Platelet Activation Linked to Development of Cerebral Malaria

Parasitologists have found that red blood cells infected with the malaria parasite Plasmodium falciparum activate platelets that secrete PF4 (platelet factor-4) protein, which causes an inflammatory response in blood vessels that obstructs capillaries in the brain.

Cerebral malaria (CM), characterized by vascular inflammation, immune stimulation, and obstruction of cerebral capillaries, is a major complication of P. falciparum infection in children. Even with the best of care, it is fatal in about 20% of cases.

Investigators from Johns Hopkins University (Baltimore, MD, USA) examined the role of blood platelets on the progression of CM. To this end, they infected three different groups of mice with malaria. One group had been treated to lack platelets, one group had the normal complement of platelets but it was treated with platelet inhibitors such as aspirin or clopidogrel, and the third group comprised normal controls.

The investigators reported in the August 13, 2008 online issue of the journal Cell Host and Microbe that the platelet-derived chemokine, platelet factor 4 (PF4)/CXCL4, promoted the development of cerebral malaria. Plasmodium-infected red blood cells (RBCs) activated platelets independently of vascular effects, resulting in increased plasma PF4. Comparing the animals in the experimental groups, the investigators found that 60% of the mice lacking PF4 were still alive 10 days after being infected, while only 30% of the mice with PF4 survived that long.

"The take-home lesson is that platelets, by releasing PF4, are playing an early role in the wind-up phase of cerebral malaria,” explained senior author Dr. Craig Morrell, assistant professor of molecular and comparative pathobiology at Johns Hopkins University. "Our mouse studies show that timing is critical; with the mice, we know when we infected them and controlled when we treated them. A big challenge in translating this to humans is that people do not know when they get infected. Platelets do not get any respect, but they are the second most abundant cell in the blood after red blood cells and packed full of factors that rally the immune system to action. By taking what we know about platelets and their activation and applying it to malaria; we have found a driver of cerebral malaria.”

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