Suppression of erythropoiesis in malarial anemia is associated with hemozoin in vitro and in vivo

Casals-Pascual, Climent; Kai, Oscar; Cheung, Joyce O. P.; Williams, Senani; Lowe, Brett; Nyanoti, Mike; Williams, Thomas N.; Maitland, Kathryn; Molyneux, Malcolm E.; Newton, Charles R.; Peshu, Norbert; Watt, Suzanne M.; Roberts, David J.

doi:10.1182/blood-2006-05-018697

Cited by 170 publications

(177 citation statements)

References 52 publications

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“…A second possible factor that may also exert an influence in erythropoiesis is the production of immune mediators, by host cells, as a response to parasite products; when released, these mediators would damage surrounding haematopoietic cells, altering their morphology and function (82). In this regard, it has been demonstrated that the presence of hemozoin, a metabolic product generated during the digestion of hemoglobin, in plasma, leukocytes, or erytroid precursors, was able to inhibit erythropoiesis (89). Studies conducted with bone marrow sections obtained from children who died as a result of severe malaria showed an association between the amount of hemozoin and the proportion of abnormal erythroid cells (90).…”

Section: Dyserythropoiesis and Immune-mediated Anemiamentioning

confidence: 99%

Potential Immune Mechanisms Associated with Anemia in Plasmodium vivax Malaria: a Puzzling Question

et al. 2014

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The pathogenesis of malaria is complex, generating a broad spectrum of clinical manifestations. One of the major complications and concerns in malaria is anemia, which is responsible for considerable morbidity in the developing world, especially in children and pregnant women. Despite its enormous health importance, the immunological mechanisms involved in malaria-induced anemia remain incompletely understood. Plasmodium vivax, one of the causative agents of human malaria, is known to induce a strong inflammatory response with a robust production of immune effectors, including cytokines and antibodies. Therefore, it is possible that the extent of the immune response not only may facilitate the parasite killing but also may provoke severe illness, including anemia. In this review, we consider potential immune effectors and their possible involvement in generating this clinical outcome during P. vivax infections.

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Section: Dyserythropoiesis and Immune-mediated Anemiamentioning

confidence: 99%

Potential Immune Mechanisms Associated with Anemia in Plasmodium vivax Malaria: a Puzzling Question

et al. 2014

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“…For a more detailed study on the changes in erythropoietin and severity of anemia during infection with P falciparum see Casals-Pascual. 72 NR indicates not reported. *Hb levels reported in this study were given as a percent of baseline values determined in noninfected mice.…”

Section: Loss Of Uninfected Erythrocytesmentioning

confidence: 99%

“…72 Moreover, bone marrow sections from children who died from severe malaria show a significant association between the quantity of hemozoin (located in erythroid precursors and macrophages) and the proportion of erythroid cells that was abnormal. These findings are consistent with a direct inhibitory effect of hemozoin on erythropoiesis and therefore warrant further investigation.…”

Section: Erythropoietic Suppression and Dyserythropoiesismentioning

confidence: 99%

“…25,[106][107][108] In fact, the Epo levels in malarial anemia are more than 3-fold higher when compared with anemic children without malaria. 72 It is possible that ineffective or inadequate Epo synthesis does contribute to malarial anemia in some settings, possibly related to age, ethnic origin, or presentation of the patient. However, in African children with malaria, Epo synthesis is indeed elevated more than expected and it is more likely that a reduced response to Epo, not an inappropriately low level of Epo, is the more significant contribution to pathology.…”

Section: Org Frommentioning

confidence: 99%

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Malarial anemia: of mice and men

Lamikanra

Brown²,

Potocnik³

et al. 2007

Blood

230

215

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Severe malaria is manifest by a variety of clinical syndromes dependent on properties of both the host and the parasite. In young infants, severe malarial anemia (SMA) is the most common syndrome of severe disease and contributes substantially to the considerable mortality and morbidity from malaria. There is now growing evidence, from both human and mouse studies of malaria, to show that anemia is due not only to increased hemolysis of infected and clearance of uninfected red blood cells (RBCs) but also to an inability of the infected host to produce an adequate erythroid response. In this review, we will summarize the recent clinical and experimental studies of malaria to highlight similarities and differences in human and mouse pathology that result in anemia and so inform the use of mouse models in the study of severe malarial anemia in humans. Malaria in humansThe vast majority of morbidity and mortality from malaria is caused by infection with Plasmodium falciparum, although P vivax, P ovale, and P malariae also are responsible for human infections. The total burden of disease has recently been estimated to 515 million episodes annually and malaria is responsible for 18% of all childhood deaths in sub-Saharan Africa, equivalent to 800 000 deaths each year. 1,2 The study of malarial anemia has somewhat belatedly excited academic and professional interest. Severe malarial anemia (SMA) certainly merits concern as a major public health problem because of the very large numbers of children affected, and it is likely that these numbers may increase as drug resistance spreads. Concerns have also been raised by data from recent vaccine studies, which suggest that monkeys immunized with erythrocytic-stage antigens, and that have acquired protection from acute infection, may succumb to severe anemia during a subacute or chronic phase of infection. 3,4 Moreover, there is increasing awareness of the difficulty of satisfactory treatment by blood transfusion outside specialist centers in many endemic areas as a result of the limited availability of a rapid and safe supply of blood. 1,5 SMA is seen most frequently in areas of very high malaria transmission and most commonly in young children and pregnant women. 6 The prevalence of anemia, defined as a hematocrit (Hct) level higher than 0.33, in malaria-endemic areas of Africa, varies between 31% and 91% in children, and between 60% and 80% in pregnant women. 7,8 Given the high degree of morbidity that is associated with SMA in children, this term will be used to refer to severe anemia in this group, unless stated otherwise.It is very difficult to determine the number of cases of severe anemia attributable to malaria as the WHO definition of SMA (a hemoglobin [Hb] concentration of Ͻ 50 g/L [5 g/dL], or a Hct Ͻ 0.15, in the presence of a parasitemia Ͼ 10 000 parasites per microliter [L], and a normocytic blood film) may exclude the considerable proportion of children admitted with severe anemia that has a blood smear negative for malaria parasites but that responds to an...

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“…Likewise, as antiretroviral therapy is increasingly available in sub-Saharan Africa; future studies among such children would be needed. It is noteworthy that the role of hemozoin in malaria pathogenesis, including PCM, has been extensively studied [15][16][17]. A recent multisite study of 26,000 pediatric malaria cases in sub-Saharan Africa concluded that PCM, while predictive of severe disease and mortality, failed to provide additional prognostic value beyond conventional markers of disease severity [18].…”

Section: Moving Toward Hematological Predictors Of Disease Severity Imentioning

confidence: 99%

All that glitters is gold?

Cott

2010

American J Hematol

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DNA testing is often considered a gold standard in clinical laboratory testing. But just how golden is the standard? In this issue of American Journal of Hematology, Emadi et al. investigate this question with regard to the two most commonly performed DNA tests in the field of coagulation: Factor V Leiden and prothrombin G20210A [1].Unlike other coagulation assays, such as protein C, protein S, or antithrombin, the presence or absence of factor V Leiden or prothrombin G20210A is constant throughout an individual's lifetime. Thus, clinicians often assume that there is no need to repeat the DNA test to confirm the findings. Is this a valid approach? In comparison, for example, protein C can be reduced by liver dysfunction, vitamin K deficiency, poor nutrition, oral anticoagulation therapy, disseminated intravascular coagulation (DIC), recent thrombosis or surgery, or patient age (protein C is lower than adults throughout childhood). In addition, some protein C activity assays may be falsely elevated by lupus anticoagulants or direct thrombin inhibitor anticoagulant therapy. Therefore, repeat testing and family studies are often needed to investigate the possibility of hereditary protein C deficiency. In contrast, DNA testing is not affected by any of these variables. Thus, is it safe to assume that the results of a DNA test truly represent the patient's genotype?Emadi and colleagues sought to answer these questions by carefully reviewing all relevant abstracts (studies comparing a factor V Leiden and/or prothrombin G20210A DNA assay to a reference method) published between 2000 and 2008, analyzing the 66 manuscripts that met their selection criteria. The reference method in most of these studies was polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP) or allele-specific PCR. Concordance with the reference method was 98-100% for all methods except for some studies with agreement as low as 90.2%. In most cases, the discrepancy resolved upon repeating the test. Many of the errors may have been attributable to human error rather than a failure of the assay itself. The authors conclude that the error rate is low. However, it is important to emphasize that errors do occur, for example, 98% concordance means that one in every 50 specimens is reported incorrectly. Furthermore, studies on external quality assurance (EQA, proficiency programs that assess a clinical laboratory's ability to correctly test unknown specimens) revealed that most laboratories were highly accurate with these tests, but errors included transcription errors (writing the wrong result when preparing the report), misinterpretation of the data, and in one study, a homozygous factor V Leiden specimen was misidentified by 15% of participating laboratories. In another EQA study, 51% of laboratories made at least one error over time (133 specimens were sent to 39 laboratories over 10 different periods of time), but the authors note that three of 39 laboratories were responsible for 46% of all errors.Additional EQA data f...

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Suppression of erythropoiesis in malarial anemia is associated with hemozoin in vitro and in vivo

Cited by 170 publications

References 52 publications

Potential Immune Mechanisms Associated with Anemia in Plasmodium vivax Malaria: a Puzzling Question

Potential Immune Mechanisms Associated with Anemia in Plasmodium vivax Malaria: a Puzzling Question

Malarial anemia: of mice and men

All that glitters is gold?

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