Sickle Cell Anemia: only one Single Point Mutation but Many Pathophysiological Issues


Sickle Cell Anemia: only one Single Point Mutation but Many Pathophysiological Issues

Corresponding author Dr. Danilo Grünig Humberto da Silva, UNESP — Sao Paulo State University, Department of Biology, 12Hemoglobin and Hematologic Genetic Diseases Laboratory, Rua Cristovão Colombo, 2265, 13 Jardim Nazareth, CEP: 15054-000, SãoJosé do Rio Preto, São Paulo, Brazil, Tel: 14 +5517 3221-2392;

It has been 100 years since Herrick published the first medical case report of the anemia 24 describing abnormal shapes of red blood cells (RBCs) and gave sickle cell anemia (SCA) its name 25 [1]. Afterwards, Vernon Ingram [2] discovered that the defect of the disease was a single 26 aminoacid substitution in the hemoglobin (Hb) molecule (HBBglu6val), and understanding has 27 gradually increased since then. Even with improved knowledge of the human genome, 28 development of new genomic tools and identification of single nucleotide polymorphisms (SNPs) 29 associated with subphenotypes of SCA by genome-wide association studies (GWAS) [3], and 30 more than 100 different blood and urine biomarkers have been described in SCA [4]. There is still 31 a major challenge to combine all these variables and establish potential predictors of the SCA 32 severity [5]. 33The last 60 years have resulted in an increasingly coherent detailed molecular-level 34 description of the SCA pathophysiology [6]. Despite our precise knowledge of the molecular 35 defect that is associated with hemoglobin S (HbS) in RBCs [7]. Furthermore, recent progress in 36 understanding the molecular events that control polymerization of HbS and sickling of 37 erythrocytes [8]. Nevertheless, these mechanisms are not sufficient to explain the heterogeneous 38 phenotype found among SCA patients, such as pain episodes, acute chest syndrome, neurological 39 complications, leg ulcers and other symptoms. In this way, despite HbS presence is indispensable 40 for the disease establishment, several other phenomena affected by a multitude of genes other 41 than the one directly involved (HBB*S) play an important role [9]. 42While great progress has been made in describing the basic disease process that accounts 43 for hemolytic anemia and the obstructive events underlying vaso-occlusive events (VOE), many 44 questions remain [6]. The simple mutation in the β6-location of globin has a profound effect on 45 all tissues and organs in the SCA patient, and because the vasculopathy affects a large variety of 46 physiologic mechanisms, the varied genetic background of individual patients makes prediction 47 of the clinical severity highly complex [6]. In this way, clinical broad spectrum of SCA can be 48 affected by a number of modifying factors including the haplotype of β-globin gene cluster [10], 49 the coinheritance of polymorphisms associated with both clinical aspects [11] and treatment 50 response [3], hemoglobin fetal (Hb F) levels [12], chronic inflammation and oxidative states [13, 51 14] as well as gender, and others [10]. 52

Among the new evidences, oxidative stress processes have been increasingly related to 53 the SCA pathophysiology [4]. The increased production of prooxidant elements is caused by 54 intrinsic disease mechanisms, such as increased activity of several oxidases (NADPH oxidase and 55 endothelial xanthine oxidase) [15, 16], HbS auto-oxidation [17], heme iron release, increased 56 asymmetric dimethylarginine (ADMA) [18], uncoupling of nitric oxide synthase (NOS) activity, 57 and decreased nitric oxide (NO) levels [19]. As the antioxidant defense systems in SCD are 58 affected and/or are not sufficient to neutralize excessive production of oxidant species [20], 59 chronic oxidative stress establishes, being a critical factor in endothelial dysfunction, 60 inflammation and damage to multiple organs [21]. In this way, oxidative stress is directly related 61 to both cause and consequence of inflammation, hemolysis, vasculopathy, vaso- occlusion, 62 infection, and injury by ischemia/reperfusion, e.g. [22]. For this reason, newer therapeutic agents 63 that can target oxidative stress may constitute valuable means for preventing or delaying the 64 development of organ complications [23, 24]. Thus, antioxidant therapy is being a worthy, 65 promising and increasing goal for SCA treatment. 66

In this context, McCarty [25] suggested the use of comprehensive nutraceutical strategy 67 for mitigating the contribution of oxidative stress to SCA pathogenesis, dubbed as ‘‘full-spectrum 68 antioxidant therapy”. Many recent studies, both in vitro and in vivo, have investigated different 69 strategies as antioxidant therapy for SCA treatment [26-28]. However, paradoxical observations 70 with regard of certain prooxidant effects of antioxidant compounds have been reported under 71 some experimental conditions, indicating the complex interdependency among the pool of 72 physiological relevant cellular antioxidants [29]. Therefore, more studies focusing newer and 73 more specific oxidative stress biomarkers can be helpful to obtain better clues about effective 74 prognostic information of SCA patients. Furthermore, it may be fundamental to the development 75 of more efficacious therapeutic drugs in order to mitigate the devastating clinical manifestations 76 of SCA. 77


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