Serum erythropoietin during autologous bone marrow transplantation: relationship to measures of erythroid activity

Summary Marked elevation of serum erythropoietin (sEPO) occurs following high dose chemotherapy for malignant disease. It has been proposed that the subsequent fall in sEPO constitutes a relative erythropoietin (EPO) deficiency, prompting trials of recombinant EPO to reduce red cell transfusion during chemotherapy. We have investigated these phenomena by serial estimations of reticulocytes and sEPO in 11 autologous marrow transplant recipients. sEPO reached two to five times baseline 0 to 5 days after transplant but the inverse relationship between sEPO and haematocrit was maintained. Observed to expected log sEPO (Epo ratio) rose and fell in parallel with sEPO, remaining greater than 1.0 throughout. A progressive fall in reticulocyte count during chemotherapy was followed by an increase during engraftment. The strong inverse relationships between reticulocytes and Epo ratio in the 10 days after initiating chemotherapy support the hypothesis that loss of EPO-receptor bearing erythroid precursors allows a rise in sEPO during chemotherapy. The elevation of Epo ratio levels during engraftment indicates that it is the availability of EPO-sensitive progenitors, rather than the supply of EPO, that limits the rate of resumption of erythropoiesis after high-dose chemotherapy.     

Erythropoietin levels in the different clinical forms of hereditary spherocytosis

Erythropoietin (EPO), the main growth factor responsible for the regulation of red blood cell production, may be overproduced when blood loss or haemolysis occurs. Patients with mild hereditary spherocytosis (HS) are able to maintain normal haemoglobin concentration, whereas typical and severe HS patients develop an anaemic state. Splenectomy usually reverses anaemia. We aimed to clarify the role of EPO in the response to enhanced spherocyte destruction, and to look for a linkage with the broad clinical spectra of HS. EPO levels, reticulocyte count and production index (RPI), other parameters used to classify HS and the protein deficiencies underlying HS were evaluated in previously diagnosed unsplenectomised (n = 24) and splenectomised (n = 10) patients presenting mild, typical or severe HS. A significant increase in EPO was observed in all unsplenectomised HS patients. In the mild form, a significant correlation of EPO with reticulocyte count and RPI was observed; however, this correlation disappeared in typical HS patients. Splenectomised HS patients presented a correction in EPO levels in all forms of HS, although the reticulocyte count and RPI sustained slightly higher values. Our data show HS as a disease linked to an overproduction of EPO, according to the severity of the disease; however, a disturbance in erythropoiesis seems to occur in typical HS. Moreover, splenectomy leads to a correction in the EPO levels.     

Serum erythropoietin levels and blood component therapy after autologous bone marrow transplantation: implications for erythropoietin therapy in this setting.

To determine the potential impact of recombinant human erythropoietin (EPO) therapy in patients undergoing autologous bone marrow transplantation (BMT) and colony-stimulating factor therapy, we assayed endogenous serum EPO levels and noted blood transfusion requirements in relapsed non-Hodgkin's lymphoma patients treated with high-dose chemo-radiation therapy and autologous BMT. Hematocrit and reticulocyte counts were determined daily, and hematocrit was maintained in the 25-30% range by transfusion according to criteria established by our hospital transfusion committee. EPO levels were measured by radioimmunoassay and were determined at baseline, throughout therapy, and 2 and 3 months after BMT. Serum EPO levels increased more than 25-fold above baseline in most subjects after initiating chemoradiation therapy. No correlation was noted between serum EPO and hematocrit, reticulocyte count or serum creatinine. Total red blood cell units transfused ranged from 4 to 15 (mean 7.7). Mean total donor exposures (red blood cell plus platelet units transfused) were 83.6 units (range 16-175). Serum EPO levels increased early in the course of preparation for autologous BMT and remained elevated for at least 2-3 weeks thereafter although at a lower level. Red blood cell transfusions were required despite very high EPO levels after BMT. Red cell transfusions, moreover, accounted for only 9.2% (69 of 746) of total donor exposures and only 5.8% (42 of 746) of donor exposures during the interval when pharmacologic doses of erythropoietin might be of benefit. In contrast to the potential benefit of colony-stimulating factors such as G-CSF and GM-CSF in BMT, our study suggests limited value for erythropoietin therapy in this setting.     

Erythropoiesis in pregnancy

The reticulocyte count, serum ferritin and serum erythropoietin concentrations were measured during the course of pregnancy in 41 women. A decrease in iron stores early in pregnancy was accompanied by a significant rise in the reticulocyte count until the 28th week. Erythropoietin levels did not rise significantly until the 28th week of pregnancy and had fallen to the post-natal level by 40 weeks. The results are consistent with an increase in erythropoietic activity early in pregnancy which did not appear to depend upon increased plasma erythropoietin levels.     

Changes in serum erythropoietin and the reticulocyte count during chemotherapy for leukemias

Abstract: We serially determined serum erythropoietin (Epo) and the reticulocyte count in patients with various types of leukemia during chemotherapy. Serum Epo increased soon after the initiation of chemotherapy and decreased after the termination of therapy irrespective of the types of leukemia or treatment regimen. However, it did not stay at low level but fluctuated. The reticulocyte count, on the other hand, showed a transient rise while serum Epo level descended. The value of serum Epo when increased was higher than the value expected from hemoglobin concentration; this finding was similar to that in aplastic anemia. These results suggest that myelosuppression is a major factor for the increase in serum Epo level during leukemia chemotherapy.     

Comparison of cost effectiveness between measuring the serum erythropoietin level and reticulocyte count for monitoring thalassemic patients: a note in Thai beta thalassemia/Hb E subjects

Iron deficiency anaemia and the thalassemia syndromes, a group of disorders resulting from inherited abnormality of globin chain production, are common causes of anaemia in Thailand, and in the Far East in general. Monitoring erythropoiesis in these patient is very important in evaluating the disease and the response to treatment. Recently, our group has just reported the feasibility in using serum erythropoietin (EPO) for monitoring purposes in thalassemia and demonstrated that the determination of serum EPO can be an alternative choice in the follow up of these conditions. This study reports a cost effectiveness analysis comparing the recently reported radioimmunoassay (RIA) for serum EPO determination and the previously used tool, the reticulocyte count. The study reports a higher detection rate for ineffective erythropoiesis when using serum EPO determination, however, the increased sensitivity is at balanced by a higher unit cost. In this analysis, the cost effectiveness for serum EPO and reticulocyte are 208.33 and 50 baht/detection, respectively. () Therefore, the reticulocyte count is more cost effective and is recommended for routine usage in our current medico-economic setting.     

In vivo effects of interleukin-11 and stem cell factor in combination with erythropoietin in the regulation of erythropoiesis

Summary. In this study we evaluated the in vivo effects of interleukin-11 (IL-11) and stem cell factor (SCF), in combination with erythropoietin (EPO) on murine erythropoiesis. Mice were treated for 7d with IL-11, SCF and EPO, each at three dose levels. In total, 27 different dose combinations were tested. IL-11 as well as SCF could only marginally stimulate erythroid progenitor cell numbers, but IL-11 in combination with SCF was able to increase BFU-E and CFU-E numbers 4-fold, in the absence of exogenous EPO. This resulted in an increased reticulocyte count. In contrast with the stimulatory effect on immature erythroid cell stages, IL-11 treatment induced a mild anaemia, which probably resulted from a plasma volume expansion. The additional treatment with EPO resulted in strong synergistic effects on CFU-E numbers. The combination of high-dose IL-11 and high-dose SCF was able to increase the overall efficiency of EPO-induced erythroid amplification, which was reflected by a left-shift of the in vivo EPO dose-response curve. The stimulating effects of IL-11 and SCF were further demonstrated when the effects on the reticulocyte count of a single high-dose EPO injection were assessed in normal and SCF + IL-11 treated mice. Whereas a single EPO dose increased the reticulocyte count by a factor of 3, IL-11 + SCF pretreatment increased this to a factor of 7. This study shows that in vivo SCF and IL-11 are important modulators of red blood cell production. First, these factors probably increase the input from the stem cell compartment into the erythroid lineage, where subsequently EPO is required for further amplification. Additionally, however, IL-11 and SCF increase the overall efficiency of EPO-induced amplification, probably due to a stimulatory effect on late-stage erythroid cells and to a redistribution of cells from marrow to spleen.     

Correction of anaemia following renal transplantation: serial changes in serum immunoreactive erythropoietin, absolute reticulocyte count and red-cell creatine levels

Improvement of erythropoiesis following successful human renal transplantation in eight patients was monitored by sequential measurements of haemoglobin, red-cell creatine, absolute reticulocyte count and estimates of serum immunoreactive erythropoietin (siEp). SiEp increased in five patients after transplant, in three cases almost immediately after a return to normal of plasma creatinine. The increase in siEp was followed by a rise in the absolute reticulocyte count and red-cell creatine and finally by an increase in the haemoglobin level. As the haemoglobin approached normal levels a decline in the absolute reticulocyte count preceded a fall in siEp levels. Red-cell creatine also fell, though more gradually than the reticulocyte count. Acute graft rejection (in two patients) was associated with a fall in siEp. Chronic rejection (in one patient) was associated with persistent increases in siEp, reticulocyte count and red-cell creatine; this patient subsequently developed erythrocytosis.     

Comparison of Cost Effectiveness between Measuring the Serum Erythropoietin Level and Reticulocyte Count for Monitoring Thalassemic Patients: A Note in Thai Beta Thalassemia/Hb E Subjects

Iron deficiency anaemia and the thalassemia syndromes, a group of disorders resulting from inherited abnormality of globin chain production, are common causes of anaemia in Thailand, and in the Far East in general. Monitoring erythropoiesis in these patient is very important in evaluating the disease and the response to treatment. Recently, our group [1] has just reported the feasibility in using serum erythropoietin (EPO) for monitoring purposes in thalassemia and demonstrated that the determination of serum EPO can be an alternative choice in the follow up of these conditions. This study reports a cost effectiveness analysis comparing the recently reported radioimmunoassay (RIA) for serum EPO determination and the previously used tool, the reticulocyte count. The study reports a higher detection rate for ineffective erythropoiesis when using serum EPO determination, however, the increased sensitivity is at balanced by a higher unit cost. In this analysis, the cost effectiveness for serum EPO and reticulocyte are 208.33 and 50 baht/detection, respectively. ( 1 USD=42 baht ) Therefore, the reticulocyte count is more cost effective and is recommended for routine usage in our current medico-economic setting.     

Treatment of the anemia of aplastic anemia patients with recombinant human erythropoietin in combination with granulocyte colony - stimulating factor: a multicenter randomized controlled study

Abstract: A multicenter randomized controlled study was undertaken in order to determine whether epoetin beta (EPO) ameliorates the anemia in aplastic anemia (AA) patients treated with granulocyte colony-stimulating factor (G–CSF). Enrolled patients were randomized into 3 groups: group C receiving G–CSF alone as the control; group L receiving G–CSF and 200 IU/kg of EPO; group H receiving G–CSF and 400 IU/kg of EPO. Throughout the study, the dose and the administration interval of G–CSF were adjusted to maintain neutrophil counts between 1000 and 5000 μl. EPO was administered subcutaneously for 12 wk as the first step in treatment and when favorable effects were observed over this period, treatment was continued for another 12 wk as the second step in treatment. Significant erythroid responses were defined as increases in untransfused hemoglobin values >1.0 g/dl or >50% decreases in RBC transfusion requirements over the treatment period. Of 131 patients enrolled, 88 patients allocated to groups L and H were evaluated for toxicity to EPO and 110 were evaluated for erythroid responses. Four of the 31 patients (12.9%) in group C, 6 of the 41 patients (14.6%) of group L, and 14 of the 38 patients (36.8%) of group H showed erythroid responses in the first step in treatment. The erythroid responses of group H were significantly higher than those of the other 2 groups (p<0.05). The significant effects of EPO were due to erythroid responses in non-severe AA. Responding patients were significantly different from non-responders with regard to disease severity, hemoglobin concentration, reticulocyte count, serum endogenous erythropoietin levels and serum transferrin receptors; non-severe AA patients were more likely to respond to EPO, and responding patients had lower serum EPO and higher hemoglobin concentration, reticulocyte count and serum transferrin receptors than non-responders. The response rate increased in the second step in treatment, suggesting that long-term treatment improved the efficacy of EPO. No serious side-effects were observed. From these results, we conclude that EPO given in combination with G–CSF is a safe and effective alternative for the treatment of anemia of a subset of AA patients.     

Effect of androgen therapy and anemia on serum erythropoietin levels in patients with aplastic anemia and myelodysplastic syndromes

Immunoreactive serum erythropoietin (EPO) was measured in anemic and non-anemic patients with acquired non-severe aplastic anemia (AA; n = 22) and myelodysplastic syndromes (MDS; n = 31) receiving or not androgens to examine the effect of androgen therapy and anemia on EPO levels in these disorders. Soluble transferrin receptor (TfR) and absolute reticulocyte count (ARC) were also assayed in order to evaluate erythropoietic activity. AA and MDS patients were stratified for anemia and androgen treatment as follows: 12 untreated anemic patients; 17 anemic patients during androgen therapy; 14 non-anemic patients without any treatment (>1 year); and 10 non-anemic patients on androgen therapy. Although EPO levels in non-anemic patients were significantly higher than in healthy controls (n = 29) no statistically significant differences in Hb and EPO values were found between non-anemic patients receiving or not androgen therapy. In the linear regression analysis between Hb and log EPO concentration, no statistically significant differences in the slopes between untreated and androgen-treated anemic groups nor between both groups and patients with iron deficiency anemia (n = 23) were observed. However, the y intercept (log EPO) of regression line was significantly higher in androgen-treated anemic patients than in the androgen therapy-free anemic group. Serum TfR levels were higher in treated than in untreated anemic patients, whereas ARC was not different between both groups. These data seemingly indicate that (1) androgens at pharmacological doses do not increase serum EPO levels in non-anemic AA and MDS patients, and (2) in patients with AA and MDS, androgen-driven EPO stimulation is appreciably enhanced by anemia. Am. J. Hematol. 57:113–118, 1998. © 1998 Wiley-Liss, Inc.     

The clearance of a single i.v. bolus of recombinant human erythropoietin from the serum of patients with myelodysplastic syndromes and its effects on erythropoiesis.

The serum erythropoietin (EPO) concentration in patients with myelodysplasia (MDS) varies widely at similar hemoglobin concentrations, although the reasons for this variation are unclear. We have studied the pharmacokinetics of an i.v. bolus of recombinant human EPO in ten subjects with myelodysplasia. Basal serum EPO concentration varied from 210 to 5984 mU/ml. Plasma half-time clearance (t1/2) varied from 3.9 to 20.0 h. A significant positive correlation was found between t1/2 and basal EPO concentration. An increase in immature peripheral blood reticulocytes was found on days 1 and 2 after EPO treatment; this may represent either an effect on hemopoiesis or on reticulocyte release from the bone marrow.     

Effects of desferrioxamine therapy on chronic disease anemia associated with rheumatoid arthritis

Objective. To investigate the effects of desferrioxamine (DFO) infusion on chronic disease anemia (CDA) of rheumatoid arthritis (RA) by evaluating interleukin-6 (IL-6) and erythropoietin (EPO) production.Patients and methods. Five patients with RA and CDA (group I) were treated with DFO, 500 mg daily, through a continuous 10-h subcutaneous infusion 5 days a week for 4 weeks. One month after withdrawal, DFO was resumed in all five group I patients (group II) with an increase to 1 g daily following the previous treatment schedule. Clinical and laboratory parameters were evaluated weekly during the two study periods. Serum EPO was measured by radioimmunoassay. IL-6 was detected by the enzyme-linked immunoabsorbent assay method.Results. No significant variations in hematological parameters, IL-6 or EPO levels were observed in group I patients. After 1 week of DFO 1 g daily, reticulocyte counts and EPO improved significantly. Hemoglobin and hematocrit rose significantly after 3 weeks of 1 g daily DFO therapy. Four weeks after DFO withdrawal, EPO, reticulocyte counts, hemoglobin and hematocrit returned to baseline levels. A significant improvement in the clinical parameters of disease activity was observed, particularly in group II patients.Conclusion. DFO improves CDA in RA patients. The beneficial effects on erythropoiesis seem to be related to improved EPO responsiveness to the anemia.     

Modulation of hematopoiesis by ketanserin in erythropoietin-treated uremic patients: evidence from platelet studies

Recombinant human erythropoietin (EPO) not only ameliorates the anemia of renal failure but also modulates platelet function and corrects uremic platelet serotonin (5-hydroxytryptamine, 5-HT) storage pool deficiency. We studied if ketanserin, a blocker of platelet and vascular smooth muscle receptors for 5-HT, could reverse any EPO-induced changes in hemostasis. A complete blood count, immunoreactive serum EPO concentration, skin bleeding time (BT) and whole blood platelet aggregation (electric impedance method) induced by ristocetin and ADP, and intraplatelet and whole blood 5-HT, were determined in seven chronic hemodialysis (HD) patients before and after 1, 2, 4 and 8 weeks of EPO therapy, and repeated after a 4-week co-treatment with oral ketanserin. Stimulation of erythropoiesis was accompanied by a rise in the platelet count ( P < 0.05), shortening of the BT ( P < 0.02), an increase in platelet aggregability, and by replenished intraplatelet 5-HT store. Ketanserin co-treatment produced an unexpected 33% fall in serum EPO level ( P < 0.02), a decrease in the platelet count ( P < 0.05), prolongation of the BT ( P < 0.05) and depressed platelet aggregation in response to both agonists. There was no change in the amount of intraplatelet 5-HT while whole blood 5-HT concentration decreased significantly ( P < 0.02). Strong positive correlations between the decrease in whole blood 5-HT and the prolongation of the BT ( r = 0.786, P < 0.05), and between the former parameter and the fall in the platelet count ( r = 0.820, P < 0.05) were found. In conclusion, we report dual erythro- and thrombocytopoietic effects of EPO combined with correction of a platelet defect in the storage of 5-HT and enhanced platelet aggregability. The ketanserin-induced falls in serum EPO concentration and the platelet count provide new evidence of the dependency of thrombocytopoiesis on EPO in the initial weeks of the therapy. The 'antiplatelet' effects of ketanserin observed in this study seem to be due to reduction in circulating thrombocyte number rather than from any inhibitory effect on their aggregation.     

Optimal timing of repeated rh-erythropoietin administration improves its effectiveness in stimulating erythropoiesis in healthy volunteers

We studied the effect of recombinant human erythropoietin (rhEPO) on erythropoiesis when given at different time intervals to healthy adults. 15 volunteers were randomly selected to receive rhEPO (2×300 U/kg) and parenteral iron (2×200mg) either within a 24 h or 72 h interval. Controls received parenteral iron only. Maximum EPO levels were found 24 h after the first intravenous injection (day 1) with a mean value of 364 and 390 U/l for the rhEPO-treated groups. When second rhEPO administration was after 72 h (group III), volunteers showed significantly higher absolute reticulocyte counts and a higher percentage of young RNA-rich reticulocytes (HFR ratio) over several days compared to those who received rhEPO within a 24 h interval (group II). Both rhEPO-treated groups showed an increase in the mean reticulocyte cell volume. Reticulocyte haemoglobin concentration was inversely correlated with the increasing cell size with a nadir on day 8. Reticulocyte haemoglobin content showed a significant decrease in group II after day 5. Serum ferritin levels showed an inverse pattern to the rate of erythropoiesis. After an initial rise, the serum ferritin decrease was most pronounced in group III. Contrary to previous reports with oral iron supplementation, functional iron deficiency was not seen during rhEPO stimulation, due to parenteral iron administration. Our data suggest that the time interval between repeated administrations of rhEPO has an important influence on its pharmacodynamics. rhEPO given within an interval of 72 h was more effective in stimulating erythropoiesis than administration within a 24 h interval for the same total dose.     

Reduced erythropoietin secretion in senile anemia.

To investigate the etiology of the age-related decrease in hemoglobin (Hb) concentration, we measured serum erythropoietin (EPO), serum iron, total iron binding capacity, and serum ferritin levels in 247 elderly subjects aged 60-99 years. EPO levels were determined by radioimmunoassay. An age-related increase in the serum EPO concentration (r = 0.220; P < 0.01) and a significant inverse relationship between EPO and Hb concentrations were found in normal elderly subjects without anemia (r = -0.302; P < 0.001), but not in 111 younger controls. Serum EPO levels were slightly higher in elderly subjects with pre-anemic iron deficiency than in the normal elderly subjects (P < 0.05). These results suggest that the EPO secretion is accelerated in the elderly even though the Hb remains above 12.0 g/dl, probably as a compensatory mechanism for peripheral tissue hypoxia. An inverse relationship between the EPO and Hb concentrations was found in the elderly subjects with iron deficiency anemia, but not in those with unexplained senile anemia. The changes of EPO levels were also assessed in 20 elderly subjects who had developed anemia when reviewed after 12 months. Serum EPO levels increased in relation to the decrease in Hb concentration in those with iron deficiency anemia, but not in those with unexplained senile anemia. Reduced EPO secretion thus seems to play a role in the progression of unexplained senile anemia, and recombinant human EPO may possibly be effective for treating this type of anemia by mobilizing excess iron.     

The effect of erythropoietin on platelet and endothelial activation markers: a prospective trial in healthy volunteers

Erythropoietin (EPO) enhances formation of red blood cells and also affects thrombopoiesis and platelet function. We hypothesized that the effect of EPO may be reflected by changes in thromboxane B2 (TXB2) and endothelial cell function. Six male and six female subjects received recombinant human epoetin alpha (Erypo?) intravenously (300?U/kg). Biomarker levels were assessed at baseline and 4, 24, 48 and 72?hours after infusion. Epoetin alpha increased TXB2 levels by 140%, which reached significance at 48?hours (6.6?±?5?ng/ml vs. 15?±?9?ng/ml; p?=?0.044) and remained at that level at 72?hours. In line, epoetin alpha increased E-selectin levels by 25% already at 24?hours (39?±?21?ng/ml vs. 49?±?26?ng/ml; p?相似文献   

Erythropoietin Response Is Inadequate in Cancer Patients Receiving Chemotherapy

The level of serum erythropoietin (EPO) is inappropriately decreased in cancer patients and has been advocated as the main cause of their anemia. In cancer patients, chemotherapy results in a cumulative anemia severe enough to require transfusion. We investigated the changes in serum EPO, hemoglobin, ceruloplasmin, and copper levels in cancer patients receiving chemotherapy. There was a weak but significant inverse relationship between hemoglobin and log[EPO] (r = -0.41; P < .001). Observed/expected serum EPO ratios decline with repeated chemotherapy indicating inadequate EPO response for the degree of anemia. There was no difference in the severity of anemia and in the degree of EPO response between platinum- and non-platinum-treated patients. Ceruloplasmin, copper, and ferritin levels did not change during chemotherapy. Our results suggest that the EPO response is inadequate for the degree of anemia and justifies the use of recombinant human EPO in cancer patients receiving chemotherapy.     

Reticulocyte counts in the aged

Reticulocytes were measured on an automated reticulocyte counter in five groups; healthy adults, non-elderly patient with low hematopoiesis, adults with anemia, healthy elderly persons and elderly patients with anemia. The reticulocyte percent, absolute reticulocyte count, and reticulocyte composition as classified by fluorescence intensity (highly, moderately, and slightly fluorescent cells) were calculated. The healthy adults had a reticulocyte count of 0.70 +/- 0.55%, an absolute reticulocyte count of 4.36 +/- 1.90 X 10(4)/microliters, 2.33 +/- 1.95% highly fluorescent cells, 18.73 +/- 5.07% of moderately fluorescent cells, and 78.82 +/- 6.55% of slightly fluorescent cells. Patients with low hematopoiesis had lower counts except for the percentage of slightly fluorescent cell. Aged persons without anemia showed no differences in reticulocytes from healthy adults. However, elderly patients with anemia had a low reticulocyte count; there was no tendency towards an increase in the percentage of highly fluorescent cells or a decrease in the percentage of slightly fluorescent cells. Their reticulocyte percent was not significantly higher than healthy controls, suggesting that anemia observed in the aged arises from low hematopoietic activity in the bone marrow.     

Plasma levels of immunoreactive erythropoietin after acute blood loss in man

S ummary . Plasma levels of immunoreactive erythropoietin (Ep) were measured after acute blood loss (50,75,200 and 450 ml) in man in order to determine the volume of blood loss required to trigger an Ep response as well as to define the reticulocyte response. There was a highly significant (P <0.01) linear increase in reticulocyte count after 200 and 450 ml of blood loss. Analysis of trends also showed a highly significant (P < 0.01) linear response of haematocrit and Ep after a 450 ml blood loss. The reticulocyte count increases were not dependent on a prior increase in Ep level indicating that at least two mechanisms are operative in restoring the red cell mass to normal after blood loss.