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. 2009 Nov 15;200(10):1522-9.
doi: 10.1086/644641.

Relationship of cell-free hemoglobin to impaired endothelial nitric oxide bioavailability and perfusion in severe falciparum malaria

Tsin W Yeo  1 , Daniel A Lampah, Emiliana Tjitra, Retno Gitawati, Enny Kenangalem, Kim Piera, Donald L Granger, Bert K Lopansri, J Brice Weinberg, Ric N Price, Stephen B Duffull, David S Celermajer, Nicholas M Anstey
Affiliations

Relationship of cell-free hemoglobin to impaired endothelial nitric oxide bioavailability and perfusion in severe falciparum malaria

Tsin W Yeo et al. J Infect Dis. .

Abstract

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.

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Conflict of interest statement

Potential conflicts of interest: N.M.A., D.L.G., and J.B.W. are named as inventors in a US patent for the use of l-arginine as treatment for severe malaria but have transferred all their rights to their respective institutional malaria research collaborations. This patent is issued for US rights only, and no rights are being sought in other countries. All other authors report no other conflicting interests.

Figures

Figure 1
Figure 1
Cell-free hemoglobin concentrations in patients with moderately severe and severe malaria and healthy controls (P < .001, by Kruskal-Wallis test). Horizontal lines indicate medians for each group. Differences among groups were compared using the Kruskal-Wallis test, and the Mann-Whitney U test was used for post hoc pairwise comparisons.
Figure 2
Figure 2
Longitudinal course of cell-free hemoglobin concentrations in patients with severe malaria. Median values (circles) and interquartile range (bars) are displayed for all time points. The x-axis values represent time from the start of antimalarial therapy (day 0, 0–12 h; day 1, 13–36 h; day 2, 37–60 h; day 3, 61–84 h; day 4, 85–109 h; and days 5–14, >110 h).
See this image and copyright information in PMC

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