INTRODUCTION:
The importance of anemia as a cause of death in malaria may well be underestimated because of difficulty in diagnosis, especially where parasitaemia may be low and the clinical picture may be confused with other causes of anemia. Two clinical presentations predominate: severe acute malaria in which anemia supervenes, and severe anemia in patients in whom there have been repeated attacks of malaria. The major mechanisms are those of red cell destruction and decreased red cell production. Potential causes of hemolysis include loss of infected cells by rupture or phagocytosis, removal of uninfected cells due to antibody sensitization or other physicochemical membrane changes, and increased reticuloendothelial activity, particularly in organs such as the spleen.
Decreased production results from marrow hypoplasia seen in acute infections, and dyserythropoiesis, a morphological appearance, which in functional terms results in ineffective erythropoiesis1.
Case Report
A 4– year-old male child presented with one months history of fever off and on, with weakness and convulsions. On examination pallor, icterus; hepatomegaly and spleenomegaly were evident. No lymphadenopathy seen. On Peripheral blood examination smear RBC shows macrocytosis, anisiocytosis, schistocytosis, polychromasia, Nrbc, and decrease rbc count with low reticulocyte count. WBc shows leucocytosis with lymphocytosis and presence of pigment laden monocyte and few macrophages as shown in figure 1. No immature cells of WBC series seen. There is thrombocytopenia. No haemoparite mainly malaria seen in examined peripheral smear. Biochemical tests show mild hyperbilirubinimia with increase in indirect fraction, SGPT within normal limit.
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Figure 1:P.S. Smear showing malarial pigment (Hemozoin) laden macrophages. |
Figure 2: B.M. Smear showing a plasmodium falciparum gamete along with dysplastic erythroid precursors. |
On bone marrow examination, smear shows moderate cellularity, M:E ratio altered, leucopoiesis mildly suppressed with normal maturation of leucocytes. The erythropoiesis is increased with presence of dysplastic erythroid precusors in the form of megaloblastosis, binucleated and fragmented erythroid precursors, the megakaryocytes are normal in number and function, plenty of brown coloured pigment laden macrophage and presence of gametocyte of plasmodium falciparum seen in figure 2.
DISCUSSION:
Severe malarial anemia is most common in endemic areas. The pathophysiology of chronic malaria is characterized by a striking degree of abnormal development of erythroid precursors (dyserythropoiesis) and an inadequate erythropoietic response in spite of elevated levels of erythropoietin 2,3. The cause of dyserythropoiesis is unclear although it has been suggested that bone-marrow macrophages release cytokines, chemokines or lipo-peroxides after exposure to hemozoin, a crystalloid form of undigested heme moieties from malarial infected erythrocytes, and so inhibit erythropoiesis. However, we have previously shown that hemozoin may directly inhibit erythroid development in vitro and the levels of hemozoin in plasma from patients with malarial anemia and hemozoin within the bone marrow was associated with reduced reticulocyte response. We hypothesized that macrophages may reduce, not enhance, the inhibitory effect of hemozoin on erythropoiesis. In an in vitro model of erythropoiesis, we now show that inhibition of erythroid cell development by hemozoin isolated from P. falciparum is characterized by delayed expression of the erythroid markers and increased apoptosis of progenitor cells. Crucially, macrophages appear to protect erythroid cells from hemozoin, consistent with a direct contribution of hemozoin to the depression of reticulocyte output from the bone marrow in children with malarial anemia 6. Moreover, hemozoin isolated from P. falciparum in vitro inhibits erythroid development independently of inflammatory mediators by inducing apoptotic pathways that not only involve activation of caspase 8 and cleavage of caspase 3 but also loss of mitochondrial potential. Taken together these data are consistent with a direct effect of hemozoin in inducing apoptosis in developing erythroid cells in malarial anemia. Accumulation of hemozoin in the bone marrow could therefore result in inadequate reticulocytosis in children that have adequate levels of circulating erythropoietin 4,7. The possible roles of parasite products, T-cell-derived cytokines produced in response to the infection, macrophage activation and hyperplasia, macrophage-derived factors such as tumour necrosis factor-alpha, and macrophage dysfunction in the pathogenesis of the hematological abnormalities is evident 5.
One important cause of impaired erythroid responses in children with SMA is dysregulation in the innate immune response. Phagocytosis of malarial pigment hemozoin (Hz) by monocytes, macrophages, and neutrophils is a central factor for promoting dysregulation in innate inflammatory mediators. As such, the role of P. falciparum-derived Hz (PfHz) in mediating suppression of erythropoiesis through its ability to cause dysregulation in pro- and anti-inflammatory cytokines, growth factors, chemokines 8.
CONCLUSION:
This case report has shown that the severe anemia in children is due to ineffective erythropoiesis induced by hemozoin laden macrophages present in blood and bone marrow. Such patient should be kept under strict observation and should be managed accordingly.
Abbreviations
RBC-Red blood cell
SGPT- Serum glutamate pyruvate
transaminase
WBC- White blood cell
SMA-Severe malarial anemia
Hz- Hemozoin
PfHz- P. falciparum hemozoin
M:E ratio – Myeloid: Erythroid
ratio
REFERENCE:
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2. The importance of anaemia in cerebral and uncomplicated falciparum malaria: role of complications, dyserythropoiesis and iron sequestration. Phillips RE, Looareesuwan S, Warrell DA, Lee SH, Karbwang J, Warrell MJ, White NJ, Swasdichai C, Weatherall DJ. Q J Med. 1986 Mar;58(227):305-23.
3. The course of anaemia after the treatment of acute, falciparum malaria. Camacho LH, Gordeuk VR, Wilairatana P, Pootrakul P, Brittenham GM, Looareesuwan S Ann Trop Med Parasitol. 1998 Jul;92(5):525-37.
4. Inappropriately low reticulocytosis in severe malarial anemia correlates with suppression in the development of late erythroid precursors. Chang KH, Tam M, Stevenson MM Blood. 2004 May 15;103(10):3727-35. Epub 2004 Jan 22.
5. Blood and bone marrow changes in malaria. Wickramasinghe SN, Abdalla SH Baillieres Best Pract Res Clin Haematol. 2000 Jun;13(2):277-99.
6. Hemozoin- and 4-hydroxynonenal-mediated inhibition of erythropoiesis. Possible role in malarial dyserythropoiesis and anemia. Giribaldi G, Ulliers D, Schwarzer E, Roberts I, Piacibello W, Arese P. Haematologica. 2004 Apr;89(4):492-3.
7. Hemozoin (malarial pigment) directly promotes apoptosis of erythroid precursors, Lamikanra AA, Theron M, Kooij TW, Roberts DJ, PLoS One. 2009 Dec 24;4(12):e8446.
8. Severe malarial anemia: innate immunity and pathogenesis, Perkins DJ, Were T, Davenport GC, Kempaiah P, Hittner JB, Ong'echa JM Int J Biol Sci. 2011;7(9):1427-42. Epub 2011 Nov 2
Received on 01.07.2012 Modified on 15.07.2012
Accepted on 18.07.2012 © AJRC All right reserved
Asian J. Research Chem. 5(8): August, 2012; Page 996-997