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International Health Nov 2023Thalassemia is a major health challenge in the United Arab Emirates (UAE), however previous studies have focused on genetics and molecular characterisation while...
Thalassemia is a major health challenge in the United Arab Emirates (UAE), however previous studies have focused on genetics and molecular characterisation while neglecting culture and society. In this commentary, we discuss how tradition and religion in the UAE (e.g. consanguinity, endogamy, illegality of abortion and in vitro fertilisation, adoption restrictions), and limited academic research, affect the prevention and management of the blood disorder. It is suggested that changing attitudes towards traditional marriage practices, education and awareness campaigns targeting families and young people, and earlier genetic testing, are culturally acceptable solutions to curbing the high incidence of thalassemia in the UAE.
Topics: Humans; Adolescent; United Arab Emirates; Thalassemia; Educational Status
PubMed: 36810680
DOI: 10.1093/inthealth/ihad011 -
Annals of Hematology Jul 2023Population-based studies and case reports suggest that there may be an increased risk of acute leukemia associated with sickle cell disease (SCD). Following the... (Review)
Review
Population-based studies and case reports suggest that there may be an increased risk of acute leukemia associated with sickle cell disease (SCD). Following the description of a new case report, an extensive review of the literature identified 51 previously described cases. Most cases study showed myelodysplastic features confirmed, when available, by genetic markers such as chromosome 5 and/or chromosome 7 abnormalities and TP53 gene mutations. The increased risk of leukemogenesis is certainly multifactorial and related to the pathophysiologic mechanisms of the clinical manifestations of SCD. Chronic hemolysis and secondary hemochromatosis may cause increased chronic inflammation, resulting in persistent marrow stress, which could potentially compromise the genomic stability of the hematopoietic stem cells generating genomic damage and somatic mutations over the course of SCD and its treatment, resulting in a clone that led to acute myeloid leukemia.
Topics: Humans; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Chromosome Aberrations; Bone Marrow; Anemia, Sickle Cell
PubMed: 37269388
DOI: 10.1007/s00277-023-05294-3 -
Orphanet Journal of Rare Diseases May 2024Brain injury in hereditary hemoglobinopathies is commonly attributed to anemia-related relative hypoperfusion in terms of impaired oxygen blood supply. Supratentorial...
BACKGROUND
Brain injury in hereditary hemoglobinopathies is commonly attributed to anemia-related relative hypoperfusion in terms of impaired oxygen blood supply. Supratentorial and infratentorial vascular watershed regions seem to be especially vulnerable, but data are very scarce.
AIMS
We investigated a large beta-thalassemia sample with arterial spin labeling in order to characterize regional perfusion changes and their correlation with phenotype and anemia severity.
METHODS
We performed a multicenter single-scanner cross-sectional 3T-MRI study analyzing non-invasively the brain perfusion in 54 transfusion-dependent thalassemia (TDT), 23 non-transfusion-dependent thalassemia (NTDT) patients and 56 Healthy Controls (HC). Age, hemoglobin levels, and cognitive functioning were recorded.
RESULTS
Both TDT and NTDT patients showed globally increased brain perfusion values compared to healthy controls, while no difference was found between patient subgroups. Using age and sex as covariates and scaling the perfusion maps for the global cerebral blood flow, beta-thalassemia patients showed relative hyperperfusion in supratentorial/infratentorial watershed regions. Perfusion changes correlated with hemoglobin levels (p = 0.013) and were not observed in the less severely anemic patients (hemoglobin level > 9.5 g/dL). In the hyperperfused regions, white matter density was significantly decreased (p = 0.0003) in both patient subgroups vs. HC. In NTDT, white matter density changes correlated inversely with full-scale Intelligence Quotient (p = 0.007) while in TDT no correlation was found.
CONCLUSION
Relative hyperperfusion of watershed territories represents a hemodynamic hallmark of beta-thalassemia anemia challenging previous hypotheses of brain injury in hereditary anemias. A careful management of anemia severity might be crucial for preventing structural white matter changes and subsequent long-term cognitive impairment.
Topics: Humans; beta-Thalassemia; Male; Female; Adult; Magnetic Resonance Imaging; Cross-Sectional Studies; Brain; Young Adult; Cerebrovascular Circulation; Adolescent; Middle Aged; Child
PubMed: 38773534
DOI: 10.1186/s13023-024-03194-x -
International Journal of Molecular... Nov 2023The design of clinical protocols and the selection of drugs with appropriate posology are critical parameters for therapeutic outcomes. Optimal therapeutic protocols... (Review)
Review
The design of clinical protocols and the selection of drugs with appropriate posology are critical parameters for therapeutic outcomes. Optimal therapeutic protocols could ideally be designed in all diseases including for millions of patients affected by excess iron deposition (EID) toxicity based on personalised medicine parameters, as well as many variations and limitations. EID is an adverse prognostic factor for all diseases and especially for millions of chronically red-blood-cell-transfused patients. Differences in iron chelation therapy posology cause disappointing results in neurodegenerative diseases at low doses, but lifesaving outcomes in thalassemia major (TM) when using higher doses. In particular, the transformation of TM from a fatal to a chronic disease has been achieved using effective doses of oral deferiprone (L1), which improved compliance and cleared excess toxic iron from the heart associated with increased mortality in TM. Furthermore, effective L1 and L1/deferoxamine combination posology resulted in the complete elimination of EID and the maintenance of normal iron store levels in TM. The selection of effective chelation protocols has been monitored by MRI T2* diagnosis for EID levels in different organs. Millions of other iron-loaded patients with sickle cell anemia, myelodysplasia and haemopoietic stem cell transplantation, or non-iron-loaded categories with EID in different organs could also benefit from such chelation therapy advances. Drawbacks of chelation therapy include drug toxicity in some patients and also the wide use of suboptimal chelation protocols, resulting in ineffective therapies. Drug metabolic effects, and interactions with other metals, drugs and dietary molecules also affected iron chelation therapy. Drug selection and the identification of effective or optimal dose protocols are essential for positive therapeutic outcomes in the use of chelating drugs in TM and other iron-loaded and non-iron-loaded conditions, as well as general iron toxicity.
Topics: Humans; Deferiprone; Deferoxamine; Pyridones; Iron Chelating Agents; Iron Overload; Chelation Therapy; Iron; beta-Thalassemia; Drug Therapy, Combination
PubMed: 38069073
DOI: 10.3390/ijms242316749 -
Blood Advances Jun 2023Gain-of-function mutations in PIEZO1 cause dehydrated hereditary stomatocytosis (DHS) or hereditary xerocytosis, an autosomal dominant hemolytic anemia characterized by...
Gain-of-function mutations in PIEZO1 cause dehydrated hereditary stomatocytosis (DHS) or hereditary xerocytosis, an autosomal dominant hemolytic anemia characterized by high reticulocyte count, a tendency to macrocytosis, and mild jaundice, as well as by other variably penetrant clinical features, such as perinatal edema, severe thromboembolic complications after splenectomy, and hepatic iron overload. PIEZO1 mutations in DHS lead to slowed inactivation kinetics of the ion channel and/or facilitation of channel opening in response to physiological stimuli. To characterize the alterations of red blood cell proteome in patients with mutated PIEZO1, we used a differential approach to compare the proteome of patients with DHS (16 patients from 13 unrelated ancestries) vs healthy individuals. We identified new components in the regulation of the complex landscape of erythrocytes ion and volume balance mediated by PIEZO1. Specifically, the main impaired processes in patients with DHS were ion homeostasis, transmembrane transport, regulation of vesicle-mediated transport, and the proteasomal catabolic process. Functional assays demonstrated coexpression of PIEZO1 and band 3 when PIEZO1 was activated. Moreover, the alteration of the vesicle-mediated transport was functionally demonstrated by an increased vesiculation rate in patients with DHS compared with healthy controls. This finding also provides an explanation of the pathogenetic mechanism underlying the increased thrombotic rate observed in these patients. Finally, the newly identified proteins, involved in the intracellular signaling pathways altered by PIEZO1 mutations, could be used in the future as potential druggable targets in DHS.
Topics: Pregnancy; Female; Humans; Gain of Function Mutation; Anemia, Hemolytic, Congenital; Proteome; Hydrops Fetalis; Erythrocytes; Mutation; Ion Channels
PubMed: 36595486
DOI: 10.1182/bloodadvances.2022008673 -
PloS One 2023Sickle cell disease (SCD) is an inherited blood disorder in which sickle hemoglobin (HbS) polymerizes, leading to red blood cell sickling and chronic hemolytic anemia,... (Meta-Analysis)
Meta-Analysis
Sickle cell disease (SCD) is an inherited blood disorder in which sickle hemoglobin (HbS) polymerizes, leading to red blood cell sickling and chronic hemolytic anemia, vaso-occlusive crises, and end-organ damage associated with early mortality. Despite standard of care, patients with SCD still experience complications and early mortality, highlighting remaining unmet treatment needs. Voxelotor is a first-in-class HbS polymerization inhibitor approved by the US Food and Drug Administration as a treatment for SCD and by the European Medicines Agency for hemolytic anemia due to SCD. In clinical studies, voxelotor has been shown to increase hemoglobin (Hb) and decrease hemolytic markers in patients with SCD. The objective of this study was to estimate the impact of voxelotor on the burden of SCD in France using a modeling approach, accounting for its anticipated adoption and diffusion over the next 5 years. We designed a sequential multi-cohort model to project and compare the cumulative incidence of SCD complications over a 20-year time horizon in a world with and without voxelotor. A distribution of patients was simulated across various levels of Hb response based on the phase 3 HOPE trial results, and relative risk reduction was adjusted using published meta-analysis results that projected risk reduction due to a 1 g/dL increase in Hb. In 6100 modeled patients with SCD treated with voxelotor, the model projected the number of deaths to decrease by 39.4%, with an increase of 1.8% in life-years gained. The model also projected life expectancy to increase by 15.8%, and incident cases of stroke, pulmonary hypertension, and chronic kidney disease to decrease by 19.8%, 24.5%, and 25.1%, respectively. The model suggests that improving Hb using a treatment such as voxelotor may have a positive public health impact by reducing the burden of SCD for patients and the healthcare system.
Topics: United States; Humans; Public Health; Anemia, Sickle Cell; Benzaldehydes; Hemoglobin, Sickle; France
PubMed: 37703228
DOI: 10.1371/journal.pone.0291211 -
BMC Medicine Oct 2023Single low-dose primaquine (SLDPQ) effectively blocks the transmission of Plasmodium falciparum malaria, but anxiety remains regarding its haemolytic potential in... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Single low-dose primaquine (SLDPQ) effectively blocks the transmission of Plasmodium falciparum malaria, but anxiety remains regarding its haemolytic potential in patients with glucose-6-phopshate dehydrogenase (G6PD) deficiency. We, therefore, examined the independent effects of several factors on haemoglobin (Hb) dynamics in falciparum-infected children with a particular interest in SLDPQ and G6PD status.
METHODS
This randomised, double-blind, placebo-controlled, safety trial was conducted in Congolese and Ugandan children aged 6 months-11 years with acute uncomplicated P. falciparum and day (D) 0 Hbs ≥ 6 g/dL who were treated with age-dosed SLDPQ/placebo and weight-dosed artemether lumefantrine (AL) or dihydroartemisinin piperaquine (DHAPP). Genotyping defined G6PD (G6PD c.202T allele), haemoglobin S (HbS), and α-thalassaemia status. Multivariable linear and logistic regression assessed factor independence for continuous Hb parameters and Hb recovery (D42 Hb > D0 Hb), respectively.
RESULTS
One thousand one hundred thirty-seven children, whose median age was 5 years, were randomised to receive: AL + SLDPQ (n = 286), AL + placebo (286), DHAPP + SLDPQ (283), and DHAPP + placebo (282). By G6PD status, 284 were G6PD deficient (239 hemizygous males, 45 homozygous females), 119 were heterozygous females, 418 and 299 were normal males and females, respectively, and 17 were of unknown status. The mean D0 Hb was 10.6 (SD 1.6) g/dL and was lower in younger children with longer illnesses, lower mid-upper arm circumferences, splenomegaly, and α-thalassaemia trait, who were either G6PDd or heterozygous females. The initial fractional fall in Hb was greater in younger children with higher D0 Hbs and D0 parasitaemias and longer illnesses but less in sickle cell trait. Older G6PDd children with lower starting Hbs and greater factional falls were more likely to achieve Hb recovery, whilst lower D42 Hb concentrations were associated with younger G6PD normal children with lower fractional falls, sickle cell disease, α-thalassaemia silent carrier and trait, and late treatment failures. Ten blood transfusions were given in the first week (5 SLDPQ, 5 placebo).
CONCLUSIONS
In these falciparum-infected African children, posttreatment Hb changes were unaffected by SLDPQ, and G6PDd patients had favourable posttreatment Hb changes and a higher probability of Hb recovery. These reassuring findings support SLDPQ deployment without G6PD screening in Africa.
TRIAL REGISTRATION
The trial is registered at ISRCTN 11594437.
Topics: Male; Female; Humans; Child; Child, Preschool; Primaquine; Antimalarials; alpha-Thalassemia; Artemether, Lumefantrine Drug Combination; Artemether; Malaria, Falciparum; Hemoglobins; Glucosephosphate Dehydrogenase Deficiency; Plasmodium falciparum
PubMed: 37858129
DOI: 10.1186/s12916-023-03105-0 -
Biosensors Feb 2024Hemoglobin (Hb) disorders are among the most common monogenic diseases affecting nearly 7% of the world population. Among various Hb disorders, approximately 1.5% of the...
Hemoglobin (Hb) disorders are among the most common monogenic diseases affecting nearly 7% of the world population. Among various Hb disorders, approximately 1.5% of the world population carries -thalassemia (-Thal), affecting 40,000 newborns every year. Early screening and a timely diagnosis are essential for -thalassemia patients for the prevention and management of later clinical complications. However, in Africa, Southern Europe, the Middle East, and Southeast Asia, where -thalassemia is most prevalent, the diagnosis and screening for -thalassemia are still challenging due to the cost and logistical burden of laboratory diagnostic tests. Here, we present Gazelle, which is a paper-based microchip electrophoresis platform that enables the first point-of-care diagnostic test for -thalassemia. We evaluated the accuracy of Gazelle for the -Thal screening across 372 subjects in the age range of 4-63 years at Apple Diagnostics lab in Mumbai, India. Additionally, 30 blood samples were prepared to mimic -Thal intermediate and -Thal major samples. Gazelle-detected levels of Hb A, Hb F, and Hb A demonstrated high levels of correlation with the results reported through laboratory gold standard high-performance liquid chromatography (HPLC), yielding a Pearson correlation coefficient = 0.99. This ability to obtain rapid and accurate results suggests that Gazelle may be suitable for the large-scale screening and diagnosis of -Thal.
Topics: Infant, Newborn; Humans; Animals; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged; beta-Thalassemia; Antelopes; Hemoglobinopathies; Chromatography, High Pressure Liquid
PubMed: 38392002
DOI: 10.3390/bios14020083 -
Cells Jan 2024Besides visceral heterotaxia, null mouse embryos exhibit general edema and perinatal lethality. In humans, congenital chylothorax (CCT) is a frequent cause of fetal...
Besides visceral heterotaxia, null mouse embryos exhibit general edema and perinatal lethality. In humans, congenital chylothorax (CCT) is a frequent cause of fetal hydrops. In 2021, Correa and colleagues reported ultrarare compound heterozygous variants in exhibiting in two consecutive fetuses with severe hydrops, implicating a direct role of in fetal hydrops formation. Here, we performed an exome survey and identified ultrarare compound heterozygous variants in in two of the five case-parent trios with CCT. In one family, the affected carried the ultrarare missense variants c.1543G>A(p.Gly515Arg) and c.3845T>A(p.Val1282Glu). In the other family, the affected carried the ultrarare loss-of-function variant (LoF) c.863delA(p.Asn288Thrfs*3) and the ultrarare missense variant c.6549G>T(p.Gln2183His). Investigation of the variants' impact on PKD1L1 protein localization suggests the missense variants cause protein dysfunction and the LoF variant causes protein mislocalization. Further analysis of mutant mouse embryos revealed about 20% of embryos display general edema and pleural effusion at 14.5 dpc. Immunofluorescence staining at 14.5 dpc in embryos displayed both normal and massively altered lymphatic vessel morphologies. Together, our studies suggest the implication of in congenital lymphatic anomalies, including CCTs.
Topics: Animals; Female; Humans; Mice; Pregnancy; Chylothorax; Fetus; Genetic Diseases, X-Linked; Hydrops Fetalis; Membrane Proteins; Mice, Knockout
PubMed: 38247840
DOI: 10.3390/cells13020149 -
JAMA Pediatrics Aug 2023Little is known about the association between sickle cell disease (SCD) and severe maternal morbidity (SMM). (Comparative Study)
Comparative Study
IMPORTANCE
Little is known about the association between sickle cell disease (SCD) and severe maternal morbidity (SMM).
OBJECTIVE
To examine the association of SCD with racial disparities in SMM and with SMM among Black individuals.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study was a retrospective population-based investigation of individuals with and without SCD in 5 states (California [2008-2018], Michigan [2008-2020], Missouri [2008-2014], Pennsylvania [2008-2014], and South Carolina [2008-2020]) delivering a fetal death or live birth. Data were analyzed between July and December 2022.
EXPOSURE
Sickle cell disease identified during the delivery admission by using International Classification of Diseases, Ninth Revision and Tenth Revision codes.
MAIN OUTCOMES AND MEASURES
The primary outcomes were SMM including and excluding blood transfusions during the delivery hospitalization. Modified Poisson regression was used to estimate risk ratios (RRs) adjusted for birth year, state, insurance type, education, maternal age, Adequacy of Prenatal Care Utilization Index, and obstetric comorbidity index.
RESULTS
From a sample of 8 693 616 patients (mean [SD] age, 28.5 [6.1] years), 956 951 were Black individuals (11.0%), of whom 3586 (0.37%) had SCD. Black individuals with SCD vs Black individuals without SCD were more likely to have Medicaid insurance (70.2% vs 64.6%), to have a cesarean delivery (44.6% vs 34.0%), and to reside in South Carolina (25.2% vs 21.5%). Sickle cell disease accounted for 8.9% and for 14.3% of the Black-White disparity in SMM and nontransfusion SMM, respectively. Among Black individuals, SCD complicated 0.37% of the pregnancies but contributed to 4.3% of the SMM cases and to 6.9% of the nontransfusion SMM cases. Among Black individuals with SCD compared with those without, the crude RRs of SMM and nontransfusion SMM during the delivery hospitalization were 11.9 (95% CI, 11.3-12.5) and 19.8 (95% CI, 18.5-21.2), respectively, while the adjusted RRs were 3.8 (95% CI, 3.3-4.5) and 6.5 (95% CI, 5.3-8.0), respectively. The SMM indicators that incurred the highest adjusted RRs included air and thrombotic embolism (4.8; 95% CI, 2.9-7.8), puerperal cerebrovascular disorders (4.7; 95% CI, 3.0-7.4), and blood transfusion (3.7; 95% CI, 3.2-4.3).
CONCLUSIONS AND RELEVANCE
In this retrospective cohort study, SCD was found to be an important contributor to racial disparities in SMM and was associated with an elevated risk of SMM among Black individuals. Efforts from the research community, policy makers, and funding agencies are needed to advance care among individuals with SCD.
Topics: Adult; Female; Humans; Pregnancy; Anemia, Sickle Cell; Black People; Cohort Studies; Morbidity; Retrospective Studies; United States; Pregnancy Outcome; Pregnancy Complications, Hematologic; White; Health Status Disparities
PubMed: 37273202
DOI: 10.1001/jamapediatrics.2023.1580