Advances in the Treatment of Sickle Cell Disease Sargam Kapoor, MD, Jane A. Little, MD, Lydia H. Pecker, MD  Mayo Clinic Proceedings  Volume 93, Issue 12, Pages 1810-1824 (December 2018) DOI: 10.1016/j.mayocp.2018.08.001 Copyright © 2018 Mayo Foundation for Medical Education and Research Terms and Conditions

Figure 1 Pathophysiology of vaso-occlusion in sickle cell disease. Hemolysis of sickle red blood cells (RBCs) releases heme that depletes nitric oxide (NO) and causes monocyte activation, thereby triggering endothelial activation. Increased activity of endothelial E-selectin and P-selectin results in leukocyte adhesion. In addition, increased erythrocyte intercellular adhesion molecule (ICAM) 4 expression binds endothelial αVβ3 integrin, and leukocyte-expressed activated αMβ2 integrin (MAC-1) traps hemoglobin S–containing RBCs, leading to adhesion and consequent vaso-occlusion. Antiadhesive therapies (yellow) may decrease adhesion as shown. ESL 1 = E-selectin ligand 1; IL 1β = interleukin 1β; IVIG = intravenous immunoglobulin; PSGL 1 = P-selectin glycoprotein ligand; TNF α = tumor necrosis factor α; VCAM = vascular cell adhesion molecule. Adapted with permission of the American Society of Hematology from Blood,6 with permission conveyed through the Copyright Clearance Center, Inc. Mayo Clinic Proceedings 2018 93, 1810-1824DOI: (10.1016/j.mayocp.2018.08.001) Copyright © 2018 Mayo Foundation for Medical Education and Research Terms and Conditions

Figure 2 Framework for categorization of current treatments for sickle cell disease. This pyramid depicts a classification of treatment modalities into primary treatments (that target the hemoglobin S (HbS) mutation and/or polymerization) and secondary treatments (that target one of the downstream consequences of HbS polymerization). The primary treatments are predicted to have more widespread effect because they treat the root cause and prevent all downstream consequences of sickling. HbF = hemoglobin F; HSCT = hematopoietic stem cell transplant; IVIG = intravenous immunoglobulin; Omega-3 FA = omega-3 fatty acid. Mayo Clinic Proceedings 2018 93, 1810-1824DOI: (10.1016/j.mayocp.2018.08.001) Copyright © 2018 Mayo Foundation for Medical Education and Research Terms and Conditions

Figure 3 Normal glutathione metabolism. Glutathione is an antioxidant that reduces reduced nicotinamide adenine dinucleotide phosphate (NAD[P]H) in the red cell. Glutathione is synthesized from the amino acids glutamate, glycine, and, cysteine by the γ-glutamylcysteine synthetase and glutathione synthetase. In patients with sickle cell disease, glutathione and glutamine levels are low despite increased availability of glutamate, cysteine, and glycine, resulting in increased oxidant stress. L-glutamine was approved by the US Food and Drug Administration in 2017 to replenish the erythrocyte reducing potential. H2O = water; H2O2 = hydrogen peroxide; NADP = nicotinamide adenine dinucleotide phosphate. Mayo Clinic Proceedings 2018 93, 1810-1824DOI: (10.1016/j.mayocp.2018.08.001) Copyright © 2018 Mayo Foundation for Medical Education and Research Terms and Conditions