Effects of short‐term administration of recombinant human erythropoietin on rat megakaryopoiesis

Yonemura, Yuji; Kawakita, Makoto; Fujimoto, Kouji; Sakaguchi, Masahiro; Takatsuki, Kiyoshi; Kusuyama, Takeshi; Hirose, Jiro; Kato, Kazuharu

doi:10.1002/stem.5530100105

Cited by 12 publications

(7 citation statements)

References 28 publications

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“…Single-cell suspensions were prepared from one of the femurs of each rat and the other was histologically examined. Cells were flushed into 4 ml of suspension medium (CATCH) (Yonemura et al, 1992a) supplemented with 10% fetal calf serum (FCS; Sera-lab, Sussex, U.K.). CATCH medium was composed of 0.129 M NaCl, 8.614 mM Na2HP04, 1.6 mM KH2P04, 13.6 mM Na smears of an untreated cell suspension.…”

Section: Methodsmentioning

confidence: 99%

Effect of recombinant human interleukin‐11 on rat megakaryopoiesis and thrombopoiesis in vivo: comparative study with interleukin‐6

et al. 1993

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The ability of recombinant human interleukin-11 (IL-11) to stimulate rat megakaryopoiesis and thrombopoiesis in vivo was investigated. Once daily subcutaneous injections of IL-11 at doses of 2, 8 and 20 micrograms/rat for 5 d caused dose-dependent increases in platelet counts. The chronic administration of 20 micrograms/rat/d for 14 d resulted in biphasic increases in platelet counts with peaks at days 8 and 15 of up to 30% over the control, continuing for more than 5 d after cessation of IL-11 injections. Moreover, a striking increase in megakaryocytic size and ploidy in bone marrow in response to IL-11 was elicited. IL-11 induced a dose-dependent elevation in bone marrow cell numbers but not in splenic weight and cell numbers. Modifications of these parameters were noted as soon as 24 h after the first IL-11 injections. IL-11 had a same potency of thrombopoietic effect in rats as compared with IL-6. However, elevation of acute phase protein such as immunosuppressive acidic protein was 2.2-fold in rats given 20 micrograms/d of IL-6 over those receiving a same dose of IL-11 (470 v 210 micrograms/ml). In addition, the rate of body-weight increase in rats receiving IL-11 for 5 d as well as 14 d did not differ from that in control animals. In IL-6 treated rats, the increase in body weight was significantly slower than the controls, which was observed even in the group given 8 micrograms/d of IL-6. These results suggest that IL-11 may be an effective strategy for the treatment of thrombocytopenia.

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Section: Methodsmentioning

confidence: 99%

Effect of recombinant human interleukin‐11 on rat megakaryopoiesis and thrombopoiesis in vivo: comparative study with interleukin‐6

et al. 1993

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“…Although some results suggest that Epo binds to megakaryocytes (but not platelets) (Fraser et al , 1988), whether functional EpoR is expressed on megakaryocytes remains unclear (Grossi et al , 1989; Yonemura et al , 1992) and high levels of endogenous Epo do not appear to elevate platelet counts in humans (Akan et al , 2000). Studies evaluating platelet counts after ESA administration have reported varying results (Grossi et al , 1989; Yonemura et al , 1992; Ait-Oudhia et al , 2010). Furthermore, a clear association between increased platelet counts and an increased incidence of VTEs has not been demonstrated (Buss et al , 1994; Basser et al , 1997).…”

Section: Esas and Disease Progression Mechanisms: Evidence From Preclmentioning

confidence: 99%

Effects of erythropoietin receptors and erythropoiesis-stimulating agents on disease progression in cancer

et al. 2012

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Erythropoiesis-stimulating agents (ESAs) increase red blood cell (RBC) production in bone marrow by activating the erythropoietin receptor (EpoR) on erythrocytic-progenitor cells. Erythropoiesis-stimulating agents are approved in the United States and Europe for treating anaemia in cancer patients receiving chemotherapy based on randomised, placebo-controlled trials showing that ESAs reduce RBC transfusions. Erythropoiesis-stimulating agent-safety issues include thromboembolic events and concerns regarding whether ESAs increase disease progression and/or mortality in cancer patients. Several trials have reported an association between ESA use and increased disease progression and/or mortality, whereas other trials in the same tumour types have not provided similar findings. This review thoroughly examines available evidence regarding whether ESAs affect disease progression. Both clinical-trial data on ESAs and disease progression, and preclinical data on how ESAs could affect tumour growth are summarised. Preclinical topics include (i) whether tumour cells express EpoR and could be directly stimulated to grow by ESA exposure and (ii) whether endothelial cells express EpoR and could be stimulated by ESA exposure to undergo angiogenesis and indirectly promote tumour growth. Although assessment and definition of disease progression vary across studies, the current clinical data suggest that ESAs may have little effect on disease progression in chemotherapy patients, and preclinical data indicate a direct or indirect effect of ESAs on tumour growth is not strongly supported.

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“…4 In dogs, mice, or rats, short-term treatment with high doses of rHuEpo has been shown to stimulate platelet production, but platelet counts tended to normalize after 7 to 15 days. [5][6][7][8][9] However, transgenic mice expressing the human Epo gene develop both polycythemia and a moderate degree of thrombocytopenia. 10 Actually, large, chronic doses of rHuEpo also caused thrombocytopenia in mice, and stem cell competition between erythroid and platelet precursors has been suggested as the cause of this phenomenon.…”

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confidence: 99%

The Effect of Recombinant Human Erythropoietin on Platelet Counts Is Strongly Modulated by the Adequacy of Iron Supply

Loo

Béguin

1999

Blood

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The effect of recombinant human erythropoietin (rHuEpo) on megakaryopoiesis remains controversial. Treatment with rHuEpo in renal failure patients has been associated with a slight elevation of platelet counts. In animal studies, high doses of rHuEpo produced an increase of platelet counts followed by a gradual return to normal after 7 to 15 days or even a substantial degree of thrombocytopenia. However, because iron deficiency is also known to be associated with thrombocytosis, (functional) iron deficiency during rHuEpo could be contributing to these observations. We investigated the impact of iron supply on changes in platelet counts induced by rHuEpo. Rats were either fed normal food (normal rats) or received 1% carbonyl iron for 2 weeks or 3 months, as well as during the experiment, to achieve iron supplementation or overload, respectively. Rats of all three categories then received daily intravenous injections of rHuEpo (10, 50, or 150 U) or normal saline (0 U) for 20 days. With 0 to 10 U rHuEpo, platelets remained stable. In normal rats receiving 50 to 150 U rHuEpo, platelets increased to 120% to 140% of baseline at 4 to 12 days to level off at 120% at 16 to 20 days. This response was less sustained in splenectomized animals. Iron-supplemented rats receiving 50 to 150 U rHuEpo also increased platelets initially, but the peak was at day 4, followed by a gradual return to baseline and even a moderate thrombocytopenia later on. Iron-overloaded rats receiving 50 to 150 U rHuEpo also had increased platelets at day 4, but the duration of platelet increase was shorter, and they experienced a more pronounced degree of thrombocytopenia in proportion to the dose of rHuEpo. Because the early elevation of platelets was of larger magnitude than hematocrit changes, it is unlikely that it could be accounted for by shrinkage of plasma volume. Because it was observed in all three iron conditions, there appears to be some direct positive effect of rHuEpo on platelet production. However, after this transient effect, expanded erythropoiesis appears to exert a negative impact upon platelet production. Secondary thrombocytopenia was not related to splenic pooling, and its very slow correction after cessation of rHuEpo therapy is not compatible with changes in platelet survival. Rather, it is consistent with stem cell competition between erythroid and megakaryocytic development. However, this secondary thrombocytopenia is masked by (functional) iron deficiency in rats not receiving an adequate iron supply from food or stores.

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Effects of short‐term administration of recombinant human erythropoietin on rat megakaryopoiesis

Cited by 12 publications

References 28 publications

Effect of recombinant human interleukin‐11 on rat megakaryopoiesis and thrombopoiesis in vivo: comparative study with interleukin‐6

Effect of recombinant human interleukin‐11 on rat megakaryopoiesis and thrombopoiesis in vivo: comparative study with interleukin‐6

Effects of erythropoietin receptors and erythropoiesis-stimulating agents on disease progression in cancer

The Effect of Recombinant Human Erythropoietin on Platelet Counts Is Strongly Modulated by the Adequacy of Iron Supply

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