release, including IL-6, and induce IL-6 receptor (IL-6R) responses to stimulate TPO production further.