RESUMEN
Acute splenic sequestration crisis (ASSC) is a potentially life-threatening complication of sickle cell disease (SCD), typically occurring in young patients under 5 years of age, with a median age at first episode of less than 2 years. Because a beneficial effect of hydroxyurea (HU) on spleen perfusion and splenic function has been suspected, we hypothesized that HU treatment might be associated with later onset of ASSC in patients with SCD. To investigate this hypothesis, we analyzed data from the ESCORT-HU study on a large cohort of patients with SCD receiving HU, enrolled between January 2009 and June 2017 with a follow-up of 7309 patient-years of observation. The median age at ASSC of the 14 patients who experienced a first episode of ASSC during the study period was 8.0 [IQR: 5.0-24.1] years. The median age at HU initiation was significantly lower in these 14 patients (4.8 [IQR: 3.3-18.7] years) compared to the 1664 patients without ASSC (19.9 [8.8-33.4] years, p = .0008). These findings suggest that ASSC may occur at an unusually late age in patients receiving HU, possibly reflecting longer preservation of spleen perfusion and function secondary to early initiation of HU. Further studies are needed to better characterize the effects of HU on spleen perfusion/function and on the occurrence of ASSC in patients with SCD (ClinicalTrials.gov identifier: NCT02516579; European registry ENCEPP/SDPP/10565).
Asunto(s)
Anemia de Células Falciformes , Hidroxiurea , Humanos , Preescolar , Niño , Adolescente , Adulto Joven , Adulto , Hidroxiurea/uso terapéutico , Bazo , Enfermedad Aguda , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/tratamiento farmacológico , Anemia de Células Falciformes/epidemiología , Sistema de Registros , Antidrepanocíticos/uso terapéuticoRESUMEN
Hypoxia-mediated red blood cell (RBC) sickling is central to the pathophysiology of sickle cell disease (SCD). The signalling nucleoside adenosine is thought to play a significant role in this process. This study investigated expression of the erythrocyte type 1 equilibrative nucleoside transporter (ENT1), a key regulator of plasma adenosine, in adult patients with SCD and carriers of sickle cell trait (SCT). Relative quantitative expression analysis of erythrocyte ENT1 was carried out by Western blot and flow cytometry. Patients with SCD with steady state conditions, either with SS or SC genotype, untreated or under hydroxycarbamide (HC) treatment, exhibited a relatively high variability of erythrocyte ENT1, but with levels not significantly different from normal controls. Most strikingly, expression of erythrocyte ENT1 was found to be significantly decreased in patients with SCD undergoing painful vaso-occlusive episode and, unexpectedly, also in healthy SCT carriers. Promoting hypoxia-induced adenosine signalling, the reduced expression of erythrocyte ENT1 might contribute to the pathophysiology of SCD and to the susceptibility of SCT individuals to altitude hypoxia or exercise to exhaustion.
Asunto(s)
Rasgo Drepanocítico , Humanos , Adenosina , Tranportador Equilibrativo 1 de Nucleósido/genética , Tranportador Equilibrativo 1 de Nucleósido/metabolismo , Eritrocitos/metabolismo , Hipoxia/metabolismoRESUMEN
Background and Objectives: Pain management poses a significant challenge for patients experiencing vaso-occlusive crisis (VOC) in sickle cell disease (SCD). While opioid therapy is highly effective, its efficacy can be impeded by undesirable side effects. Local regional anesthesia (LRA), involving the deposition of a perineural anesthetic, provides a nociceptive blockade, local vasodilation and reduces the inflammatory response. However, the effectiveness of this therapeutic approach for VOC in SCD patients has been rarely reported up to now. The objective of this study was to assess the effectiveness of a single-shot local regional anesthesia (LRA) in reducing pain and consequently enhancing the management of severe vaso-occlusive crisis (VOC) in adults with sickle cell disease (SCD) unresponsive to conventional analgesic therapy. Materials and Methods: We first collected consecutive episodes of VOC in critical care (ICU and emergency room) for six months in 2022 in a French University hospital with a large population of sickle cell patients in the West Indies population. We also performed a systematic review of the use of LRA in SCD. The primary outcome was defined using a numeric pain score (NPS) and/or percentage of change in opioid use. Results: We enrolled nine SCD adults (28 years old, 4 females) for ten episodes of VOC in whom LRA was used for pain management. Opioid reduction within the first 24 h post block was -75% (50 to 96%). Similarly, the NPS decreased from 9/10 pre-block to 0-1/10 post-block. Five studies, including one case series with three patients and four case reports, employed peripheral nerve blocks for regional anesthesia. In general, local regional anesthesia (LRA) exhibited a reduction in pain and symptoms, along with a decrease in opioid consumption post-procedure. Conclusions: LRA improves pain scores, reduces opioid consumption in SCD patients with refractory pain, and may mitigate opioid-related side effects while facilitating the transition to oral analgesics. Furthermore, LRA is a safe and effective procedure.
Asunto(s)
Anemia de Células Falciformes , Compuestos Orgánicos Volátiles , Adulto , Femenino , Humanos , Manejo del Dolor/métodos , Estudios Retrospectivos , Analgésicos Opioides/uso terapéutico , Dolor/tratamiento farmacológico , Dolor/etiología , Analgésicos/uso terapéutico , Anemia de Células Falciformes/complicacionesRESUMEN
Microparticles (MPs) are submicron extracellular vesicles exposing phosphatidylserine (PS), detected at high concentration in the circulation of sickle cell anemia (SS) patients. Several groups studied the biological effects of MPs generated ex vivo. Here, we analyzed for the first time the impact of circulating MPs on endothelial cells (ECs) from 60 sickle cell disease (SCD) patients. MPs were collected from SCD patients and compared with MPs isolated from healthy individuals (AA). Other plasma MPs were purified from SS patients before and 2 years after the onset of hydroxyurea (HU) treatment or during a vaso-occlusive crisis and at steady-state. Compared with AA MPs, SS MPs increased EC ICAM-1 messenger RNA and protein levels, as well as neutrophil adhesion. We showed that ICAM-1 overexpression was primarily caused by MPs derived from erythrocytes, rather than from platelets, and that it was abolished by MP PS capping using annexin V. MPs from SS patients treated with HU were less efficient to induce a proinflammatory phenotype in ECs compared with MPs collected before therapy. In contrast, MPs released during crisis increased ICAM-1 and neutrophil adhesion levels, in a PS-dependent manner, compared with MPs collected at steady-state. Furthermore, neutrophil adhesion was abolished by a blocking anti-ICAM-1 antibody. Our study provides evidence that MPs play a key role in SCD pathophysiology by triggering a proinflammatory phenotype of ECs. We also uncover a new mode of action for HU and identify potential therapeutics: annexin V and anti-ICAM-1 antibodies.
Asunto(s)
Anemia de Células Falciformes , Micropartículas Derivadas de Células/metabolismo , Endotelio Vascular/metabolismo , Hidroxiurea/administración & dosificación , Molécula 1 de Adhesión Intercelular/sangre , ARN Mensajero/sangre , Adolescente , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/tratamiento farmacológico , Anemia de Células Falciformes/patología , Anemia de Células Falciformes/fisiopatología , Endotelio Vascular/patología , Endotelio Vascular/fisiopatología , Femenino , Humanos , Inflamación/sangre , Inflamación/tratamiento farmacológico , Inflamación/patología , Inflamación/fisiopatología , MasculinoRESUMEN
Inflammation and oxidative stress play a key role in the pathophysiology of sickle cell disease (SCD). However, the potential influence of different sickle genotypes, or hydroxyurea (HU) treatment, on these factors remains poorly documented. The present study compared several plasma markers of inflammation and oxidative stress, as well as microvascular function, between patients with sickle SC disease (HbSC, n = 19) and patients with sickle cell anemia (HbSS) under hydroxyurea (HU) treatment (n = 16), or not (n = 13). Hemorheological parameters and levels of inflammatory (IL-6, IL-8, IFN-γ, MCP-1, MIP-1ß, TNF-α) and oxidative stress (AOPP, MDA, MPO) markers were determined. Peripheral microcirculatory cutaneous blood flow and immediate microvascular response to local heat were evaluated using laser Doppler flowmetry. Oxidative stress and inflammation were lower in HbSC patients and HbSS patients under HU therapy compared to HbSS patients not treated with HU. Blood viscosity was higher in HbSC than in HbSS patients treated with or not with HU. Vasodilation response of the cutaneous microcirculation to heat stress was higher in HbSS patients receiving HU treatment. Our results clearly established that both sickle cell genotype and HU treatment modulate inflammation and oxidative stress.
Asunto(s)
Anemia de Células Falciformes , Viscosidad Sanguínea/efectos de los fármacos , Hidroxiurea/administración & dosificación , Microcirculación/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Adulto , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/tratamiento farmacológico , Anemia de Células Falciformes/fisiopatología , Biomarcadores/sangre , Femenino , Humanos , Inflamación/sangre , Inflamación/tratamiento farmacológico , Inflamación/fisiopatología , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: The pathophysiology of sickle cell disease (SCD) and the variability of its clinical expression remain not fully understood, whether within or between different SCD genotypes. Recent studies have reported associations between lipid levels and several SCD complications. If lipid levels have been previously described as low in sickle cell anemia (SCA), few data have been provided for sickle cell SC disease (SCC). We designed our epidemiological study to isolate lipid levels and profiles by genotype in Guadeloupian cohorts of SCA and SCC adult patients, at steady state. We compared SCD lipid levels with those of the Guadeloupian general population (GGP), and analyzed potential associations between lipid levels and SCD complications (vaso-occlusive crises, acute chest syndrome and osteonecrosis). METHODS: Lipids, apolipoproteins, biological variables and anthropometric evaluation, were collected at steady state from medical files for 62 SCC and 97 SCA adult patients. Clinical SCD complications were collected from the clinical files. Analysis was conducted by genotype for all variables. RESULTS: Different SCC and SCA lipid profiles, both distinct from their GGP's, were identified. Compared to SCC and GGP, higher triglyceride (TG) levels were observed in SCA patients, independent of hydroxyurea, hemolysis, gender, age, body mass index (BMI), abdominal obesity and clinical nutritional status. Our survey highlights also subsequent anthropometrical phenotypes, with an over-representation of abdominal obesity with normal BMI in SCA patients, and affecting almost exclusively females in both genotypes. Moreover, more frequent positive history of acute chest syndrome (ACS) was observed in SCA patients with TG level higher than 1.50 g/l, and of osteonecrosis in SCC patients having non high-density lipoprotein-cholesterol level (Non HDL-C) higher than 1.30 g/l. CONCLUSIONS: This study reveals that SCA and SCC patients exhibit distinct lipid profiles and suggests that high TG and Non HDL-C levels are associated with past histories of ACS and osteonecrosis in SCA and SCC patients, respectively.
Asunto(s)
Anemia de Células Falciformes/sangre , Lípidos/sangre , Síndrome Torácico Agudo/sangre , Adulto , Índice de Masa Corporal , Estudios de Casos y Controles , Femenino , Guadalupe , Hemólisis , Humanos , Masculino , Persona de Mediana Edad , Osteonecrosis/sangre , Estudios Retrospectivos , Enfermedades Vasculares/sangreRESUMEN
Painful vaso-occlusive crisis, a hallmark of sickle cell anaemia, results from complex, incompletely understood mechanisms. Red blood cell (RBC) damage caused by continuous endogenous and exogenous oxidative stress may precipitate the occurrence of vaso-occlusive crises. In order to gain insight into the relevance of oxidative stress in vaso-occlusive crisis occurrence, we prospectively compared the expression levels of various oxidative markers in 32 adults with sickle cell anaemia during vaso-occlusive crisis and steady-state conditions. Compared to steady-state condition, plasma levels of free haem, advanced oxidation protein products and myeloperoxidase, RBC caspase-3 activity, as well as the concentrations of total, neutrophil- and RBC-derived microparticles were increased during vaso-occlusive crises, whereas the reduced glutathione content was decreased in RBCs. In addition, natural anti-band 3 autoantibodies levels decreased during crisis and were negatively correlated with the rise in plasma advanced oxidation protein products and RBC caspase-3 activity. These data showed an exacerbation of the oxidative stress during vaso-occlusive crises in sickle cell anaemia patients and strongly suggest that the higher concentration of harmful circulating RBC-derived microparticles and the reduced anti-band 3 autoantibodies levels may be both related to the recruitment of oxidized band 3 into membrane aggregates.
Asunto(s)
Anemia de Células Falciformes/complicaciones , Proteína 1 de Intercambio de Anión de Eritrocito/inmunología , Micropartículas Derivadas de Células/inmunología , Estrés Oxidativo , Adolescente , Adulto , Anemia de Células Falciformes/sangre , Arteriopatías Oclusivas , Autoanticuerpos/sangre , Biomarcadores/sangre , Eritrocitos/metabolismo , Femenino , Humanos , Masculino , Dolor , Estudios Prospectivos , Adulto JovenRESUMEN
Oxidative stress and haemolysis-associated nitric oxide (NO) depletion plays a crucial role in the development of vasculopathy in sickle cell anaemia (SS). However it remains unknown whether oxidative stress and haemolysis levels influence vascular function in patients with sickle haemoglobin C disease (SC). Microvascular response to heat (using Laser Doppler flowmetry on finger), oxidative stress biomarkers, NO metabolites, endothelin-1 and haematological parameters were compared between patients with SS and SC. Vascular function, oxidative and nitrosative markers were also measured in healthy (AA) children. SS and SC had increased plasma advanced oxidation protein products (AOPP), malondialdehyde, plasma antioxidant activities and NO end products, compared to AA. SC had lower catalase activity compared to AA and SS. Haemolytic rate, glutathione peroxidase and nitrotyrosine concentrations were significantly increased in children with SS compared to SC and AA. SS and SC had impaired microvascular reactivity compared to AA. In SS, the plateau phase of the response to local thermal heating was negatively associated with nitrotyrosine and AOPP. No association between vascular function parameters and oxidative stress markers was observed in SC. Mild haemolysis in SC, compared to SS, may limit oxidative and nitrosative stress and could explain the better preserved microvascular function in this group.
Asunto(s)
Anemia de Células Falciformes/fisiopatología , Estrés Oxidativo/fisiología , Adolescente , Productos Avanzados de Oxidación de Proteínas/sangre , Antioxidantes/metabolismo , Viscosidad Sanguínea/fisiología , Estudios de Casos y Controles , Niño , Endotelina-1/sangre , Femenino , Dedos/irrigación sanguínea , Enfermedad de la Hemoglobina SC/fisiopatología , Hemólisis/fisiología , Humanos , Flujometría por Láser-Doppler/métodos , Masculino , Malondialdehído/sangre , Microcirculación/fisiología , Óxido Nítrico/sangreRESUMEN
It is unclear whether vascular function is affected similarly in children with sickle cell anaemia (SS) and children with sickle haemoglobin C (SC) disease. Therefore, we compared micro and macrovascular functions in healthy (AA) children, children with SS and SC disease, and assessed their association with physical activity. Participants (24 SS, 22 SC and 16 AA), were compared in terms of 1) thermal hyperaemic response (finger pad warming to 42°C) measured by Laser Doppler techniques, 2) arterial stiffness determined by pulse wave velocity, 3) daily energy expenditure related to moderate and intense physical activities estimated by questionnaire and 4) fitness level, evaluated by the six-minute walk test. Response to heating differed between SS, SC and controls. Peripheral microvascular reactivity was lower and pulse wave velocity higher in SS compared to AA. SC had blunted microvascular reactivity in response to heating compared to AA but pulse wave velocity was not different within the two groups. Physical activity and fitness levels were markedly lower in sickle cell patients compared to healthy controls but no association was observed with vascular function. Microvasodilatory reserve is decreased in both SS and SC patients but only SS patients were also characterised by impaired macrovascular function.
Asunto(s)
Metabolismo Energético , Ejercicio Físico , Enfermedad de la Hemoglobina SC/fisiopatología , Microcirculación , Análisis de la Onda del Pulso , Adolescente , Niño , Femenino , Humanos , MasculinoRESUMEN
The present study investigated cerebral and muscle hemoglobin oxygen saturation (tissue oxygen index, TOI) in children with sickle cell anemia (SS), sickle cell hemoglobin C disease (SC) and healthy children (AA). TOI was measured by near-infrared spectroscopy (NIRS) and spectral analysis of the TOI variability was used to assess flowmotion and vasomotion. Arterial oxyhemoglobin saturation (SpO2), hemorheological and hematological parameters were also measured in SS and SC children. Both TOI were lower in SS compared to both AA and SC children, with SC exhibiting lower values than AA children. Cerebral vasomotion expressed in absolute values was enhanced in SS compared to AA and SC children. Muscle vasomotion did not differ between the three groups. Hematocrit, SpO2 and red blood cell deformability were positively associated with cerebral TOI in SS children. We demonstrated that 1) cerebral and muscle TOI were markedly decreased in SS children while the decrease of TOI was milder in SC children, 2) cerebral TOI level was associated with several biological markers in SS children only and 3) cerebral vasomotion was enhanced in SS, possibly to counterbalance the effects of chronic cerebral hypoxia.
Asunto(s)
Anemia de Células Falciformes/metabolismo , Anemia de Células Falciformes/fisiopatología , Corteza Cerebral/irrigación sanguínea , Corteza Cerebral/metabolismo , Músculos/irrigación sanguínea , Músculos/metabolismo , Oxígeno/metabolismo , Adolescente , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/genética , Niño , Deformación Eritrocítica , Femenino , Genotipo , Hematócrito , Hemodinámica , Hemoglobina Falciforme/genética , Hemorreología , Humanos , Masculino , Consumo de Oxígeno , Espectroscopía Infrarroja CortaRESUMEN
BACKGROUND: Sickle cell anaemia (SCA) is a severe hereditary haemoglobinopathy characterised by haemorheological abnormalities, which play a role in the occurrence of several acute and chronic clinical complications. While ßS -haplotypes and alpha-thalassaemia modulate SCA clinical severity, their effects on blood rheology have been incompletely described. The aim of this study was to test the effects of these genetic modifiers on the haemorheological properties and clinical complication of children with SCA. PROCEDURE: Steady-state haemorheological profile, biological parameters, ßS -haplotypes, alpha-globin status, vaso-occlusive crisis (VOC) and acute chest syndrome frequencies were analysed in 128 children (aged 5 to 18 years) with SCA. RESULTS: Patients with alpha-thalassaemia showed increased red blood cell (RBC) deformability and aggregation compared to those without. Median VOC rate was higher in patients with homozygous alpha-thalassaemia compared to those with a normal alpha genotype. Conversely, the haemorheological profile and clinical complications were not influenced by the ßS -haplotypes in our study. CONCLUSION: Our results demonstrate that alpha-thalassaemia is associated with higher risk for VOC events in children with SCA, which may be due in part to its effects on RBC deformability and aggregation.
Asunto(s)
Anemia de Células Falciformes/complicaciones , Eritrocitos/patología , Talasemia alfa/complicaciones , Síndrome Torácico Agudo/patología , Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , ReologíaRESUMEN
A recent study suggested that adenosine signaling pathway could promote hemolysis in patients with sickle cell anemia (SCA). This signaling pathway involves several gene coding enzymes for which variants have been described. In this study, we analyzed the genotype-phenotype relationships between functional polymorphisms or polymorphisms associated with altered expression of adenosine pathway genes, namely adenosine deaminase (ada; rs73598374), adenosine A2b receptor (adora2b; rs7208480), adenylyl cyclase6 (adcy6; rs3730071, rs3730070, rs7300155), and hemolytic rate in SCA patients. One hundred and fifty SCA patients were genotyped for adcy6, ada, and adora2b variants as well as alpha-globin gene, a genetic factor known to modulate hemolytic rate. Hematological and biochemical data were obtained at steady-state. Lactate dehydrogenase, aspartate aminotransferase, reticulocytes and total bilirubin were used to calculate a hemolytic index. Genotype-phenotype relationships were investigated using parametric tests and multivariate analysis. SCA patients carrying at least one allele of adcy6 rs3730070-G exhibited lower hemolytic rate than non-carriers in univariate analysis (p=0.006). The presence of adcy6 rs3730070-G variant was associated with a decreased hemolytic rate in adjusted model for age and alpha-thalassemia (p=0.032). Our results support a protective effect of adcy6 rs3730070-G variant on hemolysis in SCA patients.
Asunto(s)
Adenilil Ciclasas/genética , Anemia de Células Falciformes/genética , Anemia de Células Falciformes/patología , Hemólisis , Polimorfismo de Nucleótido Simple , Adenosina/genética , Adolescente , Adulto , Niño , Estudios Transversales , Femenino , Humanos , Masculino , Adulto Joven , Talasemia alfa/genética , Talasemia alfa/patologíaRESUMEN
Vascular resistance and tissue perfusion may be both affected by impaired vascular function and increased blood viscosity. Little is known about the effects of vascular function on the occurrence of painful vaso-occlusive crises (VOC) in children with sickle cell anemia (SCA). The aim of the present study was to determine which side of the balance (blood viscosity or vascular function) is the most deleterious in SCA and increases the risk for frequent hospitalized VOC. Microvascular function, microcirculatory oxygenation and blood viscosity were determined in a group of 22 SCA children/adolescents at steady state and a group of 13 healthy children/adolescents. Univariate analyses demonstrated blunted microvascular reactivity during local thermal heating test and decreased microcirculatory oxygenation in SCA children compared to controls. Multivariate analysis revealed that increased blood viscosity and decreased microcirculatory oxygenation were independent risk factors of frequent VOC in SCA. In contrast, the level of microvascular dysfunction does not predict VOC rate. In conclusion, increased blood viscosity is usually well supported in healthy individuals where vascular function is not impaired. However, in the context of SCA, microvascular function is impaired and any increase of blood viscosity or decrease in microcirculatory oxygenation would increase the risks for frequent VOC.
Asunto(s)
Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/fisiopatología , Viscosidad Sanguínea , Microvasos/fisiopatología , Oxígeno/metabolismo , Adolescente , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/metabolismo , Niño , Femenino , Humanos , Masculino , Microcirculación , Microvasos/metabolismo , Dolor/etiologíaRESUMEN
Sickle cell disease (SCD) is a significant problem in the Caribbean, where many individuals have African and Asian forebears. However, reliable prevalence data and specific health care programs for SCD are often missing in this region. Closer collaboration between Caribbean territories initiated in 2006 to set up strategies to promote better equity in the health care system for SCD patients led to the formation of CAREST: the Caribbean Network of Researchers on Sickle Cell Disease and Thalassemia. We present the effectiveness of collaborations established by CAREST to promote SCD newborn screening programs and early childhood care, to facilitate health worker training and approaches for prevention and treatment of SCD complications, and to carry out inter-Caribbean research studies.
Asunto(s)
Anemia de Células Falciformes/etnología , Promoción de la Salud/organización & administración , Tamizaje Neonatal , Investigación/organización & administración , Talasemia/etnología , Región del Caribe/epidemiología , Conducta Cooperativa , Competencia Cultural , Personal de Salud/educación , Humanos , Recién Nacido , Capacitación en Servicio , Lenguaje , PrevalenciaAsunto(s)
Anemia de Células Falciformes/genética , Eliminación de Gen , Microcirculación/genética , Globinas alfa/deficiencia , Talasemia alfa/genética , Adolescente , Adulto , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/fisiopatología , Velocidad del Flujo Sanguíneo , Presión Sanguínea , Índice de Masa Corporal , Niño , Índices de Eritrocitos , Femenino , Dedos/irrigación sanguínea , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Óxido Nítrico/fisiología , Vasodilatación , Adulto Joven , Globinas alfa/genética , Talasemia alfa/sangre , Talasemia alfa/complicaciones , Talasemia alfa/fisiopatologíaRESUMEN
Human red blood cells (RBC) express an active and functional endothelial-like nitric oxide (NO) synthase (RBC-NOS). We report studies on RBC-NOS activity in sickle cell anaemia (SCA), a genetic disease characterized by decreased RBC deformability and vascular dysfunction. Total RBC-NOS content was not significantly different in SCA patients compared to healthy controls; however, using phosphorylated RBC-NOS-Ser(1177) as a marker, RBC-NOS activation was higher in SCA patients as a consequence of the greater activation of Akt (phosphorylated Akt-Ser(473) ). The higher RBC-NOS activation in SCA led to higher levels of S-nitrosylated α- and ß-spectrins, and greater RBC nitrite and nitrotyrosine levels compared to healthy controls. Plasma nitrite content was not different between the two groups. Laser Doppler flowmetric experiments demonstrated blunted microcirculatory NO-dependent response under hyperthermia in SCA patients. RBC deformability, measured by ektacytometry, was reduced in SCA in contrast to healthy individuals, and pre-shearing RBC in vitro did not improve deformability despite an increase of RBC-NOS activation. RBC-NOS activation is high in freshly drawn blood from SCA patients, resulting in high amounts of NO produced by RBC. However, this does not result in improved RBC deformability and vascular function: higher RBC-NO is not sufficient to counterbalance the enhanced oxidative stress in SCA.
Asunto(s)
Anemia de Células Falciformes/enzimología , Deformación Eritrocítica , Eritrocitos/enzimología , Óxido Nítrico Sintasa/metabolismo , Estrés Oxidativo , Anemia de Células Falciformes/patología , Activación Enzimática , Eritrocitos/patología , Femenino , Humanos , Masculino , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Espectrina/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMEN
BACKGROUND: Autonomic nervous system (ANS) activity has been suggested to modulate the clinical severity of sickle cell anemia (SCA) by increasing the risk for vaso-occlusive events. Regular physical activity (PA) is known to improve ANS activity and health status in several cardiovascular and metabolic diseases. Whether regular PA improves the health status of SCA patients remains unknown. PROCEDURE: Twenty-two patients with SCA and 15 healthy (AA) children/adolescents participated to the study. Heart rate variability was measured in supine position and after a tilt-test to quantify the ANS activity. PA energy expenditure (PAEE) was assessed with questionnaire. RESULTS: 1) PAEE was lower in SCA compared to AA (190 ± 152 vs. 432 ± 277 kcal · d(-1), respectively, P < 0.01), 2) overall ANS activity was lower in SCA compared to AA, 3) parasympathetic withdrawal was observed in SCA with aging, 4) ANS reactivity was slightly impaired in SCA compared to AA (reduction in HFnu: -38 ± 27 vs. -58 ± 14%, respectively, P < 0.05), 5) ANS indices, PAEE, and rates of clinical events were not correlated. CONCLUSION: Both the level of PA and ANS activity are reduced in SCA compared to AA children/adolescents, particularly in those older than 15 years. Neither PAEE, nor ANS activity seem to influence the clinical severity of children/adolescents with SCA.
Asunto(s)
Anemia de Células Falciformes/fisiopatología , Sistema Nervioso Autónomo/fisiopatología , Estado de Salud , Actividad Motora , Calidad de Vida , Adolescente , Factores de Edad , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/terapia , Arteriopatías Oclusivas/etiología , Arteriopatías Oclusivas/fisiopatología , Arteriopatías Oclusivas/terapia , Niño , Femenino , Humanos , Masculino , Proyectos PilotoRESUMEN
Although pulmonary hypertension, leg ulcers, priapism, stroke and glomerulopathy in sickle cell anaemia (SCA) result from the adverse effects of chronic haemolysis on vascular function (haemolytic phenotype), osteonecrosis, acute chest syndrome and painful vaso-occlusive crises are caused by abnormal vascular cell adhesion and increased blood viscosity (viscosity-vaso-occlusion phenotype). However, this model with two sub-phenotypes does not take into account the haemorheological dimension. We tested the relationships between the biological parameters reflecting the haemolytic rate (haemolytic component) and red blood cell (RBC) rheological characteristics in 97 adults with SCA. No significant difference in the proportion of patients with low or high haemolytic component in the low and high blood viscosity groups was observed. The RBC elongation index (i.e. deformability) was negatively correlated with the haemolytic component. The RBC aggregates strength (i.e. RBC aggregates robustness) was negatively correlated with RBC elongation index. Sickle RBCs with high density had lower elongation index and higher aggregates strength. In conclusion, (i) the 'haemolytic' phenotype is characterized by decreased RBC deformability and increased RBC aggregates strength and (ii) the viscosity-vaso-occlusive phenotype is characterized by increased RBC deformability but not always by increased blood viscosity. α-thalassaemia modulates the haemorheological properties but other factors seem to be involved.