Relationship of cell-free hemoglobin to impaired endothelial nitric oxide bioavailability and perfusion in severe falciparum malaria.
BACKGROUND
Hemolysis causes anemia in falciparum malaria, but its contribution to microvascular pathology in severe malaria (SM) is not well characterized. In other hemolytic diseases, release of cell-free hemoglobin causes nitric oxide (NO) quenching, endothelial activation, and vascular complications. We examined the relationship of plasma hemoglobin and myoglobin to endothelial dysfunction and disease severity in malaria.


METHODS
Cell-free hemoglobin (a potent NO quencher), reactive hyperemia peripheral arterial tonometry (RH-PAT) (a measure of endothelial NO bioavailability), and measures of perfusion and endothelial activation were quantified in adults with moderately severe (n = 78) or severe (n = 49) malaria and control subjects (n = 16) from Papua, Indonesia.


RESULTS
Cell-free hemoglobin concentrations in patients with SM (median, 5.4 micromol/L; interquartile range [IQR], 3.2-7.4 micromol/L) were significantly higher than in those with moderately severe malaria (2.6 micromol/L; IQR, 1.3-4.5 micromol/L) or controls (1.2 micromol/L; IQR, 0.9-2.4 micromol/L; P < .001). Multivariable regression analysis revealed that cell-free hemoglobin remained inversely associated with RH-PAT, and in patients with SM, there was a significant longitudinal association between improvement in RH-PAT index and decreasing levels of cell-free hemoglobin (P = .047). Cell-free hemoglobin levels were also independently associated with lactate, endothelial activation, and proinflammatory cytokinemia.


CONCLUSIONS
Hemolysis in falciparum malaria results in NO quenching by cell-free hemoglobin, and may exacerbate endothelial dysfunction, adhesion receptor expression and impaired tissue perfusion. Treatments that increase NO bioavailability may have potential as adjunctive therapies in SM.
International Health Division, Menzies School of Health Research and Charles Darwin University, Royal Darwin Hospital, Darwin, NT 0811, Australia.
Tsin W
TW
Yeo
Daniel A
DA
Lampah
Emiliana
E
Tjitra
Retno
R
Gitawati
Enny
E
Kenangalem
Kim
K
Piera
Donald L
DL
Granger
Bert K
BK
Lopansri
J Brice
JB
Weinberg
Ric N
RN
Price
Stephen B
SB
Duffull
David S
DS
Celermajer
Nicholas M
NM
Anstey
D000328:Adult; D000743:Anemia, Hemolytic / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D006454:Hemoglobins / Q000502:physiology*; D006801:Humans; D016778:Malaria, Falciparum / Q000503:physiopathology*; D016780:Malaria, Vivax / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009211:Myoglobin / Q000097:blood; D009569:Nitric Oxide / Q000097:blood / Q000502:physiology*; D012720:Severity of Illness Index; D055815:Young Adult
D006454:Hemoglobins; D009211:Myoglobin; D009569:Nitric Oxide