Hemolysis is associated with low reticulocyte production index and predicts blood transfusion in severe malarial anemia.
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).


RESULTS
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.
Fendel
Rolf
R
Medical Research Unit, Albert Schweitzer Hospital, Lambaréné, Gabon.
Brandts
Christian
C
Rudat
Annika
A
Kreidenweiss
Andrea
A
Steur
Claudia
C
Appelmann
Iris
I
Ruehe
Bettina
B
Schröder
Paul
P
Berdel
Wolfgang E
WE
Kremsner
Peter G
PG
Mordmüller
Benjamin
B
D000740:Anemia / Q000209:etiology* / Q000628:therapy; D015415:Biomarkers; D001803:Blood Transfusion; D016022:Case-Control Studies; D002648:Child; D004905:Erythrocyte Aging; D006461:Hemolysis; D006801:Humans; D008288:Malaria / Q000097:blood / Q000473:pathology* / Q000628:therapy; D010963:Plasmodium falciparum; D012156:Reticulocytes / Q000166:cytology*; D012720:Severity of Illness Index
D015415:Biomarkers
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