Large, chronic doses of erythropoietin cause thrombocytopenia in mice [see comments]

Abstract

Both large, acute doses of erythropoietin (EPO) and short-term hypoxia increase platelet counts in mice, but long-term hypoxia causes thrombocytopenia. Therefore, we tested the hypothesis that EPO injected in large, chronic doses (a total of 80 U of EPO over a 7-day period) might cause thrombocytopenia. EPO caused increased red blood cell (RBC) production, ie, increased hematocrits, RBC counts, mean cell volume (MCV), and reticulocyte counts (from P less than .05 to P less than .0005), and decreased thrombocytopoiesis, ie, decreased platelet counts, percent 35S incorporation into platelets, and total circulating platelet counts (TCPC) (P less than .0005). Femoral marrow megakaryocyte size was unchanged, but megakaryocyte number was significantly (P less than .005) reduced in mice treated with EPO. EPO- injected mice had increased spleen volumes (P less than .0005), but blood volumes (BV) were unchanged. In EPO-treated, splenectomized mice, RBC production was also increased (P less than .05 to P less than .0005) and platelet counts, TCPC, and percent 35S incorporation into platelets were decreased (P less than .05), but BV was not altered. Therefore, the decrease in platelet counts observed in EPO-treated mice was not due to increased BV or to an enlarged spleen. In other experiments, mice were rendered acutely thrombocytopenic to increase thrombocytopoiesis, and platelet and RBC production rates were determined. In mice with elevated thrombocytopoiesis, RBC counts, hematocrits, percent 59Fe RBC incorporation values, and MCV were decreased (P less than .05 to P less than .0005). Because 59Fe RBC incorporation and MCV were not elevated, the decrease in RBC counts and hematocrits does not appear to be due to bleeding. Therefore, we show that large, chronic doses of EPO increase erythropoiesis and decrease thrombocytopoiesis. Conversely, acute thrombocytopenia causes increased thrombocytopoiesis and decreased erythropoiesis. These findings support the hypothesis of competition between precursor cells of the erythrocytic and megakaryocytic cell lines (stem-cell competition) as the cause of thrombocytopenia in EPO-treated mice and the cause of anemia in mice whose platelet production rates were increased.

Thrombopoietin has a differentiative effect on late‐stage human erythropoiesis

“…It is reasonable to assume there are some factors in the serum which have a role in balancing normal erythropoiesis and megakaryocytopoiesis in vivo . This is in agreement with in vivo data (McDonald et al , 1992), suggesting competition between erythropoiesis and megakaryocytopoiesis, and supports the notion that bipotent erythroid/megakaryocyte progenitors exist before the two lineages diverge.…”

Evaluation of the Erythroid Regenerative Response in Two Different Models of Experimentally Induced Iron Deficiency Anemia

“…17 In rats and mice, high doses of erythropoietin both stimulate and inhibit platelet production; acute administration stimulates platelet production, and chronic administration causes thrombocytopenia. [36][37][38] More recent work suggests that the effect of erythropoietin on platelet production is modulated by iron stores as well as by the dose and chronicity of erythropoietin administration. 39 It would have been useful to measure erythropoietin in this study.…”

Effect of recombinant human erythropoietin on platelets in patients with anemia of renal failure: correlation of platelet count with erythropoietic activity and iron parameters

“…Treatment of patients having anemia of end-stage renal failure with rHuEpo produced, after 2 wk, a 4-fold increase of erythroid progenitors as well as a 2-fold increase of CFU-Meg and CFU-GM, sug- (15).…”

“…All these observations appear to support the concept that rHuEpo exerted a positive effect on platelet production, which was proportional to its effect on the red cell lineage. On the other hand, as large, chronic doses of rHuEpo caused thrombocytopenia and acute thrombocytopenia caused decreased erythropoiesis in normal rats, "stem-cell competition" between erythroid and platelet precursors has been suggested as the cause of these phenomena in these situations of prolonged, intense stimulation ( 15). However, this concept of "stem-cell competition" has not been proved in appropriate in vitro experiments (43).…”