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Blood, 15 October 2006, Vol. 108, No. 8, pp. 2569-2577.
Prepublished online as a Blood First Edition Paper on June 27, 2006; DOI 10.1182/blood-2006-05-018697.
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Submitted August 22, 2005
Accepted June 8, 2006
Suppression of erythropoiesis in malarial anemia is
associated with hemozoin in vitro and in vivo
Climent Casals-Pascual*, Oscar Kai, Joyce O Cheung, Senani Williams, Brett Lowe, Mike Nyanoti, Thomas N Williams, Kathryn Maitland, Malcolm Molyneux, Charles R Newton, Norbert Peshu, Suzanne M Watt, and David J Roberts
National Blood Service, NHS
KEMRI Centre for Geographic Medicine Coast, PO Box 230, Kilifi, Kenya
Nuffield Department of Clinical Laboratory Sciences
Dept. of Pathology, Faculty of Medicine,University of Kelaniya, Sri Lanka
Malawi-Wellcome Trust Research Programme, Blantyre, Malawi
National Blood Service Oxford Centre, NHS
* Corresponding author; email: climentcasals{at}hotmail.com.
Malarial anemia is a major public health problem in
endemic areas and is characterized by a low reticulocyte
response in the presence of life-threatening hemolysis.
Although it was previously suggested that cytokines, in
particular tumor necrosis factor-
(TNF-), could suppress erythropoiesis, the
grossly abnormal bone marrow morphology in acute, as well
as in chronic malarial infection indicates that other
factors may contribute to ineffective erythropoiesis. We
hypothesized that the cytotoxic hemozoin (Hz) residues
from digested hemoglobin (Hb) significantly contribute to
this impairment of erythropoiesis. Here, we show that not
only isolated Hz, but also delipidated Hz, produces a
substantial inhibition of erythroid development in vitro,
in the absence of TNF-. However, when added to
cultures, TNF- synergizes with Hz to inhibit
erythropoiesis. Furthermore, we show that, in children
with malarial anemia, the proportion of circulating
monocytes containing Hz is associated with anemia
(P<0.001) and reticulocyte suppression (P=0.009), and that
this is independent of the level of circulating cytokines,
including TNF-. Plasma Hz is also associated with
anemia (P<0.001) and reticulocyte suppression (P=0.02).
Finally, histological examination of the bone marrow of
children who have died from malaria, shows that pigmented
erythroid and myeloid precursors are associated with the
degree of abnormal erythroid development. Taken together
these observations provide compelling evidence for inhibition of erythropoiesis by Hz.
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