1.
A Systematic review on diagnostic methods of red cell membrane disorders in Asia
Silva R, Amarasinghe D, Perera S, Premawardhena A
International journal of laboratory hematology. 2022
Abstract
Membranopathies are a group of inherited blood disorders where the diagnosis could form a challenge due to phenotype-genotype heterogeneity. In this review, the usage and limitations of diagnostic methods for membranopathies in Asian countries were evaluated. A systematic review was done using articles from PubMed, Google Scholar, and EBSCO from 2000 to 2020. Thirty-six studies conducted in seven Asian countries had used different diagnostic methods to confirm membranopathies. In 58.3% of studies, full blood count (FBC), reticulocyte count, and peripheral blood smear (PBS) were used in preliminary diagnosis. The combination of the above three with osmotic fragility (OF) test was used in 38.8%. The flowcytometric osmotic fragility (FC-OF) test was used in 27.7% where it showed high sensitivity (92%-100%) and specificity (96%-98%). The eosin-5-maleimide (EMA) assay was used in 68.1% with high sensitivity (95%-100%) and specificity (93%-99.6%). About 36.1% of studies had used sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) as a further diagnostic method to detect defective proteins. Genetic analysis to identify mutations was done using Sanger sequencing, next-generation sequencing (NGS), and whole-exome sequencing (WES) in 33.3%, 22.2%, and 13.8% of studies, respectively. The diagnostic yield of NGS ranged from 63% to 100%. Proteomics was used in 5.5% of studies to support the diagnosis of membranopathies. A single method could not diagnose all membranopathies. Next-generation sequencing, Sanger sequencing, and proteomics will supplement the well-established screening and confirmatory methods, but not replace them in hereditary hemolytic anemia assessment.
2.
A randomised double-blind placebo-controlled clinical trial of oral hydroxyurea for transfusion-dependent β-thalassaemia
Yasara N, Wickramarathne N, Mettananda C, Silva I, Hameed N, Attanayaka K, Rodrigo R, Wickramasinghe N, Perera L, Manamperi A, et al
Scientific reports. 2022;12(1):2752
Abstract
Hydroxyurea is an antimetabolite drug that induces fetal haemoglobin in sickle cell disease. However, its clinical usefulness in β-thalassaemia is unproven. We conducted a randomised, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of hydroxyurea in transfusion-dependent β-thalassaemia. Sixty patients were assigned 1:1 to oral hydroxyurea 10-20 mg/kg/day or placebo for 6 months by stratified block randomisation. Hydroxyurea treatment did not alter the blood transfusion volume overall. However, a significantly higher proportion of patients on hydroxyurea showed increases in fetal haemoglobin percentage (89% vs. 59%; p < 0.05) and reductions in erythropoietic stress as measured by soluble transferrin receptor concentration (79% vs. 40%; p < 0.05). Based on fetal haemoglobin induction (> 1.5%), 44% of patients were identified as hydroxyurea-responders. Hydroxyurea-responders, required significantly lower blood volume (77 ± SD27ml/kg) compared to hydroxyurea-non-responders (108 ± SD24ml/kg; p < 0.01) and placebo-receivers (102 ± 28ml/kg; p < 0.05). Response to hydroxyurea was significantly higher in patients with HbE β-thalassaemia genotype (50% vs. 0%; p < 0.01) and Xmn1 polymorphism of the γ-globin gene (67% vs. 27%; p < 0.05). We conclude that oral hydroxyurea increased fetal haemoglobin percentage and reduced erythropoietic stress of ineffective erythropoiesis in patients with transfusion-dependent β-thalassaemia. Hydroxyurea reduced the transfusion burden in approximately 40% of patients. Response to hydroxyurea was higher in patients with HbE β-thalassaemia genotype and Xmn1 polymorphism of the γ-globin gene.
3.
A comprehensive review of hydroxyurea for β-haemoglobinopathies: the role revisited during COVID-19 pandemic
Yasara N, Premawardhena A, Mettananda S
Orphanet Journal of Rare Diseases. 2021;16(1):114
Abstract
BACKGROUND Hydroxyurea is one of the earliest drugs that showed promise in the management of haemoglobinopathies that include β-thalassaemia and sickle cell disease. Despite this, many aspects of hydroxyurea are either unknown or understudied; specifically, its usefulness in β-thalassaemia major and haemoglobin E β-thalassaemia is unclear. However, during COVID-19 pandemic, it has become a valuable adjunct to transfusion therapy in patients with β-haemoglobinopathies. In this review, we aim to explore the available in vitro and in vivo mechanistic data and the clinical utility of hydroxyurea in β-haemoglobinopathies with a special emphasis on its usefulness during the COVID-19 pandemic. MAIN BODY Hydroxyurea is an S-phase-specific drug that reversibly inhibits ribonucleoside diphosphate reductase enzyme which catalyses an essential step in the DNA biosynthesis. In human erythroid cells, it induces the expression of γ-globin, a fetal globin gene that is suppressed after birth. Through several molecular pathways described in this review, hydroxyurea exerts many favourable effects on the haemoglobin content, red blood cell indices, ineffective erythropoiesis, and blood rheology in patients with β-haemoglobinopathies. Currently, it is recommended for sickle cell disease and non-transfusion dependent β-thalassaemia. A number of clinical trials are ongoing to evaluate its usefulness in transfusion dependent β-thalassaemia. During the COVID-19 pandemic, it was widely used as an adjunct to transfusion therapy due to limitations in the availability of blood and logistical disturbances. Thus, it has become clear that hydroxyurea could play a remarkable role in reducing transfusion requirements of patients with haemoglobinopathies, especially when donor blood is a limited resource. CONCLUSION Hydroxyurea is a well-tolerated oral drug which has been in use for many decades. Through its actions of reversible inhibition of ribonucleoside diphosphate reductase enzyme and fetal haemoglobin induction, it exerts many favourable effects on patients with β-haemoglobinopathies. It is currently approved for the treatment of sickle cell disease and non-transfusion dependent β-thalassaemia. Also, there are various observations to suggest that hydroxyurea is an important adjunct in the treatment of transfusion dependent β-thalassaemia which should be confirmed by randomised clinical trials.
4.
Hydroxyurea and blood transfusion therapy for Sickle cell disease in South Asia: inconsistent treatment of a neglected disease
Darshana T, Rees D, Premawardhena A
Orphanet journal of rare diseases. 2021;16(1):148
Abstract
BACKGROUND Hydroxyurea and blood transfusion therapies remain the main therapeutic strategies for Sickle cell disease. Preliminary data suggest substantial variation and inconsistencies in practice of these two therapeutic modalities in South Asia. In this systematic review we searched Medline, Cochrane library and Scopus for articles on usage of hydroxyurea and blood transfusion therapies for sickle cell disease in South Asia published in English between October 2005 and October 2020. RESULTS We selected 41 papers: 33 from India, 3 from Sri Lanka, 2 each from Pakistan and Bangladesh and one from Nepal. Only 14 prospective trials focused on hydroxyurea therapy from which majority (n = 10; 71.4%) adopted fixed low dose (10 mg/kg/day) regimen. With hydroxyurea therapy, 12 and 9 studies reported significant reductions in vaso-occlusive crises and transfusion requirement respectively. Severe anaemia (haemoglobin level < 6-7 g/dl) was the commonest indicator (n = 8) for transfusion therapy followed by vaso-occlusive crisis. CONCLUSIONS Published data on the hydroxyurea and transfusion therapies in South Asia are limited and heterogeneous. A clear gap of knowledge exists about the nature of the sickle cell disease in the Indian subcontinent particularly from countries outside India necessitating further evidence-based assessments and interventions.