Hypothesized cause of delayed hemolysis associated with intravenous artesunate

In recent publications, investigators described cases in which there was a delayed hemolysis following intravenous (IV) artesunate treatment. The delayed hemolysis event occurred at the nadir of blood hemoglobin concentration, i.e., at the time when blood hemoglobin concentration was switching from a progressive decline to a progressive increase. It is hypothesized that this nadir indicates the time when red cell production is resuming after having been arrested, the delayed hemolysis event is due to lysis of the first (aberrant) reticulocytes released once production is resumed and, therefore, that the hemolysis signals the resumption of red cell production. Since this delayed hemolysis has not been associated with a significant decrease in blood hemoglobin, the hemolytic event is not of particular concern even if it could be attributed to artesunate. More important than this hemolysis event was the preceding progressive anemia that lasted for up to 19 days. Both a decrease in reticulocyte production and a shortened life span of previously infected red cells likely contributed to the anemia. The question that remains to be answered is whether the progressive anemia that lasted 2-3 weeks in these patients was attributable solely to their severe malaria or was possibly enhanced and prolonged by the high plasma concentrations of artesunate associated with IV administration. Controlled clinical studies addressing this question may be needed.