losartan-potassium and Anemia--Hemolytic

Erythropoietin (EPO) is a multi-functional cytokine, which exerts erythropoietic effects but also carries anti-apoptotic and immune-modulatory activities upon binding to two distinct receptors which are expressed on erythroid, parenchymal and immune cells, respectively. Whereas EPO ameliorates hemolytic anemia in malaria or trypanosomiasis and improves the course of autoimmune diseases such as inflammatory bowel disease or autoimmune encephalomyelitis, it deleteriously inhibits macrophage functions in Salmonella infection in animal models. Thus, the specific modulation of extra-erythropoietic EPO activity forms an attractive therapeutic target in infection and inflammation.

Topics: Anemia, Hemolytic; Animals; Cell Hypoxia; Erythropoiesis; Erythropoietin; Genetic Pleiotropy; Host-Pathogen Interactions; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Macrophages; Mice; NF-kappa B; Salmonella; Salmonella Infections; Signal Transduction

Pegylated interferon and ribavirin combination therapy is accepted as the standard antiviral treatment for chronic hepatitis C regardless of HCV genotype. This combination therapy achieves higher response rates than previous therapy, but, nevertheless, a large proportion of patients suffer from treatment failure or adverse events. Recent clinical studies of viral kinetics during antiviral treatment have led to the introduction of response-guided therapy, the concept of 'customized therapy depending on viral response', which focuses on modulation of the treatment period depending on the viral response to create a sustained viral response without unnecessary medication and costs. New upcoming direct-acting antivirals (DAAs) maximize response rate, and triple therapy including DAAs along with pegylated interferon and ribavirin combination therapy could soon be the standard therapy. In this article, we reviewed the factors affecting treatment, response guided treatment, retreatment after failure of standard treatment, management of adverse events during treatment, and new treatment options.

Topics: Anemia, Hemolytic; Antiviral Agents; Drug Therapy, Combination; Erythropoietin; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Polyethylene Glycols; Precision Medicine; Protease Inhibitors; Recombinant Proteins; Ribavirin; RNA, Viral

Twenty five years ago, Finch summarized knowledge gained primarily from studies of normal individuals, patients with hereditary hemolytic anemias, and patients with hemochromatosis [1]. Under conditions of basal erythropoiesis in normal subjects, plasma iron turnover (as an index of marrow erythropoietic response) is little affected, whether transferrin saturation ranges from very low to very high levels. In contrast, the erythropoietic response in individuals with congenital hemolytic anemia, in whom erythropoiesis is chronically raised up to sixfold over basal levels [2], is affected (and limited) by serum iron levels and by transferrin saturation [3]. Patients with hemochromatosis who underwent serial phlebotomy were observed to mount erythropoietic responses of up to eightfold over basal rates, attributed to the maintenance of very high serum iron and transferrin saturation levels in these patients [4], whereas normal individuals were shown to have difficulty providing sufficient iron to support rates of erythropoiesis greater than three times basal rates [5]. These observations led Finch to identify a "relative iron deficiency" state, also known as "functional iron deficiency," which he defined as circumstances in which increased erythron iron requirements exceed the available supply of iron [6]. In another clinical setting, patients undergoing autologous blood donation represent a model for perisurgical blood loss and the erythropoietic response. Insights gained over the last 20 years regarding the relationship between erythropoietin, iron, and erythropoiesis, along with implications for clinical management, will be reviewed.

Topics: Anemia, Hemolytic; Erythropoiesis; Erythropoietin; Hemochromatosis; Humans; Iron; Transferrin

In the United States, about 2.7 million people are chronically infected with the hepatitis C virus, accounting for nearly 1.8% of the population. The current standard of therapy is a combination of pegylated interferon products and ribavirin. A common adverse effect associated with this therapy is anemia, which is frequently referred to as mixed anemia because of the synergistic contribution of the interferons and ribavirin. The effect of ribavirin on the development of anemia is considered greater than that of interferon. The current standard of practice for treating this adverse effect is reduction of the dosages of both drugs, at prespecified hemoglobin levels. However, recent findings underscore the importance of maintaining adequate dosages of interferon and ribavirin, which may be crucial in achieving an early virologic response and a sustained virologic response in treating patients with hepatitis C infection. Treatment with epoetin alfa for this mixed anemia significantly improved hemoglobin levels and quality of life, and enabled adequate dosages of ribavirin to be maintained. Future studies should address several issues: when to start epoetin alfa treatment, the duration of treatment, the drug's optimal dosage, its effects on end-of-treatment and sustained virologic response rates, and a cost analyses.

Topics: Anemia, Hemolytic; Antiviral Agents; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Health Care Costs; Hepatitis C; Humans; Interferon-alpha; Recombinant Proteins; Ribavirin; Risk Factors

Infection with the hepatitis C virus (HCV) remains chronic in 75% of infected individuals, in whom it can cause liver inflammation and progressive fibrosis leading to cirrhosis in 20% of patients. A sustained viral response (SVR) to HCV therapy, i.e. undetectable plasma HCV RNA 6 months after the end of treatment, leads to permanent eradication of the virus in 98.3% of patients. The current treatment of choice is combination therapy with pegylated interferon alfa (PEG-IFN alfa), 2a or 2b, and ribavirin (RBV), which achieves an SVR in 54-56% of patients. In patients with HCV genotype 1, RBV doses of 1000-1200 mg/day are associated with a higher SVR than 800 mg/day (51 vs 40%). However, RBV also causes dose-dependent reversible haemolytic anaemia that, in combination with the myelosuppressive effects of PEG-IFN, results in a mean drop in haemoglobin (Hb) level of 3.7 g/dL within 4 weeks. Conventionally, this acute anaemia has been managed with RBV dose reductions. However, this may result in a decreased SVR rate. Alternatively, this anaemia can be managed with administration of epoetin alfa at 40 000 IU once weekly. In a randomized placebo-controlled trial, treatment with epoetin alfa has been shown to raise Hb levels and maintain RBV doses. Furthermore, the increase in Hb level was associated with improved quality of life. Anaemia in patients treated with interferon plus RBV combination therapy can be managed effectively and safely with once weekly epoetin alfa without sacrificing optimal dosing of RBV.

Topics: Anemia, Hemolytic; Antiviral Agents; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Hematinics; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Polyethylene Glycols; Recombinant Proteins; Ribavirin

Because of shared modes of transmission, co-infection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is common. Co-infection with HIV increases HCV virus load, liver-related mortality, and the risk of sexual and perinatal transmission of HCV, and it may accelerate HCV disease progression. With combination interferon (IFN)-alpha 2b/ribavirin or pegylated IFN-alpha 2b/ribavirin therapy, long-term remission is possible for HCV-infected patients. Preliminary evidence suggests that the combination of IFN-alpha 2b/ribavirin can achieve similar response rates in HCV/HIV-co-infected individuals with no adverse effect on HIV RNA concentrations. Although adverse effects are more frequent with combination therapy than with IFN-alpha monotherapy, most are manageable. In addition, few instances of drug-drug antagonism have been reported among drugs used to treat each disease, although further study is necessary. Ribavirin-associated hemolytic anemia is a potential problem in a patient population that is already susceptible to anemia but is manageable with recombinant human erythropoietin (epoetin alfa).

Topics: Anemia, Hemolytic; Antiviral Agents; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Hematinics; Hepatitis C; HIV Infections; Humans; Interferon alpha-2; Interferon-alpha; Recombinant Proteins; Ribavirin

Brisk hemolysis due to perivalvular leak is usually an indication for valve re-replacement. Repeated surgery after multiple previous valve operations is associated with high mortality, morbidity and failure rates. The present study evaluated the role of erythropoietin (EPO) administration in deferring or obviating the need for repeated surgery.. Three patients (two men, one woman; age range 62-76 years) with two mechanical valves each and two to four previous heart valve operations, who suffered from severe mechanical hemolytic anemia, were given subcutaneous EPO for 15-17 months.. A marked reduction in red blood cell consumption was achieved with a weekly EPO dose of 18,000 U in two patients, both of whom also had mild or moderate kidney malfunction. A third patient with normal renal function and extreme hemolysis showed a transient, partial response to 30,000 U of EPO per week, and eventually needed a fifth operation.. EPO may defer or even obviate the need for repeated valve surgery in patients with severe hemolysis due to perivalvular leak, especially those with inadequate EPO response, such as those with renal malfunction.

Topics: Aged; Aged, 80 and over; Anemia, Hemolytic; Erythropoietin; Female; Heart Valve Prosthesis; Humans; Male; Middle Aged; Mitral Valve Insufficiency; Reoperation; Risk Assessment; Severity of Illness Index

Pediatricians should understand that the anemia of inflammation is second only to iron deficiency in overall incidence. When evaluating a child for mild to moderate anemia, one should always consider hemolytic anemia, both immune and congenital, and blood loss. Careful scrutiny of the peripheral blood smear is always helpful and can assist in minimizing expensive and unnecessary evaluations. When the anemia of inflammation is suggested by history or physical examination and the CBC reveals a normocytic, or possibly microcytic, mild to moderate anemia with a normal peripheral blood smear, it is prudent to not embark on an extensive evaluation for the anemia but instead wait for the inflammation to resolve. This may take as many as 3 months, depending on the degree of inflammation. Because the anemia resolves with subsiding inflammation, it is best to avoid treatment with iron or RBC transfusions. More studies need to be performed concerning the pathogenesis of the anemia of acute inflammation in children and the best course of treatment, if needed. The role of erythropoietin in the treatment of this form of anemia, though promising in some adult models of inflammation, awaits exploration in pediatric patients.

Topics: Adult; Anemia; Anemia, Hemolytic; Cytokines; Diagnosis, Differential; Erythropoietin; Humans; Infant; Infections; Inflammation

Recombinant human erythropoietin is an efficacious therapy in treatment of the anemia of end-stage renal failure. However, the scale of impact on quality of life and medical care resources remains uncertain. By reviewing the literature we evaluate cost-effectiveness of recombinant human erythropoietin and show how previous studies may have implicitly overestimated cost-effectiveness.

Topics: Anemia, Hemolytic; Blood Transfusion; Cost-Benefit Analysis; Drug Costs; Erythropoietin; Humans; Kidney Failure, Chronic; Quality of Life; Recombinant Proteins

It is apparent that exercise can influence erythropoiesis and red cell survival in a variety of fascinating ways. A number of mechanisms have been reviewed that could lead to mild changes in the Hb or red cell mean corpuscular volume. In addition, athletes may be at high-risk to develop decreased iron stores. Nevertheless, iron deficiency anemia is uncommon and the ritual of routine iron supplementation is not recommended. Clearly, most of the mechanisms discussed lead to only subtle changes in the overall red cell numbers and indices. Yet there is a small subset of athletes who will have red cell changes that can only be attributable to participation in sports. The diagnosis of sports anemia, however, remains one of exclusion.

Topics: Anemia; Anemia, Hemolytic; Anemia, Hypochromic; Erythropoietin; Exercise; Humans; Sports; Water-Electrolyte Balance

Topics: Amino Acid Sequence; Anemia, Hemolytic; Animals; Biological Assay; Erythropoiesis; Erythropoietin; Humans; Immunoassay; Kidney; Liver; Molecular Sequence Data; Rats; Recombinant Proteins

The currently available radioimmunoassay for erythropoietin (Epo) using recombinant reagents is an accurate, reproducible, sensitive and specific assay which can be used to identify whether lack of Epo is contributing to anemia and, by extension, whether therapy with recombinant Epo might be appropriate. Elevation of the serum Epo level with anemia suggests that a marrow abnormality is the cause of the anemia, while a "high" Epo level in a non-anemic or plethoric patient suggests the presence of hypoxia or autonomous Epo production. Liver disease can elevate the serum Epo level, while modest degrees of anemia do not affect it appreciably. The lowest Epo levels occur in polycythemia vera, but in a particular patient this finding is not completely diagnostic.

Topics: Anemia, Hemolytic; Erythropoietin; Female; Humans; Infant, Newborn; Infant, Premature; Infections; Inflammation; Neoplasms; Polycythemia; Pregnancy; Radioimmunoassay

Erythropoietin mRNA is detected primarily in kidney peritubular cells in response to hypoxia, and this tissue is the major adult source of the hormone. Erythropoietin can be assayed by in vivo or in vitro biological methods, or by radioimmunoassay, but only the in vivo assay can distinguish the most biologically active forms. The mature hormone consists of 166 amino acids and approximately 50% of the mature molecule (Mr 39,000) consists of carbohydrate. The gene is highly conserved among species studied, and is located on human chromosome 7, region q11-q22. Recombinant erythropoietin has been administered to haemodialysis patients and shown to increase haemoglobin levels, reticulocyte numbers and haematocrit. In transfusion-dependent patients, the need for regular transfusions was abrogated. Problems with hypertension have been noted in previously hypertensive patients, but the results of clinical trials with erythropoietin suggest that it will provide a valuable alternative therapy, for correcting some disorders of erythropoiesis.

Topics: Anemia, Hemolytic; Animals; Cloning, Molecular; Erythropoietin; Humans; Kidney Failure, Chronic; Rats

In summary, anemia developing in a patient with cancer can be due to several different factors. A relative failure of erythropoiesis, in conjunction with a modestly shortened erythrocyte survival, is the most likely explanation for the anemia and can occur in patients with or without bone marrow invasion. Several theories have been proposed to explain the mechanism of limited red cell production in cancer. Internal iron starvation and cancer toxic factors have been widely implicated. Immunoglobulin inhibitors of erythropoiesis occur in the rare entity, pure red cell aplasia, which is sometimes associated with thymomas. Autoimmune hemolytic anemia and microangiopathic hemolytic anemia can also occur in patients with solid cancers, pointing out the need for a complete evaluation of anemia in any patient with recent-onset anemia. Successful treatment and prognostic implications of anemia in cancer is dependent on proper diagnosis.

Topics: Anemia; Anemia, Aplastic; Anemia, Hemolytic; Anemia, Megaloblastic; Anemia, Myelophthisic; Bone Marrow; Erythropoiesis; Erythropoietin; Humans; Intestinal Absorption; Iron; Mononuclear Phagocyte System; Neoplasms

Topics: Anemia; Anemia, Hemolytic; Anemia, Hypochromic; Anemia, Sideroblastic; Animals; Erythrocytes; Erythropoietin; Humans; Kidney Failure, Chronic; Rats; Renal Dialysis

Uremia interferes with erythropoiesis, granulocyte, platelet, and immune functions. As a result, uremic patients are almost invariably anemic, and have a high incidence of infections and hemorrhagic complications. The anemia of renal failure, which is caused primarily by damage to the site of erythropoietin production is often complex, and complicated by hemolysis from a variety of mechanisms, iron deficiency, and so forth. Although hemodialysis ameliorates some of the hematologic complications to a variable degree, they remain a serious hinderance to the well being of this group of patients. Progress in understanding the mechanism of these problems and their therapy has been reviewed here.

Topics: Anemia; Anemia, Hemolytic; Anemia, Hypochromic; Blood Transfusion; Erythrocytes; Erythropoiesis; Erythropoietin; Folic Acid Deficiency; Hemorrhage; Humans; Kidney; Kidney Failure, Chronic; Renal Dialysis; Testosterone; Testosterone Congeners

Topics: Acute Kidney Injury; Anemia; Anemia, Hemolytic; Blood Viscosity; Bone Marrow; Diphosphoglyceric Acids; Erythrocytes; Erythropoietin; Half-Life; Hematocrit; Hemoglobins; Hemolysis; Humans; Kidney Failure, Chronic; Oxygen Consumption; Pyelonephritis; Renal Dialysis; Transfusion Reaction

Topics: Anemia, Hemolytic; Anemia, Neonatal; Bilirubin; Birth Weight; Blood Group Antigens; Diet; Erythrocytes; Erythrocytes, Abnormal; Erythropoiesis; Erythropoietin; Folic Acid Deficiency; Gestational Age; Hemoglobinometry; Hemorrhage; Humans; Immunization; Infant; Infant, Newborn; Isoantigens; Kinetics; Rh-Hr Blood-Group System; Thalassemia; Vitamin E Deficiency

Topics: Anemia, Hemolytic; Anemia, Hemolytic, Autoimmune; Animals; Body Temperature Regulation; Cell Membrane; Cell Survival; Chromium Radioisotopes; Chronic Disease; Endotoxins; Erythrocytes; Erythropoiesis; Erythropoietin; Fever; Hematocrit; Hemolysis; Hot Temperature; Iron; Lipid Metabolism; Mononuclear Phagocyte System; Phagocytosis; Rabbits; Spleen

Topics: Adolescent; Adrenocortical Hyperfunction; Adult; Anemia; Anemia, Hemolytic; Animals; Dwarfism, Pituitary; Endocrine System Diseases; Erythropoiesis; Erythropoietin; Female; Hematologic Diseases; Humans; Hypopituitarism; Male; Mice; Pituitary Diseases; Polycythemia; Rabbits; Thyroid Diseases; Thyroiditis, Autoimmune

Topics: Adult; Anemia; Anemia, Hemolytic; Anemia, Hypochromic; Blood Platelets; Blood Urea Nitrogen; Bone Marrow Cells; Chronic Disease; Erythrocytes; Erythrocytes, Abnormal; Erythropoiesis; Erythropoietin; Feedback; Female; Hemolysis; Hemostasis; Humans; Hypertension, Malignant; Iron; Kidney; Kidney Concentrating Ability; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Oxygen Consumption; Plasma Volume; Uremia

Chronic hepatitis C affects one-third of HIV(+) patients worldwide. High ribavirin (RBV) exposure is crucial to maximize the response to hepatitis C therapy in this population, although it may increase the risk for hemolytic anemia. PERICO is a prospective multicenter trial in which HIV/HCV-coinfected patients are randomized to receive peginterferon (pegIFN) alfa-2a 180 microg/week plus either weight-based RBV (1000-1200 mg/day) or RBV 2000 mg/day, the latest along with erythropoietin alfa (EPO) 30,000 IU/week from the first day until week 4. A total of 149 patients were assessed in a planned interim analysis at week 4. In both arms, 22% of patients achieved negative HCV-RNA (rapid virological response, RVR). Multivariate analysis [OR (IC 95%), p] showed that factors associated with RVR were HCV genotypes 2/3 vs. 1/4 [20 (5-100), <0.01] and baseline HCV-RNA [0.16 (0.07-0.37) per log IU/ml, <0.01]. The occurrence of severe anemia (hemoglobin <10 g/dl) did not differ when comparing RBV vs. high RBV + EPO (7% vs. 3%; p = 0.4). Moreover, RBV plasma trough levels were comparable at week 4 (1.9 vs. 2.4 microg/ml; p = 0.2). Use of high RBV doses with preemptive EPO during the first 4 weeks of hepatitis C therapy is safe, but fails to enhance significantly RBV plasma exposure and RVR rates. Extensive intraerythrocyte accumulation of RBV following boosted production of red blood cells by EPO could explain these findings.

Topics: Adult; Anemia, Hemolytic; Antiviral Agents; Epoetin Alfa; Erythrocytes; Erythropoietin; Female; Hematinics; Hepacivirus; Hepatitis C, Chronic; HIV; HIV Infections; Humans; Interferon alpha-2; Interferon-alpha; Male; Polyethylene Glycols; Prospective Studies; Recombinant Proteins; Ribavirin; RNA, Viral; Treatment Outcome

Childhood hemolytic uremic syndrome (HUS) is most often caused by enterohemorrhagic Escherichia coli (EHEC). Due to severe hemolysis, red blood cell (RBC) transfusions are often necessary, and anemia is aggravated by low erythropoietin (EPO) levels caused by acute renal failure. In a single center, prospective study, we randomized ten children with EHEC-positive HUS into two therapeutic groups: one receiving EPO treatment (median age 2 years, age range 1-3 years) and the other receiving standard therapy (median age 2 years, age range 1-6 years). Red blood cell transfusions were performed when the hemoglobin level (Hb) fell below 5 mg/dl. The number of RBC transfusions was compared in both groups. The Hb level at admission was comparable between both groups (6.4 vs. 8.1 mg/dl, P > 0.05, t-test). However, children in the EPO group required a significantly lower mean number of RBCs than those in the non-EPO group (0.2 vs. 1.4, P < 0.04, t-test). Based on these results, we suggest that the early administration of EPO at the time of hemolytic anemia and beginning renal failure may attenuate renal anemia in children with EHEC-induced HUS and thereby reduce the number of RBC transfusions required. The results of this pilot study will have to be confirmed in a larger multicenter trial.

Topics: Anemia, Hemolytic; Child; Child, Preschool; Erythrocyte Transfusion; Erythropoietin; Hemolytic-Uremic Syndrome; Humans; Infant; Pilot Projects; Prospective Studies; Recombinant Proteins

The external administration of recombinant human erythropoietin is the chosen treatment for those patients with secondary anemia due to chronic renal failure in periodic hemodialysis. The objective of this paper is to carry out an individualized prediction of the EPO dosage to be administered to those patients. The high cost of this medication, its side-effects and the phenomenon of potential resistance which some individuals suffer all justify the need for a model which is capable of optimizing dosage individualization. A group of 110 patients and several patient factors were used to develop the models. The support vector regressor (SVR) is benchmarked with the classical multilayer perceptron (MLP) and the Autoregressive Conditional Heteroskedasticity (ARCH) model. We introduce a priori knowledge by relaxing or tightening the epsilon-insensitive region and the penalization parameter depending on the time period of the patients' follow-up. The so-called profile-dependent SVR (PD-SVR) improves results of the standard SVR method and the MLP. We perform sensitivity analysis on the MLP and inspect the distribution of the support vectors in the input and feature spaces in order to gain knowledge about the problem.

Topics: Adult; Aged; Aged, 80 and over; Algorithms; Anemia, Hemolytic; Cohort Studies; Drug Therapy, Computer-Assisted; Erythropoietin; Hemoglobins; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Middle Aged; Neural Networks, Computer; Recombinant Proteins; Regression, Psychology; Renal Dialysis; Treatment Outcome

Clinical trials of erythropoietin (EPO) administration to preterm infants have not focused on infants weighing 750 gm or less, the population most likely to receive multiple transfusions because of large phlebotomy losses. It is unknown whether preterm infants weighing 750 gm or less will respond to EPO by accelerating erythropoiesis, or whether EPO administered to this population will decrease blood transfusions.. We randomly assigned 28 extremely low birth weight preterm infants (mean +/- SEM: 24.7 +/- 0.3 weeks' gestation, 662 +/- 14 gm birth weight), in the first 72 hours of life, to receive either EPO (200 U/kg/day) or placebo for 14 days and administered transfusions only according to protocol over a 21-day study period. All infants received 1 mg/kg/day iron dextran in their total parenteral nutrition solution during the 14-day treatment period.. During the 21-day study period, a lower number and volume of transfusions were received by the EPO recipients (4.7 +/- 0.7 transfusions per patient and 70 +/- 11 ml/kg per patient) than by the placebo recipients (7.5 +/- 1.1 transfusions per patient and 112 +/- 17 ml/kg per patient; p < 0.05, EPO vs placebo), whereas hematocrits remained similar in the two groups. Reticulocyte counts were similar in both groups on day 1 but were greater in the EPO recipients on day 14 (EPO day 1, 351 +/- 53; EPO day 14, 359 +/- 40 x 10(3)/microl; placebo day 1, 334 +/- 64; placebo day 14, 120 +/- 10 x 10(3)/microl; p < 0.01, EPO vs placebo). Serum ferritin concentrations were similar in both groups at the beginning of the study but were greater in the placebo recipients by day 14 (EPO, 262 +/- 44 microg/L; placebo, 593 +/- 92 microg/L; p < 0.01). No adverse effects of EPO or iron were noted.. The combination of EPO and parenteral iron stimulates erythropoiesis in preterm infants weighing 750 gm or less and results in fewer transfusions during their first 3 weeks of life.

Topics: Anemia, Hemolytic; Blood Transfusion; Combined Modality Therapy; Double-Blind Method; Erythropoietin; Ferritins; Gestational Age; Hematocrit; Humans; Infant, Newborn; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Iron; Parenteral Nutrition, Total; Recombinant Proteins; Reticulocyte Count

The management of (Rhesus) hemolytic disease of the fetus and newborn includes intrauterine transfusions to prevent the development of hydrops, treatment of the possible hyperbilirubinemia in the immediate postnatal period, and treatment of late anemia. Low levels of serum erythropoietin due to suppression of the bone marrow by multiple intrauterine transfusions is a suggested mechanism for this anemia. The aim of our study was to test whether recombinant human erythropoietin reduced the need for erythrocyte transfusions in these infants. Twenty infants with Rhesus isoimmunization were blindly randomized to treatment and control groups at the 2nd wk of life. The number of intrauterine and exchange transfusions and demographic data were similar in both groups. The infants in the treatment group received recombinant human erythropoietin, s.c. 200 U/kg of body weight three times a week for a period of 6 wk, whereas the infants in the control group received a placebo for the same period. In the treatment group, the mean number of erythrocyte transfusions was significantly lower than that of the control group (1.8 versus 4.2). The reticulocyte counts and Hb levels rose earlier in the treatment group. The platelet and neutrophil counts were similar in both groups throughout the study. This study demonstrates that recombinant human erythropoietin treatment decreases the need for erythrocyte transfusions in the late anemia of infants with Rh isoimmunization. Considering the risks of blood transfusions, this decrease in the donor exposure is worthwhile.

Topics: Anemia, Hemolytic; Blood Transfusion, Intrauterine; Double-Blind Method; Erythroblastosis, Fetal; Erythropoietin; Exchange Transfusion, Whole Blood; Female; Hemoglobins; Humans; Hydrops Fetalis; Infant, Newborn; Leukocyte Count; Male; Neutrophils; Platelet Count; Pregnancy; Recombinant Proteins; Reticulocyte Count

Topics: Anemia, Hemolytic; Anemia, Hemolytic, Autoimmune; Erythropoietin; Humans; Recombinant Proteins

Infantile pyknocytosis is a neonatal hemolytic disorder which causes anemia and icterus and is characterized by the presence of an increased number of distorted red blood cells called pyknocytes. Resolution spontaneously occurs in the first semester of life. It has been generally described as a rare entity, with an occasional family history. We report seven cases of infantile pyknocytosis observed in our hospital in 3 years. Most of the infants presented with hemolytic icterus and profound anemia that was reaching its peak by the 3rd week of life. Three neonates received one to three red blood cell transfusions, according to former recommendations. However, the following four received a treatment with recombinant erythropoietin administered subcutaneously. Only one of these four cases required a transfusion. All of them were free of hematological disease 2-3 months after completion of treatment. Infantile pyknocytosis is a recognized cause of neonatal hemolytic anemia, which requires careful examination of red cell morphology on a peripheral blood smear. The cause of this transient disorder remains unknown. Our observations show that recombinant erythropoietin therapy is effective in treating infantile pyknocytosis and increases the reticulocyte response, thus improving the hemoglobin level.

Topics: Anemia, Hemolytic; Anemia, Neonatal; Erythrocyte Transfusion; Erythrocytes, Abnormal; Erythropoietin; Female; Humans; Infant; Infant, Newborn; Male

Hemolytic anemia is a common form of anemia due to hemolysis, resulting in disordered iron homeostasis. In this study, a dose of 40mg/kg phenylhydrazine (PHZ) was injected into mice to successfully establish a pronounced anemia animal model, which resulted in stress erythropoiesis and iron absorption. We found that serum erythropoietin (EPO) concentration was dramatically elevated by nearly 5000-fold for the first 2days, and then drop to the basal level on day 6 after PHZ injection. Mirrored with serum EPO concentration, the mRNA expression of erythroferrone (ERFE) was rapidly increased in the bone marrow and spleen 3days after injection of PHZ, and then gradually decreased but was still higher than baseline on day 6. In addition, we also found that the hepcidin mRNA levels were gradually reduced almost up to 8-fold on day 5, and then was ameliorated compared to the untreated control. Mechanistic investigation manifested that the increase of serum EPO essentially determined the induction of ERFE expression particular at the first 3days after PHZ treatment. Lentiviral mediated ERFE knockdown significantly restrained hepcidin suppression under PHZ treatment. Thus, our data unearthed EPO-dependent ERFE expression acts as an erythropoiesis-driven regulator of iron metabolism under PHZ-induced hemolytic anemia.

Topics: Anemia, Hemolytic; Animals; Cytokines; Down-Regulation; Erythropoiesis; Erythropoietin; Hemolysis; Hepcidins; Iron; Male; Mice; Mice, Inbred C57BL; Muscle Proteins; Phenylhydrazines; RNA, Messenger; Up-Regulation

Hyperhemolysis is a serious transfusion reaction, most often described in patients with hemoglobinopathies. Hyperhemolysis is characterized by the destruction of host red blood cells (RBCs), in addition to donor RBCs, via an unknown mechanism.. We present the case of a 58-year-old woman with treated human immunodeficiency virus and a normal hemoglobin (Hb) electrophoresis who developed hyperhemolysis in the setting of a delayed hemolytic transfusion reaction (DHTR).. The patient was ABO group B and had a previously identified anti-Fy(b) alloantibody. After transfusion of Fy(b)--RBCs, she developed a DHTR and was found to have anti-E, anti-C(w), anti-s, and an additional antibody to an unrecognized high-frequency RBC alloantigen. Subsequent transfusion of ABO-compatible RBCs that were negative for Fy(b), E, C(w), and s antigens resulted in immediate intravascular hemolysis. In the absence of bleeding, her hematocrit (Hct) decreased to 10.2%. An extensive serologic evaluation failed to identify the specificity of the high-frequency antibody. Severe hemolytic reactions also occurred despite pretransfusion conditioning with eculizumab. The Hct and clinical symptoms slowly improved after the cessation of transfusions and treatment with erythropoietin and steroids. This case demonstrates several noteworthy features including hyperhemolysis in a patient without a Hb disorder, the development of an antibody to an unknown RBC antigen, and the failure of eculizumab to prevent intravascular hemolysis after transfusion.. Hyperhemolysis is not restricted to patients with hemoglobinopathies. Whether eculizumab offers any benefit in the hyperhemolysis syndrome or in the prevention of intravascular hemolysis due to RBC alloantibodies remains uncertain.

Topics: Acute Disease; Adrenal Cortex Hormones; Anemia, Hemolytic; Antibodies, Monoclonal, Humanized; Blood Group Incompatibility; Cholecystitis; Coombs Test; Drug Resistance; Duffy Blood-Group System; Dyspnea; Erythrocyte Transfusion; Erythropoietin; Female; Hematocrit; Hepatitis C, Chronic; HIV Infections; Humans; Isoantibodies; Middle Aged; Oxygen Inhalation Therapy; Premedication; Pulmonary Disease, Chronic Obstructive; Receptors, Cell Surface; Syndrome; Transfusion Reaction

Many acute and chronic anaemias, including haemolysis, sepsis and genetic bone marrow failure diseases such as Diamond-Blackfan anaemia, are not treatable with erythropoietin (Epo), because the colony-forming unit erythroid progenitors (CFU-Es) that respond to Epo are either too few in number or are not sensitive enough to Epo to maintain sufficient red blood cell production. Treatment of these anaemias requires a drug that acts at an earlier stage of red cell formation and enhances the formation of Epo-sensitive CFU-E progenitors. Recently, we showed that glucocorticoids specifically stimulate self-renewal of an early erythroid progenitor, burst-forming unit erythroid (BFU-E), and increase the production of terminally differentiated erythroid cells. Here we show that activation of the peroxisome proliferator-activated receptor α (PPAR-α) by the PPAR-α agonists GW7647 and fenofibrate synergizes with the glucocorticoid receptor (GR) to promote BFU-E self-renewal. Over time these agonists greatly increase production of mature red blood cells in cultures of both mouse fetal liver BFU-Es and mobilized human adult CD34(+) peripheral blood progenitors, with a new and effective culture system being used for the human cells that generates normal enucleated reticulocytes. Although Ppara(-/-) mice show no haematological difference from wild-type mice in both normal and phenylhydrazine (PHZ)-induced stress erythropoiesis, PPAR-α agonists facilitate recovery of wild-type but not Ppara(-/-) mice from PHZ-induced acute haemolytic anaemia. We also show that PPAR-α alleviates anaemia in a mouse model of chronic anaemia. Finally, both in control and corticosteroid-treated BFU-E cells, PPAR-α co-occupies many chromatin sites with GR; when activated by PPAR-α agonists, additional PPAR-α is recruited to GR-adjacent sites and presumably facilitates GR-dependent BFU-E self-renewal. Our discovery of the role of PPAR-α agonists in stimulating self-renewal of early erythroid progenitor cells suggests that the clinically tested PPAR-α agonists we used may improve the efficacy of corticosteroids in treating Epo-resistant anaemias.

Topics: Acute Disease; Anemia; Anemia, Hemolytic; Animals; Butyrates; Cell Culture Techniques; Cells, Cultured; Chromatin; Chronic Disease; Disease Models, Animal; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Female; Fenofibrate; Glucocorticoids; Humans; Liver; Mice; Phenylhydrazines; Phenylurea Compounds; PPAR alpha; Receptors, Glucocorticoid; Signal Transduction

Tight coordination of cell proliferation and differentiation is central to red blood cell formation. Erythropoietin controls the proliferation and survival of red blood cell precursors, while variations in GATA-1/FOG-1 complex composition and concentrations drive their maturation. However, clear evidence of cross-talk between molecular pathways is lacking. Here, we show that erythropoietin activates AKT, which phosphorylates GATA-1 at Ser310, thereby increasing GATA-1 affinity for FOG-1. In turn, FOG-1 displaces pRb/E2F-2 from GATA-1, ultimately releasing free, proproliferative E2F-2. Mice bearing a Gata-1(S310A) mutation suffer from fatal anemia when a compensatory pathway for E2F-2 production involving insulin-like growth factor-1 (IGF-1) signaling is simultaneously abolished. In the context of the GATA-1(V205G) mutation resulting in lethal anemia, we show that the Ser310 cannot be phosphorylated and that constitutive phosphorylation at this position restores partial erythroid differentiation. This study sheds light on the GATA-1 pathways that synchronize cell proliferation and differentiation for tissue homeostasis.

Topics: Anemia, Hemolytic; Animals; Cell Differentiation; Cell Proliferation; Enzyme Activation; Erythroid Cells; Erythropoiesis; Erythropoietin; GATA1 Transcription Factor; Gene Knock-In Techniques; Insulin-Like Growth Factor I; Mice; Mutation; Nuclear Proteins; Oncogene Protein v-akt; Phosphorylation; Protein Binding; Signal Transduction; Transcription Factors

Topics: Aged; Anemia, Hemolytic; Coombs Test; Cyclosporine; Darbepoetin alfa; Drug Therapy, Combination; Erythropoietin; Humans; Leukemia, Large Granular Lymphocytic; Male; Myelodysplastic Syndromes; Prednisolone

Samul-tang (Si-Wu-Tang, SMT), a kind of herbal medicines, has been used for the hemato-deficient disease for hundreds of years. In this work, investigate the anti-anemia activity of the H2O extracts from constituent herbal medicines of Samul-tang in an anemia model induced by intravenous infection of phenylhydrazine-HCL (PHZ) at 10 mg/kg for 4 days. After PHZ injection, female Sparague-Dawley rats were administrated extracts from constituent herbal medicines of SMT (300 mg/kg/day, p.o.) daily for 1 week. Results showed that sever hemolysis was induced by PHZ. For Paeonia lactiflora (PL2) H2O extract treated groups, the concentration of hemoglobin, hematocrit and red blood cells number increased much more significantly than PHZ-treated group. Moreover, Angelica gigas (AG), Angelica. acutiloba (AA), Paeonia lactiflora (PL2) and Rehmannia glutinosa (RG) extract administration significantly improved serum erythropoietin concentration. The activity of aminolevulinic acid dehydrates (ALDL) in liver homegenate was increased in Angelica gigas(AA), Paeonia lactiflora (PL2) and Rehmannia glutinosa (RG) treated group.

Topics: Anemia, Hemolytic; Animals; Biomarkers; Disease Models, Animal; Drugs, Chinese Herbal; Erythrocyte Count; Erythrocytes; Erythropoietin; Female; Hematinics; Hematocrit; Hematopoiesis; Hemoglobins; Humans; Liver; Phenylhydrazines; Phytotherapy; Plants, Medicinal; Porphobilinogen Synthase; Rats, Sprague-Dawley; Time Factors

Lyn is involved in erythropoietin (Epo)-receptor signaling and erythroid homeostasis. Downstream pathways influenced following Lyn activation and their significance to erythropoiesis remain unclear. To address this, we assessed a gain-of-function Lyn mutation (Lyn(up/up)) on erythropoiesis and Epo receptor signaling. Adult Lyn(up/up) mice were anemic, with dysmorphic red cells (spherocyte-like, acanthocytes) in their circulation, indicative of hemolytic anemia and resembling the human disorder chorea acanthocytosis. Heterozygous Lyn(+/up) mice became increasingly anemic with age, indicating that the mutation was dominant. In an attempt to overcome this anemia, extramedullary erythropoiesis was activated. As the mice aged, the levels of different immature erythroid populations changed, indicating compensatory mechanisms to produce more erythrocytes were dynamic. Changes in Epo signaling were observed in Lyn(+/up) erythroid cell lines and primary CD71(+) Lyn(up/up) erythroblasts, including significant alterations to the phosphorylation of Lyn, the Epo receptor, Janus kinase 2, Signal Transducer and Action of Transcription-5, GRB2-associated-binding protein-2, Akt, and Forkhead box O3. As a consequence of altered Lyn signaling, Lyn(+/up) cells remained viable in the absence of Epo but displayed delayed Epo-induced differentiation. These data demonstrate that Lyn gene dosage and activity are critical for normal erythropoiesis; constitutively active Lyn alters Epo signaling, which in turn produces erythroid defects.

Topics: Adaptor Proteins, Signal Transducing; Anemia, Hemolytic; Animals; Bone Marrow; Cell Differentiation; Cell Line; Enzyme Activation; Erythrocyte Indices; Erythrocytes; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Janus Kinase 2; Mice; Mice, Transgenic; Phosphoproteins; Proto-Oncogene Proteins c-akt; Receptors, Erythropoietin; Signal Transduction; Spleen; src-Family Kinases

Although thyroid diseases exist in patients with renal failure, thyroid function tests are not routine tests in patients on chronic hemodialysis (HD). Therefore, the impact of thyroid diseases on erythropoietin (EPO) dosage in HD patients is not well defined. This study evaluated the relationship between the dose of EPO and the presence or absence of thyroid dysfunction in HD patients.. This study included 1013 adult patients on HD who did not have a malignancy, liver cirrhosis, thalassemia, iron deficiency, gastrointestinal bleeding, or a major operation within 6 months. Patients were characterized as being euthyroid, or having the sick euthyroid syndrome, primary hypothyroidism, subclinical hypothyroidism, hyperthyroidism, or subclinical hyperthyroidism based on thyroid function tests. Routine biochemistry profiles including an index of the efficiency of HD, along with clinical data over the previous 6-month period, were collected and analyzed. Multiple regression models were employed to assess the relationship between the dose of EPO and the presence or absence of thyroid status.. The mean monthly EPO dosages were 77.7±37.0, 70.2±40.6, 90.8±68.4, 78.5±46.7, and 82.3±41.2 μg, respectively, in the sick euthyroid syndrome, euthyroid patients, hypothyroidism, subclinical hypothyroidism, and subclinical hyperthyroidism groups (p<0.05). After adjustment of all other variables in multiple regression, the mean monthly EPO dosage was 19.00±8.59 μg more in hypothyroid patients compared with euthyroid patients (p=0.027). Further, considering an interaction with the presence of diabetes, the mean monthly EPO dosage in patients with either hypothyroidism or subclinical hypothyroidism and diabetes was 54.66±17.12 μg (p=0.001) and 31.51±10.38 μg more than that of euthyroid patients, respectively (p=0.002).. In HD patients, the EPO dosage required to maintain the target hemoglobin level is significantly higher in patients having both hypothyroidism or subclinical hypothyroidism and diabetes than in euthyroid patients.

Topics: Aged; Anemia, Hemolytic; Cross-Sectional Studies; Diabetic Nephropathies; Drug Monitoring; Erythropoietin; Euthyroid Sick Syndromes; Female; Hematinics; Humans; Hyperthyroidism; Hypothyroidism; Kidney Failure, Chronic; Male; Middle Aged; Prevalence; Recombinant Proteins; Renal Dialysis; Severity of Illness Index; Taiwan; Thyroid Diseases; Thyroid Gland

Salmonella, a ubiquitous Gram-negative intracellular bacterium, is a food borne pathogen that infects a broad range of hosts. Infection with Salmonella Typhimurium in mice is a broadly recognized experimental model resembling typhoid fever in humans. Using a N-ethyl-N-nitrosurea (ENU) mutagenesis recessive screen, we report the identification of Ity16 (Immunity to Typhimurium locus 16), a locus responsible for increased susceptibility to infection. The position of Ity16 was refined on chromosome 8 and a nonsense mutation was identified in the ankyrin 1 (Ank1) gene. ANK1 plays an important role in the formation and stabilization of the red cell cytoskeleton. The Ank1(Ity16/Ity16) mutation causes severe hemolytic anemia in uninfected mice resulting in splenomegaly, hyperbilirubinemia, jaundice, extramedullary erythropoiesis and iron overload in liver and kidneys. Ank1(Ity16/Ity16) mutant mice demonstrated low levels of hepcidin (Hamp) expression and significant increases in the expression of the growth differentiation factor 15 (Gdf15), erythropoietin (Epo) and heme oxygenase 1 (Hmox1) exacerbating extramedullary erythropoiesis, tissue iron deposition and splenomegaly. As the infection progresses in Ank1(Ity16/Ity16), the anemia worsens and bacterial load were high in liver and kidneys compared to wild type mice. Heterozygous Ank1(+/Ity16) mice were also more susceptible to Salmonella infection although to a lesser extent than Ank1(Ity16/Ity16) and they did not inherently present anemia and splenomegaly. During infection, iron accumulated in the kidneys of Ank1(+/Ity16) mice where bacterial loads were high compared to littermate controls. The critical role of HAMP in the host response to Salmonella infection was validated by showing increased susceptibility to infection in Hamp-deficient mice and significant survival benefits in Ank1(+/Ity16) heterozygous mice treated with HAMP peptide. This study illustrates that the regulation of Hamp and iron balance are crucial in the host response to Salmonella infection in Ank1 mutants.

Topics: Anemia, Hemolytic; Animals; Ankyrins; Antimicrobial Cationic Peptides; Codon, Nonsense; Erythrocytes; Erythropoietin; Ethylnitrosourea; Gene Expression; Genetic Predisposition to Disease; Growth Differentiation Factor 15; Heme Oxygenase-1; Hepcidins; Heterozygote; Homozygote; Iron; Iron Overload; Liver; Membrane Proteins; Mice; Salmonella Infections; Salmonella typhimurium; Survival Analysis

Topics: Aged; Anemia, Hemolytic; Antibodies, Monoclonal, Murine-Derived; Darbepoetin alfa; Delayed Graft Function; Diagnosis, Differential; Erythropoietin; Female; Graft vs Host Disease; Hematinics; Hemolysis; Hemolytic-Uremic Syndrome; Humans; Immunologic Factors; Kidney Failure, Chronic; Kidney Transplantation; Rituximab

This study examined the effect of fermentation on the ability of antler to act as a stimulator of hematopoietic activity. Hemolytic anemia was induced by phenylhydrazine (PHZ) in female Sprague-Dawley rats. The vehicle or antler extract (nonfermented or fermented) mixed in drinking water was administered from Days 2 to 15 after PHZ injection. On Day 15, red blood cell counts in the fermented antler group (6.33×10⁶/μL) were significantly higher than those in the nonfermented antler group (5.90×10⁶/μL) (P<.05), and rats treated with fermented antler extract tended to have higher hemoglobin compared with rats treated with nonfermented antler extract, but not significantly. In addition, rats treated with fermented antler extract had slightly lower serum erythropoietin levels compared with nonfermented antler extract, which were not statistically different from serum erythropoietin levels of nonanemic rats. We conclude therefore that the hematopoietic activity of antler might be increased by the fermentation process.

Topics: Anemia, Hemolytic; Animals; Antlers; Bacillus subtilis; Deer; Erythrocyte Count; Erythropoietin; Female; Fermentation; Food, Preserved; Hematinics; Hematopoiesis; Hemoglobins; Humans; Male; Materia Medica; Medicine, East Asian Traditional; Osmotic Fragility; Phenylhydrazines; Random Allocation; Rats; Rats, Sprague-Dawley

Erythropoiesis is a dynamic, multistep process whereby hematopoietic stem cells differentiate toward a progressively committed erythroid lineage through intermediate progenitors. Although several downstream signaling molecules have been identified that regulate steady-state erythropoiesis, the major regulators under conditions of stress remain poorly defined. Rho kinases (ROCKs) belong to a family of serine/threonine kinases. Using gene-targeted ROCK1-deficient mice, we show that lack of ROCK1 in phenylhydrazine-induced oxidative stress model results in enhanced recovery from hemolytic anemia as well as enhanced splenic stress erythropoiesis compared with control mice. Deficiency of ROCK1 also results in enhanced survival, whereas wild-type mice die rapidly in response to stress. Enhanced survivability of ROCK1-deficient mice is associated with reduced level of reactive oxygen species. BM transplantation studies revealed that enhanced stress erythropoiesis in ROCK1-deficient mice is stem cell autonomous. We show that ROCK1 binds to p53 and regulates its stability and expression. In the absence of ROCK1, p53 phosphorylation and expression is significantly reduced. Our findings reveal that ROCK1 functions as a physiologic regulator of p53 under conditions of erythroid stress. These findings are expected to offer new perspectives on stress erythropoiesis and may provide a potential therapeutic target in human disease characterized by anemia.

Topics: Anemia, Hemolytic; Animals; Antimetabolites, Antineoplastic; Apoptosis; Blotting, Western; Bone Marrow; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Female; Flow Cytometry; Fluorouracil; Immunoprecipitation; Male; Mice; Mice, Knockout; Oxidants; Oxidative Stress; Phenylhydrazines; Phosphorylation; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; rho-Associated Kinases; RNA, Messenger; Signal Transduction; Spleen; Survival Rate; Tumor Suppressor Protein p53

Anemia in IBD is the result of a combination of iron deficiency and anemia of chronic disease. Therapy of IBD is relief of inflammation, but the drugs usage may cause the development hemolytic anemia and myelodysplastic syndrome. We studied the effect of basic therapy on the incidence of anemia and assess the impact of modern biological therapies on the main markers of AHZ. A total of 153 patients with ulcerative colitis (UC) and 53 patients with Crohn's disease (CD), which at the time of the study received basic anti-inflammatory therapy for at least 1 year. All patients underwent blood tests, iron metabolism parameters were determined by the level of erythropoietin and G-gepsidina C reactive protein. Modern biological therapy increases the effectiveness of the treatment of anemia in patients with IBD. The use of Remicade gives a quick positive response, which is due to the decrease of gepsidin negative influence on iron metabolism and unlocking the synthesis of erythropoietin. The use of MSCs does not inhibit the synthesis of erythropoietin, and is likely to stimulate erythropoiesis at the erythroblast precursors.

Topics: Anemia, Hemolytic; Anemia, Iron-Deficiency; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antimicrobial Cationic Peptides; C-Reactive Protein; Colitis, Ulcerative; Crohn Disease; Erythroblasts; Erythropoiesis; Erythropoietin; Hepcidins; Humans; In Vitro Techniques; Incidence; Infliximab; Male; Myelodysplastic Syndromes; Risk Factors; Time Factors

Erythropoietin (EPO) and its receptor (EPOR) are key regulators of red blood cell production in mammals and fish. We aimed to investigate the structural and functional conservation of the EPO-EPOR system in amphibian erythropoiesis, using Xenopus laevis as a model.. X. laevis epo (xlepo) complementary DNA was identified by referring to the Xenopus tropicalis genome database. Biological activity of recombinant xlEPO expressed in COS-1 cells was evaluated using xlEPOR-expressing murine FDC/P2 cells and human EPO-dependent UT-7/EPO cells. Expression of xlepo messenger RNA in adult X. laevis tissues in the normal state and under the condition of phenylhydrazine-induced anemia was evaluated by real-time reverse transcription polymerase chain reaction.. In the encoded protein, the positions of four cysteine residues were conserved; however, xlEPO had only 38% identity with human EPO. N-glycosylation sites were absent. Recombinant xlEPO induced proliferation of cell lines expressing xlEPOR and UT-7/EPO, confirming biological activity and cross-species reactivity. Despite little primary amino acid sequence similarity, the evolutionary highly conserved sequence NFLRGK was identified in the EPOR-binding site 1 region as in the human EPO protein. Strong expression of xlepo messenger RNA was detected in the lung and liver, especially in fractionated hepatocytes. No marked increase in xlepo expression was seen in the lung and liver of phenylhydrazine-induced anemic X. laevis.. We confirmed that xlEPO is the ligand to the previously reported xlEPOR in X. laevis. xlEPO shares structural and functional similarities and differences with mammalian counterparts, and regulation of xlepo expression and its influence on the erythropoietic system appears to be unique.

Topics: Amino Acid Sequence; Anemia, Hemolytic; Animals; Animals, Inbred Strains; Base Sequence; Cell Line; Conserved Sequence; DNA, Complementary; Erythropoiesis; Erythropoietin; Hepatocytes; Humans; Lung; Male; Mice; Molecular Sequence Data; Organ Specificity; Phenylhydrazines; Receptors, Erythropoietin; Recombinant Fusion Proteins; RNA, Messenger; Sequence Alignment; Sequence Homology, Amino Acid; Structure-Activity Relationship; Xenopus laevis; Xenopus Proteins

The combination therapy of antiviral peg-interferon and ribavirin has evolved as one of the better treatments for hepatitis C. In spite of its success in controlling hepatitis C infection, it has also been associated with treatment-related adverse side effects. The most common and life threatening among them is hemolytic anemia, necessitating dose reduction or therapy cessation. The presence of this side effect leads to a trade-off between continuing the treatment and exacerbating the side effects versus decreasing dosage to relieve severe side effects while allowing the disease to progress. The drug epoietin (epoetin) is often administered to stimulate the production of red blood cells (RBC) in the bone marrow, in order to allow treatment without anemia. This paper uses mathematical models to study the effect of combination therapy in light of anemia. In order to achieve this we introduce RBC concentration and amount of drug in the body as state variables in the usual immunological virus infection model. Analysis of this model provides a quantification of the amount of drug a body can tolerate without succumbing to hemolytic anemia. Indirect estimation of parameters allow us to calculate the necessary increment in RBC production to be > or =2.3 times the patient's original RBC production rate to sustain the entire course of treatment without encountering anemia in a sensitive patient.

Topics: Anemia, Hemolytic; Antiviral Agents; Computer Simulation; Drug Therapy, Combination; Erythropoietin; Hepacivirus; Hepatitis C, Chronic; Humans; Interferons; Models, Biological; Recombinant Proteins; Ribavirin

Haemolytic anaemia is a well-recognised but rare complication of heart-valve prostheses. The authors report a case of an 80-year-old woman with severe haemolytic anaemia previously treated with valvuloplasty and annuloplasty without rings. To our knowledge, no cases of haemolysis have been described with this type of surgery.

Topics: Aged, 80 and over; Anemia, Hemolytic; Atrial Fibrillation; Diagnosis, Differential; Echocardiography; Echocardiography, Transesophageal; Erythrocyte Indices; Erythrocyte Transfusion; Erythropoietin; Female; Hematocrit; Hemoglobinometry; Humans; Mitral Valve Annuloplasty; Mitral Valve Insufficiency; Postoperative Complications; Psychotic Disorders; Recombinant Proteins; Respiratory Insufficiency; Suture Techniques; Ultrasonography, Doppler, Color

The adult erythron is maintained via dynamic modulation of erythroblast survival potentials. Toward identifying novel regulators of this process, murine splenic erythroblasts at 3 developmental stages were prepared, purified and profiled. Stage-to-stage modulated genes were then functionally categorized, with a focus on apoptotic factors. In parallel with BCL-X and NIX, death-associated protein kinase-2 (DAPK2) was substantially up-modulated during late erythropoiesis. Among hematopoietic lineages, DAPK2 was expressed predominantly in erythroid cells. In a Gata1-IE3.9int-DAPK2 transgenic mouse model, effects on steady-state reticulocyte and red blood cell (RBC) levels were limited. During hemolytic anemia, however, erythropoiesis was markedly deficient. Ex vivo ana-lyses revealed heightened apoptosis due to DAPK2 at a Kit(-)CD71(high)Ter119(-) stage, together with a subsequent multifold defect in late-stage Kit(-)CD71(high)Ter119(+) cell formation. In UT7epo cells, siRNA knock-down of DAPK2 enhanced survival due to cytokine withdrawal, and DAPK2's phosphorylation and kinase activity also were erythropoietin (EPO)-modulated. DAPK2 therefore comprises a new candidate attenuator of stress erythropoiesis.

Topics: Anemia, Hemolytic; Animals; Apoptosis Regulatory Proteins; Calcium-Calmodulin-Dependent Protein Kinases; Cell Lineage; Death-Associated Protein Kinases; Erythroblasts; Erythropoiesis; Erythropoietin; Hemostasis; Mice; Mice, Transgenic; Phosphorylation; Spleen; Up-Regulation

Topics: Aged, 80 and over; Anemia, Hemolytic; Dapsone; Darbepoetin alfa; Dose-Response Relationship, Drug; Erythropoietin; Hematinics; Hemolysis; Humans; Immunosuppressive Agents; Male

Topics: Aged, 80 and over; Anemia, Hemolytic; Dapsone; Darbepoetin alfa; Dose-Response Relationship, Drug; Erythropoietin; Hematinics; Humans; Immunosuppressive Agents; Male

Hepcidin, a key regulator of iron metabolism, decreases intestinal absorption of iron and its release from macrophages. Iron, anemia, hypoxia, and inflammation were reported to influence hepcidin expression. To investigate regulation of the expression of hepcidin and other iron-related genes, we manipulated erythropoietic activity in mice. Erythropoiesis was inhibited by irradiation or posttransfusion polycythemia and stimulated by phenylhydrazine administration and erythropoietin. Gene expression of hepcidin and other iron-related genes (hemojuvelin, DMT1, ferroportin, transferrin receptors, ferritin) in the liver was measured by the real-time polymerase chain reaction. Hepcidin expression increased despite severe anemia when hematopoiesis was inhibited by irradiation. Suppression of erythropoiesis by posttransfusion polycythemia or irradiation also increased hepcidin mRNA levels. Compensated hemolysis induced by repeated phenylhydrazine administration did not change hepcidin expression. The decrease caused by exogenous erythropoeitin was blocked by postirradiation bone marrow suppression. The hemolysis and anemia decrease hepcidin expression only when erythropoiesis is functional; on the other hand, if erythropoiesis is blocked, even severe anemia does not lead to a decrease of hepcidin expression, which is indeed increased. We propose that hepcidin is exclusively sensitive to iron utilization for erythropoiesis and hepatocyte iron balance, and these changes are not sensed by other genes involved in the control of iron metabolism in the liver.

Topics: Anemia, Hemolytic; Animals; Antimicrobial Cationic Peptides; Cation Transport Proteins; Erythropoiesis; Erythropoietin; Ferritins; Gamma Rays; Gene Expression Regulation; GPI-Linked Proteins; Hemochromatosis Protein; Hemolysis; Hepcidins; Iron Compounds; Liver; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Phenylhydrazines; Polycythemia; Receptors, Transferrin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors

Treating anemia associated with chemotherapy and many cancers is often necessary. However, patient satisfaction with anemia treatment is limited by the lack of validated instruments. We developed and validated a new treatment-specific patient satisfaction instrument: the Patient Satisfaction Questionnaire for Anemia Treatment (PSQ-An). Treatment burden and overall satisfaction scales were designed for ease of use in clinical practice.. 312 cancer patients (141 breast, 69 gynecological, and 102 non-small cell lung) were targeted to complete the PSQ-An at 4 week intervals. Data from weeks 5 and 9 were analyzed. Patients also completed the MOS SF-36 Global Health assessment and questions concerning resources devoted to anemia treatment. Item reduction used endorsement rates, floor/ceiling effects, and item-item correlations. Factor analysis identified meaningful subscales. Test-retest reliability was assessed. Construct validity was tested, using Pearson's correlations, by comparing subscale scores to Global Health, hemoglobin levels, and resources devoted to anemia treatment.. The overall response rate was 92.9% (264/284) at week 5. Most (84.2%) of the patients were female, and the mean (SD) age was 60.2 (+/- 11.8) years. Two distinct subscales were identified measuring treatment burden (7 items) and overall satisfaction (2 items). Test-retest reliability was examined (ICC: 0.45-0.67); both were internally consistent (alpha = 0.83). Both subscales exhibited convergent and divergent validity with independent measures of health. ANOVA results indicated that the PSQ-An Satisfaction subscale discriminated between 5 levels of MOS SF-36 Global Health (P = 0.006).. The PSQ-An is a validated, treatment-specific instrument for measuring satisfaction with anemia treatment for cancer patients. PSQ-An subscales reflect the burden of injection anemia treatment on cancer patients and their assessment of the overall treatment value.

Topics: Aged; Anemia, Hemolytic; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Factor Analysis, Statistical; Female; Genital Neoplasms, Female; Hematinics; Humans; Karnofsky Performance Status; Male; Middle Aged; Multicenter Studies as Topic; Outcome Assessment, Health Care; Patient Satisfaction; Psychometrics; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Surveys and Questionnaires

Few observational studies have evaluated the use of epoetin alfa (EPO) and darbepoetin alfa (DARB) in chronic kidney disease (CKD) patients with anemia. The objective of this study was to investigate dosing patterns, hematologic outcomes, and intervention costs with EPO and DARB in anemic CKD patients treated in an ambulatory care setting.. This was a multicenter, retrospective, chart review of predialysis CKD patients with anemia treated with EPO or DARB. Charts were sequentially selected from 435 EPO and 432 DARB patients naive to erythropoietic therapy and treated for > or = 24 weeks. Hemoglobin (Hb) levels, dates, and EPO/DARB doses were recorded. Drug costs using 2005 wholesale acquisition costs (WAC) and Federal Supply Schedule (FSS) pricing were based on the mean cumulative drug dose over the 24-week study period.. A total of 393 EPO and 396 DARB charts met all criteria with predominantly male subjects (EPO: 94%; DARB: 96%). Mean baseline GFR and Hb levels were similar. Once-weekly and extended dosing (> or = Q2W) was common in both groups. At Weeks 4, 8, and 12 following initiation of therapy, a greater proportion of EPO than DARB patients reached target Hb levels (> or = 11 g/dL) (p < 0.0001); at Week 24, all patients reached target Hb levels. Mean 24-week cumulative doses were EPO 279 336 +/- 68 302 units and DARB 1084 +/- 246 microg. Drug cost was higher for DARB independent of pricing utilized (WAC: EPO = 3400 US dollars, DARB = 4726 US dollars; FSS: EPO = 1528 US dollars, DARB = 2379 US dollars).. Extended dosing (Q2W) was common in EPO- and DARB-treated patients with CKD-related anemia, with EPO-treated patients experiencing a significantly greater hematologic response (at Weeks 4, 8, and 12). In addition, drug cost was 39-56% higher in the DARB group. The male predominance may limit generalizability, warranting further research in other populations.

Topics: Anemia, Hemolytic; Darbepoetin alfa; Disease Progression; Dose-Response Relationship, Drug; Drug Costs; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Retrospective Studies; Time Factors; Treatment Outcome

The management of a pregnant woman with the rare Ko phenotype and anti-Ku is a special challenge, because matched blood is extremely rare and the possibility of severe hemolytic disease of the newborn is high.. A 30-year-old woman with rare Ko (Knull) phenotype presented at 18 weeks of gestation with positive indirect agglutination test results. She had anti-Ku due to previous blood transfusion, one pregnancy, and two abortions.. During this pregnancy, anti-Ku titers ranged from 1024 to 4096. At the 26th week of gestation ultrasound showed a hydropic fetus and urgent intrauterine exchange transfusion was performed with the maternal red blood cells (RBCs). Recombinant human erythropoietin (rHu-EPO) and intravenous (IV) iron were administered to the mother to ensure an adequate supply of matched RBCs for intrauterine transfusions and possible perinatal hemorrhage.. Intrauterine transfusions were repeated every 1 to 3 weeks. By 35 weeks 2 days of gestation, the mother had donated 4 units of blood, and four intrauterine transfusions had been performed. Cesarean section was then decided and a healthy male newborn was born. He was treated with phototherapy but without exchange transfusions. By the 15th day of life rHu-EPO was administrated to the newborn because of anemia. The maternal RBCs completely disappeared from the child's blood by Day 100.. As shown in this case, treatment with rHu-EPO and IV Fe has effectively increased the mother's capacity to donate RBCs for autologous use and intrauterine transfusions, with no adverse effects to the mother or the child.

Topics: Adult; Anemia, Hemolytic; Antigens, Nuclear; Blood Donors; Blood Transfusion, Intrauterine; Cesarean Section; DNA-Binding Proteins; Erythroblastosis, Fetal; Erythropoietin; Female; Humans; Infant, Newborn; Isoantibodies; Kell Blood-Group System; Ku Autoantigen; Male; Pregnancy; Recombinant Proteins; Severity of Illness Index

We report a 3-year-old boy with glutathione synthetase deficiency, who in the newborn period developed severe persistent haemolytic anaemia. Treatment with erythropoietin was introduced with good clinical and haematological response.

Topics: Anemia, Hemolytic; Child, Preschool; Erythrocytes; Erythropoietin; Fibroblasts; Gas Chromatography-Mass Spectrometry; Glutathione Synthase; Heterozygote; Humans; Male; Mass Spectrometry; Metabolism, Inborn Errors; Oxidants; Pyrrolidonecarboxylic Acid

Peroxiredoxins (Prxs) are a family of antioxidant proteins that reduce peroxide levels by using reducing agents such as thioredoxin. These proteins were characterized to have a number of cellular functions, including cell proliferation and differentiation and protection of specific proteins from oxidative damage. However, the physiological roles of the peroxiredoxins have not been determined. To clarify the physiological relevance of this protein type, we generated a mouse model deficient in Prx II, which is abundantly expressed in all types of cells. The Prx II-/- mice were healthy in appearance and fertile. However, they had splenomegaly caused by the congestion of red pulp with hemosiderin accumulation. Heinz bodies were detected in their peripheral blood, and morphologically abnormal cells were elevated in the dense red blood cell (RBC) fractions, which contained markedly higher levels of reactive oxygen species (ROS). The Prx II-/- mice had significantly decreased hematocrit levels, but increased reticulocyte counts and erythropoietin levels, indicative of a compensatory action to maintain hematologic homeostasis in the mice. In addition, a labeling experiment with the thiol-modifying reagent biotinylated iodoacetamide (BIAM) in Prx II-/- mice revealed that a variety of RBC proteins were highly oxidized. Our results suggest that Prx II-/- mice have hemolytic anemia and that Prx II plays a major role in protecting RBCs from oxidative stress in mice.

Topics: Anemia, Hemolytic; Animals; Blood Proteins; Erythrocyte Aging; Erythrocytes; Erythropoiesis; Erythropoietin; Heinz Bodies; Hematocrit; Hemosiderin; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxidative Stress; Peroxidases; Peroxiredoxin III; Peroxiredoxins; Reactive Oxygen Species; Reticulocyte Count; Splenomegaly

Ribavirin administration for chronic hepatitis C is associated with the development of haemolytic anaemia, which affects treatment efficacy and tolerability. In a pilot study, the exogenous administration of erythropoietin has been shown to be beneficial, reducing the rate of ribavirin dose reduction. How ribavirin administration affects normal erythropoietin production has not been determined.. To investigate the endogenous erythropoietin response in hepatitis C patients with ribavirin-induced anaemia.. Serum erythropoietin was measured before and during interferon-ribavirin treatment in 18 HCV-positive subjects. Mathematical analysis and modelling were applied to compare the degree of erythropoietin increase in HCV-positive and in otherwise healthy anaemic patients, and estimate the endogenous excess erythropoietin production in response to ribavirin-induced anaemia.. Erythropoietin concentration increased significantly in response to anaemia caused by ribavirin. The physiological erythropoietin response to the ribavirin-induced anaemia was as adequate in HCV-positive subjects as it is in anaemic subjects without liver disease. The recommended exogenous erythropoietin dose appears three-times greater than the endogenous erythropoietin boost.. Chronic liver damage by HCV does not affect the physiological erythropoietin response to ribavirin-induced anaemia. While the rationale for erythropoietin treatment of ribavirin-induced anaemia is not straightforward, the currently recommended dosing regimen should be reassessed.

Topics: Adult; Aged; Anemia, Hemolytic; Antiviral Agents; Drug Therapy, Combination; Erythropoietin; Female; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Male; Middle Aged; Models, Biological; Recombinant Proteins; Ribavirin

Topics: Anemia, Hemolytic; Erythropoietin; Female; Hepatitis C, Chronic; Humans; Male; Prognosis; Ribavirin; Treatment Outcome

Serum soluble transferrin receptor (sTfR) has been reported to be higher in patients with iron deficiency or with elevated erythropoiesis. In the present study, serum sTfR was measured in various anemic diseases and their clinical significance was examined in a multi-institutional joint study. Serum sTfRs in patients with the following anemic diseases were markedly higher than those in normal healthy adults: non-treated iron deficiency anemia (IDA) (9.13 +/- 7.04 mg/l, n = 52, p < 0.0001), anemia of chronic disorders (ACD) (3.45 +/- 1.38 mg/l, n = 20, p < 0.0001), hemolytic anemia (HA) (5.57 +/- 3.26 mg/l, n = 17, p < 0.0001), and myelodysplastic syndrome (MDS) (4.03 +/- 2.83 mg/l, n = 20, p < 0.0001). There were significant differences between IDA and ACD (p < 0.0001), between aplastic anemia (AA) (1.58 +/- 1.26 mg/l, n = 16) and MDS (p < 0.001), and between AA and MDS with refractory anemia (MDS-RA) (4.16 +/- 3.40 mg/l, n = 9) (p < 0.02). In patients with chronic renal failure (CRF), serum sTfR levels and serum sTfR/log serum ferritin ratios (sTfR/F index) were compared in the two classified groups according to Muirhead's criteria, as IDA and non-IDA groups with or without recombinant human erythropoietin (rHuEPO) treatment. Significantly high levels of both serum sTfR (p < 0.0001) and the sTfR/F index (p < 0.0001) were observed in IDA without rHuEPO treatment. Especially in CRF with rHuEPO treatment, the sTfR/F index showed marked elevation in the IDA group (p < 0.0001) compared with serum sTfR (p < 0.001), indicating more diagnostic efficacy of the sTfR/F index for CRF with IDA. In conclusion, the serum sTfR concentration is a useful diagnostic tool for discrimination between IDA and ACD, and between AA and MDS-RA, and for the detection of iron deficiency in CRF patients in the Japanese population.

Topics: Adult; Age Factors; Anemia; Anemia, Hemolytic; Anemia, Iron-Deficiency; Erythropoietin; Female; Ferritins; Humans; Japan; Male; Middle Aged; Myelodysplastic Syndromes; Reagent Kits, Diagnostic; Receptors, Transferrin; Recombinant Proteins; Renal Insufficiency; Sex Factors; Solubility

The study was designed to examine the impact of anemia on the antitumor efficacy of photodynamic therapy (PDT) in a murine colon-26 adenocarcinoma model syngeneic with BALB/c mice.. Acute hemolytic anemia was induced by a single i.p. injection of phenylhydrazine hydrochloride (150 mg/kg). Anemia induced by i.p. administration of carboplatin (100 mg/kg) was corrected by s.c. treatment with recombinant human erythropoietin (1000 units/kg/day). The effectiveness of PDT (10 mg/kg Photofrin, 150 J/cm2 laser dose) was evaluated by measurements of the footpad edema and tumor volume. All of the RBC-related parameters were measured from the tail vein.. Phenylhydrazine hydrochloride injection resulted in a blunted response of normal tissues to Photofrin-mediated PDT-induced edema formation. Similarly, the antitumor response in mice with hemolytic anemia was nearly completely abrogated. The antitumor effectiveness of PDT was also significantly diminished in a more realistic clinical situation when anemia was induced by administration of carboplatin. Importantly, administration of recombinant human erythropoietin completely restored the sensitivity of the tumor to PDT in carboplatin-treated mice.. These results indicate that anemia can negatively influence the therapeutic effectiveness of PDT. For optimal antitumor response anemia should be corrected before PDT procedure.

Topics: Acute Disease; Anemia; Anemia, Hemolytic; Animals; Antineoplastic Agents; Carboplatin; Disease Models, Animal; Erythropoietin; Humans; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Neoplasms, Experimental; Phenylhydrazines; Photochemotherapy; Recombinant Proteins; Tumor Cells, Cultured

Two patients are reported with hemolytic anemia due to red blood cell fragmentation in association with prosthetic heart vales. They were treated with erythropoietin which eliminated the need for packed red blood cell transfusion.

Topics: Aged; Anemia, Hemolytic; Erythropoietin; Female; Heart Valve Prosthesis; Hematocrit; Hemoglobins; Humans; Male; Mitral Valve; Recombinant Proteins; Reticulocyte Count

Topics: Anemia, Hemolytic; Antineoplastic Agents; Bone Marrow Purging; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Humans; Incidence; Neoplasms; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Assessment; Treatment Outcome

We analyse an age-structured model for haematopoiesis, describing the development of specialized cells in the blood from undifferentiated stem cells and including the controlling effects of hormones. Variation in the length of time for maturing of precursor cells in this model has a stabilizing influence. When the maturing process does not vary, then the age-structured model reduces to a delay differential equation. Depending on the death process considered, either a differential equation with two time delays or a differential equation with a state-dependent delay is obtained. Each of these is analysed in turn, for its linear stability. A sensitivity analysis of the parameters in this model shows which biochemical processes in the negative feedback most strongly affect the solutions.

Topics: Anemia, Hemolytic; Animals; Cell Differentiation; Erythropoietin; Feedback; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoiesis; Humans; Male; Models, Biological; Rabbits; Thrombopoietin

Topics: Anemia, Hemolytic; Erythrocyte Count; Erythrocyte Volume; Erythrocytes; Erythropoietin; Humans; Iron; Kidney Failure, Chronic; Peritoneal Dialysis; Recombinant Proteins; Transferrin

Serum erythropoietin (Epo) and soluble transferrin receptor (sTR) were measured in a locally defined reference population (n=100): healthy volunteers (n=50); iron- deficiency anaemia (n=41) and haemolytic anaemia (n=9) (beta-thalassaemia, n = 4; autoimmune, n=5). Our data demonstrated an inverse relationship between erythroid activity and Epo levels. The regression line between Ln Epo and haemoglobin (Hb) was highly significant: P < 0.0001, r2=0.8275, Ln Epo=8.5346-0.04275 Hb, confidence limit 95%. The mean observed/predicted (O/P) ratio of Ln (Epo) was 1.01 +/- 0.11. We demonstrated that the serum Epo concentration in this particular population correlated consistently with clinical measures of erythropoietic activity. sTR, a new index of erythropoiesis, varied from 16.1 to 148 nmol/l, mean 62.0 nmol/l in the anaemic patients' group. The relationship between Ln Epo and Ln sTR was highly significant: P < 0.0001. We conclude that locally defined regression analyses are crucial for correct data interpretation and can indicate whether or not Epo production is appropriate or inappropriate. Serial determinations of sTR could help in the assessment of response to therapeutic doses of Epo.

Topics: Adolescent; Adult; Aged; Anemia; Anemia, Hemolytic; Anemia, Iron-Deficiency; beta-Thalassemia; Erythropoietin; Female; Hemoglobins; Humans; Linear Models; Male; Middle Aged; Predictive Value of Tests; Receptors, Transferrin; Solubility

Serum erythropoietin (EPO) concentrations reportedly are depressed in patients with chronic disorders such as cancer, rheumatoid arthritis, and acquired immunodeficiency syndrome. We evaluated serum EPO levels in mice with tumors and found that the EPO response was appropriate for the associated anemia during the major part of the disease process. The levels of the hormone increased as the anemia worsened in association with progression of the disease. The increased EPO levels were comparable to those of controls with a similar degree of experimentally induced anemia. Only during the terminal stages of cancer, when the animals were severely cachectic, were serum EPO concentrations lower than in controls with a similar degree of anemia. These findings suggest that a blunted EPO response in experimental cancer occurs only in association with advanced disease.

Topics: Anemia, Hemolytic; Animals; Erythropoietin; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Tumor Necrosis Factor-alpha

Aqueous anemic mice kidney extracts (MKE) were assessed colony-promoting activity (CPA) of hematopoietic progenitor cells in serum-free cultures stimulated by interleukin-3 and erythropoietin (Epo). Mice with hemolytic anemia followed by phenylhydorazine (PHZ) injection for 3 days showed a decrease in the hematocrit (25.4%) and an increase in serum Epo by 14-fold of the control on day 3 after the treatment. At 3 days, the total number of hematopoietic progenitor cells in the bone marrow of PHZ mice decreased by 67% of the control, while these cells in the spleen increased to 22-fold of the control on day 3 and 55-fold on day 6. A significant increase in CPA was observed in MKE prepared from PHZ mice kidneys. Additionally, bone marrow suppressive anemia induced by 5-fluorouracil resulted in enhanced CPA the same as for PHZ mice, but in contrast, anemia with suppression of Epo-production due to nephrotoxicity induced by cisplatin caused a decrease in CPA. These results suggest that CPA in MKE correlates with hematopoietic conditions, and may have a definite role in hematopoiesis through the function of the kidney.

Topics: Anemia, Hemolytic; Animals; Erythropoietin; Hematocrit; Hematopoiesis; Hematopoietic Stem Cells; Kidney; Male; Mice; Phenylhydrazines; Spleen

An increase in the number of erythroblasts can be seen to some extent in the bone marrow of rats in the early stage of experimentally induced hemolytic anemia prior to any elevation in the plasma erythropoietin (Epo) level. This observation suggests that there is another erythroid stimulating factor present other than Epo. We studied the enhancing effect of serum, taken sequentially during experimentally induced hemolysis in rats, on erythroid proliferation, differentiation and maturation in vitro. Single intraperitoneal injection of 60 mg/kg of acetylphenylhydrazine (APH) induced self-limited hemolytic anemia in rats, in which the hematocrit dropped rapidly with a nadir at day 4 after APH injection, followed by a gradual increase with return to normal level by day 8. Serum obtained consecutively every day after APH injection from day 1 to day 7 was applied to an in vitro culturing system of erythroid progenitors. Addition of day 1 serum, in which an elevation of Epo level had not occurred, to a conventional methyl-cellulose culture of rat bone marrow mononuclear cells (BM-MNCs) resulted in a significant increase in the number of colonies derived from colony forming unit erythroid, but not in burst forming unit erythroid. This erythropoietic activity of the serum was particularly evident in the presence of Epo. In the liquid culture of BM-MNCs, day 1 serum also showed some enhancing effect on erythroblast formation. We were able to see significant differences in these erythroid enhancing activities induced by serum drawn on day 1 in comparison to the serum drawn on subsequent days. These results suggest that an unknown erythroid enhancing factor besides Epo stimulates erythropoiesis in the early stage of hemolytic anemia or sudden hypoxia before there is a measurable rise in the serum Epo level. We propose that this factor be termed erythroid accelerating factor (EAF).

Topics: Anemia, Hemolytic; Animals; Bone Marrow Cells; Cells, Cultured; Colony-Stimulating Factors; Erythroblasts; Erythrocytes; Erythropoiesis; Erythropoietin; Hematocrit; Phenylhydrazines; Rats; Rats, Wistar

Topics: Anemia, Hemolytic; Critical Illness; Erythropoietin; Humans

Critically ill patients often develop anaemia which can be related to a number of factors. However, the exact causes of anaemia in many patients remain unexplained. We hypothesized that the relationship between erythropoietin (EPO) and haematocrit may be altered in critically ill patients.. Serum concentrations of EPO were serially determined by the ELISA method in 36 critically ill, non-hypoxaemic patients who stayed more than 7 days in the Intensive Care Unit, including 22 patients with sepsis and 14 without. Eighteen ambulatory patients with iron-deficiency anaemia served as a control group.. Two University Hospital Intensive Care Departments.. A significant inverse correlation between serum EPO and haematocrit levels was found in the control patients (r = -0.81, p < 0.001), but not in the critically ill patients (r = -0.09, NS), except in a subgroup of non-septic patients without renal failure (r = -0.61, p < 0.01).. EPO levels can be inappropriately low in critically ill patients, so that EPO deficiency may contribute to the development of anaemia in these patients. This phenomenon is observed not only in the presence of acute renal failure, but also in the presence of sepsis.

Topics: Acute Kidney Injury; Aged; Anemia, Hemolytic; Anemia, Iron-Deficiency; Case-Control Studies; Critical Illness; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Hematocrit; Humans; Intensive Care Units; Male; Middle Aged; Regression Analysis; Respiratory Distress Syndrome; Sepsis

A new 'tissue-stamp culture' method was developed for stamping proliferating erythroblasts of mouse spleens on collagen-coated coverslips after inducing haemolytic anaemia by administration of 1-acetyl-2-phenylhydrazine, and then adherent splenic cells were cultured for a few days. We could obtain many erythroblastic islands, where cultured erythroblasts were located over macrophages and were proliferated synchronously for 10-30 h, and then the erythroblasts were differentiated and enucleated after 30-50 h in the presence of erythropoietin. To observe three-dimensional structures of the erythroblastic islands, a scanning electron microscope was used for the cultured cells treated with critical point-drying method. Immature wrinkled erythroblasts with many micropinocytic pits were attached to the central area of the flattened macrophages with many cytoplasmic projections, though matured erythroblasts were localized on their peripheral areas. Moreover, cytoplasmic projections of underlying macrophages, which were attached to the matured erythroblasts, were decreased in number. At a late stage, deep cytoplasmic invaginations of erythroblasts observed at a middle stage became shallow after their enucleation and flattened to form their concave shapes. This 'tissue-stamp culture' system would be useful for studying specific interaction between stromal macrophages and haematopoietic cells.

Topics: Anemia, Hemolytic; Animals; Cell Culture Techniques; Cell Nucleus; Cells, Cultured; Erythroblasts; Erythrocyte Membrane; Erythropoietin; Female; Hematopoiesis; Macrophages; Mice; Mice, Inbred BALB C; Phenylhydrazines; Spleen

Topics: Anemia, Hemolytic; Erythropoietin; Female; Humans; Hypertension; Kidney Failure, Chronic; Middle Aged; Renal Dialysis

Topics: Aged; Aged, 80 and over; Anemia, Hemolytic; Erythropoietin; Female; Humans; Male; Recombinant Proteins

Serum erythropoietin (EPO) and soluble transferrin receptor levels were serially measured in 74 patients with aplastic anaemia (AA). As control groups we investigated healthy controls (n = 24) and patients with iron-deficiency (n = 23) or haemolytic anaemia (n = 16). There was a significant negative correlation of log EPO on haematocrit both in AA patients and in the anaemic control group. However, for the same degree of anaemia, log EPO levels in AA were significantly higher than in iron-deficiency or haemolytic anaemia. EPO levels at diagnosis did not correlate with severity of aplastic anaemia, nor did they predict outcome after immunosuppression. During immunosuppressive treatment of AA with anti-thymocyte globulin and cyclosporine A, EPO levels were significantly lower compared with pre-treatment values without a corresponding change in haematocrit. This impaired EPO response to anaemia during immunosuppression might affect recovery of erythropoiesis. In AA patients, EPO levels declined with haemopoietic recovery. However, compared with normal controls, EPO levels in remission patients were still higher with respect to their haematocrit. Results of this study argue against the model of a simple feedback regulation of EPO via hypoxic anaemia. Our data support the hypothesis that cytokines and the erythropoietic progenitor pool are involved in the regulation of EPO production. The results illustrate that serial measurements of EPO along with therapeutic interventions are necessary to identify patients who might benefit from treatment with exogenous recombinant human EPO.

Topics: Adolescent; Adult; Age Factors; Aged; Anemia, Aplastic; Anemia, Hemolytic; Anemia, Iron-Deficiency; Biomarkers; Erythropoietin; Female; Follow-Up Studies; Hematocrit; Humans; Immunosuppression Therapy; Male; Middle Aged; Receptors, Transferrin; Sex Factors; Treatment Outcome

Iron overload has been reported with pyruvate kinase deficiency. Erythropoietin (EPO) may lead to iron deficiency; thus, patients who are unable to be phlebotomized due to anemia may benefit from EPO as a treatment of iron overload.

Topics: Adult; Anemia, Hemolytic; Erythropoietin; Female; Humans; Iron; Pyruvate Kinase

Because of inadequate renal synthesis of erythropoietin, the anemia associated with chronic renal failure has been treated successfully in most patients on hemodialysis with recombinant human erythropoietin. Hemolysis due to anti-Nform antibody in dialysis patients with the reused dialyzer may be one of the factors that cause refractoriness to erythropoietin therapy. Patients who do not respond to erythropoietin administration should be screened for anti-Nform antibody.

Topics: Anemia; Anemia, Hemolytic; Erythropoietin; Female; Formaldehyde; Humans; Kidney Failure, Chronic; Kidneys, Artificial; Middle Aged; MNSs Blood-Group System; Recombinant Proteins; Renal Dialysis

Zinc metabolism and metallothionein induction in rat bone marrow were investigated during induced erythropoiesis. Redistribution of body zinc was measured with 65Zn after acute blood loss in rats fed zinc-restricted or zinc-adequate diets. Uptake of 65Zn by bone marrow was related to time after blood loss, metallothionein induction, and dietary zinc status. Increased 65Zn uptake by marrow of zinc-restricted rats suggests a minimal amount of zinc is necessary to support expansion of the erythrocytic compartment. Zinc induction of marrow metallothionein also occurred in rats in which anemia was produced using phenylhydrazine. Anemic rats which were administered zinc had higher concentrations of marrow metallothionein compared with control rats. Induction of marrow metallothionein by zinc in nonanemic rats required prior treatment with erythropoietin. Percoll fractionation showed marrow metallothionein was most abundant in erythroblasts. These experiments suggest metallothionein synthesis occurs in erythropoietin-sensitive precursor cells in the marrow in response to increased zinc accessibility.

Topics: Anemia, Hemolytic; Animals; Biological Transport; Bone Marrow; Erythropoiesis; Erythropoietin; Hematocrit; Hematopoietic Stem Cells; Humans; Liver; Male; Metallothionein; Phenylhydrazines; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Spleen; Zinc

Serum erythropoietin (EP) concentration was measured by the recombinant EP-based radioimmunoassay and was examined to standardize the hemoglobin (Hb) related level of 144 normal control and 56 patients with iron deficiency anemia and hemolytic anemia excluding paroxysmal nocturnal hemoglobinuria. The standardization was achieved by logarithmic regression of the EP titier on Hb either by the two-phase linear form or by the third degree sigmoid form at a 95% confidence limit for each regression. The third degree regression was found to be preferable from the view point of both statistics and the negative feedback mechanism. The average and scattering of the deviation from the standard level thus determined of the disease groups indicated that the EP level is: (1) 12 fold higher than the standard level in 42 aplastic anemias (the most in excess and a few in standard). (2) three fold higher than that in 27 myelodysplastic syndromes (relatively higher dispersed state). (3) 29% of the standard level in 33 anemias associated with chronic renal failure (deficient state). (4) 105% of the extrapolated standard level in 22 polycythemia veras (standard state). The standardization of Hb-related Ep titer may provide new pathophysiological approaches in a variety of hematopoietic disorders.

Topics: Anemia, Hemolytic; Anemia, Hypochromic; Erythropoietin; Hemoglobins; Humans; Myelodysplastic Syndromes; Polycythemia Vera; Radioimmunoassay; Reference Standards

Topics: Adrenergic beta-Antagonists; Anemia, Hemolytic; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Diuretics; Erythropoietin; Humans; Hypertension, Renal; Kidney Failure, Chronic; Renal Dialysis; Sympatholytics

Infants with Rh hemolytic disease can develop a "late" anemia characterized by low serum concentrations of erythropoietin but erythroid progenitors that remain highly erythropoietin-responsive. Erythropoietin administration was evaluated in two patients as an alternative to transfusion. Reticulocyte counts increased after 5 days of treatment, and hematocrits increased after 10 days. Neither patient received erythrocyte transfusions following erythropoietin therapy.

Topics: Anemia, Hemolytic; Bone Marrow Examination; Erythropoietin; Humans; Infant; Male; Recombinant Proteins; Rh Isoimmunization

Erythropoietin has been proved extremely effective in ameliorating the anemia of chronic renal failure and is currently under intensive investigation. We describe a patient with severe anemia and secondary hemochromatosis due to prosthetic valves, who has been successfully treated with erythropoietin. During 12 months' follow-up, an acceptable hemoglobin level was maintained without any need for blood transfusions; in addition, there was evidence indicating regression of hemochromatosis. This patient illustrates that erythropoietin therapy might prove beneficial for similar cases.

Topics: Anemia, Hemolytic; Aortic Valve; Blood Transfusion; Erythropoietin; Female; Heart Valve Prosthesis; Hemochromatosis; Humans; Middle Aged; Mitral Valve

Immunohistochemically detectable erythropoietin-like substance(Epo) in granular convoluted tubule(GCT) cells of submandibular glands (SMG's) was examined in mice in which hemolytic anemia had been induced by phenylhydrazine (ph), and in mice subjected to hypoxia, nephrectomy, or testosterone (TP) injections. Staining for Epo was negative in GCT cells of SMG's in normal mice, while positive staining occurred in GCT cells of the anemic mice and mice subjected to hypoxia or nephrectomy. A positive Epo reaction was also revealed at the luminal borders of distal tubules, and in cells of proximal and distal tubules in the kidney, and in some hepatic and spleen cells, of mice that had received combination regimens producing anemia and hypoxia, or had been nephrectomized. Increased staining of Epo was found in GCT cells of SMG's, and in proximal and distal kidney tubules of mice given the combination treatment plus TP injections. The detection of Epo in GCT cells suggests these extrarenal cells to be sites of accumulation or biosynthesis of the protein under certain specific conditions such as hemolytic anemia and hypoxia.

Topics: Anemia, Hemolytic; Animals; Erythropoietin; Female; Hypoxia; Immunoenzyme Techniques; Male; Mice; Nephrectomy; Submandibular Gland; Testosterone

Topics: Anemia, Hemolytic; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins

Topics: Anemia, Hemolytic; Blood Transfusion; Combined Modality Therapy; Erythrocyte Transfusion; Erythropoietin; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Knowledge of the endogenous blood level of erythropoietin (Epo) has gained recent interest in view of the advances in Epo replacement therapy in anemic patients. By radioimmunoassay, we have carried out comparative measurements of the serum Epo level in patients suffering from chronic enterocolitis or leukemia. In chronic enterocolitis, the Epo level showed an exponential increase with the degree of anemia (up to 250 U Epo/1 serum at 70 g hemoglobin/1 blood). Similarly anemic patients with leukemia and severe bone marrow insufficiency of erythropoiesis had much higher Epo levels (usually above 500 U/1). Our findings indicate that the level of Epo is not only dependent on the blood hemoglobin concentration but also on the type of anemia. In fact, additional in vitro studies showed that immunomodulatory peptides can significantly influence the production of Epo in the hepatoma cell culture HepG2.

Topics: Adult; Anemia, Hemolytic; Carcinoma, Hepatocellular; Enterocolitis; Erythropoietin; Humans; Interferon-gamma; Interleukin-1; Leukemia; Liver Neoplasms; Radioimmunoassay; Recombinant Proteins; Tumor Cells, Cultured

Ten children with renal failure (age range 2 years 6 months to 18 years 9 months; median 11 years 10 months), maintained by long-term hemodialysis, had successful correction of their anemia after intravenous administration of recombinant human erythropoietin in a dosage escalating every 2 weeks (75 to 150 to 300 to 450 IU/kg/wk). Mean hemoglobin concentration increased from 6.4 +/- 0.9 to 11.5 +/- 1.0 gm/dl. Blood cell counts used to evaluate the correction of anemia were done after dialysis; this was especially important for children less compliant with water restriction. The higher hemoglobin concentration resulted in improvement of the quality of life, a greater tolerance for physical effort (exercise tolerance doubled and the ventilatory anaerobic threshold increased significantly), correction of some subclinical central nervous system abnormalities detected by evoked potentials testing, and reduction of bleeding time. Few side effects were noted; severe hypertension developed in one patient when postdialysis hematocrit was only 28%, and there were two episodes of hypertransaminasemia with no other evidence of liver dysfunction. We conclude that in children with renal failure the use of recombinant human erythropoietin to correct anemia is safe and strongly advisable, because of the resolution of many of the symptoms correlated with anemia.

Topics: Adolescent; Anemia, Hemolytic; Blood Coagulation Tests; Child; Child, Preschool; Erythropoietin; Evoked Potentials, Auditory, Brain Stem; Evoked Potentials, Somatosensory; Heart Function Tests; Hematocrit; Humans; Recombinant Proteins; Renal Dialysis; Respiratory Function Tests

The effects of repeated administration of recombinant human erythropoietin (rHuEPO) were investigated in mice with haemolytic anaemia. Mice with haemolytic anaemia induced by phenylhydrazine (PHZ mice) were examined as an acute model and New Zealand black mice (NZB mice) at 13 months of age were examined as a chronic model. The plasma erythropoietin (EPO) level in PHZ mice was high and showed a strong inverse correlation with the Hb in the anaemia development period. However, it was relatively low in the recovery period from anaemia. On the other hand, the plasma EPO level in NZB mice showed a simple inverse correlation with the Hb. The rHuEPO was injected every day for a week into these mice. While a high plasma EPO level was maintained in PHZ mice, no significant effect was observed by injection with rHuEPO at dose of 600 IU/kg. However, in the recovery period from anaemia, RBC and haemoglobin in PHZ mice were increased by the rHuEPO treatment and recovered more quickly to their normal levels. In NZB mice, RBC and haemoglobin were also increased by treatment with rHuEPO at dose of 600 IU/kg. Anti-RBC autoantibodies and anti-EPO antibodies did not increase, while RBC and plasma EPO levels were increased by the rHuEPO treatment. These results suggest that some types of haemolytic anaemia are not always combined with high endogenous EPO levels and that exogenous rHuEPO may be effective for use in the treatment of haemolytic anaemia.

Topics: Acute Disease; Anemia, Hemolytic; Animals; Antibodies; Blood Group Antigens; Chronic Disease; Erythropoietin; Female; Hemoglobins; Male; Mice; Mice, Inbred NZB; Phenylhydrazines; Recombinant Proteins

Topics: Anemia, Hemolytic; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins

An increase in bone marrow blood flow has been previously described in anaemic rabbits and dogs. We examined the effect of haemorrhage and haemolysis in female Sprague-Dawley rats, with the hypothesis that high blood flow was related to hyperplasia of bone marrow tissue and that the increase would affect bone as well. Blood flow was measured in tibia and femur by the microspheres trapping method. Chronic anaemia was accompanied at day 32 by a marked increase (factor of 1.7-1.9) in blood flow to bone marrow and to bone. On the other hand, no increase in blood flow was observed in chronic compensated anaemia, showing that anaemia per se and not stimulation of erythropoiesis was responsible for the increase. We then explored the effect on blood flow of two factors associated with anaemia. Erythropoietin 4 U/d for 4 d failed to induce any increase in bone and marrow blood flow. Systemic hypoxia (76 mmHg for 3 d) reduced the fraction of cardiac output conveyed to bone and marrow by 40-50%, but this decrease was more than compensated by an increase in cardiac output. We conclude that neither erythropoietin nor low tissue pO2 is the direct cause for the increase in bone and marrow blood flow observed in anaemia.

Topics: Anemia; Anemia, Hemolytic; Animals; Bone Marrow; Erythropoietin; Female; Femur; Hematocrit; Oxygen; Partial Pressure; Rats; Rats, Inbred Strains; Regional Blood Flow; Tibia

Human recombinant erythropoietin (r-huEPO) is very effective in the treatment of anemia of hemodialyzed patients. We describe 4 patients who developed symptoms of central nervous dysfunction during r-huEPO therapy. Three exhibited typical hypertensive encephalopathy, whereas signs of cerebral ischemia were found in the fourth. The increase in blood viscosity with r-huEPO treatment, leading to a rise in peripheral vascular resistance and blood pressure especially in previously hypertensive patients, may be of importance in the pathogenesis of these cerebrovascular incidents; preexistent arteriosclerosis is an possible additional risk factor.

Topics: Adult; Aged; Anemia, Hemolytic; Blood Viscosity; Brain Edema; Brain Ischemia; Cerebrovascular Disorders; Erythropoietin; Female; Humans; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Topics: Anemia, Hemolytic; Erythropoiesis; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins

Hemopoiesis was studied in homozygous lactate dehydrogenase (LDH) mutant mice not showing noticeable impairment in viability and fertility but afflicted with a severe hemolytic anemia. In order to investigate the mechanisms of erythropoietic compensation, the numbers of multipotent hemopoietic stem cells (CFU-S), myeloid (GM-CFC), and early and late erythroid progenitors (BFU-E and CFU-E) in femur and spleen were determined, and the total body content of each cell type was computed. While the total CFU-S and GM-CFC numbers showed only slight deviations from normal, the total BFU-E pool was 1.4 and the CFU-E pool 18 times enlarged. No difference in cell cycle status could be detected in these compartments by means of tritiated thymidine (3H-TdR) suicide in vitro. However, splenic erythroblasts of homozygous LDH mutants had a shorter DNA synthesis time and a higher labeling index compared to the wild type mice. It is concluded that the hemolysis is compensated at a lower level of red blood cell count primarily by an increase in the total number of late erythroid progenitors resulting from roughly four extra divisions, and secondarily by an increase in the flux through the recognizable erythroblast compartments, predominantly a space-saving mechanism.

Topics: Anemia, Hemolytic; Animals; Bone Marrow Cells; Cell Cycle; Colony-Forming Units Assay; Erythroblasts; Erythropoiesis; Erythropoietin; Granulocytes; Hematopoietic Stem Cells; Homozygote; Kinetics; L-Lactate Dehydrogenase; Macrophages; Mice; Mice, Mutant Strains; Spleen

Recombinant human erythropoietin (r-huEpo) was administered i.v. to eight anemic patients on hemodialysis in increasing doses 3 times a week. 7 out of 8 patients showed an increase in hemoglobin level by 2 g/dl over the baseline of 7.9 +/- 0.8 g/dl after a mean period of 8 +/- 2 weeks. During treatment a cumulative dose of 692 +/- 358 IU/kgBW erythropoietin was given. Before the rise in hemoglobin, reticulocytes increased from 1.6 +/- 0.7% initially to 5 +/- 1.6%. The serum ferritin concentration decreased from 426 (range 19-1223) to 250 (5-707) micrograms/l. No side effects were observed. Mean blood pressure before dialysis increased slightly from 125 mmHg to 137 mmHg systolic, and diastolic pressure from 75 to 80 mmHg. Maintenance doses to maintain hemoglobin values between 10 und 12 g/dl varied from 2 X 72 IU/kgBW to 3 X 168 IU/kgBW per week. Measurement of serum levels of erythropoietin by radioimmunoassay showed deficiency of the hormone in the patients with chronic renal failure: before treatment mean serum values were 4 +/- 6.4 mU/ml and during maintenance doses with r-huEpo 33.7 +/- 8.1 mU/ml, which is within normal ranges related to hematocrit. These data show erythropoietin to be effective in ameliorating anemia during hemodialysis treatment.

Topics: Adult; Anemia, Hemolytic; Drug Administration Schedule; Erythropoietin; Humans; Middle Aged; Radioimmunoassay; Recombinant Proteins; Renal Dialysis

The B19 parvovirus is responsible for at least three human diseases. The virus was successfully propagated in suspension cultures of human erythroid bone marrow from patients with hemolytic anemias; release of newly synthesized virus into the supernatants of infected cultures was observed. This culture system allowed study at a molecular level of events associated with the B19 life cycle. The B19 parvovirus replicated through high molecular weight intermediate forms, linked through a terminal hairpin structure. B19 replication in vitro was highly dependent on the erythropoietic content of cultures and on addition of the hormone erythropoietin.

Topics: Anemia, Hemolytic; Bone Marrow; Cells, Cultured; Culture Media; DNA, Viral; Erythropoietin; Humans; Parvoviridae; Virus Replication

The origin of metallothionein (MT) in red blood cells (RBCs) from a mouse given cadmium was studied in connection with RBC kinetics. Plasma Cd concentration rapidly decreased 3 hr following 109CdCl2 (2 mg/kg, sc) administration, whereas RBC Cd increased from 2 to 4 days, followed by a gradual decrease. RBC Cd was found to be distributed more in the high-molecular-weight fraction than in the MT fraction 12 hr after administration. But, thereafter, Cd increased rapidly in the MT fraction to show changes with time similar to Cd level in RBCs. Hepatic damage induced in a mouse given 21 injections of Cd, with resultant marked elevation of plasma MT concentrations, did not cause any change in RBC Cd concentration. MT was hardly transferred to RBC when a mouse RBC suspension was incubated with mouse hepatic MT. To examine the relationship of Cd-MT and erythropoietic function, mice in the normal group, the phenylhydrazine-induced anemia group (PH), the transfusion-induced plethora group (TR), and the erythropoietin administered plethora group (TR + EP) were given 109CdCl2. Three days after administration, Cd concentration in its RBCs and its MT fraction remarkably increased in the PH group, and was greatly decreased in the TR group. A significant increase was noted in the TR + EP group as compared with the TR group. These results indicate that MT in the RBCs is formed in erythroblasts.

Topics: Anemia, Hemolytic; Animals; Blood Transfusion; Cadmium; Cadmium Chloride; Chromatography, Gel; Erythrocytes; Erythropoiesis; Erythropoietin; Humans; Male; Metallothionein; Mice; Mice, Inbred Strains; Radioisotopes

Based on extensive own investigations of a great number of pediatric patients with chronic renal failure at the University Children's Hospital of Heidelberg, renal anemia is reviewed. After the demonstration of its clinical importance, its intensity depending on the mode of treatment (conservative therapy, regular dialysis, renal transplantation), and its diagnostic characteristics, an analysis of the three most important pathomechanisms is given: bone marrow hypoplasia, increased hemolysis and chronic blood loss. These pathomechanisms influence each other, are the result of multifactorially acting uremic toxins and can additionally be potentiated by iron-, folate-, and vitamin B12-deficiency. The hematologic mechanisms to compensate renal anemia are insufficient: first the indirect way, because the increase in erythrocyte organic phosphates is insufficient and the shift of the hemoglobin oxygen dissociation curve to the right is inadequate, second the direct way because erythropoietin is secreted inadequately. After description of the diagnostic paramenters for long-term care of renal anemia therapeutic recommendations are given with respect to each stage of treatment.

Topics: Anemia; Anemia, Hemolytic; Anemia, Hypochromic; Blood Transfusion; Bone Marrow; Child; Erythrocyte Indices; Erythropoiesis; Erythropoietin; Ferritins; Hemoglobinometry; Humans; Iron; Kidney Failure, Chronic; Kidney Transplantation; Renal Dialysis

We have compared the response of mice heterozygous for the Slj allele-which have a stromal defect resulting in mild macrocytic anemia-and their normal +/+ littermates to manipulations of the erythron to further characterize the effects of the Slj allele on hemopoiesis. CFU-S kinetics in Slj/+ mice following plethorization or induction of anemia did not differ from similarly treated +/+ littermates. Under all circumstances, however, Slj/+ mice had a smaller splenic CFU-S population than similarly treated +/+ mice. Slj/+ and +/+ mice responded similarly to induction of hemolytic anemia with a large rise in 59Fe incorporation in spleen and blood. Hypertransfused Slj/+ mice were shown to have a diminished response to exogenous erythropoietin in spleen and blood as compared with their +/+ littermates. We conclude that the regulation of CFU-S kinetics in mutant Slj/+ mice is not anomalous as has been reported to be the case in Sl/Sld mice. The defective stromal tissue of Slj/+ mice, however, does not support a normal-sized CFU-S population, which leads to decreased influx of progenitor cells into the erythropoietin-responsive cell compartment, causing the diminished response of plethorized Slj/+ mice to exogenous erythropoietin.

Topics: Anemia, Hemolytic; Anemia, Macrocytic; Animals; Blood Transfusion; Bloodletting; Bone Marrow; Erythropoietin; Female; Hematopoiesis; Hematopoietic Stem Cells; Male; Mice; Mice, Mutant Strains; Phenylhydrazines; Polycythemia; Spleen

The influence of splenectomy on erythroid burst colony formation by peripheral blood mononuclear cells from 10 patients (four with hereditary spherocytosis, two with beta-thalassaemia major, two with Hodgkin's disease and two with idiopathic thrombocytopenic purpura) was studied. In every instance splenectomy was followed by a lowering of blood BFU-E. The post-splenectomy levels ranged from 0 to 30% of the preoperative levels. Mononuclear cells from the spleens of eight patients were cultured and found to contain numerous BFU-E. The total quantity of BFU-E in the whole blood and in the spleen of the patients was generally of the same order of magnitude. The number of splenic BFU-E did not correlate with spleen size. Splenic BFU-E differed from peripheral blood BFU-E in that they were more sensitive to erythropoietin (Ep) and in that they failed to respond to burst promoting activity (BPA) produced by preincubating the spleen mononuclear cells with phytohaemagglutinin M (PHA). In contrast, media conditioned by PHA-treated spleen cells contained BPA active on peripheral blood BFU-E from normal individuals. These data suggest that the spleen may have an influence on the numbers and functional properties of BFU-E.

Topics: Adolescent; Adult; Anemia, Hemolytic; Child; Child, Preschool; Erythrocyte Count; Erythrocytes; Erythropoietin; Female; Hematopoietic Stem Cells; Hodgkin Disease; Humans; Male; Phytohemagglutinins; Purpura, Thrombocytopenic; Spleen; Splenectomy

The relative roles of the kidney and liver as a source of Ep in a fully compensated hemolytic state were investigated. A compensated hemolytic anemia was induced in rats by injections of PHZ over a 6-week period. Verification of a fully compensated hemolytic state was established by MCV, MCH, MCHC, BV, PV, CRCV, peripheral reticulocyte counts, and bone marrow counts. The kidneys and livers of the PHZ-injected rats were subjected to concurrent perfusion at weekly intervals over the treatment period and the perfusate assayed for Ep activity. The kidney was found to be the principal source of Ep during the earlier stages of the anemia and the liver became increasingly important as a source of Ep during the later stages as the anemia became progressively compensated. By the fifth and sixth weeks of treatment, when the anemia was fully compensated, the livers of the PHZ-treated rats were the principal source of Ep. During these last 2 weeks of treatment, the amount of Ep recovered from the renal effluents of PHZ-injected rats was no greater than that collected from the renal effluents of saline-injected rats. The data indicate that the liver is the primary, if not the only, source of the higher titers of Ep in the fully compensated hemolytic state induced in the rat by long-term PHZ treatment.

Topics: Anemia, Hemolytic; Animals; Erythrocyte Count; Erythrocyte Volume; Erythropoietin; Kidney; Liver; Male; Organ Size; Phenylhydrazines; Plasma Volume; Rats

A mathematical model for the control of erythropoiesis has been developed based on the balance between oxygen supply and demand at a renal oxygen detector which in turn controls erythropoietin release and red cell production. Tissue oxygen tension is regulated by adjustments of hemoglobin levels resulting from the output of a renal-bone marrow controller. Special consideration given to the determinants of tissue oxygenation included evaluation of the influence of blood flow, capillary diffusion, oxygen uptake, and oxygen-hemoglobin affinity. A theoretical analysis of the overall control system is presented including: a) dynamic and steady-state responses, b) sensitivity analysis to determine the relative importance of parameters and their influence on model behavior, c) properties of the model as a proportional controller, d) analysis of steady-state errors, and e) effectiveness of feedback regulation. Computer simulations of altitude hypoxia, descent from altitude, red cell infusion, and hemolytic anemia demonstrate the validity of the model for general human application.

Topics: Anemia, Hemolytic; Biological Transport; Bone Marrow; Cell Differentiation; Computers; Erythrocyte Aging; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Humans; Hypoxia; Kidney; Models, Biological; Oxygen; Polycythemia; Pregnancy

Topics: Anemia, Hemolytic; Erythropoietin; Humans; Kidney Failure, Chronic; Renal Dialysis

The injection of erythropoietin or the induction of anaemia with phenylhydrazine leads to changes in murine pluripotent and granulocyte-macrophage stem cells indicating migration from marrow to spleen. In order to evaluate the interrelationship between erythroid differentiation and stem cell migration we have selectively suppressed erythroid differentiation with actinomycin D. Anaemia or EP injection resulted in stem cell changes consistent with migration; actinomycin blocked these changes in anaemic but not EP injected mice while blocking erythropoiesis in both groups. The erythropoietin contained from 0.01 to 1000 microgram/ml of endotoxin as defined by the limulus test; it decreased marrow erythropoiesis and stimulated marrow granulopoiesis. Adsorption of the erythropoietin preparation with limulus lysate removed endotoxin without decreasing erythropoietin activity. Adsorbed erythropoietin stimulated erythropoiesis and not granulopoiesis, and stem cell changes induced by its administration were largely blocked by actinomycin, suggesting that endotoxin in the non-adsorbed erythropoietin caused the actinomycin resistant stem cell changes. The observation that actinomycin blocks both erythroid differentiation and stem cell migration suggests that these two physiologic events are closely linked. The effects of injected erythropoietin on murine haemopoietic stem cells may, to a significant extent, be secondary to the presence of endotoxin in the erythropoietin preparations.

Topics: Anemia, Hemolytic; Animals; Cell Differentiation; Cell Migration Inhibition; Cell Movement; Colony-Forming Units Assay; Dactinomycin; Drug Contamination; Endotoxins; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Hematopoietic Stem Cells; Limulus Test; Mice; Phenylhydrazines

The renal anaemia is characterized by a decreased new formation of erythrocytes (deficiency of erythropoetin), by haemolysis (uraemic-toxic influences) and by iron deficiency (decreased resorption of iron, blood losses, infectious-toxic component). In long-term haemolysis the iron deficiency increases, in most cases the haemolysis a little decreases, and a deficiency of erythropoietin is not to be established. However, a slight deficiency of folic acid is frequently observed. Apart from the reduction of the retention of substances normally contained in the urine the therapy consists in iron doses and slight doses of folic acid. Only occasionally blood transfusions are necessary.

Topics: Anemia, Hemolytic; Erythropoietin; Folic Acid; Humans; Iron; Kidney Failure, Chronic; Renal Dialysis

Spontaneously flowing fistulae were established in the efferent lymphatics of popliteal, prescapular and prefemoral nodes and lumbar trunk or in the afferent lymphatics draining the kidney and liver of sheep. Lymph was collected from these sites over various time intervals and assayed for erythropoietin (Ep) content. The objective of the study was to establish the anatomic site(s) of Ep production. Normal lymph did not contain detectable titers of Ep, nor did renal lymph or blood plasma from a sheep systematically treated with cobaltous chloride. Renal lymph did contain measurable levels of Ep following renal artery constriction, unilateral hydronephrosis or phenylhydrazine-induced hemolytic anemia. Phenylhydrazine treatment also produced elevated Ep levels in lymph from the liver but not in lymph efferent from either popliteal or prescapular nodes. These results indicate that Ep is generated primarily in the kidney and that the liver may be an extrarenal source of the hormone. The surgical techniques used in this study offer distinct advantages in examining the composition and physiology of lymph in sheep.

Topics: Anemia, Hemolytic; Animals; Cobalt; Erythropoietin; Female; Hydronephrosis; Kidney; Liver; Lymph; Mice; Phenylhydrazines; Renal Artery Obstruction; Sheep

The association between anemia and chronic renal failure has been recognized since the early 19th century. With the introduction of regular dialysis treatment, an understanding of all aspects of this uremic complication has become of great importance, including an appreciation of the hazards of multiple blood transfusions. This analysis of hemoglobin levels and transfusion requirements in 84 dialysis patients focuses specific attention on hemolytic mechanisms, blood loss, and the effect of bilateral nephrectomy on erythropoiesis. Because no replacement for renal erythropoietin is available, particular attention must be paid to less important, but partially correctable factors that contribute to anemia. Blood transfusion requirements can then be reduced to a minimum, together with the risks of hypersplenism, hepatitis, and sensitization of the patient to alloantigens.

Topics: Adolescent; Adult; Anemia, Hemolytic; Blood Transfusion; Erythropoietin; Humans; Kidney Failure, Chronic; Middle Aged; Nephrectomy; Renal Dialysis

Using a methylcellulose cell culture technique, we studied the serial changes in erythropoietic precursors in the femur, spleen, and blood of mice under erythropoietic stimuli. Phenylhdrazine hydrochloride, in the dosage of 60 mg/kg, was injected into mice subcutaneously on days 0, 1, and 3, and mice were sacrified on days 0, 2, 4, 7, and 10 for assessment of erythropoietic precursors. Significant changes were observed for all hemopoietic organs in the number of erythrocytic burst-forming units (BFU-E) and erythrocytic colony-forming units (CFU-E). Only BFU-E were present in blood, and their maximal increase was noted on day 2. While marrow BFU-E continuously decreased, maximal increase of CFU-E noted on day 4. Splenic BFU-E and CFU-E increased until day 4 and declined subsequently. These observations suggest the presence of significant migration of BFU-E in mice under erythropoietic stimuli and stress the importance of studies on all hemopoietic organs in the assessment of murine hemopoiesis.

Topics: Anemia, Hemolytic; Animals; Blood Cell Count; Dose-Response Relationship, Drug; Erythropoiesis; Erythropoietin; Female; Hematocrit; Male; Mice; Mice, Inbred BALB C; Phenylhydrazines; Reticulocytes; Time Factors

Topics: Age Factors; Anemia, Hemolytic; Animals; Child; Chronic Disease; Erythropoietin; Female; Humans; Kidney Diseases; Leukemia; Male; Mice; Mice, Inbred BALB C

We have reviewed erythroid cell differentiation from two points of view: 1) differences between fetal and adult human red cells with particular reference to alterations which can occur in the normal pattern of erythroid cell development during the course of leukemia; 2) beochemical events which occur during erythroid cell maturation, as a model system for the study of the control of gene expression. During the course of many leukemias there is the synthesis of red cells containing fetal hemoglobin. In most cases this phenomenon is limited to a small population or clone of red cells and probably represents a nonspecific response of the bone marrow to a hematologic stress. However, in juvenile chronic myeloid leukemia and, in rare cases of erythroleukemia, there is a major reversion to fetal erythropoiesis, with progressive increase in fetal hemoglobin levels and synthesis of red cells which contain not only fetal hemoglobin but have a true fetal pattern of protein synthesis affecting proteins other than Hb F, namely Hb A2, carbonic anhydrase and the membrane antigens i and I. In this case, the fetal erythropoiesis may be a more specific manifestation of the leukemic process and may be related to the phenomenon of fetal protein synthesis (alpha-fetoprotein of carcinoembryonic antigen) observed in other types of neoplasia. Further information on the etiology and pathogenesis of abnormal cell proliferation and differentiation in the leukemias can be obtained by the study of experimental systems permitting the investigation of the regulation of gene expression in differentiating mammalian cells. Maturing erythroid cells provide a promising system for such investigations for many reasons: differentiating erythroid cells can be obtained relatively free of other cell types; a large amount of a well characterized product, hemoglobin, is synthesized; techniques are now available that permit isolation of erythroid precursors at different stages of differentiation (5-8); and finally, highly sensitive methods of measuring globin mRNA levels by DNA-RNA hybridization are currently available (13, 26, 27). We have used such techniques to measure levels of globin mRNA in separated populations of murine erythroid cells at different stages of maturation. These studies demonstrated a correlation between globin mRNA content and degree of morphological maturation. In the least well differentiated cells, however, there appeared to be a disproportionate amount of mRNA for the lev

Topics: Anemia, Hemolytic; Animals; Blood Cell Count; Cell Differentiation; Cell Division; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Fetal Hemoglobin; Genes; Globins; Hematopoietic Stem Cells; Heme; Hemoglobin H; Humans; Leukemia; Leukemia, Erythroblastic, Acute; Mice; Phenylhydrazines; RNA, Messenger; Time Factors

Murine erythroblastosis virus (MuEV), also called murine leukemia virus-Kirsten, is a member of the murine type-C-RNA leukemia-sarcoma group of oncogenic viruses. Like other members of this group, MuEV can elicit both a hemolytic disorder and an oncogenic response. Neonatal rats infected with MuEV succumb to this hemolytic disorder unless they are treated with the synthetic double-stranded polyribonucleotide, polyinosinic-polycytidylic acid (poly I-poly C). Animals receiving poly I-poly C had markedly reduced levels of virus reproduction as measured by bioassay and electron microscopy. The proliferation of erythroblasts after MuEV infection in animals not receiving poly I-poly C appeared to be an erythropoietin-dependent compensatory response to hemolysis. The hemolysis itself seemed to require virus reproduction in the cell types affected. Administration of poly I-poly C to MuEV-infected rats inhibited virus reproduction and thus may circumvent the hemolytic disease syndrome. The ultrastructure of the virus and of the virus reproduction was also studied.

Topics: Anemia, Hemolytic; Animals; Blood Platelets; Erythroblasts; Erythropoietin; Female; Hematopoietic Stem Cells; Hemolysis; Interferons; Leukemia Virus, Murine; Male; Mice; Poly I-C; Rats; Rats, Inbred WF; Retroviridae; Spleen; Tumor Virus Infections; Virus Replication

Topics: Anemia, Hemolytic; Cell Membrane; Erythropoiesis; Erythropoietin; Ethanol; Folic Acid; Hematopoiesis; Hematopoietic Stem Cells; Hepatitis; Humans; Intestinal Absorption; Iron; Megakaryocytes; Mitochondria; Mononuclear Phagocyte System; Nutrition Disorders; Pancreatitis; Pyridoxal Phosphate

Splenomegaly accompanied by anaemia, increased reticulocyte and decreased thrombocyte counts, was induced in Wistar rats by a long-term intraperitoneal administration of methylcellulose. Compared to controls, hypersplenic rats showed significantly enhanced utilization of 59-Fe by red cells and increased titre of erythropoietin. After the exposure of rats to hypoxic hypoxia corresponding to an altitude of 7,000 m for 6 h, no difference in the erythropoietin titre was found in either group. The results suggest that experimental hypersplenism alone does not affect the production of erythropoietin and does not stimulate the formation of an inhibitor of erythropoietin or erythropoiesis. The increased titre of erythropoietin and enhanced utilization of radioiron by red cells in rats with hypersplenism were found to be due to haemolytic anaemia leading to the stimulation of erythropoiesis.

Topics: Anemia, Hemolytic; Animals; Erythrocytes; Erythropoiesis; Erythropoietin; Hypersplenism; Hypoxia; Iron; Male; Methylcellulose; Rats

Cell populations highly enriched for the different stages of erythroid cell maturation were obtained by three sequential operations: harvesting of erythroid cells after induction of erythroid hyperplasia in the spleens of mice, elimination of the more mature erythrocytes by immunologic techniques, and separation of the residual nucleated erythroid cells as a function of size by the velocity sedimentation technique. The resulting cell fractions were studied both directly and after overnight incubation in the presence or absence of erythropoietin. In short-term culture, erythropoietin stimulated proliferation of pronormoblasts and basophilic normoblasts but probably not cells at later stages of differentiation. Erythropoietin also appeared to recruit increased numbers of pronormoblasts. In this experimental system, erythroid cell differentiation was able to proceed in the absence of erythropoietin, but without proliferation of these early erythroid cells. These techniques have provided a model system for the study of erythroid cells at different stages of maturation isolated from a uniform source at one point in time. The morphologic observations indicated that erythropoietin stimulates erythroid cell proliferation at several early stages of the maturation pathway.

Topics: Anemia, Hemolytic; Animals; Cell Differentiation; Cell Separation; Cells, Cultured; Centrifugation, Density Gradient; Erythrocyte Count; Erythropoiesis; Erythropoietin; Female; Hematopoietic Stem Cells; Hemolysis; Immune Sera; Methods; Mice; Spleen

Topics: Anemia, Aplastic; Anemia, Hemolytic; Animals; Antibodies; Antibody Formation; Chromatography; Erythropoietin; Humans; Immune Sera; Immunodiffusion; Rabbits; Radioimmunoassay; Rats

Topics: Anemia; Anemia, Hemolytic; Animals; Blood Cell Count; Cell Division; Cells, Cultured; Culture Media; Erythrocytes; Erythropoiesis; Erythropoietin; Hematopoietic Stem Cells; Hemoglobins; Male; Penicillins; Polycythemia; Rabbits; Reticulocytes; Streptomycin; Time Factors

Erythropoietin, the hormone responsible for stimulating erythrocyte production, was shown to increase significantly in the serum of mice during virulent malaria infection. Although erythropoiesis was enhanced, it did not keep pace with the rate of erythocyte destruction; hence all Plasmodium berghei-infected mice quickly succumbed to the deleterious consequences of severe uncompensated hemolytic anemia. Since this apparently inadequate rate of erythropoiesis is not attributed to impaired erythropoietin generation, mechanisms relating to (i) hemopoietic stem-cell resistance to endogenous erythropoietin, (ii) deficits in numbers of hemopoietic stem cells, and/or (iii) ineffective erythropoiesis are of interest.

Topics: Anemia, Hemolytic; Animals; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Malaria; Mice; Plasmodium berghei

Topics: Adaptation, Physiological; Androgens; Anemia; Anemia, Hemolytic; Deficiency Diseases; Diet Therapy; Erythrocytes; Erythropoiesis; Erythropoietin; Hemolysis; Hemorrhage; Humans; Iron; Kidney Failure, Chronic; Nephrectomy; Oxygen Consumption; Renal Dialysis; Uremia; Vitamins

Topics: Adult; Androgens; Androstanes; Anemia, Hemolytic; Bone Marrow Diseases; Child; Erythropoiesis; Erythropoietin; Female; Growth Disorders; Hematologic Diseases; Hematopoiesis; Humans; Kidney Failure, Chronic; Male; Virilism

Topics: Anemia, Hemolytic; Animals; Animals, Newborn; Erythropoietin; Hematocrit; Iron; Iron Radioisotopes; Phenylhydrazines; Rats

Topics: Anemia, Hemolytic; Blood Transfusion; Chlorides; Cobalt; Erythropoietin; Follow-Up Studies; Hematocrit; Humans; Iron; Kidney Failure, Chronic; Kidney Transplantation; Renal Dialysis; Testosterone; Transplantation, Homologous

Topics: Anemia, Hemolytic; Diet Therapy; Erythropoietin; Humans; Kidney Diseases; Kidney Transplantation; Renal Dialysis; Transplantation, Homologous

Topics: Anemia; Anemia, Hemolytic; Bone Marrow; Erythropoietin; Hemolysis; Humans; Kidney; Kidney Diseases; Uremia

Topics: Adolescent; Adult; Aged; Anemia, Aplastic; Anemia, Hemolytic; Anemia, Sickle Cell; Bone Marrow Diseases; Creatinine; Erythropoietin; Female; Hematocrit; Hemolysis; Humans; Iron; Leukemia; Lymphoma; Male; Middle Aged; Multiple Myeloma; Sex Factors

Topics: Adolescent; Adult; Anemia, Hemolytic; Erythropoietin; Female; Hemolytic-Uremic Syndrome; Humans; Kidney Failure, Chronic; Male; Methenolone; Middle Aged; Renal Dialysis; Uremia

Topics: Anemia, Hemolytic; Anemia, Hemolytic, Autoimmune; Anemia, Myelophthisic; Anemia, Sickle Cell; Bone Marrow; Erythropoietin; Heart Diseases; Hematocrit; Humans; Hypoxia; Kidney Diseases; Reticulocytes; Spherocytosis, Hereditary

Topics: Anemia, Hemolytic; Erythropoiesis; Erythropoietin; Humans; Kidney Failure, Chronic

Topics: Anemia; Anemia, Aplastic; Anemia, Hemolytic; Anemia, Hypochromic; Anemia, Macrocytic; Bilirubin; Erythropoietin; Humans; Iron; Neoplasms

Topics: Anemia, Hemolytic; Anemia, Myelophthisic; Erythropoietin; Humans; Hypoxia; Kidney Failure, Chronic; Reticulocytes

Topics: Anemia; Anemia, Aplastic; Anemia, Hemolytic; Anemia, Hypochromic; Anemia, Macrocytic; Diagnosis, Differential; Erythrocytes; Erythropoietin; Half-Life; Hemorrhage; Humans; Iron; Neoplasms; Vitamin B 12 Deficiency

Topics: Anemia, Hemolytic; Animals; Bone Marrow; Bone Marrow Cells; Erythrocyte Count; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hematopoietic Stem Cells; Hypoxia; Mice; Phenylhydrazines; Polycythemia; Reticulocytes; Spleen; Stress, Physiological

Topics: Adenosine Triphosphatases; Anemia, Hemolytic; Blood Urea Nitrogen; Bone Marrow Cells; Cell Membrane; Erythrocytes, Abnormal; Erythropoiesis; Erythropoietin; Folic Acid Deficiency; Glycolysis; Hemolysis; Humans; Hydrogen-Ion Concentration; Iron; Kidney; Oxygen Consumption; Phosphoric Monoester Hydrolases; Uremia

Topics: Anemia, Aplastic; Anemia, Hemolytic; Animals; Bone Marrow; Erythrocytes; Erythropoietin; Female; Humans; Male; Mice; Phenylhydrazines; Rabbits

Topics: Anemia, Aplastic; Anemia, Hemolytic; Bone Marrow; Erythrocyte Count; Erythropoiesis; Erythropoietin; Humans; Reticulocytes

Topics: Adrenocorticotropic Hormone; Anemia, Hemolytic; Animals; Bone Marrow; Bone Marrow Cells; Cortisone; Erythrocyte Count; Erythropoiesis; Erythropoietin; Hematopoietic System; Hemoglobinometry; Hydrocortisone; Isoantibodies; Periodicity; Rabbits; Reticulocytes; Splenectomy

Topics: Adolescent; Anemia; Anemia, Aplastic; Anemia, Hemolytic; Anemia, Hypochromic; Anemia, Sickle Cell; Animals; Biological Assay; Blood Cell Count; Bone Marrow Examination; Child; Child, Preschool; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Hemoglobinometry; Humans; Iron; Iron Isotopes; Male; Rats; Reticulocytes; Thalassemia

Topics: Anemia; Anemia, Aplastic; Anemia, Hemolytic; Argentina; Blood Cell Count; Erythropoietin; Hemoglobinometry; Hookworm Infections; Humans; Reticulocytes; Sampling Studies

Topics: Anemia; Anemia, Hemolytic; Animals; Erythropoiesis; Erythropoietin; Female; Genetics; Hemorrhage; Hypoxia; Iron; Iron Isotopes; Male; Mice; Oxygen; Partial Pressure; Phenylhydrazines

This investigation is concerned with the kinetics of the reciprocal relationship between sheep hemoglobin (Hb) A and Hb C formation in response to anemia. The relative synthesis of the hemoglobin types was assessed at various times in bone marrow erythroid cells incubated in vitro with (59)Fe. The changeover from Hb A to Hb C formation lagged by about 3 days behind the development of anemia and was complete within about 11 days. After recovery from anemia the reciprocal change back to preanemic conditions proceeded at a much slower rate, Hb C formation gradually declining to unmeasurable levels over about 25 days. Infusions of plasma with high erythropoietin titre induced the formation of relatively large quantities of Hb C in erythroid cells of nonanemic sheep, demonstrating the central importance of a humoral mechanism in the change of expression of the hemoglobin genes. THE FOLLOWING CONCLUSIONS WERE DRAWN: hemoglobin phenotype is determined at a stem cell level. Erythroid stem cells appear to undergo gradual renewal. The identity of the plasma factor which induces Hb C formation is not yet known; it is not present in plasma from nonanemic sheep, and its production is not dependent upon hemoglobin genotype. If the plasma factor turns out to be erythropoietin, then this hormone must have an important influence on the pool of erythroid stem cells.

Topics: Anemia, Hemolytic; Animals; Bone Marrow; Bone Marrow Cells; Cytogenetics; Erythropoiesis; Erythropoietin; Female; Genes, Regulator; Hemoglobin C; Hemoglobinopathies; Hemoglobins; Hormones; Iron Isotopes; Kinetics; Models, Theoretical; Phenotype; Sheep

Topics: Anemia, Hemolytic; Animals; Erythropoiesis; Erythropoietin; Hematocrit; Hepatectomy; Kidney; Liver; Male; Methods; Nephrectomy; Nitrogen; Phenylhydrazines; Protein Deficiency; Rats; Spleen; Splenectomy

Topics: Anemia, Hemolytic; Cholecystectomy; Erythrocyte Count; Erythropoiesis; Erythropoietin; Female; Hemoglobins; Humans; Iron; Male; Reticulocytes; Spherocytosis, Hereditary; Splenectomy; Splenomegaly

Topics: Anemia, Aplastic; Anemia, Hemolytic; Anemia, Hypochromic; Animals; Erythropoietin; Hodgkin Disease; Humans; Infant; Infant, Newborn; Leukemia; Lymphatic System; Mice; Mononuclear Phagocyte System; Polycythemia; Umbilical Cord

Topics: Anemia, Hemolytic; Blood Transfusion; Bloodletting; Bone Marrow; Erythropoiesis; Erythropoietin; Hematocrit; Humans; Polycythemia Vera

Topics: Anemia; Anemia, Hemolytic; Anemia, Hypochromic; Anemia, Pernicious; Blood Coagulation; Blood Proteins; Chloramphenicol; Epidemiology; Epoetin Alfa; Erythropoietin; Haptoglobins; Hematologic Diseases; Hematology; Hemochromatosis; Humans; Iron-Dextran Complex; Leukemia; Polycythemia; Thromboplastin; Vitamin B 12

Topics: Anemia; Anemia, Hemolytic; Cell Division; DNA; Epoetin Alfa; Erythropoiesis; Erythropoietin; Hemoglobins; Metabolism; Proteins; Reticulocytes; RNA; RNA, Messenger

Topics: Anemia; Anemia, Hemolytic; Animals; Biomedical Research; Bone and Bones; Bone Marrow; Epoetin Alfa; Erythropoiesis; Erythropoietin; Hematocrit; Hemoglobinometry; Hemorrhage; Humans; Iron Isotopes; Liver; Male; Pharmacology; Phenylhydrazines; Physiology, Comparative; Rabbits; Rats; Research; Spleen

Topics: Acetylcholinesterase; Alkaline Phosphatase; Anemia; Anemia, Hemolytic; Anticoagulants; Australia; Blood Transfusion; Chromium Isotopes; Coombs Test; Dextrans; Diagnosis, Differential; Drug Therapy; Epoetin Alfa; Erythrocyte Count; Erythrocytes; Erythropoietin; Hematologic Tests; Hemoglobinuria; Hemoglobinuria, Paroxysmal; Hemosiderin; Humans; Iron; Iron Isotopes; Phenindione; Prednisone; Splenectomy; Waldenstrom Macroglobulinemia

Topics: Anemia; Anemia, Hemolytic; Antineoplastic Agents; Cytostatic Agents; Epoetin Alfa; Erythropoiesis; Erythropoietin; Pharmacology; Rats; Research; Triaziquone

Topics: Anemia; Anemia, Hemolytic; Animals; Biomedical Research; Bone Marrow; Bone Marrow Examination; Epoetin Alfa; Erythropoiesis; Erythropoietin; Humans; Iron Isotopes; Male; Phenylhydrazines; Rabbits; Radiography; Radioisotopes; Radionuclide Imaging; Rats; Research; Skeleton

Topics: Anemia; Anemia, Hemolytic; Bone Marrow Examination; Epoetin Alfa; Erythrocytes; Erythropoietin; Hematology; Humans; Infant; Infant, Newborn; Metabolism; Physiology

Topics: Anemia; Anemia, Hemolytic; Anemia, Sickle Cell; Epoetin Alfa; Erythroblastosis, Fetal; Erythrocytes; Erythropoietin; Humans; Infant, Newborn