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Erythropoietin-Induced Erythroid Precursor Pool Depletion Causes Erythropoietin Hyporesponsiveness

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Abstract

Purpose

The purpose of this study is to demonstrate that the erythroid precursor depletion in bone marrow induced by recombinant human erythropoietin (rHuEPO) treatment may be another contributing factor to erythropoietin hyporesponsiveness.

Methods

Healthy Wistar rats were given single dose (SD) or multiple doses (MD) of rHuEPO (100 IU/kg). In MD study, animals were challenged with thrice-weekly over two weeks. Blood, bone marrow and spleen (for SD only) were collected. The erythropoietic responses in bone marrow and spleen were quantified using a flow cytometric immunophenotyping technique. A mathematical approach involving measuring reticulocyte age distribution was developed to evaluate the reticulocyte loss due to neocytolysis.

Results

A reduced level of erythropoietic responses below the baseline was observed for both MD and SD studies. In SD study, the reticulocyte decreased below the baseline after day 6. A depletion of the bone marrow erythroid precursor cells was observed. However, neocytolysis of reticulocyte only occurs from day 3-5 after rHuEPO injection.

Conclusions

The findings demonstrate that EPO-induced erythroid precursor depletion in bone marrow is responsible for reduced reticulocyte response and may contribute to erythropoietin hyporesponsiveness. Therefore, this study provides further justification for reducing the doses of erythropoietin-stimulating agents in anemic patients demonstrating hyporesponsiveness.

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Acknowledgments and Disclosures

This work was supported by the National Institutes of Health Grant GM 57980

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, 370 Kapoor Hall, Buffalo, New York, 14214, USA

    Xiaoyu Yan, Sihem Ait-Oudhia & Wojciech Krzyzanski

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  1. Xiaoyu Yan
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  2. Sihem Ait-Oudhia
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  3. Wojciech Krzyzanski
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Correspondence to Wojciech Krzyzanski.

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Yan, X., Ait-Oudhia, S. & Krzyzanski, W. Erythropoietin-Induced Erythroid Precursor Pool Depletion Causes Erythropoietin Hyporesponsiveness. Pharm Res 30, 1026–1036 (2013). https://doi.org/10.1007/s11095-012-0938-7

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  • DOI: https://doi.org/10.1007/s11095-012-0938-7

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