RESUMO
PURPOSE: We evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of intravenous (IV) inclacumab, a fully human IgG4 anti-P-selectin monoclonal antibody in development for the treatment of sickle cell disease, at doses up to and exceeding those previously tested in healthy individuals. METHODS: In this phase 1, open-label, single-ascending-dose study, 15 healthy participants were enrolled into cohorts receiving 20 mg/kg (n = 6) or 40 mg/kg (n = 9) IV inclacumab and observed for up to 29 weeks post-dose. Safety, PK parameters, thrombin receptor-activating peptide (TRAP)-activated platelet-leukocyte aggregate (PLA) formation, P-selectin inhibition, plasma soluble P-selectin, and anti-drug antibodies were characterized. RESULTS: Two inclacumab-related treatment-emergent adverse events were reported in 1 participant; no dose-limiting toxicities were observed. Plasma PK parameters were generally dose-proportional, with a terminal half-life of 13 to 17 days. Mean TRAP-activated PLA formation decreased within 3 h from the start of infusion, and inhibition was sustained for ~ 23 weeks. Mean P-selectin inhibition > 90% was observed up to 12 weeks post-dose. The mean ratio of free to total soluble P-selectin decreased rapidly from pre-dose to end of infusion, then increased gradually to 78% of the baseline ratio by week 29. Treatment-emergent anti-drug antibodies were observed in 2 of 15 participants (13%), without apparent impact on safety, PK, or PD. CONCLUSIONS: Inclacumab was well tolerated, with PK as expected for a monoclonal antibody against a membrane-bound target and a long duration of PD effects after both single IV doses, supporting a prolonged dosing interval. TRIAL REGISTRATION: ACTRN12620001156976; registered November 4, 2020.
Assuntos
Anemia Falciforme , Anticorpos Monoclonais , Humanos , Voluntários Saudáveis , Anticorpos Monoclonais/efeitos adversos , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/induzido quimicamente , Selectinas , Poliésteres , Método Duplo-Cego , Relação Dose-Resposta a DrogaRESUMO
BACKGROUND: Deoxygenated sickle hemoglobin (HbS) polymerization drives the pathophysiology of sickle cell disease. Therefore, direct inhibition of HbS polymerization has potential to favorably modify disease outcomes. Voxelotor is an HbS polymerization inhibitor. METHODS: In a multicenter, phase 3, double-blind, randomized, placebo-controlled trial, we compared the efficacy and safety of two dose levels of voxelotor (1500 mg and 900 mg, administered orally once daily) with placebo in persons with sickle cell disease. The primary end point was the percentage of participants who had a hemoglobin response, which was defined as an increase of more than 1.0 g per deciliter from baseline at week 24 in the intention-to-treat analysis. RESULTS: A total of 274 participants were randomly assigned in a 1:1:1 ratio to receive a once-daily oral dose of 1500 mg of voxelotor, 900 mg of voxelotor, or placebo. Most participants had sickle cell anemia (homozygous hemoglobin S or hemoglobin Sß0-thalassemia), and approximately two thirds were receiving hydroxyurea at baseline. In the intention-to-treat analysis, a significantly higher percentage of participants had a hemoglobin response in the 1500-mg voxelotor group (51%; 95% confidence interval [CI], 41 to 61) than in the placebo group (7%; 95% CI, 1 to 12). Anemia worsened between baseline and week 24 in fewer participants in each voxelotor dose group than in those receiving placebo. At week 24, the 1500-mg voxelotor group had significantly greater reductions from baseline in the indirect bilirubin level and percentage of reticulocytes than the placebo group. The percentage of participants with an adverse event that occurred or worsened during the treatment period was similar across the trial groups. Adverse events of at least grade 3 occurred in 26% of the participants in the 1500-mg voxelotor group, 23% in the 900-mg voxelotor group, and 26% in the placebo group. Most adverse events were not related to the trial drug or placebo, as determined by the investigators. CONCLUSIONS: In this phase 3 randomized, placebo-controlled trial involving participants with sickle cell disease, voxelotor significantly increased hemoglobin levels and reduced markers of hemolysis. These findings are consistent with inhibition of HbS polymerization and indicate a disease-modifying potential. (Funded by Global Blood Therapeutics; HOPE ClinicalTrials.gov number, NCT03036813.).
Assuntos
Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/administração & dosagem , Benzaldeídos/administração & dosagem , Hemoglobina Falciforme/efeitos dos fármacos , Hemoglobinas/metabolismo , Pirazinas/administração & dosagem , Pirazóis/administração & dosagem , Adolescente , Adulto , Anemia Falciforme/sangue , Antidrepanocíticos/efeitos adversos , Antidrepanocíticos/uso terapêutico , Benzaldeídos/efeitos adversos , Biomarcadores/sangue , Criança , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Hemoglobina Falciforme/metabolismo , Hemólise/efeitos dos fármacos , Humanos , Hidroxiureia/uso terapêutico , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Polimerização/efeitos dos fármacos , Pirazinas/efeitos adversos , Pirazóis/efeitos adversos , Adulto JovemRESUMO
BACKGROUND: Sickle cell anemia is an inherited blood disorder that is characterized by painful vaso-occlusive crises, for which there are few treatment options. Platelets mediate intercellular adhesion and thrombosis during vaso-occlusion in sickle cell anemia, which suggests a role for antiplatelet agents in modifying disease events. METHODS: Children and adolescents 2 through 17 years of age with sickle cell anemia were randomly assigned to receive oral prasugrel or placebo for 9 to 24 months. The primary end point was the rate of vaso-occlusive crisis, a composite of painful crisis or acute chest syndrome. The secondary end points were the rate of sickle cell-related pain and the intensity of pain, which were assessed daily with the use of pain diaries. RESULTS: A total of 341 patients underwent randomization at 51 sites in 13 countries across the Americas, Europe, Asia, and Africa. The rate of vaso-occlusive crisis events per person-year was 2.30 in the prasugrel group and 2.77 in the placebo group (rate ratio, 0.83; 95% confidence interval, 0.66 to 1.05; P=0.12). There were no significant differences between the groups in the secondary end points of diary-reported events. The safety end points, including the frequency of bleeding events requiring medical intervention, of hemorrhagic and nonhemorrhagic adverse events that occurred while patients were taking prasugrel or placebo, and of discontinuations due to prasugrel or placebo, did not differ significantly between the groups. CONCLUSIONS: Among children and adolescents with sickle cell anemia, the rate of vaso-occlusive crisis was not significantly lower among those who received prasugrel than among those who received placebo. There were no significant between-group differences in the safety findings. (Funded by Daiichi Sankyo and Eli Lilly; ClinicalTrials.gov number, NCT01794000.).
Assuntos
Síndrome Torácica Aguda/prevenção & controle , Anemia Falciforme/tratamento farmacológico , Dor/prevenção & controle , Inibidores da Agregação Plaquetária/uso terapêutico , Cloridrato de Prasugrel/uso terapêutico , Síndrome Torácica Aguda/etiologia , Administração Oral , Adolescente , Anemia Falciforme/complicações , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Dor/etiologia , Doenças Vasculares Periféricas/etiologia , Doenças Vasculares Periféricas/prevenção & controle , Inibidores da Agregação Plaquetária/efeitos adversos , Cloridrato de Prasugrel/efeitos adversosRESUMO
BACKGROUND: Many aspects of transfusion medicine are affected by genetics. Current single-nucleotide polymorphism (SNP) arrays are limited in the number of targets that can be interrogated and cannot detect all variation of interest. We designed a transfusion medicine array (TM-Array) for study of both common and rare transfusion-relevant variations in genetically diverse donor and recipient populations. STUDY DESIGN AND METHODS: The array was designed by conducting extensive bioinformatics mining and consulting experts to identify genes and genetic variation related to a wide range of transfusion medicine clinical relevant and research-related topics. Copy number polymorphisms were added in the alpha globin, beta globin, and Rh gene clusters. RESULTS: The final array contains approximately 879,000 SNP and copy number polymorphism markers. Over 99% of SNPs were called reliably. Technical replication showed the array to be robust and reproducible, with an error rate less than 0.03%. The array also had a very low Mendelian error rate (average parent-child trio accuracy of 0.9997). Blood group results were in concordance with serology testing results, and the array accurately identifies rare variants (minor allele frequency of 0.5%). The array achieved high genome-wide imputation coverage for African-American (97.5%), Hispanic (96.1%), East Asian (94.6%), and white (96.1%) genomes at a minor allele frequency of 5%. CONCLUSIONS: A custom array for transfusion medicine research has been designed and evaluated. It gives wide coverage and accurate identification of rare SNPs in diverse populations. The TM-Array will be useful for future genetic studies in the diverse fields of transfusion medicine research.
Assuntos
Genoma Humano/genética , Medicina Transfusional/métodos , Negro ou Afro-Americano , Povo Asiático , Biologia Computacional , Frequência do Gene/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética , População BrancaRESUMO
Sickle cell disease (SCD) is a common, life-threatening genetic disorder that is best managed when diagnosed early by newborn screening. However, SCD is most prevalent in low-resource regions of the world where newborn screening is rare and diagnosis at the point-of-care is challenging. In many such regions, the majority of affected children die, undiagnosed, before the age of 5 years. A rapid and affordable point-of-care test for SCD is needed. The diagnostic accuracy of HemoTypeSC, a point-of-care immunoassay, for SCD was evaluated in individuals who had SCD, hemoglobin C disease, the related carrier (trait) states, or a normal hemoglobin phenotype. Children and adults participated in low-, medium- and high-resource environments (Ghana [n = 383], Martinique [n = 46], and USA [n = 158]). Paired blood specimens were obtained for HemoTypeSC and a reference diagnostic assay. HemoTypeSC testing was performed at the site of blood collection, and the reference test was performed in a laboratory at each site. In 587 participants, across all study sites, HemoTypeSC had an overall sensitivity of 99.5% and specificity of 99.9% across all hemoglobin phenotypes. The test had 100% sensitivity and specificity for sickle cell anemia. Sensitivity and specificity for detection of normal and trait states were >99%. HemoTypeSC is an inexpensive (<$2 per test), accurate, and rapid point-of-care test that can be used in resource-limited regions with a high prevalence of SCD to provide timely diagnosis and support newborn screening programs.
Assuntos
Anemia Falciforme/diagnóstico , Imunoensaio , Sistemas Automatizados de Assistência Junto ao Leito , Adulto , Anemia Falciforme/sangue , Anemia Falciforme/epidemiologia , Anticorpos Monoclonais/imunologia , Criança , Países em Desenvolvimento , Diagnóstico Precoce , Feminino , Gana/epidemiologia , Hemoglobina A/análise , Hemoglobina C/análise , Doença da Hemoglobina C/sangue , Doença da Hemoglobina C/diagnóstico , Doença da Hemoglobina C/epidemiologia , Hemoglobina Falciforme/análise , Humanos , Imunoensaio/economia , Recém-Nascido , Masculino , Martinica/epidemiologia , Triagem Neonatal/economia , Triagem Neonatal/métodos , Prevalência , Estudos Prospectivos , Sensibilidade e Especificidade , Traço Falciforme/sangue , Traço Falciforme/diagnóstico , Traço Falciforme/epidemiologia , Método Simples-CegoRESUMO
OBJECTIVE: Due to incomplete management of vaso-occlusive pain episodes (VOE) in patients with sickle cell disease (SCD), we sought to determine if immersive VR would be feasible for inpatients. Secondarily, we hypothesized that a single VR session would improve the VOE pain experience. PROCEDURES: Consecutive patients with SCD eight years and older admitted for VOE were offered one 15-minute VR session, utilizing a relaxing underwater world specifically created for pediatric patients and to minimize potential simulator side effects. Safety and acceptability were evaluated with a brief survey before and after the session. Pain was evaluated utilizing the validated adolescent pediatric pain tool (APPT). Survey data and pain scores were analyzed using Wilcoxon signed-rank test as the data were nonnormally distributed. RESULTS: Thirty patients, 21 female, with a median age of 16 years were enrolled, the majority having hemoglobin SS disease. The VR session had no reported side effects; all patients requested VR again in the future. Median pain intensity (pre-VR 7.3 [interquartile range, IQR, 6.1, 8.8], post-VR 5.8 [4.7, 7.9]), number of affected body areas (pre-VR 3.0 [2.0, 7.8], post-VR 2.0 [0, 4.8]), and qualitative measures including sensory, affective, evaluative, and temporal pain domains were all statistically reduced (i.e., P ≤0.01). CONCLUSIONS: VR therapy was feasible in a cohort of patients with SCD admitted for VOE. In addition to standard therapies, VR may help reduce the pain experience with SCD VOE. Further study is required to determine the impact of VR therapy on opioid usage and length of stay in hospital.
Assuntos
Anemia Falciforme/terapia , Terapias Complementares/métodos , Manejo da Dor/métodos , Terapia de Exposição à Realidade Virtual/métodos , Adolescente , Anemia Falciforme/complicações , Criança , Estudos de Viabilidade , Feminino , Humanos , Masculino , Dor/etiologiaRESUMO
Approximately 3500 children with sickle cell disease (SCD) are born in Brazil each year, but the burden of SCD morbidity is not fully characterised. A large, multi-centre cohort was established to characterise clinical outcomes in the Brazilian SCD population and create the infrastructure to perform genotype-phenotype association studies. Eligible patients were randomly selected from participating sites and recruited at routine visits. A biorepository of blood samples was created and comprehensive demographic and clinical outcome data were entered in a centralized electronic database. Peripheral blood genome-wide single nucleotide polymorphism (SNP) genotyping was performed using a customized Transfusion Medicine (TM) Array. A total of 2795 participants at six Brazilian sites were enrolled between 2013 and 2015. The cohort included slight predominance of children <18 years (55·9%) and females (53·0%). Haemoglobin (Hb) SS was the most common SCD genotype (70·7%), followed by HbSC (23%), Sß0 (3·0%) and Sß+ (2·9%). SNP data from the TM Array were analysed to evaluate the genetic ancestry of the cohort and revealed significant admixture among the population. Demographics and clinical complications, stratified by age and SCD genotype, are summarized and future studies in this cohort are discussed.
Assuntos
Anemia Falciforme/epidemiologia , Genótipo , Linhagem , Adolescente , Anemia Falciforme/sangue , Anemia Falciforme/genética , Brasil , Criança , Pré-Escolar , Estudos de Coortes , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Hemoglobina Falciforme/análise , Humanos , Masculino , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Sickle cell anaemia (SCA) is a progressive vascular disease characterized by episodic vaso-occlusive pain. Despite the broad impact of inflammation on acute and chronic clinical manifestations of SCA, no directed anti-inflammatory therapies currently exist. Statins are cholesterol-lowering agents shown to confer protection from vascular injury by suppressing inflammation. We previously documented a reduction in soluble biomarkers of inflammation in patients with sickle cell disease treated with simvastatin. To determine the potential clinical efficacy of simvastatin, we treated 19 SCA patients with single daily dose simvastatin for 3 months and assessed changes from baseline in the frequency and intensity of diary-reported pain and levels of circulating nitric oxide metabolites (NOx), high sensitivity C-reactive protein (hs-CRP), vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), ICAM-3, E-selectin, and vascular endothelial growth factor (VEGF). Treatment with simvastatin resulted in a significant reduction in the frequency of pain (P = 0·0003), oral analgesic use (P = 0·003) and circulating hs-CRP (P = 0·003), soluble (s)E-selectin (P = 0·01), sICAM-1 (P = 0·02), sICAM-3 (P = 0·02) and sVEGF (P = 0·01). Simvastatin had no effect on pain intensity or levels of NOx, sP-selectin and sVCAM-1. The observed reductions in pain rate and markers of inflammation were greatest in subjects receiving hydroxycarbamide (HC), suggesting a synergistic effect of simvastatin. These results provide preliminary clinical data to support a larger trial of simvastatin in SCA.
Assuntos
Analgésicos/uso terapêutico , Anemia Falciforme/complicações , Dor/prevenção & controle , Sinvastatina/uso terapêutico , Adolescente , Adulto , Arteriopatias Oclusivas/complicações , Biomarcadores/metabolismo , Proteína C-Reativa/metabolismo , Criança , Selectina E/metabolismo , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , Óxido Nítrico/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adulto JovemRESUMO
Sickle cell disease (SCD) is a common and life threatening inherited blood disorder, affecting over 300,000 newborns per year. Over 75% of SCD births occur in sub-Saharan Africa, where the lack of timely and accurate diagnosis results in premature death within the first few years of life for a majority of affected infants. Current methods to diagnosis SCD require expensive laboratory equipment and reagents, and adequately trained laboratory personnel. In addition, test results are often delayed due to transport and batching of samples in a central laboratory. Financial and technical limitations often preclude any form of SCD laboratory testing at the local level in regions where SCD is most prevalent. There has been a recent surge of interest in addressing the global burden of SCD, including improving and optimizing diagnostic capacities. Largely stimulated by a funding opportunity from the NIH, several point-of-care diagnostics have been developed for SCD with a focus on developing devices that are inexpensive, simple, and practical in limited resource settings. In this manuscript, we review the global burden of SCA, including the rationale for the development of POC assays, and carefully review the POC devices currently in development.
Assuntos
Anemia Falciforme/diagnóstico , Sistemas Automatizados de Assistência Junto ao Leito , Anemia Falciforme/sangue , Eletroforese em Microchip/economia , Eletroforese em Microchip/instrumentação , Eletroforese em Microchip/métodos , Desenho de Equipamento , Saúde Global , Humanos , Imunoensaio/economia , Imunoensaio/instrumentação , Imunoensaio/métodos , Sistemas Automatizados de Assistência Junto ao Leito/economia , Smartphone/economia , Smartphone/instrumentaçãoRESUMO
BACKGROUND/AIMS: Patients with sickle cell anemia can experience recurrent pain episodes, which affect quality of life. The reported prevalence of pain is higher in studies using patient diaries than in healthcare facility utilization data. Determining Effects of Platelet Inhibition on Vaso-Occlusive Events was a multinational study that assessed the efficacy and safety of prasugrel in reducing the rate of vaso-occlusive events in children with sickle cell anemia (NCT01794000) and included an electronic patient-reported outcome diary to record pain occurrence. We aimed to capture diary completion rates and compliance in children who used the electronic patient-reported outcome diary during the Determining Effects of Platelet Inhibition on Vaso-Occlusive Events study and examine factors contributing to diary completion rates and compliance. METHODS: Daily electronic patient-reported outcome diary data were collected for up to 9 months in Determining Effects of Platelet Inhibition on Vaso-Occlusive Events participants aged 4 to <18 years in Africa, the Americas, Europe, and the Middle East. The questionnaires were available in 11 languages/dialects for collecting subjective (pain intensity, activity interference) and objective (study drug use, analgesic use, school attendance) data. Pain intensity was measured using the Faces Pain Scale-Revised. Data were entered by participants or caregivers and transferred wirelessly each day to a central database. Diary completion rates were the number of daily diary entries divided by the total number of expected daily diary entries. Percentages of participants who were compliant with the diary (≥80% diary completion) were calculated. RESULTS: A total of 311 participants received a diary; 268 provided diary data through Month 9. Diary completion rates and compliance were high throughout the collection period and across all groups and regions, despite no games being included on the device. For subjective data, the overall completion rate was 94.4%, and 92.6% of participants were compliant. For objective data, the overall completion rate was 93.3%, and 89.7% of participants were compliant. Completion rates and compliance differed significantly by age and region and were higher for 4 to <12 year olds and very much higher for participants from Africa and the Middle East. Caregivers almost always entered data for participants <6 years and rarely entered data for participants ≥12 years. Comparing participant-entered and caregiver-entered data, pain intensity score data were more consistent for 4 to <12 year olds than older children, but pain intensity scores for older children were higher when entered by caregivers. CONCLUSION: With appropriate design, participant training, and sufficient monitoring, an electronic patient-reported outcome diary can capture daily sickle cell-related pain data in large multinational studies. Providing a mechanism for caregiver reporting is particularly valuable for participants <6 years and may also facilitate compliance in older children who experience high levels of pain.
Assuntos
Anemia Falciforme/complicações , Medição da Dor/métodos , Dor/epidemiologia , Cooperação do Paciente/estatística & dados numéricos , Qualidade de Vida , Autorrelato/estatística & dados numéricos , Adolescente , África , Fatores Etários , Cuidadores/estatística & dados numéricos , Criança , Pré-Escolar , Computadores de Mão , Europa (Continente) , Feminino , Humanos , Masculino , Oriente Médio , Dor/etiologia , Método Simples-Cego , Estados UnidosRESUMO
Moyamoya syndrome occurs in sickle cell disease (SCD) as a secondary complication of large-artery stenosis. Moyamoya increases the risk of stroke, but its optimal management in SCD is not established. Encephaloduroarteriosynangiosis (EDAS) is a neurosurgical revascularization procedure for moyamoya whose use has been reported in SCD patients. We report the outcomes of 11 patients with SCD systematically evaluated for EDAS by a multidisciplinary team and compare the rate of stroke in patients who received EDAS to those who did not. Moyamoya syndrome was diagnosed by flow abnormalities on magnetic resonance angiography at median age of 8.2 years. Four patients deferred surgery. Seven patients underwent EDAS at median age of 19 years. There were no intraoperative complications, perioperative strokes, or deaths. Transient postoperative complications occurred in six cases (86%). On follow-up, three patients (43%) had no evidence of flow in their EDAS grafts, and one later developed a hemorrhagic stroke. Five EDAS patients (71%) had radiographically stable vasculopathy. Compared to the four patients who deferred surgery, the incidence of stroke in EDAS group was no different. The optimal use of EDAS in patients with SCD-associated moyamoya syndrome requires further investigation by a prospective, controlled clinical trial.
Assuntos
Anemia Falciforme/complicações , Anemia Falciforme/cirurgia , Doença de Moyamoya/etiologia , Doença de Moyamoya/cirurgia , Adolescente , Anemia Falciforme/fisiopatologia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Doença de Moyamoya/fisiopatologia , Estudos RetrospectivosRESUMO
BACKGROUND: Sickle cell disease (SCD) is an inherited blood disorder characterized by painful vaso-occlusive crises (VOC) with limited treatment options, particularly for children. Emerging knowledge of the pathophysiology of SCD suggests antiplatelet therapies may hold promise for treatment of VOC. Multiple small studies have evaluated antiplatelet agents on the frequency of VOC with varying results, but there has not been an adequately powered study to definitively determine the effect of antiplatelet agents on VOC. Prasugrel, a third-generation thienopyridine that irreversibly inhibits platelet activation and aggregation, is approved in adults with acute coronary syndrome managed with percutaneous coronary intervention. PROCEDURE: Determining Effects of Platelet Inhibition on Vaso-Occlusive Events (DOVE) is a double-blind, randomized study with planned enrollment of >220 children from 14 countries across the Americas, Europe, Asia, and Africa, designed to test the hypothesis that prasugrel reduces the rate of VOC in children with sickle cell anemia (SCA) (homozygous hemoglobin S [HbSS] and hemoglobin Sß(0) thalassemia [HbSß(0)]). Secondary study endpoints include reductions in rate and intensity of vaso-occlusive pain as recorded in daily electronic diaries. Safety assessments include incidence of hemorrhagic events requiring medical intervention and treatment-emergent adverse events. DOVE incorporates a dose-titration strategy to reduce potential bleeding risks inherent with antiplatelet therapy while maintaining blinded treatment assignment. CONCLUSIONS: DOVE presents a unique opportunity to determine whether antiplatelet therapy reduces frequency of patient-reported VOC and daily vaso-occlusive pain in a global study of children with SCA.
Assuntos
Anemia Falciforme/complicações , Anemia Falciforme/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Cloridrato de Prasugrel/uso terapêutico , Doenças Vasculares/prevenção & controle , Adolescente , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Dor/etiologia , Projetos de PesquisaRESUMO
Transfusion therapy is effective in the prevention and treatment of many complications of sickle cell disease (SCD). However, its benefits must be balanced against its risks, including delayed haemolytic transfusion reactions (DHTR). Not only is the relative rate of alloimmunization higher in patients with SCD than in other patient populations, but attendant risks associated with DHTR are even greater in SCD. Clinicians' awareness of DHTR events is poor because symptoms of DHTR mimic acute vaso-occlusive pain and immunohaematology findings are often negative. Transfusions delivered in the acute rather than elective setting appear to confer a higher risk of DHTR. Management of DHTR in SCD depends on the clinical severity, ranging from supportive care to immunosuppression, and optimization of erythropoiesis. DHTR must be considered in any recently transfused patient presenting with acute sickle cell pain. Meticulous documentation of transfusion and immunohaematology history is key. We anticipate an increase in DHTR events in SCD patients with the increasing use of red blood cell transfusion therapy.
Assuntos
Anemia Falciforme/complicações , Reação Transfusional , Reação Transfusional/etiologia , Reação Transfusional/terapia , Adolescente , Anemia Falciforme/epidemiologia , Anemia Falciforme/terapia , Gerenciamento Clínico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Reação Transfusional/diagnóstico , Reação Transfusional/epidemiologiaRESUMO
Osteonecrosis of the femoral head (ONFH) is a common complication of sickle cell disease (SCD). To examine the association between microparticles and ONFH in SCD, we compared plasma microparticle levels in 20 patients with and without ONFH. Microparticles were quantified using nanoparticle tracking analysis and found to be 2·3-fold higher in patients with ONFH compared to patients without ONFH, and 2·5-fold higher than in healthy controls. These results suggest that microparticles may be a clinically useful biomarker of ONFH in SCD. Further investigations are needed to determine the functional relevance of microparticles in the pathogenesis of ONFH in SCD.
Assuntos
Anemia Falciforme/complicações , Micropartículas Derivadas de Células/metabolismo , Necrose da Cabeça do Fêmur/etiologia , Necrose da Cabeça do Fêmur/metabolismo , Adolescente , Adulto , Anemia Falciforme/diagnóstico , Biomarcadores , Estudos de Casos e Controles , Feminino , Necrose da Cabeça do Fêmur/diagnóstico , Humanos , Masculino , Projetos Piloto , Adulto JovemRESUMO
BACKGROUND: Sickle cell disease is one of the most common inherited blood disorders. Universal screening and early intervention have significantly helped to reduce childhood mortality in high-resource countries. However, persons living in low-resource settings are often not diagnosed until late childhood when they present with clinical symptoms. In addition, confirmation of disease in affected individuals in the urgent care setting is limited in both high- and low-resource areas, often leading to delay in treatment. All of the current diagnostic methods rely on advanced laboratory systems and are often prohibitively expensive and time-consuming in low-resource settings. To address this need, the Sickle SCAN™ test has been developed to diagnose sickle cell disease and sickle cell trait at the point of care without electricity or advanced equipment. METHODS: This study was conducted to evaluate and validate the diagnostic accuracy of the Sickle SCAN™ test, a novel point of care test for sickle cell disease. Thus, we describe the laboratory testing and clinical validation of the Sickle SCAN™ test in individuals >1 year of age using capillary blood. The Sickle SCAN™ test was created using advanced, qualitative lateral flow technology using capillary blood to identify the presence of hemoglobin A, S, and C allowing for detection of results with the naked eye. RESULTS: Laboratory testing using venous blood demonstrated 99 % sensitivity and 99 % specificity for the diagnosis of HbSS, HbAS, HbSC, HbAC, and HbAA. Seventy-one subjects underwent capillary blood sampling at the point of care for further validation. This test detected the correct A, S, and C presence with an overall diagnostic accuracy of 99 % at the bedside. CONCLUSION: The Sickle SCAN™ test has the potential to significantly impact the diagnosis and treatment for sickle cell disease worldwide as well as enhance genetic counseling at the point of care. Further validation testing will be conducted in newborns in resource-poor settings in upcoming studies.
Assuntos
Anemia Falciforme/diagnóstico , Testes Imediatos , Adulto , Anemia Falciforme/sangue , Feminino , Humanos , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Sensibilidade e EspecificidadeRESUMO
Stroke is a devastating complication of sickle cell anemia (SCA), occurring in 11% of patients before age 20 years. Previous studies of sibling pairs have demonstrated a genetic component to the development of cerebrovascular disease in SCA, but few candidate genetic modifiers have been validated as having a substantial effect on stroke risk. We performed an unbiased whole-genome search for genetic modifiers of stroke risk in SCA. Genome-wide association studies were performed using genotype data from single-nucleotide polymorphism arrays, whereas a pooled DNA approach was used to perform whole-exome sequencing. In combination, 22 nonsynonymous variants were identified and represent key candidates for further in-depth study. To validate the association of these mutations with the risk for stroke, the 22 candidate variants were genotyped in an independent cohort of control patients (n = 231) and patients with stroke (n = 57) with SCA. One mutation in GOLGB1 (Y1212C) and another mutation in ENPP1 (K173Q) were confirmed as having significant associations with a decreased risk for stroke. These mutations were discovered and validated by an unbiased whole-genome approach, and future studies will focus on how these functional mutations may lead to protection from stroke in the context of SCA.
Assuntos
Anemia Falciforme/complicações , Proteínas de Membrana/genética , Diester Fosfórico Hidrolases/genética , Polimorfismo de Nucleotídeo Único , Pirofosfatases/genética , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/genética , Adolescente , Anemia Falciforme/genética , Criança , Pré-Escolar , Estudos de Coortes , Exoma , Estudo de Associação Genômica Ampla , Proteínas da Matriz do Complexo de Golgi , Humanos , Mutação , Fatores de RiscoRESUMO
BACKGROUND: Red cell (RBC) blood group alloimmunization remains a major problem in transfusion medicine. Patients with sickle cell disease (SCD) are at particularly high risk for developing alloantibodies to RBC antigens compared to other multiply transfused patient populations. Hemagglutination is the classical method used to test for blood group antigens, but depending on the typing methods and reagents used may result in discrepancies that preclude interpretation based on serologic reactivity alone. Molecular methods, including customized DNA microarrays, are increasingly used to complement serologic methods in predicting blood type. The purpose of this study was to determine the diversity and frequency of RH alleles in African Americans and to assess the performance of a DNA microarray for RH allele determination. MATERIAL AND METHODS: Two sets of samples were tested: (i) individuals with known variant Rh types and (ii) randomly selected African American donors and patients with SCD. Standard hemagglutination tests were used to establish the Rh phenotype, and cDNA- and gDNA-based analyses (sequencing, PCR-RFLP, and customized RHD and RHCE microarrays were used to predict the genotype). RESULTS: In a total of 829 samples (1658 alleles), 72 different alleles (40 RHD and 32 RHCE) were identified, 22 of which are novel. DNA microarrays detected all nucleotides probed, allowing for characterization of over 900 alleles. CONCLUSIONS: High-throughput DNA testing platforms provide a means to test a relatively large number of donors and potentially prevent immunization by changing the way antigen-negative blood is provided to patients. Because of the high RH allelic diversity found in the African American population, determination of an accurate Rh phenotype often requires DNA testing, in conjunction with serologic testing. Allele-specific microarrays offer a means to perform high-throughput donor Rh typing and serve as a valuable adjunct to serologic methods to predict Rh type. Because DNA microarrays test for only a fixed panel of allelic polymorphisms and cannot determine haplotype phase, alternative methods such as Next Generation Sequencing hold the greatest potential to accurately characterize blood group phenotypes and ameliorate the clinical course of multiply-transfused patients with sickle cell disease.