Model of acute hemoglobin drop. Based on quantitative plasma proteomic and validation studies, an acute drop in hemoglobin during malaria is associated with changes in levels of several soluble mediators. These observations were integrated with processes described in the literature and presented in the model. C-20S proteasome levels are significantly higher in malaria-infected children with hemoglobin drop vs children with stable hemoglobin, and 20S proteasome chymotrypsin-like activity is higher compared with uninfected children. Previously, malaria infection has been associated with oxidative stress, in particularly among children with SMA, which results in red blood cell membrane modification. In this model, we propose that modified membrane proteins are then subjected to degradation by c-20S proteasome, leading to hemolysis and decreased hemoglobin. In parallel, levels of IGF-1, one of the growth factors required for erythroid proliferation, are significantly reduced, which may be due to increased IL-18 levels, to increased chymotrypsin-like activity, or to both. The reduction in erythroid proliferation results in reduced hemoglobin levels, in addition to that caused by hemolysis. Factors associated with hemoglobin drops in the study are in green (increased) or red (decreased); dashed lines indicate associations described here and solid lines indicate previously described relationships.