RESUMO
Previous studies suggested that erythropoietin (EPO) may protect against severe COVID-19-induced injuries, ultimately preventing mortality. This hypothesis is based on the fact that, in addition to promoting the increase in red blood cells, EPO is an anti-inflammatory, anti-apoptotic and protective factor in several non-erythropoietic tissues. Furthermore, EPO promotes nitric oxide production in the hypoxic lung and stimulates ventilation by interacting with the respiratory centers of the brainstem. Given that EPO in the blood is increased at high-altitude, we evaluated the serum levels of EPO in critical patients with COVID-19 at "Hospital Agramont" in the city of El Alto (4150 masl) in Bolivia. A total of 16 patients, 15 men, one woman, with a mean age of 55.8 ± 8.49 years, admitted to the Intensive Care Unit were studied. All patients were permanent residents of El Alto, with no travel history below 3000 masl for at least one year. Blood samples were collected upon admission to the ICU. Serum EPO concentration was assessed using an ELISA kit, and a standard technique determined hemoglobin concentration. Only half of the observed patients survived the disease. Remarkably, fatal cases showed 2.5 times lower serum EPO than survivors (2.78 ± 0.8643 mU/mL vs 7.06 ± 2.713 mU/mL; p = 0.0096), and 1.24 times lower hemoglobin levels (13.96 ± 2.56 g/dL vs 17.41 ± 1.61 g/dL; p = 0.0159). While the number of cases evaluated in this work is low, our findings strongly warrant further investigation of EPO levels in COVID-19 patients at high and low altitudes. Our results also support the hypothesis that exogenous EPO administration could help critically ill COVID-19 patients overcome the disease.
Assuntos
Altitude , COVID-19/sangue , Eritropoetina/sangue , Pulmão/diagnóstico por imagem , Idoso , Bolívia , COVID-19/diagnóstico por imagem , COVID-19/mortalidade , Feminino , Hemoglobinas/metabolismo , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , SARS-CoV-2 , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios XRESUMO
INTRODUCTION: Considering the evolving diagnostic criteria of polycythemia vera (PV), we analyzed the utility of serum erythropoietin (EPO) as a predictive marker for differentiating polycythemia vera (PV) from other etiologies of erythrocytosis. PATIENTS AND METHODS: We conducted a retrospective study after a review of electronical medical records from January 2005 to December 2016 with diagnosis of erythrocytosis using International Classification of Disease-specific codes. To evaluate the diagnostic performance of EPO levels and JAK2-V617F mutation, we constructed a receiver-operated characteristic curve of sensitivity versus 1-specificity for serum EPO levels and JAK2-V617F mutation as predictive markers for differentiating PV from other causes of erythrocytosis. RESULTS: We surveyed 577 patients with erythrocytosis. Median patient age was 59.2 years, 57.72% (n = 329) were male, 86.3% (n = 491) were white, and only 3.3% (n = 19) were African American. A total of 80.88% (n = 351) of those diagnosed with PV had a JAK2-V617F mutation compared to only 1.47% (n = 2) whose primary diagnosis was secondary polycythemia. When comparing JAK2-V617 mutation to the EPO level, the area under the curve of JAK2-V617 (0.8970) was statistically larger than that of EPO test (0.6765). Therefore, the PV diagnostic methodology using JAK2-V617 is better than the EPO test. An EPO level of < 2 mIU/mL was > 99% specific to predict PV but was only 12% sensitive. CONCLUSION: In the appropriate clinical setting, cytogenetic and molecular studies such as JAK2 mutation status prevail as the most useful tools for PV case identification. The use of isolated EPO to screen patients with erythrocytosis is not a good diagnostic approach.
Assuntos
Eritropoetina/sangue , Janus Quinase 2/genética , Policitemia Vera/diagnóstico , Policitemia/etiologia , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Institutos de Câncer , Feminino , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Policitemia Vera/sangue , Policitemia Vera/complicações , Policitemia Vera/genética , Valor Preditivo dos Testes , Curva ROC , Estudos RetrospectivosRESUMO
During human pregnancy, iron requirements gradually increase, leading to higher amounts of erythropoietin (EPO) and reticulocytes, and changes in erythrocyte size and density. Women with pregestational obesity experience "obesity hypoferremia" during pregnancy, which alters iron homeostasis. In this study we aimed to describe the relationship between EPO and iron nutrition status during nonanemic pregnancy, and to explore whether obesity and inflammation influence erythropoiesis and red cell indices. We conducted a secondary analysis of a cohort followed throughout pregnancy. Participants were nonanemic women assigned to two study groups based on pregestational body mass index (pgBMI): adequate weight (AW, n = 53) or obesity (Ob, n = 40). All received a multivitamin supplement. At gestational ages (GA) 13, 21, 28 and 34, we measured hemoglobin and red cell indices with an ACT-5DIFF hematology counter, and reticulocyte percentage by manual cell counting. EPO, interleukin (IL-6) and markers of iron status, i.e., hepcidin, serum transferrin receptor (sTfr) and ferritin, were measured by ELISA. Bivariate correlations showed that EPO was positively associated with pgBMI, GA, sTfr and IL-6, but negatively associated with hepcidin, ferritin and hemoglobin, and unrelated to iron intake. Generalized linear models adjusted for confounding factors showed that EPO and erythrocyte concentrations were significantly higher in women in the Ob group, while mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and red cell distribution width (RDW) were lower; reticulocytes and mean corpuscular hemoglobin concentration (MCHC) were not different. Differences were not altered when controlling for inflammation (IL-6). These changes suggest that, in addition to altering iron metabolism, a larger maternal body size during pregnancy results in higher erythropoiesis without increasing hemoglobin, which is exhibited in the latter being distributed among more and smaller erythrocytes.
Assuntos
Tamanho Corporal , Índices de Eritrócitos , Eritropoese/fisiologia , Fenômenos Fisiológicos da Nutrição Materna , Obesidade Materna/sangue , Gravidez/sangue , Gravidez/fisiologia , Adulto , Eritrócitos/patologia , Eritropoetina/sangue , Feminino , Humanos , Inflamação/sangue , Mediadores da Inflamação/sangue , Interleucina-6/sangue , Ferro/metabolismo , Adulto JovemRESUMO
Serum soluble Fas (sFas) levels are associated with erythropoietin (Epo) hyporesponsiveness in patients with chronic kidney disease (CKD). Whether sFas could predict the need for erythropoiesis-stimulating agent (ESA) usage and its influence in erythropoiesis remain unclear. We evaluated the relation between sFas and ESA therapy in patients with CKD with anemia and its effect on erythropoiesis in vitro. First, we performed a retrospective cohort study with 77 anemic patients with nondialysis CKD. We performed in vitro experiments to investigate whether sFas could interfere with the behavior of hematopoietic stem cells (HSCs). HSCs were isolated from umbilical cord blood and incubated with recombinant sFas protein in a dose-dependent manner. Serum sFas positively correlated with Epo levels (r = 0.30, P = 0.001) but negatively with hemoglobin (r = -0.55, P < 0.001) and glomerular filtration rate (r = -0.58, P < 0.001) in patients with CKD at baseline. Elevated sFas serum levels (4,316 ± 897 vs. 2,776 ± 749, P < 0.001) with lower estimated glomerular filtration rate (26.2 ± 10.1 vs. 33.5 ± 14.3, P = 0.01) and reduced hemoglobin concentration (11.1 ± 0.9 vs. 12.5 ± 1.2, P < 0.001) were identified in patients who required ESA therapy compared with patients with non-ESA. Afterward, we detected that the sFas level was slight correlated with a necessity of ESA therapy in patients with nondialysis CKD and anemia. In vitro assays demonstrated that the erythroid progenitor cell frequency negatively correlated with sFas concentration (r = -0.72, P < 0.001). There was decreased erythroid colony formation in vitro when CD34+ HSCs were incubated with a higher concentration of sFas protein (1.56 ± 0.29, 4.33 ± 0.53, P < 0.001). Our findings suggest that sFas is a potential predictor for ESA therapy in patients with nondialysis CKD and that elevated sFas could affect erythropoiesis in vitro.
Assuntos
Anemia/sangue , Eritropoese , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Multipotentes/metabolismo , Insuficiência Renal Crônica/complicações , Receptor fas/sangue , Adulto , Idoso , Anemia/diagnóstico , Anemia/tratamento farmacológico , Anemia/etiologia , Biomarcadores/sangue , Brasil , Células Cultivadas , Tomada de Decisão Clínica , Bases de Dados Factuais , Eritropoese/efeitos dos fármacos , Eritropoetina/sangue , Feminino , Hematínicos/uso terapêutico , Células-Tronco Hematopoéticas/efeitos dos fármacos , Hemoglobinas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Células-Tronco Multipotentes/efeitos dos fármacos , North Carolina , Seleção de Pacientes , Valor Preditivo dos Testes , Proteínas Recombinantes/farmacologia , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Estudos RetrospectivosRESUMO
Excessive erythrocytosis (EE) is the main sign of chronic mountain sickness (CMS), a maladaptive clinical syndrome prevalent in Andean and other high-altitude populations worldwide. The pathophysiological mechanism of EE is still controversial, as physiological variability of systemic respiratory, cardiovascular, and hormonal responses to chronic hypoxemia complicates the identification of underlying causes. Induced pluripotent stem cells derived from CMS highlanders showed increased expression of genes relevant to the regulation of erythropoiesis, angiogenesis, cardiovascular, and steroid-hormone function that appear to explain the exaggerated erythropoietic response. However, the cellular response to hypoxia in native CMS cells is yet unknown. This study had three related aims: to determine the hypoxic proliferation of native erythroid progenitor burst-forming unit-erythroid (BFU-E) cells derived from CMS and non-CMS peripheral blood mononuclear cells; to examine their sentrin-specific protease 1 (SENP1), GATA-binding factor 1 (GATA1), erythropoietin (EPO), and EPO receptor (EPOR) expression; and to investigate the functional upstream role of SENP1 in native progenitor differentiation into erythroid precursors. Native CMS BFU-E colonies showed increased proliferation under hypoxic conditions compared with non-CMS cells, together with an upregulated expression of SENP1, GATA1, EPOR; and no difference in EPO expression. Knock-down of the SENP1 gene abolished the augmented proliferative response. Thus, we demonstrate that native CMS progenitor cells produce a larger proportion of erythroid precursors under hypoxia and that SENP1 is essential for proliferation. Our findings suggest a significant intrinsic component for developing EE in CMS highlanders at the cellular and gene expression level that could be further enhanced by systemic factors such as alterations in respiratory control, or differential hormonal patterns.
Assuntos
Doença da Altitude/epidemiologia , Altitude , Células Precursoras Eritroides/metabolismo , Oxigênio/metabolismo , Oxigênio/farmacologia , Doença Crônica , Eritropoetina/sangue , Regulação da Expressão Gênica/efeitos dos fármacos , Predisposição Genética para Doença , Homeostase , Humanos , Hipóxia , Ferro/metabolismo , Leucócitos Mononucleares , TranscriptomaRESUMO
OBJECTIVE: To evaluate the effect of blood sampling from the placental end of the umbilical cord compared with initial blood sampling from neonates, on the need for first packed red blood cell transfusion in extremely preterm infants. We hypothesized that cord blood sampling could delay the time to first blood transfusion. STUDY DESIGN: In this single-center, assessor blind, randomized controlled trial, we included extremely low birth weight neonates <28 weeks of gestational age at birth. Five milliliter of blood for initial laboratory investigations was collected either from the placental end of the umbilical cord (study group) or from the neonate upon neonatal intensive care unit admission (control group). Both groups received similar anemia prevention strategies. The primary outcome was the time (in days) to the first packed red blood cell transfusion, and was compared using survival analysis. RESULTS: Eighty neonates were enrolled. The time to first transfusion was significantly delayed in the cord sampling group (30 vs 14 days, hazard ratio: 0.44, [95% CI 0.27-0.72], P < .001). Fewer neonates in the cord sampling group were transfused in the first 28 days of life (30% vs 75%, P < .001). Overall transfusion requirements and other clinical outcomes were similar in the groups. CONCLUSIONS: Initial blood sampling from placental end of umbilical cord, when combined with anemia prevention strategies, significantly prolonged the time to first transfusion and reduced the need for early transfusions among extremely premature neonates. TRIAL REGISTRATION: Ctri.nic.in/ (CTRI/2017/04/008320).
Assuntos
Coleta de Amostras Sanguíneas , Transfusão de Sangue , Cordocentese , Sangue Fetal/transplante , Placenta/irrigação sanguínea , Transfusão de Eritrócitos , Eritropoetina/sangue , Feminino , Idade Gestacional , Humanos , Lactente , Lactente Extremamente Prematuro , Recém-Nascido de Baixo Peso/sangue , Recém-Nascido , Masculino , Gravidez , Modelos de Riscos Proporcionais , Resultado do Tratamento , Cordão UmbilicalRESUMO
La policitemia primaria es producida por una mutación adquirida o heredada en las células progenitoras de los glóbulos rojos, mientras que la poliglobulia secundaria está relacionada con un aumento de la eritropoyetina sérica como respuesta a la hipoxia tisular o a la producción autónoma tumoral. Hace más de medio siglo que se conoce que la hidronefrosis puede actuar como una rara causa de eritrocitosis debido al aumento de producción de eritropoyetina por un riñón que censa una disminución de oxígeno, mecanismo también observado en la estenosis de la arteria renal y en los quistes renales. Se describe a continuación el caso de un paciente de 38 años con poliglobulia atendido en el Hospital Italiano de San Justo (Argentina), que presenta como hallazgo una hidronefrosis unilateral severa y cuya resolución quirúrgica a través de una nefrectomía revierte el cuadro hematológico de base. (AU)
Primary polycythemia is produced by an acquired or inherited mutation in progenitor cells of red blood cells, while secondary polyglobulia is related to an increase in serum erythropoietin in response to tissue hypoxia or autonomous tumor production. Since the middle of the twentieth century, the hydronephrosis is known to be a rare etiology of secondary polycythemia, with increased erythropoietin production caused by diminished oxygen sensing by the kidney, also seen in renal artery stenosis and kidney cysts. We describe a case of a 38 year old patient with polycythemia studied in the "Hospital Italiano de San Justo" (Argentina) that presented an incidental severe unilateral hydronephrosis, and nephrectomy was carried out as a final resolution of the hematological disorder. (AU)
Assuntos
Humanos , Animais , Masculino , Adulto , Pessoa de Meia-Idade , Policitemia/diagnóstico , Pielonefrite/diagnóstico , Infecções Urinárias/complicações , Eritropoetina/sangue , Hidronefrose/diagnóstico , Nefrectomia/tendências , Policitemia/complicações , Policitemia/etiologia , Pielonefrite/sangue , Obstrução da Artéria Renal/patologia , Dor Lombar , Hipóxia-Isquemia Encefálica/patologia , Eritrócitos/fisiologia , Doenças Renais Císticas/patologia , Disuria , Febre , Hidronefrose/cirurgia , Hidronefrose/complicações , Anemia , Nefrectomia/métodosRESUMO
Erythropoiesis-stimulating agents (ESAs) have been used in horses for doping purposes to increase the performance of these animals in endurance sports. Currently, enzyme-linked immunosorbent assay (ELISA) and mass spectrometry methods are used to detect ESA abuse in equines. However, the sarcosyl polyacrylamide gel-electrophoresis (SAR-PAGE) technique could also be used, since its application in human doping control is well established and has proven to be more sensitive. In this work, the SAR-PAGE method was used to detect recombinant human erythropoietin (rHuEPO), novel erythropoiesis stimulating protein (NESP), continuous erythropoietin receptor activator (CERA), and fusion protein of erythropoietin with human immunoglobulin heavy chain Fc region (EPO-Fc) in horse blood and urine. The purification technique for human blood using MAIIA kits worked well for horse samples. The major challenge was horse urine immunopurification, which proved difficult due to filter clogging, but heating and cooling of the horse urine followed by filtration in 30-kDa molecular weight cut-off filters solved this problem. The limits of detection (LODs) of 1.3, 1.6, 6.6, and 13.3 pg/mL for rHuEPO, NESP, CERA, and EPO-Fc, respectively, obtained in spiked urine and 40, 100, 80, and 400 pg/mL for rHuEPO, NESP, CERA, and EPO-Fc, respectively, acquired in spiked blood are lower than the LODs reported in the literature using liquid chromatography-mass spectrometry (LC-MS) methods. In addition, the presence of ESAs was detected up to 9 days after the administration of microdoses of Hemax (rHuEPO), NESP, and CERA in horse blood and urine. SAR-PAGE may be implemented in the routine analysis of horse doping control laboratories for screening and confirmation of ESA abuse, mainly due to its high sensitivity for both matrices compared to published mass spectrometric methods.