Article

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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    • "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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    • "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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    • "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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