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PubMed1995

[A quantitative parameter of ineffective erythropoiesis deduced by canonical discrimination and axis rotation on the basis of ferroerythrokinetic data].

Ferroerythrokinetic data including erythron transferrin uptake (ETU) calibration of 134 cases of control, hemolytic anemia, hypoplastic anemia and ineffective erythropoiesis (IEP) were subjected to canonical discrimination analysis. Axis rotation was then performed for the second variate so as to be parallel to the long axis of distribution ellipsoid of IEP group. The process yielded three variates. The first one, V-1, was assumed to represent the amount of effective erythropoiesis, the second one, V'-2, its efficiency ratio and the third one, V'-3, the rate of peripheral hemolysis. A definite correlation (r = -0.872) was obtained in IEP group between V'-2 and ETU, i.e. reduction in efficiency and compensatory hyperplasia in erythropoiesis. On the plane with concised parameters of V-1 and V'-2, an ellipse of 95 percent confidence of IEP group and three discrimination lines delineated five areas representing five patterns of ferroerythrokinetics, i.e. IEP, hemolytic, hypoplastic, IEP combined with hemolytic or with hypoplastic ones. This method is considered to be useful for application to those erythropoietic disorders having partial or complicated factors described above, where routine ferroerythrokinetic parameters may, be indecisive.

Calibration↗
PubMed1996

[Effect of deferoxamine on erythropoiesis in patients hemodialyzed for chronic renal insufficiency treated with erythropoietin].

The aim of the study was to evaluate the effect of deferoxamine therapy on erythropoiesis, aluminium concentration and iron metabolism in hemodialyzed patients with chronic renal insufficiency treated with human recombinant erythropoietin (Eprex, Cilag). 8 hemodialyzed patients (2 female and 6 male) in long-term programme with aluminium serum concentration over 160 micrograms/l were treated with deferoxamine (5 mg/kg b.m.) during the last hour of hemodialysis in slowly intravenous infusion since 1 months. During this treatment aluminium and iron serum concentrations, serum iron-binding capacity, transferrin and hematocrit were determined before and after 1 months of deferoxamine therapy. The significant decrease of aluminium serum concentration (p < 0.05) and increase of hematocrit (p < 0.01), iron (p < 0.05) and serum iron-binding capacity (p < 0.001) were determined. The results of performed analysis indicate that aluminium is able to inhibit erythropoiesis induced by erythropoietin. The improvement in erythropoiesis and iron metabolism after deferoxamine therapy was observed.

Adult↗
PubMed1997

Effects of various modes of androgen substitution therapy on erythropoiesis.

In order to investigate differential effects of androgens on erythropoiesis, 55 men with clincally and biochemical confirmed hypogonadism were randomly assigned to 4 groups receiving different forms of androgen substitution: Mesterolone (MES) 100 mg/d, testosterone undecanoate (TU) 160 mg/d, testosterone enanthate (TE) 250 mg i.m./21 days or 1200 mg crystalline testosterone (TPEL) subcutaneously implanted at study begin. Previous testosterone medication had been suspended at least 3 months prior to study begin. Testosterone (T), dihydrotestosterone (DHT), hemoglobin (HB) and hematocrit (HC) were assessed before, during and after substitution of androgens. MES did not increase serum T and TU raised average T levels during substitution to 5.7 +/- 0.3 nmol/l, thereby doubling baseline concentrations. TE resulted in a 6fold increase of baseline T yielding 13.5 +/- 0.7 nmol/l and TPEL increased serum T 8.5fold to 23.2 +/- 1.1 nmol/l. Average DHT levels during substitution were 4.3 +/- 0.2 (MES), 3.3 +/- 0.2 (TU), 4.0 +/- 0.4 (TE) and 5.5 +/- 0.4 (TPEL) nmol/l. The groups receiving TPEL, TU or TE showed a significant rise of HB and HC compared to baseline, whereas in the MES group these parameters did not change significantly. MES increased HB by 5.6 +/- 1.8 g/l, TU by 12.7 +/- 2.8 g/l, TE by 21.1 +/- 2.6 g/l and TPEL by 21.7 +/- 4.0 g/l. HC was raised by 1.8 +/- 0. 4% in the MES group, 3.9 +/- 1.1% in the TU group and 6.4 +/- 0.9% and 6.5 +/- 1.6% in the TE and TPEL groups, respectively. Except for 1 subject in the TPEL group, the HB and HC stayed within the normal limits. We conclude that, T, but not DHT, stimulates erythropoiesis in a dose dependent manner. T levels within the low normal range for men are required for maximal stimulation of erythropoiesis.

Adult↗
PubMed1997

Erythropoietin-receptor expression and function during the initiation of murine yolk sac erythropoiesis.

Although erythropoietin is necessary for definitive (fetal liver and bone marrow) erythropoiesis, the role of erythropoietin signaling in primitive (yolk sac) hematopoiesis has not been well defined. In situ hybridization studies have revealed that erythropoietin-receptor (EPOR) mRNA accumulation begins in mesoderm cell masses of the developing yolk sac of the neural plate stage embryo (E7.5) before the development of morphologically recognizable erythroblasts. EPOR mRNA is also present in yolk sac blood islands at early somite stages (E8.5). These findings suggest that EPOR functions during early stages of yolk sac erythropoiesis. We have used a serum-free murine yolk sac explant system (Palis et al., Blood 86:156, 1995) to investigate the initial differentiation of primitive erythroblasts from extraembryonic mesoderm cells. Exogenous erythropoietin increased both erythroblast numbers and betaH1-globin accumulation in yolk sac explants, suggesting that primary yolk sac erythroblasts are directly responsive to erythropoietin. An antisense oligodeoxynucleotide (ODN) experimental approach was used to examine the functional role of erythropoietin signaling during the initiation of yolk sac hematopoiesis in yolk sac explants. Antisense EPOR ODN produced a >50% reduction (p < 0.005) in the number of differentiating primitive erythroblasts, >95% reduction in betaH1-globin accumulation (p < 0.001), and a >50% reduction (p < 0.01) in the number of CFU-E and BFU-E compared with missense EPOR ODN-treated and untreated control explants. Antisense EPOR ODN also blocked the increase in primitive erythroblast number induced by exogenous erythropoietin. We conclude that erythropoietin/EPOR signaling is functionally active during the initial proliferation and differentiation of primary yolk sac erythroblasts. These results also suggest that other growth factor signaling cascades are active during the onset of mammalian erythropoiesis.

Animals↗
PubMedDate not supplied

Influence of erythropoiesis stimulation on 54Mn distribution in rats.

The experiments were carried out on animals in which erythropoiesis was stimulated. The rats were anaemized by blood letting or they received subcutaneous injections of erythropoietic filtrate of anaemized sheep plasma. The investigations demonstrated that enhanced 54Mn incorporation into the erytrocytes and bone marrow is induced by stimulation of the erythropoiesis process, whereas the raised 54Mn level in the plasma of anaemized rats is associated with blood loss and not with erythropoiesis.

Animals↗
PubMed1998

Effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on murine bone marrow and spleen erythropoiesis.

100 micrograms/kg of recombinant human granulocyte colony-stimulating factor was injected twice daily into normal adult CF1 female mice for a period of 15 days. After that time we have observed a decrease 59Fe marrow incorporation with a parallel increase in the spleen. During the first 9 days the marrow plus spleen erythroid cells number decreased to 60% of control approximately, but recovered thereafter and were not significantly different from normal values at 12-15 days. In addition, our studies demonstrate that the spleen erythropoiesis is quantitatively more important at the final time than marrow erythropoiesis. For this reason, splenic compensatory erythropoiesis maintained the hematocrit values between normal ranges. Regarding the granulocytic compartment, 15 days of rhG-CSF treatment produce a marked increase in total count of splenic granulocytes (a 7.7 fold rise from control values). Marrow granulocytes shows a 2-fold increment, but considering the absolute counts, bone marrow still was predominant as a granulopoieitc organ. Our results indicate that the spleen is a more important erythropoietic organ than marrow after 15 days of rhG-CSF treatment.

Animals↗
PubMed1976

On the mechanism of erythropoietin-induced differentiation. XIV. The apparent effect of etiocholanolone on initiation of erythropoiesis.

Etiocholanolone, when tested in normal mice or in mice that have been out of an hypoxic atmosphere for only a few days, stimulates erythropoiesis, but appears to have no effect on erythropoiesis when tested in plethoric mice that have very low residual red cell formation. The steroid, similarly, stimulates hemoglobin synthesis by marrow cells in culture if they are from normal mice, but has no effect on cells from transfused mice. Out data suggest that 5 beta-H androstane and pregnane derivatives do not have a primary action on the induction of erythropoiesis, but act on cells that are already differentiated.

Animals↗
PubMed1998

[The effect of calcium precipitate of double-stranded RNA on erythropoiesis in rats with acute anemia].

On the model of experimental acute anaemia of rats, induced by injection of phenilhydrazine, the influence of calcium precipitate of double-stranded RNA (Ca-ds-RNA), introduced during the crise of anaemia, on the process of erythron restoration, was studied. In the presence of Ca-ds-RNA the number of pro- and erythroblasts in fission increases by 1.5 times, compared with "pure" anaemia situation, and accordingly there is a marked decrease in the share of microcytes, which play an important role in the restoration of cell number, and in the erythron recovery after the crise of anaemia. Less pronounced is the influence of Ca-ds-RNA on the macrocytosis, which keeps its value in spite of the increase in the speed of development and of the number of normocytes after Ca-ds-RNA introduction. The mechanism of Ca-ds-RNA inclusion in the system, which controls the process of erythropoiesis during anaemia, is discussed. A conclusion is drawn that Ca-ds-RNA may directly affect the inductive stage of erythropoiesis, stimulating the formation of competent erythroid cells in population of stem haemopoiethic cells and their proliferation. Further development of bone marrow cells takes place according to the known programme of erythropoiesis whose variations are stimulated by the current conditions of its realization, but not by the presence of Ca-ds-RNA.

Acute Disease↗
PubMed1976

Mechanism of the increased splenic erythropoiesis in mice treated with estradiol benzoate.

Pharmacological doses of estrogens induce osteosclerosis of the bone marrow, and depress colony-forming units (CFU's) and platelet and leukocyte counts in mice. A compensatoryincreasts in mice. A compensatory increase in splenic erythropoiesis prevents a fall in the hematocrit. The mechanism of this compensation was investigated as follows, BDF1 female mice were injected subcutaneously thrice weekly for 6 weeks wiht 50 mugg of estradiol benzoate (EB) or sesame oil (SO). Subsequently the hematocrit, red cell mass (RCM), and 4 hour per cent of 59Fe uptake into the femurs and spleens were determined in groups of five mice for 4 consecutive days. The RCM and hematocrit were not significantly different in the two groups. The per cent of 59Fe uptake into the femurs of EB-treated mice was less than 30 per cent of that in SO-treated mice and the per cent of 59Fe uptake into the spleens of EB mice was more than two times that in SO mice. To ascertain whether the increase in plenic erythropoiesis resulted from an increase in the number of splenic erythropoietin-responsive cells (ERC), the 4 hours per cent 59Fe uptake into the spleen was determined in continuously hypertransfused EB and SO mice injected with erythropoietin (Ep). Whereas hypertransfuction depressed the splenic per cent of 59Fe uptake in EB and SO mice equally, injection of Ep increased the per cent of 59Fe uptake into the spleens of of EB mice to greater than two times that of SO mice. Next, the plasma Ep level of mice injected with EB or SO for 2, 4, or 6 weeks was determined after exposure of the animals to hypoxia. Ep titers were greater than three times higher in EB mice than in SO mice, We conclude that at least two mechanisms act to cause the compensatory increase in splenic erythropoiesis after marrow suppression by EB: (1) the Ep levels rise and (2) the splenic ERC population increases. The latter is probably not due to the increased plasma Ep level because it also occurs in mice whose Ep production is suppressed by plethora.

Animals↗
PubMed1998

Impaired erythropoiesis in transgenic mice overexpressing a truncated erythropoietin receptor.

Erythropoietin (EPO), one of the pivotal regulators of erythrocyte production, transmits signals through the EPO receptor (EPOR). We have previously reported that human bone marrow (BM) cells express two dominant forms of the EPOR, one full-length and one truncated (EPOR-F and EPOR-T). Experiments with a cell line have shown that the EPOR-T acts as a dominant-negative regulator of EPOR-F-mediated signals. Its role in erythropoiesis in vivo, however, has yet to be clarified. Here we show the presence in mouse BM of a truncated form of the EPOR that is essentially the same as EPOR-T in humans. To investigate its role in vivo, we generated transgenic mice overexpressing mouse EPOR-T (EPOR-T-Tg mice). As a result, two independent EPOR-T-Tg lines were established. One line revealed mild anemia, but another line did not. When anemia was induced experimentally in these mice, however, both lines showed apparently poor recovery resulting in higher mortality than wild-type control mice. The impaired erythropoiesis found in these mice thus strongly suggests the EPOR-T's role as a negative regulator of erythropoiesis in vivo.

Anemia, Hemolytic↗
PubMed1978

Effect of dehydration on erythropoiesis in mice: relevance to the "anemia" of space flight.

Mice deprived of water for 24 h showed an increase in hematocrit and loss of body weight comparable to that seen in men during space flight. The increase in hematocrit was entirely due to a decrease in plasma volume and was associated with suppression of erythropoiesis, but with no significant change in the serum titer of a presumptive humoral regulator of erythropoiesis, Erythroid Stimulating Activity (ESA). Mice deprived of water for 24 h may be a useful model for the study of the early hematological effects of space flight. The suppression of erythropoiesis due to a relative erythrocytosis appears to be independent of ESA.

Animals↗
PubMed2005

Successful reintroduction of a different erythropoiesis-stimulating agent after pure red cell aplasia: relapse after successful therapy with prednisone.

We report a 3-year case history that describes a 78-year-old woman with recurrent transfusion-dependent pure red cell aplasia (PRCA) secondary to recombinant epoetin use that was responsive to immunosuppressant therapy. The patient had kidney disease of unknown aetiology (estimated glomerular filtration rate of 13 ml/min/1.73 m2) and was not on dialysis. After 16 months of therapy with subcutaneous Eprex, she developed anti-erythropoietin antibody-confirmed PRCA and was started on high dose prednisone (50 mg per day). Within 5 months, the patient's serum was clear of antibodies and, under the cover of low dose prednisone (5-7.5 mg per day), therapy with a different erythropoiesis-stimulating compound (Aranesp) was initiated due to persistent fatigue and anaemia. At 3 months of therapy, the serum anti-erythropoietin antibodies remained negative and, due to the patient's requests, and after discussion, prednisone therapy was discontinued. Unfortunately, 3 months after cessation of prednisone, a recurrence of PRCA was confirmed by the development of profound anaemia and reappearance of anti-erythropoietin antibodies in the patient's serum. High dose prednisone (50 mg per day) was reinstituted, whereupon, 2 months later, antibodies were again confirmed to be negative. This case report demonstrates the responsiveness of PRCA to simple immunosuppressive therapy, and the ability to introduce different erythropoiesis-stimulating agents in the presence of such therapy. It appears that there may be problems associated with discontinuation of immunosuppressive therapy in the presence of sustained erythropoiesis-stimulating agent therapy in those in whom the condition has occurred previously.

Aged↗
PubMed2002

[Treatment of anemia in chronic renal failure by a long-activing activator of erythropoiesis].

THE INTEREST AND LIMITS OF ERYTHROPOIETIN: Chronic renal failure (CRF) is often associated with anemia, mainly because of insufficient renal synthesis of erythropoietin (EPO). This observation led in the early 1980 to the cloning of the complementary DNA coding for the EPO molecule, the large-scale production of a recombinant human EPO (rHuEPO), and its large utilisation in clinical practice. More than a decade after this outstanding research progress, the use of rHuEPO has literally transformed the treatment of anemia of CRF. The efficacy of rHuEPO is dose-dependent and corrects the anemia in the majority of the patients. However, its relative short plasma half-live (4-8 hours) requires repeated injections of the drug, usually two to three times a week. A LONG ACTING ANALOGUE: The novel erythropoiesis stimulating protein (NESP) is a hyperglycosylated analogue of rHuEPO capable of stimulating erythropoiesis by the same mechanisms as the natural EPO. NESP possesses five N-linked oligosaccharide chains and two times more sialic acid residues than rHuEPO. The addition of these extra-carbohydrate chains gives NESP greater metabolic stability and a half-life 3.6 times longer than rHuEPO. THE PROPERTIES OF NESP: Numerous studies have shown that NESP normalized and maintained stable the hemoglobin concentration when administered once a week and even at the frequency of one injection every other week. The optimal and maintenance dose is 0.45 microgram/kg/week, either intravenously or subcutaneously. Adverse events are similar to those seen with rHuEPO, and no antibodies against NESP have been detected in over 1,500 patients treated with NESP for more than 1 year. IN CONCLUSION: This novel long acting activator of the erythropoiesis is efficient and safe for the treatment of anemia of IRC patients. Its prolonged half-life, the delay between injections, and the decrease in the frequency of dose changes might result in an advantage for the patients and the medical staff.

Anemia↗
PubMed1992

Erythropoiesis in long term cultures of foetal liver cells is transiently obtained on adult but not on foetal adherent cell layers.

We have previously reported long term erythroid differentiation of adult bone marrow cells seeded onto adherent cells derived from adult bone marrow. In this paper, we show that the adherent cells obtained from foetal liver do not support the erythroid differentiation of either adult bone marrow cells or foetal liver cells. Adherent layers derived from bone marrow of adult W/Wv mice supported differentiation of adult bone marrow precursors, but foetal liver progenitors only produced erythrocytes for a few weeks and the foetal origin of these red cells was confirmed by haemoglobin typing. The duration and extent of erythropoiesis was generally inversely proportional to the cell dose. Foetal progenitors were as sensitive to erythropoietin as adult cells, but were optimally stimulated at a lower plateau concentration. These results suggest that inhibitory cells present in foetal liver may block erythropoiesis and their growing importance with age may provide an explanation for the arrest of erythropoiesis in the liver at late developmental stages.

Anemia↗
PubMed1999

Circulating cytokines response and the level of erythropoiesis in sickle cell anemia.

A hemoglobin F (HbF) level between eight and nine percent divides sickle cell anemia (SS) patients into two populations, according to the kinetics of circulating burst forming units-erythroid (BFU-E), long term culture-initialing cells (LTC-IC), and cytokine plasma concentrations. The SS patients with HbF levels lower than 8-9% are more anemic (LFSS patients) than those with HbF levels higher than 8-9% who have less severe anemia (HFSS patients). We report here that the level of erythropoiesis [evaluated by the levels of soluble transferin receptors (sTfR)] is not identical in these two patient populations, supporting the idea that a different set of regulatory mechanisms might be required to maintain the two levels of increased hematopoiesis. The plasma sTfR concentration was increased in all SS samples compared with controls (P < 0.002) and sTfR levels were negatively correlated with peripheral HbF%. (r = -0.574, P < 0.002). Furthermore, sTfR levels were higher in LFSS than in HFSS patients. Erythropoietin (Epo) levels were increased in the plasma of LFSS individuals (range = 34-215 ml U/ml), while the values in HFSS patients were in the normal range (3-20 ml U/ml). Furthermore, we identify here stem cell factor (SCF) and transforming growth factor-beta (TGF-beta) as regulatory factors specifically affected by the presence of SS genotype and its level of severity. The plasma concentrations of SCF and TGF-beta were increased compared with normal controls and high levels of SCF (up to 7,000 pg/ml) were detected in LFSS patients. The latter also showed increased proportion of SCF+ CD34 enriched circulating cells (49%). Low SCF in HFSS patients is associated with elevated TGF-beta, suggesting a regulatory role of the latter on either SCF release or c-kit expression in progenitor cells. Occasional elevation of granulocyte macrophage-colony stimulating factor (G-CSF), interleukin (IL)-7, and macrophage inflammatory protein (MIP)-1alpha in plasma of SS patients is not specific because no relation to HbF could be demonstrated. All plasma tested for leukemia inhibitory factor (LIF) were negative. Data presented here, complementing previously published information, supports a model in which HFSS patients achieve a balance between inhibitory (TGF-beta) and stimulatory (SCF, IL-3) factors, resulting in moderate erythropoietic response. In contrast, in LFSS patients, low levels of TGF-beta and the increased release of GM-CSF and SCF maintain the intense erythropoiesis in response to higher erythropoietic stress, in these more severe patients.

Adult↗
PubMed1996

Evidence suggesting a stimulatory role for interleukin-10 in erythropoiesis in vitro.

Interleukin-10 (IL-10) has been shown to exert anti-inflammatory effects by suppressing macrophage proliferation and inhibiting cytokine production. In this study we show that in the presence of erythropoietin (EPO), the addition of IL-10 results in a significant dose-dependent increase in both Burst Forming Unit-Erythroid (BFU-E) and Colony Forming Unit-Erythroid (CFU-E) colony growth in both serum-containing and serum-free murine cultures in vitro. IL-10 acts at the later stages of erythroid cell proliferation and differentiation as the increase in colony number was greater in CFU-E than in BFU-E, and was similar when IL-10 was added to BFU-E cultures at the time of culture initiation as when its addition to culture was delayed for 7 days. Furthermore, no increase in BFU-E colony number was noted when IL-10, added at the time of culture initiation, was neutralized by the addition to culture of a monoclonal anti-IL-10 antibody up to 7 days later. The increases in BFU-E by IL-10 addition were not the result of prolongation of BFU-E colony lifespan, which was not significantly different in IL-10 treated and control cultures, respectively. Rather IL-10 stimulated the proliferation of erythroid clusters that were now large enough to be recognized as colonies. IL-10-induced stimulation of erythropoiesis appeared to be independent of its inhibitory effects on macrophage function, as stimulation of erythroid colony growth was similar in macrophage-containing and depleted cultures. Studies to determine if the IL-10 effect was direct or indirect yielded equivocal results. A limiting dilution assay suggested a direct effect. However, a log/log dose response curve with IL-10 did not pass through the origin suggesting an indirect effect. These studies indicate that IL-10 acts synergistically with EPO to significantly increase stimulation of erythroid differentiation and proliferation in vitro and may be involved in the regulation of normal erythropoiesis in vivo.

Animals↗
PubMed1979

Desacetyl vinblastine amide sulfate induced ineffective erythropoiesis.

Ineffective erythropoiesis occurred during desacetyl vinblastine amide sulfate (VDS) therapy of a patient with metastatic Ewing's sarcoma. The peripheral blood was characterized by anisocytosis, poikilocytosis and reticulocytopenia. Bone marrow showed megaloblastic red cell hyperplasia with nuclear fragmentation, binuclearity and abnormal metaphases. Radioiron incorporation into red cells was markedly decreased. Electron microscopy showed red cell surface changes previously called ropalocytosis. Normal erythropoiesis promptly resumed when VDS treatment was withheld. Although less common than leukopenia, red cell abnormalities are part of the spectrum of vinca alkaloid toxicity.

Adolescent↗
PubMed1981

Erythropoiesis during an erythroblastic transformation of chronic myelocytic leukemia.

The requirement of erythropoiesis for erythropoietin were studied in a patient with Ph chronic myelocytic leukemia who had undergone an erythroblastic transformation. Transfusions resulted in a suppression of erythropoiesis. Plasma clot culture studies indicated that both the CFU-E and BFU-E in the peripheral blood of this patient were dependent upon erythropoietin for their differentiation and proliferation. Neither of these committed erythroid stem cells was cloned in the absence of erythropoietin. These studies suggest that the proliferation and differentiation of erythroid stem cells during the erythroblastic crisis of this disorder remain dependent upon physiologic regulators.

Adult↗