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The New England Journal of Medicine Aug 2014Silent cerebral infarcts are the most common neurologic injury in children with sickle cell anemia and are associated with the recurrence of an infarct (stroke or silent... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Silent cerebral infarcts are the most common neurologic injury in children with sickle cell anemia and are associated with the recurrence of an infarct (stroke or silent cerebral infarct). We tested the hypothesis that the incidence of the recurrence of an infarct would be lower among children who underwent regular blood-transfusion therapy than among those who received standard care.
METHODS
In this randomized, single-blind clinical trial, we randomly assigned children with sickle cell anemia to receive regular blood transfusions (transfusion group) or standard care (observation group). Participants were between 5 and 15 years of age, with no history of stroke and with one or more silent cerebral infarcts on magnetic resonance imaging and a neurologic examination showing no abnormalities corresponding to these lesions. The primary end point was the recurrence of an infarct, defined as a stroke or a new or enlarged silent cerebral infarct.
RESULTS
A total of 196 children (mean age, 10 years) were randomly assigned to the observation or transfusion group and were followed for a median of 3 years. In the transfusion group, 6 of 99 children (6%) had an end-point event (1 had a stroke, and 5 had new or enlarged silent cerebral infarcts). In the observation group, 14 of 97 children (14%) had an end-point event (7 had strokes, and 7 had new or enlarged silent cerebral infarcts). The incidence of the primary end point in the transfusion and observation groups was 2.0 and 4.8 events, respectively, per 100 years at risk, corresponding to an incidence rate ratio of 0.41 (95% confidence interval, 0.12 to 0.99; P=0.04).
CONCLUSIONS
Regular blood-transfusion therapy significantly reduced the incidence of the recurrence of cerebral infarct in children with sickle cell anemia. (Funded by the National Institute of Neurological Disorders and Stroke and others; Silent Cerebral Infarct Multi-Center Clinical Trial ClinicalTrials.gov number, NCT00072761, and Current Controlled Trials number, ISRCTN52713285.).
Topics: Adolescent; Anemia, Sickle Cell; Blood Transfusion; Cerebral Infarction; Child; Child, Preschool; Female; Ferritins; Hemoglobin, Sickle; Humans; Intelligence; Intention to Treat Analysis; Male; Secondary Prevention; Single-Blind Method; Transfusion Reaction
PubMed: 25140956
DOI: 10.1056/NEJMoa1401731 -
Blood Apr 2019New treatments directly targeting polymerization of sickle hemoglobin (HbS), the proximate event in the pathophysiology of sickle cell disease (SCD), are needed to... (Randomized Controlled Trial)
Randomized Controlled Trial
New treatments directly targeting polymerization of sickle hemoglobin (HbS), the proximate event in the pathophysiology of sickle cell disease (SCD), are needed to address the severe morbidity and early mortality associated with the disease. Voxelotor (GBT440) is a first-in-class oral therapy specifically developed to treat SCD by modulating the affinity of hemoglobin (Hb) for oxygen, thus inhibiting HbS polymerization and downstream adverse effects of hemolytic anemia and vaso-occlusion. GBT440-001 was a phase 1/2 randomized, double-blind, placebo-controlled, single and multiple ascending dose study of voxelotor in adult healthy volunteers and patients with SCD, followed by a single-arm, open-label extension study. This report describes results of voxelotor (500-1000 mg per day) in patients with sickle cell anemia. The study evaluated the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of voxelotor and established proof of concept by improving clinical measures of anemia, hemolysis, and sickling. Thirty-eight patients with SCD received 28 days of voxelotor 500, 700, or 1000 mg per day or placebo; 16 patients received 90 days of voxelotor 700 or 900 mg per day or placebo. Four patients from the 90-day cohort were subsequently enrolled in an extension study and treated with voxelotor 900 mg per day for 6 months. All patients who received multiple doses of voxelotor for ≥28 days experienced hematologic improvements including increased Hb and reduction in hemolysis and percentage of sickled red cells, supporting the potential of voxelotor to serve as a disease-modifying therapy for SCD. Voxelotor was well tolerated with no treatment-related serious adverse events and no evidence of tissue hypoxia. These trials were registered at www.clinicaltrials.gov as #NCT02285088 and #NCT03041909.
Topics: Adolescent; Adult; Anemia, Sickle Cell; Benzaldehydes; Case-Control Studies; Cohort Studies; Double-Blind Method; Female; Follow-Up Studies; Hematologic Agents; Humans; Male; Maximum Tolerated Dose; Middle Aged; Prognosis; Pyrazines; Pyrazoles; Tissue Distribution; Young Adult
PubMed: 30655275
DOI: 10.1182/blood-2018-08-868893 -
Blood Mar 2016
Topics: Adolescent; Blood Transfusion; Child; Erythropoiesis; Female; Hemoglobins, Abnormal; Homozygote; Humans; Hydrops Fetalis; Male; Survivors
PubMed: 26732098
DOI: 10.1182/blood-2015-10-673889 -
Blood Advances Aug 2023
Topics: Humans; Child; Hydroxyurea; Anemia, Sickle Cell; Antisickling Agents
PubMed: 37171600
DOI: 10.1182/bloodadvances.2023010099 -
Annals of Saudi Medicine Nov 1992In view of the high prevalence of clinical cases of sickle cell anemia, hemoglobin-H-disease and glucose-6-phosphate dehydrogenase deficiency in the archipelago of the...
In view of the high prevalence of clinical cases of sickle cell anemia, hemoglobin-H-disease and glucose-6-phosphate dehydrogenase deficiency in the archipelago of the State of Bahrain, a cord blood screening study was undertaken over a 15 month period (October 1984 to December 1985) to determine the gene frequency of these diseases. All the state hospitals participated in this study and a total of 10,327 cord blood samples obtained from babies born to Bahraini parents were analyzed. These presented over 80% of all neonates born in the country during the study period. The phenotypes detected included: AF, AF-Barts, SFA and SFA-Barts. Homozygous sickle cell disease was detected in 2.1%, and in 11.2%, the sickle cell trait was present. The incidence of alpha-thalassemia gene based on elevated Bart's hemoglobin was 24.3% in these neonates. The incidence of G6PD-deficiency was as high as 20.9%. Availability of these statistics has enabled the authorities in the Ministry of Health in collaboration with the National Hereditary Anemia Society to plan a comprehensive health care program for patients with hereditary diseases and their families.
PubMed: 17587043
DOI: 10.5144/0256-4947.1992.536 -
The Journal of Clinical Investigation Jun 1984A new hematologic syndrome with phenotypic features of mild Hb H disease was identified in three children from two unrelated black American families. Erythrocytes from...
A new hematologic syndrome with phenotypic features of mild Hb H disease was identified in three children from two unrelated black American families. Erythrocytes from each of these children contained Hb H (beta 4) and Hb Barts (gamma 4), as well as a slowly migrating hemoglobin fraction that made up 7-10% of the total hemoglobin. The parents of the affected children all showed mild thalassemia-like changes, with one of the parents in each family also expressing the variant hemoglobin; in the latter individuals the mutant alpha-chains made up less than 2% of the total, and were present mainly or exclusively in combination with delta-chains in the form of a slowly migrating Hb A2. Purified Hb Evanston showed an increased oxygen affinity, but its Bohr effect, cooperativity, and 2,3-diphosphoglycerate effect were normal. The mutant hemoglobin appeared to have normal stability to heat and to isopropanol, and the stability of its alpha-chain in an extended time course synthesis study also appeared to be similar to that of alpha A. However, the results from short-term globin synthesis studies, and from mRNA translation in vitro, suggest that the two types of alpha-chains were synthesized at relatively equal rates, with a major fraction of the newly synthesized variant alpha-chains undergoing rapid catabolism. The hematologic data taken in combination with DNA hybridization and globin synthesis findings indicate that the proposita in each of these families has the genotype--, alpha A/--, alpha Ev. These observations suggest that two separate mechanisms are contributing to the alpha-thalassemia-like expression of Hb Evanston : the newly synthesized alpha EV-chains are unstable and are subject to early proteolytic destruction; and the mutant alpha-allele is linked to an alpha-globin gene deletion.
Topics: Child, Preschool; Chromosome Deletion; Erythrocytes; Female; Genes; Genetic Variation; Globins; Hemoglobins, Abnormal; Humans; Infant; Macromolecular Substances; Male; Molecular Weight; Oxygen; Pedigree; Thalassemia
PubMed: 6725558
DOI: 10.1172/JCI111382 -
Indian Journal of Hematology & Blood... Jul 2021Screening of newborns for the presence of sickle hemoglobin (HbS) is aimed at reducing the morbidity and mortality associated with sickle cell disease in early...
Screening of Dry Blood Spots from Newborns by Two High Performance Liquid Chromatography (HPLC) Systems: A Comparison of Their Ability to Diagnose Both Sickle and Non-sickle Hemoglobinopathies.
Screening of newborns for the presence of sickle hemoglobin (HbS) is aimed at reducing the morbidity and mortality associated with sickle cell disease in early childhood. The high cost and limited availability of dedicated high performance liquid chromatography (HPLC) systems specially designed for screening of dry blood spots (DBS), however, restrict a wider application of this preventive approach. Therefore, we examined the ability of a commonly used HPLC system for detection of hemoglobinopathies in DBS samples in order to find an alternative for the dedicated newborn screening (NBS) HPLC system. DBS samples from 7522 newborns were first examined by Variant NBS HPLC system (Bio Rad, USA) for the presence of hemoglobinopathies. Positive samples were then analysed by Variant II system (Bio Rad, USA), another platform commonly used for hemoglobinopathy screening of anticoagulated blood samples. Eighty six newborns (1.1%) showed the presence of hemoglobinopathies (HbS 28, HbE 21, HbD 27, HbQ India 9 and Hb Barts 1) by Variant NBS system-all in heterozygous state. There was 100% correlation between the two sets of results obtained by the two HPLC systems. Newborns with HbQ India showed an additional Hb peak in HPLC resulting from combination of the abnormal alpha globin chain of HbQ India with the normal gamma chain of HbF-'HbF Q India'. Variant II HPLC system, used for routine hemoglobinopathy screening in anticoagulated , can also be used for screening samples. This obviates the need for a dedicated NBS system for hemoglobinopathy screening in newborns. We also demonstrated that both the systems are equally competent in detecting non-sickle Hb variants in DBS samples.
PubMed: 34267462
DOI: 10.1007/s12288-020-01352-2 -
British Journal of Haematology May 2020With the developing COVID-19 pandemic, patients with inherited anaemias require specific advice regarding isolation and changes to usual treatment schedules. The...
With the developing COVID-19 pandemic, patients with inherited anaemias require specific advice regarding isolation and changes to usual treatment schedules. The National Haemoglobinopathy Panel (NHP) has issued guidance on the care of patients with sickle cell disease, thalassaemia, Diamond Blackfan anaemia (DBA), congenital dyserythropoietic anaemia (CDA), sideroblastic anaemia, pyruvate kinase deficiency and other red cell enzyme and membrane disorders. Cascading of accurate information for clinicians and patients is paramount to preventing adverse outcomes, such as patients who are at increased risk of fulminant bacterial infection due to their condition or its treatment erroneously self-isolating if their fever is mistakenly attributed to a viral cause, delaying potentially life-saving antibiotic therapy. Outpatient visits should be minimised for most patients, however some, such as first transcranial dopplers for children with sickle cell anaemia should not be delayed as known risk of stroke will outweigh the unknown risk from COVID-19 infection. Blood transfusion programmes should be continued, but specific changes to usual clinical pathways can be instituted to reduce risk of patient exposure to COVID-19, as well as contingency planning for possible reductions in blood available for transfusions. Bone marrow transplants for these disorders should be postponed until further notice. With the current lack of evidence on the risk and complications of COVID-19 infection in these patients, national data collection is ongoing to record outcomes and eventually to identify predictors of disease severity, particularly important if further waves of infection travel through the population.
Topics: Anemia; Betacoronavirus; Blood Transfusion; Bone Marrow Transplantation; COVID-19; Coronavirus Infections; Cross Infection; Humans; Pandemics; Pneumonia, Viral; SARS-CoV-2
PubMed: 32330288
DOI: 10.1111/bjh.16687 -
PloS One 2020There are over 12,000 people with sickle cell disease (SCD) in the UK, and 4-12% of patients who develop Sickle Cell Nephropathy (SCN) progress to End Stage Renal...
There are over 12,000 people with sickle cell disease (SCD) in the UK, and 4-12% of patients who develop Sickle Cell Nephropathy (SCN) progress to End Stage Renal Disease (ESRD). Renal transplantation offers the best outcomes for these patients with but their access to transplantation is often limited. Regular automated exchange blood transfusions (EBT) reduce the complications of SCD and may improve outcomes. However, concerns over alloimmunisation limit its widespread implementation. In this retrospective multicenter study, data were collected on 34 SCD patients who received a kidney transplant across 6 London Hospitals between 1997 and 2017. 20/34 patients were on an EBT program, pre or post renal transplantation. Overall patient and graft survival were inferior to contemporaneous UK data in the ESRD population as a whole, a finding which is well-recognised. However, patient survival (CI 95%, p = 0.0032), graft survival and graft function were superior at all time-points in those who received EBT versus those who did not. 4/20 patients (20%) on EBT developed de novo donor specific antibodies (DSAs). 3/14 patients (21%) not on EBT developed de novo DSAs. The incidence of rejection in those on EBT was 5/18 (28%), as compared with 7/13 (54%) not on EBT. In conclusion, our data, while limited by an inevitably small sample size and differences in the date of transplantation, do suggest that long-term automated EBT post renal transplant is effective and safe, with improvement in graft and patient outcomes and no increase in antibody formation or graft rejection.
Topics: Adult; Anemia, Sickle Cell; Combined Modality Therapy; Exchange Transfusion, Whole Blood; Female; Graft Survival; Humans; Kaplan-Meier Estimate; Kidney Failure, Chronic; Kidney Transplantation; London; Male; Middle Aged; Retrospective Studies; Treatment Outcome; Young Adult
PubMed: 32790687
DOI: 10.1371/journal.pone.0236998 -
Orphanet Journal of Rare Diseases Feb 2020Thalassaemia is a potentially life-threatening yet preventable inherited hemoglobin disorder. Understanding local socio-cultural context and level of public awareness...
BACKGROUND
Thalassaemia is a potentially life-threatening yet preventable inherited hemoglobin disorder. Understanding local socio-cultural context and level of public awareness about thalassaemia is pivotal for selecting effective prevention strategies. This study attempted to assess knowledge and perceptions about thalassaemia among college students in Bangladesh.
METHODS
A supervised cross-sectional survey was conducted on 1578 college students using a self-administered structured questionnaire. The survey took place from 15 February 2018 to 17 March 2018 in the Jamalpur district in Bangladesh. Besides the attitude-related questions, the study asked a total of 12 knowledge-related questions, which were scored on a scale of 0-12 points.
RESULTS
Over two-thirds (67%) of the college students had never heard of thalassaemia. The urban-rural dichotomy was observed among those familiar with the term; (46.4% from urban vs. 25.8% from rural colleges). A similar pattern was observed for knowledge score; 5.07 ± 1.87 for students from the urban colleges compared to 3.69 ± 2.23 for rural colleges. Students from the science background had the highest knowledge score (5.03 ± 1.85), while those from arts and humanities background scored lowest (3.66 ± 2.3). Nearly 40% of the students were not sure or did not want to be a friend of a thalassaemia patient. Whereas 39% either declined or remained hesitant about helping thalassaemia patients by donating blood. However, most of the respondents (88%) showed a positive attitude towards 'premarital' screening to prevent thalassaemia.
CONCLUSIONS
This study has identified critical knowledge gaps and societal misperceptions about thalassaemia. A better understanding of these aspects will be pivotal for disseminating thalassaemia related information. As the first study of this kind in Bangladesh, findings from this study has generated baseline data that would contribute to developing effective intervention strategies in Bangladesh and other countries with a comparable socio-cultural setting.
Topics: Bangladesh; Cross-Sectional Studies; Health Knowledge, Attitudes, Practice; Humans; Students; Surveys and Questionnaires; Thalassemia
PubMed: 32085790
DOI: 10.1186/s13023-020-1323-y