Da Costa and colleagues (page 2894) shed new light on the chronology of membrane area loss in 2 hemolytic disorders, hereditary spherocytosis (HS) and autoimmune hemolytic anemia (AIHA). By cleverly combining the time-honored measurements of osmotic fragility and a contemporary flow cytometric assay of both erythrocytes and reticulocytes, Da Costa et al were able to directly measure critical hemolytic volume and, thus, cell surface area of both reticulocytes and mature erythrocytes in normal blood, HS blood, and AIHA blood. Their studies reveal that maturation of normal reticulocytes into erythrocytes is associated with the loss of approximately 9 μm2 of surface area (from 142.4 ± 2.0 to 133.6 ± 3.0) and that the spleen plays a major role in this process. In HS, a marked reduction in the surface area of reticulocytes was noted while the reduction of surface area associated with maturation into erythrocytes was the same as that of normal cells.

Thus, contrary to the general belief that surface area loss in HS is a gradual process occurring during the shortened lifetime of erythrocytes, Da Costa et al demonstrate that surface area loss occurs very early at the reticulocytes stage and is also not affected by splenectomy. In AIHA, membrane surface loss is not evident at the reticulocyte stage and occurs only in mature erythrocytes. While great progress has been made on understanding the molecular nature of HS, the pathophysiology of this disease is still unclear. This study resets the clock of membrane surface loss in HS back to the reticulocyte stage: how are reticulocytes losing cell membrane so early and what is the underlying process still remain to be defined. But this study identifies HS as a paradigm of a potentially novel category of anemias due to “reticulocyte” membrane diseases.