Putative mechanisms through which VWF secreted from ECs may influence the pathogenesis of P falciparum malaria. At an early stage following P falciparum infection, acute EC activation results in WP body exocytosis. Consequently, plasma VWF:Ag levels are significantly increased, and pathological UL-VWF multimers accumulate in the plasma. While tethered on the surface of activated ECs, UL-VWF can bind circulating platelets. These bound activated platelets further activate the underlying ECs (see dashed line). In addition, CD36 expressed on the platelet surface of these platelet-decorated UL-VWF strings can bind to PfEMP1, thereby facilitating the cytoadhesion and sequestration of IEs. This VWF-modulated IE cytoadhesion may be of particular importance in the cerebral microvasculature where there is no constitutive CD36 expression on ECs. Once again, IE cytoadhesion further stimulates EC activation and dysfunction. Finally, in addition to being important in modulating platelet and IE recruitment, VWF can also bind to neutrophils and monocytes, both of which can enhance EC damage resulting in enhanced EC permeability. ECM, experimental cerebral malaria; RBC, red blood cell.