Angiopoietin-2 and Angiopoietin-2/Angiopoietin-1 Ratio as Indicators of Potential Severity of Plasmodium vivax Malaria in Patients with Thrombocytopenia

Gomes, Luciano Teixeira; Alves-Junior, Eduardo Rodrigues; Rodrigues-Jesus, Clebson; Nery, Andréia Ferreira; Gasquez-Martin, Thamires Oliveira; Fontes, Cor Jésus Fernandes

doi:10.1371/journal.pone.0109246

Cited by 29 publications

(47 citation statements)

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“…In a retrospective cohort, patients who died from malaria had lower platelet counts in comparison to those with less severe disease (3). Moreover, P. vivax malaria patients with thrombocytopenia showed higher levels of markers of endothelial cell (EC) activation compared to those with normal platelet counts (4) and some grade of platelet activation has been reported during the disease (5). Together, these reports point out to a significant role of platelets in the pathophysiology of malaria.…”

Section: Introductionmentioning

confidence: 99%

Platelet disturbances correlate with endothelial cell activation in uncomplicated Plasmodium vivax malaria

Dos-Santos

Silva‐Filho

Judice

et al. 2019

Preprint

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23Introduction. Platelets drive endothelial cell activation in many diseases. 24 However, if this occurs in Plasmodium vivax malaria is unclear. As platelets have 25 been reported to be activated and to play a role in inflammatory response during 26 malaria, we hypothesized that this would correlate with endothelial alterations 27 during acute illness. 28Methods. We performed platelet flow cytometry of PAC-1 and P-selectin. We 29 measured Platelet markers (CXCL4, CD40L, P-selectin, Thrombopoietin, IL-11) and 30 endothelial markers (ICAM-1, von Willebrand Factor and E-selectin) in plasma with a 31 multiplex-based assay. The values of each mediator were used to generate heatmaps, K-32 means clustering and Principal Component analysis. In addition, we determined pair-wise 33 Pearson's correlation coefficients to generate correlation networks. 34 Results. Platelet counts were reduced, and mean platelet volume increased in 35 malaria patients. The activation of circulating platelets in flow cytometry did not differ 36 between patients and controls. CD40L levels (Median [IQ]: 517 [406-651] vs. 1029 [732-37 1267] pg/mL, P=0.0001) were significantly higher in patients, while P-selectin (Median 38 [IQ]: 17.0 [15.4-20.6] vs. 22.2 [17.6-25.7] ng/mL, P=0.0621) and CXCL4 showed a 39 nonsignificant trend towards higher levels in patients. The network correlation 40 approach demonstrated the correlation between markers of platelet and endothelial 41 activation, and the heatmaps revealed a distinct pattern of activation in two subsets 42 of P. vivax patients when compared to controls.43 Conclusion. platelet activation occurs in uncomplicated vivax malaria and 44 this correlates with higher endothelial cell activation, especially in a subset of 45 patients. 46 47 131 (R&D Systems): CD40L, P-selectin, PF4 and thrombopoietin (TPO), IL-11, as 132 well as circulating markers of EC activation (ICAM-1, E-selectin, von Willebrand 133Factor (vWF)). We selected 31 patients for the multiplex assay from a wide range 134 of parasitemias (260 to 25,150 Pv-IE/μL), so that a wide spectrum of disease 135 burden could be evaluated. This subgroup did not differ from the overall 136 population of patients regarding severity of disease, sex proportion, platelet counts 137 and mean parasitemia. We selected nine controls matched for age and sex. For the 138 network analysis, we used some interpolated results from below standard range. 139 140

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Section: Introductionmentioning

confidence: 99%

Platelet disturbances correlate with endothelial cell activation in uncomplicated Plasmodium vivax malaria

Dos-Santos

Silva‐Filho

Judice

et al. 2019

Preprint

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“…Three studies with PCR confirmed P. vivax malaria reported parasite density. Of these, one study showed a higher parasite density among patients with severe thrombocytopaenia in P. vivax malaria than in those with either mild thrombocytopaenia or no thrombocytopaenia ( P = 0.524) [ 26 ]. The remaining 2 studies [ 21 , 38 ] qualitatively reported almost the same P. vivax parasite density in patients with thrombocytopaenia and those without thrombocytopaenia.…”

Section: Resultsmentioning

confidence: 99%

Severe thrombocytopaenia in patients with vivax malaria compared to falciparum malaria: a systematic review and meta-analysis

Naing

Whittaker

2018

Infect Dis Poverty

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BackgroundPlasmodium vivax is the most geographically widespread species among human malaria parasites. Immunopathological studies have shown that platelets are an important component of the host innate immune response against malaria infections. The objectives of this study were to quantify thrombocytopaenia in P. vivax malaria patients and to determine the associated risks of severe thrombocytopaenia in patients with vivax malaria compared to patients with P. falciparum malaria.Main bodyA systematic review and meta-analysis of the available literature on thrombocytopaenia in P. vivax malaria patients was undertaken. Relevant studies in health-related electronic databases were identified and reviewed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Fifty-eight observational studies (n = 29 664) were included in the current review. Severe thrombocytopaenia (< 50 000/mm3) to very severe thrombocytopaenia (< 20 000/mm3) was observed in 10.1% of patients with P. vivax infection. A meta-analysis of 11 observational studies showed an equal risk of developing severe/very severe thrombocytopaenia between the patients with P. vivax malaria and those with P. falciparum malaria (OR: 1.98, 95% CI: 0.92–4.25). This indicates that thrombocytopaenia is as equally a common manifestation in P. vivax and P. falciparum malaria patients. One study showed a higher risk of developing very severe thrombocytopaenia in children with severe P. vivax malaria than with severe P. falciparum malaria (OR: 2.80, 95% CI: 1.48–5.29). However, a pooled analysis of two studies showed an equal risk among adult severe cases (OR: 1.19, 95% CI: 0.51–2.77). This indicates that the risk of developing thrombocytopaenia in P. vivax malaria can vary with immune status in both children and adults. One study reported higher levels of urea and serum bilirubin in patients with P. vivax malaria and severe thrombocytopaenia compared with patients mild thrombocytopaenia or no thrombocytopaenia, (P < 0.001 in all comparisons). A pooled analysis of two other studies showed a similar proportion of bleeding episodes with thrombocytopaenia in severe P. vivax patients and severe P. falciparum patients (P = 0.09). This implied that both P. vivax and P. falciparum infections could present with bleeding episodes, if there had been a change in platelet counts in the infected patients. A pooled analysis of another two studies showed an equal risk of mortality with severe thrombocytopaenia in both P. vivax and P. falciparum malaria patients (OR: 1.16, 95% CI: 0.30–4.60). However, due to the low number of studies with small sample sizes within the subset of studies that provided clinically relevant information, our confidence in the estimates is limited.ConclusionThe current review has provided some evidence of the clinical relevance of severe thrombocytopaenia in P. vivax malaria. To substantiate these findings, there is a need for well designed, large-scale, prospective studies among patients infected with P. vivax. These sho...

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“…Clinical studies of severe and cerebral malaria (both falciparum and vivax) in children and adults treated with antimalarial drugs have documented endothelial dysfunction: decreased plasma levels of angpt-1, increased levels of angpt-2 and increased angpt-2/angpt-1 ratios (196)(197)(198)(199)(200)(201)(202)(203). Other findings include elevated levels of several pro-inflammatory cytokines and chemokines and other biomarkers indicating endothelial [vascular/intercellular adhesion molecule-1 (VCAM-1/ICAM-1), endothelial selectin (E-selectin)), coagulation (thrombomodulin) and complement (C5a) activation.…”

Section: Implications For Treating the Host Response To Other Acute Imentioning

confidence: 99%

Treating the host response to emerging virus diseases: lessons learned from sepsis, pneumonia, influenza and Ebola

2016

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There is an ongoing threat of epidemic or pandemic diseases that could be caused by influenza, Ebola or other emerging viruses. It will be difficult and costly to develop new drugs that target each of these viruses. Statins and angiotensin receptor blockers (ARBs) have been effective in treating patients with sepsis, pneumonia and influenza, and a statin/ARB combination appeared to dramatically reduce mortality during the recent Ebola outbreak. These drugs target (among other things) the endothelial dysfunction found in all of these diseases. Most scientists work on new drugs that target viruses, and few accept the idea of treating the host response with generic drugs. A great deal of research will be needed to show conclusively that these drugs work, and this will require the support of public agencies and foundations. Investigators in developing countries should take an active role in this research. If the next Public Health Emergency of International Concern is caused by an emerging virus, a "top down" approach to developing specific new drug treatments is unlikely to be effective. However, a "bottom up" approach to treatment that targets the host response to these viruses by using widely available and inexpensive generic drugs could reduce mortality in any country with a basic health care system. In doing so, it would make an immeasurable contribution to global equity and global security.

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Angiopoietin-2 and Angiopoietin-2/Angiopoietin-1 Ratio as Indicators of Potential Severity of Plasmodium vivax Malaria in Patients with Thrombocytopenia

Cited by 29 publications

References 50 publications

Platelet disturbances correlate with endothelial cell activation in uncomplicated Plasmodium vivax malaria

Platelet disturbances correlate with endothelial cell activation in uncomplicated Plasmodium vivax malaria

Severe thrombocytopaenia in patients with vivax malaria compared to falciparum malaria: a systematic review and meta-analysis

Treating the host response to emerging virus diseases: lessons learned from sepsis, pneumonia, influenza and Ebola

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