SCD is a severe hereditary form of anemia that results from a single mutation in the sixth codon of the gene encoding the β-globin chain (from glutamic acid to valine) of the adult Hb tetramer (α2β2), which is prone to polymerization at low oxygen levels
[1]. It is an autosomal recessive disorder caused by mutations in the Hb subunit β (
HBB) gene, which encodes the β-globin subunit of HbA. It is characterized by the presence of RBCs that contain hemoglobin S (HbS) without additional normal HbA
[2]. SCD may occur as sickle cell anemia (SCA), HbSC disease, and HbS-thalassemia. Genotypically, SCA has two sickle β (β
S) alleles; HbSC disease has one sickle β allele and one β
C allele, which has another type of mutation; while HbS-thalassemia has one sickle β and one β null allele. Polymerized sickle Hb (HbS, α2βS2) leads to abnormalities in the RBC biconcave architecture and flexibility, resulting in crescent-shaped cells with an enhanced adherence to the vascular endothelium; these abnormal shaped RBCs obstruct blood flow, and are prone to hemolysis
[3]. The terminology of SCD is used for all anemias caused by mutations in the
β-globin gene. SCA is the most common form of SCD, representing 70% of SCD cases in African patients
[4].
2. Epidemiology
An epidemiological study showed that 300,000 children with SCD are born every year worldwide
[5]. Another study revealed that approximately 100,000 US nationals have SCD
[6]. The areas with the highest prevalence of SCD are India, the Democratic Republic of Congo, and Nigeria
[7]. In most areas of Africa, SCD affects approximately 1% of all births, and approximately 6–15% of affected children die before their fifth birthday. Approximately 50–90% of children develop SCD in Africa
[8]. In Sudan, the prevalence of SCA ranges from 0.8% (Central Sudan) to 30.4% (Western Sudan). A study showed that the prevalence of SCA in Sudan is approximately 2–30.4%
[9][10].
Mortality and morbidity caused by SCA in childhood are high. In the Unites States, the median survival is 48 years for women and 42 years for men
[11], though advances in treatment options may increase survival, and a report from a London Hospital showed a median survival of 67 years
[4]. A prospective cohort study in Kenya showed that children with SCD (58 per 1000 children/years) have a higher mortality than those without SCD (2.4 per 1000 children/years)
[12].
3. Pathogenesis
The main pathogenic processes of SCD include HbS polymerization, dehydration, vaso-occlusion (VOC), hemolysis-mediated endothelial dysfunction, and sterile inflammation.
The polymerization of sickle Hb due to deoxygenation or hypoxic events is the most crucial and basic molecular pathogenic mechanism of SCD. This polymerization initiates the arrangement of contiguous strands that cause the formation of misshaped or crescent-shaped RBCs. This polymerization also initiates downstream events, such as alterations of the function and structure of the RBC membrane, deteriorations in vasoactivity, the unbalanced distribution of RBC volume, and increased RBC attachment to the endothelium
[13][14].
The main etiology of the dehydration of sickled erythrocytes in SCD involves the activation of cytokines, endothelin 1 (ET-1), and prostaglandin E2 (PGE2) in the Gardos pathway
[13]. The reticulocyte-rich fractions of sickled blood exhibit a high expression of K-Cl cotransporter isoform 2 (KCC2), which maintains optimal K
+-Cl
− cotransport
[15] and cation fluxes (Ca
2+ ion entry), which are induced in a deoxygenation state
[16]. In tissues with a high oxygen demand, the intraerythrocyte deoxygenation process causes hydrophobic motifs of deoxygenated HbS tetramers to be exposed
[17].
In SCD, increased cell adhesion to the endothelium mediates VOC and biorheological disorders. Blood rheology is dependent on the viscosity of the plasma and hematocrit, as well as the deformability of erythrocytes. Because of decreased sickle erythrocyte deformability and persistent hemolysis owing to dehydration and Hb polymerization, increased plasma viscosity impedes the flow of blood through the venules of tissues with a high oxygen demand. Sickle erythrocytes have inadequate deformability and are sequestered in the microcirculation, causing transient VOC
[18][19].
VOC can be triggered by multiple factors, such as stress, inflammation, ischemia, hemolysis, activated endothelial cells, increased plasma viscosity, and diminished blood flow
[20]. E- and P-selectin, which are endothelial selectins, also play an important role in VOC. Random precapillary obstruction by a small number of dense sickle RBCs (SS-RBCs) also contributes to VOC. Epinephrine can activate intercellular adhesion molecule 1 (ICAM-4; an LW blood group glycoprotein), which is an RBC adhesion receptor that mediates SS-RBC adhesion to endothelial α-v-β-3 integrin. VOC enhances ischemia-reperfusion injury
[21][22][23]. In addition, patrolling monocytes are reduced in recent VOC episodes. Patrolling monocytes, which scavenge debris and damaged cells from the vasculature, have higher levels of the anti-inflammatory heme oxygenase 1 (HO-1) enzyme, which degrades heme. Patrolling monocytes expressing HO-1 protect the SCD vasculature from ongoing hemolytic insult and vaso-occlusion
[24].
Endothelial dysfunction is a pathognomonic factor related to SCD, and is caused by the upregulation of P- and E-selectin, ICAM-1, vascular cell adhesion molecule-1 (VCAM-1), and major leukocyte chemoattractants (i.e., keratinocyte-derived chemokine in mice or interleukin-8 in humans) on endothelial cells
[17]. Repeated vascular damage resulting from VOC may cause endothelial cell dysfunction through a mechanism resembling ischemia/reperfusion injury
[21].
Together with heme and iron, endothelial cells are key players and have an important role in SCD oxidative damage through several actions. First, they are involved in the formation of robust oxidizing species, such as ferryl-Hb and •OH, through the H
2O
2-dependent Fenton reaction. Second, increased platelet adhesion may activate endothelial cells. Third, increased inflammatory cytokine production (interleukin (IL)-1-β, IL-6, and IL-18, and tumor necrosis factor (TNF)-α), inflammasome activation, and the stimulation of Toll-like receptor-4 (TLR4) in endothelial cells occur through NF-κB-linked pathways. In addition, there is reduced anti-inflammatory cytokine IL-10 that is correlated with the frequency and severity of VOC
[25]. Fourth, activated neutrophils may influence endothelial cells and serve as neutrophil extracellular traps (NETs) for RBCs and platelets. Fifth, the expression of adhesion molecules such as P-selectin, E-selectin, ICAM-1, and VCAM-1 is increased; these are all markers of endothelial dysfunction, and can serve as receptors for leukocytes (monocytes, neutrophils, and lymphocytes). Sixth, blood coagulation is triggered by the release of intraluminal tissue factor from endothelial cells—the tissue factor then binds to factor VIIa, promoting the coagulation cascade
[26].
The association of sterile inflammation with SCD-related morbidity suggests that anti-inflammatory paradigms are treatments for SCD
[27]. Sterile inflammation may be promoted by damage-associated molecular patterns, such as heme, Hsp70, ATP, cyclophilin A, mtDNA, HMGB1, extracellular DNA, and S100A8, which may play important roles in SCD inflammatory mechanisms
[28].
CXCL1 is a fundamental inflammatory biomarker of VOC
[29]. The administration of CXCL1 exogenously is adequate to activate VOC, and the suppression of the CXCL1 receptor (namely CXCR2) may prevent VOC development because of the hemolytic transfusion reaction. The direct suppression of this pathway may be a novel therapy for VOC
[30].
SCD features a vicious circle between inflammation and abnormal RBC rheology
[31], which modulates clinical severity in patients. Chronic inflammation leads to organ dysfunction in SCD patients. High activation of coagulation factors, endothelium, monocytes, neutrophils, and platelets are key factors in this vicious cycle. Different strategies have been used to determine the effect of these factors in SCD patients
[32].