Platelet Accumulation in Brain Microvessels in Fatal Pediatric Cerebral Malaria

Abstract

The pathogenesis of fatal cerebral malaria (CM) is not well understood, in part because data from patients in whom a clinical diagnosis was established prior to death are rare. In a murine CM model, platelets accumulate in brain microvasculature, and antiplatelet therapy can improve outcome. We determined whether platelets are also found in cerebral vessels in human CM, and we performed immunohistopathology for platelet-specific glycoprotein, GPIIb-IIIa, on tissue from multiple brain sites in Malawian children whose fatal illness was severe malarial anemia, CM, or nonmalarial encephalopathy. Platelets were observed in 3 locations within microvessels: between malaria pigment and leukocytes, associated with malaria pigment, or alone. The mean surface area of platelet staining and the proportion of vessels showing platelet accumulation were significantly higher in patients with CM than in those without it. Platelet accumulation occurs in the microvasculature of patients with CM and may play a role in the pathogenesis of the disease.

Platelet profile is associated with clinical complications in patients with vivax and falciparum malaria in Colombia

“…This association may result from sensitization induced by the parasitized red blood cells in the platelet, with consequent increased platelet sensitivity to adenosine diphosphate (ADP) and higher dense-granule secretion 45,46 . These changes could ultimately promote platelet aggregation on the endothelium, which has been demonstrated in cerebral malaria 27 .…”

“…Various mechanisms have been proposed to explain thrombocytopenia during malaria episodes, including platelet destruction by immune mechanisms 14,[18][19][20] ; low medullar platelet production 14,21,22 ; low thrombopoietin (TPO) synthesis 23 ; platelet sequestration in organs, such as the spleen 24,25 or brain [26][27][28] ; and systemic sequestration [29][30][31] . These changes are transient, and in general, patients recover completely after malaria treatment 32 .…”

Platelet power: sticky problems for sticky parasites?

“…The platelet, traditionally known for its role in blood clotting, is also known for its putative involvement in malaria pathology [1,2]. However, a recent study using C57BL6 mice genetically deficient in the megakaryocyte growth and differentiation factor C-mpl (encoded by the Mpl gene), and resulting in mice with 90% fewer platelets, showed that these animals were significantly more susceptible to death when infected with Plasmodium chabaudi [3].…”

“…These results in animals seem counterintuitive, in that platelets are believed to be involved in pathological disease states that hasten death, such as cerebral malaria [1,2]. For example, mice with significantly compromised platelet function (CXCL4 or CXCR3 deficient) have been shown to survive longer than their wild-type counterparts [4].…”

“…Using specific receptor antagonists, the authors demonstrated that killing and control of parasite growth in P. falciparum cultures was dependent on platelet activation via P2Y1, an ADP-dependent metabotrophic puronergic receptor (Figure 1). These results in animals seem counterintuitive, in that platelets are believed to be involved in pathological disease states that hasten death, such as cerebral malaria [1,2]. For example, mice with significantly compromised platelet function (CXCL4 or CXCR3 deficient) have been shown to survive longer than their wild-type counterparts [4].…”