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Sickle Cell Disease
Published in Vincenzo Berghella, Maternal-Fetal Evidence Based Guidelines, 2022
Sickle cell disease describes a group of inherited disorders characterized by the presence of HbS. Sickle cell disease is associated with a mild to moderate chronic anemia. The term sickle cell disease includes sickle cell anemia (HbSS) (70% of cases), hemoglobin S combined with hemoglobin C (HbSC) (most of the remaining cases), hemoglobin S combined with β-thalassemia (HbSβ+ or HbSβ0), and other double heterozygous conditions causing sickling and thus, clinical disease (e.g., hereditary persistence of fetal hemoglobin (HgS/HPHP), and hemoglobin E (HbS/HbE) [7]. The clinical manifestations vary among these genotypes, with HbSβ0 usually with a similar severe phenotype as HbSS, HbSC associated with intermediate disease, and HbSβ+, HbSHPHP, and HbSE with mild or symptom-free disease [1, 5]. The term sickle cell anemia includes HbSS, and also HbSβ0 (due to its similar phenotype). The sickle cell trait is the heterozygous inheritance of HgbS and is characterized by benign clinical course without anemia, with protection against malaria [8].
Phylogeny of Normal and Abnormal Hemoglobin Genes
Published in S. K. Dutta, DNA Systematics, 2019
Two developmental features of the hemoglobin genome command attention. The first is the sequential nature of the expression of the globin genes. This has been touched upon earlier in this chapter. The ζ and ϵ genes are active for a brief period in the first few weeks of development. They give way, by an unknown mechanism, to the synthesis of α and γ chains. The γ chains, in turn are replaced by β chains. The sequence is summarized in Figure 4. The nature of the switching mechanism is unknown, although it has been studied extensively as a potential strategy for the treatment of thalassemia and sickle cell anemia. Comparison of deletions leading to β thalassemia, δ-β thalassemia, and hereditary persistence of fetal hemoglobin (HPFH) suggests that there is a region of DNA between the γ and δ genes which is the “switch region”.24 It has been suggested that a nearby Alu region may be the switch.25 Even if the switching can be ascribed to a specific sequence of DNA, the question remains as to how it works and how it evolved.
The Red Blood Cell In Thalassemia *
Published in Ronald L. Nagel, Genetically Abnormal Red Cells, 2019
Eliezer Rachmilewitz, Ariella Oppenheim, Oded Shalev
Although the hyperproduction of fetal hemoglobin in hemozygous thalassemia major may adversely affect the ability to compensate for the severity of the anemia, (because the left shift of the O2 equilibrium curve is associated with less O2 delivery to the tissues), it is usually perceived as conferring salutary effects of the RBC. This concept is supported by the longer turnover time of fetal hemoglobin in the circulation as compared with hemoglobin A.91 Indeed, differential centrifugation indicates that older cells contain more fetal hemoglobin92 and have fewer metabolic abnormalities.93 Thus the higher the proportion of fetal hemoglobin in any given cell, the lower will be the surplus of alpha chains. The consequent damage of the α chain inclusions will be less and the chances for survival of the RBC, both in the bone marrow and the peripheral blood, will be better. It should be noted that the content of fetal hemoglobin in RBC from β-thalassemia minors is usually in the normal range (less than 1%) or slightly elevated (1 to 5%).94,95 Higher values are uncommon and nearly always indicate that a second genetic abnormality is present (i.e., the heterocellular form of hereditary persistence of fetal hemoglobin.)96
Hematological and molecular characteristics of a novel α-globin variant Hb Liangqing (HBA2:c.224A>G)
Published in Hematology, 2023
Youqiong Li, Shulin Liang, Liang Liang, Lihong Zheng, Xiaocai Lu
Until the second family (F2), we finally collected an adult blood sample (male) with Hb Liangqing. As shown in Figure 2(A), there was an additional peak (19.0%) for Hb F on CE, indicating the presence of the Hb variant. In contrast, HPLC revealed an Hb variant peak in the Hb S-window and an unknown peak, accounting for 16.9% and 0.5% of total Hb, respectively. It has been suggested that Hb Liangqing and Hb F cannot be separated using CE but must be separated using HPLC. Assume the electrophoretogram did not reveal a variant relative to Hb A2 (a clear feature of the α-globin chain mutation). In that case, it might be suspected of being hereditary persistence of fetal hemoglobin (HPFH). Of course, there is another possibility that the β-globin chain variant electrophoreses to the Hb F position and is similar to the Hb Jiangnan we reported previously [14]. If this is the case, it could mislead the direction of our gene identification.
Phenotypic variation in sickle cell disease: the role of beta globin haplotype, alpha thalassemia, and fetal hemoglobin in HbSS
Published in Expert Review of Hematology, 2022
Sickle cell disease covers a variety of conditions in which pathology results from the inheritance of sickle hemoglobin (HbS) [2]. The more common genotypes at birth, in populations of West African ancestry, include homozygous sickle cell disease (HbSS), sickle cell-hemoglobin C disease (HbSC), sickle cell-beta+ thalassemia (Sβ+ thal.) and sickle cell-betao thalassemia (Sβo thal.). Less common genotypes include sickle cell-HbD Punjab, sickle cell-HbO Arab, and sickle cell-HbLepore. Excluded from this definition is the sickle cell trait (HbAS) in which 20–45% HbS is not sufficient under normal conditions to cause serious pathology, although under unusual condition of environmental hypoxia, cyanotic congenital heart disease or respiratory depression, symptoms may occur [3]. Also excluded is the condition, sickle cell-hereditary persistence of fetal hemoglobin (HbS/HPFH) in which the inheritance of an HPFH gene from one parent is associated with 20–30% HbF distributed evenly throughout the red cell population, which inhibits intravascular sickling and is asymptomatic [4].
KFL1 Gene Variants in α-Thalassemia Individuals with Increased Fetal Hemoglobin in a Chinese Population
Published in Hemoglobin, 2018
Fan Jiang, Yan-Xia Qu, Gui-Lan Chen, Jian Li, Jian-Ying Zhou, Lian-Dong Zuo, Can Liao, Dong-Zhi Li
Krüppel-like factor 1 (KLF1) is a pleiotropic erythroid transcription factor that is a master regulator of definitive erythropoiesis. The KLF1–/– mice develop fatal anemia during fetal liver erythropoiesis, due to a defect in the maturation of red blood cells (RBCs), and die by embryonic day 16 [1–3]. Similarly, KLF1-null fetuses or neonates can display hydrops fetalis and a deranged erythroid transcriptome [4,5]. However, heterozygous mutations in the KLF1 gene alone are not pathologically relevant, although there are a number of scenarios in which KLF1 can interact with other conditions and lead to a broad spectrum of human RBC phenotypes. For example, KLF1 haploinsufficiency has been associated with hereditary persistence of fetal hemoglobin (Hb) (HPFH), borderline elevated levels of Hb A2, and marginal microcytosis and/or hypochromia [6].