losartan-potassium and Bone-Marrow-Diseases

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

The use of hematopoietic growth factors, although well established for the management of chemotherapy-induced neutropenia, remains controversial for the treatment of aplastic anemia and inherited bone marrow failure syndromes. The most commonly used factors are granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, and erythropoietin. Newer growth factors such as stem cell factor, thrombopoietin, Flt3 ligand, and interleukins have shown promising results in the laboratory, and some have been used in clinical trials. This article reviews the clinical use of old and new hematopoietic growth factors in acquired and inherited bone marrow failure, and discusses emerging concerns about long term toxicity of these factors.

Topics: Anemia, Aplastic; Bone Marrow Diseases; Clinical Trials as Topic; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Humans; Stem Cell Factor

An erythrocytosis describes an increased peripheral blood packed cell volume (PCV) and is deemed to be absolute or apparent depending on whether or not the measured red cell mass (RCM) is above the reference range. This reference range must be related to the individual's height and weight to avoid erroneous interpretations using ml/kg total body weight expressions in obesity. Absolute erythrocytoses are divided into primary, where the erythropoietic compartment is intrinsically abnormal, secondary, where the erythropoietic compartment is normal but is responding to external pathological events leading to an increased erythropoietin drive, and idiopathic, where neither a primary nor a secondary erythrocytosis can be established. Both primary and secondary erythrocytoses have congenital and acquired forms. The only form of primary acquired erythrocytosis that has been defined is the clonal myeloproliferative disorder, polycythaemia vera (PV). Modified diagnostic markers for PV are proposed. Thrombocytoses can be classified into primary, where megakaryopoiesis is intrinsically abnormal, secondary, where megakaryopoiesis is normal but increased platelet production is a reaction to some other unrelated pathology, and finally idiopathic. This latter new group would be used for patients not satisfying the criteria for primary or secondary thrombocytoses, if these were more precise and rigidly used than currently is the case. While theoretically congenital and acquired forms of primary and secondary thrombocytoses might exist, only one cause of secondary congenital thrombocytosis has been established, and primary congenital thrombocytosis has not yet been precisely defined. Primary (essential) thrombocythaemia (PT) is one of the forms of primary acquired thrombocytoses. The diagnostic criteria of PT traditionally involve the exclusion of secondary thrombocytoses and other myeloproliferative disorders but marrow histology could hold a key positive diagnostic role if objective histological features of PT were agreed.

Topics: Anthropometry; Bone Marrow; Bone Marrow Diseases; Cells, Cultured; Diagnostic Imaging; Diagnostic Tests, Routine; Erythrocyte Volume; Erythroid Precursor Cells; Erythropoietin; Female; Hematocrit; Hemoglobinopathies; Humans; Hypoxia; Kidney Diseases; Liver Diseases; Male; Neoplasms; Polycythemia; Receptors, Erythropoietin; Thrombocytosis

Bone marrow suppression is a substantial problem in patients infected with HIV. Contributing factors include the underlying HIV infection, alterations in the marrow microenvironment (resulting in abnormal cytokine regulation of hematopoiesis), and opportunistic infections and their associated medical treatments. Hematopoietic stimulants offer the promise of correcting peripheral blood cytopenias, augmenting host immune function, and permitting the continued use of potentially beneficial myelosuppressive therapies, which would otherwise result in dose-limiting side effects. The bone marrow abnormalities and mechanisms that contribute to alterations in hematopoiesis in HIV infection are briefly reviewed. Attention is then focused on the expanding clinical role of myeloid colony-stimulating factors (CSFs) and recombinant human erythropoietin (rHuEPO [Epogen, Procrit]) in the treatment of patients with AIDS.

Topics: Acquired Immunodeficiency Syndrome; Anemia; Bone Marrow; Bone Marrow Diseases; Colony-Stimulating Factors; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoiesis; Humans; Neutropenia; Neutrophils; Recombinant Proteins

Topics: Antineoplastic Agents; Bone Marrow Diseases; Cell Lineage; Clinical Trials as Topic; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Recombinant Proteins

Erythropoietin, the glycoprotein which regulates erythropoiesis is unique amongst the hematopoietic growth factors since it is the only one which behaves like a hormone. Produced primarily in the kidneys in adults, erythropoietin interacts with erythroid precursors in the marrow to increase red cell production. Because erythropoietin behaves like a hormone, measurements of erythropoietin in the serum have proved useful in determining when production of this hormone is inadequate. Tissue hypoxia is the only physiologic stimulus for erythropoietin production and thus, with anemia, serum erythropoietin levels should be increased. Assuming normal marrow function and adequate nutrient supplies, when anemia is associated with a low serum erythropoietin level, it can be concluded that the anemia is in part due to erythropoietin lack and should be correctable by administration of erythropoietin. As a corollary, a high serum erythropoietin level (greater than 500 mU/ml) in the presence of anemia suggests that there is end organ failure, and erythropoietin therapy is not likely to be useful.

Topics: Anemia; Bone Marrow Diseases; Erythropoietin; Humans; Neoplasms; Renal Insufficiency

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

Human immunodeficiency virus infection causes multilineage hematopoietic defects. Defects in the production and function of CD4+ helper cells have been the focus of the majority of HIV research, but anemia, neutropenia, and thrombocytopenia are significant clinical problems as well. Bone marrow suppression is the dose-limiting toxicity for a number of antiviral and prophylactic medications. Hematopoietic growth factors such as granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor are used to optimize the delivery of antiretroviral and prophylactic therapy. Because of the expense involved, the most appropriate use of these hematopoietic growth factors remains a subject of intense investigation. This review focuses on recent experimental results.

Topics: AIDS-Related Opportunistic Infections; Bone Marrow Diseases; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; HIV Infections; Humans; Neutropenia; Virus Replication

Recombinant human growth factors are expected to have a significant impact on the use of allogeneic blood components. For example, subsequent to the approval of recombinant human erythropoietin, blood transfusions in renal dialysis patients declined substantially. Likewise, myeloid growth factors have reduced infections and hospital stay by promoting hematologic recovery after high dose ablative chemotherapy. The high costs of these agents mandate that their use be limited to settings where they are clinically indicated. The use of growth factors may be monitored at medical centers by hospital transfusion committees. This chapter reviews the emerging clinical guidelines for the use of hematopoietic growth factors.

Topics: Adult; Anemia; Animals; Bone Marrow Diseases; Child; Clinical Trials as Topic; Erythropoietin; Guidelines as Topic; Hematopoietic Cell Growth Factors; Humans; Immunologic Factors; Infant, Newborn; Mice; Recombinant Proteins

Hematopoiesis is regulated in a very precise fashion by a balance between both positive and negative growth factor signals in the hematopoietic microenvironment. Many of these growth factor signals have been identified and are available as recombinant proteins. At the present time, the approved uses for hematopoietic growth factors involve their use to facilitate blood cell production in situations of hematopoietic suppression or in cases where endogenous growth factor production is inappropriately low. Recent studies with the hematopoietic growth factors are looking at innovative strategies for their use and new clinical situations in which to evaluate their effectiveness. This review looks at some of these new uses for hematopoietic growth factors.

Topics: Animals; Bone Marrow Diseases; Bone Marrow Transplantation; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leukemia, Myeloid

Topics: AIDS-Related Opportunistic Infections; Anemia; Anemia, Hemolytic, Autoimmune; Antiviral Agents; Bone Marrow Diseases; Erythropoietin; Hematopoietic Cell Growth Factors; HIV Infections; Humans; Neoplasms; Recombinant Proteins

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: Animals; Antineoplastic Agents; Bone Marrow Diseases; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Humans; Interleukin-2; Macrophage Colony-Stimulating Factor

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

Topics: Animals; Antineoplastic Agents; Bone Marrow Diseases; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Humans; Interleukin-2; Macrophage Colony-Stimulating Factor

Severe malaria, a leading cause of mortality among children and nonimmune adults, is a multisystemic disorder characterized by complex clinical syndromes that are mechanistically poorly understood. The interplay of various parasite and host factors is critical in the pathophysiology of severe malaria. However, knowledge regarding the pathophysiological mechanisms and pathways leading to the multisystemic disorders of severe malaria in humans is limited. Here, we systematically investigate infections with Plasmodium coatneyi, a simian malaria parasite that closely mimics the biological characteristics of P. falciparum, and develop baseline data and protocols for studying erythrocyte turnover and severe malaria in greater depth. We show that rhesus macaques (Macaca mulatta) experimentally infected with P. coatneyi develop anemia, coagulopathy, and renal and metabolic dysfunction. The clinical course of acute infections required suppressive antimalaria chemotherapy, fluid support, and whole-blood transfusion, mimicking the standard of care for the management of severe malaria cases in humans. Subsequent infections in the same animals progressed with a mild illness in comparison, suggesting that immunity played a role in reducing the severity of the disease. Our results demonstrate that P. coatneyi infection in rhesus macaques can serve as a highly relevant model to investigate the physiological pathways and molecular mechanisms of malaria pathogenesis in naïve and immune individuals. Together with high-throughput postgenomic technologies, such investigations hold promise for the identification of new clinical interventions and adjunctive therapies.

Topics: Anemia; Animals; Blood Coagulation; Bone Marrow Diseases; Disease Models, Animal; Erythropoiesis; Erythropoietin; Macaca mulatta; Malaria; Male; Monkey Diseases; Plasmodium; Random Allocation; Time Factors

Serous atrophy or gelatinous transformation of the bone marrow (GMT), often seen with severe nutritional deprivation in Anorexia Nervosa (AN), is characterized by hypocellularity and patchy or diffuse replacement of the bone marrow with hyaluronic acid-like mucopolysaccharide material. Treatment with nutritional support alone is often temporary due to the relapsing nature of AN. We present the case of a patient with pancytopenia due to GMT who had multiple prior hospitalizations for infections and blood transfusions. Nutritional support was inadequate in restoring her bone marrow function. She was successfully treated with hematopoietic growth factors and achieved a sustained hematopoietic recovery. In addition, use of growth factors resulted in a 91% reduction in the cost of health care delivered to this patient.

Topics: Adult; Anorexia Nervosa; Bone Marrow; Bone Marrow Diseases; Darbepoetin alfa; Erythropoietin; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematinics; Hematopoietic Cell Growth Factors; Humans; Pancytopenia; Polyethylene Glycols; Recombinant Proteins; Treatment Outcome

Anemia is an important cause of morbidity in patients suffering from chronic renal failure, and erythropoietin is a milestone of anemia treatment. Various factors may cause erythropoietin resistance. Herein, we describe the case of 32-year-old man who presented with anemia and weakness. He developed progressive renal failure secondary to recurrent kidney stones. One year before admission, he developed anemia for which he had been treated with erythropoietin. However, the anemia persisted. Examination of bone marrow biopsy specimen showed that the marrow was extensively replaced with oxalate crystals and fibrous connective tissue with severe decrease of hematopoietic cells. To the best of our knowledge, our patient represents the first case in the literature describing the association between the oxalate deposition and EPO resistance.

Topics: Adult; Anemia; Biopsy, Needle; Bone Marrow Diseases; Chronic Disease; Drug Resistance; Erythropoietin; Follow-Up Studies; Humans; Hyperoxaluria; Immunohistochemistry; Kidney Calculi; Kidney Failure, Chronic; Male; Oxalates; Renal Dialysis; Risk Assessment; Severity of Illness Index; Treatment Failure

Severe anaemia can develop in the aftermath of Plasmodium falciparum malaria because of protracted bone marrow suppression, possibly due to residual subpatent parasites.. Blood was collected from patients with recent malaria and negative malaria microscopy. Detection of the Plasmodium antigens, lactate dehydrogenase (Optimal), aldolase and histidine rich protein 2 (Now malaria) were used to differentiate between patients with (1) no malaria, (2) recent cleared malaria, (3) persistent P. falciparum infection. Red cell distribution width (RDW), plasma levels of soluble transferrin receptor (sTfR) and erythropoietin (EPO) were measured as markers of erythropoiesis. Interleukin (IL) 10 and tumour necrosis factor (TNF)alpha were used as inflammation markers.. EPO was correlated with haemoglobin, irrespective of malaria (R = -0.36, P < 0.001). Persistent P. falciparum infection, but not recent malaria without residual parasites, was associated with bone marrow suppression i.e., low RDW (P < 0.001 vs. P = 0.56) and sTfR (P = 0.02 vs. P = 0.36). TNF-alpha and IL-10 levels were not associated with bone marrow suppression.. In the treatment of malaria, complete eradication of parasites may prevent subsequent development of anaemia. Severely anaemic children may benefit from antimalarial treatment if antigen tests are positive, even when no parasites can be demonstrated by microscopy.

Topics: Anemia; Animals; Bone Marrow Diseases; Child; Child, Preschool; Erythropoiesis; Erythropoietin; Female; Hemoglobins; Humans; Infant; Interleukin-10; L-Lactate Dehydrogenase; Malaria, Falciparum; Male; Parasitemia; Proteins; Receptors, Transferrin; Tumor Necrosis Factor-alpha

The resistance to erythropoietin, which is used to treat normochromic, normocytic anemia in chronic renal failure, can develop in patients with conditions such as iron deficiency, aluminum toxicity, hyperparathyroidism, chronic inflammatory diseases, and primary hematological disorders. We found amyloidosis in the bone marrow of a woman without any other etiology for erythropoietin resistance who was undergoing chronic hemodialysis. Her anemia did not improve, despite 6 months of erythropoietin therapy. Bone marrow amyloidosis was found to be the reason for erythropoietin-resistant anemia in our patient with chronic renal failure and renal anemia. We present the case of bone marrow amyloidosis because it is a very rare cause of erythropoietin resistance.

Topics: Adult; Amyloidosis; Anemia; Bone Marrow Diseases; Drug Resistance; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Renal Dialysis

Bone marrow hypoplasia seems to be uncommon in anorexia nervosa. This marrow abnormality is rapidly reversible with intensive nutritional rehabilitation. The patient described in this case report had anorexia nervosa.. She presented with complete serous atrophy of the bone marrow associated with pancytopenia.. She was cured with recombinant human erythropoietin administered subcutaneously. After 25, days, the hematological situation was normalized.. The possible advantage and practical implications of the administration of erythropoietin are discussed.

Topics: Adult; Anorexia Nervosa; Bone Marrow Diseases; Erythropoietin; Female; Humans; Prognosis; Treatment Outcome

We have characterized the proliferation kinetics of hematopoietic cells in long-term marrow cultures (LTMC) from five normal children and seven children with congenital bone marrow failure (four with Fanconi anemia [FA] and three with congenital pure red cell aplasia [PRCA]). Total nonadherent and adherent cells, as well as nonadherent progenitors, were determined weekly in the presence or in the absence of rhGM-CSF (10 ng/ml) or rhEPO (3 U/ml). As compared to normal LTMC, hematopoiesis was drastically reduced in cultures from FA patients. Myeloid and erythroid progenitor cells reached undetectable levels after only 3 and 1 weeks of culture, respectively. This was observed even in cultures supplemented with rhGM-CSF, in which no response to this cytokine occurred. In LTMC from PRCA children, the growth of erythroid and multipotent progenitors was also drastically reduced. Myelopoiesis, on the other hand, showed normal levels during the first three weeks of culture; however, from week 4, there was a significant decrease in the levels of both progenitor and mature cells, reaching undetectable levels several weeks before normal cells did. Response to rhGM-CSF and rhEPO was transient and deficient. Our results suggest that in FA, alterations at the level of primitive progenitor cells are so severe that myeloid, erythroid and multipotent progenitors are unable to proliferate in LTMC, even in the presence of rhGM-CSF. In patients with PRCA the erythroid arm of hematopoiesis is preferentially affected and addition of rhGM-CSF and/or rhEPO to these cultures had little or no effect on erythroid cell production. Interestingly, myelopoiesis in this culture system was deficient as well and response to rhGM-CSF was defective, suggesting that the myeloid lineage is also altered in congenital PRCA.

Topics: Bone Marrow Cells; Bone Marrow Diseases; Cell Adhesion; Cell Division; Cell Nucleus; Cells, Cultured; Child; Child, Preschool; Erythropoietin; Fanconi Anemia; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cells; Humans; Kinetics; Male; Recombinant Proteins; Red-Cell Aplasia, Pure

To study the importance of bone marrow inhibition in the pathogenesis of malarial anaemia, haematological and parasitological parameters were followed in patients with acute malaria. Three patient categories were studied, severe malarial anaemia (SA), cerebral malaria (CM) and uncomplicated malaria (UM). Red cell distribution width (RDW) was used as a surrogate marker of release of young erythrocytes and reticulocytes. Initially RDW was low in all patients in spite of markedly increased concentrations of erythropoietin (EPO). 3 d after institution of treatment and coinciding with parasite clearance RDW increased dramatically, reaching the highest levels 1-2 weeks later. Although severe anaemia was corrected by blood transfusion during the first 3 d of treatment, the peak RDW correlated significantly with the initial EPO levels. This suggests that Plasmodium falciparum infection causes a rapidly reversible suppression of the bone marrow response to EPO. Furthermore, the inhibition of bone marrow response was a general finding irrespective of initial haemoglobin levels suggesting that the severity of anaemia depends upon the degree of peripheral erythrocyte destruction in patients with suppressed bone marrow response to EPO.

Topics: Antimalarials; Bone Marrow; Bone Marrow Diseases; Child; Child, Preschool; Chloroquine; Erythropoiesis; Erythropoietin; Hemoglobins; Humans; Malaria, Falciparum

The response of megakaryocytes and cytokines to the administration of romurtide, a synthetic muramyl dipeptide derivative, was investigated in monkeys with myelosuppression by carboplatin-treatment. Romurtide increased the number of megakaryocytes and promoted the shift of megakaryocytes towards high ploidy class indicative of the promotion of the proliferation and maturation of megakaryocytes. The serum levels of interleukin-6, stem cell factor, and erythropoietin elevated significantly before the enhanced response of megakaryocytes induced by romurtide was observed. Romurtide also enhanced production of colony-stimulating factors (CSFs), such as granulocyte-CSF, macrophage-CSF, and granulocyte-macrophage CSF by monkey mononuclear cells. The stimulating effect of romurtide on the production of those cytokines and CSFs is likely to be responsible for the subsequent promotion of the proliferation and maturation of marrow megakaryocytes.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Adjuvants, Immunologic; Animals; Blood Cell Count; Bone Marrow; Bone Marrow Diseases; Carboplatin; Cell Differentiation; Cell Nucleus; Cells, Cultured; Colony-Stimulating Factors; Cytokines; Erythropoietin; Female; Hematopoiesis; Interleukin-6; Leukocytes, Mononuclear; Macaca fascicularis; Megakaryocytes; Ploidies; Stem Cell Factor

Previous studies have suggested that Steel factor (SF) can influence the behavior of many types of hematopoietic progenitor cells both in vivo and in vitro, although whether these may include the most primitive populations of totipotent repopulating cells remains controversial. To approach this question, we measured the number of Sca1+Lin-WGA+ cells, the number of cells with demonstrable myeloid (long-term culture-initiating cell [LTC-IC]) or both myeloid and lymphoid (LTC-IC(ML)) potential in 4- to 5-week-old long-term cultures containing irradiated primary marrow feeder layers, and the number of multilineage long-term in vivo repopulating cells (competitive repopulating unit [CRU]) present in the marrow of W42/+ or W41/W41 mice compared to +/+ controls. There was no significant effect of either of these W mutations on the number of Sca1+Lin-WGA+ cells and, in W41/W41 mice, neither LTC-IC nor LTC-IC(ML) populations appeared to be affected. On the other hand, although W41/W41 and W42/+ cells could both be detected in the in vivo CRU assay, their numbers were markedly reduced (17- and seven-fold, respectively) in spite of the fact that both of these W mutant genotypes contained near normal numbers of day-9 and -12 colony-forming units-spleen (CFU-S). In vitro quantitation of erythroid (burst-forming units-erythroid [BFU-E]), granulopoietic (CFU-granulocyte/macrophage [CFU-GM]), multilineage (CFU-granulocyte/erythrocyte/monocyte/macrophage [CFU-GEMM]), and pre-B clonogenic progenitors (CFU-pre-B) also revealed no differences in the numbers (or proliferative potential) of any of these cells when W41/W41 or W42/+ and normal mice were compared, although day 3 BFU-E from both types of W mutant mice showed no response to the typical enhancing effect exerted by SF on their +/+ counterparts. Taken together, these findings are consistent with the view that SF activation of c-kit receptor-induced signaling events is not a rate-limiting mechanism controlling red blood cell production during normal development until hematopoietic cells differentiate beyond the day-3 BFU-E stage. Nevertheless, normal hematopoietic stem cells do appear to be responsive to SF, since their W mutant counterparts display a disadvantage in the in vivo setting which is exaggerated under conditions of hematopoietic regeneration. On the other hand, alternative mechanisms also appear to contribute to the regulation of hematopoietic stem cell numbers in vivo and to their detection as LTC-IC in vi

Topics: Anemia; Animals; Bone Marrow; Bone Marrow Diseases; Bone Marrow Transplantation; Cell Differentiation; Colony-Forming Units Assay; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Graft Survival; Hematopoiesis; Hematopoietic Stem Cells; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Proto-Oncogene Proteins c-kit; Radiation Chimera; Stem Cell Factor

Long-term follow-up data are presented on changes in peripheral blood counts and Hb requirements of 11 patients with myelodysplastic syndromes (MDS) during iron chelation treatment with desferrioxamine for up to 60 months. The erythroid marrow activity was indirectly evaluated by repeated determinations of the serum transferrin receptor concentration. The efficacy of iron chelation was evaluated by repeated quantitative determination of the liver iron concentration by magnetic resonance imaging. Reduction in the Hb requirement ( > or = 50%) was seen in 7/11 (64%) patients. Five patients (46%) became blood transfusion independent. Platelet counts increased in 7/11 (64%) patients and the neutrophil counts in 7/9 (78%) evaluable patients. All patients in whom iron chelation was highly effective showed improvement of erythropoietic output accompanied by an increase in the serum transferrin receptor concentration. It is concluded that reduction in cytopenia in MDS patients may be accomplished by treatment with desferrioxamine, if the iron chelation is efficient and the patients are treated for a sufficiently long period of time. Exactly how treatment with desferrioxamine works remains a challenge for further investigation.

Topics: Adolescent; Aged; Bone Marrow Diseases; Chromosome Aberrations; Deferoxamine; Erythropoietin; Female; Follow-Up Studies; Hematopoiesis; Hemoglobins; Hemosiderosis; Humans; Iron; Karyotyping; Leukocyte Count; Male; Middle Aged; Myelodysplastic Syndromes; Platelet Count; Receptors, Transferrin; Transfusion Reaction; Treatment Outcome

Similar to other lymphoid organs, the bone marrow (BM) is a potential reservoir for HIV-1. Although hematologic abnormalities are common in AIDS patients, the mechanisms by which HIV-1 contributes to these abnormalities are poorly understood. Hemapoietic suppression can be mediated by HIV-1 and some of its associated proteins. We have previously reported that AIDS peripheral blood sera inhibit normal CFU-granulocyte macrophage (GM). In this study, we have found that sera obtained from AIDS BM patients are more inhibitory to CFU-GM than those from peripheral blood (p < 0.05). To determine a candidate suppressor factor, we studied the role of p24 and found that it exerts varying degrees of suppression to CFU-GM, but minimal inhibition on erythroid colonies. We have found that the suppressive levels of p24 in in vitro assays are similar to the average circulating levels in AIDS patients. We have also observed that most of the inhibition caused by p24 is mediated by soluble factor(s) produced by the BM stroma. Cross-linking studies with membrane proteins from normal BM stroma and CD34+ cells indicated a putative 26-kDa p24 receptor, indicating that p24 binds to a receptor present on normal BM cells. These results implicate another HIV-1 protein, p24, in hemapoietic suppression and add another plausible mechanism by which HIV-1 contributes to BM failure in AIDS. Furthermore, these findings suggest a potential risk for similar in vivo suppression in the early phase of HIV-1 infection when viremia is elevated, and also in long-term survivors who have low, although persistent, HIV-1 replication.

Topics: Acquired Immunodeficiency Syndrome; Adipose Tissue; Bone Marrow; Bone Marrow Diseases; Cells, Cultured; Colony-Forming Units Assay; Connective Tissue; Erythropoietin; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoiesis; HIV Core Protein p24; HIV-1; Humans; Immunoglobulin G; Interleukin-3; Recombinant Proteins

A case of adult osteopetrosis Type I was diagnosed in a 22-year-old female. She presented for investigation of anaemia with 'myelophthisic' characteristics and extramedullary haemopoiesis which was resistant to haematinics, nandrolone and low-dose corticosteroids. She became progressively transfusion-dependent with gradually worsening thrombocytopenia. She was successfully treated with recombinant erythropoietin. Anaemia as well as thrombocytopenia were corrected. There appeared to be a synergistic action of erythropoietin with steroids.

Topics: Adult; Anemia; Bone Marrow Diseases; Erythropoietin; Female; Humans; Osteopetrosis; Recombinant Proteins; Thrombocytopenia

Topics: Adult; Amyloidosis; Anemia; Bone Marrow; Bone Marrow Diseases; Drug Resistance; Erythropoietin; Humans; Male; Recombinant Proteins

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

Immunoreactive erythropoietin levels were measured in 42 patients with lymphoid malignancies with anaemia and bone marrow involvement. Results were compared to a control group of 16 patients suffering from anaemia due to other causes. Significant inverse correlations between serum erythropoietin level and haemoglobin concentration were shown for the patients with lymphoid malignancies and also for the control subjects. Overall, the erythropoietin levels of patients with lymphoid malignancies with bone marrow infiltration and with normal renal function did not differ significantly from erythropoietin levels of the anaemic controls. We conclude that anaemia in patients with lymphoproliferative disorders with bone marrow infiltration and normal renal function is caused primarily by a diminished/inadequate response to erythropoietin at the level of the target cell.

Topics: Anemia; Bone Marrow Diseases; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Lymphoma; Lymphoproliferative Disorders; Male; Multiple Myeloma; Neoplasm Metastasis

Topics: Anemia; Bone Marrow Diseases; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins

Topics: Animals; Bone Marrow Diseases; Cell Differentiation; Cloning, Molecular; Colony-Stimulating Factors; Erythropoietin; Granulocytes; Hematopoiesis; Humans; Macrophages; Mice; Receptors, Cell Surface; Receptors, Colony-Stimulating Factor; Recombinant Proteins

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

Conditioned media (CM) were prepared according to previously published techniques from the bone marrow of dogs with cyclic haematopoiesis (CH). CM prepared from day 9 marrows inhibited mouse bone marrow CFU-s proliferation rate while CM from day 10 marrows were stimulatory and also contained an erythroid stimulating factor which appeared to be erythropoietin. In addition a highly significant trend from CM containing CFU-s inhibitory materials to media with CFU-s stimulatory activity was observed through cycles day 1 to 8. These studies further support the concept that CH is due to a defect in factors controlling stem cell proliferation and suggest that a major event occurs in CH dog marrow on days 9 and/or 10 of the cycle.

Topics: Animals; Bone Marrow; Bone Marrow Diseases; Colony-Forming Units Assay; Culture Media; Dog Diseases; Dogs; Erythropoietin; Hematopoietic Stem Cells; Mice; Time Factors

Topics: Anticonvulsants; Arsphenamine; Bone Marrow Diseases; Chloramphenicol; Erythropoietin; Hematopoietic Stem Cells; Hepatitis B; Humans; Quinacrine; Regeneration; Solvents; Sulfonamides; T-Lymphocytes

Topics: Androgens; Anti-Bacterial Agents; Antilymphocyte Serum; Azathioprine; Blood Platelets; Blood Transfusion; Bone Marrow Diseases; Bone Marrow Transplantation; Cyclophosphamide; Erythrocytes; Erythropoietin; Hematopoietic Stem Cells; Histocompatibility; Humans; Prednisone; Prognosis; Transplantation, Homologous

Topics: Androgens; Anemia; Bone and Bones; Bone Marrow Diseases; Erythropoietin; Estrogens; Female; Folic Acid; Gonadal Steroid Hormones; Hematopoiesis; Humans; Hyperparathyroidism; Kidney; Male; Osteoporosis; Polycythemia; Primary Myelofibrosis; Uremia

Topics: Adolescent; Adult; Aged; Bone Marrow Diseases; Cell Differentiation; Erythrocytes; Erythropoietin; Female; Hematopoietic Stem Cells; Humans; Male; Middle Aged

Topics: Bone Marrow Diseases; Cell Division; Erythropoietin; Hematopoiesis; Hematopoietic Stem Cells; Hemoglobins; Humans

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

Topics: Animals; Bone Marrow Diseases; Cell Division; Erythropoiesis; Erythropoietin; Female; Hematopoietic Stem Cells; Iron Isotopes; Mice; Pregnancy; Radiation Effects; Rats; Thymidine; Tritium

Topics: Adult; Aged; Alkaline Phosphatase; Anemia, Aplastic; Aspartate Aminotransferases; Bilirubin; Blood Transfusion; Bone Marrow Diseases; Chromium Isotopes; Erythropoiesis; Erythropoietin; Female; Hematocrit; Humans; Iron; Iron Isotopes; Lymphoma; Male; Middle Aged; Multiple Myeloma; Oxymetholone; Primary Myelofibrosis

Topics: Animals; Bone Marrow Diseases; DNA; Erythropoiesis; Erythropoietin; Fetus; Globins; Hematopoietic Stem Cells; Heme; Hemoglobins; Humans; Iron; Mitosis; Models, Biological; Polycythemia; Reticulocytes

The serum level of erythropoietin was measured in 31 patients with anemia secondary to chronic infection or malignancy and compared with erythropoietin levels in 23 patients with iron-deficiency anemia and 14 patients with primary hematopoietic diseases. Erythropoietin levels varied directly with the degree of anemia in patients with iron deficiency or primary hematopoietic disorders. There was no correlation of erythropoietin and the degree of anemia in patients with chronic infection or malignancy and the erythropoietin levels were significantly lower than in patients with iron deficiency or primary hematopoietic disease and the same degree of anemia. A major factor in the anemia of chronic disorders is a decrease in levels of erythropoietin.

Topics: Anemia; Anemia, Hypochromic; Animals; Biological Assay; Bone Marrow Diseases; Carcinoma; Chronic Disease; Erythropoietin; Hodgkin Disease; Humans; Infections; Lymphoma, Non-Hodgkin; Male; Mice; Middle Aged; Neoplasms; Neutralization Tests

Topics: Adult; Bone Marrow; Bone Marrow Cells; Bone Marrow Diseases; Cells, Cultured; Dose-Response Relationship, Drug; Erythropoietin; Female; Heme; Humans; Kinetics; Male; Middle Aged; Time Factors

Topics: Adult; Aged; Anemia; Anemia, Aplastic; Anemia, Hypochromic; Anemia, Macrocytic; Animals; Bone Marrow; Bone Marrow Diseases; Daunorubicin; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Phenylhydrazines; Rabbits; Radiation Effects

Topics: Adolescent; Adult; Aged; Blood Platelets; Bone Marrow Diseases; Diagnosis, Differential; Erythrocyte Count; Erythropoietin; Female; Hematocrit; Hemoglobinometry; Humans; Leukemia, Myeloid; Leukocyte Count; Male; Middle Aged; Myeloproliferative Disorders; Polycythemia Vera; Primary Myelofibrosis; Retrospective Studies

Topics: Adolescent; Adult; Aged; Anemia, Aplastic; Anemia, Sideroblastic; Bone Marrow Diseases; Erythropoietin; Female; Humans; Iron; Iron Isotopes; Kidney Failure, Chronic; Male; Middle Aged; Myeloproliferative Disorders; Oxymetholone

Topics: Acute Disease; Anemia, Aplastic; Animals; Biological Assay; Bone Marrow; Bone Marrow Cells; Bone Marrow Diseases; Erythropoiesis; Erythropoietin; gamma-Globulins; Hodgkin Disease; Humans; Iron Isotopes; Leukemia; Mediastinal Neoplasms; Mice; Osteosarcoma; Thymoma

Topics: Animals; Autoimmune Diseases; Bone Marrow Diseases; Erythropoiesis; Erythropoietin; Female; gamma-Globulins; Humans; Mice; Middle Aged; Nucleoproteins

Topics: Animals; Blood Cell Count; Bone Marrow Diseases; Bone Marrow Examination; Cobalt; Cobalt Isotopes; Dogs; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hemoglobinometry; Hyperplasia; Male; Mice; Nephrectomy; Phenylhydrazines; Reticulocytes

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

Topics: Aged; Bone Marrow Diseases; Erythropoiesis; Erythropoietin; Female; Humans

Topics: Animals; Bone Marrow Diseases; Chromium Isotopes; Constriction; Epoetin Alfa; Erythrocyte Count; Erythropoietin; Hemoglobinometry; Juxtaglomerular Apparatus; Kidney; Lagomorpha; Pathology; Polycythemia; Rabbits; Renal Artery; Renal Artery Obstruction; Research; Urine