Increased microerythrocyte count in homozygous alpha(+)-thalassaemia contributes to protection against severe malarial anaemia.
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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ABSTRACT: Background. The mechanisms by which α-thalassemia and sickle cell traits confer protection from severe Plasmodium falciparum malaria are not yet fully elucidated. We hypothesized that hemoglobinopathic erythrocytes reduce the intraerythrocytic multiplication of P. falciparum, potentially delaying the development of life threatening parasite densities until parasite clearing immunity is achieved.Methods. We developed a novel in-vitro assay to quantify the number of merozoites released from an individual schizont, termed the "intraerythrocytic multiplication factor" (IMF).Results. P. falciparum (3D7 line) schizonts produce variable numbers of merozoites in all erythrocyte types tested, with median IMFs of 27, 27, 29, 23, and 23 in control, HbAS, HbSS, and α- and β-thalassemia trait erythrocytes, respectively. IMF correlated strongly (r(2)=0.97, p<0.001) with mean corpuscular hemoglobin concentration, and varied significantly with mean corpuscular volume and hemoglobin content. Reduction of IMFs in thalassemia trait erythrocytes was confirmed using clinical parasite isolates with different IMFs. Mathematical modeling of the effect of IMF on malaria progression indicates that the lower IMF in thalassemia trait erythrocytes limits parasite density and anemia severity over the first 2 weeks of parasite replication.Conclusions. P. falciparum IMF, a parasite heritable virulence trait, correlates with erythrocyte indices and is reduced in thalassemia trait erythrocytes. Parasite IMF should be examined in other low-indices erythrocytes.The Journal of Infectious Diseases 03/2014; · 5.85 Impact Factor
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ABSTRACT: The burden of anemia attributable to non-falciparum malarias in regions with Plasmodium co-endemicity is poorly documented. We compared the hematological profile of patients with and without malaria in southern Papua, Indonesia. Clinical and laboratory data were linked for all patients presenting to a referral hospital between April 2004 and December 2012. Data were available on patient demographics, malaria diagnosis, hemoglobin concentration, and clinical outcome, but other potential causes of anemia could not be identified reliably. Of 922,120 patient episodes (837,989 as outpatients and 84,131 as inpatients), a total of 219,845 (23.8%) were associated with a hemoglobin measurement, of whom 67,696 (30.8%) had malaria. Patients with P. malariae infection had the lowest hemoglobin concentration (n = 1,608, mean = 8.93 [95% CI 8.81-9.06]), followed by those with mixed species infections (n = 8,645, mean = 9.22 [95% CI 9.16-9.28]), P. falciparum (n = 37,554, mean = 9.47 [95% CI 9.44-9.50]), and P. vivax (n = 19,858, mean = 9.53 [95% CI 9.49-9.57]); p-value for all comparisons <0.001. Severe anemia (hemoglobin <5 g/dl) was present in 8,151 (3.7%) patients. Compared to patients without malaria, those with mixed Plasmodium infection were at greatest risk of severe anemia (adjusted odds ratio [AOR] 3.25 [95% CI 2.99-3.54]); AORs for severe anaemia associated with P. falciparum, P. vivax, and P. malariae were 2.11 (95% CI 2.00-2.23), 1.87 (95% CI 1.74-2.01), and 2.18 (95% CI 1.76-2.67), respectively, p<0.001. Overall, 12.2% (95% CI 11.2%-13.3%) of severe anemia was attributable to non-falciparum infections compared with 15.1% (95% CI 13.9%-16.3%) for P. falciparum monoinfections. Patients with severe anemia had an increased risk of death (AOR = 5.80 [95% CI 5.17-6.50]; p<0.001). Not all patients had a hemoglobin measurement, thus limitations of the study include the potential for selection bias, and possible residual confounding in multivariable analyses. In Papua P. vivax is the dominant cause of severe anemia in early infancy, mixed P. vivax/P. falciparum infections are associated with a greater hematological impairment than either species alone, and in adulthood P. malariae, although rare, is associated with the lowest hemoglobin concentration. These findings highlight the public health importance of integrated genus-wide malaria control strategies in areas of Plasmodium co-endemicity. Please see later in the article for the Editors' Summary.PLoS Medicine 12/2013; 10(12):e1001575. · 14.00 Impact Factor
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ABSTRACT: Abstract In populations with high prevalences of iron deficiency and thalassemia trait, many apparently healthy individuals have abnormal erythroid parameters, which may cause diagnostic problems in clinical practice. We studied the prevalence and causes of red cell parameter values outside their reference ranges in 394 healthy individuals of Bedouin Arab origin, who had complete blood counts (CBCs), hemoglobin (Hb) analyses and serum ferritin tests done. Their mean age ± standard deviation (SD) was 24.8 ± 4.9 years and 51.8% were females. Overall, 53.0% (209/394) had low Hb, MCV or MCH or high RDW. Anemia was present in 27.0% (55/204) of the women and 3.0% (6/190) of the men. Overall prevalence of MCV <80.0 fL was 45.0% (176/394) and MCH <27.0 pg was 48.0% (190/394); RDW >14.0% was found in 21.0% (43/204) of women and 7.0% (14/190) of men. Of the women, 16.0% had iron deficiency anemia (33/204) and 65.0% had ferritin values of <30.0 μg/L (133/204). The estimated prevalence of α-thalassemia (α-thal) trait in men was 32.0% (60/190) and that of β-thalassemia (β-thal) trait in both sexes was 3.0% (12/394). In conclusion, half of the healthy Emirati population have abnormal CBC values. For clinical purposes, they require reference standards for red cells that are derived from their own population. Screening of women for iron deficiency is justified due to a high prevalence of iron deficiency.Hemoglobin 11/2013; · 0.96 Impact Factor
Increased Microerythrocyte Count in
Homozygous aþ-Thalassaemia Contributes to
Protection against Severe Malarial Anaemia
Freya J. I. Fowkes1,2, Stephen J. Allen3¤a, Angela Allen3, Michael P. Alpers4¤b, David J. Weatherall3, Karen P. Day2*
1 Peter Medawar Building for Pathogen Research and Department of Zoology, University of Oxford, Oxford, United Kingdom, 2 Department of Medical Parasitology, New
York University School of Medicine, New York, New York, United States of America, 3 The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe
Hospital, Oxford, United Kingdom, 4 PNG Institute of Medical Research, Goroka, Papua New Guinea
Funding: This work was supported
by the Wellcome Trust (grant
number 035893), The European
Community (E.C.) (E.C. grant number
IC18-CT98–0359), and the Medical
Research Council. KPD and FJIF were
supported by a Programme Grant
from The Wellcome Trust (grant
number 041354). The funders had
no role in study design, data
collection and analysis, decision to
publish, or preparation of the
Competing Interests: The authors
have declared that no competing
Academic Editor: Geoffrey Pasvol,
Imperial College London, United
Citation: Fowkes FJI, Allen SJ, Allen
A, Alpers MP, Weatherall DJ, et al.
(2008) Increased microerythrocyte
count in homozygous aþ-
thalassaemia contributes to
protection against severe malarial
anaemia. PLoS Med 5(3): e56. doi:10.
Received: April 10, 2007
Accepted: January 21, 2008
Published: March 18, 2008
Copyright: ? 2008 Fowkes et al.
This is an open-access article
distributed under the terms of the
Creative Commons Attribution
License, which permits unrestricted
use, distribution, and reproduction
in any medium, provided the
original author and source are
Abbreviations: Hb, haemoglobin;
MCH, mean cell haemoglobin; MCV,
mean cell volume; PNG, Papua New
Guinea; SMA, severe malarial
* To whom correspondence should
be addressed. E-mail: karen.day@
¤a Current address: School of
Medicine, Swansea University,
Swansea, United Kingdom
¤b Current address: Centre for
International Health, Curtin
University of Technology, Perth,
A B S T R A C T
The heritable haemoglobinopathy aþ-thalassaemia is caused by the reduced synthesis of
a-globin chains that form part of normal adult haemoglobin (Hb). Individuals homozygous for
aþ-thalassaemia have microcytosis and an increased erythrocyte count. aþ-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 aþ-thalassaemia homozygosity
provide a haematological benefit during acute malaria.
Methods and Findings
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 aþ-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 3 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 aþ-thalassaemia lose less Hb than children of normal genotype for a reduction
in erythrocyte count of .1.1 3 1012/l as a result of the reduced mean cell Hb in homozygous
aþ-thalassaemia. In addition, children homozygous for aþ-thalassaemia require a 10% greater
reduction in erythrocyte count than children of normal genotype (p ¼ 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 aþ-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 ¼ 0.09).
The increased erythrocyte count and microcytosis in children homozygous for
aþ-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.
The Editors’ Summary of this article follows the references.
PLoS Medicine | www.plosmedicine.org March 2008 | Volume 5 | Issue 3 | e560494
P PL Lo oS S MEDICINE
The heritable haemoglobinopathy a-thalassaemia is one
of the most common monogenic disorders of humans .
The different forms of aþ-thalassaemia result from deletions
(3.7 or 4.2 kb) or point mutations in one of the duplicated
a-globin genes (aa/aa) on Chromosome 16 . The hetero-
zygous (?a/aa) and homozygous (?a/?a) states for
aþ-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, micro-
cytic anaemia is more pronounced in individuals homo-
zygous for aþ-thalassaemia compared to heterozygous
Haldane’s proposal that the high frequencies of thalassae-
mias in malaria endemic regions were due to natural
selection by malaria  is consistent with the strong
geographical correlation between the frequency of
aþ-thalassaemia and malaria in the Pacific region . It has
been suggested that aþ-thalassaemia protects by a direct
interaction between the parasite (Plasmodium falciparum) and
the altered thalassaemic erythrocyte, resulting in reduced
parasite load . However, in vitro experiments have failed
to consistently demonstrate either a reduced ability of the
malaria parasite to grow in and/or invade thalassaemic
erythrocytes [7–17], and epidemiological studies have failed
to demonstrate any consistent effect of aþ-thalassaemia
against P. falciparum density [18–22]. These findings argue
against an altered physical interaction between the eryth-
rocyte and the parasite.
Case-control studies in Papua New Guinea (PNG)  and
Africa [19,20,22,23] have demonstrated the protective effect
of aþ-thalassaemia against severe malaria. Most studies show
that aþ-thalassaemia homozygotes have considerable protec-
tion against SMA compared to heterozygotes [18,20,22,23],
although one study showed equal odds of heterozygotes and
homozygotes developing SMA . We hypothesised that this
striking protection against SMA may be due to the micro-
cytosis and increased erythrocyte count in children homo-
zygous for aþ-thalassaemia.
We have reported previously a case-control study of
children living in the north coastal region of PNG that showed
that the odds ratio for SMA was 0.34 (95% confidence interval
[CI] 0.16–0.73) in homozygous aþ-thalassaemia compared to
normal individuals . In the present study, we explore the
consequences of a range of reductions of erythrocyte count on
genotype-specific Hb levels by modelling the observed
haematological data from the original case-control study.
Materials and Methods
The north coast of PNG provides a unique site to investigate
the protective effect of aþ-thalassaemia against malaria. The
frequency of aþ-thalassaemia is very high (68%) , and other
host erythrocyte polymorphisms such as Southeast Asian
ovalocytosis and glucose-6-phosphate dehydrogenase defi-
ciency are relatively uncommon in this population (,7%)
[18,21]. Importantly, sickle cell trait, a haemoglobinopathy
proposed to be a serious confounder in epidemiological
studies of aþ-thalassaemia in Africa [24,25], is absent in PNG.
In the case-control study, children with acute malaria were
recruited from outpatient clinics and Madang General
Hospital between October 1993 and February 1996 . In
children admitted to hospital, malaria was defined as a febrile
illness with any degree of P. falciparum parasitaemia (as they
had often received antimalarial treatment before admission),
but without an alternative cause of illness identified during
detailed clinical and laboratory investigation. Some of these
children developed one or more severe manifestations of
malaria, defined according to World Health Organization
criteria [26,27]. For each case of severe malaria, a control
child living in the community was selected randomly and
individually matched to the index case for age, sex, ethnicity,
season, and village. Children in the community frequently
harbour chronic, asymptomatic P. falciparum, P. vivax, P.
malariae, and P. ovale . Analysis of the protective effect of
aþ-thalassaemia against severe manifestations of malaria
accounted for the matched pair design. Children attending
clinics with P. falciparum parasitaemia ?10,000/ll and no
clinical or laboratory features of severe malaria or an
alternative cause of an acute febrile illness were also
recruited. To investigate the effect of the haematological
characteristics according to aþ-globin genotype on anaemia
associated with malaria infection of varying severity, we have
pooled children from our original clinic and hospital malaria
Venous blood was collected from all children at presenta-
tion. Thick and thin blood films were prepared, stained with
Giemsa, and examined by microscopy for the presence of
malaria parasites. Blood collected into EDTA was used for
measurement of Hb, erythrocyte count, MCV, and MCH
(Coulter MD8 instrument, Coulter Electronics). These meas-
urements were done promptly after sample collection, and
reliability of results was ensured by participation in the
Coulter instruments quality control scheme. P. falciparum
density per microlitre of whole blood was calculated
accurately by using the individual measured leukocyte count
and parasites per 200 leukocytes counted in thick films.
These calculations of parasitaemia differ from standard
malariological methods that use only a population average
leukocyte count to calculate parasites per microlitre of
blood. Percentage parasitaemia was calculated by dividing an
individual child’s P. falciparum count per microlitre by the
number of erythrocytes per microlitre of whole blood
measured for that child.
Informed consent was obtained from all individuals and/or
their parents or guardian. The study was approved by the
Medical Research Advisory Committee of PNG, the Central
Oxford Research Ethics Committee, and the Oxford Tropical
Research Ethics Committee.
Analysis of all haematological data revealed a linear
relationship between Hb and erythrocyte count (Figure S1).
Children with acute malaria, regardless of conventional
severity definitions, demonstrated a reduction in erythrocyte
counts and Hb concentrations compared to community
control children (Figure S1). Given that Hb concentration
was used as a definition for severe disease, and the continuous
nature of Hb data, we decided to pool acute malaria data for
the purpose of analysis. The association of malaria severity
PLoS Medicine | www.plosmedicine.orgMarch 2008 | Volume 5 | Issue 3 | e56 0495
aþ-Thalassaemia and Malarial Anaemia
and aþ-thalassaemia genotype with categorical variables were
assessed using chi-squared tests or Fisher’s exact test, and
continuous data by Mann Whitney U or Kruskal-Wallis tests.
The association of aþ-thalassaemia genotype with risk of SMA
was assessed using logistic regression. SPSS (for Windows
Release 13.0. 2004, SPSS) was used for data analysis.
Children who are homozygous for aþ-thalassaemia have
smaller erythrocytes containing less Hb and a greater
erythrocyte count than children of normal genotype both
when living in the community and during episodes of acute
malaria. We proposed that this haematological profile
protects against SMA because homozygous children lose less
Hb from their total erythrocyte pool of Hb, for a given degree
of erythrocyte loss, compared with those of normal genotype.
A simple model was developed, using data from community
children, which predicts total Hb concentration after acute
malaria infection as a function of three parameters; (1)
baseline level of Hb, (2) MCH, and (3) the reduction in
erythrocyte count during a malaria infection. The linear
equation yi¼ b ? mix was used to predict Hb concentrations
where yirefers to predicted Hb concentration in the ith child,
b is the observed genotype-specific median Hb concentration
observed in community children prior to acute malarial
infection, mirepresents the observed genotype-specific MCH
in the ith child, and x represents a fixed number of
erythrocyte loss during a malaria infection. Values for b and
mi were taken from values observed in the community
children, among which all aþ-thalassaemia genotypes were
represented. A range of values for x were imputed into the
equation in order to derive a slope line for total Hb by
reduction in erythrocyte count; separate slope lines were
developed for each aþ-thalassaemia genotype.
Characteristics of Study Population
We reanalysed the data from 547 children with acute
malaria (median [interquartile range] age 3.0 years [1.8–4.7];
53.7% male) and 280 children living in the community (3.1
years [1.7–4.5], p ¼ 0.81; 53.3% male, p ¼ 0.88) who had
participated in the earlier study .
Haematological Indices by Disease Status and aþ-
The frequency of aþ-thalassaemia was high (.80%) in this
population (Table 1). Total erythrocyte count was found in
the order of normal , heterozygote , homozygote within
each clinical group (p ? 0.001) (Table 1). Values for MCH and
MCV were found in the opposite order, i.e., normal
. heterozygote . homozygote (p , 0.001) (Table 1). As
noted in previous studies in Melanesia [2,3], erythrocyte
counts, MCH, and MCV were age-dependent (unpublished
data). Age was distributed equally among aþ-thalassaemia
genotypes in community children (p ¼ 0.17) and those with
acute malaria (p ¼ 0.98), so it was not a confounder in the
analysis presented here. Furthermore, adjustments for age
made no difference in the association between aþ-thalassae-
mia genotype and haematological indices.
Although Hb concentration was found in the order of
normal . heterozygote . homozygote in children living in
the community, the increased erythrocyte count in children
with aþ-thalassaemia appeared to compensate somewhat for
the microcytosis as there was no significant difference in Hb
concentrations according to genotype (p ¼ 0.15) (Table 1).
Interestingly, the order in Hb concentration was reversed in
children with acute malaria, i.e., normal , heterozygote
, homozygote (Table 1). The difference in median Hb
concentration between community controls and acute ma-
laria groups was lower in children homozygous for
aþ-thalassaemia than in children of normal genotype (Table 1).
This difference in Hb loss according to genotype could not
be accounted for by differences in parasitaemia. Children
with acute malaria had significantly higher P. falciparum
densities (18,880 parasites/ll [3,142–73,950]) than children
living in the community (n ¼ 104, 1,974 parasites/ll [308–
9,233], p , 0.001). Parasite counts per microlitre of blood and
percent parasitaemia (which adjusts for genotype-specific
differences in erythrocyte count) were similar among
aþ-thalassaemia genotypes in both children living in the
community and those with acute malaria (Figure 1, p ? 0.3).
Table 1. Haematological Indices in Community Children and Children with Acute Malaria According to aþ-Thalassaemia Genotype
Haematological IndicesClinical Group
nn Median[IQR] Median[IQR]Median [IQR]
Erythrocytes (3 1012/l)Community
p-Values represent differences in median values among aþ-thalassaemia genotypes as assessed by Kruskal-Wallis tests.
aDifference in value of haematological indices between community children and those with acute malaria.
Hb, haemoglobin; IQR, interquartile range; MCH, mean cell haemoglobin; MCV, mean cell volume.
PLoS Medicine | www.plosmedicine.orgMarch 2008 | Volume 5 | Issue 3 | e560496
aþ-Thalassaemia and Malarial Anaemia
The median erythrocyte count was 1.5 3 1012/l lower in
children with acute malaria (3.27 3 1012/l [2.11–4.44]) than
community children (4.7831012/l [4.24–5.24], p , 0.001) and,
in contrast to Hb concentration, this difference in eryth-
rocyte count was remarkably similar across all genotypes
Decrease in Hb According to Genotype-specific
Differences in MCH
MCH was 20% lower in community children homozygous
for aþ-thalassaemia than in individuals of normal genotype (p
, 0.001, Table 1). Thus, for a given degree of reduction in
erythrocyte count, children who are homozygous for
aþ-thalassaemia will release 20% less Hb from the erythrocyte
pool of Hb than those of normal genotype. Using the MCH
values for each child living in the community and on the basis
of the linear relationship between Hb and erythrocyte count
represented by the linear equation yi¼ b ? mix, we calculated
the reduction in Hb concentration for the range of differ-
ences in erythrocyte count observed between community
controls and acute malaria (Figure 2A and 2B). This simple
model predicted that at degrees of reduction in erythrocyte
count ,1.131012/l, aþ-thalassaemia homozygotes had a lower
Hb concentration compared to normal individuals. In
contrast, at levels of reduction in erythrocyte count .1.1 3
1012/l, children homozygous for aþ-thalassaemia had a higher
Hb concentration than those of normal genotype (Figure 2B
Erythrocyte Count Cutoff for SMA According to Genotype
Children homozygous for aþ-thalassaemia with lower MCH
and increased erythrocyte count may require a greater
reduction in erythrocyte count to develop SMA, defined as
Hb concentration ,50 g/l . To determine the genotype-
specific erythrocyte count cutoff for a Hb concentration of 50
g/l, erythrocyte count was plotted against Hb concentration
for all children with acute malaria and a line of best fit drawn
for each genotype (Figure 3). The erythrocyte count cutoff for
SMA was determined to be 2.4 3 1012/l in homozygous
aþ-thalassaemia, 2.231012/l in heterozygotes, and 2.031012/l
in normal individuals (Figure 3), because of differences in
MCH values among genotypes.
For each child living in the community, the reduction in
erythrocyte count required to reach an Hb concentration of
50 g/l was calculated. The median (interquartile range)
erythrocyte loss was higher in homozygous aþ-thalassaemia
(2.58 3 1012/l [2.14–3.02]), than heterozygous aþ-thalassaemia
(2.4631012/l [1.86–2.8], p¼0.08), and normal individuals (2.35
3 1012/l [1.63–2.82], p ¼ 0.02). In other words, children
homozygous for aþ-thalassaemia would require 10% greater
reduction in erythrocyte count than children of normal
genotype, for Hb concentration to fall to 50 g/l. This result
should be considered in relation to our observation that
similar degrees of reduction in erythrocyte count were found
among aþ-thalassaemia genotypes in acute disease, relative to
community controls (;1.5 3 1012/l; Table 1).
To determine whether microcytosis and increased eryth-
rocyte count could explain the protection observed against
SMA in aþ-thalassaemia homozygotes, we applied the
reduction of 2.3531012/l erythrocytes (the median reduction
in erythrocyte count observed in children of normal
genotype in the estimated transition between community
control and SMA) to all children living in the community. The
proportion of community children predicted to develop
SMA, defined by the genotype-specific erythrocyte count
definitions for SMA, was lower in children who were
homozygous for aþ-thalassaemia (n ¼ 50, 35.7%) than in
heterozygous children (n ¼ 36, 43.9%), and those of normal
genotype (n ¼ 17, 51.5%). Compared with normal children,
the risk of a community child being defined as having SMA
was 0.52 (95% confidence interval [CI] 0.24–1.12, p ¼ 0.09) in
aþ-thalassaemia homozygotes and 0.74 (95% confidence
interval [CI] 0.33–1.66, p ¼ 0.46) in heterozygotes for this
degree of reduction in erythrocyte count. This simple model
based on observed haematological data predicted that
children who were homozygous for aþ-thalassaemia would
be 48% less likely to develop SMA than children of normal
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 eryth-
ropoiesis, due to the combination of defective haemoglobi-
nisation of the erythrocytes and a highly proliferative bone
marrow . We investigated whether the microcytosis and
increased erythrocyte count associated with aþ-thalassaemia
may be a haematological advantage in the face of the
Figure 1. Parasite Density in Community Children and Those with Acute
Malaria According to aþ-Thalassaemia Genotype
Parasite density is represented by (A) the number of P. falciparum-
infected erythrocytes per microlitre of blood and (B) the proportion of P.
falciparum-infected erythrocytes. Values are median (interquartile range).
There was no statistically significant difference in parasite density or
percent parasitaemia among aþ-thalassaemia genotypes, in either
children living in the community or those with acute malaria (p ? 0.3).
PLoS Medicine | www.plosmedicine.orgMarch 2008 | Volume 5 | Issue 3 | e56 0497
aþ-Thalassaemia and Malarial Anaemia
estimated .30% reduction in erythrocyte count, which we
observed in PNG children with acute malaria.
Modelling observed data, we show that a lower concen-
tration of Hb per erythrocyte and a larger population of
erythrocytes may be a biologically advantageous host strategy
against a pathogen that significantly lowers erythrocyte
count. We define a crossover point of reduction in
erythrocyte count due to acute malaria (1.131012/l) at which
microcytosis and an increased erythrocyte count becomes an
advantage to the host. This erythrocyte cutoff is considerably
lower than the median erythrocyte reduction we estimated to
be associated with acute malaria (;1.5 3 1012/l). This result
would account for the reversal of Hb concentrations in
children with acute malaria (normal , heterozygote
, homozygote), a phenomenon that has been noted
previously [16,29]. We show that the erythrocyte count
associated with this Hb concentration cutoff is genotype-
specific and found in the order normal , heterozygous
, homozygous. We also show that children homozygous for
aþ-thalassaemia would require a greater reduction in
erythrocyte count to reach the SMA cutoff. We therefore
propose that a higher microcytic erythrocyte count in
children homozygous for aþ-thalassaemia enables them to
maintain their Hb concentration above the 50 g/l threshold,
thereby reducing the risk of SMA. Indeed, given the degree of
malaria haemolysis associated with SMA in normal individ-
uals, children who were homozygous for aþ-thalassaemia
would be 48% less likely to develop SMA than children of
normal genotype. This result suggests that microcytosis and
increased erythrocyte count contribute considerably to the
66% protection against SMA observed in individuals homo-
zygous for aþ-thalassaemia in this population .
We found no significant difference in parasite counts per
microlitre of blood or percent parasitaemia among
aþ-thalassaemia genotypes in community children, nor in
those with acute malaria, in concordance with earlier studies
[15–19]. This finding is surprising given that the increased
erythrocyte count in homozygous children may be expected
to lower the proportion of infected erythrocytes. After
adjustments for individual erythrocyte counts, the variance
of parasitology data was more comparable among
aþ-thalassaemia genotypes compared to parasites per micro-
litre of blood. It is possible that density-dependent mecha-
nisms  may regulate parasitaemia and reduce genotype-
Malarial anaemia is attributed to parasite-induced haemol-
ysis, destruction of unparasitised erythrocytes, and dysery-
thropoiesis . It has been proposed that individuals with
aþ-thalassaemia have increased phagocytosis of erythrocytes
[31–33] and expanded erythroid marrow , but the balance
between erythrocyte survival and production among
aþ-thalassaemia genotypes is unknown. The model shown in
Figure 2 predicts the total Hb concentration for a given
reduction in erythrocyte count and fixed MCH. It does not
take into account potential differences in the balance
between destruction of erythrocytes and production of
reticulocytes among aþ-thalassaemia genotypes, and this area
merits further research.
Other mechanisms may also contribute to the protection
against SMA. aþ-Thalassaemia homozygosity has also been
shown to be associated with low complement receptor 1
(CR1) expression . This molecule has been shown to be
Figure 2. Consequence of Reduction in Erythrocyte Count on Total
Haemoglobin Concentration According to aþ-Thalassaemia Genotype
The linear relationship between Hb concentrations and reduction in
erythrocyte count can be described by the following linear equation: yi¼
b?mix, where yirefers to predicted Hb concentration in the ith child, b is
the observed Hb value in the community children prior to acute malaria
infection taken from Table 1, mirepresents observed MCH in the ith
child, and x represents the reduction in erythrocyte count.
(A and B) Predicted total Hb concentration of children of normal
genotype together with (A) aþ-thalassaemia heterozygotes and (B) aþ
-thalassaemia homozygotes during reductions in erythrocyte count.
Thick lines represent median values and thin lines represent the
interquartile range. The equations are y ¼ 104 ? 24.3x [y ¼104 ? 25.5,
y¼104?23.1x] for normal individuals; y¼103?22.5x [y¼103?23.9, y
¼103?21.0x] for heterozygous; and y¼99?19.8x [y¼99?18.8x, y¼99
? 21.1x] for children homozygous for aþ-thalassaemia.
(C) Difference in total predicted Hb (y) between those of normal
genotype and heterozygous children (y ¼ 1.8x ? 1, red line, data from
[A]), and between those of normal genotype and homozygous children
(y ¼ 4.5x ? 5, green line, data from [B]). The crossover point where
heterozygous individuals have a greater Hb concentration relative to
those of normal genotype is an erythrocyte reduction of 0.56 x1012/l (red
arrow). The crossover point where homozygous individuals have a
greater Hb concentration relative to those of normal genotype is an
erythrocyte reduction of 1.1 x1012/l (green arrow). These crossovers are
also seen in (A) and (B) but are better visualised here.
PLoS Medicine | www.plosmedicine.org March 2008 | Volume 5 | Issue 3 | e56 0498
aþ-Thalassaemia and Malarial Anaemia
important in the binding of infected erythrocytes to non-
infected erythrocytes (rosetting) , as well as the clearance
of erythrocytes as they age . Increased rosetting has been
implicated in the pathogenesis of severe disease . While
aþ-thalassaemic erythrocytes are less likely to form rosettes in
vitro [39,40], further studies are required to investigate the
contribution of complement receptor 1 (CR1) to the
protection aþ-thalassaemia affords against SMA. Both poly-
morphisms could synergise to minimise the reduction in
erythrocyte count during acute disease.
Malaria is a complex multisystem disorder, and in children,
in addition to anaemia, important severe manifestations
include cerebral malaria, acidosis, and hyperlactataemia .
No protection of aþ-thalassaemia was observed against
malaria coma in the matched-pair analysis in the PNG study
, whereas studies in Africa have shown a protective effect
against cerebral malaria of heterozygosity [19,20,23] and
homozygosity . There is also evidence that children
heterozygous and homozygous for aþ-thalassaemia are pro-
tected against acidosis [18,20,23] and hyperlactataemia .
Comparison of the effects of potential protective factors
between studies is complicated because the criteria used to
define severe manifestations of malaria often differ between
studies. Also, the pathophysiological mechanisms underlying
severe malaria may differ between populations. It is unclear
how anaemia may be related with these other clinical
pathologies but a key role for pro-inflammatory cytokines
has been implicated in all clinical sub groups . Hb is an
extremely toxic molecule. Outside the erythrocyte and its
constituent antioxidant defence systems, the oxidative po-
tential of Hb can cause substantial oxidative tissue damage
and release of pro-inflammatory cytokines such as tumour
necrosis factor-a [42,43]. Children homozygous for
aþ-thalassaemia release less Hb per erythrocyte during
haemolysis and therefore it is plausible that they do not
stimulate pro-inflammatory responses as readily as do those
of normal genotype. Interestingly, children homozygous for
aþ-thalassaemia have also been shown to be protected against
severe nonmalaria disease in this population . Lower Hb
concentrations per cell may reduce inflammation during any
We propose that the microcytosis and higher erythrocyte
count associated with aþ-thalassaemia homozygosity is a
selective advantage against SMA. In contrast, the parasite/
erythrocyte interaction hypothesis cannot account for pro-
tection against SMA as it implies differences in parasite
counts by genotype, which we failed to find in any disease
state. Whilst our analysis has focused on P. falciparum, this
haematological mechanism may protect against other Plasmo-
dium species, such as P. vivax. P. vivax infection can be
associated with severe anaemia, and it is interesting to note
that the highest frequencies of aþ-thalassaemia are found in
areas where P. vivax is prevalent [1,44]. Since other common
disorders of Hb that appear to provide relative protection
against severe malaria, notably carriers of beta thalassaemia
and homozygous Hb E, also have relatively high micro-
erythrocyte counts [1,45], this haematological mechanism of
protection may have broader implications for our under-
standing of the selection of these host erythrocyte poly-
morphisms by malaria.
Figure S1. The Association of Hb Concentration and Erythrocyte
Count in Study Children
Hb is positively associated with erythrocyte count, r¼0.94, p , 0.001.
Horizontal and vertical lines represent observed median Hb (g/l) and
erythrocyte count respectively for each definition of malaria. Solid
green line represents acute malaria, dashed green line all hospital
malaria. Median (interquartile range) Hb and erythrocyte counts are
as follows: severe malaria, 47 g/l (38–79), 2.12 3 1012/l (1.58–3.52); all
hospital malaria, 61 g/l (44–91), 2.7631012/l (1.89–4.09); acute malaria,
72 g/l [47–97], 3.27 3 1012/l [2.11–4.44]; mild malaria, 90 g/l [67–103],
4.0331012/l [3.12–4.84]; community children, 100 g/l [88–109], 4.783
Found at doi:10.1371/journal.pmed.0050056.sg001 (158 KB JPG).
Our sincere thanks to the children and their parents from Madang,
Papua New Guinea, for their participation in this study, Willie
Depsone for invaluable help with field work, and to Marta Mellombo
for laboratory assistance.
Author contributions. FJIF performed data analysis. SJA and AA
undertook fieldwork. MPA, DJW, and KPD initiated and obtained
funding for the project. FJIF, SJA, AA, MPA, DJW, and KPD discussed
the results and produced the final manuscript.
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aþ-Thalassaemia and Malarial Anaemia
Background. Mutations (changes in the DNA that encodes proteins)
continually arise within human populations. Harmful mutations that
affect an individual’s ability to reproduce usually disappear, but most
other mutations persist at a low frequency. Some mutations, however,
protect their human carriers against specific disease-causing organisms,
and consequently occur at high frequencies in human populations that
live in places where these organisms are common. For example, the
inherited blood disorder aþ-thalassemia, which is common in Africa and
Southeast Asia, provides protection against malaria, a parasitic disease
that occurs in tropical and subtropical parts of the world. aþ-Thalassemia
is caused by the loss of one or more of the genes that encode the a
chains of hemoglobin, the red blood cell (erythrocyte) protein that
carries oxygen around the body. These a chains are normally encoded by
four genes, two on each Chromosome 16 (all chromosomes come in
pairs). People with heterozygous aþ-thalassemia lack one copy of the a
chain gene and have a –a/aa genotype (genetic makeup). People with
homozygous aþ-thalassemia lack one copy of the gene on each
chromosome (they have a –a/–a genotype) and have mild ‘‘microcytic
anemia,’’ a condition characterized by increased numbers of abnormally
small erythrocytes (microcytosis) that contain reduced amounts of
Why Was This Study Done? Paradoxically, although homozygous
aþ-thalassemia causes mild anemia, it provides protection against severe
malarial anemia, a potentially fatal complication of malaria. Malaria
parasites cause anemia because they multiply inside erythrocytes and
rupture them. Scientists originally thought that aþ-thalassemia protects
against malaria by interfering with the parasite’s ability to infect
erythrocytes, but the evidence collected so far does not support this
hypothesis. In this study, therefore, the researchers have investigated
whether the microcytosis and increased erythrocyte count associated
with aþ-thalassemia might be responsible for the protection that this
blood disorder provides against severe malarial anemia. Specifically, they
asked whether this hematological (blood) profile protects against severe
malarial anemia because people with the –a/–a genotype lose less
hemoglobin for a given degree of malaria-induced erythrocyte loss than
do those with the normal genotype.
What Did the Researchers Do and Find? A study done in the mid 1990s
in children living on the north coast of Papua New Guinea (where 68% of
the population has aþ-thalassemia) showed that homozygous
aþ-thalassemia protects against severe malaria. To investigate why, the
researchers re-analyzed the genotype-specific reduction in erythrocyte
counts and hemoglobin levels associated with acute malarial disease in
these children and developed a simple mathematical model to predict
hemoglobin levels after malaria infection. They found that when malarial
infection reduced the number of erythrocytes per liter of blood by more
than 1.1 3 1012(the average measured loss of erythrocytes in this
population because of malaria was 1.5 3 1012per liter), children with
homozygous aþ-thalassemia lost less hemoglobin than did those with
the normal genotype. Furthermore, children with homozygous
aþ-thalassemia needed a 10% greater reduction in their red blood cell
count than children with the normal genotype for their hemoglobin
levels to fall below the value that defines severe malarial anemia.
What Do These Findings Mean? These findings suggest that the
increased number of abnormally small erythrocytes associated with
homozygous aþ-thalassemia might be responsible for the protection
against severe malarial anemia that this blood disorder provides,
because more erythrocytes have to be destroyed by the parasite to
reduce hemoglobin concentrations to a dangerous level than in people
with the normal genotype. In other words, a lower concentration of
hemoglobin per erythrocyte coupled with a larger population of
erythrocytes might be advantageous in the face of the large reduction
in erythrocyte numbers caused by infection with malaria parasites. The
researchers note that their study population was infected with only one
type of malaria parasite (Plasmodium falciparum), but speculate that the
hematological profile associated with aþ-thalassemia might also prevent
other Plasmodium species causing anemia. Futhermore, they suggest,
other mutations that increase the erythrocyte count and cause micro-
cytosis might protect against severe malaria anemia in a similar fashion.
Additional Information. Please access these Web sites via the online
version of this summary at http://dx.doi.org/10.1371/journal.pmed.
? The MedlinePlus encyclopedia contains pages on thalassemia and on
malaria (in English and Spanish)
? Detailed information is available on thalassemia (including useful links
to other resources) from the US National Heart Lung and Blood
Institute, from the US National Human Genome Research Institute,
from the Cooley’s Anemia Foundation, and from MedlinePlus
? The US Centers for Disease Control and Prevention provide informa-
tion on malaria (in English and Spanish)
? Information is also available from the World Health Organization on
malaria (in English, Spanish, French, Russian, Arabic, and Chinese)
PLoS Medicine | www.plosmedicine.orgMarch 2008 | Volume 5 | Issue 3 | e56 0501
aþ-Thalassaemia and Malarial Anaemia