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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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HEMATOPOIESIS
Suppression of erythropoiesis in malarial anemia is associated with hemozoin in vitro and in vivo
Climent Casals-Pascual,
Oscar Kai,
Joyce O. P. Cheung,
Senani Williams,
Brett Lowe,
Mike Nyanoti,
Thomas N. Williams,
Kathryn Maitland,
Malcolm Molyneux,
Charles R. J. C. Newton,
Norbert Peshu,
Suzanne M. Watt, and
David J. Roberts
From the Nuffield Department of Clinical Laboratory Sciences and National Blood Service Oxford Centre, Nuffield Department of Paediatrics, and the Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, United Kingdom; Kenya Medical Research Institute (KEMRI) Centre for Geographic Medicine-Coast, Kilifi, Kenya; the Department of Pathology, Faculty of Medicine, University of Kelaniya, Kelaniya, Sri Lanka; the Department of Paediatrics, Imperial College of Medicine at St Mary's Hospital, Norfolk Place, London, United Kingdom; Malawi-Liverpool-Wellcome Trust Clinical Research Programme (MLW), College of Medicine, Blantyre, Malawi; the School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool, United Kingdom; and the Neurosciences Unit, Institute for Child Health, London, United Kingdom.
Malarial anemia is a global public health problem and is characterized by a low reticulocyte response in the presence of life-threatening hemolysis. Although cytokines, in particular tumor necrosis factor- (TNF-), can suppress erythropoiesis, the grossly abnormal bone marrow morphology indicates that other factors may contribute to ineffective erythropoiesis. We hypothesized that the cytotoxic hemozoin (Hz) residues from digested hemoglobin (Hb) significantly contribute to abnormal erythropoiesis. Here, we show that not only isolated Hz, but also delipidated Hz, inhibits 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 < .001) and reticulocyte suppression (P = .009), and that this is independent of the level of circulating cytokines, including TNF-. Plasma Hz is also associated with anemia (P < .001) and reticulocyte suppression (P = .02). Finally, histologic 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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