Relationship of Cell-Free Hemoglobin to Impaired Endothelial Nitric Oxide Bioavailability and Perfusion in Severe Falciparum Malaria

Tsin Yeo, D LAMPAH, E TJITRA, R GITAWATI, Enny Kenangalem, Kim Piera, D GRANGER, B LOPANSRI, J WEINBERG, Ric Price, S DUFFULL, D CELERMAJER, Nicholas Anstey

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    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 ( ) np78 or severe (np49) malaria and control subjects (np16) from Papua, Indonesia. Results: Cell-free hemoglobin concentrations in patients with SM (median, 5.4 ?mol/L; interquartile range [IQR], 3.2-7.4 ?mol/L) were significantly higher than in those with moderately severe malaria (2.6 ?mol/L; IQR, 1.3-4.5 ?mol/L) or controls (1.2 ?mol/L; IQR, 0.9-2.4 ?mol/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 (Pp.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. � 2009 by the Infectious Diseases Society of America. All rights reserved.
    Original languageEnglish
    Pages (from-to)1522-1529
    Number of pages8
    JournalJournal of Infectious Diseases
    Volume200
    Issue number10
    Publication statusPublished - 2009

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    Yeo, T., LAMPAH, D., TJITRA, E., GITAWATI, R., Kenangalem, E., Piera, K., GRANGER, D., LOPANSRI, B., WEINBERG, J., Price, R., DUFFULL, S., CELERMAJER, D., & Anstey, N. (2009). Relationship of Cell-Free Hemoglobin to Impaired Endothelial Nitric Oxide Bioavailability and Perfusion in Severe Falciparum Malaria. Journal of Infectious Diseases, 200(10), 1522-1529.