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Aboderin, F.I.; Oduola, T.; Davison, G.M.; Oguntibeju, O.O. Pathogenesis of Sickle Cell Anaemia. Encyclopedia. Available online: (accessed on 20 June 2024).
Aboderin FI, Oduola T, Davison GM, Oguntibeju OO. Pathogenesis of Sickle Cell Anaemia. Encyclopedia. Available at: Accessed June 20, 2024.
Aboderin, Florence Ifechukwude, Taofeeq Oduola, Glenda Mary Davison, Oluwafemi Omoniyi Oguntibeju. "Pathogenesis of Sickle Cell Anaemia" Encyclopedia, (accessed June 20, 2024).
Aboderin, F.I., Oduola, T., Davison, G.M., & Oguntibeju, O.O. (2023, September 08). Pathogenesis of Sickle Cell Anaemia. In Encyclopedia.
Aboderin, Florence Ifechukwude, et al. "Pathogenesis of Sickle Cell Anaemia." Encyclopedia. Web. 08 September, 2023.
Pathogenesis of Sickle Cell Anaemia

Sickle cell anaemia (SCD) is a life-threatening haematological disorder which is predominant in sub-Saharan Africa and is triggered by a genetic mutation of the β-chain haemoglobin gene resulting in the substitution of glutamic acid with valine. This mutation leads to the production of an abnormal haemoglobin molecule called haemoglobin S (HbS). When deoxygenated, haemoglobin S (HbS) polymerises and results in a sickle-shaped red blood cell which is rigid and has a significantly shortened life span. Various reports have shown a strong link between oxidative stress, inflammation, the immune response, and the pathogenesis of sickle cell disease. 

sickle cell anaemia chronic inflammation immune system

1. Immune Mechanisms Involved in the Pathogenesis of Sickle Cell Anaemia

Leukocytes such as neutrophils, eosinophils, basophils, monocytes, lymphocytes, and platelets have been implicated in the pathogenesis of SCD, as evidenced by several studies [1][2][3][4]. These cells are reported to be responsible for promoting inflammation, adhesion, and the painful crises characteristic of SCD [1][5]. Even in the absence of infection, leukocytosis and immune activation is a common phenomenon. In support of this, studies using flow cytometry were adopted to analyse peripheral blood neutrophils for the expression of CD18. CD18 is upregulated during inflammation and binds to the adhesion molecules ICAM-1 and ICAM-4 on the endothelium, resulting in activation and inflammation. These experiments revealed that CD18 expression was increased in SCD patients and that the neutrophils had a higher affinity for the vascular endothelium and increased adherence, which resulted in the recruitment of sickled red cells and an elevated risk of vaso-occlusive crises (VOC) [6][7].
Further contributions have demonstrated that polymorphonuclear leukocytes (PMNs) have high CD64 expression and elevated levels of L-selectin, SCD 16 and elastase, resulting in further amplification of the adhesiveness to the endothelium [8]. According to Antwi-boasiako et al. [9], both male and female SCD patients who experience complications have noticeably higher leukocyte counts than their healthy counterparts with the white blood cell count frequently being used by clinicians to predict stroke and acute chest syndrome [10]. Free haemoglobin and heme released during haemolysis have been identified as key players in the activation of the innate and adaptive immune response [1][11] with reports suggesting that patients with high haemolysis rates are at greater risk of early mortality [12][13]. The continual breakdown and destruction of red blood cells result in sustained activation of innate immune cells resulting in a chronic inflammatory state [2][14][15].
Endothelial cells are one of the first cell types to be activated in the presence of heme. Heme activates endothelial cells inducing the expression of adhesion molecules (E-selectin, intercellular P-selectin, vascular cell adhesion molecule 1) which initiates the activation and recruitment of other immune cells, including macrophages, neutrophils, mast cells, and platelets. The activated macrophages secrete several pro-inflammatory cytokines, including IL-1β, through stimulation of the NLRP3 inflammasome which further contributes to the creation of a pro-inflammatory and pro-coagulant environment [1]. Consequently, this sustained inflammatory state results in a VOC which is commonly described in patients with SCD [16][17].
Heme also has a direct link with the activation of neutrophils by acting as a prototypical pro-inflammatory molecule and recruiting neutrophils to the site of injury via the stimulation of protein kinase C and ROS generation [12][16]. In addition, heme inhibits neutrophil apoptosis via the modulation of phosphoinositide 3-kinase and NF-κB signalling, which further contributes to the development of chronic inflammation [18]. Neutrophils have been identified as playing a significant role in the development of VOC with increased counts being associated with clinical complications, including earlier death and haemorrhagic stroke [17].
Platelets, which are small anucleate cells and play a role in the immune response, have also been implicated in the pathogenesis of SCD. Malik [19] and Nolfi et al. [20] reported that platelet activation together with a decrease in nitric oxide (NO) is triggered by the release of heme into the circulation. Once activated, the platelets release several soluble mediators such as CD40 ligand and thrombospondin which have the potential to initiate thrombosis and pulmonary hypertension [1][19]. Molecules secreted by the platelet bind to CD36, also known as glycoprotein IV, on sickled RBCs and endothelial cells. Platelets go on to associate and bind to other immune cells, including neutrophils, macrophages, and monocytes [15]. It has been demonstrated that activated platelets bind to neutrophils and monocytes in a P-selectin signalling pathway to form aggregates that promote VOC, inflammation, and thrombosis through various mechanisms [3]. In SCD mice, Allali et al. [1] reported that platelet–neutrophil aggregates may be an important factor in the development of pulmonary arteriole micro-emboli.
Although many studies have investigated the role of the innate immune system, the role of the adaptive immune response is still poorly understood. Studies performed on human and animal subjects have reported that in SCD, both T and B lymphocytes are dysfunctional [21][22]. To further analyse this, the relationship between splenic size and lymphocyte counts has been investigated by several researchers [2][23][24][25][26]. Ojo et al. [27] used flow cytometry to analyse CD4+ T-lymphocytes in blood samples from 40 steady-state SCD patients and correlated the counts with ultrasonography used to determine spleen size. They reported that in patients with auto-splenectomy, the mean CD4+ count was not significantly different to HbS patients with a normal-sized spleen. Several studies have further investigated the effect of hydroxyurea (HU) on lymphocyte subset counts [22][28][29] and have shown that SCD patients receiving HU had lower total lymphocytes, T cells, CD4+ T cells, memory CD4+ T cells, and memory CD8+ T cells compared to those who were untreated [2]. These findings may be explained by the fact that HU is often used as a chemotherapeutic drug and acts by inhibiting DNA synthesis, resulting in cytotoxicity and cell death.
Alloimmunisation is an important complication resulting from chronic blood transfusions. Studies investigating the effects of alloimmunisation on the lymphocyte counts of patients with SCD have reported significant changes [2][24][30][31][32][33]. One such study demonstrated a significant decline in regulatory CD4+ T lymphocytes and an increase in regulatory CD8+ T lymphocytes [34], suggesting that these patients may be at risk of developing autoimmunity.
Further investigations of the B cell lineage have demonstrated that they are also functionally abnormal. Abnormalities include decreased antigen-specific B cell proliferation and IgM secretion. According to Ochocinski et al. [35], defects in B cell lymphocyte function in children affect the production of natural anti-polysaccharide antibodies, making children with SCD more susceptible to infection and disease. In a study where the effects of haemolysis were examined on human B- cell responses and alloimmunisation risk in SCD patients, two pathways were tested and included the STAT3 and HO-1 pathways.

2. The Role of Oxidative Stress in the Pathogenesis of Sickle Cell Anaemia

Oxidative stress is an important contributor to the pathogenesis of sickle cell anaemia (SCD) and associated complications such as sickling, vaso-occlusion, and ischemia–reperfusion injury [9][12][36][37][38]. Oxidative stress occurs due to an imbalance between the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and the ability of antioxidant agents, including enzymes such as superoxide dismutases, catalase, and glutathione peroxidase, to neutralise them [9][39][40]. Patients with SCD are frequently exposed to oxidative stress, and studies have found higher levels of ROS in the RBCs of SCD patients compared to healthy controls. The concentration of the reactive intermediates generated from the oxidative reactions has often been used as markers of disease severity [39][41], and the mechanisms leading to oxidative stress in SCD patients’ red blood cells (RBCs) are well established. Some of these include haemoglobin (Hb) autoxidation. When SaQ1234567890 */haemoglobin is released into the bloodstream as a result of haemolysis, superoxide (O2) produced, which can dismutate into hydrogen peroxide (H2O2) and serve as a starting point for additional oxidative reactions [11][42]. Apart from haemoglobin (Hb) oxidation, other factors enhancing ROS production include ischemia–reperfusion injury caused by oxygen deprivation [43], which has been reported to promote the activation of pro-inflammatory mediators such as xanthine oxidase, NADPH oxidase, nitric oxide synthase, and lipoxygenase [12][39]. Another factor contributing to the excessive ROS in SCD patients is the release of iron and heme from unstable HbS, which may catalyse the Fenton reaction. Iron (II) will react with hydrogen peroxide ions leading to the formation of ion (III) and hydroxyl radical [43].
To counteract radicals, the body produces antioxidants [14][44][45]. These include non-enzymatic antioxidants, such as microelements carotenoids and ascorbic acid [46], and enzymatic antioxidants including dismutase, catalase, glutathione peroxidase and heme oxygenase-1 [12][39]. However, due to the high levels of oxidative stress in SCD patients, antioxidants are overwhelmed by the continual source of ROS. Some unneutralised ROS have been reported to oxidise membrane lipids, proteins, and DNA, causing cell death and organ damage [47]. This damage leads to further ROS production, thereby aggravating the disease. The oxidative damage to lipids known as lipid peroxidation happens when membrane phospholipids are exposed to a hydroxyl radical (HO) and hydroperoxyl (HO 2), which have been reported as the two most prevalent ROS affecting lipids [48][49]. During lipid peroxidation, highly toxic molecule end products, including malondialdehyde (MDA) and 4-hydroxy-2-nonenal (HNE), can easily interact with proteins and DNA, causing damage [12][46]. Malondialdehyde (MDA) is an important marker for evaluating oxidative stress in patients with SCD [39]. A study in Cameroon observed an increase in MDA in SCD patients compared to healthy individuals [50]. Similarly, in Ghana, Antwi-Boasiako et al. [9] reported that MDA levels were significantly higher in SCD patients with VOC, which was followed by patients in steady-state. F2-isoprostanes, as a marker of oxidative stress, has been reported to be higher in sickle cell patients compared to healthy controls [51][52]. Nader et al. 2020 [53] assessed the contributions of NO and oxidative stress on eryptosis (apoptosis of red cells) and the release of RBC microparticles (RBC-MPs) on vascular dysfunction. It was reported that oxidative stress initiates eryptosis, and the release of MPs, generated during this process, may be significant in microvascular dysfunction. RBC-MPs could be harmful to the microcirculation’s endothelial cells by activating Toll-like receptor-4 (TLR4) and promoting the expression of adhesion molecules as well as the release of cytokines which in turn fuels vascular dysfunction. Although this investigation offers fresh insight into the underlying processes of vascular dysfunction in SCD, more research is required. New therapeutic targets that aim to prevent eryptosis and/or TLR4 activation are suggested [53].
Oxidative stress in SCD is associated with worsening symptoms, including accelerated haemolysis [54], endothelial damage [48], decreased NO bioavailability [12], and hypercoagulability [55]. Oxidative stress is inevitable in a patient with SCD; however, antioxidant therapeutic strategies, including the use of L-glutamine, N-acetylcysteine, and manganese porphyrins, have the potential to reduce the detrimental effects [37].

3. The Role of Inflammation in the Pathogenesis of Sickle Cell Anaemia

Inflammation is the body’s natural response to toxic chemicals, infection, and injury. Although it is difficult to determine the exact events that trigger the chronic inflammatory state in sickle cell disease (SCD), some mechanisms have been reported [4][22]. The sources of inflammation in SCD include red cell alterations, haemolysis, vaso-occlusive processes, ischemia–reperfusion injury, infections, release of histamine, oxidative stress, thrombin generation and activation of complement [4][52]. Many reported complications such as acute chest syndrome, stroke, leg ulcers, nephropathy, and pulmonary hypertension have been linked to inflammatory processes [56].
Haemolysis is the major inflammatory trigger affecting the bioavailability and function of anti-inflammatory molecules such as nitric oxide (NO) and heme oxygenase 1 (HO-1) [55][57][58]. Heme oxygenase 1 (HO-1) is an enzyme with numerous anti-inflammatory properties, including the breakdown of heme and the generation and release of reaction products, including carbon monoxide, ferrous ions, and biliverdin [59][60][61][62][63]. Continuous haemolysis leads to the overproduction of heme, which in turn accelerates the HO reaction, causing an excessive accumulation of reaction products, and if not sufficiently sequestered, it will have serious consequences [59]. During haemolysis, free haemoglobin and heme destroy nitric oxide (NO) produced by endothelial nitric oxide synthase. Nitric oxide functions in preventing endothelial activation as well as controlling leukocyte activation and emigration from blood vessels to tissue [12]. Researchers have demonstrated that free haemoglobin in the plasma destroys NO 1000-fold faster than haemoglobin encapsulated within the red blood cells [11].
Neutrophils are one of the first cells to respond to infections. Their movement to the site of injury is triggered by Pathogen-Associated Molecular Patterns (PAMPs) from microbes or Damage-Associated Molecular Patterns (DAMPs) derived from damaged host cells. Activated neutrophils release ROS, proteases, myeloperoxidase, defensins, cathepsin G, and elastase to combat foreign organisms at the site of infection [64]. These enzymatic proteins are all involved in inflammatory processes [65] and when cell adhesion takes place, chemokines and cytokines are produced which go on to stimulate dendritic cells resulting in the presentation of antigens to memory CD4+ T cells as well as to naïve CD8+ T cells. This leads to activation of the adaptive immune response [66].
ROS, produced by activated neutrophils, hinders the function of effector NK cells, while GM-CSF cytokines and IFN-γ produced by NK cells prolong the survival of neutrophils in an in vitro system [67].
Due to the prominent role neutrophils play in the inflammatory response, it has been hypothesised that they could be important in the response to plasma methaemoglobin produced during haemolysis. This was investigated, and the results showed that methaemoglobin is an endogenous DAMP ligand for TLR2 and that neutrophils actively respond to the (metHb + LTA) induced production of ROS. Interestingly, it was also observed that this response diminishes in the presence of other white cells, indicating that cells of the immune system communicate with each other to modulate cellular responses during a haemolytic reaction [68]
Vaso-occlusive crises (VOCs) occur when sickled red blood cells obstruct blood flow to the tissues [2][69][70]. This, in turn, triggers an inflammatory reaction as the body attempts to correct the condition. In SCD, vaso-occlusive processes generate ischemia–reperfusion injury, known as tissue damage, which is caused by a disruption in blood supply [12][70][71]. Ischemia–reperfusion damage increases oxidant generation and leukocyte adhesion, contributing to chronic inflammation.
Transforming growth factor (TGF-), interleukin-17 (IL-17), tumour necrosis factor (TNF-), IL-6, and IL-8 are all significantly elevated in steady-state SCD patients when compared to controls. These studies all confirm the chronic inflammatory environment present in patients with SCD [17][71].


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Subjects: Hematology
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