A unified hypothesis for the genesis of cerebral malaria: sequestration, inflammation and hemostasis leading to microcirculatory dysfunction.
A unifying hypothesis for the genesis of cerebral malaria proposes that parasite antigens (released by replication in blood, surface molecules on parasitized erythrocytes, or merozoites) activate platelets that, in turn, contribute to the activation of the inflammatory response and increased levels of endothelial cell adhesion molecules (eCAMs). Increased levels of eCAMs result in further parasitized-erythrocyte sequestration and marked local inflammation that might disrupt the brain microvasculature, which cannot be repaired by the hemostasis system because of its procoagulant state. Disruption of the brain microvasculature can result in vascular leak and/or hemorrhaging into the brain; similar processes can occur in other vascular beds, including the lung. The blockage of functional capillaries by parasitized and/or unparasitized erythrocytes with decreased deformability or rosettes is also a key interaction between hemostasis and mechanical obstruction leading to pathogenesis. The events resulting in the development of cerebral malaria complications are multi-factorial, encompassing a dynamic interaction between three processes, thereby explaining the complexity of this deadly syndrome.
van der Heyde
Henri C
HC
La Jolla Bioengineering Institute, La Jolla, CA 92037, USA. hvande@ljbi.org
Nolan
John
J
Combes
Valéry
V
Gramaglia
Irene
I
Grau
Georges E
GE
D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000469:parasitology; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000378:metabolism*; D002560:Cerebrovascular Circulation; D004730:Endothelium, Vascular; D004912:Erythrocytes / Q000469:parasitology*; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000209:etiology; D016779:Malaria, Cerebral / Q000469:parasitology / Q000473:pathology*; D016778:Malaria, Falciparum / Q000469:parasitology / Q000473:pathology*; D010963:Plasmodium falciparum / Q000472:pathogenicity
D015815:Cell Adhesion Molecules