Abstract
Coagulopathy and leak, specific to the brain vasculature, are central pathogenetic components of cerebral malaria (CM). It is unclear how the parasite, Plasmodium falciparum, triggers these processes. Extracellular histones, released from damaged host cells, bind to cell membranes, causing coagulation activation, platelet aggregation and vascular leak in diverse critical illnesses. In CM patients, serum histones correlate with fibrin formation, thrombocytopenia, and endothelial activation; predicting brain swelling on MRI and fatal outcome. Post-mortem, histones bind to the luminal vascular surface, co-localizing with P. falciparum-infected erythrocytes (IE), and with thrombosis and leak. Purified P. falciparum histones or serum from patients with CM cause toxicity and barrier disruption in cultured human brain endothelial cells, reversed by anti-histone antibodies and non-anticoagulant heparin. These data implicate parasite histones as a key trigger of fatal brain swelling in CM. Neutralizing histones with agents such as non-anticoagulant heparin warrant exploration to prevent brain swelling and improve outcome.