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[Effective and ineffective erythropoiesis in long-term hemorrhages].

The investigation of effective and ineffective erythropoiesis in long-term hemorrhages has shown that the index of normal erythroblasts maturation is decreased down to 0.7 +/- 0.01 (P < 0.01) that evidences disorders in the process of proliferation and differentiation of the erythron cells. A rise of ineffective erythropoiesis was observed at the level of polychromatophilic normal erythroblasts , the mean number of PAS (positive cells) comprised 22.9 +/- 4.1% (P < 0.05). Erythropoiesis intensity was lowered and erythrocyte life was shortened. The data obtained are important for the evaluation of the erythron system lesion and purposeful therapy.

Adult↗

Effects of intravenous ascorbic acid on erythropoiesis and quality of life in unselected hemodialysis patients.

BACKGROUND: Intravenous ascorbic acid (IVAA) administration is reported to enhance erythropoiesis in hemodialysis (HD) patients with functional iron deficiency. We explored the effects of IVAA on erythropoiesis and health-related quality of life (HRQOL) in unselected HD patients. METHODS: Sixty-one HD patients were divided into two groups; 30 patients received 100 mg of IVAA (IVAA group) and 31 patients did not (control group) after each dialysis session. Hematocrit (Hct), reticulocyte hemoglobin content, transferrin saturation, ferritin, weekly recombinant human erythropoietin (rHuEPO) dosage, weekly intravenous iron (IVFE) dosage, and MOS Short Form 36 (SF-36) scale scores were measured at baseline and after 6 months of treatment. RESULTS: Mean changes in Hct in the IVAA and control groups were -0.5 and -0.6 mg/dL, respectively, while mean changes in SF-36 scale scores were: physical functioning -1.6 in the IVAA group and 0.38 in the controls; role physical (RP) 3.8 and 9.4; bodily pain 9.7 and 0.81; general health perception 3.7 and -0.68; vitality 4.3 and -7.5; social functioning 2.7 and 0.43; role emotional (RE) 6.9 and 4.9; mental health 3.6 and -1.7. The IVAA group showed significantly higher adverse events (chest pain: n=1, nausea: n=2 and fatigue: n=2) compared to the controls (no event). CONCLUSIONS: The beneficial effects of IVAA on erythropoiesis and HRQOL were not demonstrated in unselected HD patients. Indication of IVAA for HD patients leaves room for further study.

Adolescent↗

[Characteristics of erythropoiesis regulation in population living at high altitude].

AIM: To study characteristics of iron deficiency anemia (IDA) in native population of high altitude territories. MATERIAL AND METHODS: 1300 women living in Tien-Shan areas were examined for serum and erythrocytic ferritins (SF and EF), general iron-binding capacity of the serum, transferrin saturation with iron, transferrin, soluble transferrin receptor (TR), erythropoietin (EP), Hb, erythrocytes, erythrocytic indices. RESULTS: Regulation of erythropoiesis in women living at high altitude is specific, i.e. disagreement between complete depletion of iron (by SF and EF) and normal level of Hb, erythrocytes, EP and TR. CONCLUSION: It is suggested that in population living at high altitudes (3000 m above the sea level and higher) long-term adaptation to hypoxia gave rise to an original mechanism of erythropoiesis regulation when all coming iron participates in hemoglobin synthesis without iron deposition. Under hypoxic hypoxia regulation of erythropoiesis is directed to prevention of tissue hypoxia.

Adaptation, Physiological↗

Benefits of early intervention with erythropoiesis- stimulating proteins in chemotherapy-induced anemia.

Anemia is common in patients treated with chemotherapy for both solid and hematologic malignancies, contributing to fatigue and diminished quality of life and exposing them to the inherent risks of red blood cell transfusions. Erythropoiesis-stimulating proteins have been shown to increase hemoglobin levels, reduce the need for transfusions, and improve quality of life. The current practice guidelines recommend treating moderate to severe chemotherapy-induced anemia with erythropoiesis-stimulating proteins, but the risk of transfusions may be less with earlier intervention at higher hemoglobin levels. A review of the literature suggests that treating mild chemotherapy-induced anemia with erythropoiesis-stimulating proteins reduces the risks of transfusions and the development of more-severe anemia. Weighing the clinical evidence together with other clinical and economic considerations should provide greater insight into the benefits of treating mild anemia in patients treated with chemotherapy.

Anemia↗

[Local mechanisms of the regulatory action of Scutellaria baicalensis and ginseng extracts on the erythropoiesis after paradoxical sleep deprivation].

The influence of ginseng and skullcap (Scutellaria baicalensis) extracts on the local mechanisms of erythropoiesis control under the conditions paradoxical sleep deprivation has been studied. The regulatory action of both preparations on the bone marrow erythropoiesis is based on their ability to influence the proliferation and differentiation in erythroid cells-precursors via modulation of the functional activity of cellular hemopoiesis-inducing microenvironment elements. In particular, the drugs induce changes in the structural and functional organization of the bone marrow and in the production of short-range humoral erythropoiesis regulatory elements.

Animals↗

Positive effect of granulocyte-colony stimulating factor on erythropoiesis in humans.

We studied the effects of granulocyte-colony stimulating factor (G-CSF) on human erythropoiesis in vivo. Changes in the peripheral blood were analyzed in 9 subjects; 3 healthy volunteers, 3 patients with pancytopenia and hypersplenism and 3 patients with chronic renal failure and severe anemia being treated with hemodialysis. We monitored erythropoiesis according to the number of highly fluorescent cells (HFC) present in the peripheral blood after staining with Auramine 0. These cells are relatively immature reticulocytes that contain much RNA. All subjects received recombinant human G-CSF at a daily dose of 100 micrograms/m2 administered intravenously for 3 to 5 days. Plasma erythropoietin was measured in patients receiving dialysis before and several times after its administration. The number of HFC increased significantly in all subjects. In 1 of 3 patients receiving dialysis, the plasma erythropoietin increased transiently but insignificantly. These findings show that G-CSF affects human erythropoiesis in vivo, but that the mechanism of its effect did not involve an increase in plasma erythropoietin.

Adult↗

[The spatial-temporal organization of erythropoiesis in exposure of the body to hyperbaric oxygenation].

A systemic approach to appraisal of the mechanisms of changes of erythropoiesis biorhythms in stress is suggested. The authors studied the daily and seasonal rhythms of serum erythropoietin (EP) level, the production of erythrocytes (PE), the kinetics of bone marrow erythroid cells, and the activity of lipid peroxidation (LPO) and G-6-PDG in peripheral blood erythrocytes in albino rats. As a stress factor hyperbaric oxygenation initiated LPO acceleration and change of PE circadian rhythm with mesor decrease. Increased production of erythrocytes with reduction of their life span was simultaneously revealed. The differences in acrophases and amplitudes of erythropoiesis values in different seasons are caused by changes of erythroid cell kinetics due to mobilization of terminal erythropoiesis.

Animals↗

Delayed erythropoiesis after major ABO-incompatible bone marrow transplantation: report of a case.

Major ABO-incompatible bone marrow transplantation (BMT) may be associated with delayed erythropoiesis. A 38-year-old man (blood group O) with chronic myelogenous leukemia received a BMT from his histocompatibility antigen (HLA) identical brother (blood group A). The pre-BMT anti-A titer of the patient was 1:4. The harvested marrow was depleted of RBC by 6% hydroxyethyl starch sedimentation and Ficoll-Hypaque gradient centrifugation. No acute hemolysis occurred after marrow infusion. Myeloid and megakaryocytic series engrafted promptly. However, delayed erythropoiesis up to day 266 was found. Prolonged presence of anti-A antibody was noted for more than 250 days after BMT, although the peak titer was only 1:8. After the reconstitution of bone marrow, the erythroid series was confirmed as donor origin (RBC cell typing A). It is proposed that the prolonged presence of anti-A antibody probably produced from the residual host B lymphocytes, would destroy the regenerating erythroid precursors. Also, use of cyclosporin A may be associated with higher rates of prolonged production of anti-A/B antibodies and the subsequent delayed erythropoiesis.

ABO Blood-Group System↗

In vivo suppression of erythropoiesis by tumor necrosis factor-alpha (TNF-alpha): reversal with exogenous erythropoietin (EPO).

Tumor necrosis factor-alpha (TNF-alpha) selectively kills tumor cells in vitro and in vivo and is being tested as a cancer therapeutic agent. We have shown that TNF-alpha significantly suppresses late-stage erythropoiesis, leading to anemia in chronically treated mice. These erythropoietic effects could limit the clinical use of TNF-alpha. Therefore, we have examined whether erythropoietin (EPO) could be used to prevent TNF-alpha-induced erythroid suppression. Normal mice were treated with a single dose of recombinant murine TNF-alpha (10(5) U/mouse, i.p.) with and without various concentrations of recombinant human EPO. After 3 days, effects on late-stage erythropoiesis were measured by determining the number of mature erythroid colony-forming cells (CFU-E) in the spleen and bone marrow. Simultaneous treatment with EPO abrogated the suppressive effect of TNF-alpha in a dose-dependent manner. EPO treatment also prevented the decrease in peripheral blood-hematocrit that was observed with chronic (5 x 10(4) U/mouse/day for 5 days) administration of TNF-alpha. TNF-alpha-induced hemorrhagic necrosis of tumors and stimulation of macrophage (CFU-M) progenitors were unaffected by EPO treatment. These results demonstrate that simultaneous injection of EPO can abrogate the TNF-alpha-induced suppressive effects on erythropoiesis.

Anemia↗

Developmental regulation of erythropoiesis by hematopoietic growth factors: analysis on populations of BFU-E from bone marrow, peripheral blood, and fetal liver.

Fetal hematopoiesis is characterized by expanding erythropoiesis to support a continuously increasing RBC mass. To explore the basis for this anabolic, nonhomeostatic erythropoiesis, the proliferative effect of recombinant hematopoietic growth factors on highly enriched hematopoietic progenitor cells from fetal and adult tissues were compared. Fetal hepatic BFU-E, unlike adult bone marrow (BM) or peripheral blood (PB) BFU-E, were capable of proliferating in response to erythropoietin in the absence of added GM colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3), and erythropoietin (Epo) directly stimulated the expansion of the fetal BFU-E pool in suspension culture. A murine monoclonal antibody (MoAb), Ep 3, was raised against enriched fetal liver progenitor cells, which detected all fetal BFU-E and which reacted with the erythropoietin-responsive, GM-CSF/IL-3-independent fraction of adult BM BFU-E and CFU-E. All adult PB BFU-E were Ep 3- but became Ep 3+ after stimulation with GM-CSF or IL-3. These data indicate that Epo plays a unique role in fetal hepatic erythropoiesis, stimulating proliferation of immature BFU-E in addition to promoting terminal differentiation of later erythroid progenitor cells. In addition, these results demonstrate a MoAb which detects all erythropoietin-responsive progenitor cells and distinguishes the BFU-E compartments in adult BM and PB.

Age Factors↗

T cell chronic lymphocytic leukemia: presence in bone marrow and peripheral blood of cells that suppress erythropoiesis in vitro.

The pathogenesis of the anemia associated with malignancy was investigated in a patient with T cell chronic lymphocytic leukemia. The plasma clot culture system was used as a measure in vitro of erythropoiesis. The patient's peripheral blood and marrow T lymphocytes obtained both before and after transfusion therapy suppressed erythroid colony formation by normal human bone marrow cells. Pretreatment of the patient's bone marrow T cells by antithymocyte globulin (ATG) and complement reversed this suppression. In addition, pretreatment of the patient's marrow cells with ATG and complement markedly augmented erythropoiesis in vitro. The expression of erythroid activity caused by the selective destruction of the suppressor T lymphocytes in the patient's bone marrow with ATG and the suppression of normal erythropoiesis by the patient's bone marrow and peripheral blood lymphocytes suggest that interaction between the malignant T cell and the erythropoietin-responsive stem cell is important in production of anemia in this patient.

Aged↗

Receptor-specific inhibition of bone marrow erythropoiesis by recombinant DNA-derived interleukin-2.

Interleukin-2 (IL-2) induces differential secretion of lymphokines by IL-2 receptor (IL-2R)-positive and IL-2R-negative T cells. We studied T cell IL-2R-specific modulation of adult bone marrow erythropoiesis by recombinant IL-2 (rIL-2). I3-2R were induced by CD3 T cell surface determinant-triggering and analyzed by cytofluorography. Bone marrow monocyte and T cell-depleted (NAB-T) target cells were assessed for early erythroid progenitor expression (BFU-E) in the presence of 0 to 10(3) U/mL of rIL-2, rIL-2 had no significant effect on BFU-E expression in the absence of T cells or in the presence of IL-2R-negative T cells. rIL-2 caused a dose-dependent inhibition (75% to 90%) of BFU-E in the presence of autologous IL-2R-positive T cells. The addition of anti-IL2-receptor antibody to cultures containing rIL-2 plus IL-2R-positive T cells entirely abrogated rIL-2-mediated inhibition of BFU-E. In the presence of rIL-2 (10(2) U/mL) production of interferon gamma (IF-gamma) by adult marrow CD3-triggered IL-2R-positive T cells was increased 37- to 125-fold compared to IL-2R-negative T cells. rIF-gamma caused a dose-dependent (88% +/- 17% at 10(3) U/mL) inhibition of adult BFU-E in the presence of CD3-triggered autologous T cells. rIL2-mediated inhibition of adult BFU-E in the presence of IL-2R-positive T cells was partially abrogated (52% +/- 16%) following addition of monospecific IF-gamma antibody. These results demonstrate (a) rIL-2 modulation of adult marrow erythropoiesis is selectively dependent upon both the presence or absence of autologous T cells and the IL-2R status of these T cells; and (b) rIL-2-induced inhibition of adult marrow erythropoiesis is mediated in part by release of IF-gamma from IL-2R-positive T cells.

Adult↗

Mechanism of macrophage reversal of Friend erythroleukemia: macrophage regulation of normal and leukemic erythropoiesis.

The acute erythroleukemia induced in mice by the anemia-inducing strain of the Friend virus complex is caused to regress by normal macrophages. We examined the possibility that reversal of leukemia is related to a macrophage regulatory function in erythropoiesis. We found that the ability of macrophages to induce leukemia regression correlates with nonimmunological, in vivo suppression of normal and susceptible leukemic erythroid progenitors. The macrophage effect on erythropoiesis appears to be due to changes in a humoral regulator, related to but independent of erythropoietin. The results suggest a novel regulatory system for erythropoiesis, operative in vivo, and involving macrophages as accessory or suppressor cells. This regulation appears to be disrupted in erythroleukemic mice, but can be restored, and the disease can be made to regress by treatment with normal macrophages.

Animals↗

T-cell regulation of erythropoiesis during acute lymphoblastic leukemia.

How and where erythropoiesis is maintained during advanced leukemic disease is an important and, as yet, unresolved question in hematology. To address the potential role of T-lymphocytes as cells that regulate CFU-E differentiation during leukemogenesis, an experimental model of disease has been developed in inbred Balb/c mice. Specifically, three-week-old Balb/c By mice were injected with murine sarcoma virus-murine leukemia virus-Moloney (MSV-MuLV-M), which resulted 6-8 months later in the development of immunoblastic T-cell sarcomas with a leukemic phase. Splenic T cells from either normal or tumor-bearing mice were assessed for their relative ability to modulate erythroid differentiation. Quantitatively, T cells, Ly1 or Ly 2,3 T-cell subsets isolated from tumor-bearing animals significantly enhanced erythropoiesis when compared with comparable normal T-cell subsets. These data suggest that the compensatory shift of erythropoiesis from the bone marrow to the spleen observed during leukemogenesis was facilitated by splenic T cells. In this circumstance, the enhanced erythropoietic function may be mediated by splenic T cells, which are selectively activated by virus.

Animals↗

The influence of erythrocyte age on estimations of erythrocyte insulin binding in healthy children and adults and in conditions with increased erythropoiesis.

Insulin binding to erythrocytes was shown to lack any relationship to age-related factors of the erythrocyte such as the pyruvate kinase activity and the reticulocyte count in individuals with a normal erythropoiesis. After density separation of the erythrocytes in both normal adults and children and in individuals with increased erythropoiesis, a correlation to age-factors was evident (pyruvate kinase activity/insulin binding r = 0.59, p less than 0.01, reticulocyte count/insulin binding r = 0.44, p less than 0.01). An estimate of the components of variation in the binding showed that the unexplained variance is 60%. In the density separated samples the insulin binding correlated closer to the pyruvate kinase activity than to the number of reticulocytes. During treatment of haematopoietic diseases in the 4 patients with increased erythropoiesis, the disappearance rate for the reticulocyte count was much faster (T 1/2 = 9 days) than that of the insulin binding to erythrocytes (T 1/2 = 37 days) and that of pyruvate kinase activity (T 1/2 = 36 days). In one patient studied after splenectomy, the decrease in insulin binding paralleled the disappearance curve for 51Cr-tagged erythrocytes. These results suggest that insulin binds to erythrocytes, not only during the reticulocyte stage, but throughout their life span, though the binding, which is very closely related to their pyruvate kinase activity, steadily declines as the erythrocytes age.

Adolescent↗

Contamination of erythropoietin by endotoxin: in vivo and in vitro effects on murine erythropoiesis.

Endotoxin was detected in all erythropoietin preparations tested and was removed from four lots, without loss of erythropoietic activity, by adsorption with limulus amebocyte lysate. Comparison of adsorbed (endotoxin-depleted) and nonadsorbed (endotoxin-containing) erythropoietin preparations demonstrated significant inhibition of CFU-e and BFU-e in vitro by nonadsorbed erythropoietin at concentrations higher than 0.25 U/ml and 2.0 U/ml, respectively. CFU-e and BFU-e were inhibited significantly by readdition in vitro of 10(-5)-10(-3) mug of endotoxin per unit of limulus-adsorbed erythropoietin. Administration of saline or 6 U of nonadsorbed or adsorbed erythropoietin twice a day for 4 days of CF1 mice resulted in reticulocyte counts of 2.1%, 9.9%, and 15.9%, respectively. Nonadsorbed erythropoietin resulted in a 29% decrease in erythropoiesis, a 42% decrease in CFU-e, and a 16% increase in granulopoiesis in the marrow, whereas adsorbed erythropoietin caused a 28% increase in erythropoiesis, no significant change in CFU-e and a 19% decrease in granulopoiesis in the marrow. Both preparations resulted in marked increases in splenic erythropoiesis and granulopoiesis. The effects of adsorbed erythropoietin are similar to those produced following stimulation of hematopoiesis by endogenous erythropoietin. Hemopoietic changes induced by nonadsorbed erythropoietin in vivo and in vitro are affected substantially by contamination of the erythropoietin preparations with endotoxin.

Adsorption↗

Production of erythropoietic colony-forming units and erythrocytes during chick embryo development: an attempt at modelization of chick embryo erythropoiesis.

The enumeration of erythropoietic colony-forming cells in vitro has allowed us to complete previous data on changes in the various erythroid cell populations during chick embryo-genesis. Erythrocytic colony-forming units in culture (CFU-cE) which are sensitive to avian erythropoietin appear in the blastoderm as soon as the 24th hour of development. They represent most likely precursors of the megalocytic erythropoiesis, and do not seem to derive from stem cells common with normocytic erythropoiesis. Data concerning vitelline normocytic erythropoiesis were analysed in a kinetic model based on stochastic change of the stem cells. From this model it appears that 17-20 cell divisions are required for differentiation of erythrocytes from stem cells.

Animals↗

Effect of beta adrenergic blocking agents on erythropoiesis in rats.

The purpose of the present study was to analyze the effect of two different beta blocking agents, metipranolol (Trimepranol) and dl-propranolol (Inderal), upon erythropoietin production, erythropoietin responsive cell compartment and erythrocyte production. The effect on erythropoietin production: in rats metipranolol or dl-propranolol was injected daily in a single dose of 10 mg/kg b.wt. On the 5th day, the rats were exposed to an atmospheric pressure of 353.7 torr (47.1 kPa, 6000 m) to stimulate erythropoietin production. The onset of hypoxic exposure was started 1, 4, 12 or 24 hr after the last injection of beta blocking drugs. After the termination of hypoxia, erythropoietin plasma levels were determined in polycythemic mice. The rats treated with metipranolol 1 and 4 hr before hypoxia produced significantly less erythropoietin in response to hypoxia than saline-treated control animals. The effect on erythropoietin responsive cell compartment: polycythemic mice were treated with metipranolol or dl-propranolol in doses of 10 to 40 mg/kg b.wt. and with an erythropoietin standard. Radioiron incorporation into red blood cells in control mice and in mice pretreated with beta blocking agents was not significantly different. The effect on erythrocyte production: in rats treated daily with metipranolol in a single dose of 10 mg/kg b.wt., for a period of 10 days, the rate of erythropoiesis measured by the incorporation of 59Fe into red blood cells was decreased, dl-propranolol (10 mg/kg b.wt.) did not reduce the rate of erythropoiesis. Our results demonstrate that the changes in erythropoiesis after administration of metipranolol may be caused by reduction of erythropoietin production with a consequent reduction of the erythrocyte production rate.

Adrenergic beta-Antagonists↗