Hemostatic and protein C pathway dysfunction in the pathogenesis of experimental cerebral malaria

Accumulating data suggest that hemostatic dysfunction contributes to Plasmodium falciparum malaria pathogenesis. In addition, specific mechanisms through which the protein C pathway modulates P. falciparum pathogenesis have been described. We hypothesized that the anticoagulant and anti-inflammatory activities of recombinant activated protein C (APC) may possess therapeutic value in the setting of cerebral malaria (CM). In order to address this hypothesis, we assessed hemostatic parameters in an established murine model of experimental cerebral malaria (ECM), and using the same model, investigated the ability of recombinant APC to ameliorate ECM. In keeping with findings in patients with severe P. falciparum malaria, we observed that dysregulated thrombin generation and protein C pathway dysfunction were both late features of ECM. Furthermore, pretreatment with a monoclonal anti-EPCR antibody that blocks protein C/APC binding prior to P. berghei inoculation significantly reduced overall survival. Conversely, mice treated with recombinant APC exhibited a marked attenuation in clinical ECM progression and parasitemia, in parallel with a significant increase in overall survival. All together, these findings confirm that hemostatic and protein C pathway dysfunction are both consistent features in human and ECM, and demonstrate for the first time a role for recombinant APC in reducing clinical progression and mortality in ECM.