Increased microerythrocyte count in homozygous alpha(+)-thalassaemia contributes to protection against severe malarial anaemia.

Peter Medawar Building for Pathogen Research and Department of Zoology, University of Oxford, Oxford, United Kingdom.
PLoS Medicine (Impact Factor: 14). 03/2008; 5(3):e56. DOI: 10.1371/journal.pmed.0050056
Source: PubMed

ABSTRACT The heritable haemoglobinopathy alpha(+)-thalassaemia is caused by the reduced synthesis of alpha-globin chains that form part of normal adult haemoglobin (Hb). Individuals homozygous for alpha(+)-thalassaemia have microcytosis and an increased erythrocyte count. Alpha(+)-thalassaemia homozygosity confers considerable protection against severe malaria, including severe malarial anaemia (SMA) (Hb concentration < 50 g/l), but does not influence parasite count. We tested the hypothesis that the erythrocyte indices associated with alpha(+)-thalassaemia homozygosity provide a haematological benefit during acute malaria.
Data from children living on the north coast of Papua New Guinea who had participated in a case-control study of the protection afforded by alpha(+)-thalassaemia against severe malaria were reanalysed to assess the genotype-specific reduction in erythrocyte count and Hb levels associated with acute malarial disease. We observed a reduction in median erythrocyte count of approximately 1.5 x 10(12)/l in all children with acute falciparum malaria relative to values in community children (p < 0.001). We developed a simple mathematical model of the linear relationship between Hb concentration and erythrocyte count. This model predicted that children homozygous for alpha(+)-thalassaemia lose less Hb than children of normal genotype for a reduction in erythrocyte count of >1.1 x 10(12)/l as a result of the reduced mean cell Hb in homozygous alpha(+)-thalassaemia. In addition, children homozygous for alpha(+)-thalassaemia require a 10% greater reduction in erythrocyte count than children of normal genotype (p = 0.02) for Hb concentration to fall to 50 g/l, the cutoff for SMA. We estimated that the haematological profile in children homozygous for alpha(+)-thalassaemia reduces the risk of SMA during acute malaria compared to children of normal genotype (relative risk 0.52; 95% confidence interval [CI] 0.24-1.12, p = 0.09).
The increased erythrocyte count and microcytosis in children homozygous for alpha(+)-thalassaemia may contribute substantially to their protection against SMA. A lower concentration of Hb per erythrocyte and a larger population of erythrocytes may be a biologically advantageous strategy against the significant reduction in erythrocyte count that occurs during acute infection with the malaria parasite Plasmodium falciparum. This haematological profile may reduce the risk of anaemia by other Plasmodium species, as well as other causes of anaemia. Other host polymorphisms that induce an increased erythrocyte count and microcytosis may confer a similar advantage.

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Available from: Stephen J Allen, Jul 14, 2015
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    • "The interactions between thalassemic red cells and plasmodia appear to play a major role in natural and acquired protection to malaria. Heterozygous í µí»¼-and í µí»½-thalassemias are extremely frequent in malaria endemic areas displaying a well-balanced hematological situation [27], while there is a widespread consensus that thalassemias determine an efficient resistance to severe malaria [28]. In particular, í µí»¼-thalassemias are the most common mutation in malaria endemic regions and are considered to confer protection against clinical manifestations related to both severe forms [29] [30] [31] [32] or uncomplicated malaria [33]. "
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    ABSTRACT: β -thalassemia is a worldwide distributed monogenic red cell disorder, characterized by the absence or reduced β -globin chain synthesis. Despite the extensive knowledge of the molecular defects causing β -thalassemia, less is known about the mechanisms responsible for the associated ineffective erythropoiesis and reduced red cell survival, which sustain anemia of β -thalassemia. The unbalance of alpha-gamma chain and the presence of pathological free iron promote a severe red cell membrane oxidative stress, which results in abnormal β -thalassemic red cell features. These cells are precociously removed by the macrophage system through two mechanisms: the removal of phosphatidylserine positive cells and through the natural occurring antibody produced against the abnormally clustered membrane protein band 3. In the present review we will discuss the changes in β -thalassemic red cell homeostasis related to the oxidative stress and its connection with production of microparticles and with malaria infection. The reactive oxygen species (ROS) are also involved in ineffective erythropoiesis of β -thalassemia through still partially known pathways. Novel cytoprotective systems such as ASHP, eIF2 α , and peroxiredoxin-2 have been suggested to be important against ROS in β -thalassemic erythropoiesis. Finally, we will discuss the results of the major in vitro and in vivo studies with antioxidants in β -thalassemia.
    Oxidative Medicine and Cellular Longevity 09/2013; 2013:985210. DOI:10.1155/2013/985210 · 3.36 Impact Factor
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    • "Recently, it has been proposed that the mechanism of a + -thalassemia protection is restricted to severe malarial anemia. Different groups have suggested different pathways of protection, either against hemolysis during the acute malaria phase (Wambua et al., 2006; May et al., 2007), against gradual reduction of hemoglobin levels during repeated episodes of uncomplicated malaria (Oppenheimer et al., 1987; Veenemans et al., 2008) or by an induced increase in erythrocyte count in a + -thalassemic individuals (Fowkes et al., 2008a). Such an effect may be related to changes in cellular (Urban et al., 2006) or inflammatory/active phase (Imrie et al., 2006) responses and may not be restricted to malaria, but also apply to other causes of anemia (Pasvol, 2006; Wambua et al., 2006). "
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    ABSTRACT: Despite consistent evidence of a protective effect of α(+)-thalassemia against severe Plasmodium falciparum disease, the mechanisms underlying this protection remain unknown. An increase in risk of Plasmodium vivax malaria in early childhood resulting in a cross-species protection against severe P. falciparum malaria has been proposed as a possible mechanism in Melanesian children. The association of α(+)-thalassemia genotypes with a risk of P. falciparum and P. vivax infection and uncomplicated illness was reassessed in a cohort of 1,112 Papua New Guinean children, followed from 3 to 21months of age. Three hundred and eighty-nine (35.0%) children were homozygous for α(+)-thalassemia (-α/-α), 506 (45.5%) heterozygous (αα/-α) and 217 (19.5%) homozygous for the wild-type allele. No significant differences in the incidence of P. falciparum (Pf) or P. vivax (Pv) malaria were observed between α(+)-thalassemia homozygote (Pf: incidence rate ratio (IRR)=1.13, CI(95) (0.82, 1.56), P=0.45, Pv: IRR=1.15, CI(95) (0.9881.56), P=0.31), heterozygote (Pf: IRR=0.98, CI(95) (0.71, 1.34), P=0.93, Pv: IRR=1.14, CI(95) (0.88, 1.48), P=0.33) and wild-type children. The prevalence of infection with either species did not differ between α(+)-thalassemia genotypes, although densities of P. vivax (but not of P. falciparum) infections were significantly higher in α(+)-thalassemia homozygote and heterozygote children. An excessive risk of moderate-to-severe anemia (Hb<8g/dl) was observed in α(+)-thalassemia homozygote children (IRR=1.54, CI(95) (1.12, 2.11), P=0.008). This study therefore failed to confirm an increased risk of P. vivax or P. falciparum malaria in very young, α(+)-thalassemic children without significant levels of acquired immunity. This confirms the lack of protection by α(+)-thalassemia against uncomplicated P. falciparum and challenges the hypothesis of immunological cross-protection between P. falciparum and P. vivax as a mechanism underlying α(+)-thalassemia protection against severe P. falciparum disease in Melanesian children.
    International journal for parasitology 10/2012; 42(12). DOI:10.1016/j.ijpara.2012.10.001 · 3.40 Impact Factor
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    • "For example, although SCD may be partially protective against infection with malaria, affected children who do become infected are at substantial risk of subsequent death (Williams & Obaro 2011). In addition, a + -thalassaemia has also been shown to ameliorate malaria risk (Wambua et al. 2006b), possibly by limiting the decline in Hb concentration that normally results from malaria infection (Mockenhaupt et al. 2004; Fowkes et al. 2008; Veenemans et al. 2008). Glucose-6-phosphate dehydrogenase (G6PD) deficiency, also common in Africa, may protect against malaria, although it can also result in serious clinical outcomes caused by red blood cell haemolysis (Guindo et al. 2007). "
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    ABSTRACT: Although inherited blood disorders are common among children in many parts of Africa, limited data are available about their prevalence or contribution to childhood anaemia. We conducted a cross-sectional survey of 858 children aged 6-35 months who were randomly selected from 60 villages in western Kenya. Haemoglobin (Hb), ferritin, malaria, C-reactive protein (CRP) and retinol binding protein (RBP) were measured from capillary blood. Using polymerase chain reaction (PCR), Hb type, -3.7 kb alpha-globin chain deletion, glucose-6-phosphate dehydrogenase (G6PD) genotype and haptoglobin (Hp) genotype were determined. More than 2 out of 3 children had at least one measured blood disorder. Sickle cell trait (HbAS) and disease (HbSS) were found in 17.1% and 1.6% of children, respectively; 38.5% were heterozygotes and 9.6% were homozygotes for α(+) -thalassaemia. The Hp 2-2 genotype was found in 20.4% of children, whereas 8.2% of males and 6.8% of children overall had G6PD deficiency. There were no significant differences in the distribution of malaria by the measured blood disorders, except among males with G6PD deficiency who had a lower prevalence of clinical malaria than males of normal G6PD genotype (P = 0.005). After excluding children with malaria parasitaemia, inflammation (CRP > 5 mg L(-1) ), iron deficiency (ferritin < 12 μg L(-1) ) or vitamin A deficiency (RBP < 0.7 μg L(-1) ), the prevalence of anaemia among those without α(+) -thalassaemia (43.0%) remained significantly lower than that among children who were either heterozygotes (53.5%) or homozygotes (67.7%, P = 0.03). Inherited blood disorders are common among pre-school children in western Kenya and are important contributors to anaemia.
    Maternal and Child Nutrition 09/2012; 10(1). DOI:10.1111/j.1740-8709.2012.00454.x · 2.97 Impact Factor
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