losartan-potassium and Hemolysis

Kidney transplantation represents a renal replacement therapy for end-stage renal failure, with outcomes improving from year to year. With the improved survival prognosis, treatment of complications of chronic kidney disease after transplantation is becoming increasingly important. In particular, posttransplantation anemia (PTA) is often protracted, which could be related to a variety of factors, including the renal function status, graft rejection episodes, and infectious causes. PTA occurs in about 30-40% of transplant recipients, and is known to affect the function of the transplanted kidney as well as patient survival. Early PTA is associated with a risk of death and cardiovascular disorders, however, during this phase, priority is given to the appropriate maintenance of immunosuppression rather than to the treatment of anemia. Maintenance-phase PTA exerts a strong influence on the survival, prognosis of the transplanted kidney, quality of life, etc. Unlike the disease state and treatment of usual renal anemia, it has been suggested that PTA may possibly reflect the functional state of the transplanted kidney. Therefore, it has been suggested that proper renal function may be maintained by ensuring a normal hemoglobin level in kidney transplant recipients. Proper management of PTA could be expected to be associated with an improved prognosis of the transplanted kidney and improved patient survival in kidney transplant recipients. It is advisable to provide appropriate treatment by setting target levels in accordance with the dialysis vintage, primary disease, cardiovascular complications, and kidney transplant function and delineation of the transplant recipient characteristics.

Topics: Anemia; Anemia, Iron-Deficiency; Anti-Bacterial Agents; Antiviral Agents; Blood Transfusion; Erythropoietin; Graft Rejection; Hematinics; Hemolysis; Humans; Immunosuppressive Agents; Infections; Iron Compounds; Kidney Failure, Chronic; Kidney Transplantation; Neoplasms; Sex Factors; Time Factors

Anemia, a common complication associated with inflammatory bowel disease (IBD), is frequently overlooked in the management of IBD patients. Unfortunately, it represents one of the major causes of both decreased quality of life and increased hospital admissions among this population. Anemia in IBD is pathogenically complex, with several factors contributing to its development. While iron deficiency is the most common cause, vitamin B12 and folic acid deficiencies, along with the effects of pro-inflammatory cytokines, hemolysis, drug therapies, and myelosuppression, have also been identified as the underlying etiology in a number of patients. Each of these etiological factors thus needs to be identified and corrected in order to effectively manage anemia in IBD. Because the diagnosis of anemia in IBD often presents a challenge, combinations of several hematimetric and biochemical parameters should be used. Recent studies underscore the importance of determining the ferritin index and hepcidin levels in order to distinguish between iron deficiency anemia, anemia due to chronic disease, or mixed anemia in IBD patients. With regard to treatment, the newly introduced intravenous iron formulations have several advantages over orally-administered iron compounds in treating iron deficiency in IBD. In special situations, erythropoietin supplementation and biological therapies should be considered. In conclusion, the management of anemia is a complex aspect of treating IBD patients, one that significantly influences the prognosis of the disease. As a consequence, its correction should be considered a specific, first-line therapeutic goal in the management of these patients.

Topics: Anemia; Anemia, Iron-Deficiency; Cytokines; Dietary Supplements; Erythropoietin; Ferritins; Folic Acid Deficiency; Hemolysis; Hepcidins; Humans; Inflammatory Bowel Diseases; Iron; Prognosis; Quality of Life; Vitamin B 12 Deficiency

Iron is an important mineral element required for diverse life processes. Its metabolism is almost synonymous to erythrocyte maintenance, erythropoiesis and erythrophagocytosis. Consequently, exercise exertion impacts significantly on red cell haematology. Here, the interactions between exercise and erythropoiesis are explored. Hepcidin, the peptide hormone that regulates systemic iron metabolism, decreases in response to erythropoiesis by facilitating increased iron efflux from ferroportin into circulation. However, during exercise, there is an alarming increase in the expression of hepcidin resulting in a negative iron balance in athletes. In this review, the confounding cause and effect scenarios of exercise, athlete training and haematology and hepcidin interactions are discussed.

Topics: Anemia; Antimicrobial Cationic Peptides; Athletes; Erythropoiesis; Erythropoietin; Exercise; Hemolysis; Hepcidins; Humans; Hypoxia; Iron

Patients with chronic kidney disease (CKD) are exposed to extremely higher risks of atherothrombotic complications of the cardio- and cerebrovascular systems. In pertinent meta-analyses, overviews, editorials and comments, it has been considered unproven, on the basis of current data from randomized controlled trials, that a higher hemoglobin (Hb) value provides overall-survival benefits for CKD. At present, there is a "gray zone" between the intervention threshold of Hb < 9 g/dl and an Hb level > 13 g/dl, at which CKD is associated with a higher risk of cardiovascular events. This paper discusses in depth the hemostaseological hypothesis of increased mortality as a result of higher Hb levels during treatment of renal anemia with erythropoiesis-stimulating agents (ESA). It seems to be clearly evident that ESA activate platelets directly and indirectly, and that pathologically extended bleeding time is normalized when an Hb level of 10 g/dl is reached; from the hemostaseological perspective, a threshold level for treatment of renal anemia with ESA is thus defined. According to the present state of knowledge, an Hb target range of 10-11 g/dl seems reasonable for renal anemia; this is also compatible with current recommendations by ESA producers and the Food and Drug Administration (FDA). This target range avoids the upper and lower risk levels for Hb, and probably ensures a positive ESA effect on quality of life; it is much more cost-efficient than the target range of 11-12 g/dl recommended by the Kidney Disease Outcomes Quality Initiative (KDOQI) in 2007.

Topics: Age Factors; Aged; Anemia; Bleeding Time; Blood Transfusion; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Follow-Up Studies; Hematinics; Hemoglobinometry; Hemoglobins; Hemolysis; Humans; Kidney Diseases; Meta-Analysis as Topic; Platelet Activation; Practice Guidelines as Topic; Quality of Life; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Survival Analysis; Time Factors

Anemia is common in patients with cancer. The incidence and severity of anemia depend on the type and extent of the malignancy. Anemia may be the result of the malignancy itself, cancer treatment, blood losses, hemolysis or inflammatory cytokines associated with chronic disease. Anemia can have a profound impact on physical and psychosocial function and quality of life. However, in Japan, only iron supplementation and blood transfusion were available for the treatment of anemia with cancer. On the other hand, in Europe and America, erythropoietic agents such as erythropoietin and novel erythropoiesis stimulating protein (NESP) have been clinically used for anemia in patients with cancer.

Topics: Anemia; Antineoplastic Agents; Erythropoietin; Hematinics; Hemolysis; Hemorrhage; Humans; Iron Metabolism Disorders; Neoplasms; Prognosis; Recombinant Proteins

Anemia is a common complication of chronic kidney disease. Although mechanisms involved in the pathogenesis of renal anemia include chronic inflammation, iron deficiency, and shortened half-life of erythrocytes, the primary cause is deficiency of erythropoietin (EPO). Serum EPO levels in patients with chronic kidney disease are usually within the normal range and thus fail to show an appropriate increase with decreasing hemoglobin levels, as found in nonrenal anemias. Studies elucidating the regulation of EPO expression led to the identification of the hypoxia inducible factor-hypoxia responsive element system. However, despite much progress in understanding the molecular mechanisms through which cells can sense oxygen availability and translate this information into altered gene expression, the reason why EPO production is inappropriately low in diseased kidneys remains incompletely understood. Both alterations in the function of EPO-producing cells and perturbations of the oxygen-sensing mechanism in the kidney may contribute. As with other anemias, the consequences of renal anemia are a moderate decrease in tissue oxygen tensions and counterregulatory mechanisms that maintain total oxygen consumption, including a persistent increase in cardiac output.

Topics: Anemia; Animals; Diabetic Nephropathies; Erythropoiesis; Erythropoietin; Hemolysis; Humans; Hypoxia-Inducible Factor 1; Inflammation; Iron Deficiencies; Kidney; Kidney Failure, Chronic; Receptors, Erythropoietin; Uremia

We have uncovered a physiologic process which negatively regulates the red cell mass by selectively hemolyzing young circulating red blood cells. This allows fine control of the number of circulating red blood cells under steady-state conditions and relatively rapid adaptation to new environments. Neocytolysis is initiated by a fall in erythropoietin levels, so this hormone remains the major regulator of red cell mass both with anemia and with red cell excess. Physiologic situations in which there is increased neocytolysis include the emergence of newborns from the hypoxic uterine environment and the descent of polycythemic high-altitude dwellers to sea level. The process first became apparent while investigating the mechanism of the anemia that invariably occurs after spaceflight. Astronauts experience acute central plethora on entering microgravity resulting in erythropoietin suppression and neocytolysis, but the reduced blood volume and red cell mass become suddenly maladaptive on re-entry to earth's gravity. The pathologic erythropoietin deficiency of renal disease precipitates neocytolysis, which explains the prolongation of red cell survival consistently resulting from erythropoietin therapy and points to optimally efficient erythropoietin dosing schedules. Implications should extend to a number of other physiologic and pathologic situations including polycythemias, hemolytic anemias, 'blood-doping' by elite athletes, and oxygen therapy. It is likely that erythropoietin influences endothelial cells which in turn signal reticuloendothelial phagocytes to destroy or permit the survival of young red cells marked by surface molecules. Ongoing studies to identify the molecular targets and cytokine intermediaries should facilitate detection, dissection and eventual therapeutic manipulation of the process.

Topics: Altitude; Anemia; Erythrocytes; Erythropoietin; Hemolysis; Humans

Reduction in red blood cell mass, as well as structural and functional alterations of erythrocytes, occurs in critical illness. This review discusses these changes in red blood cell physiology, emphasizing the pathogenesis of anemia in intensive care unit patients.. Studies published in biomedical journals.. Anemia in intensive care unit patients resembles the anemia of chronic disease, being characterized by diminished erythropoietin production relative to decreased hematocrit, altered iron metabolism, and impaired proliferation and differentiation of erythroid progenitors in the bone marrow. Inflammatory mediators play a major role in the development of insufficient erythropoiesis and altered iron metabolism. Furthermore, a proinflammatory milieu promotes structural and functional alterations of erythrocytes, impairing their deformability and possibly impairing microvascular perfusion. Collectively, these changes in red blood cell physiology can impair oxygen transport to tissues and, thereby, might contribute to the development of multiple organ failure in critical illness.

Topics: Anemia; Critical Care; Erythrocytes; Erythroid Precursor Cells; Erythropoietin; Hemolysis; Hemorrhage; Humans; Iron; Occult Blood; Phlebotomy

Allogenic blood transfusion may be required for the treatment of anemia due to a hematologic disease, the consequences of chemotherapy or other circumstances, such as haemorrage and/or surgery. Transfusion becomes indispensable to prevent the side effects of anemia, such as hypoxia, palpitations, tachycardia, cardiac ischemia and fatigue. However, frequent transfusions can cause several acute problems such as hemolysis, anaphylactic shock and septic shock but also chronic problems such as iron overload (hemochromatosis), alloimmunisation and metabolic disturbances. Each of these complications can produce serious consequences and could even be sometimes fatal. Therefore we should recognise, prevent and if necessary treat all these hazards. Our article emphasises the potential chronic problems. For hemochromatosis, an iron chelator (deferoxamine) should be administered. In the presence of allo-immunisation the more compatible ABO blood group must be chosen and blood products be eliminated by filtration, when there has been blood reaction. When an allo-graft of hematopoitic tissues is considered an irradiation of blood products is necessary. Research is being carried out to develop substitute products for transfusion (haemoglobine solutions) or molecules acting on the syntheses of haemoglobine (butyrate arginine). The efficacy of erythropoitine, (EPO) is well recognised for stimulation of haemoglobine syntheses in renal failure and oncology.

Topics: Anaphylaxis; Chronic Disease; Erythropoietin; Hemolysis; Humans; Iron Overload; Shock, Septic; Transfusion Reaction

While the crucial role of haemoglobin in aerobic exercise has been well accepted, there is still a great deal of controversy about the optimal haematological parameters in the athletic population. The initial part of this review will examine the question of anaemia in athletes. The most common finding in athletes is a dilutional pseudoanaemia that is caused by a plasma volume expansion, rather than an actual blood loss. It is not a pathological state and normalises with training cessation in 3 to 5 days. This entity should be distinguished from conditions associated with lowered blood counts, such as intravascular haemolysis or iron deficiency anaemia. The evaluation of true anaemia states in the athlete must take into account not only blood losses secondary to exercise, such as foot strike haemolysis or iron losses through sweat, but non-athletic causes as well. Depending on the age and sex of the athlete, consideration must be given to evaluation of the gastrointestinal or genitourinary systems for blood loss. Finally, a comprehensive nutritional history must be taken, as athletes, especially women, are frequently not consuming adequate dietary iron. The second section of the paper will deal with the very contentious issue of sickle cell trait. While there have been studies demonstrating an increased risk of sudden death in people with sickle cell trait, it is still quite rare and should not be used as a restriction to activity. Further, studies have demonstrated that patients with sickle cell trait have an exercise capacity that is probably normal or near normal. However, in the cases of sudden death, it has been secondary to rhabdomyolysis occurring among sickle cell trait athletes performing at intense exertion under hot conditions, soon after arriving at altitude. The recommendations are that athletes with sickle cell trait adhere to compliance with the general guidelines for fluid replacement and acclimatisation to hot conditions and altitude. The final section of the paper examines the issue of haematological manipulation for the purposes of ergogenic improvement. Although experiments with blood doping revealed improvements in running time to exhaustion and maximal oxygen uptake, the introduction of recombinant erythropoietin has rendered blood doping little more than a historical footnote. However, the improvements in performance are not without risk, and the use of exogenous erythropoietin has the potential for increased viscosity of the blood a

Topics: Adaptation, Physiological; Anemia; Blood Volume; Doping in Sports; Erythropoietin; Hemolysis; Humans; Iron; Iron Deficiencies; Recombinant Proteins; Sickle Cell Trait; Sports; Sports Medicine

Topics: Anemia; Apoptosis; Erythropoietin; Hematocrit; Hemolysis; Humans; Kidney Failure, Chronic; Peritoneal Dialysis; Recombinant Proteins; Uremia

Iron deficiency is the most frequently encountered cause of suboptimal response to recombinant human erythropoietin (rHuEPO). Carefully assessing iron status is of paramount importance in chronic renal failure patients prior to or during rHuEPO therapy. Because there is great need for iron in the EPO-stimulated erythroid progenitors, it is essential that serum ferritin and transferrin saturation levels should be maintained over 300 microg/liter and 30%, respectively. Investigators have shown that oral iron is unlikely to keep pace with the iron demand for an optimal rHuEPO response in uremics. Therefore, patients with iron deficiency will always require intravenous iron therapy. The early and prompt iron supplementation can lead to reductions in rHuEPO dose and hence cost. After the iron deficiency has been corrected or excluded, we must remember all of the possible causes of hyporesponsiveness in every rHuEPO-treated patient. As dose requirements vary, it is not clear which dose of rHuEPO causes this hyporesponsiveness. However, if the patient with iron repletion does not respond well after the induction period, the major causes blunting the response to rHuEPO should be investigated. Most factors are reversible and remediable, except resistant anemia associated with hemoglobinopathy or bone marrow fibrosis, which requires a further increase in the rHuEPO dose. By means of early detection and correction of the possible causes, the goal of increasing therapeutic efficacy can be achieved. Iron overload may lead to an enhanced risk for infection, cardiovascular complication, and cancer. Over-treatment with iron should be avoided in dialysis patients, despite the fact that the safe upper limit of serum ferritin to avoid iron overload is not clearly defined. On the other hand, functional iron deficiency may develop even when serum ferritin levels are increased. Controversy remains as to whether intravenous iron therapy can overcome this form of hyporesponsiveness in iron-overloaded patients. Moreover, a treatment option of iron supplementation is not warranted in these patients, as the potential hazards of iron overload will be worsened. We demonstrated that the mean hematocrit significantly increased from 25.1+/-0.9% to 31+/-1.2% after eight weeks of intravenous ascorbate therapy (300 mg three times a week) in 12 hemodialysis patients with serum ferritin levels of more than 500 microg/liter. The enhanced erythropoiesis paralleled with a rise in transferrin sa

Topics: Aluminum; Anemia; Erythropoietin; Hemoglobinopathies; Hemolysis; Humans; Infections; Inflammation; Iron; Iron Deficiencies; Iron Overload; Kidney Failure, Chronic; Recombinant Proteins; Thalassemia

Topics: Anemia; Cardiovascular Diseases; Chronic Kidney Disease-Mineral and Bone Disorder; Erythropoiesis; Erythropoietin; Glutathione; Hemolysis; Humans; Kidney Failure, Chronic; Nutrition Disorders; Oxidation-Reduction

The pathogenesis, diagnosis and treatment of the anaemia of chronic disorders (ACD) in rheumatoid arthritis (RA) were reviewed. Causes of anaemia other than ACD frequently present in RA. Decreased iron absorption was shown to be the result of active RA rather than a cause of ACD or iron deficiency. It has been hypothesized that bone marrow iron availability decreases due to decreased iron release by the mononuclear phagocyte system or that the anaemia in ACD is due to ineffective erythropoiesis; these remain controversial theories. Studies considering a decreased erythropoietin responsiveness have not produced consistent results. Erythroid colony growth is suppressed in vitro by interleukins and tumour necrosis factor but their role in vivo in ACD is unknown. The diagnosis of ACD is made by exclusion. Iron deficiency is detected by transferrin, ferritin, and cellular indices after adaptation of their normal values. Treatment of the anaemia consists merely of antirheumatic treatment. Iron administration is counterproductive since iron chelators or exogenous erythropoietin administration might increase erythropoiesis.

Topics: Absorption; Anemia; Arthritis, Rheumatoid; Cell Survival; Diagnosis, Differential; Erythrocytes; Erythropoiesis; Erythropoietin; Ferritins; Hemolysis; Humans; Iron; Lactoferrin; Phagocytes; Stem Cells

Several factors contribute to the pathogenesis of anemia due to renal failure. Hypoproliferation of red cell progenitors may be caused partially by an inhibitory effect of some 'uremic toxins' whose existence certainly is very controversial. Iron deficiency due to gastrointestinal and dialysis-related blood losses and occasionally aluminum intoxication may interfere with the maturation of the erythron. Moderate hemolysis with shortening of red cell survival to some 50% of normal may be an additional factor. The main cause of anemia is, however, inadequate production of erythropoietin by the diseased kidney. This latter factor has now become amenable to treatment.

Topics: Anemia; Erythropoiesis; Erythropoietin; Hemolysis; Humans; Kidney Failure, Chronic; Renal Dialysis; Uremia

Topics: Anemia; Animals; Erythropoiesis; Erythropoietin; Hemolysis; Hemorrhage; Humans; Kidney Failure, Chronic

PTH may participate in the genesis of the anemia of uremia through at least three pathways. These include inhibition of erythropoiesis, shortening survival of RBCs and inducing fibrosis of bone marrow cavity. A possible fourth mechanism through which PTH may contribute to the anemia of uremia is its effect on platelets. PTH inhibits platelet aggregation [53] and, as such, may play an important role in the genesis of the bleeding tendencies and the consequent blood loss in uremia.

Topics: Anemia; Anemia, Hypochromic; Anemia, Sideroblastic; Animals; Colony-Forming Units Assay; Erythrocyte Aging; Erythropoiesis; Erythropoietin; Folic Acid Deficiency; Hematopoietic Stem Cells; Hemolysis; Hemorrhage; Humans; Hyperparathyroidism, Secondary; In Vitro Techniques; Mice; Parathyroid Hormone; Uremia

Topics: Absorption; Anemia; Anemia, Hypochromic; Arthritis, Rheumatoid; Bone Marrow; Erythropoiesis; Erythropoietin; Hemolysis; Humans; Iron; Iron-Dextran Complex; Synovial Membrane; Synovitis

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

Anemia is a frequent complication of renal failure. As in anemias of other origin, the resulting tissular hypoxia is partially compensated by an increased production of 2,3-diphosphoglycerate in red cells and a shift to the right of the oxygen hemoglobin dissociation curve. Two mechanisms are implicated in this anemia: increased hemolysis and depressed production of red cells. Decreased production of erythropoietin is probably the cause of reduced erythropoiesis, but the role of uremic intoxication has not been unequivocally excluded. In the course of chronic hemodialysis, iron deficiency anemia and occasionally hypersplenism develop. It is noteworthy that blood requirements in anephric patients are two to three times greater than those of nonanephric hemodialyzed patients. Accordingly, bilateral nephrectomy should be restricted to carefully selected cases. At the present time, androgens seem to be the best treatment of renal anemia. Qualitative anomalies of platelets are the main factor responsible for uremic bleeding and are corrected by hemodialysis.

Topics: Anemia; Animals; Cell Survival; Erythrocytes; Erythropoiesis; Erythropoietin; Hematologic Diseases; Hemolysis; Hemorrhagic Disorders; Humans; Kidney Failure, Chronic; Kidney Transplantation; Renal Dialysis; Transplantation, Homologous; Uremia

Topics: Animals; Aspirin; Blood Coagulation; Blood Platelets; Blood Preservation; Blood Transfusion; Chromium Radioisotopes; Cyclic AMP; Dimethyl Sulfoxide; Erythrocytes; Erythropoiesis; Erythropoietin; Hematocrit; Hemolysis; Humans; Hypertension; Kidney; Osmotic Fragility; Platelet Adhesiveness; Prostaglandins; Receptors, Cell Surface; Shock

Topics: Adenosine Triphosphate; Biological Transport, Active; Blood Cells; Blood Platelets; Erythrocyte Aging; Erythrocytes; Erythropoietin; Glomerular Filtration Rate; Guanidines; Hemolysis; Hemolytic-Uremic Syndrome; Humans; Kidney; Kidney Glomerulus; Lymphocytes; Osmotic Fragility; Sodium; Succinates; Urea

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: Anemia; Erythrocytes; Erythropoiesis; Erythropoietin; Hematocrit; Hemolysis; Humans; Iron; Kidney Failure, Chronic; Oxygen; Renal Dialysis

Topics: Anemia; Anemia, Hypochromic; Bone Marrow; Bone Marrow Cells; Erythrocyte Aging; Erythrocyte Count; Erythrocytes; Erythropoiesis; Erythropoietin; Hematocrit; Hemoglobins; Hemolysis; Humans; Iron; Reticulocytes

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

Previous studies have suggested that erythropoietin (Epo) levels may be inappropriately low in patients with sickle cell disease compared to the extent of the related anemia they demonstrate. Here, we evaluate Epo level vs. renal function, oxygenation, and markers of inflammation for patients treated for sickle cell disease at our institution. Blood was drawn from 54 patients with sickle cell disease during routine visits to the outpatient hematology office and analyzed for hemoglobin (Hb) level, Epo, markers of inflammation, oxygenation, and renal function. Erythropoietin levels were lower than expected for patients with sickle cell disease, compared to the degree of anemia demonstrated in these patients. In addition, a correlation between Hb level and Epo was not consistently observed. Higher Epo levels were seen in patients receiving hydroxyurea (HU), but no correlation with oxygenation, hemolysis, renal function, or inflammation was observed.

Topics: Adult; Aged; Anemia, Sickle Cell; Antisickling Agents; Biomarkers; Erythropoietin; Female; Hemoglobins; Hemolysis; Humans; Hydroxyurea; Inflammation; Kidney Function Tests; Male; Middle Aged

Anaemia in diabetes mellitus (DM) and/or chronic renal failure (CRF) may be caused by a decreased production of erythropoietin (EPO), EPO resistance, and by the lysis of the young circulating red blood cells (neocytolysis) induced by subclinical inflammation and low EPO level. Aims of this study were to detect EPO resistance in patients with DM and/or CRF and to prove, that acetylsalicylic acid (ASA) is able to improve the haemopoietic status by decreasing neocytolysis.. In a cross-sectional study, three groups of selected patients (patients with DM; patients with DM+CRF; patients with CRF without DM, n=15 each) and a group of controls (non-diabetic, nonazotemic subjects, n = 10) were compared. In the intervention part of the study, the effect of a single dose of 1 gram ASA on neocytolysis was investigated in a subgroup of these patients.. Despite the similar EPO level (p = 1.000), all three patient groups had lower haemoglobin and haematocrit than control persons (p < 0.05 in all cases). Patients with DM+CRF had lower haemoglobin than patients with DM or CRF alone (p < 0.05). Single dose of ASA induced a fast increase in serum EPO level, a concomitant rise of the Rtc number and rate, red blood cell count, haematocrit and haemoglobin p < 0.01 for each). These changes were accompanied by a marked decrease in serum lactate dehydrogenase activity (p < 0.01).. DM and CRF may induce erythropoietin resistance. In these patients, ASA treatment increases serum EPO level. The higher EPO level and the anti-inflammatory effect of ASA may decrease neocytolysis.

Topics: Aged; Anemia; Aspirin; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Erythropoietin; Female; Hemolysis; Humans; Kidney Failure, Chronic; L-Lactate Dehydrogenase; Male; Middle Aged

Chronic hemodialysis (HD) patients manifest anemia and atherosclerosis with associated oxidative stress. We explored whether intravenous infusion of vitamin C (VC) and/or use of vitamin E (VE)-coated dialysis membrane could palliate HD-evoked oxidative stress. Eighty patients undergoing chronic HD were enrolled and randomly assigned into four groups: HD with intravenous VC (n=20), HD with VE-coated dialyzer (n=20), HD with both (n=20), and HD with neither (n=20). We evaluated oxidative stress in blood and plasma, erythrocyte methemoglobin/ferricyanide reductase (red blood cells (RBC)-MFR) activity, plasma methemoglobin, and pro-inflammatory cytokines in these patients. All patients showed marked increases (14-fold) in blood reactive oxygen species (ROS) after HD. The types of ROS were mostly hydrogen peroxide, and in lesser amounts, O2*- and HOCl. HD resulted in decreased plasma VC, total antioxidant status, and RBC-MFR activity and increased plasma and erythrocyte levels of phosphatidylcholine hydroperoxide (PCOOH) and methemoglobin. Intravenous VC significantly palliated HD-induced oxidative stress, plasma and RBC levels of PCOOH, and plasma methemoglobin levels and preserved RBC-MFR activity. The VE-coated dialyzer effectively prevented RBCs from oxidative stress, although it showed a partial effect on the reduction of total ROS activity in whole blood. In conclusion, intravenous VC plus a VE-coated dialyzer is effective in palliating HD-evoked oxidative stress, as indicated by hemolysis and lipid peroxidation, and by overexpression of proinflammation cytokines in HD patients. Using VE-coated dialyzer per se is, however, effective in reducing lipid peroxidation and oxidative damage to RBCs.

Topics: Antioxidants; Ascorbic Acid; Cytokines; Erythropoietin; Female; Hemolysis; Humans; Hydrogen Peroxide; Infusions, Intravenous; Kidney Failure, Chronic; Lipid Peroxidation; Male; Membranes, Artificial; Methemoglobin; NADH, NADPH Oxidoreductases; Oxalates; Oxidative Stress; Phosphatidylcholines; Reactive Oxygen Species; Renal Dialysis; Spectrophotometry, Atomic; Vitamin E

Continuous Erythropoietin Receptor Activator (C.E.R.A.) is a new agent that is in development for the treatment of anemia with extended administration intervals in patients who have chronic kidney disease (CKD), both those on and those not on dialysis. This was an open-label, randomized, multicenter, two-period, crossover study in erythropoiesis-stimulating agentnaïve patients who had CKD and anemia and were receiving peritoneal dialysis. After a 1-wk run-in period, 16 patients were randomly assigned to receive a single administration of intravenous C.E.R.A. 0.4 microg/kg (n = 8) or subcutaneous C.E.R.A. 0.8 microg/kg (n = 8). Six weeks after the first administration of C.E.R.A. (4-wk assessment, 2-wk washout), the route of administration was switched so that all patients received single administrations of both intravenous C.E.R.A. 0.4 microg/kg and subcutaneous C.E.R.A. 0.8 microg/kg. C.E.R.A. had a prolonged and comparable half-life after intravenous (mean 134 h) and subcutaneous (mean 139 h) administration. Reticulocyte counts peaked at a median of 8 d after intravenous and subcutaneous administration with no difference in the time course between administration routes. This resulted in similar mean values for the area under the reticulocyte count-time curve (1191 x 10(9) and 1193 x 10(9).d per L, respectively) and the maximum absolute increase in reticulocyte counts (36 x 10(9) and 41 x 10(9)/L, respectively). C.E.R.A. has a prolonged and comparable half-life after intravenous or subcutaneous injection, suggesting that extended administration intervals may be feasible in patients with CKD.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Cross-Over Studies; Erythropoietin; Female; Hemolysis; Humans; Infusions, Intravenous; Infusions, Parenteral; Kidney Failure, Chronic; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins

Butyrate analogues have been shown to increase fetal hemoglobin (HbF) production in vitro and in vivo. Sodium phenylbutyrate (SPB), an oral agent used to treat individuals with urea-cycle disorders, has been shown to increase HbF in nonanemic individuals and in individuals with sickle cell disease. We have treated eleven patients with homozygous beta thalassemia (three transfusion dependent) and one sickle-beta-thalassemia patient with 20 g/d (forty 500-mg tablets) of SPB for 41 to 460 days. All patients showed an increase in the percent of F reticulocytes associated with treatment, but only four patients responded by increasing their Hb levels by greater than 1 g/dL (mean increase, 2.1 g/dL; range, 1.2 to 2.8 g/dL). None of the transfusion-dependent thalassemia subjects responded. Increase in Hb was associated with an increase in red blood cell number (mean increase, 0.62 x 10(12)/L), and mean corpuscular volume (mean increase, 6 fL). Changes in percent HbF, absolute HbF levels, or alpha- to non-alpha-globin ratios as measured by levels of mRNA and globin protein in peripheral blood did not correlate with response to treatment. Response to treatment was not associated with the type of beta-globin mutation, but baseline erythropoietin levels of greater than 120 mU/mL was seen in all responders and only two of eight nonresponders to SPB. Compliance with treatment was greater than 90% as measured by pill counts. Side effects of the drug included weight gain and/or edema caused by increase salt load in 2/12, transient epigastric discomfort in 7/12, and abnormal body odor in 3/12 subjects. Two splenectomized patients who were not on prophylactic antibiotics developed sepsis while on treatment. We conclude that SPB increases Hb in some patients with thalassemia, but the precise mechanism of action is unknown.

Topics: Adult; Anemia, Sickle Cell; beta-Thalassemia; Blood Transfusion; Erythropoietin; Female; Fetal Hemoglobin; Globins; Hemoglobins; Hemolysis; Homozygote; Humans; Male; Mutation; Patient Compliance; Phenylbutyrates; Reticulocytes

In 4 chronic hemodialysis patients we have tested whether the administration of reduced glutathione (GSH; Glutamed, Boehringer Mannheim Italia; 1,200 mg i.v.) at the end of each hemodialytic session during 90 days could minimize oxidative damage to the red blood cells (RBC) and reduce the recombinant human erythropoietin requirements. Treatment with GSH was followed by an increase in RBC GSH content (n = 3), a normalization of the ascorbine cyanide test (n = 4), an increase in RBC survival (n = 3), and a reduction in 2 patients of the erythropoietin need (41 and 26%, respectively, after 3 months of therapy). When the GSH supplements were terminated, we noticed after 3 months a re-establishment of the baseline values. On the other hand, malonyldialdehyde, RBC deformability, and RBC splenic pool were abnormal before and remain abnormal during the test period. Since no adverse reactions were noticed, these findings seem to indicate the GSH could ameliorate the intraerythrocytic oxidative defense and could be as useful drug in the treatment of anemia in patients affected by chronic renal failure.

Topics: Aged; Anemia; Erythrocyte Count; Erythrocyte Deformability; Erythrocytes; Erythropoietin; Female; Glutathione; Hemolysis; Humans; Male; Malondialdehyde; Oxidative Stress; Recombinant Proteins; Reference Values; Renal Dialysis; Time Factors

The oxidative injury to erythrocytes, red blood cell (RBC) rigidity and splenic hemolysis was assayed in 17 chronically hemodialyzed patients before and during recombinant erythropoietin (EPO) treatment. When a stable hematocrit between 30 and 35% had been established for at least 4 months, a statistically significant increase in RBC volume, hemoglobin concentration, hematocrit, reticulocyte count, and several RBC enzymes (2,3-diphosphoglycerate, glucose 6-phosphate dehydrogenase, pyruvate kinase, hexokinase) was noted. This indicated significant RBC rejuvenation under the influence of EPO. However, no significant improvement in the RBC oxidative sensitivity, RBC deformability, splenic RBC volume, slow mixing splenic RBC volume, and the intrasplenic RBC transit time could be disclosed. These data confirm the existence of an extra-erythrocytic factor in uremic plasma, which is partly responsible for a reduced RBC life span in hemodialysis patients despite EPO treatment.

Topics: Adult; Aged; Anemia; Erythrocyte Aging; Erythrocyte Deformability; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hemolysis; Humans; Kidney Failure, Chronic; Male; Middle Aged; Oxidation-Reduction; Reactive Oxygen Species; Renal Dialysis; Sensitivity and Specificity; Spleen; Uremia

Topics: Anemia; Darbepoetin alfa; Erythropoietin; Fetus; Hematologic Diseases; Hemolysis; Humans; Infant, Newborn

We studied the mechanisms of anemia and the influence of anemia on renal pathology in Dahl/Salt Sensitive (Dahl/SS) rat, a model of cardio-renal-anemia syndrome. Erythrocyte lifespan was shortened and associated with decreased hemoglobin level in the Dahl/SS rats given high-salt diet. Serum haptoglobin decreased, reticulocytes increased, and erythropoiesis in the bone marrow and extramedullary hematopoiesis in the spleen was markedly stimulated by increased serum erythropoietin in them. As a mechanism of hemolysis, we investigated the incidence of eryptosis, suicidal death of erythrocytes. Eryptosis was increased, and red blood cell-derived microparticles, small particle which are generated in hemolytic disease, were also increased in Dahl/SS rats fed with high-salt diet. Deposition of hemosiderin and mitochondrial morphologic abnormality, a sign of ferroptosis, in proximal renal tubules was associated with intravascular hemolysis. Treatment with deferasirox, an oral iron chelator, reduced the renal proximal tubular injury and the glomerular sclerosis in Dahl/SS rats fed with high-salt diet. In conclusion, reduced half-life of erythrocytes induced by hemolysis is the major cause of anemia in Dahl/SS rat. Iron accumulation induced by hemolysis causes renal proximal tubule injury and accelerates renal damage in this model.

Topics: Animals; Bone Marrow Cells; Cellular Senescence; Epithelial Cells; Erythrocytes; Erythroid Cells; Erythropoietin; Half-Life; Hematopoiesis; Hemolysis; Iron Chelating Agents; Kidney Tubules, Proximal; Male; Mitochondria; Rats, Inbred Dahl; Sodium Chloride, Dietary; Spleen

The aim of this study was to investigate the expression pattern of CD55 and CD59 on red blood cells (RBCs) in anemic chronic kidney disease (CKD) patients, and factors that might influence their expression.. Nighty-one adult anemic CKD patients and 80 healthy controls (HCs) were enrolled. Anemic CKD patients were divided into 3 subgroups based on receiving erythropoietin and renal replacement therapies. Flow cytometric analysis of CD55 and CD59 expression was performed on RBCs from blood samples obtained from CKD patients and HCs.. CD59 deficiency was significantly higher among CKD patients than HCs (n = 68, 74.7%, vs. n = 13, 16.3%, respectively; p < 0.001). The median proportions of CD55- and CD59-deficient RBCs in CKD patients were significantly higher compared to HCs (0.34 vs. 0.15, and 4.3 vs. 2.0, p < 0.001 and p < 0.001, respectively). The mean fluorescence intensity (MFI) of CD55 and CD59 expression was significantly lower in CKD patients compared to HCs (1.2 vs. 2.8, and 17.0 vs. 20.3, p < 0.04 and p < 0. 001, respectively). The hemoglobin level was inversely correlated with the proportions of CD55- and CD59-deficient RBCs (r = -0.37, p < 0.001, and r = -0.22, p < 0.02, respectively). The number of CD59-deficient patients was significantly different between the 3 subgroups of CKD patients (p = 0.001), and a significant difference was present in the MFI of CD55 and CD59 expression among the 3 subgroups (p = 0.04 and p = 0.03, respectively).. The expression pattern of CD55 and CD59 on RBCs is altered in anemic CKD patients, which could play a role in the pathogenesis of anemia in CKD.

Topics: Adult; Aged; Anemia; Biomarkers; CD55 Antigens; CD59 Antigens; Erythrocytes; Erythropoietin; Female; Flow Cytometry; Hemolysis; Humans; Male; Middle Aged; Renal Insufficiency, Chronic

Neonatal unconjugated hyperbilirubinemia might cause severe bilirubin neurotoxicity in especially hemolytic conditions. The study aimed to elucidate the potential neuroprotective effects of erythropoietin (EPO) in hemolysis-induced hyperbilirubinemia. In newborn rats, hyperbilirubinemia secondary to hemolysis was induced by injecting with phenylhydrazine hydrochloride (PHZ) and rats were injected with either vehicle or EPO. At 54th hour of the PHZ injection, rats were decapitated. Serum levels of TNF-α, IL-1β, IL-10, brain-derived neurotrophic factor (BDNF) and S100-B and brain malondialdehyde, glutathione levels and myeloperoxidase activities were measured. TUNEL staining and NF-κB expression were evaluated. As compared to control pups, in vehicle-treated PHZ group, TNF-α and IL-1β levels, malondialdehyde level and myeloperoxidase activity were increased with concomitant decreases in IL-10 and glutathione. All EPO regimens reversed PHZ-induced alterations in IL-10, TNF-α, malondialdehyde and glutathione levels. Three-day-treatment abolished increases in myeloperoxidase activity and IL-1β levels, while BDNF and S100-B were elevated. Increased TUNEL (+) cells and NF-κB expressions in the brain of PHZ group were reduced in the 3-day-treated group. EPO exerted anti-inflammatory effects on PHZ-induced neural damage in newborn rats, while the neuroprotection was more obvious when the treatments were repeated successively. The results suggest that EPO treatment may have a therapeutic potential in supporting neuroplasticity in the hyperbilirubinemic neonates.

Topics: Animals; Animals, Newborn; Erythropoietin; Female; Hemolysis; Hyperbilirubinemia; Male; Neuroprotective Agents; Phenylhydrazines; Rats; Rats, Sprague-Dawley; Treatment Outcome

Rapid body mass loss (RBML) before competition was found to decrease hemoglobin mass (Hbmass ) in elite boxers. This study aimed to investigate the underlying mechanisms of this observation. Fourteen well-trained combat athletes who reduced body mass before competitions (weight loss group, WLG) and 14 combat athletes who did not practice RBML (control group, CON) were tested during an ordinary training period (t-1), 1-2 days before an official competition (after 5-7 days RBML in WLG, t-2), and after a post-competition period (t-3). In WLG, body mass (-5.5%, range: 2.9-6.8 kg) and Hbmass (-4.1%) were significantly (P < 0.001) reduced after RBML and were still decreased by 1.6% (P < 0.05) and 2.6% (P < 0.001) at t-3 compared with t-1. After RBML, erythropoietin, reticulocytes, haptoglobin, triiodothyronine (FT3 ), and free androgen index (FAI) were decreased compared with t-1 and t-3. An increase occurred in ferritin and bilirubin. Peak treadmill-running performance and VO2peak did not change significantly, but performance at 4-mmol lactate threshold was higher after RBML (P < 0.05). In CON, no significant changes were found in any parameter. Apparently, the significant decrease in Hbmass after RBML in combat athletes was caused by impaired erythropoiesis and increased hemolysis without significant impact on aerobic performance capacity.

Topics: Adolescent; Adult; Anaerobic Threshold; Androgens; Boxing; Erythropoiesis; Erythropoietin; Exercise; Haptoglobins; Hemoglobins; Hemolysis; Humans; Male; Martial Arts; Plasma Volume; Reticulocyte Count; Sports; Triiodothyronine; Weight Loss; Wrestling; Young Adult

Renal hypoplasia due to a congenitally reduced number of nephrons progresses to chronic kidney disease and may cause renal anemia, given that the kidneys are a major source of erythropoietin in adults. Hypoplastic kidney (HPK) rats have only about 20% of the normal number of nephrons and develop CKD. This study assessed the renal function and hematologic changes in HPK rats from 70 to 210 d of age. HPK rats demonstrated deterioration of renal excretory function, slightly macrocytic erythropenia at all days examined, age-related increases in splenic hemosiderosis accompanied by a tendency toward increased hemolysis, normal plasma erythropoietin levels associated with increased hepatic and decreased renal erythropoietin production, and maintenance of the response for erythropoietin production to hypoxic conditions, with increased interstitial fibrosis at 140 d of age. These results indicate that increases in splenic hemosiderosis and the membrane fragility of RBC might be associated with erythropenia and that hepatic production of erythropoietin might contribute to maintaining the blood Hgb concentration in HPK rats.

Topics: Age Factors; Anemia; Animals; Biomarkers; Carrier Proteins; Disease Models, Animal; Disease Progression; Erythrocytes; Erythropoietin; Fibrosis; Genetic Predisposition to Disease; Hemolysis; Hemosiderosis; Iron; Kidney; Kidney Diseases; Male; Mutation; Osmotic Fragility; Phenotype; Rats; Rats, Inbred Strains; Renal Insufficiency, Chronic; Spleen

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

Aquaporin-1 (AQP1) is the membrane water channel responsible for changes in erythrocyte volume in response to the tonicity of the medium. As the aberrant distribution of proteins in hereditary spherocytosis (HS) generates deficiencies of proteins other than those codified by the mutated gene, we postulated that AQP1 expression might be impaired in spherocytes. AQP1 expression was evaluated through flow cytometry in 5 normal controls, 1 autoimmune hemolytic anemia, 10 HS (2 mild, 3 moderate, 2 severe, and 3 splenectomized), and 3 silent carriers. The effect of AQP1 inhibitors was evaluated through water flow-based tests: osmotic fragility and hypertonic cryohemolysis. Serum osmolality was measured in 20 normal controls and 13 HS. The effect of erythropoietin (Epo) on AQP1 expression was determined in cultures of erythroleukemia UT-7 cells, dependent on Epo to survive. Independent of erythrocyte size, HS patients showed a lower content of AQP1 in erythrocyte membranes which correlated with the severity of the disease. Accordingly, red blood cells from HS subjects were less sensitive to cryohemolysis than normal erythrocytes after inhibition of the AQP1 water channel. A lower serum osmolality in HS with respect to normal controls suggests alterations during reticulocyte remodeling. The decreased AQP1 expression could contribute to explain variable degrees of anemia in hereditary spherocytosis. The finding of AQP1 expression induced by Epo in a model of erythroid cells may be interpreted as a mechanism to restore the balance of red cell water fluxes.

Topics: Adolescent; Adult; Anemia, Hemolytic, Autoimmune; Aquaporin 1; Biological Transport; Body Water; Cell Line; Child; Child, Preschool; Erythrocyte Membrane; Erythrocytes; Erythropoietin; Gene Expression Regulation; Hemolysis; Heterozygote; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Middle Aged; Osmolar Concentration; Osmotic Fragility; Spherocytosis, Hereditary; Splenectomy

Although the importance of native bone marrow and spleen macrophages in enhancing baseline and stress erythropoiesis has been emphasized over several decades, their kinetic and phenotypic changes during a variety of stress responses have been unclear. Furthermore, whether monocyte-derived recruited macrophages can functionally substitute for inadequate or functionally impaired native macrophages has been controversial and seem to be not only tissue- but also stress-type dependent. To provide further insight into these issues, we made detailed observations at baseline and post-erythroid stress (E-stress) in 2 mouse models with genetically depressed macrophage numbers and compared them to their controls. We documented that, irrespective of the stress-induced (hemolytic or post-erythropoietin [Epo]) treatment, only native CD11b(lo) splenic macrophages expand dramatically post-stress in normal mice without significant changes in the monocyte-derived CD11b(hi) subset. The latter remained a minority and did not change post-stress in 2 genetic models lacking either Spi-C or VCAM-1 with impaired native macrophage proliferative expansion. Although CD11b(lo) macrophages in these mice were one-fifth of normal at their peak response, surprisingly, their erythroid response was not compromised and was similar to controls. Thus, despite the prior emphasis on numerical macrophage reliance to provide functional rescue from E-stress, our data highlight the importance of previously described non-macrophage-dependent pathways activated under certain stress conditions to compensate for low macrophage numbers.

Topics: Animals; Bone Marrow; DNA-Binding Proteins; Erythropoiesis; Erythropoietin; Hemolysis; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Phenylhydrazines; Recombinant Proteins; Spleen; Stress, Physiological; Vascular Cell Adhesion Molecule-1

Prolonged running is known to induce hemolysis. It has been suggested that hemolysis may lead to a significant loss of red blood cells; however, its actual impact on the erythrocyte pool is unknown. Here, we test the hypothesis that prolonged running with high hemolytic potential decreases total red blood cell volume (RCV). Hemolysis (n = 22) and RCV (n = 19) were quantified in ultra-marathon runners before and after a 166-km long mountain ultra-endurance marathon (RUN) with 9500 m of altitude gain/loss. Assessment of total hemoglobin mass (Hbmass) and RCV was performed using a carbon monoxide rebreathing technique. RUN induced a marked acute-phase response and promoted hemolysis, as shown by a decrease in serum haptoglobin (P < 0.05). Elevated serum erythropoietin concentration and reticulocyte count after RUN were indicative of erythropoietic stimulation. Following RUN, runners experienced hemodilution, mediated by a large plasma volume expansion and associated with a large increase in plasma aldosterone. However, neither Hbmass nor RCV were found to be altered after RUN. Our findings indicate that mechanical/physiological stress associated with RUN promotes hemolysis but this has no impact on total erythrocyte volume. We therefore suggest that exercise 'anemia' is entirely due to plasma volume expansion and not to a concomitant decrease in RCV.

Topics: Adult; Aldosterone; Altitude; Erythrocyte Count; Erythrocyte Volume; Erythropoietin; Haptoglobins; Hemoglobins; Hemolysis; Humans; Male; Middle Aged; Physical Endurance; Plasma; Reticulocyte Count; Running; Water-Electrolyte Balance

Anthrax is a disease caused by the bacterium Bacillus anthracis, which results in high mortality in animals and humans. Although some of the mechanisms are already known such as asphyxia, extensive knowledge of molecular pathogenesis of this disease is deficient and remains to be further investigated. Lethal toxin (LT) is a major virulence factor of B. anthracis and a specific inhibitor/protease of mitogen-activated protein kinase kinases (MAPKKs). Anthrax LT causes lethality and induces certain anthrax-like symptoms, such as anemia and hypoxia, in experimental mice. Mitogen-activated protein kinases (MAPKs) are the downstream pathways of MAPKKs, and are important for erythropoiesis. This prompted us to hypothesize that anemia and hypoxia may in part be exacerbated by erythropoietic dysfunction. As revealed by colony-forming cell assays in this study, LT challenges significantly reduced mouse erythroid progenitor cells. In addition, in a proteolytic activity-dependent manner, LT suppressed cell survival and differentiation of cord blood CD34(+)-derived erythroblasts in vitro. Suppression of cell numbers and the percentage of erythroblasts in the bone marrow were detected in LT-challenged C57BL/6J mice. In contrast, erythropoiesis was provoked through treatments of erythropoietin, significantly ameliorating the anemia and reducing the mortality of LT-treated mice. These data suggested that suppressed erythropoiesis is part of the pathophysiology of LT-mediated intoxication. Because specific treatments to overcome LT-mediated pathogenesis are still lacking, these efforts may help the development of effective treatments against anthrax.

Topics: Anemia; Animals; Anthrax; Antigens, Bacterial; Apoptosis; Bacterial Toxins; Biocatalysis; Cell Differentiation; Colony-Forming Units Assay; Disease Progression; Erythroid Cells; Erythropoiesis; Erythropoietin; Hemolysis; Humans; Male; Mice; Mice, Inbred C57BL; Proteolysis; Survival Analysis

Topics: Biochemistry; Erythropoietin; Hemoglobin, Sickle; Hemoglobins; Hemolysis; History, 20th Century; History, 21st Century; Humans; Hypoxia-Inducible Factor 1

Topics: Adrenal Cortex Hormones; Aged, 80 and over; Darbepoetin alfa; Erythropoietin; Hematinics; Hemolysis; Humans; Lymphoma, Mantle-Cell; Male; Syndrome; Transfusion Reaction

Erythropoietin (EPO) plays a key regulatory role in the formation of new red blood cells (RBCs). Erythropoietin may also have a role as a therapeutic agent to counteract ischemic injury in neural, cardiac and endothelial cells. One of the limitations preventing the therapeutic application of EPO is its short half-life. The goal of this study was to develop a gene delivery system for the prolonged and controlled release of EPO. The arginine grafted bioreducible polymer (ABP) and its PEGylated version, ABP-PEG10, were utilized to study the expression efficiency and therapeutic effectiveness of this erythropoietin gene delivery system in vitro. Poly(ethylene glycol) (PEG) modification of the ABP was employed to inhibit the particle aggregation resulting from the interactions between cationic polyplexes and the negatively charged proteins typically present in serum. Both the ABP and the ABP-PEG10 carriers demonstrated efficient transfection and long-term production of EPO in a variety of cell types. The expressed EPO protein stimulated hematopoietic progenitor cells to form significant numbers of cell colonies in vitro. These data confirm that this EPO gene delivery system using a bioreducible polymeric carrier, either ABP or ABP-PEG 10, merits further testing as a potential therapeutic modality for a variety of clinically important disease states.

Topics: Animals; Apoptosis; Arginine; Cell Line; Cell Survival; DNA; Drug Carriers; Erythrocytes; Erythropoietin; Hemolysis; Leukocytes, Mononuclear; Nanoparticles; Polymers; Rats; Rats, Sprague-Dawley; Transfection

The total artificial heart (TAH) replaces the heart with 2 pneumatic pumps and 4 tilting disk mechanical valves. It was hypothesized that patients receiving TAH support have persistent hemolysis that resolves after heart transplantation (HT).. Hematocrit (HCT) was compared in patients on TAH to left ventricular assist device (LVAD) support for bridge to HT. Data were compared with t tests. The TAH (n = 36; mean age 47 ± 13 years) and LVAD patients (n = 14; mean age 53 ± 12 years) were supported for a median of 83 (interquartile range [IQR] 43-115) and 106 days (IQR 84-134), respectively. Hematocrit was similar between the TAH and LVAD patients (34 ± 6% vs 37 ± 5%; P = .07) at baseline. After placement, TAH patients had lower HCT at 2 (20 ± 2% vs 24 ± 3%), 4 (22 ± 3% vs 26 ± 3%), 6 (22 ± 4% vs 30 ± 4%), and 8 weeks (23 ± 4% vs 33 ± 5%; P < .001 for all). There were no differences in HCT at 1 (30 ± 4% vs 29 ± 7%; P = .42) and 3 months (35 ± 7% vs 35 ± 4%; P = .98) after removal of the devices for HT. TAH patients had undetectable haptoglobin in 96% of assessments, increased lactate dehydrogenase (1,128 ± 384 units/L), and detectable plasma free hemoglobin in 40% of measurements (21 ± 15 mg/dL). High sensitivity C-reactive protein (52 ± 50 mg/dL) was elevated, and reticulocyte production index was decreased (1.6 ± 0.6).. Patients implanted with a TAH have persistent anemia that resolves only after HT. The association of hemolysis, ineffective erythropoiesis, and inflammation with the TAH warrants further study.

Topics: Adult; Aged; Anemia; C-Reactive Protein; Erythropoietin; Female; Heart Transplantation; Heart Ventricles; Heart-Assist Devices; Hematocrit; Hemolysis; Humans; Luminescent Measurements; Male; Middle Aged; Retrospective Studies

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

We report the perioperative management of a woman expressing an antibody against high frequency red cell antigen (anti-Kel4 antibody anti-kpb) who was scheduled for a total knee replacement. A specific strategy was designed to afford this major orthopedic surgery, considering specially the occurrence of unusual bleeding higher than the average bleeding assessed in our hospital in this indication. The transfusion of incompatible red cells may be responsible for acute hemolytic reaction. An autologous transfusion program, including cryopreservation, erythropoietin and iron support, was provided. Three autologous red cells units were collected before surgery. Compatible homologous red cells units were also available at the French bank for rare blood groups. We report logistical and medical problems that have occurred during the perioperative period.

Topics: Aged, 80 and over; Antigens; Arthroplasty, Replacement, Knee; Blood Loss, Surgical; Blood Preservation; Blood Transfusion, Autologous; Cryopreservation; Erythrocyte Transfusion; Erythrocytes; Erythropoietin; Female; Hemoglobins; Hemolysis; Humans; Iron; Patient Care Planning; Recombinant Proteins

Cadmium is a toxic heavy metal and distributed widely in the environment. In addition to damaging the liver, kidneys, and bone, cadmium causes anemia through hemolysis, iron deficiency, and insufficient erythropoietin (EPO) production (renal anemia) along with changes in iron metabolism. Here, we investigated the role of iron in the interdependent progress of three types of anemia in cadmium-injected rats fed iron-sufficient or iron-deficient diets for 1 or 3 months. Cadmium injections for 1 month induced renal anemia without renal injury. Injections for 3 months induced hemolysis, iron deficiency, and renal anemia, accompanied by hepatic and renal damage. Iron concentrations in the liver, kidney, and spleen were increased, derived from internally released iron from hemolyzed red blood cells, increased duodenal iron absorption, insufficient erythropoiesis, and hepatic ferritin overproduced by cadmium-induced interleukin-6. Therefore, the iron deficiency anemia was actually apparent. Cadmium suppressed renal EPO production through a direct effect, accumulated iron, and destruction of EPO-producing cells. Increased duodenal iron absorption could be attributed to hypertrophy of the duodenal mucosa derived from anemia. Thus, insufficient EPO production and iron accumulation are the central factors driving anemia in cadmium toxicity.

Topics: Anemia, Iron-Deficiency; Animals; Cadmium; Erythrocyte Count; Erythropoiesis; Erythropoietin; Female; Ferritins; Hemolysis; Interleukin-6; Iron, Dietary; Kidney; Liver; Rats; Rats, Wistar; RNA, Messenger; Spleen

Severe malaria is difficult to differentiate from other forms of malaria or other infections with similar symptoms. Any parameter associated to malaria-attributable severe disease could help to improve severe malaria diagnosis.. This study assessed the relation between erythropoietin (EPO) and malaria-attributable severe disease in an area of Mozambique with moderate malaria transmission. 211 children <5 years, recruited at Manhiça District Hospital or in the surrounding villages, were included in one of the following groups: severe malaria (SM, n = 44), hospital malaria without severity (HM, n = 49), uncomplicated malaria (UM, n = 47), invasive bacterial infection without malaria parasites (IBI, n = 39) and healthy community controls (C, n = 32). Malaria was diagnosed by microscopy and IBI by blood/cerebrospinal fluid culture.. Mean EPO concentration in the control group was 20.95 U/l (SD = 2.96 U/l). Values in this group were lower when compared to each of the clinical groups (p = 0.026 C versus UM, p<0.001 C vs HM, p<0.001 C vs SM and p<0.001 C vs IBI). In the 3 malaria groups, values increased with severity [mean = 40.82 U/l (SD = 4.07 U/l), 125.91 U/l (SD = 4.99U/l) and 320.87 U/l (SD = 5.91U/l) for UM, HM and SM, respectively, p<0.001]. The IBI group [mean = 101.75 U/l (SD = 4.12 U/l)] presented lower values than the SM one (p = 0.002). In spite of the differences, values overlapped between study groups and EPO levels were only associated to hemoglobin. Hemoglobin means of the clinical groups were 93.98 g/dl (SD = 14.77 g/dl) for UM, 75.96 g/dl (SD = 16.48 g/dl) for HM, 64.34 g/dl (SD = 22.99 g/dl) for SM and 75.67 g/dl (SD = 16.58 g/dl) for IBI.. Although EPO levels increase according to malaria severity and are higher in severe malaria than in bacteremia, the utility of EPO to distinguish malaria-attributable severe disease is limited due to the overlap of values between the study groups and the main role of hemoglobin in the expression of EPO.

Topics: Bacteremia; Bilirubin; Child, Preschool; Diagnosis, Differential; Erythropoietin; Female; Hemoglobins; Hemolysis; Humans; Infant; L-Lactate Dehydrogenase; Malaria; Male; Mozambique

To understand the molecular mechanisms underlying compound-induced hemangiosarcomas in mice, and therefore, their human relevance, a systems biology approach was undertaken using transcriptomics and Causal Network Modeling from mice treated with 2-butoxyethanol (2-BE). 2-BE is a hemolytic agent that induces hemangiosarcomas in mice. We hypothesized that the hemolysis induced by 2-BE would result in local tissue hypoxia, a well-documented trigger for endothelial cell proliferation leading to hemangiosarcoma. Gene expression data from bone marrow (BM), liver, and spleen of mice exposed to a single dose (4 h) or seven daily doses of 2-BE were used to develop a mechanistic model of hemangiosarcoma. The resulting mechanistic model confirms previous work proposing that 2-BE induces macrophage activation and inflammation in the liver. In addition, the model supports local tissue hypoxia in the liver and spleen, coupled with increased erythropoeitin signaling and erythropoiesis in the spleen and BM, and suppression of mechanisms that contribute to genomic stability, events that could be contributing factors to hemangiosarcoma formation. Finally, an immunohistochemistry method (Hypoxyprobe) demonstrated that tissue hypoxia was present in the spleen and BM. Together, the results of this study identify molecular mechanisms that initiate hemangiosarcoma, a key step in understanding safety concerns that can impact drug decision processes, and identified hypoxia as a possible contributing factor for 2-BE-induced hemangiosarcoma in mice.

Topics: Animals; Bone Marrow; Cell Cycle; Cell Differentiation; Cell Hypoxia; Cell Proliferation; Cell Transformation, Neoplastic; Disease Models, Animal; Endothelial Cells; Erythropoiesis; Erythropoietin; Ethylene Glycols; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genomic Instability; Hemangiosarcoma; Hematopoietic Stem Cells; Hemolysis; Hepatitis; Immunohistochemistry; Liver; Macrophage Activation; Male; Mice; Models, Biological; Signal Transduction; Spleen; Systems Biology; Time Factors

There are different approaches for treating recurrent hepatitis C viral infection after a liver transplant. However, sustained virologic response is achieved in < 40% of infected allografts. We examined sustained virologic response improvement using a prolonged course of peginterferon and aggressive use of ribavirin.. From October 1998 to May 2008, 24 patients (13 male, 11 female; mean age at transplant, 49.4 +/- 7.7 years) received a prolonged course of peginterferon and ribavirin (range, 48-180 weeks). The mean interval from liver transplant to hepatitis C antiviral therapy was 26.6 +/- 27.8 months. Patients began weight-based standard dosages of peginterferon and ribavirin. In case of hemolysis, patients were treated with Epogen, with and without blood transfusions.. Fourteen patients (58.3%) had an end of treatment response, and 8 patients (33.3%) maintained sustained virologic response after the first course of therapy. Of 10 patients who did not respond to the first course, 6 received an extended course of antiviral therapy after a mean of 15 +/- 4.6 weeks from completion of first course. Five of these 6 patients achieved end of treatment response and maintained a sustained virologic response, resulting in an overall end of treatment response in 17 patients and a sustained virologic response in 13 patients. Twenty-two patients experienced hemolysis and were treated with Epogen. Fifteen patients received blood transfusions. Ribavirin dosage was reduced in 12 patients, and peginterferon dosage was reduced in 2 patients.. Aggressive use of ribavirin and prolonged course of peginterferon provided sustained virologic response in 54.1% of liver transplant recipients with recurrent hepatitis C virus-infection. More prospective studies are warranted to evaluate the benefit of this approach fully.

Topics: Adult; Antiviral Agents; Blood Transfusion; Drug Administration Schedule; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Female; Genotype; Hematinics; Hemolysis; Hepacivirus; Hepatitis C; Humans; Interferon alpha-2; Interferon-alpha; Liver Transplantation; Male; Middle Aged; Pennsylvania; Polyethylene Glycols; Recombinant Proteins; Recurrence; Retrospective Studies; Ribavirin; RNA, Viral; Time Factors; Treatment Outcome; Viral Load

Topics: Acetylcysteine; Aged; Aortic Valve; Aortic Valve Insufficiency; Aspartate Aminotransferases; Bilirubin; Cardiac Catheterization; Drug Administration Schedule; Erythropoietin; Ferrous Compounds; Folic Acid; Glucose; Heart Valve Prosthesis; Hematinics; Hemoglobinuria; Hemolysis; Humans; Infusions, Intravenous; L-Lactate Dehydrogenase; Male; Mitral Valve; Mitral Valve Insufficiency; Renal Insufficiency; Treatment Outcome; Ultrasonography

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

Whether structural changes of the erythrocyte membrane increase the susceptibility to hemolysis particularly of the relatively older cell population during the early phase of a 216-km ultrarace was tested in six male runners (age 53.6 +/- 10.4 yr, height 175.8 +/- 11.1 cm, body mass 75.9 +/- 8.4 kg). Erythrocyte membrane spectrins were lowest (P < 0.001) after 42 km (75.59 +/- 5.25% of prerace) and increased (P < 0.001) toward 216 km (88.27 +/- 3.37%). Susceptibility to osmotic hemolysis was highest (P < 0.01) after 42 km (107.34 +/- 3.02 mOsm sodium phosphate buffer) with almost identical (P > 0.05) values prerace (97.98 +/- 3.41 mOsm) and postrace (98.61 +/- 3.26 mOsm). Haptoglobin indicated intravascular hemolysis of 9.27 x 10(9) cells/l (P < 0.05) during the initial 84 km. Changes in hematocrit and plasma proteins indicated an estimated total net erythrocyte loss of 3.47 x 10(11) cells/l (P < 0.05) after 21 km. This was compensated by a gain in erythrocytes (P < 0.05) of 3.31 x 10(11) cells/l during the final 132 km. A main effect (P < 0.05) on erythropoietin suggests increased erythropoiesis throughout the race. Exercise-induced hemolysis reflects alterations in erythrocyte membrane spectrins and occurs particularly in the early phase of an ultraendurance race because of a relative older cell population.

Topics: Adult; Aging; Erythrocyte Membrane; Erythropoiesis; Erythropoietin; Exercise; Haptoglobins; Hemolysis; Humans; Male; Membrane Proteins; Middle Aged; Physical Endurance; Running; Spectrin

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by intravascular hemolysis leading to anemia and other clinical manifestations. Transfusions are often required to support hemoglobin at tolerable levels. A PNH patient with aplastic anemia was treated with the complement inhibitor eculizumab, followed by concurrent treatment with recombinant human erythropoietin (rHuEpo). Eculizumab alone reduced hemolysis, increased PNH red blood cell (RBC) mass, and decreased transfusions. Addition of rHuEpo during eculizumab therapy, enhanced erythropoiesis, further increased PNH RBC mass and hemoglobin levels, and rendered the patient transfusion independent for more than two years. These data show that driving erythropoiesis during eculizumab treatment provided further benefit to a patient with PNH and underlying bone marrow failure.

Topics: Anemia, Aplastic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Blood Transfusion; Complement C5; Drug Synergism; Erythrocyte Indices; Erythropoiesis; Erythropoietin; Hemoglobins; Hemoglobinuria, Paroxysmal; Hemolysis; Humans; Male; Middle Aged; Recombinant Proteins; Treatment Outcome

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

Clinical uses for recombinant human erythropoietin (rHuEPO) therapy continue to expand. Initial use was in anaemia associated with end-stage renal disease, but more recently there have been many reports of the benefits of erythropoietin in other clinical situations such as cancer-related anaemia. Recombinant erythropoietin reduces the need for blood transfusion and hence exposure to donor blood products as well as improving quality of life. We report four patients who were transfusion dependent, none of whom had licensed indications for the use of recombinant erythropoietin. Two patients had microangiopathic haemolytic anaemia secondary to mechanical valve haemolysis and were unsuitable for any further cardiac intervention. One patient had anaemia of chronic disease and anti-Vel red cell antibodies, making compatible blood transfusions difficult to obtain. The fourth patient had primary thrombocythaemia and developed transfusion-dependent anaemia secondary to myelosuppressive agents. All four patients had a relative deficiency in endogenous erythropoietin levels ranging between 7 and 41 IU/l. After commencing recombinant erythropoietin therapy, all had a response in haemoglobin of at least 1 g/dl with an overall improvement in their quality of life. We conclude that rHuEPO is a very convenient and useful form of treatment in transfusion-dependent anaemia and in some cases beyond the licensed indications.

Topics: Adult; Aged; Anemia; Antineoplastic Agents; Blood Group Antigens; Drug Approval; Erythropoietin; Female; Hemolysis; Humans; Kidney Failure, Chronic; Middle Aged; Neoplasms; Recombinant Proteins; Transfusion Reaction

The in vitro growth of erythroid colonies in the absence of erythropoietin, known as endogenous erythroid colonies (EEC) forms part of the diagnostic criteria for polycythaemia vera (PV). The availability of EEC culture in routine laboratory setting is limited as culture methods are technically demanding, difficult to standardize, expensive and laborious. In this study, we assessed the performance characteristics of a simplified method using ammonium chloride red cell lysis followed by culture on commercially available, batch-tested, methylcellulose media. Seventy-six patients were included; four were secondarily excluded on the basis of culture failure. Of the 14 patients with PV, 13 (93%) were positive for EEC on at least one occasion: 90% (nine of 10) of bone marrow and 67% (six of nine) of peripheral blood specimens were positive. All 30 patients with secondary polycythaemia (n = 12) or apparent polycythaemia (n = 18) were negative for EEC. The incidence of EEC in idiopathic erythrocytosis was 40% (eight of 28); 50% (five of 10) in those who met one of the minor criteria for PV and 17% (three of 18) in those who did not. We conclude that our EEC assay yield results comparable with that of more elaborate methods.

Topics: Ammonium Chloride; Bone Marrow; Cell Culture Techniques; Colony-Forming Units Assay; Erythroid Precursor Cells; Erythropoietin; Female; Hemolysis; Humans; Male; Polycythemia Vera; Predictive Value of Tests; Sensitivity and Specificity

Hepatitis C virus (HCV) is currently the most common etiology for liver transplantation (LTx) in the United States. A significant number of patients develop recurrent HCV after LTx. Although there is no completely satisfactory treatment for recurrent HCV, a combination of interferon-alpha (INF) and ribavirin remains the most widely used. Ribavirin is eliminated through the kidneys and tends to accumulate in the presence of renal dysfunction. The primary side effect of ribavirin is hemolysis. The goal of the present study was to correlate the incidence of hemolysis with renal function in LTx patients with recurrent HCV who were being treated with ribavirin. The incidence of hemolysis and the renal function were examined in 72 liver transplant patients (58 male and 14 female patients) with recurrent HCV receiving INF (3 million units, three times per week) and ribavirin (initial dose of 400 mg twice daily). Patients were grouped according to the decrease in the percentage of hematocrit after the introduction of ribavirin, with their baseline serum creatinine and creatinine clearance calculated using the Cockcroft-Gault formula. The decrease in the percentage of hematocrit after ribavirin treatment was also examined with respect to creatinine clearance as a continuous variable. In addition, for purposes of presentation, patients were analyzed in three groups: creatinine clearance of >/= 70 mL/min (group A), creatinine clearance < 70 mL/min and >/= 40 mL/min (group B), and creatinine clearance < 40 mL/min (group C). Forty-five (62.5%) patients experienced a decrease in hematocrit (Hct) >/=15% after starting INF and ribavirin. The mean serum creatinine was 1.3 +/- 0.5 mg/dL (median, 1.3) in this group, and the mean calculated creatinine clearance was 71 +/- 29 mL/min (median, 66.47). In the 27 patients who did not show a significant decrease (< 15%) in hematocrit, the mean serum creatinine was 1.1 +/- 0.3 mg/dL (median, 1.0) and the mean creatinine clearance was 95 +/- 39 (median, 96) mL/min (P =.018). On continuous variable of calculated creatinine clearance, there was a trend in the decrease in hematocrit after ribavirin treatment compared with pretreatment (P =.09). However, the rate of hemolysis was significantly different in group A (53.7%), group B (70.8%), and group C (100%) (P =.042). Patients on INF and ribavirin therapy who experienced hemolysis had significantly higher serum creatinine levels and lower creatinine clearances compared with those who d

Topics: Adult; Antiviral Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Erythropoietin; Female; Hemolysis; Hepatitis C; Humans; Interferon-alpha; Kidney; Liver; Liver Transplantation; Male; Middle Aged; Retrospective Studies; Ribavirin

Studies of space-flight anemia have uncovered a physiologic process, neocytolysis, by which young red blood cells are selectively hemolyzed, allowing rapid adaptation when red cell mass is excessive for a new environment.. 1) To confirm that neocytolysis occurs in another situation of acute plethora-when high-altitude dwellers with polycythemia descend to sea level; and 2) to clarify the role of erythropoietin suppression.. Prospective observational and interventional study.. Cerro de Pasco (4380 m) and Lima (sea level), Peru.. Nine volunteers with polycythemia.. Volunteers were transported to sea level; three received low-dose erythropoietin.. Changes in red cell mass, hematocrit, hemoglobin concentration, reticulocyte count, ferritin level, serum erythropoietin, and enrichment of administered(13)C in heme.. In six participants, red cell mass decreased by 7% to 10% within a few days of descent; this decrease was mirrored by a rapid increase in serum ferritin level. Reticulocyte production did not decrease, a finding that establishes a hemolytic mechanism.(13)C changes in circulating heme were consistent with hemolysis of young cells. Erythropoietin was suppressed, and administration of exogenous erythropoietin prevented the changes in red cell mass, serum ferritin level, and(13)C-heme.. Neocytolysis and the role of erythropoietin are confirmed in persons with polycythemia who descend from high altitude. This may have implications that extend beyond space and altitude medicine to renal disease and other situations of erythropoietin suppression, hemolysis, and polycythemia.

Topics: Adaptation, Physiological; Adult; Altitude; Cell Count; Erythrocytes; Erythropoietin; Ferritins; Hematocrit; Hemoglobins; Hemolysis; Humans; Male; Middle Aged; Polycythemia; Prospective Studies; Reticulocytes

Topics: Aerospace Medicine; Altitude; Erythrocytes; Erythropoietin; Hemolysis; Humans; Sports Medicine

We have described the rapid destruction of young red blood cells (neocytolysis) in astronauts adapting to microgravity, in polycythemic high altitude dwellers who descend to sea level, and in patients with kidney disorders. This destruction results from a decrease in erythropoietin (EPO) production. We hypothesized that such EPO withdrawal could trigger physiological changes in cells other than red cell precursors and possibly lead to the uptake and destruction of young red cells by altering endothelial cell-macrophage interactions, most likely occurring in the spleen.. We identified EPO receptors on human splenic endothelial cells (HSEC) and investigated the responses of these cells to EPO withdrawal.. A monolayer of HSEC, unlike human endothelial cells from aorta, glomerulus, or umbilical vein, demonstrated an increase in permeability upon EPO withdrawal that was accompanied by unique morphological changes. When HSEC were cultured with monocyte-derived macrophages (but not when either cell type was cultured alone), EPO withdrawal induced an increased ingestion of young red cells by macrophages when compared with the constant presence or absence of EPO.. HSEC may represent a unique cell type that is able to respond to EPO withdrawal by increasing permeability and interacting with phagocytic macrophages, which leads to neocytolysis.

Topics: Adaptation, Physiological; Cells, Cultured; Endothelium, Vascular; Epoetin Alfa; Erythrocyte Aging; Erythrocytes; Erythropoietin; Hemolysis; Humans; In Vitro Techniques; Macrophages; Microscopy, Electron; Models, Biological; Receptors, Erythropoietin; Recombinant Proteins; Spleen; Weightlessness

Topics: Erythropoietin; Female; Heart Valve Prosthesis; Hemolysis; Humans; Middle Aged; Mitral Valve Stenosis; Uremia

Haptoglobin knockout (Hp-/-) mice are more sensitive to phenylhydrazine-induced hemolysis than Hp+/+ mice.. Hemolysis was induced in Hp-/- and Hp+/+ mice using phenylhydrazine. Relative renal tissue damage and function were then assessed.. Hp-/- mice had higher basal levels of renal lipid peroxidation, as evidenced by levels of malonaldehyde and 4-hydroxy-2(E)-nonenal (MDA/HNE). After the administration of phenylhydrazine, levels of 8-hydroxyguanine (but not other products of oxidative DNA damage) were significantly elevated in the renal DNA. There was also increased induction of heme oxygenase-1. The more severe renal damage in Hp-/- mice was also evident in the delayed erythropoietin gene expression and poorer renal clearance of 3H-inulin. This reduction in glomerular filtration function in Hp+/+ and Hp-/- mice could be restored to baseline by vasodilators (prazosin or diazoxide), implicating renal vasoconstriction as a major mechanism of acute renal failure during induced hemolysis. Precipitation of hemoglobin in the kidney was not increased in Hp-/- mice.. Haptoglobin appears to play an important physiological role as an antioxidant, particularly during hemolysis.

Topics: Acute-Phase Reaction; Aldehydes; Animals; Antioxidants; DNA; Erythropoietin; Gene Expression Regulation, Enzymologic; Guanine; Haptoglobins; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Hemoglobins; Hemolysis; Inulin; Kidney; Kidney Function Tests; Lipid Peroxidation; Liver; Malondialdehyde; Membrane Proteins; Mice; Mice, Knockout; Oxidative Stress; Phenylhydrazines; Tritium

The butyrate derivative isobutyramide (IBT) increases fetal hemoglobin (HbF) in patients with beta-hemoglobinopathies, but little is known about its usefulness for prolonged therapeutic use. We treated 8 patients with transfusion-dependent beta-thalassemia with 350 mg/kg of body weight per day of oral IBT for 126 to 384 days. During the trial period, the hemoglobin level was maintained between 85 g/L (range 82-87 g/L) (pretransfusion) and 115 g/L (range 110-119 g/L) (post-transfusion) (median, interquartile range), corresponding to 4-week transfusion intervals in all patients during the pretreatment phase. Adverse effects (bitter taste, epigastric discomfort) did not cause discontinuation of IBT. HbF increased in all patients from 3.1% (range 1.9%-4.8%) to 6.0% (range 3.3%-8.7) (P =.0017), while free Hb dropped from 0.48 g/L (range 0.39-0.81 g/L) to 0.19 g/L (range 0.16-0.24 g/L) (P <.0001). Transfusion intervals were consistently extended to 8 or 9 weeks in 1 patient, resulting in a decrease of daily iron load from 455 microgram/kg per day (range 451-459 microgram/kg per day) before therapy to 211 microgram/kg per day (range 203-286 microgram/kg per day) during the 12-month treatment period. Prolongation of transfusion intervals achieved by IBT was less consistent in another patient, whose parenteral iron load nevertheless decreased from 683 microgram/kg per day (range 618-748 microgram/kg per day) to 542 microgram/kg per day (340-596 microgram/kg per day). In the other 6 patients, no prolongation of transfusion intervals was achieved. Response to treatment was associated with high pretreatment HbF (> 4.5%), high parental HbF, and increased erythropoietin levels (> 150 IU/L). We conclude that IBT prolongs transfusion intervals and reduces parenteral iron burden in some patients with transfusion-dependent beta-thalassemia.

Topics: Administration, Oral; Adolescent; Adult; Amides; Antineoplastic Agents; beta-Thalassemia; Blood; Blood Transfusion; Child; Child, Preschool; Drug Evaluation; Erythrocyte Indices; Erythropoietin; Female; Fetal Hemoglobin; Genotype; Hemoglobins; Hemolysis; Homozygote; Humans; Iron; Longitudinal Studies; Male; Patient Compliance; Time Factors

Neocytolysis is a recently described physiological process affecting the selective hemolysis of young red blood cells in circumstances of plethora. Erythropoietin (EPO) depression appears to initiate the process, providing the rationale to investigate its contributions to the anemia of renal disease. When EPO therapy was withheld, four of five stable hemodialysis patients showed chromium 51 (51Cr)-red cell survival patterns indicative of neocytolysis; red cell survival was short in the first 9 days, then normalized. Two of these four patients received oral 13C-glycine and 15N-glycine, and there was a suggestion of pathological isotope enrichment of stool porphyrins when EPO therapy was held, again supporting selective hemolysis of newly released red cells that take up the isotope (one patient had chronic hemolysis indicated by isotope studies of blood and stool). Thus, neocytolysis can contribute to the anemia of renal disease and explain some unresolved issues about such anemia. One implication is the prediction that intravenous bolus EPO therapy is metabolically and economically inefficient compared with lower doses administered more frequently subcutaneously.

Topics: Adult; Aged; Anemia; Cell Survival; Erythrocytes; Erythropoietin; Hemolysis; Humans; Kidney Failure, Chronic; Middle Aged; Recombinant Proteins; Terminology as Topic; Time Factors

Topics: Anemia; Erythropoietin; Hemolysis; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

Topics: Bacteremia; Erythropoietin; Hemolysis; Humans; Renal Dialysis; Uremia

In December 1996 we identified an outbreak of erythropoietin (rHuEpo) resistance requiring a substantial increase in rHuEpo dosage in one of our four haemodialysis (HD) units. The dialysate chloramine levels in this unit had risen from <0.1 p.p.m. in 1996 to 0.25-0.3 p.p.m. in 1997. In the other three HD units levels remained <0.1 p.p.m. Other parameters of water quality were within accepted standards.. Monthly records of haemoglobin level and rHuEpo dose were available for 148 patients between January 1996 and May 1998. Seventy-two patients, with no recognized cause of rHuEpo resistance, were analysed in detail (August 1997 to April 1998). A subgroup of 15 patients was examined for evidence of haemolysis during HD (methaemoglobin and haptoglobin levels, reticulocyte counts and Heinz bodies). Larger carbon columns were installed in December 1997 to effect chloramine removal.. There was an increase in mean methaemoglobinaemia of 23% (P<0.01) and a 21% fall in mean haptoglobin (P<0.01) across HD, although no patient had a reticulocytosis and only one patient with G6PD deficiency had Heinz bodies. Following installation of larger carbon columns there was an 18.6% rise (P<0.001) in mean haemoglobin level and a subsequent 25.0% reduction (P<0.001) in mean rHuEpo dose. Intradialytic changes in methaemoglobin and haptoglobin were abolished. The dialysate chloramine levels fell to < 0.1 p.p.m. Water company records subsequently revealed a sustained twofold increase in mains water chloramine from November 1996.. This is the first report linking chloramine exposure and rHuEpo resistance, with only subtle signs of haemolysis. Unheralded changes in mains water constituents can directly affect dialysate water quality and clinical outcomes.

Topics: Adult; Aged; Chloramines; Drug Resistance; Erythropoietin; Female; Hemoglobins; Hemolysis; Humans; Male; Medical Audit; Methemoglobin; Middle Aged; Quality Control; Recombinant Proteins; Renal Dialysis; Retrospective Studies; Water Supply

The glucocorticoid receptor (GR) coordinates a multitude of physiological responses in vivo. In vitro, glucocorticoids are required for sustained proliferation of erythroid progenitors (ebls). Here, we analyze the impact of the GR on erythropoiesis in vivo, using GR-deficient mice or mice expressing a GR defective for transactivation. In vitro, sustained proliferation of primary ebls requires an intact GR. In vivo, the GR is required for rapid expansion of ebls under stress situations like erythrolysis or hypoxia. A particular, GR-sensitive progenitor could be identified as being responsible for the stress response. Thus, GR-mediated regulation of ebl proliferation is essential for stress erythropoiesis in vivo.

Topics: Anemia; Animals; Cells, Cultured; Chickens; Culture Media, Serum-Free; Dimerization; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Hematopoiesis, Extramedullary; Hematopoietic Stem Cell Transplantation; Hemolysis; Hypoxia; Leukemia, Erythroblastic, Acute; Liver; Mice; Mice, Knockout; Radiation Chimera; Receptors, Glucocorticoid; Stem Cell Factor; Stress, Physiological; Transcriptional Activation

A compensated haemolytic state is defined by decreased red cell life-span without anaemia, i.e. by increased erythropoiesis in the absence of the physiological stimulus for erythropoietin (Epo) production. We evaluated s-Epo levels and the expansion of erythropoiesis (as measured by circulating transferrin receptor, s-TfR) in 32 patients with hereditary spherocytosis (HS) with the aim of verifying whether the enhanced erythropoiesis of compensated haemolysis was Epo-dependent. 20 of the patients (62.5%) had normal Hb values (> 12 g/dl in females and > 13 g/dl in males). Their compensated haemolytic state was the result of up to 8.2 times normal s-Epo and up to 3.9 times normal s-TfR levels, which were maintained by physiological regulation of erythropoiesis, as documented by the inverse dependence of Hb on s-Epo levels. Considering that patients with iron-deficiency anaemia represented the predicted physiological Epo response to anaemia, the observed/predicted in s-Epo ratio (O/P ratio) was calculated in HS patients with anaemia and was used as an index of the adequateness of Epo production. All the anaemic HS patients had an O/P ratio > 1, documenting inappropriately high s-Epo levels. This work demonstrates that the compensated haemolytic state of HS patients is produced by an inappropriately high s-Epo level, and that the pattern of Epo overproduction is a biological characteristic of the disease.

Topics: Adolescent; Adult; Anemia, Iron-Deficiency; Child; Erythropoiesis; Erythropoietin; Female; Hemolysis; Humans; Male; Middle Aged; Receptors, Transferrin; Reference Values; Spherocytosis, Hereditary

Tissue hypoxia is less effective in increasing erythropoietin plasma levels in animals with post-transfusion polycythaemia. Since more red blood cells are decomposed under this condition, the effects of exogenous haemin and of lysed or heat-damaged red blood cells on activation of the erythropoietin gene have been studied in mice rendered hypoxic. Total RNA was extracted from the kidney and the liver and subjected to northern blot analysis with a probe containing part of the murine erythropoietin gene. Blood plasma was collected and erythropoietin levels were determined by radioimmunoassay. Erythropoietin gene activation was suppressed by haemin and increased red blood cell haemolysis. Tin (Sn) protoporphyrin, a haeme analogue which cannot bind oxygen, did not share the effect of haemin. On the other hand, when injected with haemin, Sn-protoporphyrin potentiated the suppressive effect of haemin, probably through inhibition of haemin catabolism. We conclude that the intracellular haeme concentration inhibits the kidney oxygen sensor and that this inhibition, mediated by products red blood cell degradation, is a physiological safeguard mechanism against excessive polycythaemia and its deleterious effects upon blood circulation.

Topics: Animals; Blotting, Northern; Erythrocytes; Erythropoietin; Hemolysis; Hot Temperature; Hypoxia; Kidney; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Oxygen; RNA, Messenger

The effects of active oxygen species on the in vivo activity of recombinant human erythropoietin (EPO) treated by Fenton system, xanthine (X) plus xanthine oxidase (XO) system and hydrogen peroxide (H2O2) has been studied by means of counting the increase in number of hemolyser-resistant cells (HRCs) in EPO-injected mice. The results showed that both Fenton and X plus XO systems caused a significant reduction of the activity in proportion to the concentration of generated active oxygen species. Meanwhile, the treatment of EPO with H2O2 alone resulted in a relatively slight reduction of the activity. Electrophoretic studies on the structure of EPO revealed that its main protein band on sodium dodecyl sulfate-polyacrylamide gel (SDS-PAGE) disappeared in proportion with the extent of exposure to active oxygen generating systems. Both Fenton and X plus XO systems caused a significant loss of fluorescence in the pyridylamino (PA-) sugar chain in proportion to the concentration of generated active oxygen species, and no degradation products in the sugar chain part of the PA-sugar chain were detected. This showed that aromatic groups in EPO were sensitive to attack by active oxygen species. These results provide evidence that hydroxyl radical and other active oxygen species have a potential to react with EPO, leading to a reduction of its in vivo activity.

Topics: Animals; Erythropoietin; Female; Hemolysis; Humans; Mice; Mice, Inbred ICR; Reactive Oxygen Species; Recombinant Proteins

Topics: Aged; Anemia, Refractory; Erythropoietin; Heart Valve Diseases; Hemolysis; Humans; Kidney Failure, Chronic; Male; Renal Dialysis

To determine whether antepartum pyelonephritis causes an acute or delayed alteration in erythropoietin production.. Serum erythropoietin concentrations were determined prospectively using an enzyme-linked immunosorbent technique in 36 pregnant women admitted to Parkland Hospital with pyelonephritis. Healthy nonanemic pregnant women served as controls.. Serum erythropoietin levels in women with antepartum pyelonephritis were not different from those measured in normal pregnant women. Specifically, there were no differences in erythropoietin levels in women who had anemia at admission (n = 6; 13.8 mU/mL), hemolysis (15.4 versus 12.9 mU/mL), or renal insufficiency (14.5 versus 12.9 mU/mL) secondary to renal infection as compared to controls.. We conclude that antepartum pyelonephritis does not alter erythropoietin production either acutely or within several days of infection. Because erythropoietin production was not decreased, we suggest that hemolysis is the major factor contributing to anemia associated with renal infection.

Topics: Adult; Anemia; Erythropoietin; Female; Ferritins; Gestational Age; Haptoglobins; Hemolysis; Humans; L-Lactate Dehydrogenase; Pregnancy; Pregnancy Complications; Pyelonephritis

Recently, we reported a new in vivo assay method for erythropoietin (Epo) by means of counts of the number of haemolyser-resistant cells (HRCs) increased in Epo-injected mice. Here, we attempted to characterize the HRCs. Flow-cytometric studies revealed that HRCs obtained from Epo-injected mice expressed the transferrin receptor on their surface membranes. Furthermore, a fluorophotometric study suggested that the number of transferrin receptor-positive cells increased in a dose-dependent manner in response to treatment with Epo. On the other hand, flowcytometric and fluorophotometric studies of glycophorin A on HRCs using a rabbit antiglycophorin A antibody also showed a high expression of glycophorin A on them as compared with on HRCs from vehicle-treated animals (control). The results indicated that HRCs could be defined by their expression of both transferrin receptors and glycophorin A. We concluded that HRCs might be immature reticulocytes.

Topics: Animals; Biological Assay; Dose-Response Relationship, Drug; Erythrocyte Count; Erythrocytes; Erythropoietin; Female; Glycophorins; Hemolysis; Mice; Mice, Inbred ICR; Receptors, Transferrin; Reticulocytes

Delayed immune hemolysis can be observed after major ABO-incompatible bone marrow transplants (BMT). The management of these hemolytic episodes includes transfusion of group O red blood cells and increases of immunosuppression. Here we report the case of a 25-year-old patient who developed overt immune hemolysis on day +50 after a HLA-identical ABO-incompatible BMT. To avoid added immunosuppression, erythropoietin was started: an increase in reticulocytes sufficient to maintain hemoglobin despite persistent hemolysis was observed. We conclude that erythropoietin may have a role in the management of delayed-onset hemolysis of major ABO-incompatible BMT, especially when added immunosuppression is undesirable.

Topics: ABO Blood-Group System; Adult; Blood Group Incompatibility; Bone Marrow Transplantation; Erythropoietin; Hemolysis; Humans; Male

We evaluated the quantitative value of a simple model of erythropoiesis, based on the basic assumptions that the red blood cell (RBC) mass determines erythropoietin (Epo) production, which in turn stimulates erythropoietic activity. The RBC mass was quantitated by direct isotopic measurement (RCM), Epo production by serum Epo levels, and erythropoiesis by the ferrokinetic measurement of the erythron transferrin uptake (ETU), the serum transferrin receptor (TfR) level, and the reticulocyte (retic) index, and was completed by an evaluation of overall marrow erythron cellularity. We studied a total of 195 subjects, including 31 normal individuals, 38 patients with polycythemia, and 126 patients with various forms of anemia. Instead of only quantitating Epo and erythropoiesis in absolute terms, we also evaluated them in relation to the degree of anemia or polycythemia, and expressed the results as a ratio of observed values to values predicted from the regression equations between hematocrit (Hct) on the one hand, and Epo, TfR, and ETU on the other, obtained in a carefully selected subpopulation. The slope of the regression of TfR (as well as ETU) versus Hct was very similar to the slope of the regression of Epo versus Hct. Average EPO and TfR (as well as ETU) values predicted from the regression equations were quite comparable to observed values in most groups of subjects, with exceptions predictable from knowledge of the pathophysiology of these hematologic disorders. We identified four major patterns of erythropoiesis, ie, normal, hyperdestruction (with variants of hemolysis or ineffective erythropoiesis), intrinsic marrow hypoproliferation, and defective Epo production. Dissecting out groups of patients showed much greater heterogeneity than when patients were analyzed by group. This was particularly true in the case of a hypoproliferative component being combined with hyperdestruction, giving what we called a "mixed disorder of erythropoiesis." We conclude that the pathophysiology of anemia can be assessed by a simple measurement of Hct, retic index, Epo, and TfR levels, with Epo and TfR being more informative when expressed in relation to the degree of anemia. The model is particularly useful for detecting the presence of multiple mechanisms of anemia in the same patient. However, it has limitations inherent to the relative invalidity of TfR in iron deficiency, the imprecision of a retic count, and the difficulty in distinguishing hemolysis from ineffec

Topics: Adolescent; Adult; Aged; Anemia; Erythrocyte Count; Erythropoiesis; Erythropoietin; Hematocrit; Hemolysis; Humans; Middle Aged; Polycythemia; Receptors, Transferrin; Regression Analysis; Reticulocytes

Topics: Acute Kidney Injury; Adult; Anemia; Erythropoietin; Female; Hemolysis; Humans; Postoperative Complications; Transfusion Reaction

We examined the conditions necessary for performing a reliable erythropoietin (EPO) assay based on CFU-E colony formation in fetal mouse liver cell (FMLC) microcultures using 96-well microtiter plates. Both linearity of colony numbers with the number of cells plated and comparison among the colony ratios at various densities of seeding cells indicated that the colonies originated from a single progenitor cell when 7500 or fewer cells were plated into individual microtiter wells. About a twofold CFU-E enrichment in 12- to 13-day FMLC was achieved by Ficoll-Paque centrifugation. Plasma treated with acid-boiling stimulated the colony formation most and contained no colony inhibitor. Dose-response curve for the plasma was parallel to the EPO standard curve. The "erythroid colony-stimulating activity" in the plasma was additive to that in the standard EPO, and was completely neutralized by a monoclonal antibody against recombinant human EPO. Using the assay procedure thus established, plasma EPO titer was determined in normal subjects, in patients with nonuremic anemia and polycythemia vera, and in dialysis patients with chronic renal failure. The use of different preparations of standard EPO resulted in a significant difference in the titers because their dose-response curves differed from one another. An inverse relationship was found between EPO titers and hemoglobin concentrations in the nonuremic anemic patients, but not in the dialysis patients with about one half the normal EPO level.

Topics: Anemia; Animals; Biological Assay; Cell Separation; Cells, Cultured; Centrifugation, Density Gradient; Colony-Forming Units Assay; Dose-Response Relationship, Drug; Erythropoietin; Fetus; Hemolysis; Humans; Kidney Failure, Chronic; Liver; Mice; Mice, Inbred ICR; Polycythemia Vera; Reference Values

Topics: Adult; Aged; Aged, 80 and over; Anemia; Erythropoiesis; Erythropoietin; Female; Ferritins; Hemolysis; Heparin; Humans; Iron; Male; Middle Aged; Neoplasms; Protein Binding; Recombinant Proteins

Hydroxyurea increases the production of fetal hemoglobin (hemoglobin F) in patients with sickle cell anemia and therefore has the potential for alleviating both the hemolytic and vaso-occlusive manifestations of the disease. There is preliminary evidence that recombinant human erythropoietin may also increase hemoglobin F production.. We treated five patients with sickle cell disease with escalating doses of intravenous erythropoietin for eight weeks. Three of these patients were subsequently treated with daily doses of oral hydroxyurea. After the optimal dose was determined, erythropoietin was then given along with hydroxyurea for four weeks. Treatment with erythropoietin, either alone or in combination with hydroxyurea, had no significant effect on the percentage of hemoglobin F-containing reticulocytes (F reticulocytes) or red cells (F cells). In contrast, hydroxyurea treatment was associated with a 3-to-25-fold increase in F reticulocytes, a 1.6-to-7-fold increase in F cells, and a 2.3-to-16-fold increase in the percentage of hemoglobin F. In all three patients given hydroxyurea, treatment with this drug was associated with reduced hemolysis, shown by decreases in serum bilirubin and lactic dehydrogenase and prolongation of red-cell survival. Hydroxyurea treatment also resulted in a decrease in the percentage of irreversibly sickled cells and sickling at partial oxygen saturation, an increase in oxygen affinity and total red-cell cation content, and a reduction in potassium-chloride cotransport. All three patients had a decrease in the number of pain crises.. This study confirms that hydroxyurea therapy increases hemoglobin F production and provides objective evidence that hydroxyurea reduces the rate of hemolysis and intracellular polymerization of hemoglobin S. In contrast, recombinant human erythropoietin, whether alone or in combination with hydroxyurea, offers no measurable benefit.

Topics: Administration, Oral; Anemia, Sickle Cell; Drug Administration Schedule; Drug Evaluation; Drug Therapy, Combination; Erythrocytes; Erythropoietin; Fetal Hemoglobin; Hemoglobin, Sickle; Hemolysis; Humans; Hydroxyurea; Recombinant Proteins; Reticulocytes

A compensated hemolytic state was induced in rats by injection of phenylhydrazine (PHZ) over a 6-week period. The liver and kidney were perfused to determine the levels and time of appearance of a hepatic erythropoietic factor (HEF) which induces the production of hepatic erythropoietin (Ep) and its antagonist, a renal inhibitory factor (RIF). Erythropoietin assays on the perfusates have been previously reported. The amount of HEF in perfusates recovered from the livers of the PHZ-treated rats was significantly higher during the 4th to 5th weeks of treatment, coinciding with the time of increased liver production of Ep. During the 6th week of PHZ treatment, the titer of RIF in perfusates recovered from the kidney was markedly increased and the HEF titer was decreased to near the control level, suggesting inhibitory action of RIF on HEF synthesis and/or effect. These findings indicate that an HEF/RIF control mechanism regulates hepatic Ep production in this compensated hemolytic condition.

Topics: Animals; Blood Proteins; Erythropoietin; Female; Hemolysis; Hepatocyte Growth Factor; Hypoxia; Kidney; Liver; Male; Mice; Perfusion; Phenylhydrazines; Rats; Time Factors

Splenic erythroblasts obtained from BALB/c mice infected with the anemia strain of Friend virus were compared with "matured" cells and adult erythrocytes for their sensitivity to staphylococcal alpha-toxin. Matured cells were obtained by treating erythroblasts in culture with erythropoietin for 48 h. Sensitivity to staphylococcal alpha-toxin, measured both by release of 86Rb and by cell lysis, failed to demonstrate significant differences among the cell types. Since maturation of erythroblasts to matured cells or erythrocytes is associated with synthesis of band 3, hemoglobin, and spectrin and the loss of transferrin receptors, we conclude that none of these compounds serves as the specific receptor for staphylococcal alpha-toxin in BALB/c mice.

Topics: Animals; Bacterial Toxins; Cell Differentiation; Cells, Cultured; Erythroblasts; Erythrocytes; Erythropoietin; Female; Friend murine leukemia virus; Hemolysin Proteins; Hemolysis; Mice; Mice, Inbred BALB C; Rubidium

Studies of red cell metabolism, erythropoeitin concentration, iron and folate status were made in 48 children with protein-energy malnutrition in Johannesburg (altitude 1800 m). Biochemical evidence of iron deficiency was presented in 26% cases on admission and developed in 90% during recovery. Biochemical evidence of folate deficiency was present in 14% of cases on admission and resolved on dietary therapy alone. Serum erythropoeitin was increased on admission and remained elevated during recovery. There was no relationship between serum erythropoeitin and Hb concentrations. Key enzymes in the red cell glycolytic and hexose monophosphate pathways and red cell membrane showed increased activity. Red cell adenosine triphosphate concentration was increased and unstable. Red cell potassium was decreased and, in the fatal cases, red cell sodium was increased. The possible significance and practical implications of these findings are discussed.

Topics: Adenosine Triphosphatases; Anemia, Hypochromic; Child, Preschool; Erythrocytes; Erythropoietin; Folic Acid; Hemolysis; Humans; Infant; Iron; Potassium; Protein-Energy Malnutrition; Sodium; South Africa

Synchronized erythroid precursors obtained from the bone marrow of rabbits and plated in methyl-cellulose were used as a bioassay for the measurement of erythropoietin (Ep). Rabbits were given five daily injections of phenylhydrazine followed by a single dose of actinomycin-D. This treatment resulted in a rapid repopulation of bone marrow by synchronized erythroid precursors which can be stored at -180 degrees C for long periods. Grown in vitro for 2 days in the presence of added Ep these cells divided to form colonies (CFUE). The erythroid nature of these colonies was confirmed by 59Fe incorporation into heme. Preliminary studies indicate that this system is suitable for the measurement of Ep in human sera. It is simple, inexpensive, reproducible, and permits measurements at the physiologic range of Ep concentrations.

Topics: Animals; Bone Marrow Cells; Cell Aggregation; Cell Division; Colony-Forming Units Assay; Dactinomycin; Dose-Response Relationship, Drug; Erythrocytes; Erythropoiesis; Erythropoietin; Hemolysis; Phenylhydrazines; Rabbits

Topics: Anemia; Autoantibodies; Chronic Disease; Erythropoietin; Hemolysis; Humans; Infections; Iron; Neoplasms

Topics: Anemia; Animals; Dogs; Erythropoiesis; Erythropoietin; Hemolysis; Humans; Kidney Failure, Chronic; Rabbits; Rats; Uremia

Rats were rendered anaemic by a single bleeding or by a single injection of phenylhydrazine. At various times after the onset of anaemia they were nephrectomized and challenged with a 6 h exposure to hypoxia. The erythropoietin titre observed at the end of this hypoxic period was corrected for renal erythropoietin induced by the anaemia alone, and the resulting extrarenal component was compared to total erythropoietin production of nephric rats in response to anaemia plus 6 h hypoxia. Extrarenal erythropoietin production was found to increase from 10.3% in normal rats to 12.5% in moderately anaemic rats to 15.1% in rats with severe bleeding anaemia. In phenylhydrazine-treated rats this extrarenal component was found to be 18.3% possibly due to stimulation of extrarenal erythropoietin by haemolysed red cells. Chronic phenylhydrazine administration resulted in splenomegaly and Kupffer cell hyperactivity but not in any further stimulation of extrarenal erythropoietin production.

Topics: Anemia; Animals; Erythropoietin; Hemolysis; Kidney; Male; Nephrectomy; Oxygen; Phenylhydrazines; Rats

Topics: Anemia; Erythrocyte Aging; Erythropoiesis; Erythropoietin; Hemolysis; Hemorrhage; Humans; Hypersplenism; Iron; Kinetics; Renal Dialysis; Uremia

Using several immunological techniques, it was possible to demonstrate that toxicity of human serum in the foetal mouse liver cell bioassay for erythropoietin was due to complement-dependent IgM hetero antibodies to mouse foetal liver cells. The titre of the antibodies in 50 normal human sera ranged between 2 and 64 as measured in an agglutination test with mouse erythrocytes. Specificity of the antibodies for the ABO-or Ii-blood group system could not be established. Inactivation of complement by heating a serum for 30 minutes at 56 degrees C abolished toxicity.

Topics: Agglutination Tests; Animals; Antibodies; Biological Assay; Blood; Complement System Proteins; Erythropoietin; Fluorescent Antibody Technique; Heme; Hemolysis; Hot Temperature; Humans; Immunoglobulin Fragments; Immunoglobulin G; Immunoglobulin M; Liver; Mice

Various factors are involved in the pathogenesis of anemia in dialysis patients. Reduced erythropoiesis is mainly attributed to erythropoietin deficiency. Stimulation of erythropoiesis may be promoted by androgens. Substitution of iron is recommended in case of iron deficiency. As a rule, supplementation of vitamin B12 is not necessary, but administration of folic acid is recommended. Treatment of anemia in renal failure is rendered more effective by increased technical efficiency in hemodialysis permitting a relatively protein-rich diet. Blood transfusions are not necessary during routine treatment of dialysis. Since bilateral nephrectomy will always provoke severe anemia, it should be reserved to special cases of severe hypertension. Until now, no conservative therapy has been developed which would allow optimal treatment of anemia in dialysis patients. Successful renal transplantation still is, and will be, the best therapeutic intervention.

Topics: Androgens; Anemia, Hypochromic; Blood Transfusion; Erythrocytes; Erythropoiesis; Erythropoietin; Folic Acid; Folic Acid Deficiency; Hemoglobins; Hemolysis; Histidine; Humans; Iron; Kidney Failure, Chronic; Renal Dialysis; Splenectomy; Vitamin B 12 Deficiency

Murine blood was examined for circulating erythropoietic precursors. Blood mononuclear cells harvested using a slight modification of the Ficoll-Hypaque technique were cultured using the methylcellulose clonal cell culture technique. Only erythropoietic burst forming units (BFU-E) were present in the blood. Erythropoietin dose response studies revealed a progressive increment in the number of erythropoietic bursts up to a concentration of 4 U/ml of sheep plasma erythropoietin. A linear correlation existed between the numbers of nucleated cells plated and the erythropoietic bursts for both normal mice and mice with phenylhydrazine-induced (PHZ) anemia. No individual erythrocytic colonies were detected in cultures from blood taken before or after PHZ injections. These results suggest that erythrocytic colony-forming units (CFU-E) do not participate in the migration of erythropoietic precursors in mice.

Topics: Animals; Clone Cells; Dose-Response Relationship, Drug; Erythropoiesis; Erythropoietin; Female; Hematopoietic Stem Cells; Hemolysis; Mice; Mice, Inbred BALB C; Monocytes; Phenylhydrazines; Stimulation, Chemical

Topics: Animals; Antibodies; Bone Marrow; Bone Marrow Cells; Erythropoietin; Hemolysis; Immune Sera; Polycythemia; Rats

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

Topics: Animals; Blood Transfusion; Erythrocytes; Erythropoietin; Female; Hemolysis; Hypoxia; Methods; Mice; Polycythemia

We report experiments to determine the availability for new hemoglobin production of radioiron from nonviable red cells at various times after deposition in the reticulo-endothelial system and to determine the relative availability of radioiron derived from hemolysates versus that derived from nonviable red cells. When heated nonviable red cells labeled with 59Fe are injected into polycythemic mice the iron is deposited in the reticulo-endothelial system, and less than 1% of it is reutilized for hemoglobin synthesis. If the polycythemic mice are given nonviable red cells 48 hours after exposure to hypoxia, when hemoglobin synthesis is maximal, 25% of the iron is reutilized. When the cells are given 36 hr after exposure to hypoxia, iron reutilization declines to 16%, and when exposure to hypoxia is further delayed, reutilization of the iron falls to a plateau level of 11%. Radioiron from hemolysates, primarily deposited in parenchymal cells of the liver, is less available for new hemoglobin synthesis than is radioiron from nonviable red cells, which is primarily deposited in Kupffer cells of the liver. When transferrin-bound iron is given to polycythemic mice, this iron is also deposited in parenchymal cells of the liver and is also less available for new hemoglobin synthesis. Thus, in relation to an erythropoietic stimulus, the site and time of deposition of iron influence its accessibility for erythropoiesis.

Topics: Animals; Cell Survival; Erythrocytes; Erythropoiesis; Erythropoietin; Femur; Hemoglobins; Hemolysis; Hypoxia; Iron; Kidney; Liver; Mice; Mononuclear Phagocyte System; Spleen; Time Factors; Transferrin

Two main aspects of the in vitro mouse foetal liver cell assay for Erythroid Stimulating Factor (ESF) in human sera have been investigated. The haem extraction process has been shown to give specific and quantitative recovery of 59Fe labelled haem from haemoglobin thus confirming that the material assayed in human sera is stimulating the synthesis of this protein. The extraction procedure can be simplified considerably by prior mixing of the reagents without significantly influencing the results. Several serum constituents (citrate, testosterone, B12, folic acid and iron) have been investigated over a range of concentrations for possible effects on the cultures. Generally only small effects on haem synthesis were observed. It is concluded that variations in the levels of these factors in sera from treated patients will not produce any significant alterations in the estimated ESF concentrations.

Topics: Animals; Biological Assay; Cells, Cultured; Citrates; Culture Media; Erythropoietin; Evaluation Studies as Topic; Fetus; Folic Acid; Heme; Hemoglobins; Hemolysis; Hydrogen-Ion Concentration; In Vitro Techniques; Iron; Liver; Mice; Testosterone; Vitamin B 12

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

Seven patients with sickle cell anemia were treated with oxymetholone for at least 2 mo. Markedly increased basal rates of hemolysis and erythropoiesis were confirmed. The urinary erythropoietin excretion was either normal or lower than expected for the red cell mass, and an expanded blood volume was due primarily to an increased plasma volume. After androgen therapy, six patients demonstrated more than a fivefold increase in urinary erythropoietin, with an increase in red cell mass ranging from 17%-75% above the control value. All showed a decline in serum iron level to the 25-75 mug/100 ml range within 4 wk after the start of therapy. Less marked changes followed lower oxymetholone doses. Reversible hepatic toxicity, with a serum bilirubin concentration exceeding 50 mg/100 ml, occurred in one patient. Androgenic hormone therapy may be useful for selected adult patients with sickle cell disease when severe anemia contributes to disease morbidity.

Topics: Adolescent; Adult; Androgens; Anemia, Sickle Cell; Bilirubin; Blood Volume; Cell Survival; Chromium Radioisotopes; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hemolysis; Humans; Iron; Iron Radioisotopes; Liver; Liver Function Tests; Male; Middle Aged; Oxymetholone

A previous report have shown that both intact red blood cells (RBC) and an equal number of haemolyzed cells were able to inhibit erythropoiesis on ESF-induced erythropoiesis, suggesting a cell compound to be responsible for the inhibitiory effect. Haeme and haeme compounds have been found to stimulate or inhibit both erythropoiesis and haeme synthesis. The present work presents data on the inhibitory effect of haemolyzed RBC and compounds from intact RBC on erythropoiesis. The inhibiting factor was found to be of a small molecular size and of the same range as a urinary erythorpoiesis inhibiting factor (EIF). The inhibitor did not contain haeme. Both Fe+2 and Fe+3 were tested, showing no reduction of the 59-Fe incorporation into RBC in the test animals. The inhibition could not be due to dilution of the 59-Fe with unlabelled iron from the haemolyzed cells. On the contrary, Fe+3-ions rather stimulated erythropoiesis, probably due to increased amounts of available iron. Haemolysates were prepared from RBC with different amounts of immature cells. With increasing amounts of reticulocytes, a reduction of the inhibitory effect occurred. Also foetal cells showed less inhibition than an equal amount of adult cells. After high speed centrifugation, the inhibitory effect of haemolysates was found in the supernatant, while ghost cells exerted no inhibition. No species differences were found using both exhypoxic polycythaemic mice and rats. An inhibiting factor was liberated into the incubation medium when RBC were incubated for 20 h. No haemolysis occurred during the incubation period. Mature, adult RBC therefore contain a substance which is different from haeme, with a negative feedback on erythropoiesis.

Topics: Animals; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Hemolysis; Mice; Mice, Inbred Strains; Polycythemia Vera; Rats; Stimulation, Chemical

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: Animals; Erythropoietin; Hematopoiesis; Hemolysis; Mice; Polycythemia; Rabbits; Rats; Time Factors

Topics: Adaptation, Physiological; Adolescent; Adult; Cardiac Output; Erythropoietin; Female; Germany, West; Hematocrit; Hemoglobinopathies; Hemoglobins; Hemoglobins, Abnormal; Hemolysis; Humans; Kidney; Male; Oxygen; Oxygen Consumption; Polycythemia; Regional Blood Flow

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: 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: Adult; Blood Cell Count; Carbon Monoxide; Cell Survival; Chromium Isotopes; Ecological Systems, Closed; Environmental Exposure; Erythrocyte Count; Erythrocytes; Erythropoiesis; Erythropoietin; Gravitation; Hematocrit; Hematopoiesis; Hemoglobins; Hemolysis; Humans; Male; Oxygen; Physical Exertion; Reticulocytes; Space Flight; Time Factors

Immature erythroid cell precursors from 12- and 13-day fetal mouse livers were concentrated by differential antibody-mediated hemolysis. The effect of erythropoietin on these purified erythroid cell precursors was studied in vitro. Addition of erythropoietin stimulates erythroid cells to proliferate, and to differentiate to cells that actively synthesize hemoglobin. This erythropoietin-induced erythropoiesis is sustained in culture for at least 48 hr.

Topics: Animals; Antigen-Antibody Reactions; Cell Differentiation; Complement System Proteins; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Fetus; Gestational Age; Guinea Pigs; Hemoglobins; Hemolysis; Humans; Immune Sera; Immunization; Liver; Mice; Mice, Inbred Strains; Rabbits; Species Specificity; Stimulation, Chemical

Topics: Acute Kidney Injury; Adult; Anemia; Animals; Blood Platelets; Disseminated Intravascular Coagulation; Erythropoietin; Female; Folic Acid; Hemolysis; Humans; Kidney Diseases; Kidney Failure, Chronic; Kidney Transplantation; Polycythemia; Pre-Eclampsia; Pregnancy; Rabbits; Renal Dialysis; Transplantation, Homologous

Topics: Animals; Blood Transfusion; Cobalt; Erythropoiesis; Erythropoietin; Female; Hemolysis; Iron; Iron Isotopes; Male; Nandrolone; Norethandrolone; Oxygen; Oxygen Consumption; Partial Pressure; Rats; Testosterone

Topics: Erythropoiesis; Erythropoietin; Female; Hemolysis; Histocompatibility; Humans; Kidney Transplantation; Male; Polycythemia; Postoperative Complications; Transplantation Immunology; Transplantation, Homologous

Topics: Animals; Blood Transfusion; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Hemoglobins; Hemolysis; Immune Sera; Injections, Intraperitoneal; Iron Isotopes; Kidney; Mice; Nephrectomy; Polycythemia; Rats

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; Animals; Chromatography, DEAE-Cellulose; Erythropoietin; Genes; Goats; Hemoglobin C; Hemolysis; Humans; Immune Sera; Phenylhydrazines

The level of nucleoside deaminase was determined in extracts of mouse tissues obtained during a period of accelerated erythropoiesis induced by hypoxia, hemorrhage, or the injection of phenylhydrazine. Under these conditions a striking (10- to 100-fold) elevation of the enzyme activity occurred in the spleen. Similar results were obtained with the injection of purified erythropoietin. In control animals, only a trace of nucleoside deaminase activity was detected in the blood. During the reticulocyte response which followed erythropoietic stimulation, there was a sharp increase in the blood level of nucleoside deaminase, which rose up to 120 times that of control animals. By differential centrifugation, the enzyme was localized to the reticulocyte-rich fraction. Erythrocyte nucleoside deaminase remained elevated even after the reticulocyte count had fallen to normal in the phenylhydrazine-treated mice or to zero after the cessation of hypoxia. There was a very gradual decline in the enzyme activity in the blood which fell to the barely detectable control levels about 45 days after the initial reticulocyte response, a time period which corresponds to the survival of the mouse red blood cell. The persistence of high levels of nucleoside deaminase for the full life span of a generation of erythrocytes formed during stress, viewed in contrast to the virtual absence of the enzyme from normal erythrocytes of all ages, represents an enzymatic difference between the normal red blood cell and the cell produced under conditions of accelerated erythropoiesis.

Topics: Aminohydrolases; Animals; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Friend murine leukemia virus; Guinea Pigs; Hematocrit; Hemolysis; Hemorrhage; Hypoxia; Male; Mice; Nucleic Acids; Nucleosides; Phenylhydrazines; Rabbits; Rats; Reticulocytes; Spleen; Stress, Physiological; Time Factors

Topics: Animals; Dogs; Erythropoiesis; Erythropoietin; Hemolysis; Hemorrhage; Methods

Topics: Anemia; Animals; Blood Cell Count; Bone Marrow Cells; Erythrocytes; Erythropoiesis; Erythropoietin; Hemoglobinometry; Hemolysis; Iron Isotopes; Phenylhydrazines; Rabbits; Rats; Reticulocytes

Topics: Animals; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hemoglobinometry; Hemolysis; Male; Mice; Rabbits; Reticulocytes

Topics: Anemia; Erythrocyte Aging; Erythropoietin; Heme; Hemoglobins; Hemolysis; Humans; Iron; Kidney Diseases; Kidney Failure, Chronic; Metabolic Diseases; Porphyrins; Uremia

Topics: Anemia, Hemolytic, Autoimmune; Autoantibodies; Complement System Proteins; Erythropoietin; Female; Heart; Hemolysis; Humans; In Vitro Techniques; Insulin Antibodies; Ovarian Neoplasms

Topics: Anemia; Animals; Epoetin Alfa; Erythrocyte Count; Erythropoietin; Hemoglobinometry; Hemolysis; Mice; Phenylhydrazines; Physiology; Polycythemia; Rabbits; Research; Toxicology

Topics: Anemia; Blood Chemical Analysis; Bone Marrow; Dietary Proteins; Epoetin Alfa; Erythrocytes; Erythropoietin; Hemoglobins; Hemolysis; Iron; Iron Isotopes; Liver; Phenylhydrazines; Protein Deficiency; Rats; Research; Reticulocytes