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PubMed1991

Iron-restricted erythropoiesis as a limitation to autologous blood donation in the erythropoietin-stimulated bone marrow.

Recombinant human erythropoietin has been demonstrated to significantly increase autologous blood procurement. To determine the importance of dietary or prescribed iron absorption, we analyzed iron-restricted erythropoiesis in this setting. No differences were found when premenopausal placebo and erythropoietin treatment groups were compared for hematocrit changes, number of units donated, percentage of phlebotomies deferred, and total blood volume procured. Seven of 10 women who had not reached menopause donated more blood iron than the apparent amount of total mobilizable iron available, demonstrating that dietary or prescribed iron had to be absorbed to donate the amount of blood iron stored. Thus oral iron absorption can potentially be a limitation to erythropoiesis in the presence of erythropoiesis therapy in women who have not reached menopause. In contrast, none of 16 women who had reached menopause and only two of 21 men required oral absorption of dietary or prescribed iron for the amount of blood iron donated. We conclude that although oral iron supplementation may not be necessary in men and in women who have reached menopause, alternatives to oral ferrous salt supplementation could be tested to determine whether such alternatives would improve the response to erythropoiesis in premenopausal women.

Adult↗

PubMed1991

Blunted erythropoietin production and decreased erythropoiesis in early pregnancy.

After decreasing in the first trimester of pregnancy, the total red blood cell mass increases in the second and third trimesters to peak at term at about 120% to 125% of nonpregnant values, but how this is brought about by changes in the rate of erythropoiesis is not known. We evaluated erythropoiesis by measuring serum transferrin receptor (TfR) levels in 406 women during normal pregnancy (N = 317), at delivery (N = 63), or in the early postpartum (N = 27). Despite the presence of the placenta and the frequent occurrence of iron deficiency, TfR levels remained low in the first two trimesters and increased in the third trimester and at delivery. To explain why erythropoiesic activity was relatively low in early pregnancy, we also measured serum immunoreactive erythropoietin (Epo) in relation to the degree of anemia. There was a very strong correlation between serum TfR and Epo levels in the entire group (r = .59, P less than .0001) as well as in each period of pregnancy. Epo levels remained low for the degree of anemia and did not correlate with hematocrit in the first two trimesters, but recovered afterwards. In the early postpartum, Epo production and erythropoiesis were normal. We conclude that: (1) erythropoiesis is decreased in the first part of pregnancy but increases afterwards; and (2) blunted Epo production in early pregnancy could be responsible for that observation.

Adolescent↗

PubMed1989

Lymphoid differentiation of the hematopoietic stem cell that reconstitutes total erythropoiesis of a genetically anemic W/Wv mouse.

We investigated whether the stem cell that reconstitutes total erythropoiesis of a WBB6F1-W/Wv mouse differentiates into lymphoid lineage. The electrophoretic pattern of hemoglobin was used as a marker of the reconstitution; 3-phosphoglycerate kinase (PGK), an X chromosome-linked enzyme was used as a tool for estimating clonality. We injected 10(5) bone marrow cells of 5-FU treated C57BL/6-Pgk-1b/Pgk-1a female mice, in which each stem cell had either A-type PGK or B-type PGK due to random inactivation of one of two X chromosomes, into genetically anemic (WB x C57BL/6)F1-W/Wv (hereafter WBB6F1-W/Wv) mice that contained only B-type PGK. The recipient WBB6F1-W/Wv mice, in which erythropoiesis was reconstituted with donor cells for a long term, were killed and the PGK patterns of bone marrows, thymus, lymph nodes, and Peyer's patches were examined. A considerable amount of A-type PGK was detected in the lymphoid organs of the WBB6F1-W/Wv mice in which erythrocytes showed only A-type PGK when killed. In contrast, A-type PGK was scarcely detectable in the lymphoid organs of the WBB6F1-W/Wv mice in which erythrocytes showed only B-type PGK when killed. The present results suggest that the hematopoietic stem cells estimated by the erythropoiesis reconstituting assay differentiate into lymphoid lineage and that the long-term erythropoiesis reconstitution assay is useful for detecting the true primitive hematopoietic stem cells.

Anemia↗

PubMed1989

Haemopoiesis in murine bone marrow and spleen after fractionated irradiation and repeated bone marrow transplantation. I. Erythropoiesis.

Erythropoiesis was studied in mice repeatedly subjected to individual doses of 3 Gy of 60Co gamma-rays at 4-day intervals up to a total dose of 24 Gy on the basis of total bone marrow and spleen cellularity follow-up and analysis of myelograms and splenograms. Half of the mice received 10(6) nuclear cells of syngeneic bone marrow after each fractional radiation dose. It was mainly the spleen which was involved in the adaptation and regeneration of erythropoiesis, its contribution to total erythropoiesis in bone marrow recipients having been as much as 73.9% (day 20 of experiment, total dose 15 Gy). In mice only irradiated, the number of nuclear cells of erythroid lineage decreased to zero values sooner in the spleen (day 16 of experiment, total dose 12 Gy) when compared to the bone marrow (day 24 of experiment, total dose 18 Gy). Analysis of the results of collections made on day 9 after the last irradiation, however, revealed that the haemopoietic microenvironment of the spleen and haemopoietic cells capable of differentiation in the erythroid direction are so resistant to irradiation in only irradiated mice that erythropoiesis in their spleens exhibits signs of regeneration even after the highest total dose of 24 Gy.

Animals↗

PubMed1984

Twin transfusion syndrome causing cutaneous erythropoiesis.

Two cases of twin transfusion syndrome are described in which the donor twin exhibited blueberry muffin-like macules and papules associated with cutaneous erythropoiesis. No evidence was found in either case for intrauterine viral infection, the most common cause of cutaneous erythropoiesis. Cutaneous erythropoiesis is these two cases is considered to be due to persistence or reactivation of fetal dermal erythropoiesis secondary to prolonged, severe intrauterine anemia.

Adult↗

PubMed1978

Suppressive effects of an extramedullary tumor on bone marrow erythropoiesis and stroma.

Mice, bearing a solid extramedullary Ehrlich ascites tumor developed anemia, reticulocytosis, and leukocytosis after 3 weeks of tumor growth. Erythopoiesis in the marrow, as measured by erythroblast counts and radioiron uptake of the humerus and femur, was suppressed to less than 30% of normal. However, striking erythroblastic and granulocytic hyperplasia in the spleen occurred to compensate for suppression of erythropoiesis in the marrow. Accompanying the medullary erythropoietic insufficiency was a similar suppression to 30% of normal in the growth of bone marrow stromal colonies in vitro. The fact that erythropoiesis was suppressed in the marrow, but not in the spleen, and bone marrow stromal colony growth was concomitantly suppressed, suggest that a change in the cellular component of the hemopoietic microenvironment had occurred. Splenectomy, prior to tumor inoculation, did not ameliorate the anemia. However, removing this potentially compensatory site for erythropoiesis prevented the severe suppression of erythroblast counts and stromal colony growth from the marrow. Thus, it appeared that, with sufficient stimulus, the suppression of erythropoiesis in the marrow was preventable.

Anemia↗

PubMed1982

Erythropoiesis in ha/ha and sph/sph mice, mutants which produce spectrin-deficient erythrocytes.

In order to characterize chronically accelerated erythropoiesis, we studied the ultrastructure of bone marrow and spleen of ha/ha and sph/sph mice, two mutants with profound hemolytic anemia secondary to deficiency of the erythrocyte membrane protein spectrin. The marrows and spleens of both varieties were extremely erythropoietic and were without histological abnormalities directly related to spectrin deficiency. Erythropoiesis was consistently associated with distinctive, dark branched cells which constituted large proportions of the stroma of the mutant spleens and marrow. These dark cells were not present in untreated and acutely bled controls. Plasma clot assays for erythroid progenitors revealed that CFU-E concentrations in the mutant marrows were significantly increased over those in untreated controls while BFU-E concentrations were approximately half. In addition, mutant CFU-E often gave rise to abnormal appearing colonies. Spectrin, though crucial to erythrocyte function is probably not important to the process of erythroid differentiation and maturation. The status of erythroid precursors in the marrows of the spectrin deficient mice is similar to that of mice subjected to an acute bleed. The divergent changes in CFU-E and BFU-E may indicate that these two cells play different roles in accelerated erythropoiesis. The dark cells that we describe are similar to stromal cells observed in models of the early stages of erythropoiesis.

Anemia, Hemolytic↗

PubMed1993

[Iron deficient erythropoiesis in the young females--analysis by Percoll discontinuous density gradient].

To observe changes in erythropoiesis in iron deficient subjects, we fractioned red cells by discontinuous density gradient using Percoll. Blood samples were taken from 57 young females of 19-21 years old without abnormal history or abnormal biochemical profiles except anemia or iron deficiency. 6 layers gradient were made and 7 fractions (F1 to F7, from the top to the bottom) were obtained. In the lightness fraction (F3 in nonanemic subjects), reticulocytes were concentrated. From patterns of Hemoglobin A1c concentrations of the fractions, it was inferred that red cells with heavier density were older in ages. In cases with iron deficiency or resulting anemia, low density fraction(s) increased in percentage, with relative decrease in that of higher density fractions, as a result of impairment in hemoglobin production. Subjects in whom the lowest density fraction (F3) was less than 5% were regarded to be normal in terms of erythropoiesis, because the fractional pattern was comparable to that of the normal adult males. Among 57 females examined, 24 (52.6%) showed iron deficient erythropoiesis and 6 (10.5%) were iron deficiency anemia (hemoglobin < 120 g/l). The density gradient fractionation of the red cells was proved to be useful in analyzing abnormal erythropoiesis.

Adult↗

PubMed1993

Insulin-like growth factors stimulate erythropoiesis in serum-substituted umbilical cord blood cultures.

The stimulatory effects of the insulin-like growth factors (IGFs) on erythroid colony formation by hematopoietic progenitor cells derived from adult bone marrow and peripheral blood have been well demonstrated. To enhance our understanding of the potential role of IGFs in human newborn erythropoiesis, we studied the effects of IGF-I and IGF-II on neonatal erythropoiesis in vitro. Erythroid progenitor cells were recovered from umbilical cord blood collected at scheduled Cesarean sections from women with term, uncomplicated pregnancies. Light-density cord blood mononuclear cells were cultured for 7 days in a serum-substituted culture system supplemented with and without purified human recombinant erythropoietin (0.5 to 2.0 U/mL) and recombinant human IGFs. Addition of IGF-I (1 to 100 ng/mL) resulted in up to a 4-fold increase over baseline erythropoietin-dependent colony formation at 7 days with a maximal effect at 10 ng/mL. While subphysiologic doses of IGF-II caused a modest stimulation of erythropoiesis, addition of a physiologic concentration (100 ng/mL) resulted in up to a 4-fold enhancement in erythroid colony formation. This stimulatory effect persisted in cultures of mononuclear cells that were depleted of monocytes, myeloid cells, T cells and B cells prior to culture, suggesting that enhancement is the result of a direct IGF effect on progenitor cells. Addition of IGFs in the absence of erythropoietin resulted in erythroid colony formation in some but not all experiments. Whereas IGF-I was the primary regulator of erythropoietin-independent erythroid colony formation by adult erythroid progenitors, IGF-II was the predominant regulator of erythropoietin-independent erythroid colony formation by neonatal progenitor cells. We conclude that IGFs in physiologic doses directly stimulate neonatal cord blood erythroid progenitor cells and may play a role in developmental control of human erythropoiesis.

Blood↗

PubMed1998

The influence of acute sterile inflammation on erythropoiesis in rats.

Many different cell types, coordinated by proinflammatory mediators, take part in the acute inflammatory reaction, but there is a lack of evidence regarding the role of erythroid cells in such conditions. In this study, changes in bone marrow, splenic, and peripheral blood erythroid cells and in erythropoietin (Epo) blood levels were investigated up to 72 hours after polyvinylpyrrolidone (PVP)-induced sterile inflammation in male Wistar rats (two intraperitoneal injections of 15 mL 3.5% PVP at 18-hour intervals). Transient changes within progenitor erythroid cells were observed in the bone marrow. Significant increases in the number of splenic immature erythroid progenitors (BFU-E) 6 hours and mature erythroid progenitors (CFU-E), erythroblasts, and orthochromatic erythroblasts 48 and 72 hours after the induction of inflammation pointed to stimulated splenic erythropoiesis. This was confirmed by semiquantitative assessment of splenic smears, which demonstrated expansion of erythroid cells at hours 48 and 72. The changes observed in the bone marrow and spleen indicated that during acute inflammation erythropoiesis was stimulated and that the spleens of PVP-treated rats were favorable to erythroid development. The significant increase in the percentage of peripheral blood reticulocytes 48 and 72 hours after PVP-induced inflammation provided evidence that effective erythropoiesis occurred. In spite of the stimulated erythropoiesis, serum levels of Epo remained unchanged, implying that other non-Epo regulatory molecules may be responsible for erythroid cellular changes.

Acute Disease↗

PubMed1979

Fetal erythropoiesis in stress hematopoiesis.

Fetal erythropoiesis occurs during chronic bone marrow failure, or during recovery from marrow suppression. Fetal erythrocytes have HB F, with more G gamma than A gamma chains, "i" antigen, large MCV, characteristic enzyme levels, low carbonic anhydrase, low HB A2, and short life span. Many of these fetal characteristics are present in the red cells of patients with temporary or chronic hematopoietic stress. In those in whom normal hematopoiesis ensues, the fetal erythrocytes disappear. The fetal phase of recovery may be with homologous stem cells after bone marrow engraftment, or with autologous cells. Chronic fetal erythropoiesis is seen in patients with constitutional aplastic anemia, such as Fanconi's anemia or Diamond-Blackfan anemia. In one patient with the latter disorder, fetal erythropoiesis accompanied chronic anemia, and actually decreased slightly during the acute phase of clinical improvement. Culture of late erythroid precursor cells (CFU-Es) from a patient with transient erythroblastopenia of childhood led to in vitro development of colonies with HB F, an event not seen in normal marrow cultures. Thus fetal erythropoiesis occurs during hematopoietic stress, whether chronic or transient, if there is some marrow activity, and may be due to expansion of fetal clones.

Anemia, Hemolytic↗

PubMed1976

Erythropoiesis-inhibiting factor(s) (EIF): methodologic studies.

Erythropoiesis-inhibiting factors (EIF) have been demonstrated in plasma from hypertransfused animals and from polycythemic individuals during periods of hyperoxia, but there is a decided discrepancy in the data published. In the present paper methodologic variations of a bioassay for demonstrating the erythropoiesis-inhibiting factor are discussed. In these studies no inhibitor of erythropoiesis could be demonstrated in plasma from hypoxia-induced polycythemic mice (HPM) on posthypoxic day 5. Injections of RBC or an equal amount of hemolyzed RBC were capable of suppressing the stimulatory effects of ESF, indicating that a red cell constituent may be responsible for the inhibitory effect observed. Transfusion-induced polycythemic mice (TPM) were therefore considered to be less suitable for demonstrating erythropoiesis inhibitors. Our results from testing several doses of a urinary EIF in normal mice, TPM and HPM, indicated that the HPM provided the most sensitive assay system. A similar effect was obtained with hypoxia-induced polycythemic rats. The most marked effect was seen in HPM when the EIF was injected shortly before administering the ESF, while the effect was less pronounced when the EIF was injected 24 hr before or after the ESF.

Animals↗

PubMed1979

[Erythropoietin and erythropoiesis inhibition factor in the newborn and infants with cyanotic heart abnormalities].

In the present study, hematocrit, pO2 in the capillary blood, reticulocyte count, erythropoietin activity in plasma and activity of the erythropoiesis inhibition factor in 24-h collective urine were determined in newborns and infants with cyanotic malformations of the heart (transpositions of the big arteries). The plasma of the healthy newborns shows immediately after birth an erythropoietin activity below 1%, as measured by the 59Fe incorporation. The erythropoietin activity of the plasma of infants with cyanotic malformations of the heart is enhanced up to the 14th day of life. In the period of day 14--30 it corresponds to the values of healthy newborns despite the persistence of hypoxia. After the 30th day of life there is again demonstrable an increased erythropoietin activity in the plasma of infants with cyanotic malformations of the heart. Obviously, the low values of 59Fe incorporation from day 14--30 are due to the occurrence of the erythropoiesis inhibition factor. In the urine of infants with cyanotic malformations of the heart there could be demonstrated distinct inhibitions of the stimulated erythropoiesis of the polycythemic mouse. The present studies suggest that the erythropoiesis inhibition factor occurs in postnatal development irrespectively of the degrees of O2-supply of the tissue, and is possibly dependent on the gestational age.

Aging↗

PubMed1999

Serum transferrin receptor as a marker of erythropoiesis suppression in patients on chronic transfusion.

In the management of patients requiring chronic transfusion, various parameters may be used to evaluate the degree of erythroid marrow suppression. The aim of our study was to assess which of these parameters provide the most useful assessment of erythropoiesis. We studied 27 chronically transfused patients, 19 with sickle cell disease (SS patients) and 8 with thalassemia. Thirty-one nonchronically transfused SS patients and 74 healthy children served as controls. We measured serum transferrin receptor levels, reticulocyte counts, hemoglobin (Hb) concentrations and erythropoietin levels. The serum transferrin receptor levels were very elevated in control SS patients and remained significantly elevated in those on transfusion therapy, but were normal in thalassemia patients, indicating a more complete suppression of erythropoiesis. The reticulocyte counts were elevated in all SS patients, even when on chronic transfusion, but were in the normal range in patients with thalassemia. Erythropoietin levels were elevated in patients with thalassemia and in all the SS patients. Hb levels negatively correlated with serum transferrin receptor and erythropoietin in all SS patients. In the transfused SS patients, a higher HbS level correlated with higher reticulocyte counts, transferrin receptor, and erythropoietin levels. In thalassemia patients, erythropoiesis was more completely suppressed, as reflected both by normal reticulocyte counts and near-normal transferrin receptor levels. Though the reticulocyte counts were not significantly different in the transfused SS patients, the serum transferrin receptor levels were less elevated than in SS patients not on transfusion. The serum transferrin receptor level appears to be the most useful marker of marrow erythropoietic activity in chronically transfused SS patients. We recommend that reticulocyte counts be integrated with periodic measurements of serum transferrin receptor levels.

Adolescent↗

PubMed1994

Improvement of sickle cell anemia by iron-limited erythropoiesis.

We report the hematologic and clinical features of four adult patients (Pts.) with sickle cell anemia and iron-limited erythropoiesis. Two of the Pts. had spontaneous iron deficiency (chronic GI bleeding, low-grade hemoglobinuria). In the other two Pts. iron restriction was induced by periodic RBC aphereses as part of a pilot protocol designed to decrease intracellular HbS polymerization by MCHC reduction. Iron-limited erythropoiesis was defined by reduction in red cell indices (MCV range 60.4-67 fl) in the presence of low serum ferritin (range < 10-20 ng/ml). In these Pts. iron restriction did not cause clinically significant worsening of the anemia (Hb 7.8-9.0 g/dl). In two Pts. the anemia actually improved. Other hematologic effects of iron restriction were: decreased MCHC, reticulocyte count, RDW, and dense cells. A reduced hemolytic rate was suggested by a lowering of serum bilirubin and LDH. In one of the Pts. the 51Cr RBC T1/2 survival increased from 12 to 16 days. The intracellular HbS polymer fractions (fp) were determined at 25% O2 by Csat and with the use of the conservation of mass equation. The baseline fp values ranged from 0.48-0.53. After iron restriction they ranged from 0.33-0.48. The fp decreased even though iron-limited erythropoiesis also lowered the Hb F concentration in three of our Pts. In one of the two Pts. with induced iron depletion, hospitalization days for pain crises decreased from an average of 4.5 days/month (2 year baseline period) to an average of 0.5 days/month in the 3 year follow-up after iron depletion. The second patient with induced iron restriction experienced the rapid healing of a leg ulcer. Controlled iron restriction should be explored as a therapeutic strategy in selected SS patients.

Adult↗

PubMed2001

The 5'HS4 core element of the human beta-globin locus control region is required for high-level globin gene expression in definitive but not in primitive erythropoiesis.

To assess the contribution of DNase I-hypersensitive site 4 (HS4) of the beta-globin locus control region (LCR) to overall LCR function we deleted a 280 bp fragment encompassing the core element of 5'HS4 from a 248 kb beta-globin locus yeast artificial chromosome (beta-YAC) and analyzed globin gene expression during development in beta-YAC transgenic mice. Four transgenic lines were established; each contained at least one intact copy of the beta-globin locus. The deletion of the 5'HS4 core element had no effect on globin gene expression during embryonic erythropoiesis. In contrast, deletion of the 5'HS4 core resulted in a significant decrease of gamma and beta-globin gene expression during definitive erythropoiesis in the fetal liver and a decrease of beta-globin gene expression in adult blood. We conclude that the core element of 5'HS4 is required for globin gene expression only in definitive erythropoiesis. Absence of the core element of HS4 may limit the ability of the LCR to provide an open chromatin domain and/or enhance gamma and beta-globin gene expression in the adult erythroid cells.

Animals↗

PubMed1989

Tumor necrosis factor alpha and the anemia of chronic disease: effects of chronic exposure to TNF on erythropoiesis in vivo.

The anemia of chronic disease is associated with conditions in which macrophage activation occurs. Activated marrow macrophages suppress erythropoiesis in vitro, and produce tumor necrosis factor (TNF). Therefore, we tested the effects of chronic in vivo exposure to TNF to determine if it were a candidate for a mediator of the anemia of chronic disease. Nude mice were inoculated with CHO cells expressing the human TNF gene, or with control cells containing the transfection vector alone. The TNF mice promptly became reticulocytopenic, and after 3 weeks their corrected reticulocytes were 2.6 +/- .7% compared to 7.3 +/- 4% in control mice. The hematocrit at 3 weeks was 28.4 +/- 1.7% in TNF mice compared to 46 +/- 8% in control mice. This anemia was also associated with low serum iron and normal iron stores and increased erythropoietin levels. The TNF mice showed an absolute monocytosis with twice the number of circulating monocytes as control mice. The TNF mice also became mildly thrombocytopenic. Marrow CFU-E and BFU-E were profoundly decreased (1.2 +/- 2 x 10(3) vs 8.6 +/- 2 x 10(4) CFU-E per femur, and 6.5 +/- 1 x 10(2) vs 8.5 +/- .2 x 10(4) BFU-E per femur). Splenic CFU-E and BFU-E were similarly depressed. In contrast, marrow CFU-GM and CFU-GEMM were not affected. Administration of recombinant human erythropoietin to these mice failed to reverse the suppressed erythropoiesis in mice bearing TNF producing tumors. These data demonstrated that TNF preferentially inhibits erythropoiesis in vivo, and may be important in the pathogenesis of the anemia of chronic disease.

Anemia↗

PubMed1989

Erythropoiesis in murine long term marrow cultures.

We utilized a system of long-term bone marrow cultures that favored erythropoiesis and allowed the production of CFU-E for four weeks. Certain conditions of culture were crucial for erythropoiesis to occur. These conditions have been discussed. This system should allow further in vitro study of the regulation of erythropoiesis.

Animals↗