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Pathophysiologic basis of haemolysis in patients with sickle cell disease in steady state and in hyperhaemolytic states: Aetiopathogenesis, management, and mitigation
Sagir G Ahmed1, Umma A Ibrahim2
1 Department of Haematology, Aminu Kano Teaching Hospital, Kano, Nigeria
2 Department of Paediatrics, Aminu Kano Teaching Hospital, Kano, Nigeria
| Date of Submission | 05-Nov-2022 |
| Date of Decision | 17-Jan-2023 |
| Date of Acceptance | 30-Jan-2023 |
| Date of Web Publication | 10-Apr-2023 |
Correspondence Address:
Sagir G Ahmed,
Department of Haematology, Aminu Kano Teaching Hospital, Kano
Nigeria
 Source of Support: None, Conflict of Interest: None DOI: 10.4103/njbcs.njbcs_55_22
Sickle cell disease (SCD) is characterized by red cell sickling, tissue infarcts, pain and haemolysis. Haemolysis leads to anaemia, transfusion and vasculopathic multi-organ damage (VMOD). Every SCD patient maintains a chronic steady state haemolysis (SSH), which is often aggravated to hyperhaemolysis (HH) by inherited and/or acquired comorbidities. Hence, this article aims to present an updated and comprehensive narrative literature review of aetiopathogenesis, management and mitigation of SCD haemolysis in steady state and in various hyperhaemolytic states. Literature search revealed SSH is initiated by steady state sickling due to tissue hypoxia and is driven by lactic acidemia, Bohr effect, low pyruvate kinase activity, reduced oxygen affinity of HbS, lipid peroxidation, eryptosis, senescence antigen expression, Fc-receptor or ligand mediated erythro-phagocytosis, xanthine oxidase (XO) hyperactivity and intravascular red cells lysis. SSH is often aggravated to chronic or acute HH by various acquired and/or inherited haemolytic comorbidities such as G6PD deficiency, hereditary spherocytosis (HS), acute/chronic hypersplenic or acute hepatic sequestration, infective erythrocytotropism and erythrocytopathy, haemophagocytic syndrome, transfusion reaction, alloimmune, autoimmune and drug-induced haemolysis. While transfusion provides short-term solution for severe haemolysis and anaemia in SCD, long-term solution must include mitigation of haemolysis by using HbF enhancers, HbS oxygen affinity modifiers, XO inhibitors, immune modulators for immune-haemolysis, use of anti-oxidants to minimize peroxidation, avoidance of oxidants if patient is also G6PD deficient, administering antibiotics/vaccinations to treat/prevent infections, splenectomy for comorbid HS or any recalcitrant hypersplenic splenomegaly. This narrative review underscores importance of managing SSH and HH in order to alleviate anaemia, minimize transfusion, and prevent VMOD in SCD.
Keywords: Aetiology, anaemia, hyperhaemolysis, management, pathogenesis, prevention, sickle cell disease, steady state haemolysis
How to cite this URL:
Ahmed SG, Ibrahim UA. Pathophysiologic basis of haemolysis in patients with sickle cell disease in steady state and in hyperhaemolytic states: Aetiopathogenesis, management, and mitigation. Niger J Basic Clin Sci [Epub ahead of print] [cited 2023 Jun 10]. Available from: https://www.njbcs.net/preprintarticle.asp?id=373999 |
| Introduction | |  |
Haemoglobin-S (HbS) is a variant of the normal HbA. HbS arose as a result of GAG > GTG base transition at codon-6 of the β-globin gene on chromosome-11, which corresponds to a substitution of glutamic acid (a polar amino acid) by valine (a neutral amino acid) in the sixth position of the β-globin chain (βGlu6Val).[1],[2] As a result of this substitution, HbS has less anionic potential, slower electrophoretic mobility and reduced deoxygenated solubility that leads to polymerization and red cell sickling.[1],[2] The prevalence of sickle β-gene in tropical African countries is as high as 25-30%.[3] The prevalence is high because sickle cell trait (SCT) protects against severe malaria[3] and confers survival advantage through natural selection,[4] balanced polymorphism,[5] as well as immunological and biochemical protective mechanisms against the infection.[6] There are at least five different sickle β-gene mutation haplotypes that vary in HbF levels and disease severity. The Arab-Asian and Senegal haplotypes are associated with relatively higher HbF levels and milder sickle cell disease (SCD), while the Benin, Bantu and Cameroon haplotypes are associated with relatively lower HbF levels and severer SCD.[7]
The red cells of individuals with SCT have the HbAS phenotype, thus containing both HbS (20-40%) and HbA (60-80%).[8] The relative preponderance of HbA in SCT red cells prevents sickling and undue haemolysis under physiological circumstances.[8] Consequently, SCT red cells have a normal life span, and SCT carriers have normal life expectancy.[9] HbS gene is thus genetically recessive, and SCT carriers are essentially asymptomatic except for the occasional occurrence of renal papillary necrosis,[8] splenic infarction at high altitude[10] or bone pain upon exposure to certain haematopoietic growth factors.[11] SCD arises from the homozygous inheritance of HbS gene or double heterozygosity of HbS gene with another haemoglobinopathy gene (e.g. HbSC, HbSD, HbSE, HbSO and HbSβthal).[1] The clinical course of SCD is characterized by pain-free and stable periods of relative well-being referred to as 'steady state', which is intermittently interrupted by painful and unstable periods referred to as 'crisis'.[12] Painful vaso-occlusive crisis (VOC) is the commonest type of crisis in SCD, and it is clinically pathognomonic of SCD.[12] Clinical transition from steady state to VOC results from tissue necrosis due to deoxygenation of HbS and red cell sickling, which is usually triggered by several factors that vary from physiological factors (e.g., menstruation) to pathological factors (e.g., infections) on the one hand, and from psychological factors (e.g., emotional stress) to physical factors (e.g., extreme weather conditions) on the other hand.[12]
Red cell sickling is a significant and pathognomonic feature of SCD. Red cells of patients with SCD go through repeated cycles of deoxygenation (in the tissues) and re-oxygenation (in the lungs). This sequence of events creates a dynamic scenario of red cell sickling and un-sickling until the red cell membrane sustains a significant degree of damage, which eventually leads to the formation of irreversibly sickled cells that are invariably and prematurely haemolyzed.[13] Consequently, the red cell life span in SCD is shortened to less than 20 days,[14] which cannot be adequately compensated even by maximum erythroid hyperplasia of the bone marrow.[15] Thus, every patient with SCD maintains a certain degree of clinically tolerable steady state haemolysis, which can be aggravated to a chronic or acute hyperhaemolytic state by various inherited and acquired haemolytic comorbidities or triggers. These hyperhaemolytic states are characterized by precipitous or gradual fall in haemoglobin concentration to a clinically intolerable level, which invariably increases the transfusion requirements of affected patients. Haemolysis is therefore an important cause of anaemia in SCD.[14] However, apart from anaemia, haemolysis is also associated with other important and serious life-threatening consequences. This is because haemolysis has dual adverse effects on patients with SCD. First, haemolysis causes anaemia thus predisposing patients to transfusion with concomitant risks of iron overload, transfusion transmissible infections, immune sensitization and reactions, as well as immune modulation and suppression.[16] Second, haemolysis increases the availability of cell-free Hb and haem in the blood wherein they support bacterial growth and sepsis,[17] quench vaso-modulatory effect of nitric oxide and cause vasculopathy with multi-organ dysfunctions such as stroke, nephropathy, leg ulcer, priapism and pulmonary hypertension.[18] There is therefore the need to understand the clinico-pathological perspectives of haemolysis in patients with SCD. The clinico-pathological perspectives of haemolysis in SCD are fragmented and not comprehensively appraised. Hence, the objective of this article is to present an updated and comprehensive narrative literature review of the aetiopathogenesis, management and mitigation of haemolysis in patients with SCD in steady state and in various types of hyperhaemolytic states.
| Methodology: Literature Search and Selection | | |
Literature search was conducted using search terms: 'sickle cell disease, steady state haemolysis, infection, chronic hyperhaemolysis, acute hyperhaemolytic crisis, splenomegaly, hepatomegaly, enzymopathy, membranopathy, vasculopathy, pathogenesis, organ damage, transfusion reactions, red cell alloantibodies, autoantibodies, severe anaemia, pancytopenia' in various combinations in PubMed, Medline, Bing, Google-Scholar and other on-line search engines. We selected articles that examined aetiology and pathophysiology of red cell sickling and/or haemolysis; immuno-pathology and infective pathology of haemolysis; sickle cell splenopathies; comorbidity of SCD and other haemolytic anaemias; laboratory variables and clinical outcomes of haemolysis in SCD: anaemia, transfusion and vasculopathy; management and prevention of steady state sickling and haemolysis and/or any hyperhaemolytic states in SCD. Articles that concentrated on other aspects of SCD were excluded from this narrative literature review. Overall, 141 relevant publications were selected, which included 139 peer reviewed journal articles, 1 World Health Organization (WHO) technical report, and 1 chapter of an edited text book as listed in the reference section.
| Results | | |
Steady state haemolysis is initiated by steady state sickling, which is triggered by tissue hypoxia and is driven by lactic acidemia, Bohr effect, low pyruvate kinase activity, reduced oxygen affinity of HbS, lipid peroxidation, eryptosis, senescence antigen expression, Fc-receptor or ligand mediated erythro-phagocytosis, xanthine oxidase (XO) hyperactivity and intravascular red cells lysis. Steady state haemolysis is often aggravated to chronic or acute hyperhaemolysis by various acquired and/or inherited haemolytic comorbidities including G6PD deficiencies, hereditary spherocytosis (HS), acute and chronic hypersplenic or hepatic sequestration and haemolysis, infective erythrocytotropism and erythrocytopathy, haemophagocytic syndrome, transfusion reaction, alloimmune, autoimmune and drug-induced haemolysis as outlined in [Table 1]. The aetiopathogenesis, management and mitigation of haemolysis in steady state and in various hyperhaemolytic states are expatiated in the discussion section as follows. | Table 1: Aetiopathogenesis, management and mitigation of haemolysis in sickle cell disease (SCD)
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| Discussion | | |
Steady state sickling and haemolysis
Steady state haemolysis is a chronic process that is initiated by steady state sickling due to tissue hypoxia and is perpetuated by the combined effects of low pyruvate kinase activity, reduced oxygen affinity of HbS, eryptosis, erythro-phagocytosis, elevated activity of XO and direct lysis of sickled red cells. Thus, steady state sickling is the pathogenetic forerunner of steady state haemolysis, which has both intravascular and extravascular components as described below.
Steady state sickling: Tissue hypoxia, lactic acidemia, Bohr effect, low pyruvate kinase activity and reduced oxygen affinity of HbS
Although red cell sickling is more prominent during SCD crisis, continuous sub-clinical sickling does occur at a lower rate in steady state.[19] However, steady state sickling is painless and it is induced and initiated by tissue hypoxia encountered by HbS-containing red cells as they perform their physiological function of delivering oxygen to the tissues.[19] In addition, steady state sickling is thought to be driven and 'auto-facilitated' by low pyruvate kinase activity of SCD red cells and reduced oxygen affinity of HbS.[20],[21],[22],[23] The low oxygen affinity of HbS is attributable to two pathophysiologic mechanisms. First, HbS polymerization is thought to cause structural alterations of its oxygen binding sites, thereby decreasing its affinity for oxygen.[21],[22] Second, tissue hypoxia in SCD causes elevation in the concentration of 2,3-DPG, thereby shifting the oxygen dissociation curve of HbS to the right, which further decreases the oxygen affinity of HbS.[23] This physiologically desirable action of 2,3-DPG is beneficial in normal persons, but it unfortunately facilitates HbS deoxygenation, red cell sickling and haemolysis in persons with SCD.[21],[22] Moreover, a recent study had revealed a decrease in the activity and stability of pyruvate kinase enzyme in the red cells of patients with SCD.[24] The exact cause of this 'acquired' pyruvate kinase defect in SCD red cells is not precisely known, but it may be related to inhibition of the enzyme via oxidation of its cysteine residues in similarity to what had previously been observed in cancer cells in which oxidation of cysteine residues of pyruvate kinase contributes to cellular anti-oxidant responses.[25] In any case, decreased pyruvate kinase activity in SCD red cells is undesirably as it would decrease the levels of ATP in the red cells (thus compromising membrane integrity), and raise the level of 2,3-DPG via the Rapoport-Luebering shunt, which would lead to further reduction in the oxygen affinity of HbS and a greater shift of the dissociation curve to the right.[24] Moreover, even at rest in steady state, SCD patients have elevated tissue hypoxia with commensurate high levels of lactic acidemia.[26] Lactic acid is a potent trigger of the 'Bohr effect', which further reduces the oxygen affinity of HbS, thereby causing additional shift of the dissociation curve to the right.[27] It is therefore obvious that multiple physico-chemical factors act synergistically in reducing oxygen affinity and causing a right shift in the dissociation curve of HbS, which ultimately facilitates deoxygenation, polymerization, sickling and haemolysis in persons with SCD even in steady state.[21],[22],[23],[24],[25],[26],[27]
The aforementioned pathophysiologic effects of low oxygen affinity of HbS vis-à -vis its polymerization and red cell sickling create an ideal therapeutic target for the use of Voxelotor, a novel inhibitor of HbS deoxygenation and polymerization.[28] Voxelotor binds reversibly to haemoglobin, thereby stabilizing the oxygenated HbS and preventing its polymerization by increasing its affinity for oxygen.[28] A phase-III multiple-dose-randomized clinical trial had shown Voxelotor to safely reduce rate of steady state sickling and haemolysis, increase haemoglobin concentration and significantly improve anaemia in patients with SCD.[28] Another potential drug for reducing haemolysis and anaemia in SCD is Mitapivat.[24] Mitapivat is an allosteric activator of pyruvate kinase that had previously been shown to decrease haemolysis and improve anaemia in patients with congenital pyruvate kinase deficiency.[29] Moreover, it had been demonstrated that ex-vivo treatment of HbS containing red cells with Mitapivat restored pyruvate kinase activity, reduced 2,3-DPG levels and increased oxygen affinity of HbS with a commensurate reduction of rate of polymerization, sickling and haemolysis.[24] Thus, targeting the 'acquired' pyruvate kinase defect in SCD red cells with Mitapivat represents a potentially novel therapy for SCD patients for whom it can be administered alone or in combination with hydroxyurea.[24]
Steady state haemolysis: Extravascular
Two thirds of the haemolysis in SCD is extravascular and is attributable to the interactions between sickled red cells and the reticuloendothelial system.[30] There are basically three inter-related mechanisms that lead to extravascular haemolysis in SCD as described below.
Extravascular steady state haemolysis: Senescence antigen exposure and Fc-receptor mediated erythro-phagocytosis
The major mechanism involved in chronic extravascular haemolysis in SCD is IgG Fc-receptor mediated macrophage erythro-phagocytosis.[30] The propensity for sickled red cells to interaction with macrophages is an important determinant of chronic steady state extravascular haemolysis in SCD.[30] The pertinent mechanism appears to involve modification of sickled red cell membranes by sickling-induced membrane injury and appearance of senescence antigens.[30] Senescence antigens are identified as 'non-self', which results in abnormal acquisition of membrane surface IgG leading to Fc-receptor mediated erythro-phagocytosis of sickled red cells by macrophage.[30] It is interesting to note that red cell survival in SCD remains greatly attenuated at less than 20 days even after autosplenectomy,[14] which suggests that extravascular haemolysis in SCD is equitably attributed to each and every component of the entire reticuloendothelial system of the human body within and outside the spleen.[30]
Extravascular steady state haemolysis: Lipid peroxidation ad ligands mediated erythro-phagocytosis
Another mechanism underlying extravascular haemolysis of sickled red cells is related to auto-oxidation through which sickle red cells spontaneously generate excessive amounts of dialdehyde by-products of lipid peroxidation (DBLP) and mannose N-glycans (MNG).[30],[31] Both DPLP and MNG are cross-linked to red cell membranes where they act as phagocytosis ligands and opsonizers in the process of erythro-phagocytosis of sickled red cells.[30],[31] This process by which macrophages recognize and phagocytose DBLP and MNG-coated sickled red cells is an Fc-receptor-independent mechanism of extravascular haemolysis in SCD.[30],[31] Because L-glutamine is a precursor for nitric oxide and the anti-oxidant NADPH,[32] it can be pharmacologically inferred that L-glutamine would mitigate the afore-mentioned auto-oxidation-induced sickle cell haemolysis as one of its therapeutic benefits. However, previous clinical studies and therapeutic trials of L-glutamine in SCD only reported significant improvement in energy levels with reduction in episodes of pain and acute chest syndrome, but there were no significant differences in Hb concentration, haematocrit or reticulocyte count between treatment and placebo groups,[32],[33],[34],[35],[36] which suggested lack of significant anti-haemolytic efficacy of L-glutamine. This therapeutic shortfall is at variance with the pharmacological expectation that L-glutamine, being an anti-oxidant precursor,[32] would also mitigate haemolysis in SCD. Hence, the need for further studies to re-assess the anti-haemolytic effect of L-glutamine alone or in synergistic combination with other mitigators of oxidative stress such as N-Acetylcysteine, L-Arginine, α-Lipoic Acid or Acetyl-L-Carnitine.[37]
Extravascular steady state haemolysis: Eryptosis-triggered erythro-phagocytosis
Suicidal death of red cells (eryptosis) is another important factor in the pathogenesis of chronic extravascular haemolysis in patients with SCD.[38] Eryptosis is biochemically accomplished by a sequential cascade triggered by sickling-induced oxidative activation of caspases, followed by formation of prostaglandin-E2, activation of calcium cation channels, phospholipase-A2 mediated release of platelet-activating factor, activation of sphingomyelinase and synthesis of ceramide.[39] Eryptosis is morphologically characterized by cytoplasmic shrinkage, membrane blebbing, protease activation and exposure of membrane phosphotidylserine, which is recognized by macrophages leading to erythro-phagocytosis of eryptotic red cells.[39] Therefore, eryptosis is an important aetiologic mechanism of extravascular haemolysis and anaemia in SCD.
We, therefore, surmise that red cell sickling is the pathophysiologic initiator of red cell injury leading to lipid auto-oxidation, appearance of senescent antigens and activation of eryptosis.[30],[31],[37],[38],[39] The success of hydroxyurea (epigenetic enhancer of HbF) in ameliorating steady state haemolysis[40],[41] is therefore related to the benefit of its 'anti-sickling effect' through which it prevents sickling-induced red cell injury, thereby mitigating auto-oxidation, appearance of senescence antigens, eryptosis and erythro-phagocytosis, thus reducing haemolysis and improving anaemia as clinically observed in treated patients.[40]
Steady state haemolysis: Intravascular
About one third of the steady state haemolysis in SCD is intravascular[30] and is attributable to dual effects of increased fragility of irreversibly sickled red cells and elevated XO activity as explained below.
Intravascular steady state haemolysis: Spontaneous lysis of fragile sickled red cells
One of the important drivers of steady state haemolysis in SCD is the spontaneous intravascular lysis of the most fragile and dense sub-population of the circulating irreversibly sickled red cells.[30],[42] On the basis of the markers of steady state intravascular haemolysis vis-à -vis the frequency of VOC, the clinical phenotypes SCD patients can be broadly classified as hyperhaemolytic phenotype (HHP) or viscosity-vaso-occlusive phenotype (VVOP). Patients with VVOP have lower haemolytic rate, less severe anaemia, higher blood viscosity and frequent VOC.[43],[44] In contradistinction, patients with HHP have higher haemolytic rate as a result of which they have severe anaemia with florid markers of intravascular haemolysis, which include higher plasma haemoglobin, lower total haemoglobin, higher erythrocyte micro-particles, higher serum bilirubin, higher reticulocyte count, higher lactate dehydrogenase levels, raised alanine aminotransferase levels, increased urine haemosiderin concentration and elevated level of cell-free haemoglobin.[43],[44] Cell-free haemoglobin quenches and depletes nitric oxide in the circulation, thereby causing widespread vasculopathic changes that lead to the development of several HHP-associated sub-phenotypes, which include pulmonary hypertension, cerebro-vascular disease, peri-malleolar leg ulcers, ischaemic priapism and sickle cell nephropathy.[43],[44] Hydroxyurea raises HbF and makes SCD red cells 'resistant' to sickling and haemolysis.[41] Hence, hydroxyurea can effectively mitigate chronic hyperhaemolysis and ameliorate HHP-associated anaemia, and if started early, it can down-regulate production of cell-free Hb, raise nitric oxide levels and prevent the development of HHP-associated vasculopathic organ dysfunction such as pulmonary hypertension, cerebro-vascular disease, peri-malleolar leg ulcers, ischemic priapism and sickle cell nephropathy.[40],[42],[45] Of course, hydroxyurea will also attenuate the frequency of VOC if given to SCD patients with VVOP.[40],[41],[45] Thus hydroxyurea is a therapeutically useful ameliorator of SCD severity in patients with any of the two clinical phenotypes (HHP or VVOP).
Intravascular steady state haemolysis: Xanthine oxidase (XO)-mediated lysis of sickled cells
Chronic haemolysis in SCD is associated with a commensurate increase in erythroid hyperplasia and high cell turnover in the bone marrow. The DNA derived from high erythroid turnover and discarded nuclei of erythroid precursors is degraded by marrow histiocytes and metabolized to produce uric acid, leading to hyperuricemia.[46] Radioisotope studies using carbon-14 labelled uric acid and glycine coupled with biochemical renal function tests have indicated that both overproduction of uric acid and diminished excretion of urate due to decreased nephron mass contribute to hyperuricemia in patients with SCD.[46] Consequently, studies have found a higher incidence of gout in patients with SCD as compared to the general population.[47],[48] Moreover, clinical indices such as older age, hyperuricemia, low haemoglobin concentration and poor renal function, which are more or less in keeping with HHP,[43],[44] have been identified as risk factors for gout in SCD patients among whom it usually presents as acute mono or oligo-articular joint pain.[47],[48] Hence, it may be difficult to distinguish 'gouty flare' from 'VOC' whenever SCD patients with pre-existing comorbid gout present with acute musculo-skeletal pain involving the joints. Both gouty flare and VOC may co-present in such patients, but if the two conditions present separately, they can be differentiated on the basis of careful clinical assessment coupled with estimation of leukocyte count, lactate dehydrogenase and uric acid levels.[48] Leukocyte count and lactate dehydrogenase level are usually elevated in VOC but not in gouty flare, while joint pain in the presence of hyperuricemia without elevation of leukocyte count and lactate dehydrogenase level would suggest a gouty flare rather than VOC.[48] Interestingly, previous studies had found that uric acid possesses some in vitro anti-sickling effect on sickled red cells, which led to the speculation that elevated serum uric acid might be beneficial in reducing haemolysis and the frequency of VOC in SCD patients with comorbid gout.[49] However, any beneficial reduction in rate of VOC in such patients would most likely be counter-balanced by frequent articular pains due to recurrent gouty flares.[48]
More recent studies on uric acid metabolism in SCD are focusing on the role of XO in the pathogenesis of intravascular haemolysis in SCD.[50] Like in other haemolytic anaemia, XO has been shown to be increased in SCD patients.[50],[51],[52] XO catalyzes the oxidation of hypoxanthine to uric acid, reduces oxygen to superoxide and hydrogen peroxide and generates other reactive oxygen species.[51],[52] Reactive oxygen species cause endothelial and tissue damage, diminish nitric oxide bioavailability[51],[52] and cause red cell membrane rigidity and fragility, resulting in further haemolysis in patients with various haemolytic disorders including SCD.[51],[53] Accordingly, a recent study had identified XO, which is usually elevated in many haemolytic diseases,[52] as a key driver of steady state intravascular haemolysis in SCD.[50] And it had been demonstrated in chimeric SCD mice that Febuxostat, an FDA-approved XO inhibitor for gout was able to decrease steady state haemolysis, improve haematologic parameters and ameliorate pulmonary vascular function.[50] The results of the aforementioned study suggested that XO inhibitors could be used alone or in combination with current SCD therapies to decrease haemolysis and improve haemolysis-associated pathologies of SCD patients with respect to anaemia, vasculopathy and multi-organ damage.[50] We thus reckon that XO inhibitors would be particularly useful for SCD patients with comorbid hyperuricemia and/or gout.
The hyperhaemolytic states
Steady state haemolysis is often aggravated to chronic or acute hyperhaemolysis by various acquired and/or inherited haemolytic comorbidities, which include G6PD deficiencies, hereditary spherocytosis, acute and chronic hypersplenic or hepatic sequestration, infective erythrocytotropism and erythrocytopathy, haemophagocytic syndrome, autoimmune haemolysis, post-transfusion alloimmune haemolysis and/or drug-induced haemolysis as described below.
Chronic and/or acute hyperhaemolysis: Comorbidity between SCD and G6PD deficiency or hereditary spherocytosis (HS)
G6PD deficiency and hereditary spherocytosis have been associated with aggravated chronic haemolysis in patients with SCD. G6PD deficiency is inherited as a X-linked recessive enzymopathy, which is prevalent in areas of the world where sickle cell gene is also prevalent.[54] SCD and G6PD deficiency exhibits similar geospatial epidemiology within malaria endemic zones because the prevalence of both conditions are selectively propagated by the anti-malarial protection provided by heterozygous inheritance of any of the two conditions (i.e. SCT and G6PD carrier); hence, coinheritance of SCD and G6PD deficiency is not uncommon.[54] It is noteworthy that G6PD deficient red cells are unduly susceptible to oxidative injury that may manifest as both intravascular or extravascular chronic haemolysis, which can be acutely aggravated by infection and/or exposure to oxidant drugs or chemicals.[54] Consequently, it has been observed that SCD patients who coinherited G6PD deficiency had lower steady state Hb concentrations and higher reticulocyte counts, which are suggestive of a chronic hyperhaemolytic state.[55],[56] Moreover, SCD patients with comorbid G6PD deficiency may also present with acute hyperhaemolysis in the presence of oxidant drugs, chemicals or acute infections.[56] These findings suggest that G6PD deficiency exacerbates the severity of haemolysis and worsens the degree of anaemia in SCD when the two diseases coexist.[55],[56] On the other hand, hereditary spherocytosis (HS) is an autosomal dominant or recessive membranopathy characterized by defective cytoskeletal structure of the red cell membrane.[57] Comorbid inheritance of HS is occasionally seen in children with SCD in whom it is associated with persistent splenomegaly, recurrent sequestration crisis and acute or chronic hyperhaemolysis, which can be successfully mitigated by splenectomy.[57],[58] However, splenectomy should only be considered as a last resort, because it may predispose patients to the risk of post-splenectomy infections, which must be pre-empted by peri-operative vaccinations coupled with post-operative chemoprophylaxis against locally endemic infections.[59] While prompt treatment of infections is paramount in extenuating acute and chronic hyperhaemolysis due to G6PD deficiency, it is important that caution should be exercised with respect to choice of drugs for treating infections such malaria (i.e., avoid oxidant anti-malarial drugs) in SCD patients with comorbid G6PD deficiency.[56] This is essential to prevent oxidant drug-induced acute hyperhaemolytic crisis, which in addition to causing unnecessary blood transfusion, may also cause severe haemoglobinuria and acute renal failure.[56] Because red cells of SCD patients with comorbid G6PD deficiency would be particularly susceptible to oxidative injury and haemolysis, there is need for clinical studies and trials on the potential anti-haemolytic benefits of mitigators of oxidative stress such as L-glutamine, N-Acetylcysteine, L-Arginine, α-Lipoic Acid or Acetyl-L-Carnitine among such 'oxidation-susceptible' category of SCD patients.[37]
Spleen in SCD: Splenomegaly, sequestration and haemolysis
The spleen provides a myriad of haematological and immunological functions, which include haematopoiesis during intrauterine life; compensatory haematopoiesis in adults as seen in myeloproliferative disorders; red blood cells remodelling and maturation; destruction of old and abnormal red blood cells; removal and filtration of particles, including red blood cell inclusions; antibody production, opsonization, phagocytosis and cell-mediated immune response; removal of particulate pathogens, antigens and immune complexes; and storage of platelets, iron and factor VIII.[60] Unfortunately, one of the many organs that are usually affected by SCD is the spleen. The spleen is commonly enlarged during the first decade of life, but it subsequently undergoes progressive atrophy due to repeated attacks of vaso-occlusive infarctions that shrinks it into a small compacted structure, which is histologically described as a sidero-fibrotic nodule.[61] This pathological condition, which is ultrasonographically demonstrable, is clinically referred to as autosplenectomy.[62],[63] However, in patients with mild types of SCD (such as HbSC, HbSβ-thalassemia, HbSS with high HbF or α-thalassemia trait), splenomegaly may persist into older age and adult life.[64],[65] Persistent splenomegaly in SCD can manifest as 'acute splenic enlargement with acute sequestration crisis'[66] or 'chronic splenomegaly with hypersplenism, chronic sequestration, and hyperhaemolysis'.[64] Moreover, the 'hepatic equivalent' of splenic sequestration crisis, which is referred to as 'hepatic sequestration crisis' may also occur as a rare but serious complication of SCD.[67] All acutely or chronically sequestered red cells are ultimately haemolyzed (i.e., phagocytosed by macrophages) within the enlarged organ (spleen or liver). However, unlike in chronic hypersplenism, both acute splenic and hepatic sequestration crises can be further complicated by unpredictable and potentially dangerous phenomenon of 'reversal of sequestration'.[63],[68] as explained below.
SCD with acute splenic or hepatic sequestration: With or without reversal of sequestration
Acute splenic sequestration crisis (ASSC) is one of the earliest life-threatening complications seen in patients with SCD, with the first occurrence described as early as 5 weeks of age[69] and a median age at first episode of 1-4 years.[66] While 75% of first cases of ASSC occur before the age of 2 years,[66] ASSC is rarely observed after 6 years, except in patients with high HbF levels or in those on regular blood transfusion.[70] ASSC is defined as an acute splenic enlargement with a concomitant fall in the haemoglobin concentration of at least 20 g/l from baseline level and a normal or increased basal reticulocyte count.[71] It occurs when red cells are acutely trapped in the splenic vasculature resulting in abdominal pain and distension, pallor and haemodynamic symptoms of tachycardia, hypotension and lethargy.[63] Severe episodes may lead to hypovolemic shock and death from cardiovascular collapse within just a few hours.[63] The precise sequence of pathogenetic events leading to ASSC is not fully understood, but it may be precipitated by fever or infection that may trigger or amplify red cell sickling in the splenic red pulp.[63] Accumulation of sickled red cells that lie in a zone close to a draining vein are thought cause mechanical obstruction of venous blood flow, which causes intra-splenic stasis, congestion and hypoxia, leading to amplification and extension of sickling.[63] This acute event may be self-limited and transient or persistent, leading to extensive irreversible infarction (causing tender splenomegaly), massive sequestration and eventual haemolysis of red cells (causing severe anaemia) and reduction of circulation blood volume (causing hypovolemic shock).[63]
In similarity with ASSC, acute hepatic sequestration crisis (AHSC) may also occur in the hepatic vasculature, leading to tender hepatomegaly, severe anaemia, hypovolemic shock and deep jaundice with raised hepatic enzyme levels.[67] Both ASSC and AHSC are medical emergencies that require immediate restoration of Hb levels and blood volume by whole blood or red cell concentrates with intravenous fluids as well as treating any associated triggering infection.[63] The trapped sickled red cells in ASSC and AHSC are invariably haemolyzed by splenic and hepatic macrophages, which leads to gradual reduction in the size of the organomegaly. However, sometimes blood transfusion inadvertently triggers the 'release' of a significant proportion of the sequestered but un-haemolyzed red cells resulting in higher than expected post-transfusion haematocrit.[63] This situation is referred to as 'reversal of sequestration', which can occur in both ASSC and AHSC.[63],[68] Reversal of sequestration typically manifests as a rapid rise of haemoglobin concentration that is unrelated to blood transfusion, or a higher than expected post-transfusion rise in haemoglobin, followed by hypertension, congestive cardiac failure, and/or intra-cerebral haemorrhage.[63],[68] Reversal of sequestration is a clinical emergency that may necessitate urgent phlebotomy in order to bring down the haematocrit, alleviate blood viscosity and reduce blood pressure.
Recurrent episodes of ASSC are very life-threatening and must be mitigated by chronic transfusion or splenectomy as a last resort.[63],[72] The use of splenectomy is controversial, as it may predispose patients to post-splenectomy infections, which must be prevented by peri-operative vaccinations coupled with post-operative chemoprophylaxis.[59] However, a Cochrane review found no evidence in favour of splenectomy vis-à -vis conservative management in improving survival of SCD patients with recurrent ASSC, which calls for randomized studies in order to define the best management strategy.[73]
SCD with chronic splenomegaly: Hypersplenism, chronic sequestration and hyperhaemolysis
Chronic hypersplenism is defined as a chronic condition characterized by persistent splenomegaly in association with anaemia, leucopenia and/or thrombocytopenia, occurring either singly or in combination.[63],[72] These cytopenias occur as a result of pooling of blood in the vasculature of the enlarged spleen with a resultant hyperhaemolysis and simultaneous destruction of other blood cells.[63],[72] In patients with SCD and chronic hypersplenism, the extent of hyperhaemolysis and anaemia is judged by the trend in transfusion requirements; and surgical intervention is usually contemplated if transfusion requirement exceeds 250mL/kg of packed red cells per year and/or the fall in haemoglobin concentration exceeds 0.5 g/week.[72] Although the first line of therapy for hypersplenism often includes an increasing number of blood transfusions,[63],[72] the long-term benefits of blood transfusion have to be weighed against the attendant risks of alloimmunization and transmission of blood-borne infections, hence the need to consider splenectomy.[63],[72] As in the case of recurrent ASSC, splenectomy for chronic hypersplenism should only be considered as a last resort due to the high risk of post-splenectomy infection, which should be pre-empted by ensuring optimum peri-operative vaccinations with complementary post-operative chemoprophylaxis.[59] Moreover, in order to obviate the risks of total splenectomy, it can be substituted with 'less radical interventions' such as partial splenectomy, embolization or per-cutaneous intra-luminal occlusion of the splenic artery.[63],[72]
SCD with alloimmune anti-red cell antibodies: Delayed haemolytic transfusion reaction and hyperhaemolytic syndrome
One of the most serious haemolytic complications of blood transfusion in SCD is post-transfusion hyperhaemolysis (PTH).[74],[75],[76] PTH can occur as a result of delayed haemolytic transfusion reaction (DHTR) or hyperhaemolytic syndrome (HHS).[74],[75],[76] Both DHTR and HHS have similarities and dissimilarities from at least four perspectives. First, both conditions manifest within a few days after transfusion.[74],[75],[76] Second, both conditions are mediated by anamnestic formation of alloantibodies against previously encountered antigens and are thus associated with a positive direct anti-globin test (DAT), complement activation, intravascular and extravascular haemolysis; however, while DHTR is associated with haemolysis of donor cells, HHS causes haemolysis of both donor and recipient red cells.[74],[75],[76] Third, both conditions present with clinical features of acute haemolytic reaction such as back, loin, abdominal and joint pain, weakness, haemoglobinuria, jaundice, fever and lower post-transfusion Hb concentration; however, DHTR is generally clinically less severe than HHS.[74],[75],[76] Fourth, DHTR does not show particular predilection for any particular group of patients, while the vast majority of the cases of HHS occur in patients with SCD and it occurs only rarely in patients with other haematological conditions such as anaemias of chronic disease and inflammation, thalassemia, chronic lymphocytic leukaemia, myelodysplastic syndromes and lymphomas.[74],[75],[76]
Despite the similarities between the two conditions, the pathophysiology of HHS is more complex than that of DHTR because antibodies may even be absent in some clinical subtypes of HHS as described below. On the basis of time frame of onset, HHS is clinically categorized as acute or delayed.[74],[75] The acute type of HHS usually occurs within 7 days after the last blood transfusion and is not associated alloantibodies against the transfused donor RBCs; hence, DAT is found to be negative in these cases.[74],[75] Delayed type of HHS is usually seen after more than 7 days post-transfusion, and it is classically linked to anamnestic formation of alloantibodies against a previously encountered antigens and is thus typically associated with a positive DAT.[74],[75] The haemolytic mechanism underlying acute type of HHS that occurs without detectable alloantibodies is poorly understood, but it is postulated that both donor and recipient red cells are destroyed by activated macrophages via antibody-independent mechanisms leading to contact lysis and erythro-phagocytosis.[75] Haemolysis in the delayed type of HHS is attributed to alloantibody-mediated mechanisms, which include complement activation, opsonization and erythro-phagocytosis of both donor and recipient red cells.[74],[75] While haemolysis of donor red cells is due to the direct effect of alloantibodies,[74],[75] haemolysis of autologous recipient red cells has been attributed to the so-called innocent bystander mechanism through which complements activated by alloantibodies against antigens on donor cells lead to a collateral (i.e. off-target) haemolysis of contiguous autologous recipient red cells.[74],[75] Moreover, the anaemia of HHS is often exacerbated by reticulocytopenia, which is attributed to hyperactivity of macrophages that phagocytose erythroid precursors within the bone marrow[74] and/or excessive intravascular haemolysis of patient reticulocytes outside the bone marrow.[75]
It is difficult to prevent the occurrence of DHTR and HHS, since the offending antibodies are usually not detectable in patient serum at the time of pre-transfusion cross-match procedures.[74],[75],[76] Nonetheless, the occurrence of both conditions (DHTR and HHS) can be mitigated by pre-transfusion extended red cell phenotyping and matching of donor and recipient red cells[74],[75],[76]; this serological procedure is unfortunately expensive and unavailable in many tropical developing countries where the vast majority SCD patients live.[77] Once, DHTR or HHS is established, impulsive transfusion of red cells is not advisable as it may exacerbate haemolysis and worsen anaemia.[74],[75],[76] Hence, it is paramount that the culprit alloantibodies should be urgently identified in all cases of DHTR and HSS in order to avoid further transfusion of the culprit antigens. In cases of life-threatening anaemia, antigenically-matched donor red cells that lack the culprit antigens can be judiciously transfused.[74],[75],[76] In addition, a range of complimentary non-transfusional therapeutic modalities is available for managing DHTR and HHS. These therapeutic modalities include the removal of culprit antibodies (e.g., therapeutic plasma exchange), the use of immunosuppressants to mitigate production of culprit antibodies (e.g., intravenous immunoglobulin, steroids, rituximab/anti-CD20 monoclonal antibody) and/or the use of anti-complement monoclonal antibodies to mitigate complement activation (e.g., eculizumab), while patients with reticulocytopenia should also be given erythropoietin to stimulate red cell production and hasten recovery from anaemia.[74],[75],[76] Moreover, it is important to ensure that future transfusions for patients with previous diagnosis of DHTR or HHS should only be done with properly phenotyped red cells that lack the culprit antigens responsible for the previous episodes of DHTR or HHS.
SCD with autoimmune anti-red cell antibodies: Idiopathic or secondary to transfusion, drugs or infections
Because SCD is associated with immunosuppression, infections and inflammations occur more frequently in patients with SCD as compared to the general populations.[78] The literature suggests a modulatory role of infections and inflammation on the immune system within the concept of the so-called second hit hypothesis in the cascade of events leading up to the development of autoimmune diseases (AID).[79] Accordingly, a study had demonstrated a higher prevalence of a myriad of AIDs with multi-organ affectations in adult patients with SCD as compared to previously reported prevalence of AID in the general population.[80] That was interpreted to be the consequence of autoimmunity-inducing effects of chronic inflammation[81],[82] on the immune system of patients with SCD.[80] Moreover, it has been suggested that patients with SCD could be at increased risk of AID resulting from decreased self-tolerance due to defective splenic function and multiple transfusion-associated chronic immune stimulation.[83]
Like other transfusion-dependent hereditary anaemias, SCD increases the risk of developing red cell autoantibodies (RCAAs) and autoimmune haemolytic anaemia (AIHA).[84] The pathophysiology underlying development of RCAAs and AIHA in SCD and other transfusion-dependent congenital anemias includes exposure to blood-associated foreign antigens, infection-induced molecular mimicry, release of hidden neo-antigenic epitopes during hemolytic episodes and liberation of free haem, which is involved in post-translational diversification of circulating antibodies, thus increasing the risk of autoimmune reactions.[84] It is therefore not surprising that there are several cases of DAT-positive AIHA complicating SCD.[84],[85],[86],[87],[88] While the majority of cases of AIHA in SCD were apparently idiopathic,[84],[85],[86] other cases were drug-induced by commonly used cephalosporin antibiotics such as Cefotetan and Ceftriaxone.[87],[88] It is also noteworthy that Mycoplasma pneumoniae, which is one of the most important atypical bacterial causes of respiratory tract infection and acute chest syndrome in patients with SCD[89] is sometimes associated with the development of complement fixing IgM anti-I cold reacting red cell auto-antibodies that can cause hyperhaemolysis in the colder peripheral parts of the body.[90] In rare cases, mycoplasma infection may also be associated with warm IgG red cell auto-antibodies that can initiate hyperhaemolysis at core body temperature of 37°C.[91] It is thus imperative that caregivers for SCD patients should screen all cases of hyperhaemolysis in SCD by using DAT for early diagnosis of autoimmune-mediated hyperhaemolysis in order to initiate early immune modulation therapy,[84],[85],[86],[87],[88] withdraw any offending medication if autoimmune haemolysis is drug-induced,[87],[88] and/or administer macrolide antibiotics to treat patients with mycoplasma-induced autoimmune haemolysis.[89],[90],[91],[92]
SCD with red cell-invading infections: Erythrocytotropism and erythrocytopathy
Because SCD causes immuno-suppression, various infections have been associated with hyperhaemolysis in patients with SCD.[93] However, red cell invasive infections are particularly notorious for causing hyperhaemolysis in SCD.[93] Such infections are caused by pathogens that have special predilections for red cells (i.e., erythrocytotropism) within which they proliferate and disrupt cellular architecture (i.e., erythrocytopathy), leading to direct lysis and/or excessive erythro-phagocytosis of the infected red cells, which ultimately lead to an acute hyperhaemolytic state. There are at least three prototypes of erythrocytotropic infections (Malaria, Babesiosis, Bartonellosis) that have been associated with classical erythrocytopathy-associated acute hyperhaemolytic crisis in SCD as described below.
Malaria and hyperhaemolysis in SCD
Malaria is endemic in many tropical countries,[94] wherein SCD is most prevalent.[95] Five mosquito transmissible Plasmodium species: P. falciparum, P. vivax, P. malariae, P. ovale and P. knowlesi, have been associated with human infections, with the first two being the most important species.[94] SCD patients in tropical countries are at double risk of acquiring malaria via mosquito bites and via blood transfusions because a significant proportion of tropical blood donors have asymptomatic malaria infections.[96],[97] Interestingly, a recent study has demonstrated that in comparison with blood donors with SCT (i.e. HbAS), donors with HbAA phenotype were associated with higher risk of asymptomatic malarial parasitemia, which implied that HbAA blood carries higher risk of transfusion transmitted malaria (TTM).[98],[99] Therefore, patients who are selectively transfused with HbAA blood, such as SCD patients, could be at greater risks of acquiring TTM.[98],[99]
In addition to having special tropism for hepatocytes during the hepatic phase of its lifecycle, the malaria parasites are also both erythrocytotropic and erythrocytopathic, hence the parasites invade and replicate within the patients red cells during the erythrocytic phase of their life cycles.[100] Consequently, malaria is strongly associated with anaemia even in immune competent non-SCD patients.[101] It is, therefore, conceivable that malaria is an important aetiological factor in the pathogenesis of acute hyperhaemolytic crisis and severe anaemia in immuno-suppressed patients including those with SCD.[102],[103] Hence, it is essential to mitigate the risk of malaria-associated hyperhaemolysis by providing prompt treatment for acute malaria and continuous lifelong anti-malarial chemoprophylaxis in the standard of care for managing SCD in malaria endemic countries.[104] Long-term protection can also be achieved by barrier protection against mosquito vectors at home, and serological screening and deferral of malaria infected prospective blood donors at donation centres.[105] However, malaria vaccine remains the ultimate strategy for sustainable and cost-effective control measure against malaria in tropical countries. Unfortunately, the RTS, S/AS01 vaccine had shown only modest efficacy in preventing symptomatic P. falciparum malaria.[106] Despite its modest efficacy, the RTS, S/AS01 vaccine can be adopted as another addition to the existing list of malaria control strategies, but it should not be considered as an independent malaria prevention tool.[106] Accordingly, in 2021, the RTS, S/AS01 vaccine was endorsed by the WHO for use in children in conjunction with other malaria control strategies such as the use of insecticide-treated nets and environmental vector control.[107] Therefore, SCD patients living in P. falciparum endemic countries should be encouraged to receive the RTS, S/AS01 vaccine. The vaccine is a non-live recombinant protein-based vaccine,[107] hence it can be given to all SCD patients including those with pre-existing HIV infections.
Babesiosis and hyperhaemolysis in SCD
Babesiosis is a zoonotic tick-borne malaria-like febrile illness caused species of the intra-erythrocytic protozoan parasite called Babesia, which is requires a biological stage in rodents or deers.[108] Babesiosis is particularly common in mid-western and north-eastern Unites States, but is also seen sporadically throughout the world in parts of Europe, Asia and Africa.[108] The four identified Babesia species that cause infection in humans are B. microti, B. divergens, B. duncani and B. venatorum.[108] However, the life cycle of all four species within humans remain essentially the same.[108] Babesia parasites are intracellular obligate parasites that target the red blood cells.[108] Besides its natural route of transmission via the infected tick vector bites, the parasite is also transmissible by transfusion via the red blood cells of infected donors.[109] Immuno-compromised persons, especially those with splenectomy or hyposplenism, such as SCD patients, are at increased risk of babesiosis.[109] Like malaria parasites, Babesia parasites are both erythrocytotropic and erythrocytopathic; hence, the parasites invade and replicate within the patients red cells.[108] Consequently, babesiosis is an important cause of morbidity and haemolytic anaemia even in non-SCD patients.[108] Thus, patients with SCD living in areas that are endemic for babesiosis are at high risk of infection and hyperhaemolysis due to the combined effects of auto-splenectomy, immune suppression and recurrent transfusion.[109],[110],[111],[112] Nonetheless, it is possible to minimize the risk of babesiosis-associated hyperhaemolysis by providing prompt diagnosis and standard anti-babesia chemotherapy for patients with SCD.[108] Long-term prevention strategy is achievable through personal barrier protection against tick vectors coupled with environmental vector control programmes,[108] while molecular donor screening methods for babesiosis is currently being evaluated for detection and deferral of infected donors within endemic areas.[113] Unlike malaria, an effective vaccine has not yet been developed against babesiosis, but there are potential candidate vaccines in pre-clinical stages of development that will hopefully be available for clinical use in the near future.[114]
Bartonellosis and hyperhaemolysis in SCD
Three zoonotic species of Bartonella (B. henselae, B. quintana and B. bacilliformis) are known to be responsible for the vast majority of human infections.[115] While the infection caused by B. henselae has a worldwide distribution, B. quintana and B. bacilliformis cases are more geographically restricted infection: B. quintana in Europe and USA, and B. bacilliformis in Peru, Ecuador and Colombia.[115] Bartonella spp are intracellular fastidious Gram-negative bacteria that cause a wide range febrile illnesses in both immuno-competent and immuno-suppressed persons, with the later being more severely affected.[115] Bartonella spp are spread from animals to humans by fleas, lice, sand flies or contact with flea-infested animals such as cats.[115] In addition to having special tropism for endothelial cells, Bartonella spp are also erythrocytotropic and erythrocytopathic.[115] The biological ability of Bartonella spp to invade and destroy human red cells is of double clinical significance. First, Bartonella spp can be transmitted from a asymptomatic blood donors to blood recipients.[116] Second, Bartonella spp can cause significant haemolysis in persons with symptomatic infections.[117],[118] Consequently, bartonellosis is an important cause of haemolytic anaemia even in non-SCD patients.[117],[118] Thus, patients with SCD living in areas that are endemic for bartonellosis are at high risk of infection due to the effects of auto-splenectomy, immunosuppression and recurrent transfusion.[111],[118] Several cases of bartonellosis had been reported in SCD patients in whom the infection often run severe course, cause hyperhaemolytic crisis, aggravate anaemia and eventually increase the risk of blood transfusion.[119],[120],[121] It is therefore important for clinicians to raise their clinic indices of suspicion and investigate all cases of fever in SCD patients living in bartonellosis endemic areas in order to proffer early diagnosis[122] and initiate appropriate antibiotic therapy,[123] so as to avert the risk of hyperhaemolytic crisis. Long-term prevention strategy is achievable through personal barrier protection against vectors coupled with environmental vector control programmes,[115] while serological screening and deferral of asymptomatic infected blood donors should be enshrined in the national transfusion services of endemic countries.[116],[122] An effective vaccine has not yet been developed against bartonellosis, but there are promising candidate vaccines that are in early stages of development.[124]
SCD with haemophagocytosis-triggering infections: Haemophagocytic syndrome and intra-medullary haemolysis
Haemophagocytic lympho-histiocytosis (HLH), which manifests as haemophagocytic syndrome, is characterized by fever, hyper-inflammation, multi-organ dysfunction, hepato-splenomegaly, hyper-ferritinemia, hyper-triglyceridemia, excessive intra-medullary haemophagocytic destruction of erythroid, myeloid and megakaryocytic haematopoietic precursors in the bone marrow and life-threatening peripheral pancytopenia.[125],[126] HLH can be primary (inherited) or secondary. Primary HLH is generally seen in infancy and is associated with mutations that affect cytotoxic T-cell or inflammasome receptor functions.[127],[128] Secondary HLH is more common in older children and adults and is often triggered by infections, haematologic malignancies, autoimmune disorders or drugs.[129] The most common form of secondary HLH is infection-associated HLH.[130],[131] The spectrum of infectious triggers of HLH includes a wide range of bacteria, viruses, parasites and fungi infections,[130],[131] which are not uncommon in patients with SCD.[78]
However, even non-infectious causes such as VOC[132] and blood transfusion[133] were reported to have triggered HLH in patients with SCD, while the majority of cases of HLH that were reported among SCD patients in the literature were triggered by infections due a myriad of pathogens such as unspecified periodontal bacteria,[134] Epstein-Barr virus,[135] Cytomegalovirus,[135] Parvovirus-B19,[136] Histoplasma spp[137] and atypical mycobacteria.[138] The afore-cited literature suggests that infections, VOC and transfusion are important risk factors for HLH in SCD.[132],[133],[134],[135],[136],[137],[138] Once, the diagnosis of HLH is made, treatment becomes urgent. Previously reported cases of HLH in SCD in the literature[132],[133],[134],[135],[136],[137],[138] were essentially managed with a variable combination of antimicrobials, supportive transfusion, immune modulation therapy with corticosteroids, immunoglobulin, etoposide and/or interleukin-1 receptor antagonists in accordance with standard therapeutic guidelines.[126] Nonetheless, systemic corticosteroids must always be used judiciously in patients with SCD because of the potential risk of steroid-induced VOC.[139] Healthcare providers for patients with SCD should apply high index of suspicion for HLH in patients who present with fever, pancytopenia and/or multi-organ dysfunction. Such patients should be evaluated vis-à -vis standard diagnostic criteria for early diagnosis and prompt initiation of concurrent transfusion therapy, anti-microbial chemotherapy and immune modulation therapy.[126],[140] Since any infection is a potential trigger of HLH, the risk of HLH in SCD should be mitigated by ensuring that SCD patients are optimally immunized against all locally prevalent 'vaccine-preventable' diseases, while the application of chemoprophylaxis in combination with good personal and environmental hygiene should be an important defence against infectious diseases for which vaccines are not currently available.
| Conclusion and Recommendations | | |
The most important driver of vasculopathic organ damage in SCD is chronic steady state haemolysis, which can be aggravated to hyperhaemolysis by inherited and/or acquired comorbidities. Thus, managing SCD haemolysis should be two-fold. On short-term, transfuse patients to correct anaemia, administer antimicrobials for infection-triggered hyperhaemolysis, but withhold offending drugs in case of drug-induced hyperhaemolysis. On long-term, mitigate sickling and haemolysis by using HbF enhancers, HbS oxygen affinity modifiers, xanthine oxidase inhibitors, immune modulators for immune-haemolysis, use of anti-oxidants to minimize peroxidation, avoidance of oxidant exposure if patient is also G6PD deficient, administering vaccinations to prevent infections, considering splenectomy for hereditary spherocytosis or any recalcitrant hypersplenic splenomegaly. Controlling haemolysis is the most important measure for alleviating anaemia, mitigating transfusion and preventing vasculopathic multi-organ damage in SCD.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Flint J, Harding RM, Boyce AJ, Clegg JB. The population genetics of the haemoglobinopathies. Baillieres Clin Haematol 1993;6:215-62.  |
| 2. | Kaul DK, Fabry ME, Nagel RL. The pathophysiology of vascular obstruction in the sickle syndromes. Blood Rev 1996;10:29-44. |
| 3. | Fleming AF, Storey J, Molineaux L, Iroko EA, Attai ED. Abnormal haemoglobins in the Sudan savanna of Nigeria. I. Prevalence of haemoglobins and relationships between sickle cell trait, malaria and survival. Ann Trop Med Parasitol 1979;73:161-72. |
| 4. | Elguero E, Délicat-Loembet LM, Rougeron V, Arnathau C, Roche B, Becquart P, et al. Malaria continues to select for sickle cell trait in Central Africa. Proc Natl Acad Sci 2015;112:7051-4. |
| 5. | Olatunji PO. Malaria and the sickle gene: Polymorphism balanced in favour of eradication. Ann Health Res 2018;4:88-96. |
| 6. | Gong L, Parikh S, Rosenthal PJ, Greenhouse B. Biochemical and immunological mechanisms by which sickle cell trait protects against malaria. Malar J 2013;12:317-7. |
| 7. | Loggetto SR. Sickle cell anemia: Clinical diversity and beta S-globin haplotypes. Rev Bras Hematol Hemoter 2013;35:155-7. |
| 8. | Ahmed SG, Ibrahim UA. Haemoglobin-S in sickle cell trait with papillary necrosis. Br J Haematol 2006;135:415-6. |
| 9. | Barbedo MM, McCurdy PR. Red cell life span in sickle cell trait. Acta Haematol 1974;51:339-43. |
| 10. | Fernando C, Mendis S, Upasena AP, Costa YJ, Williams HS, Moratuwagama D. Splenic syndrome in a young man at high altitude with undetected sickle cell trait. J Patient Exp 2018;5:153-5. |
| 11. | Kasi PM, Patnaik MM, Peethambaram PP. Safety of pegfilgrastim (neulasta) in patients with sickle cell trait/anemia. Case Rep Hematol 2013;2013:146938. doi: 10.1155/2013/146938. |
| 12. | Ahmed SG, Ibrahim UA. A compendium of pathophysiologic basis of etiologic risk factors for painful vaso-occlusive crisis in sickle cell disease. Niger J Basic Clin Sci 2017;14:57-77. [Full text] |
| 13. | Goodman SR. The role of the membrane skeleton in formation of the irreversibly sickled cell: A review. Cell Mol Biol Lett 1996;1:105-17. |
| 14. | McCurdy PR, Sherman AS. Irreversibly sickled cells and red cell survival in sickle cell anemia: A study with both DF32P and 51CR. Am J Med 1978;64:253-8. |
| 15. | Hillman RS, Finch CAErythropoiesis: Normal and abnormal. Semin Hematol 1967;4:327-36. |
| 16. | Youssef LA, Spitalnik SL. Transfusion-related immunomodulation: A reappraisal. Curr Opin Hematol 2017;24:551-7. |
| 17. | Martins R, Maier J, Gorki AD, Huber KV, Sharif O, Starki P, et al. Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions. Nat Immunol 2016;17:1361-72. |
| 18. | Taylor JG, Nolan VG, Mendelsohn L, Kato GJ, Gladwin MT. Chronic hyper-hemolysis in sickle cell anemia: Association of vascular complications and mortality with less frequent vaso-occlusive pain. PLoS One 2008;3:e2095. doi: 10.1371/journal.pone.0002095. |
| 19. | Akinola NO, Stevens SME, Franklin IM, Nash GV, Stuart J. Subclinical ischaemic episodes during the steady state of sickle cell anaemia. J Clin Pathol 1992;45:902-6. |
| 20. | Safo MK, Kato GJ. Therapeutic strategies to alter the oxygen affinity of sickle hemoglobin. Hematol Oncol Clin North Am 2014;28:217-31. |
| 21. | Abdu A, Gómez-Márquez J, Aldrich TK. The oxygen affinity of sickle hemoglobin. Respir Physiol Neurobiol 2008;161:92-4. |
| 22. | Seakins M, Gibbs WN, Milner PF, Bertles JF. Erythrocyte Hb-S concentration. An important factor in the low oxygen affinity of blood in sickle cell anemia. J Clin Invest 1973;52:422-32. |
| 23. | Charache S, Grisolia S, Fiedler AJ, Hellegers AE. Effect of 2,3-diphosphoglycerate on oxygen affinity of blood in sickle cell anemia. J Clin Invest 1970;49:806-12. |
| 24. | Rab MAE, Bos J, van Oirschot BA. Decreased activity and stability of pyruvate kinase in sickle cell disease: A novel target for Mitapivat therapy. Blood 2021;137:2997-3001. |
| 25. | Anastasiou D, PoulogiannisG, Asara JM, Boxer MB, Jiang JK, Shen M, et al. Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science 2011;334:1278-83. |
| 26. | Petto J, de Jesus JB, Vasques LM, Pinheiro RL, Oliveira AM, Spinola KA, et al. Resting blood lactate in individual with sickle cell disease. Rev Hematol Hemoter 2011;33:26-30. |
| 27. | Boning D, Hollnagel C, Boecker A, Goke S. Bohr shift by lactic acid and the supply of O 2 to skeletal muscle. Respir Physiol 1991;85:231-43. |
| 28. | Glaros AK, Razvi R, Shah N, Zaidi AU. Voxelotor: Alteration of sickle cell disease pathophysiology by a first-in-class polymerization inhibitor. Ther Adv Hematol 2021;12:1-16. doi: 10.1177/20406207211001136. |
| 29. | Grace RF, Rose C, Layton DM, Galacteros F, Barcellini W, Morton DH, et al. Safety and efficacy of Mitapivat in pyruvate kinase deficiency. N Engl J Med 2019;381:933-44. |
| 30. | Hebbel RP, Miller WJ. Phagocytosis of sickle erythrocytes: Immunologic and oxidative determinants of hemolytic anemia. Blood 1984;64:733-41. |
| 31. | Cao H, Antonopoulos A, Henderson S, Wassall H, Brewin J, Masson A, et al. Red blood cell mannoses as phagocytic ligands mediating both sickle cell anaemia and malaria resistance. Nat Comm 2021;12:1792. |
| 32. | Sadaf A, Quinn CT. L-glutamine for sickle cell disease: Knight or pawn? Exp Biol Med 2020;245:146-54. |
| 33. | Niihara Y, Mh Eckman JR, Koh H, Cooper ML, Ziegler TR, Razon R, et al. L-Glutamine therapy reduces hospitalization for sickle cell anemia and sickle β-thalassemia patients at six months – a phase II randomized trial. Clin Pharmacol Biopharm 2014;3:116. |
| 34. | Niihara Y, Miller ST, Kanter J, Lanzkron S, Smith WR, Hsu LL, et al. A phase-3 trial of L-Glutamine in sickle cell disease. N Engl J Med 2018;379:226-35. |
| 35. | Niihara Y, Zerez CR, Akiyama DS, Tanaka KR. Oral L-glutamine therapy for sickle cell anemia: I. Subjective clinical improvement and favorable change in red cell NAD redox potential. Am J Hematol 1998;58:117-21. |
| 36. | Williams R, Olivi S, Li CS, Storm M, Cremer L, Mackert P, et al. Oral glutamine supplementation decreases resting energy expenditure in children and adolescents with sickle cell anemia. J Pediatr Hematol Oncol 2004;26:619-25. |
| 37. | Vona R, Sposi NM, Mattia L, Gambardella L, Straface E, Pietraforte D. Sickle cell disease: Role of oxidative stress and antioxidant therapy. Antioxidants 2021;10:296. doi: 10.3390/antiox10020296. |
| 38. | Moumni I, Khalfaoui K, Safra I, Chebbi M, Barmate M, chaouechi D, et al. Eryptosis and circulating blood cells microparticules in sickle cell diseases. Eur J Public Health 2020;30:ckaa166.1147. doi: 10.1093/europub/ckaa166.1147. |
| 39. | Lang E, Lang F. Triggers, inhibitors, mechanisms and significance of eryptosis: The suicidal erythrocyte death. BioMed Res Int 2015;2015:513518. doi: 10.1155/2015/513518. |
| 40. | Keikhaei B, Yousefi H, Bahadoram M. Hydroxyurea: Clinical and hematological effects in patients with sickle cell anemia. Glob J Health Sci 2015;8:252-6. |
| 41. | Platt OS, Orkin SH, Dover G, Beardsley GP, Miller B, Nathan DG. Hydroxyurea enhances fetal hemoglobin production in sickle cell anemia. J Clin Invest 1984;74:652-6. |
| 42. | Presley T, Bain L, Ballas S, Nichols J, Sabio H, Galdwin M, et al. The mechanism of hemolysis in sickle cell anaemia. Blood 2008;112:1439. doi: 10.1182/blood.V112.11.1439.1439. |
| 43. | Dubert M, Elion J, Tolo A, Diallo DA, Diop S, Diagne I, et al. Degree of anaemia, indirect markers of haemolysis, and vascular complications of sickle cell disease in Africa. Blood 2017;130:2215-23. |
| 44. | Kato GJ, Steinberg MH, Gladwin MT. Intravascular hemolysis and the pathophysiology of sickle cell disease. J Clin Invest 2017;127:750-60. |
| 45. | Wong TE, Brandow AM, Lim W, Lottenberg R. Update on the use of hydroxyurea therapy in sickle cell disease. Blood 2014;124:3850-7. DO |
| 46. | Ball GV, Sorensen LB. The pathogenesis of hyperuricemia and gout in sickle cell anemia. Arthritis Rheum 1970;13:846-8. |
| 47. | Akintayo R, Adelowo OO, Chijioke A, Olanrewaju T, Yerima A, Akpabio AA, et al. Gout is more frequent in sickle cell disease than in haemoglobin AA among sub-Saharan Africans. Afr J Rheumatol 2021;9:83-90. |
| 48. | Gupta S, Yui JC, Xu D, Fitzhugh CD, Clark C, Siddiqui S, et al. Gout and sickle cell disease: Not all pain is sickle cell pain. Br J Haematol 2015;171:872-5. |
| 49. | Ekeke GI, Nduka N. The anti-sickling role of uric acid in sickle cell disease. Trop Geogr Med 1987;39:152-6. |
| 50. | Schmidt HM, Wood KC, Lewis SE, Hahn SA, Williams XM, McMahon B, et al. Xanthine oxidase drives hemolysis and vascular malfunction in sickle cell disease. Arterioscler Thromb Vasc Biol 2021;41:769-82. |
| 51. | Aslan M, Ryan TM, Adler B, Townes TM, Parks DA, Thompson JA, et al. Oxygen radical inhibition of nitric oxide-dependent vascular function in sickle cell disease. Proc Natl Acad Sci 2001;98:15215-20. |
| 52. | Schmidt HM, Kelley EE, Straub AC. The impact of xanthine oxidase (XO) on hemolytic diseases. Redox Biol 2019;21:101072. doi: 10.1016/j.redox.2018.101072. |
| 53. | Diederich L, Suvorava T, Sansone R, Keller TCS, Barbarino F, Sutton TR, et al. On the effects of reactive oxygen species and nitric oxide on red blood cell deformability. Front Physiol 2018;9:332. doi: 10.3389/fphys. 2018.00332. |
| 54. | Howes RE, Piel FB, Patil AP, Nyangiri OA, Gething PW, Dewi M, et al. G6PD deficiency prevalence and estimates of affected populations in malaria endemic countries: A geostatistical model-based map. PLoS Med 2012;9:e1001339. doi: 10.1371/journal.pmed.1001339. |
| 55. | Ahmed SG, Ibrahim UA. Clinical significance of G6PD deficiency in Nigerian patients with sickle cell disease. Niger Postgrad Med J 2002;9:181-5. |
| 56. | Fasola FA, Fowodu FO, Shokunbi WA, Kotila TR. The effect of the coinheritance of glucose-6-phosphate dehydrogenase deficiency on the severity of sickle cell disease. Niger Postgrad Med J 2019;26:118-22. [ PUBMED] [Full text] |
| 57. | Selcut DN, Celkan T, Civilibal M, Ozbek NO, Elevli M. Coinheritance of sickle cell anaemia and hereditary spherocytosis. Pediatr Blood Cancer 2008;51:560-3. doi: 10.1002/pbc.21642. |
| 58. | Warkentin TE, Barr RD, Ah MAM, Mohandas N. Recurrent acute splenic sequestration crisis due to interacting genetic defects: Hemoglobin SC disease and hereditary spherocytosis. Blood 1990;75:266-70. |
| 59. | Sureshkumar S, Nachiappan DS, Anandhi A, Post-splenectomy prohylaxis-changes and challenges in the adherence to standard vaccination guidelines over ten years. Indian J Surg 2021;83:889-96. |
| 60. | Mebius R, Kraal G. Structure and function of the spleen. Nat Rev Immunol 2005;5:606-16. |
| 61. | Diggs LW. Siderofibrosis of the spleen in sickle cell anemia. JAMA 1930;104:538-41. |
| 62. | Babadoko AA, Ibinaye PO, Hassan A, Yusuf R, Ijei IP, Aiyekomogbon J, et al. Autosplenectomy of sickle cell disease in Zaria, Nigeria: An ultrasonographic assessment. Oman Med J 2012;27:121-3. |
| 63. | Brousse V, Buffet P, Rees D. The spleen and sickle cell disease: The sickled spleen. Br J Haematol 2014;166:165-76. |
| 64. | Asnani MR, Williams A, Reid M. Splenic enlargement in adults with homozygous sickle cell disease: The Jamaican experience. Hematology 2013;18:46-9. |
| 65. | Charlotte EE, Nicole AYA, Yolande DP, Line CK, Edgar MML, Foute FNN, et al. Factors associated with splenomegaly amongst patients with sickle cell disease in Cameroon. Open J Pediatr 2022;12:33-46. |
| 66. | Brousse V, Elie C, Benkerrou M, Odievre M, Lesprit E, Bernaudin F, et al. Acute splenic sequestration crisis in sickle cell disease: Cohort study of 190 paediatric patients. Br J Haematol 2012;156:643-8. |
| 67. | Bradford W, Fernando G, Laurence S. Acute hepatic sequestration crisis: A rare complication of sickle cell disease. Am J Gastroenterol 2010;105:5289-90. |
| 68. | Lee ESH, Patrick Chu PCM. Reverse sequestration in a case of sickle crisis. Postgrad Med J 1996;72:487-500. |
| 69. | Airede AI. Acute splenic sequestration in a five-week-old infant with sickle cell disease. J Pediatr 1992;120:160. doi: 10.1016/s0022-3476(05)80623-7. |
| 70. | Emond AM, Collis R, Darvill D, Higgs DR, Maude GH, Serjeant GR. Acute splenic sequestration in homozygous sickle cell disease: Natural history and management. J Pediatr 1985;107:201-6. |
| 71. | Topley JM, Rogers DW, Stevens MC, Serjeant GR. Acute splenic sequestration and hypersplenism in the first five years in homozygous sickle cell disease. Arch Dis Child 1981;56:765-9. |
| 72. | Al-Salem AH. The role of splenectomy in patients with sickle cell disease. Ann Saudi Med 1997;17:316-20. |
| 73. | Owusu-Ofori S, Hirst C. Splenectomy versus conservative management for acute sequestration crises in people with sickle cell disease. Cochrane Database Syst Rev 2013;5:CD003425. |
| 74. | Madu AJ, Ugwu AO, Efobi C. Hyperhaemolytic syndrome in sickle cell disease: Clearing the cobwebs. Med Princ Pract 2021;30:236-43. |
| 75. | Win N. Hyperhemolysis syndrome in sickle cell disease. Expert Rev Hematol 2009;2:111-5. |
| 76. | Pirenne F, Yazdanbakhsh K. How I safely transfuse patients with sickle cell disease and manage delayed hemolytic transfusion reactions. Blood 2018;131:2773-81. |
| 77. | Ahmed SG. Transfusion services in tropical Africa: Challenges and prospects from the Nigerian perspective. Niger J Haematol 2022;3:1-17. |
| 78. | Cannas G, Merazga S, Virot E. Sickle cell disease and infections in high and low income countries. Mediterr J Hematol Infect Dis 2019;11:e2019042. doi: 10.4084/MJHID.2019.042. |
| 79. | Ercolini AM, Miller SD. The role of infections in autoimmune disease. Clin Exp Immunol 2009;155:1-15. doi: 10.1111/j. 1365-2249.2008.03834.x. |
| 80. | Tang MW, Nur E, Van Tuijn CFJ, Biemond BJ. Higher prevalence of autoimmune diseases in patients with sickle cell disease. Blood 2021;138:982-4. |
| 81. | Sundd P, Ofori-Acquah SF. Sterile inflammation in sickle cell disease. In: Mark T, Gladwin MT, Kato GJ, Novelli EM, editors. Sickle Cell Disease. New York: McGraw Hill; 2021. |
| 82. | Conran N, Belcher JD. Inflammation in sickle cell disease. Clin Hemorheol Microcirc 2018;68:263-99. |
| 83. | Li-Thiao-Te V, Uettwiller F, Quartier P, Lacaille F, Bader-Meunier B, Brousse V, et al. Coexistent sickle cell anemia and autoimmune disease in eight children: Pitfalls and challenges. Pediatr Rheumatol 2018;16:5. doi: 10.1186/s12969-017-0221-x. |
| 84. | Motta I, Giannotta J, Ferraresi M, Barbullushi K, Revelli N, Graziadei G, et al. Autoimmune hemolytic anemia as a complication of congenital anemias. A case series and review of the literature. J Clin Med 2021;10:3439. doi: 10.3390/jcm10153439. |
| 85. | Chaplin H, Zarkowsky HS. Combined sickle cell disease and autoimmune hemolytic anemia. Arch Intern Med 1981;141:1091-3. |
| 86. | Comenzo RL, Malachowski ME, Berkman EM. Clinical correlation of positive direct anti-globulin tests in patients with sickle cell disease. Immunohematology 1992;8:13-6. |
| 87. | Marques MB, Carr KD, Brumfield CG, Huang ST. Pregnant patient with sickle cell disease and Cefotetan-induced immune hemolysis. Lab Med 2000;31:541-3. |
| 88. | Khurana M, Raj SS. Drug-induced hemolytic anemia: A fatal complication further under-recognized in sickle cell disease. Open J Blood Dis 2017;7:79-85. |
| 89. | Neumayr L, Lennette E, Kelly D, Earles A, Embury S, Groncy P, et al. Mycoplasma disease and acute chest syndrome in sickle cell disease. Pediatrics 2003;112:87-95. |
| 90. | Inaba H, Geiger TL, Lasater OE, Wang WC. A case of hemoglobin SC disease with cold agglutinin-induced hemolysis. Am J Hematol 2005;78:37-40. |
| 91. | Cassimos D, Bezirgiannidou Z, Pantelidou D, Christoforidis A, Chatzimichael A, Maritinis G. Warm autoimmune hemolytic anemia following recurrent mycoplasma pneumonia infections in a child with Down syndrome. Pediatr Hematol Oncol 2008;25:693-8. |
| 92. | Biondi E, McCulloh R, Alverson B, Klein A, Dixon A, Ralston S. Treatment of mycoplasma pneumonia: A systematic review. Pediatrics 2014;133:1081-90. |
| 93. | Ahmed SG, Ibrahim UA. A review of the role of infections in the aetiology of haemolysis in patients with sickle cell diseases: Pathogenesis, management, and prevention. Afr J Clin Exper Microbiol 2022;23:345-57. |
| 94. | Sato S. Plasmodium-A brief introduction to the parasites causing human malaria and their basic biology. J Physiol Anthropol 2021;40:1. doi: 10.1186/s40101-020-00251-9. |
| 95. | Odame, I. Developing a global agenda for sickle cell disease: Report of an international symposium and workshop in Cotonou, republic of Benin. Am J Prev Med 2010;38:S571-5. |
| 96. | Ezeonu CM, Adabara NU, Garba SA, Kuta F, Ewa E, Oloruntola PO, et al. The risk of transfusion transmitted malaria and the need for malaria screening of blood donors in Abuja, Nigeria. Afr J Clin Exper Microbiol 2019;20:195-201. |
| 97. | Ahmed SG, Ibrahim UA, Ibrahim G. Prevalence and clinical significance of malaria parasitemia in donor blood in Maiduguri, Nigeria. Niger J Parasitol 2001;22:29-34. |
| 98. | Kani KM, Ibrahim Z, Habeeb A, Ibrahim UA, Ahmed SG. Haemoglobin phenotypes and the risk of asymptomatic malaria parasitemia among blood donors in northwest Nigeria: Clinical implications in the practice of tropical transfusion medicine. Afr J Clin Exper Microbiol 2021;22:179-86. |
| 99. | Ahmed SG, Ibrahim UA. Merits and demerits of sickle cell trait donor blood in tropical transfusion medicine: Are there any indications for specific use of blood donated by carriers of sickle cell trait? Afr Sanguine 2021;23:49-59. |
| 100. | Venugopal K, Hentzschel F, Valkiūnas G, Marti M. Plasmodium asexual growth and sexual development in the haematopoietic niche of the host. Nat Rev Microbiol 2020;18:177-89. |
| 101. | Sumbele IUN, Sama SO, Kimbi HK, Taiwe GS. Malaria, moderate to severe anaemia, and malarial anaemia in children at presentation to hospital in the Mount Cameroon area: A cross-sectional study. Anemia 2016;2016:5725634. doi: 10.1155/2016/5725634. |
| 102. | Montgomery CP, Hoehn KS, Glikman D. Hyperhemolytic crisis caused by severe P. falciparum malaria in a boy with sickle cell anemia. Crit Care Med 2006;34:A164. doi: 10.1097/00003246-200612002-00569. |
| 103. | Juwah AI, Nlemadim EU, Kaine W. Types of anaemic crises in paediatric patients with sickle cell anaemia seen in Enugu, Nigeria. Arch Dis Child 2004;89:572-6. |
| 104. | Oniyangi O, Omari AA. Malaria chemoprophylaxis in sickle cell disease. Cochrane Database Syst Rev 2019;11. doi: 10.1002/14651858.CD3489.pub2. |
| 105. | Mangano VD, Perandin F, Tiberti N, Guerriero M, Migliaccio F, Prato M, et al. Risk of transfusion-transmitted malaria: Evaluation of commercial ELISA kits for the detection of anti-Plasmodium antibodies in candidate blood donors. Malar J 2019;18:17. |
| 106. | Arora NC, Anbalagan L, Pannu AK. Towards eradication of malaria: Is the WHO's RTS, S/AS01 vaccination effective enough? Risk Manag Health Policy 2021;14:1033-9. |
| 107. | |
| 108. | Ord RL, Lobo CA. Human babesiosis: Pathogens, prevalence, diagnosis, and treatment. Curr Clin Micro Rpt 2015;2:173-81. |
| 109. | Fang DC, McCullough J. Transfusion-transmitted Babesia microti. Transfus Med Rev 2016;30:132-8. |
| 110. | Krause PJ, Gewurz BE, Hill D, Marty FM, Vannier E, Foppa IM, et al. Persistent and relapsing babesiosis in immuno-compromised patients. Clin Infect Dis 2008;46:370-6. |
| 111. | Inah GB, Ekanem EE. Ultrasonographically determined autosplenectomy rates in Nigerian sicklers. IOSR J Dent Med Sci 2018;17:61-4. |
| 112. | Karkoska K, Louie J, Appiah-Kubi AO, Wolf L, Rubin L, Rajan S, et al. Transfusion-transmitted babesiosis leading to severe hemolysis in two patients with sickle cell anemia. Pediatr Blood Cancer 2018;65. |
| 113. | Tonnetti L, Young C, Kessler DA, Williamson PC, Reik R, Proctor MC, et al. Transcription-mediated amplification blood donation screening for Babesia. Transfusion 2020;60:317-25. |
| 114. | Al-Nazal HA, Cooper E, Ho MF, Eskandari S, Majam V, Giddam AK, et al. Pre-clinical evaluation of a whole-parasite vaccine to control human babesiosis. Cell Host Microbe 2021;29:894-903.e5. |
| 115. | Raoult D. Infections humaines à Bartonella [ Bartonella infection in humans]. Presse Med 1999;28:429-34. |
| 116. | Diniz PP, Velho PE, Pitassi LH, Drummond MR, Lania BG, Barjas-Castro ML, et al. Risk factors for Bartonella species infection in blood donors from southeast Brazil. PLoS Negl Trop Dis 2016;10:e0004509. doi: 10.1371/journal.pntd.0004509. |
| 117. | Hendrix LR. Contact-dependent hemolytic activity distinct from deforming activity of Bartonella bacilliformis. FEMS Microbiol Lett 2000;182:119-24. doi: 10.1111/j.1574-6968.2000.tb08884.x. |
| 118. | Orf K, Cunnington AJ. Infection-related hemolysis and susceptibility to Gram-negative bacterial co-infection. Front Microbiol 2015;6:666. doi: 10.3389/fmicb.2015.00666. |
| 119. | Velho PE, Ericson ME, Mair D, Gupta K. Sickle cell disease and bartonella spp. infection. Mediterr J Hematol Infect Dis 2012;4:e2012046. doi: 10.4084/MJHID.2012.046. |
| 120. | Schaiblich SB, Moreira SATM, Lacet DFR, Cupolilo SMN, Grunewald STF. Cat scratch disease in a child with sickle cell anemia. Residência Pediátrica 2016;6:145-8. |
| 121. | Soares TCB, Isaias GAB, Almeida AR, Drummond MR, da Silva MN, Lania BG et al. Prevalence of Bartonella spp. infection in patients with sickle cell disease. Vector Borne Zoonotic Dis 2020;20:509-12. doi: 10.1089/vbz.2019.2545. |
| 122. | Łysakowska ME, Brzezińska O, Szybka M, Konieczka M, Moskwa S, Brauncajs M, et al. The seroprevalence of Bartonella spp. in the blood of patients with musculoskeletal complaints and blood donors, Poland: A pilot study. Clin Rheumatol 2019;38:2691-8. |
| 123. | Prutsky G, Domecq JP, Mori L, Bebko S, Matzumura M, Sabouni A, et al. Treatment outcomes of human bartonellosis: A systematic review and meta-analysis. Int J Infect Dis 2013;17:e811-9. |
| 124. | Henriquez-Camacho C, Ventosilla P, Minnick MF, Ruiz J, Maguiña C. Proteins of Bartonella bacilliformis: Candidates for vaccine development. Int J Pept 2015;2015:702784. doi: 10.1155/2015/702784. |
| 125. | Janka GE, Lehmberg K. Hemophagocytic syndromes-an update. Blood Rev 2014;28:135-42. |
| 126. | Henter JI, Horne AC, Aricó M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH- 2004 Diagnostic and therapeutic guidelines for haemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007;48:124-31. |
| 127. | Schmid JP, Cote M, Menager MM, Burgess A, Nehme N, Menasche G, et al. Inherited defects in lymphocyte cytotoxic activity. Immunol Rev 2010;235:10-23. |
| 128. | Canna SW, de Jesus AA, Gouni S, Brooks SR, Marrero B, Liu Y, et al. An activating NLRC4 inflammasome mutation causes auto-inflammation with recurrent macrophage activation syndrome. Nat Genet 2014;46:1140-6. |
| 129. | Ramos-Casals M, Brito-Zeron P, Lopez-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet 2014;383:1503-16. |
| 130. | Maakaroun NR, Moanna A, Jacob JT, Albrecht H. Viral infections associated with haemophagocytic syndrome. Rev Med Virol 2010;20:93-105. |
| 131. | Rouphael NG, Talati NJ, Vaughan C, Cunningham K, Moreira R, Gould C. Infections associated with haemophagocytic syndrome. Lancet Infect Dis 2007;7:814-22. |
| 132. | Kio E, Onitilo A, Lazarchick J, Hanna M, Brunson C, Chaudhary U. Sickle cell crisis associated with hemophagocytic lymphohistiocytosis. Am J Hematol 2004;77:229-32. |
| 133. | Thung I, Broome HE. Hemophagocytosis in a patient with sickle cell disease. Blood 2016;127:369. doi: 10.1182/blood-2015-11-680082. |
| 134. | Shoman W, El Chazli Y, Elsharkawy A, Mikhael N, Deghaidy A, Al Battashi A, et al. Hemophagocytic lymphohistiocytosis in a child with sickle cell disease. Hematol Transfus Int J 2018;6:180-2. |
| 135. | Leiva O, McMahon L, Sloan JM, Lee J, Lerner A. Recognition of hemophagocytic lymphohistiocytosis in sickle cell vaso-occlusive crises is a potentially lifesaving diagnosis. Haematologica 2019;104:e167. doi: 10.3324/haematol.2018.206458. |
| 136. | Sahu S, Agrawal A, Das P. The dilemma of diagnosing haemophagocytic lymphohistiocytosis in sickle cell disease. Cureus 2020;12:e12255. doi: 10.7759/cureus.12255. |
| 137. | Kashif M, Tariq H, Ijaz M, Gomez-Marquez J. Disseminated histoplasmosis and secondary haemophagocytic syndrome in a non-HIV patient. Case Reports Crit Care 2015;2015:295735. doi: 10.1155/2015/295735. |
| 138. | Chamsi-Pasha MAR, Alraies MC, Alraiyes AH, His ED. Mycobacterium avium complex-associated hemophagocytic lymphohistiocytosis in a sickle cell patient: An unusual fatal association. Case Rep Hematol 2013;2013:291518. doi: 10.1155/2013/291518. |
| 139. | Darbari DS, Fasano RS, Minniti CP, Castro OO, Gordeuk VR, Taylor JG, et al. Severe vaso-occlusive episodes associated with use of systemic corticosteroids in patients with sickle cell disease. J Natl Med Assoc 2008;100:948-51. doi: 10.1016/S0027-9684(15)31410-3. |
| 140. | Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult patient. Blood 2015;125:2908-14. |
[Table 1]
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