Asunto(s)
Glicina/análogos & derivados , Isoquinolinas/administración & dosificación , Aplasia Pura de Células Rojas/tratamiento farmacológico , Eritropoyetina/uso terapéutico , Glicina/administración & dosificación , Hemoglobinas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Proteínas Recombinantes , Aplasia Pura de Células Rojas/sangre , Aplasia Pura de Células Rojas/inmunología , Aplasia Pura de Células Rojas/fisiopatologíaRESUMEN
Patients with myasthenia gravis (MG) may have various non-motor symptoms in addition to fatigability and weakness of skeletal muscles. Thymomas contain abundant immature thymocytes and developing CD4 and CD8 T cells. Thymomas are found in 15-25% of patients with MG and are associated with severe symptoms. We suggest that non-motor symptoms are based on the autoimmune disorders probably owing to an abnormal T cell repertoire from thymomas. Using previously reported cases and cases from our multicentre cooperative study, we review the clinical characteristics of patients with thymoma-associated MG who have non-motor symptoms. CD8 T cell cytotoxicity against haematopoietic precursor cells in bone marrow and unidentified autoantigens in hair follicles lead to the development of pure red cell aplasia, immunodeficiency and alopecia areata. In contrast, neuromyotonia, limbic encephalitis, myocarditis and taste disorders are autoantibody-mediated disorders, as is MG. Autoantibodies to several types of voltage-gated potassium channels and the related molecules can evoke various neurological and cardiac disorders. About 25% of patients with thymoma-associated MG have at least one non-motor symptom. Non-motor symptoms affect many target organs and result in a broad spectrum of disease, ranging from the impairment of quality of life to lethal conditions. Since relatively little attention is paid to non-motor symptoms in patients with thymoma-associated MG, the symptoms may be overlooked by many physicians. Early diagnosis is important, since non-motor symptoms can be treatable. A complete understanding of non-motor symptoms is necessary for the management of patients with thymoma-associated MG.
Asunto(s)
Miastenia Gravis/patología , Alopecia Areata/complicaciones , Alopecia Areata/fisiopatología , Humanos , Síndromes de Inmunodeficiencia/inmunología , Síndromes de Inmunodeficiencia/patología , Síndrome de Isaacs/complicaciones , Síndrome de Isaacs/fisiopatología , Encefalitis Límbica/complicaciones , Encefalitis Límbica/fisiopatología , Miastenia Gravis/diagnóstico , Miastenia Gravis/etiología , Miocarditis/complicaciones , Aplasia Pura de Células Rojas/complicaciones , Aplasia Pura de Células Rojas/fisiopatología , Trastornos del Gusto/etiología , Timoma/complicaciones , Timoma/patología , Neoplasias del Timo/complicaciones , Neoplasias del Timo/patologíaRESUMEN
A 26-year-old female with the classic major and minor components of autoimmune polyglandular syndrome type 1 was diagnosed as having pure red cell aplasia. Treatment with 1.5 g/d mycofenolate mofetil for 3 months failed to restore erythroid production. Treatment with cyclosporine A produced a good partial response but led to renal toxicity and was therefore substituted with cyclophosphamide, which had a good partial effect and lasted for 18 months. The relapse of anemia was not observed during the 6-month follow-up period after the cessation of treatment.
Asunto(s)
Ciclofosfamida/uso terapéutico , Inmunosupresores/uso terapéutico , Poliendocrinopatías Autoinmunes/complicaciones , Aplasia Pura de Células Rojas/tratamiento farmacológico , Adulto , Femenino , Humanos , Mutación , Poliendocrinopatías Autoinmunes/genética , Poliendocrinopatías Autoinmunes/fisiopatología , Aplasia Pura de Células Rojas/complicaciones , Aplasia Pura de Células Rojas/fisiopatología , Factores de Transcripción/genética , Proteína AIRERESUMEN
Identification of serious adverse drug reactions (sADRS) associated with commonly used drugs can elude detection for years. Reye's syndrome (RS), nephrogenic systemic fibrosis (NSF), and pure red cell aplasia (PRCA) among chronic kidney disease (CKD) patients were recognized in 1951, 2000, and 1998, respectively. Reports associating these syndromes with aspirin, gadodiamide, and epoetin, were published 29, 6, and 4 years later, respectively. We obtained primary information from clinicians who identified causes of these sADRs and reviewed factors contributing to delayed identification of these toxicities. Overall, 3,500 aspirin-associated RS cases in the United States, 1,605 gadolinium-associated NSF cases, and 181 epoetin-associated PRCA cases were reported. Delays in FDA regulation of over-the- counter medications and administration of aspirin to children contributed to development of RS. For NSF, in 1996, the Danish Medicine Agency approved high-dose gadodiamide administration to chronic kidney disease (CKD) patients undergoing MR scans. Overall, 88 % of Danish NSF cases were from two hospitals and 97 % of United States' NSF cases were from 60 hospitals. These hospitals frequently administered high-doses of gadodiamide to CKD patients. Another factor was the decision to administer linear chelated contrast agents versus lower risk macrocyclic chelated agents. For PRCA, increased use of subcutaneous epoetin formulations to CKD patients, in part due to convenience and cost-savings considerations, and a European regulatory requirement requiring removal of albumin as a stabilizer, led to toxicity. Overall, 81, 13, and 17 years elapsed between drug introduction into practice and identification of a causal relationship for aspirin, erythropoietin, and gadodiamide, respectively. A substantial decline in new cases of these sADRs occurred within two years of identification of the offending drug. Clinicians should be vigilant for sADRs, even for frequently-prescribed pharmaceuticals, particularly in settings where formulation or regulatory changes have occurred, or when over-the-counter, off-label, or pediatric use is common.
Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/inducido químicamente , Dermopatía Fibrosante Nefrogénica/inducido químicamente , Aplasia Pura de Células Rojas/inducido químicamente , Síndrome de Reye/inducido químicamente , Aspirina/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/fisiopatología , Eritropoyetina/efectos adversos , Femenino , Gadolinio/efectos adversos , Humanos , Masculino , Dermopatía Fibrosante Nefrogénica/epidemiología , Dermopatía Fibrosante Nefrogénica/fisiopatología , Prevalencia , Pronóstico , Aplasia Pura de Células Rojas/epidemiología , Aplasia Pura de Células Rojas/fisiopatología , Síndrome de Reye/epidemiología , Síndrome de Reye/fisiopatología , Medición de Riesgo , South Carolina , Tasa de SupervivenciaRESUMEN
Recombinant human erythropoietin (rHuEPO) is a biopharmaceutical drug given to patients who have a low hemoglobin related to chronic kidney disease, cancer or anemia. However, some patients repeatedly receiving rHuEPO develop anti-rHuEPO neutralizing antibodies leading to the development of pure red cell aplasia (PRCA). The immunogenic antibody response activated by rHuEPO is believed to be triggered by T-cells recognizing EPO epitopes bound to MHC molecules displayed on the cell surface of APCs. Previous studies have reported an association between the development of anti-rHuEpo-associated PRCA and the HLA-DRB1*09 gene, which is reported to be entrenched in the Thai population. In this study, we used computational design to screen for immunogenic hotspots recognized by HLA-DRB1*09, and predicted seventeen mutants having anywhere between one through four mutations that reduce affinity for the allele, without disrupting the structural integrity and bioactivity. Five out of seventeen mutants were less immunogenic in vitro while retaining similar or slightly reduced bioactivity than rHuEPO. These engineered proteins could be the potential candidates to treat patients who are rHuEpo-dependent and express the HLA-DRB1*09 allele.
Asunto(s)
Eritropoyetina/inmunología , Eritropoyetina/metabolismo , Alelos , Anemia/tratamiento farmacológico , Formación de Anticuerpos/genética , Técnicas de Cultivo de Célula , Línea Celular , Eritropoyetina/genética , Humanos , Complejo Mayor de Histocompatibilidad/genética , Ingeniería de Proteínas/métodos , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/metabolismo , Aplasia Pura de Células Rojas/tratamiento farmacológico , Aplasia Pura de Células Rojas/inmunología , Aplasia Pura de Células Rojas/fisiopatología , Diálisis RenalAsunto(s)
Eritropoyetina , Isoniazida , Aplasia Pura de Células Rojas , Tuberculosis Pulmonar/tratamiento farmacológico , Anciano de 80 o más Años , Anemia/diagnóstico , Anemia/terapia , Antituberculosos/administración & dosificación , Antituberculosos/efectos adversos , Examen de la Médula Ósea , Transfusión de Eritrocitos/métodos , Eritropoyetina/administración & dosificación , Eritropoyetina/efectos adversos , Hematínicos/administración & dosificación , Hematínicos/efectos adversos , Humanos , Isoniazida/administración & dosificación , Isoniazida/efectos adversos , Masculino , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Aplasia Pura de Células Rojas/inducido químicamente , Aplasia Pura de Células Rojas/diagnóstico , Aplasia Pura de Células Rojas/fisiopatología , Aplasia Pura de Células Rojas/terapia , Resultado del Tratamiento , Privación de TratamientoAsunto(s)
Ciclosporina/farmacocinética , Resistencia a Medicamentos , Inmunosupresores/farmacocinética , Aplasia Pura de Células Rojas/tratamiento farmacológico , Adulto , Anemia/etiología , Anemia/prevención & control , Química Farmacéutica , Ciclosporina/administración & dosificación , Ciclosporina/sangre , Ciclosporina/uso terapéutico , Emulsiones , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/sangre , Inmunosupresores/uso terapéutico , Quimioterapia de Mantención , Masculino , Persona de Mediana Edad , Medicina de Precisión , Aplasia Pura de Células Rojas/metabolismo , Aplasia Pura de Células Rojas/fisiopatología , Aplasia Pura de Células Rojas/prevención & control , Prevención Secundaria , Resultado del TratamientoAsunto(s)
Leucemia-Linfoma Linfoblástico de Células T Precursoras/complicaciones , Aplasia Pura de Células Rojas/complicaciones , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Preescolar , Resultado Fatal , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/fisiopatología , Aplasia Pura de Células Rojas/tratamiento farmacológico , Aplasia Pura de Células Rojas/fisiopatologíaRESUMEN
BACKGROUND/AIMS: The prevalence of anti-erythropoietin antibodies in renal patients without clinical evidence of pure red cell aplasia (PRCA) who respond poorly to epoetin is unknown. This study tested for anti-erythropoietin antibodies in hemodialysis patients who were either hypo- or normoresponsive to epoetin treatment. METHODS: Epoetin hyporesponsiveness (hemoglobin < or =10.5 g/dl and epoetin > or =9,000 IU/week) and normoresponsiveness (hemoglobin >10.5 g/dl and epoetin <7,000 IU/week) were arbitrarily defined. Prevalence of anti-erythropoietin antibodies in hemodialysis patients without symptoms of PRCA was determined by screening sera of 536 patients from 35 German KfH dialysis units, using enzyme-linked immunosorbent assay (ELISA). Positive results were verified by radioimmunoprecipitation assay (RIP) and neutralizing activity was determined by bioassay. RESULTS: Anti-erythropoietin antibodies were detected in 3 hyporesponsive and 3 normoresponsive patients using ELISA. One patient per group was verified as borderline by RIP testing; the other 4 were negative. The bioassay was negative for 1 patient; the other died unrelated to PRCA before testing. Follow-up with RIP testing after 15 months under continuous epoetin treatment was negative (4 patients, 2 deceased). CONCLUSION: This survey did not identify anti-erythropoietin antibodies in hemodialysis patient's hyporesponsive to epoetin and does not support presumptive antibody screening as a routine work-up in these patients.
Asunto(s)
Anemia/tratamiento farmacológico , Anemia/inmunología , Anticuerpos/sangre , Eritropoyetina/inmunología , Eritropoyetina/uso terapéutico , Diálisis Renal , Insuficiencia Renal/complicaciones , Anciano , Anemia/etiología , Estudios de Cohortes , Resistencia a Medicamentos , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ensayo de Radioinmunoprecipitación , Proteínas Recombinantes , Aplasia Pura de Células Rojas/fisiopatología , Insuficiencia Renal/terapiaRESUMEN
Many processes lead to anemia. This review covers anemias that are less commonly encountered in the United States. These anemias include hemoglobin defects like thalassemia, bone marrow failure syndromes like aplastic anemia and pure red cell aplasia, and hemolytic processes such as paroxysmal nocturnal hemoglobinuria. The pathogenesis, diagnostic workup, and treatment of these rare anemias are reviewed.
Asunto(s)
Anemia/etiología , Anemia/fisiopatología , Anemia/terapia , Anemia Aplásica/tratamiento farmacológico , Anemia Aplásica/fisiopatología , Anemia Hemolítica/fisiopatología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Enfermedades de la Médula Ósea/fisiopatología , Trastornos de Fallo de la Médula Ósea , Quemaduras/complicaciones , Cobre/deficiencia , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Hemoglobinuria Paroxística/tratamiento farmacológico , Hemoglobinuria Paroxística/fisiopatología , Humanos , Inmunosupresores/uso terapéutico , Desnutrición/complicaciones , Aplasia Pura de Células Rojas/inducido químicamente , Aplasia Pura de Células Rojas/fisiopatología , Talasemia/fisiopatologíaRESUMEN
Diamond Blackfan anemia (DBA) is a genetically and clinically heterogeneous disorder characterized by erythroid failure, congenital anomalies, and a predisposition to cancer. Faulty ribosome biogenesis is hypothesized to be the underlying defect, leading to erythroid failure due to accelerated apoptosis in affected erythroid progenitors/precursors. Since first observed in DBA, pro-apoptotic hematopoiesis has been recognized as a common mechanism for hematopoietic failure in virtually all of the inherited bone marrow failure syndromes. Inherited as an autosomal dominant trait, one of what appears to be multiple DBA genes, coding for ribosomal protein RPS19, has been cloned. The discovery of additional genes will no doubt clarify the molecular pathophysiology of this disorder. Even within families, individuals may vary dramatically as to the degree of anemia, treatment response, and the presence of congenital anomalies. The study of DBA has been facilitated by the creation of international patient registries that provide more reliable information regarding clinical presentation, genetics, and outcome, as well as descriptions of congenital malformations and cancer predisposition, than can be culled from the literature. Analysis of registry data has led to improvements in clinical care and provides patients and research specimens for clinical and laboratory investigations.
Asunto(s)
Anemia de Diamond-Blackfan , Aplasia Pura de Células Rojas , Anemia de Diamond-Blackfan/genética , Anemia de Diamond-Blackfan/fisiopatología , Anemia de Diamond-Blackfan/terapia , Humanos , Aplasia Pura de Células Rojas/genética , Aplasia Pura de Células Rojas/fisiopatología , Aplasia Pura de Células Rojas/terapia , Proteínas Ribosómicas/genética , Ribosomas/metabolismo , Tasa de Supervivencia , Resultado del TratamientoAsunto(s)
Aplasia Pura de Células Rojas/fisiopatología , Timoma/cirugía , Timo/cirugía , Neoplasias del Timo/cirugía , Adulto , Humanos , Síndromes Paraneoplásicos , Aplasia Pura de Células Rojas/etiología , Aplasia Pura de Células Rojas/cirugía , Inducción de Remisión , Timoma/complicaciones , Neoplasias del Timo/complicacionesRESUMEN
The case history, laboratory findings and clinical course of a patient with pure red cell aplasia (PRCA) combined with myasthenia gravis and thymoma are reported herein. In vitro study revealed bilineage complement-dependent IgG inhibitor(s) in both the granulocyte-macrophage and erythroblastic progenitor cells. His serum showed high anti-acetylcholine receptor antibody levels associated with activity of myasthenia gravis as well as PRCA. Patient history of thymectomy 7 years previously followed by extensive cutaneous candidiasis with abnormal T lymphocyte subsets (decreased T4/T8 ratio and increased number of activated T lymphocytes) in both the bone marrow and peripheral blood suggested primary T lymphocyte dysfunction, whereas the erythropoiesis was not inhibited by T lymphocytes. This case is of interest in the context of a possible immunological pathogenesis for other hematopoietic disorders, including some cases of aplastic anemia.
Asunto(s)
Hematopoyesis/fisiología , Miastenia Gravis/fisiopatología , Aplasia Pura de Células Rojas/fisiopatología , Linfocitos T/fisiología , Timoma/fisiopatología , Neoplasias del Timo/fisiopatología , Anticuerpos/sangre , Anticuerpos Monoclonales/análisis , Anticuerpos Monoclonales/inmunología , Relación CD4-CD8 , Proteínas del Sistema Complemento/fisiología , Citometría de Flujo , Granulocitos/citología , Células Madre Hematopoyéticas/efectos de los fármacos , Humanos , Inmunoglobulina G/análisis , Macrófagos/citología , Masculino , Persona de Mediana Edad , Miastenia Gravis/complicaciones , Miastenia Gravis/patología , Receptores Colinérgicos/análisis , Receptores Colinérgicos/inmunología , Aplasia Pura de Células Rojas/complicaciones , Aplasia Pura de Células Rojas/patología , Células Madre/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/patología , Subgrupos de Linfocitos T/fisiología , Linfocitos T/patología , Linfocitos T/ultraestructura , Timoma/complicaciones , Timoma/patología , Neoplasias del Timo/complicaciones , Neoplasias del Timo/patologíaRESUMEN
Pure red-cell aplasia is an anemia characterized by a near absence of nucleated red blood cells. It can be congenital or acquired. The congenital form is probably induced by intrauterine damage to early erythroid stem cells. The acquired form can be transient and self-limited or sustained and lifelong. Many, if not most, cases of transient pure red-cell aplasia are caused by the B19 parvovirus, which has a special affinity for erythroid progenitor cells. When complicating an underlying hemolytic anemia, the anemia may be acute and severe. Sustained aplasia is caused by viral invasion, immune rejection or toxic destruction of progenitor or precursor cells. It occurs most often in patients with a benign or malignant lymphoid disease. Treatment with immunosuppressive drugs--especially corticosteroids--will in most cases cause a temporary or permanent remission. The final outcome depends primarily on the underlying disorder.
Asunto(s)
Aplasia Pura de Células Rojas , Humanos , Aplasia Pura de Células Rojas/etiología , Aplasia Pura de Células Rojas/fisiopatología , Aplasia Pura de Células Rojas/terapiaRESUMEN
Two patients with pure red cell aplasia and a T cell lymphoproliferative disorder were studied in order to define the mechanism of suppression of erythropoiesis and the patients' response to cytotoxic therapy. In vitro assays demonstrated enhanced formation of both erythroid colonies and bursts following T-cell depletion. Erythroid colony formation was suppressed by the readdition of autologous T cells to a null cell fraction of marrow mononuclear cells. Media conditioned by the patients' T cells did not exhibit any inhibitory effect on erythroid colony formation by autologous T cell-depleted marrow cells. These in vitro results suggested that T cell-mediated suppression of erythropoiesis was responsible for the generation of pure red cell aplasia. In both patients, cyclophosphamide therapy resulted in clinical remissions manifested by normalization of the hematocrits associated with a reduction in circulating lymphocytes from more than 10,000/mm3 to under 500/mm3. Maintenance chemotherapy has caused persistent inhibition of lymphocyte counts along with durable remissions with normal hematocrits.
Asunto(s)
Eritropoyesis , Linfocitosis/complicaciones , Aplasia Pura de Células Rojas/complicaciones , Anciano , Anciano de 80 o más Años , Medios de Cultivo , Ciclofosfamida/uso terapéutico , Femenino , Células Madre Hematopoyéticas , Humanos , Linfocitosis/tratamiento farmacológico , Linfocitosis/fisiopatología , Aplasia Pura de Células Rojas/tratamiento farmacológico , Aplasia Pura de Células Rojas/fisiopatología , Linfocitos T/clasificaciónRESUMEN
Systemic disorders, often immune in nature, can sometimes be associated with the presence of thymic pathology. Thymic enlargement due to lymphoid hyperplasia or thymoma is a common occurrence in patients with myasthenia gravis. In patients with pure red cell aplasia, at least 10% to 15% of patients are found to have thymoma, usually of spindle cell or medullary type. Pure red cell aplasia with demonstrable thymic enlargement due to lymphoid follicular hyperplasia is distinctly unusual, and has not been previously reported. The authors report such a case developing in a patient with end-stage renal failure maintained on hemodialysis and erythropoietin therapy. Because the red cell aplasia resolved after thymectomy, the disease process was considered etiologically related to the reactive lymphoid hyperplasia.
Asunto(s)
Eritropoyetina/farmacología , Aplasia Pura de Células Rojas/etiología , Timoma/complicaciones , Adulto , Resistencia a Medicamentos , Femenino , Humanos , Hiperplasia , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/tratamiento farmacológico , Aplasia Pura de Células Rojas/fisiopatología , Timoma/patología , Timoma/fisiopatología , Timo/patologíaRESUMEN
A 57-year-old woman with thymoma-associated pure red cell aplasia (PRCA) manifested spontaneous recovery of erythropoiesis. Anemia recurred before the surgical removal of her thymoma, however, and the second anemic remission following surgery did not occur promptly. In this report, we describe a rare occurrence of spontaneous remission in PRCA.
Asunto(s)
Aplasia Pura de Células Rojas/etiología , Timoma/complicaciones , Neoplasias del Timo/complicaciones , Eritropoyesis , Femenino , Humanos , Persona de Mediana Edad , Recurrencia , Aplasia Pura de Células Rojas/fisiopatología , Linfocitos T/inmunología , Timectomía , Timoma/cirugía , Neoplasias del Timo/cirugíaRESUMEN
We report the case of a 34-year-old woman with recurrent pure red cell aplasia and evidence of hepatitis B and C infection. Review of the English literature identified 19 prior cases in which pure red cell aplasia was associated with hepatitis. This case is the first in which serologic evidence of hepatitis C infection was documented. This patient also had porphyria cutanea tarda and marked hepatic siderosis but no active hepatitis or cirrhosis. Treatment with cyclophosphamide and prednisone produced complete remission of the pure red cell aplasia. Erythroid colony formation (colony-forming unit-erythroid and erythroid burst-forming unit) was reduced in cultures of bone marrow obtained during relapse but was normal in remission marrow. However, addition of the patient serum, whether collected during relapse or remission, inhibited erythroid colony formation by her bone marrow. These observations, and the known extrahepatic immunologic manifestations of hepatitis C infection, suggest that the pure red cell aplasia occurred because of autoimmune mechanism provoked by the infection.
Asunto(s)
Médula Ósea/fisiopatología , Eritropoyesis , Hepatitis C/complicaciones , Aplasia Pura de Células Rojas/fisiopatología , Adulto , Células Precursoras Eritroides , Femenino , Hepatitis C/fisiopatología , Humanos , Recurrencia , Aplasia Pura de Células Rojas/etiologíaRESUMEN
Morphologically, bone marrow is made up of a relatively mature but heterogenous population, fueled by a tiny pool of microscopically unrecognizable stem and progenitor cells. This complex tissue has the responsibility of maintaining our hematopoietic and, to a large extent, immunologic integrity, both of which are indispensable for health and, indeed, survival. Perhaps not surprisingly, bone marrow is the target of genetic, autoimmune, and environmental insults. Although robust, it has only a limited number of responses, one of which is reduction in cellular output, sometimes with superimposed qualitative abnormalities, and this is defined as bone marrow failure. Bone marrow failure is a diverse entity but can be logically explained and classified on a pathophysiologic basis. Thus the major recognizable categories of bone marrow failure are congenital and acquired defects. Each of these is subdivided according to the number of cell lines involved, over and above which the severity of the damage will determine reversibility. In each case, the natural history dictates management, and this ranges from short-term growth factor support to biologic immune response modulation and finally to bone marrow transplantation. In the past, many clinicopathologic variants of bone marrow failure were described, although their etiology was obscure and effective therapy was unavailable. This changed dramatically, however, when experimental hematologists, using radiobiology models, uncovered the dynamic nature of blood formation. Cardinal observations included the way in which spontaneous recovery followed irradiation, the central role played by pluripotential stem cells, and the integral participation of stroma in modulating this entire process. Understanding was refined once bone marrow cultures became available while, in parallel, the use of in-bred mouse strains launched the era of allogeneic transplantation. These approaches were combined, and the broad principles that govern basal or constitutive production emerged. Stem cells, with their characteristic commitment to self-renewal, exist at the apex of a hierarchy and generate a tier of proliferating progenitors that, in turn, give rise to a large postmitotic compartment of precursors that mature into distinctive myeloid and lymphoid lineages. The reserve potential is enormous, and output can be induced to meet even greatly increased demands. These events reflect the interaction of growth factors with a balancing set of negative regulators. The link between such diverse functions resides, to a large extent, in accessory cells and matrix geographically organized in what is now described as the hematopoietic inductive microenvironment. Many details of these meticulously orchestrated processes are obscure.(ABSTRACT TRUNCATED AT 400 WORDS)