Schematic representation of different transfusion strategies in ATM underlying its unique pathophysiology. In patients who received conventional transfusion (A), over time, preserved reticulocytosis will lead to an increased proportion of endogenous erythrocytes that exclusively contain nonfunctional HbH (HbH cells; shown as “blue golf ball” cells) (B). In this setting, despite a stable pretransfusion Hb, the proportion of functional Hb is decreased. The tissue hypoxia will subsequently lead to further increase of erythropoietin (EPO) and expansion of bone marrow erythron. Furthermore, the increased circulating HbH cells will lead to increased extravascular and intravascular hemolysis. (C) In contrast, a more aggressive transfusion (hypertransfusion) aimed at reduction of HbH and increase in functional Hb (non-HbH) will result in improved tissue oxygenation, reduction in EPO, reduced erythropoiesis, and diminished hemolysis. (D- E) Peripheral blood smear supravital stain of an adolescent with ATM, before (HbH, 64%) and after 4 cycles of exchange transfusion and subsequent hypertransfusion (HbH, 14%), respectively. Note the significant reduction in the HbH cells in peripheral blood smear, leading to improved functional Hb.