Platelet-mediated clumping of Plasmodium falciparum-infected erythrocytes is associated with high parasitemia but not severe clinical manifestations of malaria in African children

Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom.
The American journal of tropical medicine and hygiene (Impact Factor: 2.7). 11/2007; 77(5):943-6.
Source: PubMed


Platelet-mediated clumping of Plasmodium falciparum-infected erythrocytes is an adhesive phenotype commonly found in field isolates that has previously been associated with severe malaria. Here, clumping was assessed in 131 isolates from Malian children. The clumping phenotype was seen in 6% (N = 51) of uncomplicated malaria, 24% (N = 51) of severe malaria, and 45% (N = 29) of high parasitemia non-severe malaria isolates. Multivariate analysis indicated that clumping was strongly positively associated with parasitemia (F(1,122) = 24.1, P < 0.001) but not with disease category (F(2,122) = 1.8, P = 0.17). Therefore platelet-mediated clumping in Malian P. falciparum isolates is primarily associated with high parasitemia and not with severe clinical manifestations of malaria.

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Available from: Ogobara K Doumbo
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    • "However, a study in Mali found an association with high parasitaemia, but not severe disease (Ref. 142). The above field-isolate studies each used different experimental methods to assess platelet-mediated clumping, and these different conditions have a profound effect on the outcome of the assay (Ref. "
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    ABSTRACT: Severe malaria has a high mortality rate (15-20%) despite treatment with effective antimalarial drugs. Adjunctive therapies for severe malaria that target the underlying disease process are therefore urgently required. Adhesion of erythrocytes infected with Plasmodium falciparum to human cells has a key role in the pathogenesis of life-threatening malaria and could be targeted with antiadhesion therapy. Parasite adhesion interactions include binding to endothelial cells (cytoadherence), rosetting with uninfected erythrocytes and platelet-mediated clumping of infected erythrocytes. Recent research has started to define the molecular mechanisms of parasite adhesion, and antiadhesion therapies are being explored. However, many fundamental questions regarding the role of parasite adhesion in severe malaria remain unanswered. There is strong evidence that rosetting contributes to severe malaria in sub-Saharan Africa; however, the identity of other parasite adhesion phenotypes that are implicated in disease pathogenesis remains unclear. In addition, the possibility of geographic variation in adhesion phenotypes causing severe malaria, linked to differences in malaria transmission levels and host immunity, has been neglected. Further research is needed to realise the untapped potential of antiadhesion adjunctive therapies, which could revolutionize the treatment of severe malaria and reduce the high mortality rate of the disease.
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    • "Kenya 5% variable 15, 30, 60, 120 Severe malaria (impaired consciousness, respiratory distress, Hb < 5 g/dl) Chotivanich et al 2004 [7] Thailand 1% variable 15 Cerebral malaria and parasitaemia but not other forms of severe malaria (mostly multi-organ failure) Arman et al 2007 [8] Mali 2% variable 30 Parasitaemia but not severe disease Wassmer et al 2008 [10] Malawi 5% Adjusted to 10% 15, 30, 60, 120 Cerebral malaria and severe malarial anaemia Platelet-mediated clumps of P. falciparum infected erythrocytes (IE) detected by in vitro clumping assays "
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    ABSTRACT: Platelet-mediated clumping of Plasmodium falciparum-infected erythrocytes (IE) is a parasite adhesion phenotype that has been associated with severe malaria in some, but not all, field isolate studies. A variety of experimental conditions have been used to study clumping in vitro, with substantial differences in parasitaemia (Pt), haematocrit (Ht), and time of reaction between studies. It is unknown whether these experimental variables affect the outcome of parasite clumping assays. The effects of Pt (1, 4 and 12%), Ht (2, 5 and 10%) and time (15 min, 30 min, 1 h, 2 h) on the clumping of P. falciparum clone HB3 were examined. The effects of platelet freshness and parasite maturity were also studied. At low Ht (2%), the Pt of the culture has a large effect on clumping, with significantly higher clumping occurring at 12% Pt (mean 47% of IE in clumps) compared to 4% Pt (mean 26% IE in clumps) or 1% Pt (mean 7% IE in clumps) (ANOVA, p=0.0004). Similarly, at low Pt (1%), the Ht of the culture has a large effect on clumping, with significantly higher clumping occurring at 10% Ht (mean 62% IE in clumps) compared to 5% Ht (mean 25% IE in clumps) or 2% Ht (mean 10% IE in clumps) (ANOVA, p=0.0004). Combinations of high Ht and high Pt were impractical because of the difficulty assessing clumping in densely packed IE and the rapid formation of enormous clumps that could not be counted accurately. There was no significant difference in clumping when fresh platelets were used compared to platelets stored at 4 degrees C for 10 days. Clumping was a property of mature pigmented-trophozoites and schizonts but not ring stage parasites. The Pt and Ht at which in vitro clumping assays are set up have a profound effect on the outcome. All previous field isolate studies on clumping and malaria severity suffer from potential problems in experimental design and methodology. Future studies of clumping should use standardized conditions and control for Pt, and should take into account the limitations and variability inherent in the assay.
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    • "This has been observed in some [17] [20] [37] [38] but not all studies [18]. In the few studies investigating both types of cytoadherence, rosetting was invariably associated with elevated parasite densities and rosetting rate was higher in severe malaria compared to uncomplicated malaria [17] [18] [20]. "
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    ABSTRACT: The capacity of Plasmodium falciparum-infected red blood cells to bind uninfected red blood cells ("rosetting") has been associated with high parasite density in numerous geographic areas and with severe malaria in African children. We summarize here the associations that have emerged from field studies and describe the various experimental models of rosetting that have been developed. A variety of erythrocyte receptors, several serum factors and a number of rosette-mediating PfEMP1 adhesins have been identified. Several var genes code for rosette-forming PfEMP1 adhesins in each P. falciparum genome, so that each clonal line has the capacity to generate distinct types of rosettes. To clarify their respective role in malaria pathogenesis, each of the multiple ligand/receptor interactions should be further studied for fine specificity, binding affinity and the impact of the large population polymorphism of the parasite variant repertoires should be assessed. Interestingly, some major human erythrocyte surface polymorphisms have been identified as affecting rosette formation, consistent with a role for rosetting in life-threatening falciparum malaria.
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