RESUMO
ABSTRACT: Chronic kidney disease (CKD) is a major contributor to morbidity and mortality in sickle cell disease (SCD). Anemia, induced by chronic persistent hemolysis, is associated with the progressive deterioration of renal health, resulting in CKD. Moreover, patients with SCD experience acute kidney injury (AKI), a risk factor for CKD, often during vaso-occlusive crisis associated with acute intravascular hemolysis. However, the mechanisms of hemolysis-driven pathogenesis of the AKI-to-CKD transition in SCD remain elusive. Here, we investigated the role of increased renovascular rarefaction and the resulting substantial loss of the vascular endothelial protein C receptor (EPCR) in the progressive deterioration of renal function in transgenic SCD mice. Multiple hemolytic events raised circulating levels of soluble EPCR (sEPCR), indicating loss of EPCR from the cell surface. Using bone marrow transplantation and super-resolution ultrasound imaging, we demonstrated that SCD mice overexpressing EPCR were protective against heme-induced CKD development. In a cohort of patients with SCD, plasma sEPCR was significantly higher in individuals with CKD than in those without CKD. This study concludes that multiple hemolytic events may trigger CKD in SCD through the gradual loss of renovascular EPCR. Thus, the restoration of EPCR may be a therapeutic target, and plasma sEPCR can be developed as a prognostic marker for sickle CKD.
Assuntos
Anemia Falciforme , Receptor de Proteína C Endotelial , Heme , Camundongos Transgênicos , Insuficiência Renal Crônica , Animais , Anemia Falciforme/complicações , Anemia Falciforme/patologia , Anemia Falciforme/metabolismo , Anemia Falciforme/sangue , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/etiologia , Receptor de Proteína C Endotelial/metabolismo , Receptor de Proteína C Endotelial/genética , Camundongos , Heme/metabolismo , Humanos , Masculino , Feminino , Hemólise , Rim/metabolismo , Rim/patologiaRESUMO
Within the spectrum of sickle cell disease (SCD) are sickle cell anemia (SCA), presence of hemoglobin SS (HbSS), hemoglobin SC disease (HbSC), and sickle cell ß-thalassemia (Sß-thal). Asymmetric dimethylarginine (ADMA) competitively inhibits the binding of arginine to NOS, reducing NO production. In patients with HbSS, increased levels of ADMA have been reported, as well as changes in many hemostatic biomarkers, including the plasminogen activator inhibitor type 1 (PAI-1). We hypothesized that high levels of ADMA and PAI-1 may be associated with more severe SCD. Thus, ADMA and PAI-1 levels were determined in 78 individuals including 38 adult patients with SCD and 40 control subjects. Higher levels of ADMA were shown in HbSS and Sß-thal patients compared to controls. Concerning PAI-1, all patients showed high levels of PAI-1 compared to controls. As a role of NO in the pathogenesis of SCD has already been established, we concluded that high levels of ADMA should compromise, at least in part, NO synthesis, resulting in endothelial dysfunction. Elevated plasma levels of PAI-1 in all patients may indicate not only endothelial dysfunction but also a hypofibrinolytic state favoring thrombotic complications. Finally, high levels of ADMA and PAI-1 may be associated with more severe SCD.
Assuntos
Anemia Falciforme/sangue , Arginina/análogos & derivados , Inibidor 1 de Ativador de Plasminogênio/sangue , Adolescente , Adulto , Anemia Falciforme/patologia , Arginina/sangue , Biomarcadores/sangue , Criança , Estudos Transversais , Endotélio/patologia , Feminino , Humanos , Masculino , Índice de Gravidade de Doença , Adulto JovemRESUMO
BACKGROUND: Priapism impairs quality of life and has a predilection for males with sickle cell disease (SCD). The Priapism Impact Profile (PIP) is a novel 12-item instrument designed to measure general health-related impact of priapism. The aim of the study was to evaluate the validity and reliability of the PIP in a Jamaican cohort of SCD patients experiencing priapism. METHODS: One hundred SCD patients with a history of priapism were recruited from a sickle cell clinic in Kingston, Jamaica and administered the PIP questionnaire. Patients rated each item of the PIP for clarity and importance. Statistical testing was employed to evaluate the psychometric performance of the PIP. Content validation was assessed based on patient descriptive rating of the items based on clarity, and importance and criterion-oriented validity were assessed by evaluating the PIP's ability to distinguish between patient subgroups. Test-retest repeatability was assessed in 20 of the 100 patients. RESULTS: Patients were stratified into active (54) and remission (46) priapism groups based on their experience of priapism within the past year. Patients in the active priapism group were younger (p = 0.011), had a shorter duration of disease (p = 0.023), and had more frequent priapism episodes (p = 0.036) than the remission group. PIP questionnaire scores differed significantly with respect to priapism activity (p < 0.001) and prevalence of erectile dysfunction (p < 0.05) but not by priapism severity (p = 0.62). The PIP questionnaire had good content validity, with questions rated as having medium or high clarity and importance by an average of 82.8% and 69.2% of patients, respectively. CONCLUSION: The PIP questionnaire was successfully validated in a Jamaican cohort of SCD patients and adequately discriminated patients with active priapism from those in remission. The instrument may be utilized in routine clinical management of patients with SCD-associated priapism. Further clinical investigations are warranted in other populations.
Assuntos
Anemia Falciforme/patologia , Priapismo/psicologia , Adulto , Anemia Falciforme/complicações , Estudos de Coortes , Humanos , Jamaica , Masculino , Avaliação de Resultados em Cuidados de Saúde , Aptidão Física , Priapismo/complicações , Qualidade de Vida , Índice de Gravidade de Doença , Disfunções Sexuais Fisiológicas/etiologia , Inquéritos e Questionários , Adulto JovemRESUMO
Brain injury in sickle cell disease (SCD) comprises a wide spectrum of neurological damage. Neurocognitive deficits have been described even without established neurological lesions. DTI is a rapid, noninvasive, and non-contrast method that enables detection of normal-appearing white matter lesions not detected by conventional magnetic resonance imaging (MRI). The aim of the study was to evaluate if stem cell transplantation can revert white matter lesions in patients with SCD. Twenty-eight SCD patients were evaluated with MRI and DTI before and after allogeneic hematopoietic stem cell transplantation (HSCT), compared with 26 healthy controls (HC). DTI metrics included fractional anisotropy (FA), mean diffusivity (MD), radial (RD), and axial (AD) diffusivity maps, global efficiency, path length, and clustering coefficients. Compared to HC, SCD patients had a lower FA (p = 0.0086) before HSCT. After HSCT, FA increased and was not different from healthy controls (p = 0.1769). Mean MD, RD, and AD decreased after HSCT (p = 0.0049; p = 0.0029; p = 0.0408, respectively). We confirm previous data of white matter lesions in SCD and present evidence that HSCT promotes recovery of brain injury with potential improvement of brain structural connectivity.
Assuntos
Anemia Falciforme , Lesões Encefálicas , Transplante de Células-Tronco Hematopoéticas , Substância Branca , Anemia Falciforme/patologia , Anemia Falciforme/terapia , Lesões Encefálicas/patologia , Imagem de Tensor de Difusão/métodos , Humanos , Substância Branca/diagnóstico por imagem , Substância Branca/patologiaRESUMO
Intravascular hemolysis, a major manifestation of sickle cell disease (SCD) and other diseases, incurs the release of hemoglobin and heme from red blood cells, in turn triggering inflammatory processes. This study investigated the in vitro effects of heme, a major inflammatory DAMP, on the adhesive properties of isolated human neutrophils. Heme (20 and 50 µM) significantly increased the adhesion of neutrophils to fibronectin and to recombinant ICAM-1, under static conditions, even more efficiently than the potent pro-inflammatory cytokine, tumor necrosis factor-α (TNF); a microfluidic assay confirmed that heme stimulated neutrophil adhesion under conditions of shear stress. Heme-induced neutrophil adhesion was associated with the increased activities, but not expressions, of the Mac-1 and LFA-1 integrin subunits, CD11b and CD11a, on the cell surface. Notably, heme (50 µM) significantly induced NFκB translocation in neutrophils, and inhibition of NFκB activity with the BAY11-7082 molecule abolished heme-induced cell adhesion to fibronectin and significantly decreased CD11a activity. Flow cytometric analysis demonstrated major reactive oxygen species (ROS) generation in neutrophils following heme stimulation that could be inhibited by the antioxidant, α-tocopherol, and by BAY11-7082. Furthermore, co-incubation with α-tocopherol abrogated both heme-stimulated neutrophil adhesion and CD11a/CD11b activation. Thus, our data indicate that heme, at clinically relevant concentrations, is a potent activator of neutrophil adhesion, increasing the ligand affinity of the ß2 integrins via a mechanism that may be partially mediated by an NFkB-dependent pathway and the generation of ROS. Given the fundamental role that the adhesion of neutrophils to the vascular wall plays in SCD vaso-occlusion and other vascular inflammatory processes, our findings provide further evidence that cell-free heme is a major therapeutic target in the hemolytic diseases.
Assuntos
Endotélio Vascular/efeitos dos fármacos , Heme/farmacologia , NF-kappa B/metabolismo , Neutrófilos/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Anemia Falciforme/metabolismo , Anemia Falciforme/patologia , Antígenos CD18/metabolismo , Adesão Celular/efeitos dos fármacos , Células Cultivadas , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Hemólise , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Leucócitos Mononucleares , Neutrófilos/metabolismo , Neutrófilos/patologia , Transdução de SinaisRESUMO
BACKGROUND: Physical inactivity is an important risk factor for cardiovascular disease. The benefits of exercise in patients with chronic diseases, including cardiovascular diseases, are well established. For patients with sickle cell disease, medical recommendation was to avoid physical exercise for fear of triggering painful crises or increasing the impairment of the cardiopulmonary function. Only recently, studies have shown safety in exercise programs for this population. Despite that, there is no report that assess the effects of physical exercise on cardiac parameters in patients with sickle cell disease. OBJECTIVE: This study aimed to evaluate the impact of regular physical exercise (a home-based program) on cardiovascular function in patients with sickle cell disease. DESIGN: A quasi-randomized prospective controlled trial. SETTING: During the years 2015 and 2016, we started recruiting among adult patients treated at a Brazilian Center for Patients with Sickle Cell Disease to participate in a study involving a home exercise program. The experimental (exercise) and control groups were submitted to clinical evaluation and cardiovascular tests before and after the intervention. Analysis of variance was applied to compare groups, considering time and group factors. PARTICIPANTS: Twenty-seven adult outpatients with a sickle cell disease diagnosis. INTERVENTIONS: Exercise group (N = 14): a regular home-based aerobic exercise program, three to five times per week not exceeding give times per week, for eight weeks; no prescription for the control group (N = 13). MAIN OUTCOME MEASURES: Echocardiographic and treadmill test parameters. RESULTS: The exercise group showed significant improvement in cardiovascular tests, demonstrated by increased distance traveled on a treadmill (p<0.01), increased ejection fraction (p < 0.01) and improvement of diastolic function assessed by mitral tissue Doppler E' wave on echocardiography (p = 0.04). None of the patients presented a sickle cell crisis or worsening of symptoms during the exercise program. CONCLUSION: The selected home-based exercise program is safe, feasible, and promotes a favorable impact on functional capacity and cardiovascular function in sickle cell disease patients.
Assuntos
Anemia Falciforme/terapia , Adulto , Anemia Falciforme/patologia , Ecocardiografia , Exercício Físico/fisiologia , Terapia por Exercício/métodos , Feminino , Humanos , Masculino , Adulto JovemRESUMO
Antecedentes: el fármaco antimetabolito aumenta el nivel de hemoglobina fetal y reduce la frecuencia de crisis en pacientes con anemia de células falciformes. Objetivo: Evaluar el efecto de los antimetabolitos (hidroxiurea) en casos con crisis falciforme frecuente de anemia de células falciformes y talasemia no dependiente de transfusiones en el hospital de formación de Karbala desde abril de 2016 hasta diciembre de 2020. Pacientes y métodos: de 81 pacientes realizados en este estudio de casos y controles, cuarenta recibieron hidroxiurea y los otros cuarenta y un pacientes no. Se realizaron monitoreos cada dos semanas en los primeros tres meses mediante el envío para análisis (Hb, WBC, recuento de plaquetas y urea en sangre y creatinina sérica) LA PRENSA MÉDICA ARGENTINA Antimetabolite drug in patients with sickle cell diseases in hematological center of kerbalaa training hospital 161 V.107/Nº 3 además de la evaluación de los efectos secundarios de los medicamentos. Los cuarenta y un pacientes restantes que rechazaron la terapia con medicamentos los consideramos un grupo de control. Resultado: el grupo de casos que recibió hidroxilurea tuvo crisis principalmente después de 12 semanas desde la última crisis, mientras que el grupo de control tuvo crisis principalmente cada 3 a 7 semanas con un valor P=0,0001. No hubo efectos secundarios en el 77,5% de los casos que recibieron hidroxiurea. El 22,5% restante de los casos tuvo efectos secundarios menores o inespecíficos. Conclusión: En pacientes con drepanocitosis que sufrieron episodios recurrentes de crisis, la terapia con Hidroxiurea disminuye significativamente la frecuencia de la crisis dolorosa, con un bajo nivel de efectos secundarios en comparación con el grupo control.
Background: the antimetabolite drug increase fetal hemoglobin level and reduce the frequency of crisis in sickle cell disease patients. Aim: To evaluate the effect of antimetabolites (hydroxyurea) in cases with frequent sickling crisis of sickle cell disease and non-transfusion dependent thalassemia in Karbala training hospital from APRIL 2016 till December 2020. Patient and methods: from eighty-one patients conducted in this case control study, forty were received hydroxyurea and the other forty-one patients were not. Monitoring every two weeks in the first three months by sending for investigations (Hb, WBC, platelet count and blood urea and serum creatinine) in addition to assessment of drug side effects. The remaining forty-one patients who refused drug therapy we consider them as a control group. Result: the case group who received hydroxylurea had crisis mostly after 12 weeks from last crisis, whereas the control group had crisis mostly each 3 to 7 weeks in P value 0.0001. There was no side effect in 77.5% of cases received hydroxyurea.The remaining 22.5% of cases had less or nonspecific side effects. Conclusion: In patient with sickle cell diseases who suffered from recurrent episodes of crisis, Hydroxyurea therapy significantly decreases the frequency of the painful crisis, with low level of side effects in comparison with control group
Assuntos
Humanos , Hemoglobina Fetal , Estudos de Casos e Controles , Técnicas de Laboratório Clínico , Hidroxiureia/uso terapêutico , Anemia Falciforme/patologia , AntimetabólitosRESUMO
The pathophysiology of sickle cell anemia, a hereditary hemoglobinopathy, has fascinated clinicians and scientists alike since its description over 100 years ago. A single gene mutation in the HBB gene results in the production of abnormal hemoglobin (Hb) S, whose polymerization when deoxygenated alters the physiochemical properties of red blood cells, in turn triggering pan-cellular activation and pathological mechanisms that include hemolysis, vaso-occlusion, and ischemia-reperfusion to result in the varied and severe complications of the disease. Now widely regarded as an inflammatory disease, in recent years attention has included the role of leukocytes in vaso-occlusive processes in view of the part that these cells play in innate immune processes, their inherent ability to adhere to the endothelium when activated, and their sheer physical and potentially obstructive size. Here, we consider the role of sickle red blood cell populations in elucidating the importance of adhesion vis-a-vis polymerization in vaso-occlusion, review the direct adhesion of sickle red cells to the endothelium in vaso-occlusive processes, and discuss how red cell- and leukocyte-centered mechanisms are not mutually exclusive. Given the initial clinical success of crizanlizumab, a specific anti-P selectin therapy, we suggest that it is appropriate to take a holistic approach to understanding and exploring the complexity of vaso-occlusive mechanisms and the adhesive roles of the varied cell types, including endothelial cells, platelets, leukocytes, and red blood cells.
Assuntos
Anemia Falciforme/patologia , Eritrócitos/patologia , Leucócitos/patologia , Animais , Plaquetas/patologia , Adesão Celular/fisiologia , Hemoglobina Falciforme/fisiologia , Humanos , Doenças Vasculares/patologiaRESUMO
Sickle cell disease (SCD) is caused by a homozygous mutation in the ß-globin gene, which leads to erythrocyte sickling, vasoocclusion, and intense hemolysis. P-selectin inhibition has been shown to prevent vasoocclusive events in patients with SCD; however, the chronic effect of P-selectin inhibition in SCD remains to be determined. Here, we used quantitative liver intravital microscopy in our recently generated P-selectin-deficient SCD mice to show that chronic P-selectin deficiency attenuates liver ischemia but fails to prevent hepatobiliary injury. Remarkably, we find that this failure in resolution of hepatobiliary injury in P-selectin-deficient SCD mice is associated with the increase in cellular senescence and reduced epithelial cell proliferation in the liver. These findings highlight the importance of investigating the long-term effects of chronic P-selectin inhibition therapy on liver pathophysiology in patients with SCD.
Assuntos
Anemia Falciforme/patologia , Isquemia/patologia , Fígado/irrigação sanguínea , Selectina-P/deficiência , Anemia Falciforme/fisiopatologia , Animais , Arteriopatias Oclusivas/etiologia , Arteriopatias Oclusivas/patologia , Senescência Celular , Células Epiteliais/patologia , Heme Oxigenase-1/análise , Hemólise , Fígado/patologia , Fígado/fisiopatologia , Proteínas de Membrana/análise , Camundongos , Camundongos Knockout , Modelos Animais , Selectina-P/genéticaRESUMO
Individuals with sickle cell anemia (SCA) present chronic anemia, hemolysis, an exacerbated inflammatory response, and heterogeneous clinical complications, which may be modulated by the transforming growth factor beta (TGF-ß) pathway. Thus, we aimed to investigate polymorphisms (rs1805110 and rs7526590) of the transforming growth factor beta receptor III gene (TGFBR3) with regard to laboratory biomarkers and clinical manifestations in individuals with SCA. Hematological, biochemical, immunological, and genetic analyses were carried out, as well as serum endothelin-1 measurements. The minor allele (A) of the TGFBR3 rs1805110 polymorphism was associated with increased hemoglobin, hematocrit, reticulocyte counts, total cholesterol, low-density lipoprotein, uric acid, and endothelin levels, as well as decreased platelet distribution width (PDW) and the occurrence of bone alterations. The minor allele (T) of TGFBR3 rs7526590 was associated with increased red cell distribution width, PDW, alkaline phosphatase, aspartate aminotransferase, total and indirect bilirubin, and lactate dehydrogenase levels, as well as lower ferritin levels and the occurrence of leg ulcers. Our data suggest that the minor allele (A) of TGFBR3 rs1805110 is associated with inflammation and bone alterations, while the minor allele (T) of TGFBR3 rs7526590 is related to hemolysis and the occurrence of leg ulcers.