Date Published: March 18, 2008
Publisher: Public Library of Science
Author(s): Freya J. I Fowkes, Stephen J Allen, Angela Allen, Michael P Alpers, David J Weatherall, Karen P Day, Geoffrey Pasvol
Abstract: BackgroundThe heritable haemoglobinopathy α+-thalassaemia is caused by the reduced synthesis of α-globin chains that form part of normal adult haemoglobin (Hb). Individuals homozygous for α+-thalassaemia have microcytosis and an increased erythrocyte count. α+-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 α+-thalassaemia homozygosity provide a haematological benefit during acute malaria.Methods and FindingsData from children living on the north coast of Papua New Guinea who had participated in a case-control study of the protection afforded by α+-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 ∼1.5 × 1012/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 α+-thalassaemia lose less Hb than children of normal genotype for a reduction in erythrocyte count of >1.1 × 1012/l as a result of the reduced mean cell Hb in homozygous α+-thalassaemia. In addition, children homozygous for α+-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 α+-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).ConclusionsThe increased erythrocyte count and microcytosis in children homozygous for α+-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.
Partial Text: The heritable haemoglobinopathy α-thalassaemia is one of the most common monogenic disorders of humans . The different forms of α+-thalassaemia result from deletions (3.7 or 4.2 kb) or point mutations in one of the duplicated α-globin genes (αα/αα) on Chromosome 16 . The heterozygous (−α/αα) and homozygous (−α/−α) states for α+-thalassaemia are characterised by lower haemoglobin (Hb) concentration, mean cell volume (MCV) and mean cell Hb (MCH), but increased erythrocyte count compared with normal individuals [1–3]. This mild hypochromic, microcytic anaemia is more pronounced in individuals homozygous for α+-thalassaemia compared to heterozygous individuals [1–3].
The reasons for the microcytosis and relatively high erythrocyte count in carriers for alpha or beta thalassaemia are not understood. It has been proposed that it reflects an increased number of terminal cell divisions during erythropoiesis, due to the combination of defective haemoglobinisation of the erythrocytes and a highly proliferative bone marrow . We investigated whether the microcytosis and increased erythrocyte count associated with α+-thalassaemia may be a haematological advantage in the face of the estimated >30% reduction in erythrocyte count, which we observed in PNG children with acute malaria.