Model proposed by Koury and Bondurant33 for expansion of erythropoiesis by prevention of apoptosis in erythroid progenitors (see also Wu et al37 and Koury and Bondurant39 ). Late erythroid progenitors (CFU-Es and proerythroblasts) are dependent on the continuous presence of Epo to suppress apoptosis and are heterogeneous with respect to their Epo sensitivity. Under normal conditions (A), only a portion of late erythroid progenitors (those with lower Epo requirement) survive, generating erythroid precursors that produce normal amounts of mature RBCs. In conditions characterized by blunted Epo production (B), eg, renal failure, the large majority of erythroid progenitors undergo apoptosis due to the low Epo level within the bone marrow. Only a subpopulation of progenitors with very high Epo sensitivity and very low requirement survive; RBC production is inadequate and anemia develops. Administration of rHuEpo may allow a substantial expansion of erythropoiesis by preventing apoptosis of large numbers of late erythroid progenitors with intermediate Epo sensitivity. In anemia due to peripheral hemolysis or acute blood loss (C), renal Epo production is increased several fold and high levels of erythroid hormone are present in the bone marrow. Nearly all erythroid progenitors, even those with high Epo requirements, survive, with maximum preamplification of erythropoiesis. Administration of rHuEpo is unlikely to further enhance RBC production, because levels capable of preventing apoptosis of least sensitive cells cannot be reasonably achieved.