| Abstrakt: |
Little information is available on the evolution of hematological parameters after cessation of intensive treatment with rHuEpo. Groups of 3–5 rats were iron overloaded to avoid functional iron deficiency and received daily IV injections of 150 U rHuEpo for 20 days. During treatment, reticulocytes, soluble transferrin receptor (sTfR, a quantitative measure of total erythropoiesis) and Hct increased progressively (p<0.0001). This was accompanied by a substantial expansion of spleen erythropoiesis (p<0.01) but a decrease in the bone marrow (p<0.01), as assessed by erythroid cellularity, iron incorporation into heme and the number of erythroid colonies. After treatment, Hct returned to baseline by day 25, then fell to 80% by day 35 (p<0.0002), before returning to baseline by day 60. Reticulocytes decreasd to 40% at days 14-25 (p<0.02), then peaked to 300% at days 40–50 (p<0.005), before stabilizing to baseline after day 70. sTfR showed the same diphasic pattern (p<0.05 and p<0.02), but variations remained within 50% of baseline. The activity of erythroid progenitors and precursors in the bone marrow and spleen was severely depressed 3 weeks after cessation of rHuEpo therapy (p<0.01). Although erythroid cellularity and iron incorporation into heme normalized before day 40, the number of erythroid progenitors recovered only partially by day 40. Serum Epo levels remained elevated for several weeks, possibly due to non-utilization by a suppressed erythroid marrow, 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 inhibit erythropoiesis in vitro. 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 Epo production or a loss of sensitivity to Epo. This may represent intrinsic erythroid marrow exhaustion, at the level of erythroid progenitors but also at later stages of erythropoiesis. |
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