title: Cessation of intensive treatment with recombinant human erythropoietin is followed by secondary anemia.
abstract: Little information is available on the evolution of erythropoiesis after interruption of recombinant human erythropoietin (rHuEpo) therapy. Iron-overloaded rats received 20 daily injections of rHuEpo. During treatment, reticulocytes, soluble transferrin receptor (sTfR), and hematocrit increased progressively. This was accompanied by a substantial expansion of spleen erythropoiesis but a decrease in the bone marrow. Five weeks after treatment, rats developed a significant degree of a regenerative anemia. Erythropoietic activity, as assessed by reticulocytes, sTfR, erythroid cellularity, iron incorporation into heme, and the number of erythroid colonies, was severely depressed 3 weeks after cessation of rHuEpo. This was followed by regeneration of erythroblasts and reticulocytes at weeks 6 to 7 post-Epo, but erythroid progenitors recovered only partially by that time. The anemia was definitely corrected 2 months after cessation of rHuEpo treatment. Serum Epo levels remained elevated for several weeks, but the sensitivity of marrow erythroid precursors to Epo was preserved. No rat antibodies to rHuEpo were detected, and serum from post-Epo animals did not exert any inhibitory activity on erythropoiesis. In conclusion, after cessation of intensive rHuEpo therapy, there was a strong inhibition of erythropoietic activity with secondary anemia followed by late recovery. This was not due to antibodies or other soluble inhibitory factors, a defect in endogenous Epo production, or a loss of sensitivity to Epo. This may rather represent intrinsic erythroid marrow exhaustion, mostly at the level of erythroid progenitors but also at later stages of erythropoiesis.
authors.affiliation: Department of Medicine, Division of Hematology, and the Department of Clinical Biology, Division of Laboratory Hematology, University of Liège, Liège, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Piron
authors.forename: M
authors.initials: M
authors.lastname: Loo
authors.forename: A
authors.initials: A
authors.lastname: Gothot
authors.forename: F
authors.initials: F
authors.lastname: Tassin
authors.forename: G
authors.initials: G
authors.lastname: Fillet
authors.forename: Y
authors.initials: Y
authors.lastname: Beguin
mesh_terms: D000740:Anemia / Q000139:chemically induced*; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D015672:Erythroid Precursor Cells / Q000187:drug effects; D004920:Erythropoiesis / Q000187:drug effects*; D004921:Erythropoietin / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D006400:Hematocrit; D006801:Humans; D019190:Iron Overload / Q000139:chemically induced / Q000188:drug therapy; D019266:Iron, Dietary / Q000008:administration & dosage; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011990:Receptors, Transferrin / Q000187:drug effects; D011994:Recombinant Proteins; D017701:Reticulocyte Count; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013156:Splenectomy; D013375:Substance Withdrawal Syndrome / Q000097:blood* / Q000503:physiopathology; D013997:Time Factors
chemical_list: D019266:Iron, Dietary; D011990:Receptors, Transferrin; D011994:Recombinant Proteins; D004921:Erythropoietin