Intravascular haemolysis in severe Plasmodium knowlesi malaria

Association with endothelial activation, microvascular dysfunction, and acute kidney injury article

Bridget E. Barber, Matthew J. Grigg, Kim A. Piera, Timothy William, Daniel J. Cooper, Katherine Plewes, Arjen M. Dondorp, Tsin W. Yeo, Nicholas M. Anstey

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    Abstract

    Plasmodium knowlesi occurs throughout Southeast Asia, and is the most common cause of human malaria in Malaysia. Severe disease in humans is characterised by high parasite biomass, reduced red blood cell deformability, endothelial activation and microvascular dysfunction. However, the roles of intravascular haemolysis and nitric oxide (NO)-dependent endothelial dysfunction, important features of severe falciparum malaria, have not been evaluated, nor their role in acute kidney injury (AKI). In hospitalised Malaysian adults with severe (n = 48) and non-severe (n = 154) knowlesi malaria, and in healthy controls (n = 50), we measured cell-free haemoglobin (CFHb) and assessed associations with the endothelial Weibel-Palade body (WPB) constituents, angiopoietin-2 and osteoprotegerin, endothelial and microvascular function, and other markers of disease severity. CFHb was increased in knowlesi malaria in proportion to disease severity, and to a greater extent than previously reported in severe falciparum malaria patients from the same study cohort. In knowlesi malaria, CFHb was associated with parasitaemia, and independently associated with angiopoietin-2 and osteoprotegerin. As with angiopoietin-2, osteoprotegerin was increased in proportion to disease severity, and independently associated with severity markers including creatinine, lactate, interleukin-6, endothelial cell adhesion molecules ICAM-1 and E-selectin, and impaired microvascular reactivity. Osteoprotegerin was also independently associated with NO-dependent endothelial dysfunction. AKI was found in 88% of those with severe knowlesi malaria. Angiopoietin-2 and osteoprotegerin were both independent risk factors for acute kidney injury. Our findings suggest that haemolysis-mediated endothelial activation and release of WPB constituents is likely a key contributor to end-organ dysfunction, including AKI, in severe knowlesi malaria.

    Original languageEnglish
    Article number106
    Pages (from-to)1-10
    Number of pages10
    JournalEmerging Microbes and Infections
    Volume7
    DOIs
    Publication statusPublished - 6 Jun 2018

    Fingerprint

    Plasmodium knowlesi
    Plasmodium malariae
    Osteoprotegerin
    Hemolysis
    Acute Kidney Injury
    Angiopoietin-2
    Malaria
    Weibel-Palade Bodies
    Hemoglobins
    Falciparum Malaria
    Nitric Oxide
    Southeastern Asia
    E-Selectin
    Parasitemia
    Malaysia
    Cell Adhesion Molecules
    Intercellular Adhesion Molecule-1
    Biomass
    Lactic Acid
    Interleukin-6

    Cite this

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    title = "Intravascular haemolysis in severe Plasmodium knowlesi malaria: Association with endothelial activation, microvascular dysfunction, and acute kidney injury article",
    abstract = "Plasmodium knowlesi occurs throughout Southeast Asia, and is the most common cause of human malaria in Malaysia. Severe disease in humans is characterised by high parasite biomass, reduced red blood cell deformability, endothelial activation and microvascular dysfunction. However, the roles of intravascular haemolysis and nitric oxide (NO)-dependent endothelial dysfunction, important features of severe falciparum malaria, have not been evaluated, nor their role in acute kidney injury (AKI). In hospitalised Malaysian adults with severe (n = 48) and non-severe (n = 154) knowlesi malaria, and in healthy controls (n = 50), we measured cell-free haemoglobin (CFHb) and assessed associations with the endothelial Weibel-Palade body (WPB) constituents, angiopoietin-2 and osteoprotegerin, endothelial and microvascular function, and other markers of disease severity. CFHb was increased in knowlesi malaria in proportion to disease severity, and to a greater extent than previously reported in severe falciparum malaria patients from the same study cohort. In knowlesi malaria, CFHb was associated with parasitaemia, and independently associated with angiopoietin-2 and osteoprotegerin. As with angiopoietin-2, osteoprotegerin was increased in proportion to disease severity, and independently associated with severity markers including creatinine, lactate, interleukin-6, endothelial cell adhesion molecules ICAM-1 and E-selectin, and impaired microvascular reactivity. Osteoprotegerin was also independently associated with NO-dependent endothelial dysfunction. AKI was found in 88{\%} of those with severe knowlesi malaria. Angiopoietin-2 and osteoprotegerin were both independent risk factors for acute kidney injury. Our findings suggest that haemolysis-mediated endothelial activation and release of WPB constituents is likely a key contributor to end-organ dysfunction, including AKI, in severe knowlesi malaria.",
    author = "Barber, {Bridget E.} and Grigg, {Matthew J.} and Piera, {Kim A.} and Timothy William and Cooper, {Daniel J.} and Katherine Plewes and Dondorp, {Arjen M.} and Yeo, {Tsin W.} and Anstey, {Nicholas M.}",
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    Intravascular haemolysis in severe Plasmodium knowlesi malaria : Association with endothelial activation, microvascular dysfunction, and acute kidney injury article. / Barber, Bridget E.; Grigg, Matthew J.; Piera, Kim A.; William, Timothy; Cooper, Daniel J.; Plewes, Katherine; Dondorp, Arjen M.; Yeo, Tsin W.; Anstey, Nicholas M.

    In: Emerging Microbes and Infections, Vol. 7, 106, 06.06.2018, p. 1-10.

    Research output: Contribution to journalArticleResearchpeer-review

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    T2 - Association with endothelial activation, microvascular dysfunction, and acute kidney injury article

    AU - Barber, Bridget E.

    AU - Grigg, Matthew J.

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    AU - William, Timothy

    AU - Cooper, Daniel J.

    AU - Plewes, Katherine

    AU - Dondorp, Arjen M.

    AU - Yeo, Tsin W.

    AU - Anstey, Nicholas M.

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    AB - Plasmodium knowlesi occurs throughout Southeast Asia, and is the most common cause of human malaria in Malaysia. Severe disease in humans is characterised by high parasite biomass, reduced red blood cell deformability, endothelial activation and microvascular dysfunction. However, the roles of intravascular haemolysis and nitric oxide (NO)-dependent endothelial dysfunction, important features of severe falciparum malaria, have not been evaluated, nor their role in acute kidney injury (AKI). In hospitalised Malaysian adults with severe (n = 48) and non-severe (n = 154) knowlesi malaria, and in healthy controls (n = 50), we measured cell-free haemoglobin (CFHb) and assessed associations with the endothelial Weibel-Palade body (WPB) constituents, angiopoietin-2 and osteoprotegerin, endothelial and microvascular function, and other markers of disease severity. CFHb was increased in knowlesi malaria in proportion to disease severity, and to a greater extent than previously reported in severe falciparum malaria patients from the same study cohort. In knowlesi malaria, CFHb was associated with parasitaemia, and independently associated with angiopoietin-2 and osteoprotegerin. As with angiopoietin-2, osteoprotegerin was increased in proportion to disease severity, and independently associated with severity markers including creatinine, lactate, interleukin-6, endothelial cell adhesion molecules ICAM-1 and E-selectin, and impaired microvascular reactivity. Osteoprotegerin was also independently associated with NO-dependent endothelial dysfunction. AKI was found in 88% of those with severe knowlesi malaria. Angiopoietin-2 and osteoprotegerin were both independent risk factors for acute kidney injury. Our findings suggest that haemolysis-mediated endothelial activation and release of WPB constituents is likely a key contributor to end-organ dysfunction, including AKI, in severe knowlesi malaria.

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