Increased Microerythrocyte Count in Homozygous α+-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: 14.43). 03/2008; 5(3):e56. DOI: 10.1371/journal.pmed.0050056
Source: PubMed


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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    • "Most studies showed that α+-thalassaemia homozygotes have better protection against severe malarial anaemia compared to heterozygotes [24,25]. Moreover, patients with microcytosis and higher erythrocyte count associated with α+-thalassaemia homozygosity had an advantage against severe malarial anaemia during acute infection with Plasmodium falciparum[26]. "
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    ABSTRACT: Background Malaria is a major mosquito-borne public health problem in Thailand with varied haematological consequences. The study sought to elucidate the haematological changes in people who suspected malaria infection and their possible predictive values of malaria infection. Methods Haematological parameters of 4,985 patients, including 703 malaria-infected and 4,282 non-malaria infected, who admitted at Phop Phra Hospital, Tak Province, an area of malaria endemic transmission in Thailand during 2009 were evaluated. Results The following parameters were significantly lower in malaria-infected patients; red blood cells (RBCs) count, haemoglobin (Hb), platelets count, white blood cells (WBCs) count, neutrophil, monocyte, lymphocyte and eosinophil counts, while mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), Mean corpuscular haemoglobin concentration (MCHC), neutrophil-lymphocyte ratio (NLR), and monocyte-lymphocyte ratio (MLR) were higher in comparison to non-malaria infected patients. Patients with platelet counts < 150,000/uL were 31.8 times (odds ratio) more likely to have a malaria infection. Thrombocytopenia was present in 84.9% of malaria-infected patients and was independent of age, gender and nationality (P value < 0.0001). Conclusion Patients infected with malaria exhibited important changes in most of haematological parameters with low platelet, WBCs, and lymphocyte counts being the most important predictors of malaria infection. When used in combination with other clinical and microscopy methods, these parameters could improve malaria diagnosis and treatment.
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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.
    Full-text · Article · Sep 2013 · Oxidative Medicine and Cellular Longevity
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    • "Another case-control study demonstrated that complement receptor 1 (CR1) expression required for rosette formation, is reduced on α-thalassemia red cells [25,27]. Recently, Fowkes et al. suggested that the increased erythrocyte count and microcytosis in children homozygous for α+-thalassemia may confer an advantage during acute infection with the malaria parasite P. falciparum[28]. This may provide an underlying mechanism for the --SEA protection against malaria, considering that the phenotypic effect of α0-thalassemia heterozygotes appears to be the same as α+-thalassemia homozygotes. Moreover, many genetic variants against malaria are involved in hemoglobin-inherited disorders, erythrocyte polymorphisms, enzymopathies, and immunogenetic variants, which may be only a small proportion of the complex interaction between Plasmodium parasites and humans. "
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    ABSTRACT: Background The Southeast Asian deletion (--SEA) is the most commonly observed mutation among diverse α-thalassemia alleles in Southeast Asia and South China. It is generally argued that mutation --SEA, like other variants causing hemoglobin disorders, is associated with protection against malaria that is endemic in these regions. However, little evidence has been provided to support this claim. Results We first examined the genetic imprint of recent positive selection on the --SEA allele and flanking sequences in the human α-globin cluster, covering a genomic region spanning ~410 kb, by genotyping 28 SNPs in a Chinese population consisting of 76 --SEA heterozygotes and 138 normal individuals. The pattern of linkage disequilibrium (LD) and the long-range haplotype test revealed a signature of positive selection. The network of inferred haplotypes suggested a single origin of the --SEA allele. Conclusions Thus, our data support the hypothesis that the --SEA allele has been subjected to recent balancing selection, triggered by malaria.
    Full-text · Article · Mar 2013 · BMC Evolutionary Biology
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