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, 5 (4), e10038

Hemolysis Is Associated With Low Reticulocyte Production Index and Predicts Blood Transfusion in Severe Malarial Anemia

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Hemolysis Is Associated With Low Reticulocyte Production Index and Predicts Blood Transfusion in Severe Malarial Anemia

Rolf Fendel et al. PLoS One.

Abstract

Background: Falciparum Malaria, an infectious disease caused by the apicomplexan parasite Plasmodium falciparum, is among the leading causes of death and morbidity attributable to infectious diseases worldwide. In Gabon, Central Africa, one out of four inpatients have severe malarial anemia (SMA), a life-threatening complication if left untreated. Emerging drug resistant parasites might aggravate the situation. This case control study investigates biomarkers of enhanced hemolysis in hospitalized children with either SMA or mild malaria (MM).

Methods and findings: Ninety-one children were included, thereof 39 SMA patients. Strict inclusion criteria were chosen to exclude other causes of anemia. At diagnosis, erythrophagocytosis (a direct marker for extravascular hemolysis, EVH) was enhanced in SMA compared to MM patients (5.0 arbitrary units (AU) (interquartile range (IR): 2.2-9.6) vs. 2.1 AU (IR: 1.3-3.9), p<0.01). Furthermore, indirect markers for EVH, (i.e. serum neopterin levels, spleen size enlargement and monocyte pigment) were significantly increased in SMA patients. Markers for erythrocyte ageing, such as CD35 (complement receptor 1), CD55 (decay acceleration factor) and phosphatidylserine exposure (annexin-V-binding) were investigated by flow cytometry. In SMA patients, levels of CD35 and CD55 on the red blood cell surface were decreased and erythrocyte removal markers were increased when compared to MM or reconvalescent patients. Additionally, intravascular hemolysis (IVH) was quantified using several indirect markers (LDH, alpha-HBDH, haptoglobin and hemopexin), which all showed elevated IVH in SMA. The presence of both IVH and EVH predicted the need for blood transfusion during antimalarial treatment (odds ratio 61.5, 95% confidence interval (CI): 8.9-427). Interestingly, this subpopulation is characterized by a significantly lowered reticulocyte production index (RPI, p<0.05).

Conclusions: Our results show the multifactorial pathophysiology of SMA, whereby EVH and IVH play a particularly important role. We propose a model where removal of infected and non-infected erythrocytes of all ages (including reticulocytes) by EVH and IVH is a main mechanism of SMA. Further studies are underway to investigate the mechanism and extent of reticulocyte removal to identify possible interventions to reduce the risk of SMA development.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Study-flow chart.
Figure 2
Figure 2. Phagocytosis rate in severe malarial anemia (SMA) and mild malaria (MM) patients: The plot shows individual values of relative phagocytosis of autologous samples (patients monocytes phagocytosing autologous RBCs) and positive control samples (patients monocytes phagocytosing anti-D IgG opsonized control RBCs).
Thick lines represent median values. Phagocytosis rates were investigated on admission and after reconvalescence on day 56. In A) phagocytosis rates are shown for SMA patients. Phagocytosis rates of autologous samples at day 0 are as high as positive control. On day 56, autologous sample is significantly lower than positive control (p<0.05, ○ SMA - non-transfused, • SMA - transfused). In B), phagocytosis rates of MM patients are illustrated. Phagocytosis rates of autologous samples are significantly lower on day 0 as well as on day 56 (p<0.05, Δ MM).
Figure 3
Figure 3. Distribution of enhanced intravascular and extravascular hemolysis across the patient groups and its correlation with reduced RPI: In figure A), a dot plot of α-HBDH vs. hemopexin concentration, both makers for IVH, at presentation is shown on the x and y axis, respectively.
The size of the data symbols represents erythrophagocytosis activity, a direct marker of EVH (the bigger the symbol, the higher the autologous erythrophagocytosis). Classification criteria for “elevated IVH and EVH” match for those symbols bigger than the borderline levels shown in the plot and laying in the white region. Figure B: The Group having both “elevated EVH and IVH” had significantly lower reticulocyte productions indices than the other patients (p<0.05). Δ MM; ○ SMA - non transfused; • SMA - blood transfused.

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