von Willebrand factor in experimental malaria-associated acute respiratory distress syndrome.

Malaria-associated acute respiratory distress syndrome (MA-ARDS) is a lethal complication of severe malaria, characterized by marked pulmonary inflammation. Patient studies have suggested a link between von Willebrand factor (VWF) and malaria severity.To investigate the role of VWF in the pathogenesis of experimental MA-ARDS.

Plasmodium berghei NK65-E (PbNK65) parasites were injected in Vwf^+/+ and Vwf^-/- mice. Pathological parameters were assessed following infection.

In accordance with patients with severe malaria, plasma VWF levels were increased and ADAMTS13 activity levels were reduced in experimental MA-ARDS. ADAMTS13- and plasmin-independent reductions of high molecular weight VWF multimers were observed at the end stage of disease. Thrombocytopenia was VWF-independent because it was observed in both Vwf^+/+ and Vwf^-/- mice. Interestingly, Vwf^-/- mice had a shorter survival time compared with Vwf^+/+ controls following PbNK65 infection. Lung edema could not explain this shortened survival because alveolar protein levels in Vwf^-/- mice were approximately two times lower than in Vwf^+/+ controls. Parasite load, on the other hand, was significantly increased in Vwf^-/- mice compared with Vwf^+/+ mice in both peripheral blood and lung tissue. In addition, anemia was only observed in PbNK65-infected Vwf^-/- mice. Of note, Vwf^-/- mice presented with two times more reticulocytes, a preferential target of the parasites.

This study suggests that parasite load together with malarial anemia, rather than alveolar leakage, might contribute to shortened survival in PbNK65-infected Vwf^-/- mice. VWF deficiency is associated with early reticulocytosis following PbNK65 infection, which potentially explains the increase in parasite load.