losartan-potassium and Hematologic-Diseases

Erythropoietin (EPO), a humoral regulator of erythropoiesis and replacement therapy for selected red blood cell disorders in EPO-deficient patients, has been implicated in a wide range of activities on diverse cell, tissue, and organ types. EPO signals via two receptors, one comprising EPO receptor (EPOR) homodimers and the other a heterodimer of EPOR and CD131-the common β chain component of the GM-CSF, interleukin (IL)-3, and IL-5 receptors. Ligation of EPORs triggers various signaling pathways, including the JAK2-STAT5 and MAPK-NF-κB pathways, depending both on the receptor and the target cell type. A new study in this issue reveals a novel EPO-triggered pathway involving a Spi2A serpin-lysosome-cathepsin cascade that is initiated through the homodimeric EPOR complex and is required for the survival of erythroid progenitors. A full understanding of EPO's effects on various cell types and their potential clinical relevance requires more work on the signaling events initiated through both EPORs, the effects of other cytokines and growth factors that modulate EPO's actions, and a comparison of the effects of full-length versus truncated forms of EPO.

Topics: Animals; Cytokines; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Hematologic Diseases; Humans; Receptors, Erythropoietin; Recombinant Proteins; Signal Transduction

Patient blood management (PBM) is a patient-specific multidisciplinary, multimodal, evidence-based concept to appropriately conserve and manage a patient's own blood as a vital resource. PBM is based on 3 pillars: the first is the optimization of the patient's endogenous red cell mass, the second is the minimization of bleeding and blood loss and the third involves harnessing and optimizing the patient-specific physiological tolerance of anemia, including adopting more restrictive transfusion thresholds. PBM primarily identifies patients at risk of transfusion and provides a management plan aimed at reducing or eliminating the need for allogeneic transfusion, thus reducing the inherent risks, inventory pressures and the escalating costs associated with transfusion. PBM is applicable to surgical and medical patients. The application of PBM systematically reduces the impact of 3 major contributors to negative outcome: anemia, blood loss and transfusion.

Topics: Anemia; Austria; Benchmarking; Blood Transfusion; Erythrocyte Transfusion; Erythrocyte Volume; Erythropoietin; Hematologic Diseases; Humans; Intraoperative Care; Operative Blood Salvage; Patient Care Management; Perioperative Care; Plasma Substitutes; Platelet Transfusion; Postoperative Care; Postoperative Complications; Preoperative Care

Although the concept of a humoral regulator of erythropoiesis was introduced more than 100 years ago, its existence was first firmly established a little more than 50 years ago. This review briefly describes the historical development of information about erythropoietin. It then describes our current understanding of where erythropoietin is produced; the factors that regulate its rate of production; how erythropoietin acts at the cellular level to stimulate erythropoiesis; and its role in the regulation of the rate of erythropoiesis. Finally, it discusses the clinical uses of erythropoietin in the diagnosis and therapy of hematopoietic diseases.

Topics: Animals; Erythropoiesis; Erythropoietin; Hematologic Diseases; Humans

Haematopoietic growth factors constitute an important group of proteins that predominantly regulate the process of haematopoiesis. While some of these proteins have a very broad array of action on very early haematopoietic progenitors leading to multi-lineage increases in haematopoietic cell production and differentiation, others act in a restricted manner on specific committed terminally differentiated cell types. On the basis of their unique spectrum of activities, several factors are approved for clinical use in various indications while others are under investigation in the clinic either alone or as combination therapy. In this review, we have described factors which directly and in some cases indirectly influence haematopoiesis with particular focus on those factors which are either approved or show potential for clinical use. A brief description of the products that are currently available for clinical use is also provided. At present, several new products which include fusion proteins, peptide mimetics are either at the pre-clinical stage or in clinical development for various indications and these are also briefly described.

Topics: Animals; Biological Products; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematologic Diseases; Hematopoiesis; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cells; Humans; Interleukin-11; Interleukin-3; Macrophage Colony-Stimulating Factor; Recombinant Proteins; Stem Cell Factor; Thrombopoietin

Hematologic dysfunction, including thrombocytopenia, anemia, neutropenia, thromboses, and coagulopathy, occur commonly during critical illnesses. A major challenge is to identify drug-induced causes of hematologic dysfunction. Given the wide variety of drug-induced hematologic effects, clinicians always should consider any concomitant drugs in the differential diagnosis of acquired hematologic dysfunction. The most severe effects include drug-induced aplastic anemia, heparin-induced thrombocytopenia, and drug-induced thrombotic microangiopathy. Certain drugs are associated with multiple hematologic effects. For example, cisplatin can cause hemolytic uremia syndrome and erythropoietin deficiency, and quinine can precipitate immune-mediated thrombocytopenia, immune-mediated thrombocytopenia, and thrombotic microangiopathy.

Topics: Anemia, Aplastic; Anticoagulants; Erythropoietin; Hematologic Diseases; Heparin; Humans; Methyltransferases; Severity of Illness Index; Thrombocytopenia

Pegylated (PEG)-interferon and ribavirin combination therapy are the standard of care for the treatment of chronic hepatitis C and are associated with a high rate of sustained virologic response. However, there is a high incidence of hematologic side effects with this therapeutic regimen. Hematologic side effects are particularly common; bone marrow suppression caused by interferon may result in neutropenia and thrombocytopenia. Ribavirin is directly toxic to red blood cells and is associated with hemolysis, which is usually dose-related but self-limited. Historically, the traditional management of hematologic side effects of interferon therapy has been dose reduction. However, recent studies have shown that response to therapy is strongly influenced by adherence to optimal doses of interferon and particularly ribavirin. Therefore, there is increasing emphasis on the use of growth factors such as filgrastim and erythropoietin to stimulate bone marrow production of erythrocytes and leukocytes to allow patients to receive the optimal doses of interferon and ribavirin. The incidence, magnitude, and possible mechanisms of hematologic complications associated with interferon and ribavirin are described in this review.

Topics: Anemia, Hypochromic; Antiviral Agents; Clinical Trials as Topic; Drug Therapy, Combination; Erythropoietin; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematologic Diseases; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Neutropenia; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Thrombocytopenia

Hematologic side effects (anemia, neutropenia, and thrombocytopenia) of combination therapy with pegylated (PEG)-interferon alfa and ribavirin are commonly encountered during antiviral therapy for chronic hepatitis C (HCV). An important consequence of these side effects is dose modification of PEG-interferon alfa, ribavirin, or both. Dose modification (including discontinuation) diminishes the efficacy of optimal treatment regimen for HCV and may have a negative impact on sustained virologic response. Additionally, fatigue associated with anemia may impair patients' quality of life. The clinical implications of neutropenia or thrombocytopenia are less clear than for anemia; nevertheless, severe infection and bleeding are uncommon. Dose adjustments effectively treat these hematologic side effects, but the resulting suboptimal dosing and potential impact on virologic response are major concerns. Recent attempts to maximize adherence to the optimal treatment regimen have used hematopoietic growth factors rather than dose adjustment to treat side effects. Research on growth factor support has focused on anemia and neutropenia. Epoetin alfa and darbepoetin alfa are erythropoietic growth factors that effectively increase hemoglobin while maintaining the optimal ribavirin dose and improving patients' quality of life. Preliminary work suggests that filgrastim, granulocyte colony stimulating factors, may be an effective treatment of interferon-induced neutropenia. Although this early work shows tremendous promise for managing hematologic side effects of combination therapy for HCV, and potentially enhancing adherence, further research is needed to clarify the efficacy, safety, and cost-effectiveness of growth factors in the management of patients with chronic HCV.

Topics: Anemia, Hypochromic; Antiviral Agents; Darbepoetin alfa; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Granulocyte Colony-Stimulating Factor; Growth Substances; Hematinics; Hematologic Diseases; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Neutropenia; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Thrombocytopenia

Consensus guidelines are in place for treating chronic hepatitis C virus infection. This article highlights some of the hematologic complications of hepatitis C therapy. Management options are presented.

Topics: Anemia; Antiviral Agents; Bone Marrow; Epoetin Alfa; Erythropoietin; Hematologic Diseases; Hepatitis C, Chronic; Humans; Interferon Type I; Neutropenia; Recombinant Proteins; Ribavirin; Thrombocytopenia

The utilisation of nonviral gene delivery methods has been increasing steadily, however, a drawback has been the relative low efficiency of gene transfer with naked DNA compared with viral delivery methods. In vivo electroporation, which has previously been used clinically to deliver chemotherapeutic agents, also enhances the delivery of plasmid DNA and has been used to deliver plasmids to several tissue types, particularly muscle and tumour. Recently, a large number of preclinical studies for a variety of therapeutic modalities have demonstrated the potential of electrically mediated gene transfer. Although clinical trials using gene transfer with in vivo electroporation have not as yet been realised, the tremendous growth of this technology suggests that the first trials will soon be initiated.

Topics: Animals; Carcinoma, Squamous Cell; Electroporation; Erythropoietin; Forecasting; Gene Expression Regulation; Gene Transfer Techniques; Genetic Therapy; Growth Substances; Hematologic Diseases; Humans; Injections, Intramuscular; Interleukin-12; Melanoma; Plasmids; Protein Deficiency; Toxins, Biological; Vaccines, DNA

Pharmacological approaches to reduce blood transfusion include the protease inhibitor aprotinin, lysine-analogue antifibrinolytics synthetic arginine-vasopressin derivatives (DDAVP) and recombinant factor VII (rfVIIa). These agents are known to prevent the need for blood after major surgery (cardiac, hepatic, and orthopaedic). Among the nonhemostatic agents erythropoietin (EPO) may be effective to reduce blood requirements in medical and surgical patients. Aprotinin is consistently effective in reducing blood transfusion in cardiac and hepatic surgical procedures, but there is little data to support its use in elective orthopaedic surgery. Antifibrinolytics show no evidence of efficacy in cardiac and hepatic surgery and its use is not warranted in orthopaedic surgery. Limited data suggest that DDAVP may be effective when a defect in platelet function is demonstrated. rFVIIa emerges as a promising haemostatic agent with proven benefit to reduce bleeding in haemophiliacs with inhibitors but might also be effective in patients with thrombocytopenia and thrombopathy, as well as in life-threatening hemorrhage in postsurgical patients. Ongoing studies will established its role a possible "universal haemostatic agent". Hematopoietic cytokines, such as EPO, may have a place to avoid blood transfusion in a variety of clinical conditions, including cancer and critically ill patients.

Topics: Antifibrinolytic Agents; Aprotinin; Blood Loss, Surgical; Blood Transfusion; Deamino Arginine Vasopressin; Erythropoietin; Factor VIIa; Hematologic Diseases; Hemorrhage; Hemostatics; Humans

Sepsis with acute organ dysfunction (severe sepsis) results from a systemic proinflammatory and procoagulant response to infection. Organ dysfunction in the patient with sepsis is associated with increased mortality. Although most organs have discrete anatomical boundaries and carry out unified functions, the hematologic system is poorly circumscribed and serves several unrelated functions. This review addresses the hematologic changes associated with sepsis and provides a framework for prompt diagnosis and rational drug therapy. Data sources used include published research and review articles in the English language related to hematologic alterations in animal models of sepsis and in critically ill patients. Hematologic changes are present in virtually every patient with severe sepsis. Leukocytosis, anemia, thrombocytopenia, and activation of the coagulation cascade are the most common abnormalities. Despite theoretical advantages of using granulocyte colony-stimulating factor to enhance leukocyte function and/or circulating numbers, large clinical trials with these growth factors are lacking. Recent studies support a reduction in the red blood cell transfusion threshold and the use of erythropoietin treatment to reduce transfusion requirements. Treatment of thrombocytopenia depends on the cause and clinical context but may include platelet transfusions and discontinuation of heparin or other inciting drugs. The use of activated protein C may provide a survival benefit in subsets of patients with severe sepsis. The hematologic system should not be overlooked when assessing a patient with severe sepsis. A thorough clinical evaluation and panel of laboratory tests that relate to this organ system should be as much a part of the work-up as taking the patient's blood pressure, monitoring renal function, or measuring liver enzymes.

Topics: Blood Transfusion; Erythropoietin; Hematologic Diseases; Humans; Incidence; Sepsis

Anemia is a frequent symptom encountered in hematological malignancies at diagnosis or in the course of the disease. Allogeneic transfusions were, until recently, the only treatment available and used only for severe anemia. Erythropoietin is currently an important alternative especially for treatment and even to prevent severe anemia. It has been assessed for the treatment of chemotherapy related anemia in NHL, myeloma and CLL with a significant reduction of blood transfusions and prevention of grade 3-4 anemia in 51% of patients. In myelodysplasia, the more effective regimen is the association of G-CSF and Epo. In the setting of allogeneic bone marrow transplantation, it reduces the time to red cell engraftment and probably the number of blood cell unit per patient in contrast with autologous stem cell transplant. All these studies assessed the efficacy of Epo in hematological malignancies but needs further trials including the assessment of the quality of life and economical parameters.

Topics: Anemia; Erythropoietin; Hematologic Diseases; Hematologic Neoplasms; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cell Transplantation; Humans; Myelodysplastic Syndromes; Recombinant Proteins

Erythropoietin (EPO) is a glycoprotein synthesized by the kidney, which has a stimulating effect on bone marrow erythroid precursors. It has been identified many years ago, but its clinical use has been developed only since 1985 with the introduction of recombinant molecle (rHuEPO). In the past decade, rHuEPO has been employed in neoplastic as well as in chronic inflammatory diseases associated with anemia, that recognizes a multifactorial pathogenesis: defective endogenous EPO production, impaired erythroid proliferation due to excessive release of inflammatory cytokines, intrinsic abnormalities of erythroid precursors, reticulo-endothelial blockage with reduced erythroid uptake of iron. Anemia of neoplastic diseases, moreover, may be induced or worsened by marrow toxicity of chemotherapy. The efficacy of rHuEPO in these conditions is still unclear.

Topics: Erythropoietin; Hematologic Diseases; Humans

The major function of the erythrocyte is to transport oxygen from the lungs to the other tissues, a function ensured by the glycoprotein hormone erythropoietin which couples red cell production to long term tissue oxygen requirements. Tissue hypoxia is the only physiological mechanism for increasing erythropoietin production but there are a variety of mechanisms for its down regulation including hyperoxia, increased catabolism by an expanded erythroid progenitor cell pool, blood hyperviscosity independently of its oxygen content, renal disease and the cytokines produced in inflammatory, infectious and neoplastic disorders. Erythropoietin lack results in severe and often transfusion-dependent anemia but if bone marrow function is otherwise normal, recombinant human erythropoietin therapy can restore the red cell mass and alleviate the transfusion need. However, elevation of the red cell mass by recombinant human erythropoietin is associated with a reduction in plasma volume and in some patients, hypertension is induced. Elevation of the red cell mass is also associated with a reduction in cerebral blood flow. When used to gradually elevate the hematocrit to 36% in anemic patients, recombinant human erythropoietin therapy is usually uneventful. However, when the normal hematocrit level is exceeded, the risk for thrombotic events increases since blood viscosity varies exponentially with the hematocrit. Increasing the hematocrit by autologous blood transfusions can enhance athletic performance in fit individuals and recombinant human erythropoietin administration is an obvious surrogate for autologous blood transfusions. However, paradoxically, its effects are the opposite of those of endurance training, namely a change in red cell mass without an increase in the total blood volume. Thus, the use of recombinant human erythropoietin as a performance-enhancing agent is dangerous, particularly in the less fit athlete, and probably of little benefit in the highly conditioned one. Differences in the carbohydrate content of native and recombinant human erythropoietin are identifiable by isoelectric focusing, providing a direct means for detecting erythropoietin abuse using urine specimens; a panel of surrogate blood markers of enhanced erythropoiesis such as soluble transferrin receptors, serum erythropoietin, reticulocyte hematocrit and percent macrocytes provide an indirect means for this purpose. Timing of surveillance is, of course, critical due to biological l

Topics: Animals; Blood Transfusion; Doping in Sports; Erythropoietin; Hematologic Diseases; Humans; Recombinant Proteins

The production of erythroid cells is a dynamic and exquisitely regulated process. The mature red cell is only the final phase of a complex but orderly series of genetic events that are initiated at the time a multipotent stem cell becomes committed to expressing the erythroid programme. Aberrations either in the intrinsic generation and/or amplification of functional erythroid cells or in the regulatory influences of microenvironment or cytokines form the basis for a number of blood diseases. In this review we focus upon abnormalities in red blood cell production and discuss how alterations in cytokine regulation of red blood cell production may contribute to these disease processes. We discuss clinical states in which blood red cell numbers are altered, including primary familial and congenital polycythaemia, the myeloproliferative disorder polycythaemia vera, erythroleukaemia, and Diamond-Blackfan anaemia. These disorders are briefly described and evidence supporting a potential role of specific cytokine receptor signalling defects as contributing to these phenotypes is discussed.

Topics: Erythropoietin; Fanconi Anemia; Hematologic Diseases; Hematopoiesis; Humans; Leukemia, Erythroblastic, Acute; Mutation; Polycythemia; Polycythemia Vera; Receptors, Cytokine; Receptors, Erythropoietin; Signal Transduction

Automated counting of reticulocytes has markedly increased the precision and accuracy of this assay compared with the traditional manual counts. In addition, several new reticulocyte parameters are now available to clinicians and pathologists. This review examines the potential role of these parameters in the diagnosis and management of anemias. Reticulocyte maturity can now be assessed based on the staining intensity of reticulocytes, which is proportional to their RNA content. However, the clinical value of the numerical estimate of the immature reticulocyte fraction has not been yet demonstrated. In the bone marrow transplant setting, there is no clear evidence that the use of this index results in improved care of these patients, and many studies have failed to show its superiority compared with the traditional white cell count, especially for autologous transplants. Direct measurement of reticulocyte volume, hemoglobin concentration, and hemoglobin content are now available. Studies have shown that these parameters, and hemoglobin content in particular, allow a real-time assessment of the functional state of the erythroid marrow. In the setting of recombinant human erythropoietin therapy, studies of hemoglobin content have shown that this index allows an early detection of functional iron deficiency. Preliminary studies have also shown that this index may be helpful in the diagnosis of iron deficiency and in the monitoring of iron replacement therapy.

Topics: Anemia, Hypochromic; Anemia, Megaloblastic; Anemia, Sickle Cell; Bone Marrow; Bone Marrow Diseases; Bone Marrow Transplantation; Cell Size; Cellular Senescence; Erythropoietin; Graft Survival; Hematologic Diseases; Hemoglobins; Humans; Iron Deficiencies; Recombinant Proteins; Reference Values; Reticulocyte Count; Reticulocytes; RNA; Staining and Labeling

Topics: Adult; Anemia; Blood Loss, Surgical; Blood Transfusion, Autologous; Cost-Benefit Analysis; Erythropoiesis; Erythropoietin; Feedback; Hematologic Diseases; Humans; Infant, Newborn; Iron Deficiencies; Kidney; Neoplasms; Recombinant Proteins; Uremia

Multilineage hematopoietic defects occur in patients with human immunodeficiency virus (HIV) infection and affect therapy of the disease and of associated opportunistic infections and neoplasms. Anemia and neutropenia are common in HIV patients, and can occur as a result of HIV-related myelosuppression or complications or may be secondary effects of antiretroviral or other agents used in management of the disease. With the advent of combination drug therapy for the treatment of HIV infection and prophylaxis and treatment of infectious complications, myelosuppression is frequently encountered and may be treated with synthetic hematopoietic growth factors. Erythropoietin has been shown to increase mean hematocrit levels and to reduce transfusion requirements in anemic HIV-infected patients receiving zidovudine. Granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor have been shown to increase neutrophil counts in patients with AIDS-related bone marrow failure and those receiving zidovudine, interferon-alpha, or ganciclovir. Although recent research using interleukin-2 (IL-2) has shown that use of this cytokine in AIDS patients can lead to increases in CD4 cell counts that appear to be functional, further study is needed to determine whether cytokines can play a role other than palliation in HIV-infected patients.

Topics: Cytokines; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematologic Diseases; HIV; HIV Infections; Humans; Interleukin-2; Interleukin-3; Virus Replication

During the course of HIV disease a broad spectrum of hematologic disorders develop including abnormalities in blood cell generation, survival, and function Alterations in coagulation parameters may evolve associated with disruption of immunoglobulin or factor production. This article reviews the manifestations and pathophysiology of these abnormalities and discusses the role for growth factor support.

Topics: Blood Coagulation Disorders; Erythropoietin; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Substances; Hematologic Diseases; HIV Infections; Humans; Lymphopenia

Cytokines are a class of signal peptides which represent a major communication network in living organism. Over the last decade, the discovery, cloning and purification of hematopoietic cytokines (interleukins, hematopoietic growth factors) has increased our understanding of the regulation, proliferation, differentiation and function of hematopoietic cells. More recently, the large scale production of the recombinant forms of these molecules has enabled to treat the patients with pharmacologic doses of cytokines. The therapeutic activity of interferon-alpha (IFN-alpha) has been demonstrated in patients with chronic myeloid leukaemia and other chronic myeloproliferative syndromes. IFN-gamma is useful in the prevention of infections in patients with chronic granulomatous disease. Erythropoietin (EPO) was the first hematopoietic growth factor available for clinical use, initially to treat anaemia in renal failure patients. The next cytokines introduced into the clinic were granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF). They are used successfully in haematological malignant disorders to stimulate granulopoiesis after chemotherapy or bone marrow transplantation and to help mobilise marrow stem cells for peripheral blood stem cell transplantation. Interleukin (IL)-1, -2, -3, -4, -6 and -11 have been tested in clinical trials. However, the value of these agents remains to be established.

Topics: Cytokines; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematologic Diseases; Humans; Interferon-alpha; Interferon-gamma; Interleukin-2

Hematopoietic growth factors have already had an enormous impact on transfusion practice by eliminating or reducing the need for red blood cell transfusions in a variety of anemic states characterized by an absolute or relative decrease in erythropoietin. In addition, GM-CSF and G-CSF have stimulated the production of autologous neutrophils in febrile neutropenic patients in whom granulocyte transfusions had been considered ineffective. With the discovery of c-Mpl ligand and the promising results obtained with IL-11 and IL-3, a combination of growth factors that successfully stimulate platelet production may soon be identified. This first era in the clinical application of hematopoietic growth factors has been characterized largely by treatment of the patient to stimulate production of autologous cells or to enhance the ability of transplanted hematopoietic progenitor cells to repopulate the patient. The use of G-CSF to increase the yield of granulocytes harvested by apheresis procedures and to mobilize peripheral blood stem cells in allogeneic donors has initiated a new era in which the cell donor is treated to enhance cell production and enhance the repopulating ability of hematopoietic progenitor cells. As our understanding of hematopoiesis grows, scientists will be able to identify growth factors to overcome or correct deficient hematopoiesis. Increasingly, component transfusions will be reserved for life-threatening situations in which endogenous cell production cannot be stimulated or cell production will be too slow to prevent life-threatening events.

Topics: Animals; Antineoplastic Agents; Blood Transfusion; Blood Transfusion, Autologous; Bone Marrow Diseases; Bone Marrow Transplantation; Clinical Trials as Topic; Erythropoietin; Hematologic Diseases; Hematopoiesis; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cell Transplantation; Humans; Infant, Newborn; Infant, Premature; Interleukins; Mice; Neoplasms; Recombinant Proteins; Retrospective Studies

Topics: Animals; Bone Marrow Diseases; Bone Marrow Transplantation; Cytokines; Erythropoietin; Graft Survival; Hematologic Diseases; Hematopoiesis; Hematopoietic Cell Growth Factors; Humans; Immunologic Factors; Neoplasms; Recombinant Proteins

Topics: alpha-2-Antiplasmin; Antifibrinolytic Agents; Antithrombin III; Erythropoietin; Fibrin Fibrinogen Degradation Products; Fibrinolysin; Fibrinopeptide A; Fibrinopeptide B; Hematologic Diseases; Humans; Immunoglobulin G; Peptide Fragments; Peptide Hydrolases; Protein C

Hematopoietic growth factors were found as factors stimulating hematopoietic colony formation in in vitro culture system using bone marrow cells as a source of hematopoietic progenitor cells. Erythropoietin, a growth factor stimulating erythroid lineage has now been clinically used as an therapeutic agent for anemia of chronic renal failure. Macrophage colony-stimulating factor (M-CSF), a growth factor stimulating the production of leukocytes including monocytes and neutrophils has been clinically used as an agent for leukopenic patients after anti-cancer therapy. M-CSF improves a survival rate after bone marrow transplantation (BMT) through the reduction of mortality rate associated with BMT such as bleeding, engraftment failure and GVHD. M-CSF accelerated platelet production when injected to thrombopenic patients with solid tumor after anticancer therapy. Granulocyte CSF (G-CSF) is a most powerful agent for various kinds of neutropenia such as neutropenia after anti cancer therapy, neutropenia after BMT, aplastic anemia, chronic neutropenia of children and myelodysplastic syndrome. However, since G-CSF stimulates growth of leukemic cells in vitro, careful observations should be required when clinically used on leukemic patients. Clinical studies of granulocyte-macrophage CSF (GM-CSF) and interleukin 3 (IL-3) are now in progress, in which a promoting activity of leukocyte production of these factors is evaluated.

Topics: Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematologic Diseases; Humans; Interleukin-3; Macrophage Colony-Stimulating Factor; Recombinant Proteins

To study the effectiveness of hemopoietic growth factors in older patients.. Literature review. All articles published in English language between 1987 and 1990 were reviewed. Those reporting studies without age limits as entry criteria and describing the effects of growth factors in individual patients were suitable for analysis. Bone marrow transplantation related articles were excluded.. The meanfold increase of granulocytes for Granulocyte-Colony Stimulating Factor, Granulocyte Macrophage-Colony Stimulating Factor, and Interleukin 3 and of hemoglobin for erythropoietin were compared in subjects younger and older than 65, by Mann-Whitney U test.. Of 68 studies, 23 were suitable for analysis. These included patients with myelodysplastic syndromes, aplastic anemia, chemotherapy-induced myelosuppression, chronic granulocytopenia, anemia, and myelosuppression of malignancies and of chronic disease. Of 204 patients, 67 were 65 years of age or older and 42 were over 70. No difference was seen in meanfold increase of granulocyte and hemoglobin in time of response to growth factors or in response in presence of an absolute neutrophil count lower than 1000/microliters between younger and older patients.. Early response to hemopoietic growth factors appears well maintained with advanced age. Prospective studies of the prolonged effects of these factors in older and younger patients are needed.

Topics: Aged; Aging; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Granulocytes; Hematologic Diseases; Hematopoiesis; Hematopoietic Cell Growth Factors; Hemoglobins; Humans; Interleukin-3; Leukocyte Count; Meta-Analysis as Topic; Recombinant Proteins

The haemopoietic growth factors are a diverse group of hormones with effects on different haemopoietic cell lineages and at various points in their developmental differentiation. The biology of many of these factors is now well understood. They have entered clinical trials and have demonstrated benefits in particular clinical situations. The thrust of current phase II and III clinical investigations now is to use these factors, alone or in combinations, to modify various disease states and to ameliorate many of the side-effects of other therapeutic agents, particularly cytotoxic anticancer agents. Many other disease states also lend themselves to therapy with these growth factors. Other haemopoietic growth factors have not been as extensively studied in humans but hold great promise. In this chapter, the current status of the haemopoietic growth factors presently under clinical trial has been reviewed. In addition, several factors which have been recently described but which have not yet entered clinical trials have been discussed.

Topics: Acquired Immunodeficiency Syndrome; Animals; Antineoplastic Agents; Bone Marrow Diseases; Bone Marrow Transplantation; Clinical Trials as Topic; Drug Evaluation; Drug Evaluation, Preclinical; Erythropoietin; Haplorhini; Hematologic Diseases; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cells; Humans; Immunologic Factors; Leukemia, Myeloid, Acute; Mice; Neoplastic Stem Cells; Neutropenia; Recombinant Fusion Proteins

Recent literature on nonneoplastic hematologic disease in the rheumatic disorders has been reviewed, and current concepts on the anemia of rheumatoid arthritis and its treatment have been expanded. The anemia of chronic renal failure and of acquired immunodeficiency syndrome has responded to treatment with recombinant human erythropoietin. Recent studies document that the anemia of rheumatoid disease can also be alleviated with intermittent intravenous or subcutaneous administration of erythropoietin without apparent adverse reaction. However, no improvement is evident in the underlying rheumatoid disease or functional abilities of these patients. Further data are needed to determine the utility of erythropoietin therapy in rheumatoid arthritis and in other rheumatic diseases. Other mechanisms of anemia of rheumatoid disease have been studied, and as the underlying defects become known, other therapies may become available to patients with rheumatoid arthritis and other rheumatic diseases.

Topics: Anemia; Erythropoietin; Felty Syndrome; Hematologic Diseases; Humans; Rheumatic Diseases

In the paper the role of interleukin-3, granulocyte-macrophage colony stimulating factor (GM-CSF), granulocyte-colony stimulating factor (G-CSF) and macrophage colony stimulating factor (M-CSF), in the proliferation and differentiation of haemopoietic cells and pathogenesis of leukaemia are reviewed. Role of erythropoietin, thrombopoietin and other thrombopoiesis-stimulating factors in the development of hematopoietic is presented. Potential applications of recombinant haemopoietic growth factors in the treatment of myelodysplastic syndromes. AIDS and other haematologic, infections and neoplastic disorders are also discussed.

Topics: Acquired Immunodeficiency Syndrome; Erythropoietin; GPI-Linked Proteins; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematologic Diseases; Hematopoiesis; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cells; Humans; In Vitro Techniques; Interleukin-3; Membrane Glycoproteins; Mesothelin; Proteins

Topics: Acquired Immunodeficiency Syndrome; Anemia, Aplastic; Colony-Stimulating Factors; Erythropoietin; Hematologic Diseases; Hematopoiesis; Humans; Myelodysplastic Syndromes; Recombinant Proteins

In order to maintain adequate circulating numbers of blood cells, the bone marrow must produce billions of cells each day and must be able to rapidly increase production by 10-20-fold in response to infection and hemorrhage. The existence of circulating factors that regulate this process has been suspected for over 100 years. Recently, the genes encoding these growth factors were cloned and their functions are now identified. Interleukin-3 (IL-3) acts on the most primitive hematopoietic stem cell, driving this self-renewing cell to produce progeny of all hematopoietic lineages. Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates the granulocyte-macrophage progenitor cell, as well as cells committed to the erythroid lineage, to differentiate. G-CSF and M-CSF stimulate the most differentiated myeloid progenitors to produce granulocytes and monocytes/macrophages, respectively. Erythropoietin stimulates the differentiation of late erythroid progenitors. In the lymphoid progenitor lineage, IL-2 stimulates T cell differentiation; IL-4 and IL-6 stimulate differentiation of B cells. The colony-stimulating factors also enhance function and cause activation of the mature cells whose production they induce. In clinical trials, these hormones have successfully ameliorated anemia in renal failure, chronic disease, and in prematurity. They have improved pancytopenias in aplastic anemia, myelodysplastic syndromes, and congenital cytopenias, and they have hastened recovery from chemotherapy and bone marrow transplantation.

Topics: Cloning, Molecular; Colony-Stimulating Factors; Erythropoietin; Hematologic Diseases; Hematopoiesis; Humans

Topics: Biological Products; Deltaretrovirus; Erythropoietin; Genetic Engineering; Hematologic Diseases; HIV; Humans; Immunoglobulins; Leukemia; Lymphoma; Oncogenes; Receptors, Antigen, T-Cell; Transfection; Translocation, Genetic

Topics: Animals; Colony-Stimulating Factors; Erythropoietin; Hematologic Diseases; Hematopoietic Stem Cells; Humans

Topics: Animals; Blood Cells; Cell Differentiation; Colony-Stimulating Factors; Erythropoietin; Hematologic Diseases; Humans; Leukemia, Lymphoid; Oncogenes

Topics: Animals; Colony-Stimulating Factors; Erythropoietin; Hematologic Diseases; Humans; Mice; Mice, Nude; Middle Aged; Neoplasm Transplantation; Neoplasms

Topics: Anemia, Aplastic; Animals; Bone Marrow Cells; Cell Differentiation; Cell Division; Cells, Cultured; Clone Cells; Colony-Forming Units Assay; Erythrocytes; Erythropoiesis; Erythropoietin; Hematologic Diseases; Hemoglobins; Humans; Immunosuppression Therapy; Mice; Myeloproliferative Disorders; Syndrome; T-Lymphocytes; Time Factors

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

After allogeneic stem cell transplantation (allo-SCT) some patients develop persistent anemia in association with an inadequate erythropoietin (Epo) secretion. We determined the frequency and risk factors for this complication and the response to treatment with erythropoiesis stimulating proteins (ESP). Of 83 evaluable allo-SCT patients, 63 (76%) developed persistent anemia at a median of 34 (range: 30-244) days after allo-SCT. Forty-one (49%) patients had anemia considered as primary, and in all of them inadequate serum Epo levels (median 43.3, range: 2.5-134, mU/mL) were found. A high creatinine level during the first month after allo-SCT was associated with primary anemia (relative risk [RR] 2.5, P = .01). Of the 41 patients, 35 received ESP. Transfusion independence and an Hb level higher than 10 g/dL was achieved in 29 of 30 (97%) evaluable patients. Median ferritin levels at the beginning and at the end of the ESP treatment was 1628 (range: 168-5208) and 805 (range: 14-7443) ng/mL, respectively (P = .04). In conclusion, anemia associated with impaired Epo secretion after allo-SCT is more frequent than usually recognized and it is associated to early postransplantation renal damage. This complication easily reverts with ESP, which seems to contribute to reduce iron overload.

Topics: Adult; Anemia; Erythropoiesis; Erythropoietin; Female; Hematinics; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Incidence; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Risk Factors; Time Factors; Transplantation, Homologous; Treatment Outcome

On day 30 after autologous peripheral blood stem cell transplantation (PBSCT), 20 patients were randomized to receive either erythropoietin at a dose of 500 U/kg/week s.c. (Epo group) or no treatment (control group). After 3 weeks, hemoglobin (p<0.0001) and serum transferrin receptor (p<0.0001) concentrations were higher in the Epo group. Hb response (+2 g/dL) was achieved in 100% vs 28% (p<0.0001) and Hb correction (> or =13 g/dL) in 70% vs 10% (p=0.0238) of the patients, respectively. This is the first randomized study showing an efficacy of erythropoietin therapy on Hb levels after autologous PBSCT.

Topics: Aged; Erythropoietin; Female; Hematologic Diseases; Humans; Male; Middle Aged; Peripheral Blood Stem Cell Transplantation; Recombinant Proteins; Transplantation, Autologous

A phase II trial was performed to determine the antitumour efficacy and tolerance of combined paclitaxel and cisplatin with or without hematopoetic growth factor support in patients with advanced gastric cancer. Forty-five patients with histologically confirmed metastatic gastric cancer were entered in this trial. Treatment consisted of 2-weekly courses of paclitaxel 160 mg per m2 and cisplatin 60 mg per m2 both given on day 1. Depending on absolute neutrophil counts on the days of scheduled chemotherapeutic drug administration (1000-2000 per microl), a 5-day course of human granulocyte colony-stimulating factor 5 microg x kg(-1) per day was given subcutaneously; in addition, if haemoglobin was <12.0 mg dl(-1), erythropoietin 10 000 IU was administered subcutaneously three times per week. The confirmed overall response rate (intent-to-treat) was 44%, including five complete (11%) and 15 partial remissions (33%). Twelve patients had stable disease (27%), 11 (24%) progressed while on chemotherapy, and two patients were not evaluable. The median time to response was 3 months, the median time to progression 7.0 months, and the median survival time was 11.2 months with 12 patients currently alive. Haematologic toxicity was common, though WHO grade 4 neutropenia occurred in only five patients (11%). Apart from total alopecia in 16 patients (36%), severe non-haematologic adverse reactions included grade 3 peripheral neuropathy in six (13%) and anaphylaxis in two patients. In addition, there was one patient each who experienced grade 3 emesis, diarrhea, and infection, respectively. Our data suggest that the combination of paclitaxel and cisplatin with or without G-CSF and/or erythropoietin has promising therapeutic activity in patients with advanced gastric cancer.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Hematologic Diseases; Humans; Male; Middle Aged; Paclitaxel; Stomach Neoplasms; Survival Rate; Treatment Outcome

In vitro studies have indicated that granulocyte-macrophage colony-stimulating factor (GM-CSF) synergizes with erythropoietin (EPO) for the production of erythroid precursors in patients with myelodysplastic syndrome (MDS). We performed a clinical trial to evaluate whether the combination of these growth factors was effective in relieving the cytopenias associated with MDS. 31 anaemic patients with low and intermediate-risk primary MDS were enrolled in a 12-week study. Therapy was initiated with GM-CSF at 1 microgram/kg/d.s.c., and then adjusted to either normalize or double the absolute neutrophil count. EPO was given subcutaneously on alternate days starting from day 2. The EPO dose was initiated at 150 U/kg and increased to 300 U/kg if after 6 weeks there was no or suboptimal erythroid response. 26 patients completed the study treatment. All evaluable cases had a neutrophil response. Clinically significant erythroid responses with increases of haemoglobin levels of at least 1 g/dl and/or reduction of transfusion needs were seen in 9/26 (34.6%), five patients improving their response after dose escalation of EPO. Treatment had no apparent effect on mean platelet counts, a single case displaying a trilineage response. An elevated bone marrow erythroid infiltration and low concentrations of circulating tumour necrosis factor-alpha were the only predictors of haemoglobin response both in univariate and in multivariate analysis. We conclude that the combination GM-CSF + EPO can abrogate neutropenia and substantially relieve transfusion requirements in a large proportion of patients with low and intermediate risk MDS. However, in vivo synergy between these growth factors for the production of erythroid precursors is not supported by our data.

Topics: Adult; Aged; Aged, 80 and over; Drug Therapy, Combination; Erythropoietin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hematologic Diseases; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Platelet Count

The present report describes the non-haematological toxicity and the influence of growth factor administration on haematological toxicity and haematopoietic recovery observed after high-dose carboplatin (1200 mg m(-2)), etoposide (900 mg m(-2)) and melphalan (100 mg m(-2)) (CEM) followed by peripheral blood progenitor cell transplantation (PBPCT) in 40 patients with high-risk cancer during their first-line treatment. PBPCs were collected during the previous outpatient induction chemotherapy programme by leukaphereses. CEM administration with PBPCT was associated with low non-haematological toxicity and the only significant toxicity consisted of a reversible grade III/IV increase in liver enzymes in 32% of the patients. Haematopoietic recovery was very fast in all patients and the administration of granulocyte colony-stimulating factor (G-CSF) plus erythropoietin (EPO) or granulocyte-macrophage colony-stimulating factor (GM-CSF) plus EPO after PBPCT significantly reduced haematological toxicity, abrogated antibiotic administration during neutropenia and significantly reduced hospital stay and patient's hospital charge compared with patients treated with PBPCT only. None of the patients died early of CEM plus PBPCT-related complications. Low non-haematological toxicity and accelerated haematopoietic recovery renders CEM with PBPC/growth factor support an acceptable therapeutic approach in an adjuvant or neoadjuvant setting.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Chemotherapy, Adjuvant; Erythropoietin; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Hematopoietic System; Humans; Length of Stay; Melphalan; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Recombinant Proteins; Survival Rate

Patients with haematological malignancies undergoing allogeneic BMT were randomised to treatment with recombinant human erythropoietin (rHuEPO) (n = 25) or placebo (n = 25). rHuEPO was given at 200 U/kg daily for 4 weeks and 200 U/kg twice weekly for a further 4 weeks. The groups were similar regarding several prognostic factors. There were no differences between the two groups regarding time to engraftment, fever, hospitalisation, GVHD, infections, haemorrhages, transplant-related mortality, relapse and survival. However, more patients in the control group had a raised serum creatinine (43% vs 14%; p = 0.04). Red blood cell (RBC) transfusion requirements for the first 2 months after BMT were significantly lower in the rHuEPO group compared with the control group (5 units vs 10; p = 0.04). Time to unsupported Hb > 70 g/l was less in patients treated with rHuEPO (14 days vs 24; p = 0.03). No effect was seen on platelet engraftment or the number of transfused platelet units. Two patients in the control group compared with none in the rHuEPO group became refractory to platelet transfusions. According to the protocol the study drug was reduced (Hb > 100) or discontinued (Hb > 120) for a mean of 3.6 weeks among 11 rHuEPO patients compared with 1.9 weeks among 7 controls (p = 0.02). Seven of the treated patients compared with none of the controls reached Hb > 120 during the study period (p = 0.004). Among the rHuEPO treated patients, EPO-levels were significantly higher than in the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Blood Cell Count; Blood Transfusion; Bone Marrow Transplantation; Child; Double-Blind Method; Erythropoiesis; Erythropoietin; Female; Hematologic Diseases; Hemoglobins; Humans; Immunologic Factors; Incidence; Leukemia; Male; Middle Aged; Recombinant Proteins; Reticulocytes; Survival Analysis; Weight Loss

We have used recombinant human erythropoietin (rHuEPO) in a phase I/II clinical trial to evaluate its ability to reverse refractory anemia in hematologic disorders. rHuEPO was administered subcutaneously 5 days per week at escalating doses (50 to 150 U/kg per day). The aim of treatment was a hemoglobin (Hb) level greater than or equal to 10 g/dL without blood transfusion. Of 25 patients treated, 17 were evaluable, most of them with a regular need for transfusion. Eight of these had lymphoproliferative disorders (three cases of malignant lymphoma and five of monoclonal gammopathy) and were exposed to cytotoxic therapy. The other nine patients had hematopoietic stem cell disorders (four cases of myelodysplastic syndrome, three of idiopathic myelofibrosis, and two of chronic myelogenous leukemia). All patients with lymphoproliferative disorder had serum EPO levels inappropriately low for the degree of anemia, while patients with stem cell disorder showed variable values. Erythroid marrow activity was inadequate in all cases. Seven of eight patients with lymphoproliferative disorder responded to treatment maintaining Hb above 10 g/dL without transfusion. The median dose of rHuEPO required for correction of anemia was 75 U/kg. In four cases response was maintained with 50 U/kg, three times per week. There was no complete response among patients with hematopoietic stem cell disorder, although transfusion requirement was eliminated or reduced in four cases. Four patients developed functional iron deficiency during rHuEPO treatment and required iron supplementation to obtain response. Aggravation of splenomegaly was observed in two cases of myeloproliferative disorder. We conclude that: (1) subcutaneous administration of rHuEPO can be effective and safe in patients with lymphoproliferative disorder exposed to chemotherapy and showing inappropriate EPO response to anemia; (2) this is less likely in hematopoietic stem cell disorders, although favorable responses may be observed in occasional patients; and (3) functional iron deficiency as a cause of nonresponse to rHuEPO is frequent also in nonrenal anemia.

Topics: Adult; Aged; Anemia, Refractory; Bone Marrow; Drug Evaluation; Erythroid Precursor Cells; Erythropoietin; Female; Ferritins; Hematologic Diseases; Humans; Iron; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lymphoproliferative Disorders; Male; Middle Aged; Myelodysplastic Syndromes; Primary Myelofibrosis; Receptors, Transferrin; Recombinant Proteins

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

Topics: Age Factors; Antineoplastic Combined Chemotherapy Protocols; Asian People; Carcinoma, Non-Small-Cell Lung; Cisplatin; Erythropoietin; Female; Genotype; Hematologic Diseases; Humans; Lung Neoplasms; Male; Middle Aged; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Severity of Illness Index; Sex Factors; Treatment Outcome

This article focuses on the use of rEpo, IVIG, and rG-CSF in the NICU. It discusses the most recent studies and the most definitive and clinically relevant evidence, rather than summarizing all published studies. The last section was written for NICU practice groups that choose to use any of these medications and are seeking a consistent approach for doing so. The section provides the author's approach to the use of rEpo, IVIG, and rG-CSF, revealing personal preferences, interpretations, and experiences, and is based on the dictum, "if you are going to use it, use it the same way each time."

Topics: Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematologic Diseases; Humans; Immunoglobulins, Intravenous; Infant, Newborn; Infant, Newborn, Diseases; Infections; Intensive Care Units, Neonatal; Neuroprotective Agents; Recombinant Proteins

Impaired erythropoiesis is a key abnormality described in untreated HIV-1 disease. Most of the available data on HIV-associated hematopoietic abnormalities were obtained using unfractionated bone marrow-derived mononuclear cells, thus resulting in significant inter (and intra)-individual variability in the number of cultured precursors. Aim of this study was to assess the erythropoietic capability of purified CD34+ progenitors through a longitudinal analysis of burst-forming units-erythroid (BFU-E) growth before and after antiretroviral therapy (ART).. Twelve HIV-infected individuals were studied before and after ART; 31 HIV-uninfected individuals were enrolled as controls. CD34+ progenitors were purified from peripheral blood by immunomagnetic sorting and cultured in methylcellulose-based medium containing stem cell factor, granulocyte-monocyte colony-stimulating factor, interleukin-3, and erythropoietin. Serum levels of iron, transferrin, transferrin saturation index, soluble transferrin receptor, ferritin, and erythropoietin were also evaluated.. Baseline BFU-E levels were increased in untreated HIV-infected individuals when compared with controls but declined significantly after successful ART. In contrast, serum levels of erythropoietin and soluble transferrin receptor increased significantly after ART.. These findings suggest that, in untreated HIV-infected individuals, chronic inflammation and/or immune activation is associated with defective erythropoiesis and accumulation of erythroid precursors. ART-induced suppression of HIV-1 replication is associated with normalization of BFU-E levels.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cell Differentiation; Cells, Cultured; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hematologic Diseases; HIV Infections; HIV-1; Humans; Interleukin-3; Longitudinal Studies; Male; Middle Aged; Stem Cell Factor

The aim of the present study was to evaluate the radioprotective effect of diltiazem (DTZ) on Swiss albino mice exposed to gamma radiation. In the present study, radioprotective efficacy of DTZ (a calcium channel blocker) was studied against radiation induced haematological and biochemical alterations. Swiss albino mice of 6-8 weeks old were administered diltiazem (100 mg kg(-1) by weight) intraperitoneally prior to whole body gamma-irradiation (7.5 Gy). Radiation exposure resulted in a significant decline in different bone marrow cells (pro- and normoblasts) and blood constituents (erythrocytes, leukocytes, differential leukocyte count, haematocrit, haemoglobin and erythrocyte sedimentation rate). Pro- and normoblasts, erythrocytes, leukocytes, haematocrit and haemoglobin values showed a significant (p<0.0051) decline until day 3, following a gradual recovery from day 7, but normal values were not recorded until 28 days post-exposure. In contrast, erythropoietin levels increased significantly and reached a maximum on day 3. In DTZ pre-treated irradiated animals, a significant increase in pro- and normoblasts, erythrocytes, leukocytes, differential leukocyte count, haematocrit and haemoglobin values, and a significant decrease in erythropoietin values, were observed compared with control. A significant elevation above normal in lipid peroxidation level was recorded in gamma irradiated mice, whereas this increase was considerably less in DTZ pre-treated animals. Similarly, pre-treatment of DTZ caused a significant increase in erythropoietin and glutathione levels in serum in comparison with irradiated animals. From our study it is clear that DTZ provides protection against radiation-induced haematological and biochemical alterations in Swiss albino mice.

Topics: Animals; Diltiazem; Drug Evaluation, Preclinical; Erythropoietin; Gamma Rays; Glutathione; Hematologic Diseases; Lipid Peroxidation; Mice; Radiation Injuries, Experimental; Radiation-Protective Agents; Whole-Body Irradiation

Topics: Erythropoietin; Granulocyte-Macrophage Colony-Stimulating Factor; Hematologic Diseases; Humans; Thrombopoietin

We examined whether women aged 60 years or older with ovarian cancer who were treated with surgery and postoperative chemotherapy are at higher risk of developing grade 4 hematological toxicity. Seventy-five patients were included: 34 patients aged < 60 years (group I) were compared with 41 patients aged > or =60 years (group II) after postoperative treatment with single-agent carboplatin or carboplatin/taxane combination chemotherapy. Secondary prophylaxis with granulocyte colony-stimulating factors was performed to avoid dose reduction and chemotherapy delay. A total of 450 chemotherapy cycles was completed. Anemia and thrombocytopenia were mild in both groups. Overall, grade 4 neutropenia developed in 41% (group I) and in 49% (group II) (p=0.51). Febrile neutropenia occurred in 12% and 2%, respectively (p=0.17). The carboplatin/taxane combination was associated with grade 4 neutropenia in 42% (group I) and 58% (group II) (p=0.21). Women > or =60 years are not at higher risk of developing severe myelotoxicity than their younger counterparts, particularly after treatment with carboplatin/taxane combination chemotherapy.

Topics: Adult; Age Factors; Aged; Anemia; Antineoplastic Agents; Carboplatin; Drug Therapy, Combination; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Hematologic Diseases; Humans; Middle Aged; Neutropenia; Ovarian Neoplasms; Postoperative Complications; Recombinant Proteins; Retrospective Studies; Risk Factors; Taxoids; Thrombocytopenia

Algorithms that combine scores from multiple blood parameters are demonstrably effective in highlighting recombinant human erythropoietin (rHuEPO) administration, and have been used to deter rHuEPO use by athletes. These models are sensitive to atypical levels of blood parameters encountered during altered states of red cell production. Because hematologic abnormalities can also result in unusual blood profiles, the aim of this study was to document the incidence and magnitude of such abnormalities in an elite athlete population.. We screened blood samples obtained from 413 female and 739 male elite athletes from 12 countries for known hematologic abnormalities, and compared the algorithm scores for these athletes with those of their healthy counterparts. We also established the magnitude of blood parameters required for model scores to exceed cut-offs associated with rHuEPO use.. We found that 0.7% of male and 2.4% of female athletes were iron deficient either with our without anemia. An additional 1.4% of males and 1.0% of females had hemoglobinopathies. On average these athletes' model scores were at or below the score of their healthy counterparts. The greatest influence on our models was hemoglobin concentration. Values of other parameters must exceed normal ranges by a substantial margin in order for model scores to approach levels associated with rHuEPO use.. The hematologic disorders we encountered in elite athletes were not associated with model scores that exceeded the nominal cut-offs that we have previously recommended to delineate rHuEPO use. We did not find any abnormalities among elite endurance athletes that were associated with high model scores.

Topics: Adolescent; Anemia; Anemia, Iron-Deficiency; Doping in Sports; Erythrocyte Indices; Erythropoiesis; Erythropoietin; Female; Hematologic Diseases; Hematologic Tests; Hemoglobinopathies; Hemoglobins; Humans; Male; Models, Biological; Recombinant Proteins; Reticulocyte Count; Sensitivity and Specificity; Sex Characteristics; Sex Distribution; Sports

Topics: Cytokines; Erythroblasts; Erythropoietin; Female; Hematologic Diseases; Humans; Male; Middle Aged

To define the incidence, course, and etiology of hematologic abnormalities in children on tacrolimus-based immunosuppression, we reviewed records of 106 transplant patients (70 heart, 16 heart and lung, 20 double lung), 0-21 yr of age, who were transplanted at the Children's Hospital of Pittsburgh from 1989 to 1997. Fifty-four of the 106 patients (51%) developed 65 abnormal hematologic episodes (32 anemia, nine neutropenia, nine thrombocytopenia, 15 simultaneous anemia and neutropenia with or without thrombocytopenia). Common etiologies included: infections, post-transplant lymphoproliferative disease, and medications. Eleven episodes (seven anemia, one neutropenia, and three simultaneous anemia and neutropenia) had unclear etiologies and process of elimination suggested an association with tacrolimus. Interventions included filgrastim (effective in 15 of 15 patients, with resolution of neutropenia in a median of 5 days) and epoetin alfa (effective in five of 16 patients, including four of four patients with anemia possibly related to tacrolimus). Five patients (two with neutropenia and three with simultaneous neutropenia and anemia) were switched to cyclosporin A (CsA); rapid resolution occurred in four of the five patients, suggesting a possible association of the hematologic abnormalities with tacrolimus. In summary, hematologic abnormalities are common in children on tacrolimus-based immunosuppression. Most of these hematologic abnormalities are caused by common etiologies; however, a sub-population exists where tacrolimus may be the etiologic agent. Anemia and neutropenia respond to treatment with epoetin alfa and filgrastim. After thorough investigation, a trial switch to CsA may be warranted.

Topics: Adolescent; Adult; Anemia; Child; Child, Preschool; Epoetin Alfa; Erythropoietin; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Heart Transplantation; Heart-Lung Transplantation; Hematologic Diseases; Humans; Immunosuppressive Agents; Infant; Lung Transplantation; Male; Neutropenia; Recombinant Proteins; Retrospective Studies; Tacrolimus; Thrombocytopenia

Topics: Antineoplastic Combined Chemotherapy Protocols; Choriocarcinoma; Chorionic Gonadotropin; Combined Modality Therapy; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Hematologic Diseases; Humans; Middle Aged; Pregnancy; Recombinant Proteins; Uterine Neoplasms

Topics: Erythrocyte Transfusion; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocytes; Hematologic Diseases; Hematology; Humans; Immunoglobulins, Intravenous; Infant, Newborn; Intensive Care Units, Neonatal; Neonatology; Platelet Transfusion; Preventive Medicine; Recombinant Proteins

Previously, flow cytometric determination of peroxidase activity, cell size, and reactivity to lymphocyte antibodies were used to produce bone marrow differentials in untreated rats. In the present study, abnormal hematologic profiles were induced with erythropoietin (EPO), recombinant murine stem cell factor (rm-SCF), granulocyte-macrophage stimulating factor (GM-CSF), and cyclophosphamide (CP). Manual and flow cytometric data showed comparable levels of erythroid and myeloid hyperplasia in EPO- and rm-SCF/GM-CSF-treated animals, respectively. In CP-treated animals, flow cytometric data revealed significant decreases in cellularity at concentrations of CP > or = 5 mg/kg. In contrast, 20 mg/kg CP were necessary to induce microscopically apparent hypoplasia in histologic bone sections, showing that the automated methodology was a more sensitive indicator of bone marrow hypocellularity than was the more conventional manual method. Megakaryocyte counts were consistently higher by flow cytometer than by manual counts performed on cytocentrifuge preparations made from the same cell suspensions but were similar to megakaryocyte counts performed on histologic sections of femur, indicating that the automated methodology produced a more accurate reflection of true megakaryocyte numbers. Induction of hematologic abnormalities in the present study showed that manual bone marrow differentials can be replaced with the more efficient and reliable flow cytometric method in most preclinical toxicology studies.

Topics: Animals; Bone Marrow Cells; Bone Marrow Examination; Cell Count; Cyclophosphamide; Erythropoietin; Female; Flow Cytometry; Granulocyte-Macrophage Colony-Stimulating Factor; Hematologic Diseases; Hyperplasia; Male; Rats; Rats, Wistar; Stem Cell Factor

Topics: Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematologic Diseases; Humans; Thrombopoietin

Topics: Acquired Immunodeficiency Syndrome; Anemia; Arthritis, Rheumatoid; Autoimmune Diseases; Blood Donors; Erythropoietin; Hematologic Diseases; Humans; Kidney Failure, Chronic; Neoplasms; Recombinant Proteins

Topics: Acquired Immunodeficiency Syndrome; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematocrit; Hematologic Diseases; Humans; Leukocyte Count; Lymphoma, AIDS-Related; Neutrophils; Recombinant Proteins

In vitro models of hematopoiesis are used increasingly in investigative hematopathology. Such models complement in vivo animal testing and have been shown to be predictive for hematotoxicity associated with anticancer and antiviral agents in humans. In vitro models of hematopoiesis consist of short-term cloning assays for various hematopoietic progenitor cells and long-term functional assays for the marrow hematopoietic microenvironment. In our laboratories, the cloning assays have been used as investigative tools to study the pathogenetic mechanisms of drug-induced blood disorders and as screening systems to investigate the possible hematotoxic potential of candidate drugs in various animal species. Data in support of these applications are presented in this paper.

Topics: Animals; Cells, Cultured; Dogs; Dose-Response Relationship, Drug; Erythropoiesis; Erythropoietin; Female; Hematologic Diseases; Hematopoiesis; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cells; Male; Stem Cell Factor; Zidovudine

Topics: Anemia; Anemia, Refractory; Blood Preservation; Blood Transfusion, Autologous; Erythropoiesis; Erythropoietin; Hematologic Diseases; Humans; Inflammation; Neoplasms; Receptors, Erythropoietin; Recombinant Proteins; Renal Dialysis

A sensitive radioimmunoassay (RIA) for the detection of erythropoietin (EPO) was developed using antibody directed against EPO from human urine. With 100 microL of sample, the assay is sensitive to 7 U/L, well below the mean EPO level in normal males (15.1 +/- 3.5 U/L) or females (15.4 +/- 4.8 U/L). Dilutions of a variety of human serum samples show a parallel relationship with the standard EPO. Clinical validation of the RIA was confirmed by appropriate increases or decreases of EPO levels in various types of anemia and polycythemia. Serum EPO levels were also measured in volunteers participating in an autologous blood donation study. The RIA proved to be quite sensitive, detecting small increases even after a single unit phlebotomy. This RIA of human EPO meets all the requirements of a routine clinical assay in terms of specificity and clinical sensitivity and can be easily conducted in routine clinical laboratories.

Topics: Erythropoietin; Female; Hematologic Diseases; Humans; Kidney Failure, Chronic; Male; Radioimmunoassay; Recombinant Proteins; Reference Values; Sensitivity and Specificity

With a newly developed enzyme linked immunosorbent assay kit TOYOBO Co. in which 2 anti-EPO monoclonal antibodies were used, we assayed EPO concentration in sera from normal adults, 168 patients with renal failure and 333 patients with hematological disorders. In the patients with renal failure, serum EPO level was normal (52.9%) or reduced (42.9%), and there was no correlation to their hematocrits. However, there was an increment in EPO concentration correlated to their severity of anemia in the most patients with hematological disorders, such as iron deficiency anemia (correlation coefficient r = -0.74), aplastic anemia (r = -0.89), leukemia (r = -0.81), and MDS (r = -0.65). On the other hand, EPO concentration in sera from all the untreated patients with polycythemia vera were significantly low level. But the concentrations of EPO from the patients successfully treated, with normal hematocrit were recovered to normal level. In the patients with secondary polycythemia, there were much varieties in EPO level. Assay of EPO in blood is important not only for diagnosis of polycythemia but also for the analysis of anemia and clinical use of EPO in vivo. The method described here is accurate and technically not complicated, and could be widely induced in most laboratories.

Topics: Adolescent; Adult; Anemia; Antibodies, Monoclonal; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Hematologic Diseases; Humans; Male; Middle Aged; Renal Insufficiency

With a newly developed short term enzyme linked immunosorbent assay kit (TOYOBO Co.), in which 2 kinds of anti-EPO monoclonal antibodies were used, we assayed EPO concentration in sera from patients with renal failure and hematological disorders. In this report, the EPO data were analysed in relation to serum iron concentrations, with ferritin and UIBC. In the patients with renal failure, there was no significant correlation between EPO concentration and serum iron, ferritin, nor UIBC concentration. On the other hand, in the patients with hematological disorders, there were two types. One was in patients with iron deficiency anemia, whose serum EPO was negatively correlated to serum iron (r = -0.64) and ferritin (r = -0.59), but positively related to UIBC (r = 0.27). The another was the pattern in patients with aplastic anemia, leukemia and MDS, whose serum EPO positively correlated to iron and ferritin but negatively correlated to UIBC. In the patients with aplastic anemia serum EPO had good correlation to serum iron (r = 0.62), ferritin (r = 0.60) and UIBC (r = -0.46). The relationship of EPO to iron in the patients with leukemia (r = 0.54), and EPO to ferritin in the patients with MDS (r = 0.42) show significantly positive correlation coefficient.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Enzyme-Linked Immunosorbent Assay; Erythropoietin; Ferritins; Hematologic Diseases; Humans; Iron; Renal Insufficiency

We evaluated a newly developed enzymeimmunoassay for serum erythropoietin (Epo) and investigated relationship between Epo levels and hematological disorders. This method has several advantages including simplicity, high sensitivity, good precision. Moreover, the procedure requires only about 2.5 hours. Samples from 134 healthy subjects showed a normal logarithmic distribution, and its normal range was 4.5 approximately 21.3 mU/ml. The levels of Epo in normal subjects and various hematological disorders were as follows: 10.5 +/- 4.1 (mean +/- SD mU/ml) in normal subjects, 2.2 +/- 1.7 in polycythemia vera (PV), 6.1 +/- 3.1 in essential thrombocythemia, 17.8 +/- 27.3 in chronic myelogeneous leukemia, 3.6 +/- 1.8 in stress erythrocytosis, 39.4 and 14.1 in two cases of primary myelofibrosis, 1289 +/- 4798 in iron deficiency anemia and 6564 +/- 10870 in aplastic anemia. In patients with PV, serum Epo were low and did not correlate with hemoglobin concentration. However, inverse correlation was found between changes of Epo levels and hemoglobin levels in most patients. In cases in which PV progressed into myelofibrosis, anemia developed and Epo levels increased accordingly. These results suggest that the method is thought to be useful and reliable for the diagnosis and monitoring of PV and related hematological disorders.

Topics: Erythropoietin; Hematologic Diseases; Hemoglobins; Humans; Immunoenzyme Techniques; Polycythemia Vera; Primary Myelofibrosis; Sensitivity and Specificity

Stem cell factor (SCF) enhances normal hematopoiesis. We examined its effect in vitro on bone marrow and blood progenitors from patients with inherited bone marrow failure syndromes, including 17 patients each with Diamond-Blackfan anemia (DBA) and Fanconi's anemia (FA), 3 with dyskeratosis congenita (DC), and 1 each with amegakaryocytic thrombocytopenia (amega) and transient erythroblastopenia of childhood (TEC). Mononuclear cells were cultured with erythropoietin (Ep) alone or combined with SCF or other factors. SCF increased the growth of erythroid progenitors in cultures from 50% of normal controls, 90% of DBA, 70% of FA, 30% of DC, and the amega and TEC patients; normal numbers were reached in 25% of DBA studies. Improved in vitro erythropoiesis with SCF in all types of inherited marrow failure syndromes does not suggest a common defect involving kit or SCF, but implies that SCF may be helpful in the treatment of hematopoietic defects of varied etiologies.

Topics: Adolescent; Adult; Blood Transfusion; Bone Marrow; Bone Marrow Diseases; Cells, Cultured; Child; Child, Preschool; Colony-Forming Units Assay; Erythropoiesis; Erythropoietin; Fanconi Anemia; Female; Hematologic Diseases; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cells; Humans; Infant; Male; Recombinant Proteins; Reference Values; Stem Cell Factor

A method is described for the quantitative analysis of in vivo organ measurements of 59Fe activity in ferrokinetic investigations. The time-activity curves obtained by sequential surface monitoring over sacrum, liver and spleen can be resolved quantitatively into their different components contributing to the recorded count rate. The analysis is performed in three steps: (1) Count rate contributions from activity in other organs and from scattered radiation from regions outside the organ under investigation are corrected. (2) Distinction is made between radioactivity uptake of the tissue and radioactivity contained in the perfusing blood. (3) The resulting net organ activity is then further resolved into an erythropoietic and a storage iron component by use of a computer program (SAAM-27) and assuming a compartmental model for internal iron exchange. The method was tested in three groups of patients with different haematological disorders and in normal controls. Characteristic patterns of the parameters are found for different diseases and the results correlated well with the clinical findings. It is concluded that in vivo organ measurements of 59Fe activity, when performed and analysed with sufficient care, can provide an insight into the dynamics of the iron exchange that is taking place in an organ. This analytical approach may improve the diagnostic predictions of ferrokinetic investigations.

Topics: Erythropoietin; Hematologic Diseases; Humans; Iron; Iron Radioisotopes; Liver; Sacrum; Software; Spleen

A sandwich, non-competitive enzyme-linked immunosorbent assay (ELISA) for erythropoietin (EPO) is described. The ELISA utilizes a monospecific, polyclonal antibody raised in rabbits against human recombinant EPO (rhu EPO) and purified over a rhu EPO affinity chromatography column. The ELISA procedure can be summarized as follows: Anti-EPO is coated onto 96-well ELISA microtitre plates; standard EPO or sample is added and left to bind to this catching antibody; this is followed by the addition of the same antibody which has been biotinylated; finally, anti-biotin conjugated to alkaline phosphatase is added and the enzyme reaction developed and read at 405 nm. All parameters of the assay have been optimized. Recombinant human EPO was standardized against the World Health Organization 2nd International Reference Preparation for erythropoietin. The minimal detectable concentration of rhu EPO was 0.3-0.5 mU/ml, which corresponded to 1.2-2 mU/ml of EPO in serum (serum diluted 1:4). No reaction was obtained with a variety of blood components and cytokines, indicating that the anti-EPO antibody did not cross-react with those substances to produce false-positive results. The intra-assay variation ranged from 3% to 10%, while the inter-assay variation ranged from 8.5% to 24%. Serum dose-response curves were parallel to the standard dose-response curve. The assay is easy to use, rapid, reproducible, but above all quantitative, specific and sensitive to measure the EPO content in all serum samples.

Topics: Enzyme-Linked Immunosorbent Assay; Erythropoietin; Hematocrit; Hematologic Diseases; Humans; Immunoglobulin G; Radioimmunoassay; Sensitivity and Specificity

We studied 24 recipients of autologous bone marrow transplantation (ABMT) or allogeneic BMT (BMT) to determine whether impaired erythropoietin (Epo) response to anemia could delay full erythropoietic recovery. Observed Epo levels were compared with predicted levels based on the relationship between Epo and hematocrit in 125 control subjects. Circulating Epo levels were normal during conditioning and the early posttransplant period. Between days 21 and 180, Epo levels remained normal in ABMT patients but were inappropriately low for the degree of anemia in BMT patients. Median time to full erythropoietic engraftment was longer in BMT than in ABMT recipients. Circulating Epo returned to appropriate levels after day 180, except in patients with active cytomegalovirus infection. We conclude that impaired Epo response to anemia can contribute to delayed erythropoietic recovery after allogenic BMT. Renal toxicity of ciclosporin, interaction between host and donor marrow, and cytomegalovirus infection might play a role. This study could support the use of recombinant human Epo to accelerate erythropoietic engraftment after BMT.

Topics: Adolescent; Adult; Anemia; Bone Marrow Transplantation; Child; Child, Preschool; Cytomegalovirus Infections; Erythropoietin; Female; Graft Survival; Graft vs Host Disease; Hematocrit; Hematologic Diseases; Humans; Male; Middle Aged; Transplantation, Autologous; Transplantation, Homologous

Topics: Colony-Stimulating Factors; Epidermal Growth Factor; Erythropoietin; Fibroblast Growth Factors; Hematologic Diseases; Humans; Interleukins; Platelet-Derived Growth Factor; Transforming Growth Factor beta

We report here the performance of a recently commercialized radioimmunoassay kit for determining erythropoietin (EPO) in serum or plasma. The lower detection limit of the method was 3 U/L. Precision, analyzed by the variation coefficients between different assay runs and in the same experiment, was always less than 10%; accuracy was assessed by recovery and dilution tests. In anemic patients (hematocrit 18-39%), the concentration of EPO was logarithmically related to hematocrit. A relatively large dispersion of the results was noted, as reported by others with various RIAs. Patients with severe renal failure demonstrated a very low EPO value, whatever the degree of their anemia. In some chronic anemias resulting from malignancy, EPO concentrations were also relatively low. In the polycythemia vera group, the EPO mean was below normal for greater than 95% of the patients, whatever their clinical stage (first evaluation, relapse, or remission). In contrast, 91% of the patients with pure erythrocytosis had a normal or increased EPO value, even when the etiology was unknown. Measurement of EPO concentration may be useful for the clinical differentiation of myeloproliferative disorders and, subsequently, for their prognosis and choice of treatment.

Topics: Erythropoietin; Hematologic Diseases; Humans; Radioimmunoassay; Reagent Kits, Diagnostic

For clinical studies with erythropoietin (EPO), enzyme-linked immunosorbent assays for the determination of EPO and EPO antibodies were developed. Using polyclonal and monoclonal EPO antibodies in a sandwich technique, serum EPO levels greater than 10 pg/ml (corresponding to 1 mU/ml, calibrated with the 2nd WHO IRP EPO) can be determined. In 103 healthy blood donors, a mean (+/- SD) value of 36 +/- 19 pg EPO/ml was found. Very high EPO concentrations were found in patients suffering from myelodysplastic syndrome and aplastic anemia; elevated levels were associated with rheumatoid arthritis and myelomatosis. No EPO antibodies were detectable in EPO-treated patients.

Topics: Antibodies; Antibodies, Monoclonal; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Hematologic Diseases; Humans; Radioimmunoassay

In vitro cultures of erythroid progenitors and radioimmunoassay of erythropoietin (Epo) are 2 recently available techniques. It is possible to assess their relevance in various hematological disorders. Erythroid cultures can be performed in the investigation of polycythemias, pure red cell aplasias (PRCA) and refractory anemias. In primary polycythemias "spontaneous" colonies appear in vitro whereas this phenomenon is never observed in secondary polycythemias. These so called "spontaneous" colonies have been demonstrated with a lower incidence in all myeloproliferative disorders. Therefore, if the absence of spontaneous colonies does not permit us to eliminate the presence of a myeloproliferative syndrome aside from polycythemia vera, their presence does seem pathognomonic of a myeloproliferative disorder. In acquired chronic pure red cell aplasia in adults, a strong correlation is found between the in vitro growth of erythroid colonies and the results of immuno-suppressive treatment. In refractory anemias erythroid cultures do not have either diagnostic, or prognostic interest. Serum epo level does not have a high discriminatory value in distinguishing between primary and secondary erythrocytosis. Indeed in PV, the Epo level is generally low or normal, in secondary polycythemias Epo level is high or normal. There is an important overlap between the two groups. Epo level determination can have a therapeutic incidence. Administration of recombinant Epo seems justified only in patients both sufficiently anemic to warrant transfusions and in whom Epo level is low in comparison with the degree of anemia.

Topics: Erythroid Precursor Cells; Erythropoietin; Hematologic Diseases; Humans; Immunosuppression Therapy; Polycythemia; Radioimmunoassay; Red-Cell Aplasia, Pure; Remission Induction; Reproducibility of Results

The accurate measurement of biologically active erythropoietin (Ep) in human serum and plasma using present in vivo and in vitro bioassays is difficult because of the presence of both inhibitors and non-Ep stimulators of erythropoiesis. We have developed a simple procedure to quantitatively purify Ep from serum and plasma for subsequent testing in the phenylhydrazine-treated mouse spleen cell assay. The method involves absorption of Ep to an immobilized high-affinity anti-Ep monoclonal antibody and acid elution of the antibody-bound material. After neutralization, the eluted EP is then tested directly in the in vitro bioassay without interference by other serum proteins. By using magnetic beads as a solid support for the antibody, washing and elution steps can be performed rapidly and efficiently. Recoveries of Ep after this procedure show very little sample-to-sample variation and are consistently between 45% and 55%, which is close to the maximum binding expected for the anti-Ep antibody. Coupled with the 7.4-fold concentration that this procedure affords, there is an overall increase in sensitivity of three- to fourfold, which makes this assay suitable for accurately measuring Ep levels in patients with below-average titers. Results with this magnetic bead assay indicate that accurate and reproducible estimates for Ep levels in the serum and plasma from healthy donors as well as from patients with hematologic disorders can be obtained. Titers of biologically active Ep in the sera from a group of patients with either leukemia or lymphoma were found to be elevated, and the values correlated well with titers of immunoreactive Ep measured in the Ep radioimmunoassay. Because of its specificity and high sensitivity, the magnetic bead assay is a valuable alternative to immunoassays for the measurement of elevated, normal, and even subnormal Ep levels in human serum and plasma.

Topics: Antibodies, Monoclonal; Antibody Affinity; Biological Assay; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Hematologic Diseases; Humans; Magnetics; Plasma; Radioimmunoassay; Spleen

Topics: Bone Marrow; Colitis, Ulcerative; Crohn Disease; Erythropoiesis; Erythropoietin; Hematologic Diseases; Humans; Leukemia

Topics: Cell Differentiation; Diagnosis, Differential; Erythroid Precursor Cells; Erythropoietin; Hematologic Diseases; Humans; Recombinant Proteins

Topics: Animals; Cell Differentiation; Colony-Stimulating Factors; Erythropoietin; Hematologic Diseases; Hematopoiesis; Hematopoietic Stem Cells; Humans; Interleukins

Topics: Colony-Stimulating Factors; Erythropoietin; Growth Substances; Hematologic Diseases; Humans; Interleukins; Recombinant Proteins

Erythropoietin titers when related to the hematocrit percentage and measured by bioassay in 33 normal volunteers and in 61 patients with anemias not complicated by renal or chronic disease were found to overlap with titers measured by radioimmunoassay in 20 normals and 28 patients with similar anemias. Erythropoietin titers measured by radioimmunoassay in 34 patients with rheumatoid arthritis, 25 patients with sickle cell anemia (58 separate samples), and 28 patients with erythroid hypoplasia caused by hematologic malignancies were compared with those in the control group of patients with uncomplicated anemias and found not to differ significantly from titers in this group. Erythropoietin titers measured by bioassay in 12 patients with aplastic anemia also fell within the range of those in the control group. Consequently, erythropoietin titers in these anemias appear to be determined primarily by the degree of anemia and not by any specific effect of these illnesses on the production of erythropoietin.

Topics: Anemia; Anemia, Aplastic; Anemia, Sickle Cell; Arthritis, Rheumatoid; Biological Assay; Erythropoietin; Female; Hematologic Diseases; Humans; Male; Radioimmunoassay; Red-Cell Aplasia, Pure

In order the investigate mechanisms of diminished red cell production in malignancy, we assayed erythroid progenitor cell proliferative responses to erythropoietin in plasma clot cultures of bone marrow cells from 34 cancer patients. Erythroid colony growth by marrow cells of 11 healthy donors (means of 58 CFU-E and 19 BFU-E derived colonies/6 X 10(4) cells) was similar to that in cultures of cells from patients either with (means of 44 CFU-E and 22 BFU-E derived colonies/6 X 10(4) cells) or without (means of 50 CFU-E and 19 BFU-E derived colonies/6 X 10(4) cells) myelophthisis. Colony formation was normal at all erythropoietin concentrations tested, indicating that both the CFU-E and BFU-E retain normal erythropoietin sensitivity in vitro. CFU-E proliferation correlated negatively (r = -0.56; P less than 0.001) with the level of hemoglobin. In contrast to marrow cell proliferative responses to erythropoietin, serum erythropoietin levels were inappropriately reduced in all 19 patients in whom they were measured, a finding which may be important in the pathogenesis of anemia in patients with cancer.

Topics: Carcinoma, Squamous Cell; Cell Division; Cells, Cultured; Erythropoiesis; Erythropoietin; Female; Hematologic Diseases; Hematopoietic Stem Cells; Hemoglobins; Humans; Leukemia; Lymphoma; Male; Middle Aged

Cyclic hematopoiesis in gray Collies was first described in 1967. These dogs are anemic in comparison with the healthy littermates, and their erythropoiesis is abnormal. Although the basic disorder appears to be an as yet unidentified abnormality of hematopoietic progenitor cells, an inherent difference in responses to blood gas control mechanisms remains as a possible cause. In a study of these mechanisms in dogs with cyclic hematopoiesis, the P50 and 2,3-diphosphoglyceric acid concentrations were increased. Differences in pH, PCO2, PO2, and oxygen saturation were not observed.

Topics: 2,3-Diphosphoglycerate; Animals; Blood Gas Analysis; Bone Marrow Diseases; Carbon Dioxide; Diphosphoglyceric Acids; Dog Diseases; Dogs; Erythropoietin; Female; Hematologic Diseases; Male; Oxygen; Oxygen Consumption; Oxyhemoglobins; Periodicity

An RIA for Ep has been developed that is highly sensitive and specific. A homogeneous Ep preparation was labeled with 125 I by the chloramine-T method to a specific activity of 90 to 136 micro Ci/microgram and immunoreactivity of 80%. Ep antiserum, which was produced to a human urinary Ep preparation (80 U/mg of protein), was adsorbed with normal human urinary and serum proteins without any loss in sensitivity of the RIA to increase the specificity of the assay. A good correlation was seen between the RIA and the exhypoxic polycythemic mouse assay (corr. coef. 0.967; slope 1.05 and "y" intercept 0.75). Ep titers in sera from 175 hematologically normal human subjects exhibited a normal frequency distribution and ranged between 5.8 and 36.6 mU/ml with a mean of 14.9 +/- 4.7 (S.D.) and median of 14.3 Serum Ep titers were markedly elevated in seven patients with aplastic anemia and one patient with pure red cell aplasia (1350 to 20,640 mU/ml) and were lower than normal in two patients with polycythemia vera (8.1 and 9.4 mU/ml). The serum Ep titers in a prenephrectomy patient with chronic glomerulonephritis (32.1 mU/ml) decreased to below normal levels (9.04 mU/ml) after nephrectomy. The cord serum erythropoietin titers in 10 IDM [90.82 +/- 134.1 (S.D.) mu/ml] returned to values within the normal range (13.86 +/- 5.55) on day 3 after birth, suggesting the utility of the RIA in elucidating the role of hypoxia and/or insulin in increased erythropoiesis in IDM. The serum Ep titers in patients with anemias and polycythemias were compared to those of normal human subjects and agreed well with pathophysiologic mechanisms of these hemopoietic disorders, confirming the validity of the RIA.

Topics: Anemia; Dose-Response Relationship, Drug; Erythropoietin; Evaluation Studies as Topic; Fetal Blood; Hematologic Diseases; Humans; Iodine; Iodine Radioisotopes; Polycythemia Vera; Radioimmunoassay

Granulocytic (colony-forming units in culture, or CFU-c) and erythrocytic (erythropoietin-responsive cells, or ERC) progenitor cells in canine cyclic hematopoiesis (CH) have been shown to fluctuate over the cycle and in the same phases as one another. The ERC cycle is preceded by 3 or 4 days by a rise in serum erythroid-stimulating activity and is followed by a reticulocytosis. During the cycle CFU-c show a differential sensitivity to two sera, one normal and one containing elevated amounts of colony-stimulating activity. The proliferation rate of CFU-c also fluctuates from well above normal to considerably less than normal over the cycle. These results are discussed in the light of present knowledge of the pathogenesis of canine CH. We suggest that these results support the contention that CH is a disorder of hemopoietic stem cells and that the cycling of humoral factors and peripheral blood cells may follow as a consequence.

Topics: Animals; Cell Cycle; Cytological Techniques; Dogs; Erythropoietin; Female; Granulocytes; Hematologic Diseases; Hematopoietic Stem Cells; Kinetics; Male; Periodicity

Topics: Animals; Cell Division; Cells, Cultured; Clone Cells; Erythropoiesis; Erythropoietin; Hematologic Diseases; Hematopoietic Stem Cells; Hemoglobins; Humans; In Vitro Techniques; Mice

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

Topics: Animals; Body Weight; Depression, Chemical; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hematologic Diseases; Hyperemia; Immune Sera; Iron; Iron Isotopes; Rats

Topics: Anemia; Animals; Bone Marrow Examination; Castration; Disease Models, Animal; Erythrocyte Aging; Erythrocyte Count; Erythropoietin; Estrogens; Female; Hematocrit; Hematologic Diseases; Hemoglobinometry; Homozygote; Leukocyte Count; Leukopenia; Male; Rats; Rodent Diseases; Sex Factors; Spleen; Splenectomy; Splenomegaly

Topics: Androgens; Anemia; Blood Cells; Epinephrine; Erythropoiesis; Erythropoietin; Female; Glucocorticoids; Growth Hormone; Hematologic Diseases; Hormones; Humans; Hyperthyroidism; Hypothyroidism; Lymphocytosis; Middle Aged; Thyroid Hormones

Topics: Adult; Aged; Anemia, Aplastic; Animals; Bone Marrow Diseases; Erythropoiesis; Erythropoietin; Female; Hematologic Diseases; Humans; Leukemia; Male; Middle Aged; Rats

Topics: Animals; Erythropoiesis; Erythropoietin; Hematologic Diseases; Nephrectomy; Postoperative Complications; Rats; Testosterone

Topics: Bone Marrow; Erythropoiesis; Erythropoietin; Hematologic Diseases; Hemoglobins; Humans; Iron Isotopes; Mononuclear Phagocyte System; Phagocytosis; Technetium

Topics: Animals; Blood Platelets; Erythropoiesis; Erythropoietin; Hematologic Diseases; Hematopoiesis; Humans; In Vitro Techniques; Leukocytes; Lymphocytes; Mice

Topics: Epoetin Alfa; Erythropoiesis; Erythropoietin; Hematologic Diseases; Hematology; Humans

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

Topics: Epoetin Alfa; Erythropoiesis; Erythropoietin; Hematologic Diseases; Humans; Kidney Diseases

Topics: Blood Physiological Phenomena; Epoetin Alfa; Erythrocytes; Erythropoietin; Hematologic Diseases; Hematology; Humans

Topics: Anemia; Anemia, Hypochromic; Epoetin Alfa; Erythrocytes; Erythropoietin; Hematologic Diseases; Humans

Topics: Anemia; Epoetin Alfa; Erythrocytes; Erythropoietin; Hematologic Diseases; Hematopoiesis; Humans; Hypoxia

Topics: Epoetin Alfa; Erythrocytes; Erythropoietin; Hematologic Diseases; Hematopoiesis; Research

Topics: Epoetin Alfa; Erythroblastosis, Fetal; Erythropoietin; Fetal Blood; Hematologic Diseases; Incidence