Erythropoiesis Stimulating Factors Research Articles

Understanding iron homeostasis in MDS: the role of erythroferrone.

Myelodysplastic neoplasms (MDS) are a heterogenous group of clonal stem cell disorders characterized by dysplasia and cytopenia in one or more cell lineages. Anemia is a very common symptom that is often treated with blood transfusions and/or erythropoiesis stimulating factors. Iron overload results from a combination of these factors together with the disease-associated ineffective erythropoiesis, that is seen especially in MDS cases with SF3B1 mutations. A growing body of research has shown that erythroferrone is an important regulator of hepcidin, the master regulator of systemic iron homeostasis. Consequently, it is of interest to understand how this molecule contributes to regulating the iron balance in MDS patients. This short review evaluates our current understanding of erythroferrone in general, but more specifically in MDS and seeks to place in context how the current knowledge could be utilized for prognostication and therapy.

Anemia – definition, symptoms and treatment

Anemia is a decrease in the hemoglobin concentration, with a consequent reduction in the ability of erythrocytes to carry oxygen to the tissues. The main causes of anemia are blood loss, decreased red blood cell (RBC) production or excessive RBC destruction. The main causes of defects in RBC formation are inadequate supply of iron, vitamin B12 or folic acid. Hemolytic anemias may also have numerous causes, intrinsic or extrinsic to erythrocytes. Medication is based on the type of anemia present. Iron-deficiency anemia is treated with iron compounds, given orally, or, in some cases, parenterally. In megaloblastic anemia due to vitamin B12 and/or folic acid deficiency, these nutrients are administered. Anemia from chronic kidney disease, other chronic diseases, inflammation, cancers, or in AIDS patients is treated with erythropoiesis-stimulating factors. If anemia has other causes beyond nutrients deficiency, these should be corrected.

Boceprevir and telaprevir safety in routine clinical practice

To compare the safety profile of telaprevir (TLV) and boceprevir (BOC) with each other and with those described in clinical trials (CT). Retrospective multicenter observational study. Variables collected: age, sex, type of patient (naive, nonresponder or recurrent), fibroscan, Hb nadir, neutrophil and platelet count, presence of rash, anorectal discomfort, number of patients treated with erythropoiesis stimulating factors (EPO) and colony stimulating factors granulocyte (G-CSF). BOC vs CT: anemia (56.5% vs. 49%.), Thrombocytopenia (56.5% vs 32%, p = 0.023). neutropenia (17.4% vs. 29.5%). Use of EPO (13% vs 43%;. p = 0.008), pruritus (13% vs. 21.1%), rash (16.1% vs. 8.7%), anorectal discomfort (4.3% vs. 0%, p = 0.0001), dysgeusia (47.8% vs. 37%). TLV vs. CT: anemia (51.2% vs. 32%, p = 0.014), neutropenia (2.3 vs 3.6%), thrombocytopenia (41.9% vs. 27.4%, p = 0.05), pruritus (39.5% vs 47), rash (16.3% vs 55%, P <0.001), anorectal discomfort (39.5% vs 26%), dysgeusia (14% vs. 9.5%). BOC vs TLV: anemia (56.5% vs 51.2%), neutropenia (17.4% vs 2.3%), thrombocytopenia (56.5% vs 41.9%), rash (8.7% vs 16.3%), pruritus (39.5% vs 13%) and anorectal discomfort (4.3% vs 39.5%, P = 0.006), dysgeusia (14% vs 47.8%, P = 0.007), EPO (13% vs. 25.6%). GCSF was used for a patient treated with TLV. 1. BOC and TLV have shown a worse safety profile for anemia, thrombocytopenia and anorectal discomfort than those described in CT. 2. As in CT, anemia, neutropenia and thrombocytopenia were more common with BOC. Patients treated with TLV experienced more pruritus, rash and anorectal discomfort.

Implementation of a pharmaceutical care process in patients with anaemia and chronic kidney disease in treatment with erythropoiesis stimulating factors

BackgroundThe authors have implemented a process of pharmaceutical care in the pharmacy hospital in patients with anaemia and chronic kidney disease in predialysis patients in treatment with erythropoiesis stimulating factors...

Valoración de la eficacia de una pauta más lenta y frecuente en la administración de hierro intravenoso en pacientes en hemodiálisis durante un año

Uno de los problemas más frecuentes de los pacientes con enfermedad renal crónica (ERC) en hemodiálisis (HD) es la anemia, tratada habitualmente con factores estimuladores de la eritropoyesis. Esta estimulación requiere una mayor disponibilidad de los depósitos corporales de hierro (Fe)1. Para alcanzar los niveles que recomiendan las guías (Ferritina entre 200 y 400ng/ml - IST entre 30 y 40%) se administra hierro por vía intravenosa (Fe IV)2. Las pautas de administración varían en función de las necesidades de los pacientes, siendo habitual la infusión de 100mg de Fe sacarosa diluidos en 100cc de suero fisiológico semanal, quincenal o mensualmente3,4,5. Esta pauta de administración se realiza en los últimos 45 minutos de la sesión de HD, no estando establecida la velocidad ideal de perfusión de la dilución. Por ello, nos realizamos la pregunta de si la rapidez en la pauta de administración del hierro intravenoso podría influir en la eficacia del tratamiento, así como en la presentación de efectos adversos6. Para ello nos planteamos los siguientes objetivos: 1. Comparar la eficacia entre una pauta lenta y una pauta más frecuente y ultra lenta de administración de Fe IV, con respecto a los parámetros de la cinética del hierro, así como en los aportes de eritropoyetina y Fe que se realizaron. 2. Analizar si se originan menos efectos adversos por intolerancia con la administración de Fe IV con la pauta ultra lenta.

Efficacy of Hemopoietic-Stimulating Factors in Patients Undergoing Chronic Hemodialysis

Anemia has been linked to increased mortality and morbidity in renal hemodialysis patients. Other risk factors that contribute to an adverse outcome include the variability of hemoglobin (Hb) levels and the decreased response to erythropoiesis-stimulating factors (ESFs). In this study we evaluated the effectiveness of four different ESFs (epoetin-A, epoetin-B, darbepoetin, and CERA), assessed the variability of Hb levels, and compared ESF dosages which contributed to the achievement of Hb levels in each individual patient with renal failure undergoing chronic hemodialysis maintenance. In conclusion, the four ESFs administered are equally effective in the treatment of anemia in renal hemodialysis patients and they do not influence in a different manner the variability of Hb. The administration of darbepoetin-A and CERA might possibly cause more patients to overshoot the target level of Hb.

Gonadal dysfunction in men with chronic kidney disease: clinical features, prognostic implications and therapeutic options

Gonadal dysfunction is a frequent finding in men with chronic kidney disease and with end-stage renal disease. Testosterone deficiency, usually accompanied by elevation of serum gonadotropin concentrations, is present in 26-66% of men with different degrees of renal failure. Uremia-associated hypogonadism is multifactorial in its origin, and rarely improves with initiation of dialysis, although it usually normalizes after renal transplantation. Experimental and clinical evidence suggests that testosterone may have important clinical implications with regards to kidney disease progression, derangements in sexual drive, libido and erectile dysfunction, development of anemia, impairment of muscle mass and strength, and also progression of atherosclerosis and cardiovascular disease. Additionally, low testosterone levels in hemodialysis patients have been associated with increased mortality risk in some studies. Currently, we count with available therapeutic options in the management of uremic hypogonadism, from optimal delivery of dialysis and adequate nutritional intake, to hormone replacement therapy with different testosterone preparations. Other potential options for treatment include the use of antiestrogens, dopamine agonists, erythropoiesis-stimulating factors, vitamins, essential trace elements, chorionic gonadotropin and renal transplantation. Potential adverse effects of androgen replacement therapy in patients with kidney disease comprise, however, erythrocytosis, prostate and breast cancer growth, reduced fertility, gynecomastia, obstructive sleep apnea and fluid retention. Androgen preparations should be used with caution with stringent monitoring in uremic men. Although there are encouraging data suggesting plausible benefits from testosterone replacement therapy, further studies are needed with regards to safety and effectiveness of this therapy.

Die individualisierte Riskoeinschätzung und Therapieplanung bei myelodysplastischen Syndromen

Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and a tendency to transition to acute myeloid leukemia. Due to the increasing number of older patients in Austria and the high frequency of therapy-associated MDS following successful chemo- and/or radiotherapy of a primary tumor, the frequency and relevance of MDS are continuously increasing. While therapeutic options were until recently limited to best supportive care, AML-like induction chemotherapy and hematopoietic stem cell transplantation (HSCT) in younger patients, in recent years new therapeutic options have become available. Supportive care was improved through the introduction of effective iron chelation and the availability of hematopoietic growth factors like erythropoiesis-stimulating factors (ESF) and granulocyte colony-stimulating factors (G-CSF). In addition, immune-modulating drugs (IMiDs) like lenalidomide or epigenetically effective agents like the cytosine analogues or histone deacetylase (HDAC) inhibitors have become available and are highly effective in distinct subgroups of MDS patients. The development of state-of-the art recommendations is one of the major aims of the MDS Platform of the Austrian Society of Hematology and Oncology. This manuscript reviews recent developments in clinical scoring and targeted and individualized MDS therapy and discusses their relevance in and potential applicability to daily practice.

Congenital and Acquired Polycythemias: Key Role of HIF-2a

This excellent review article follows on seamlessly from August 2007’s Essential Thrombocythemia. It remains to be seen whether the two other chronic myeloproliferative disorders – chronic myeloid leukemia and myelofibrosis – will also be reviewed so comprehensively. In figure 2, the authors illustrate the cycle of erythropoiesis via erythropoietin and the central role of HIF-2 α in cellular oxygen sensing. Further to the mutations described by the authors, a mutation of the HIF-2A gene (G1909T) (1) and of the prolyl hydroxylase domain-containing protein 2 (PHD2) in other familial erythrocytoses has been described (2). This is particularly notable because initial clinical studies have started and have been published on the basis of our understanding of the regulation of erythropoietin production. Oral medications are used to inhibit PHD2 and treat anemias. In light of the current discussion about erythropoiesis stimulating factors, molecular insights into the key role of HIF-2α will enable the deduction of new strategies to stimulate erythropoiesis and therefore potentially new treatment options for anemia (3).

Prediction of the Responsiveness to Treatment with Erythropoiesis-Stimulating Factors: A Prospective Clinical Study in Patients with Solid Tumors

Treatment with erythropoiesis-stimulating factors (ESFs) can ameliorate anemia associated with cancer and chemotherapy. However, half of anemic cancer patients do not respond even to high doses. To determine factors that are predictive of a treatment response, a multicenter, prospective study was performed. Investigated factors were baseline erythropoietin, reticulocytes and soluble transferrin receptor (sTfR) after 2 weeks, and reticulocytes and hemoglobin after 4 weeks. Anemic patients with solid tumors received 150 microg/week of darbepoetin concomitantly with chemotherapy. The dose was doubled if hemoglobin did not increase by >1 g/dl after 4 weeks. Patients were considered responders if hemoglobin increased by >or=2 g/dl or reached a level >or=12 g/dl within 8-12 weeks. In total, 196 patients were enrolled; 61% of the intention-to-treat (ITT) and 68% of the per-protocol population were responders. In the ITT population, the hemoglobin increase after 4 weeks indicated an 11-fold higher chance of response (odds ratio, 11.0; 95% confidence interval [CI], 5.1-23.6; sensitivity, 88%; specificity, 60%). In a multiple logistic regression model including all factors, the area under the receiver operating characteristic curve was 0.78 (95% CI, 0.71-0.84). The combination of sTfR after 2 weeks and hemoglobin after 4 weeks was as predictive as the combination of all five tested factors. So far, an early hemoglobin increase remains the single most predictive factor for response to ESF treatment. In contrast to anemic patients with lymphoproliferative malignancies, serum erythropoietin had little predictive value in patients with solid tumors.

Evaluation of predictive factors for response to darbepoetin alfa (DA): A prospective study

18514 Background: Therapy with erythropoiesis-stimulating factors (ESF) can ameliorate the anaemia associated with cancer and chemotherapy, reduce the need for transfusions and improve quality of life. However, as many as 30–50% of pts. do not respond, even to very high doses of ESF. Methods: In January 2003, we commenced a prospective phase-2 study to evaluate the value of predictive factors for response to DA. The following 5 factors, which had been previously determined as predictive factors in several retrospective studies, were investigated: serum erythropoietin &lt; 100 mU/ml before therapy (Epo-d0); increase in reticulocytes &gt; 40,000/μl (Reti-d14) and in soluble transferrin receptor ≥ 25% (sTfR-d14), both after 2 weeks; increase in reticulocytes &gt; 40,000/μl (Reti-d28) and in Hb &gt; 1 g/dl (Hb-d28), both after 4 weeks. Response was defined as Δ Hb &gt; 2 g/dl or Hb ≥ 12 g/dl within 8–12 weeks. Pts. with solid tumours receiving chemotherapy, ECOG &lt; 2 and Hb &lt; 11g/dl or significant decrease in Hb &gt; 1.5 g/dl within 4 weeks received DA 150 μg/QW or 300 μg/Q2W sc. and 300 μg/QW if Hb &lt; 1 g/dl at d28. Results: Between 01/03 and 09/05 196 pts., 112 female and 84 male, median age 66 years, were treated and evaluated for response. 119 pts. (60.7%) had a response as defined (PP analysis: 68.3%). The predictive value of the 5 factors are given in the Table . In a multiple logistic regression analysis of all 5 factors the ROC has an AUC of 0.78 (95% CI 0.71–0.84). The reduced logistic classification rule (with cutoff 0.5) based on an increase in sTfR &gt; 25% on day14, reticulocytes &gt; 40,000/μl and Hb &gt; 1 g/dl, both on day 28, had the same AUC and its positive / negative predictive value was 88.1% (=74/84) and 59.8% (=67/112) respectively. Conclusions: In contrast to observations made in pts. with lymphoproliferative malignancies, the pretherapeutic serum erythropoietin level has no or very little predictive value for response to DA in anaemic pts. with solid tumours. Supported by AMGEN, Germany with an unrestricted grant. [Table: see text] [Table: see text]

Estudio de utilización y descripción de costes de eritropoyetina en pacientes hematológicos

To assess the effectiveness of erythropoietin use in hematologic patients; to analyze the extent to which recommendations are applied as provided by Spanish prescribing information, American Society of Clinical Oncology (ASCO) and American Society of Hematology (ASH) guidelines, as well as specific recommendations for myelodysplastic syndromes (MDSs), and to perform a descriptive analysis of costs. A descriptive retrospective study. Patient selection was performed by Unidad de Atención Farmacéutica a Pacientes Externos (UFPE: Pharmaceutical Outpatient Care Unit) during a 3-month period of time. Follow-up was performed to month 9 after selection. Thirty-six patients (37% males) were included. In the group of patients with multiple myeloma and lymphomas, effectiveness was 57%; while in the MDS group it was 45-64% (depending on criteria used to measure erythroid response). Of all 24 patients (MDSs excluded) only 4 (17%) met indication criteria--adjustment to erythroid response at 4 and 8 weeks, and dosage titration when needed. Continued treatment with erythropoietin in all non-responders amounted to 59-69% of total expense for non-responders. There is a high percentage of therapy failures and inconsistency between erythropoietin use recommendations and clinical practice. This circumstance, as well as the high financial impact it entails, makes it essential that monitoring and follow-up strategies are implemented to contribute to an optimal usage of erythropoiesis stimulating factors.

News and Traditional Indications from Short Daily Dialysis: Different Schemes to Optimized ESF Response

Interest in quotidian (daily) hemodialysis (DHD) seems to be growing. DHD improves quality of life, blood pressure control, and nutrition, and decreases the need of medications, including erythropoiesis stimulating factors (ESF). We evaluate the short daily dialysis (SDHD) efficacy in 14 patients in conventional hemodialysis (HD) (3 weekly sessions/4 h), mean age 52.1 years, range 25–75, 10 males and 4 females, and found that they needed to increase dialysis efficiency by different medical indications: in 11 cases traditional indications – 5 cases with hypertensive myocardiopathy and severe LVH (2 of them with low left ventricle ejection fraction), 2 cases with symptomatic, ischemic cardiopathy 2 patient with big body‐surface area and elevated phosphorus levels, and 2 patients by inadequate dialysis (infradialysis conditioning malnutrition status) secondary to HD with permanent catheter. In one female (25 yr old), SDHD was prescribed to improve cardiac toxicity secondary to chemotherapy for acute promyelocytic leukemia. The index resistance of ESF decreased since the first month, and the Aranesp doses decreased by more than 40%. 1 male (49 years) with nephrogenic fibrosing dermopathy showed skin lesions with osteoblastic transformation. The skin lesions were improving since the first week, obtaining a decrease of the index resistance ESF higher than 60% in the first month. 1 male with symptomatic obstructive hypertrophic myocardiopathy showed improvement of symptoms and quality of life since the first weeks, as well as echocardiograpic signs and improvement in Hb levels and decreasing dose of ESF. The schedule in all of them was 5–6 days/week sessions between 2.15 h and 3 h, depending on body‐surface area. To obtain a weekly Kt/V nearest to 4, HD sessions were realized in the hospital (7 pts) or in satellite unit (7 pts). The time remaining in this schedule was between 1 and 42 months. All the patients showed clinical improvement, subjective and objective, since the first week of start of SDHD. 3 patients could be included in Tx waiting list again. Anemia improved, decreasing index resistance of ESF. In relation with this, the time necessary to improve the response to ESF was different, showing a decrease in the first month higher than 40% in two cases dialyzing with a membrane high‐flux with pore size 100 A, appearing high Hb levels also in a polycystic patient always without ESF. We observed by analyzing the results in 12 stable patients; the patients with high‐flux dialyzers showed better response to ESF. Perhaps it could offer a better clearance of large molecules (inhibitor erythropoiesis factor and high molecular weight toxins) that participate to respond to ESF.Conclusion: Our experience shows new indications for SDHD with very good results. Anemia was improved in relation with SDHD, when synthetic high‐flux membranes and high pore size were used.

THE EARLY ANEMIA OF MAMMALS, COMPARATIVE STUDIES

Since hematocrit is one of the main determinants of blood viscosity, the regulation of erythrocyte production is important in maintaining nomral blood viscosity. Hemoglobin/hematocrit, erythropoiesis stimulating factors,ESF, 2.3.DPG and P50% were studied in preterm infants, rabbits, rats and mice. Only the human newborn has postnatal polyglobulia, the other species had hematocrit similar to the adult levels. Following birth hb/hct drop in almost all mammals reaching the nadir at the time of weaning. In the human the nadir is unrelated to this event. The development of the anemia occurs when the animals are growing rapidly and in rabbits there is a correlation between degree of anemia and weight gain. The anemia does not hamper growth rate. At the nadir ESF is increased in the species studied and there is a correlation between the concentration of ESF and weight gain. In rabbits 2.3.DPG increases following birth and the available oxygen does not change during the development of the anemia. Thus the low hb cone. does not reduce the oxygenation of the tissues to a degree which give marked changes. The early anemia is iron respon sive in most species studied, suggesting that it may be re lated to environmental causes. The early anemia of prematurity is not alleviated by peroral iron. The rapid changes in hematocrit observed following birth must be taken into consideration in all hemorheological studies.

Progenitor cells of erythroblasts: an in vitro investigation of erythropoietin-responsive cells of guinea pig bone marrow.

The experiments were designed to test whether or not erythroblast progenitor cell function could be demonstrated in a morphological cell type designated as "transitional cells." Two cell fractions, were obtained from the bone marrow of normal and polycythemic guinea pigs. One fraction (F1) was enriched in transitional cells and contained few, if any, other cell types which could be considered as candidates for erythropoietin responsive cells (ERC). The other fraction (F2) contained undifferentiated blast cells as well as transitional cells. The effect of human urinary erythropoiesis stimulating factors (ESF) on heme synthesis was compared in these two fractions by measuring 59Fe incorporation into heme. ESF was more effective in stimulating heme synthesis in guinea pig bone marrow cells than homologous sera obtained from anemic or hypoxic animals. The majority of ERC sedimented in F2, but the stimulation index was comparable in the two fractions. It was confirmed by radioautography that the ESF response in F1 was due to the generation of proerythroblasts and basophilic erythroblasts that incorporated 55Fe. The generation of these cells in F1 was dependent on the addition of ESF to the cultures, whereas 55Fe-labeled erythroblasts were recovered from cultured of F2 not supplemented with ESF. ESF induced a proportion of transitional cells to incorporate 55Fe in both F1 and F2. Transitional cells were the only cell type in which heme synthesis was dependent on ESF. in other cells of clearly nonerythroid morphology (mononuclear phagocytes and reticular cells), 55Fe incorporation occurred independent of ESF. Although the fractionation procedure employed is unsuitable for the separation of ERC from bone marrow, it permitted the enrichment of transitional cells, a cell type defined by morphology. Radioautography with 55Fe identified a proportion of these cells as ERC in both F1 and F2 fractions of bone marrow obtained from normal and polycythemic guinea pigs. Although there may be other cell types in F2 capable of responding to ESF, the present studies show that some transitional cells function as progenitors of erythroblasts because they respond to ESF by initiation of heme synthesis and by transformation into the earliest recognizable erythroid cells.

Interrelationship of Erythropoietic Recovery, Marrow Recovery, Colony-Forming Units, and Erythropoiesis-Stimulating Factors after Sublethal X-Irradiation

Studies have been performed to compare the injury and recovery of various elements of the erythropoietic system after sublethal (200 R) exposure to x-rays. In the peripheral blood a distinct fall and an early (6-7 day) abortive rise in reticulocytes and newly formed hemoglobin could be seen, followed by a second drop and final recovery to normal levels at 2-3 weeks after exposure. A similar drop in total nucleated cells could be seen in both femoral marrow and spleen. However, splenic recovery was slow, whereas recovery to normal nucleated cell levels occurred by 5 days in the marrow. Transplantable marrow colony-forming units also showed delayed recovery reaching normal proportions at 16 days with no abortive rise. Total blood and plasma volumes showed only minimal changes, although there was a significant drop in hematocrit. Levels of erythropoiesis-stimulating factors (ESF) showed a slight increase consistent with the fall in hematocrit but no large fluctuations which could be easily correlated with th...

Erythropoiesis stimulating factors.

A urine concentrate of erythropoietin, obtained by chromatography on diethylamino‐ethyl (DEAE)‐cellulose, contained regulators of erythropoiesis that could be fractionated by selective membrane permeability. Two erythropoiesis stimulating factors (ESF) were obtained after exhaustive dialysis, one that diffused through the membrane and one in the retentate. A biochemical study of the ESF in the diffusate showed no appreciable sialic acid or fucose, a trace of hexosamine and a relatively small amount of protein. The remainder of the complex appeared to be an adrenocorticosteroid(s). The protein appeared to be a fragment of a glycoprotein.After exhaustive dialysis the retentate‐ESF had the characteristics of an ESF‐generating factor. The optimum pH for activity was about 7.4. It is suggested that an ESF(s) remains inactive when bound to a glycoprotein such as α1‐acid glycoprotein or the corticosteroid‐binding globulin. A role of an ESF‐generating factor would be to act on the complex to produce a fragment of the glycoprotein steroid complex, thereby activating the hormone.

The erythropoiesis-stimulating factors produced by tumors.

The erythropoiesis-stimulating factors produced by tumors.

Effects of hypothalamic stimulation on erythropoiesis and on the production of erythropoiesis-stimulating factors in intact and nephrectomized rabbits.

Effects of hypothalamic stimulation on erythropoiesis and on the production of erythropoiesis-stimulating factors in intact and nephrectomized rabbits.

A Comparison of Some Physical and Chemical Properties of Erythropoiesis-Stimulating Factors from Different Sources

Abstract In the present study we have compared some molecular characteristics of factors stimulating erythropoiesis found in the serum from patients with (a) aplastic anemia and (b) with erythremia due to anoxia, and in cyst fluid from patients with erythremia secondary to (c) a renal cyst and (d) a cerebellar hemangioblastoma. The biological activity of each of the four materials was found to migrate as an α2-globulin on zonal electrophoresis and was destroyed by treatment with sialidase and trypsin; this implies that these materials are mucoproteins with similar electrophoretic mobility. The erythropoietin activity was also completely neutralized by an antiserum made in rabbits to an extract of urine of anemic patients. This implies that these materials share common antigenic determinants. Thus, the erythropoiesisstimulating factors in human anemic and anoxic serum, cerebellar hemangioblastoma cyst fluid, and renal cyst fluid appear to be similar, if not identical. Therefore, the pathogenesis of the erythrocytosis seen in association with renal cysts and cerebellar hemangioblastomas appears to be due to the secretion of erythropoietin by these lesions.