title: Suppression of erythropoiesis in malarial anemia is associated with hemozoin in vitro and in vivo.
abstract: 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-alpha (TNF-alpha), 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-alpha. However, when added to cultures, TNF-alpha 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-alpha. 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.
authors.affiliation: Nuffield Department of Clinical Laboratory Sciences and National Blood Service Oxford Centre, John Radcliffe Hospital, Oxford OX3 9BQ, United Kingdom. climentcasals@hotmail.com
authors.forename: Climent
authors.initials: C
authors.lastname: Casals-Pascual
authors.forename: Oscar
authors.initials: O
authors.lastname: Kai
authors.forename: Joyce O P
authors.initials: JO
authors.lastname: Cheung
authors.forename: Senani
authors.initials: S
authors.lastname: Williams
authors.forename: Brett
authors.initials: B
authors.lastname: Lowe
authors.forename: Mike
authors.initials: M
authors.lastname: Nyanoti
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Williams
authors.forename: Kathryn
authors.initials: K
authors.lastname: Maitland
authors.forename: Malcolm
authors.initials: M
authors.lastname: Molyneux
authors.forename: Charles R J C
authors.initials: CR
authors.lastname: Newton
authors.forename: Norbert
authors.initials: N
authors.lastname: Peshu
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Watt
authors.forename: David J
authors.initials: DJ
authors.lastname: Roberts
mesh_terms: D000740:Anemia / Q000097:blood* / Q000209:etiology / Q000473:pathology; D000818:Animals; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000097:blood; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology; D004920:Erythropoiesis / Q000187:drug effects*; D006420:Hemeproteins / Q000633:toxicity*; D006801:Humans; D066298:In Vitro Techniques; D007223:Infant; D016778:Malaria, Falciparum / Q000097:blood* / Q000150:complications / Q000473:pathology; D010963:Plasmodium falciparum / Q000472:pathogenicity; D017701:Reticulocyte Count; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology
chemical_list: D016207:Cytokines; D006420:Hemeproteins; D014409:Tumor Necrosis Factor-alpha; C020753:hemozoin