Sickle Cell Anemia and Its Phenotypes

Abstract

In the 100 years since sickle cell anemia (SCA) was first described in the medical literature, studies of its molecular and pathophysiological basis have been at the vanguard of scientific discovery. By contrast, the translation of such knowledge into treatments that improve the lives of those affected has been much too slow. Recent years, however, have seen major advances on several fronts. A more detailed understanding of the switch from fetal to adult hemoglobin and the identification of regulators such as BCL11A provide hope that these findings will be translated into genomic-based approaches to the therapeutic reactivation of hemoglobin F production in patients with SCA. Meanwhile, an unprecedented number of new drugs aimed at both the treatment and prevention of end-organ damage are now in the pipeline, outcomes from potentially curative treatments such as allogeneic hematopoietic stem cell transplantation are improving, and great strides are being made in gene therapy, where methods employing both antisickling β-globin lentiviral vectors and gene editing are now entering clinical trials. Encouragingly, after a century of neglect, the profile of the vast majority of those with SCA in Africa and India is also finally improving.

Keywords: Africa; genetic modifiers; genetics; genomics; sickle cell anemia.

Figure 1

Time line of key discoveries and significant events in SCA. Abbreviations: DOVE, Determining Effects of Platelet Inhibition on Vaso-Occlusive Events; FDA, US Food and Drug Administration; Gluβ6Val, substitution of valine for glutamic acid at position 6 of the β-globin chain of hemoglobin; GWAS, genome-wide association study; HbA/F/S, hemoglobin A/F/S; HSCT, hematopoietic stem cell transplantation; MAGiC, Magnesium for Children in Crisis; MSH, Multicenter Study of Hydroxyurea in Sickle Cell Anemia; SCA, sickle cell anemia; SCD, sickle cell disease; STOP, Stroke Prevention Trial in Sickle Cell Anemia; SUSTAIN, Study to Assess Safety and Impact of SelG1 with or without Hydroxyurea Therapy in Sickle Cell Disease Patients with Pain Crises; TWiTCH, Transcranial Doppler with Transfusions Changing to Hydroxyurea.

Figure 2. The global distribution of sickle cell anemia in relation to the historical distribution of Plasmodium falciparum malaria.

(a) The geospatial distribution of the HbS allele; these data were derived by using a Bayesian geostatistical model with data from published and unpublished population surveys for allele frequencies. (b) The historical distribution of malaria based on Reference . Abbreviation: HbS, hemoglobin S. Figure adapted from Reference .

Figure 3

Pathophysiology, inflammatory stimuli, and cellular interactions in SCA. Polymerization of deoxy-HbS eventually leads to the formation of dehydrated and misshapen erythrocytes, typically with a sickled shape. The sickled cells trigger microvascular occlusion through interactions with activated neutrophils and platelets and adhesion to vascular endothelium, leading to ischemia and tissue hypoxia followed by vasodilation and reperfusion injury. The damaged erythrocytes are short lived, continuously releasing hemoglobin, and oxidized hemoglobin releases heme. Heme functions as a damage-associated molecular pattern that activates endothelial cells, macrophages, and neutrophils and promotes the formation of NETs (NETosis) via TLR4 binding. Abbreviations: HbS, hemoglobin S; NET, neutrophil extracellular trap; NO, nitric oxide; RBC, red blood cell; ROS, reactive oxygen species; SCA, sickle cell anemia; sRBC, sickle red blood cell; VWF, von Willebrand factor.

Figure 4

Common complications of SCA that add to morbidities. While many complications are related to age, it is also clear that some patients are genetically predisposed to some complications. Predisposing or protective genetic variants have been identified for some complications, such as bilirubin levels and gallstones, as well as sickle nephropathy. Clearly some patients are also predisposed to stroke, avascular necrosis, and pulmonary complications, but genetic variants for these complications need genetic and functional validation. Abbreviation: SCA, sickle cell anemia.