Platelets have multifactorial roles in malaria pathogenesis. Platelets can directly impact malaria pathogenesis through a number of different mechanisms. First, platelets can protect against malaria progression by binding to IEs and inducing Plasmodium killing through release of PF4 (A). In contrast, platelets tethered to ultralarge VWF strings secreted from activated ECs can promote cytoadhesion and sequestration of IEs, thereby promoting vascular occlusion (B). Finally, platelets can further promote malaria progression by driving proinflammatory effects directly, and by activating circulating leukocytes (C). WPB, Weibel-Palade body.