Cohort profile: targeted antenatal screening for haemoglobinopathies in Basel.

PURPOSE: The pregnancy cohort was established to examine the prevalence and variety of haemoglobinopathies in a high-risk group of pregnant women. PARTICIPANTS: The pregnancy cohort is located in the Department of Obstetrics and Antenatal Care, University Hospital of Basel. The pregnant women were recruited in the first trimester between June 2015 and May 2019. Family origin questionnaires were used to screen pregnant women for the risk of a haemoglobin variant. Based on the questionnaire, pregnant women were divided into two groups: women with a high risk and women with a low risk of a haemoglobin variant. In women with a high risk, red blood cell indices, iron status and chromatography were conducted. FINDINGS TO DATE: 1785 pregnant women were recruited. Out of the 1785 women, 929 were identified as a part of the high-risk group. Due to the missing data of 74 pregnant women with a high risk, the final analysis was conducted in the remaining 855 women. The prevalence of haemoglobinopathies in the high-risk group was 14.5% (124/855). FUTURE PLANS: This cohort will be used to: (1) implement the screening in prenatal care in Basel; (2) recommend the screening among pregnant women with a high risk of a haemoglobin variant in Switzerland; (3) improve prenatal and neonatal care in patients with a haemoglobin variant; (4) examine adverse pregnancy outcomes in women with a haemoglobin variant and (5) reduce maternal and neonatal morbidity and mortality in the future. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT04029142).

The Importance of Characterizing the Hemoglobin Instability of New Variants: The Case of Hb Dompierre [ß29(B11)Gly→Arg, HBB: c.88G>C].

Hb Dompierre [ß29(B11)Gly→Arg, HBB: c.88G>C] is a rare ß-globin gene variant that was previously described in the heterozygous state in a 24-year-old female patient. It is defined in the HbVar database as being clinically and biologically asymptomatic. A few years after the first description, we had an opportunity of reassessing the index case because she presented with splenomegaly and clinical and biological manifestations of hemolysis. After ruling out the most common causes of hemolysis, further analyses on the variant hemoglobin (Hb) using brilliant cresyl blue staining, indicated that it showed mild instability, which may explain the clinical and biological manifestations. A structural bioinformatic analysis on the Hb variant suggested that the amino acid replacement may be deleterious to the integrity of the Hb. This report confirms the importance of completely characterizing all new Hb variants in order to guide the patients' clinical management and follow-up, as well as to provide the probands and their family members with appropriate genetic counseling.

Iron status and inherited haemoglobin disorders modify the effects of micronutrient powders on linear growth and morbidity among young Lao children in a double-blind randomised trial.

Some studies found that providing micronutrient powder (MNP) causes adverse health outcomes, but modifying factors are unknown. We aimed to investigate whether Fe status and inherited Hb disorders (IHbD) modify the impact of MNP on growth and diarrhoea among young Lao children. In a double-blind controlled trial, 1704 children of age 6-23 months were randomised to daily MNP (with 6 mg Fe plus fourteen micronutrients) or placebo for about 36 weeks. IHbD, and baseline and final Hb, Fe status and anthropometrics were assessed. Caregivers provided weekly morbidity reports. At enrolment, 55·6 % were anaemic; only 39·3 % had no sign of clinically significant IHbD. MNP had no overall impact on growth and longitudinal diarrhoea prevalence. Baseline Hb modified the effect of MNP on length-for-age (LAZ) (P for interaction = 0·082). Among children who were initially non-anaemic, the final mean LAZ in the MNP group was slightly lower (-1·93 (95 % CI -1·88, -1·97)) v. placebo (-1·88 (95 % CI -1·83, -1·92)), and the opposite occurred among initially anaemic children (final mean LAZ -1·90 (95 % CI -1·86, -1·94) in MNP v. -1·92 (95 % CI -1·88, -1·96) in placebo). IHbD modified the effect on diarrhoea prevalence (P = 0·095). Among children with IHbD, the MNP group had higher diarrhoea prevalence (1·37 (95 % CI 1·17, 1·59) v. 1·21 (95 % CI 1·04, 1·41)), while it was lower among children without IHbD who received MNP (1·15 (95 % CI 0·95, 1·39) v. 1·37 (95 % CI 1·13, 1·64)). In conclusion, there was a small adverse effect of MNP on growth among non-anaemic children and on diarrhoea prevalence among children with IHbD.

Anaemia in pregnancy.

BACKGROUND: Anaemia in pregnancy is a common medical condition managed by general practitioners (GPs) in Australia. OBJECTIVE: The aim of this article is to raise awareness of anaemia that occurs in pregnancy, understand its increasing complexities with an expanding migrant population, identify at-risk groups and promote appropriate management. DISCUSSION: With anaemia reportedly occurring in 25% of women in pregnancy and GPs managing the majority of preconception and early pregnancy care, it is important to have a sound understanding of the aetiology, risks and management options. While iron deficiency anaemia is most commonly seen, a more complex understanding in regard to other causes and haemoglobinopathy screening is required.

Integrative microRNA and gene expression analysis identifies new drug repurposing candidates for fetal hemoglobin induction in ß-hemoglobinopathies.

Therapeutic induction of fetal hemoglobin (HbF) is one of the most promising approaches to ameliorate the severity of hemoglobinopathies like ß-thalassemia and sickle cell anemia. Although several pharmacological agents have been investigated for HbF induction in adults, the majority of these are associated with significant side-effects. While drug repurposing is known to open new doors for the use of approved drugs in unexplored clinical conditions, the primary challenge lies in identifying such candidates. In this study, we aimed to identify repurposing candidates for HbF induction using a novel in silico approach utilizing microRNA-pathway-drug relationships. A computational drug repurposing strategy identified several unique candidates for HbF induction; among which Curcumin, Ginsenoside, Valproate, and Vorinostat were found to be most suitable for future trials. This study identified new drug repurposing candidates for HbF induction and demonstrates an easily adaptable methodology that can be used for other pathophysiological conditions.

Hemoglobina Lansing. Una variant de l'hemoglobina causant de baixa saturació d'oxigen detectada per pulsioximetria / Hemoglobina lansing. Una variante de la hemoglobina causante de baja saturación de oxigeno detectada por pulsioximetría / Hemoglobin lansing. A hemoglobin variant causing falsely low oxygen saturation in pulse oximetry

Introducció: Avui en dia hi ha més de mil variants de l'hemoglobina conegudes i probablement encara en resten moltes per conèixer. De vegades poden donar lloc a hemoglobines inestables que provoquen hemòlisi, alteracions en l'afinitat per l'oxigen, o poden no alterar la funció de la molècula, però sí ser causa de lectures anòmales per pulsioximetria, una eina molt estesa avui en dia en la nostra pràctica diària. Cas clínic: Presentem el cas d'un pacient asimptomàtic sense antecedents, del qual, a partir d'una falsa baixa saturació d'oxigen detectada per pulsioximetria al servei d'urgències, arribem al diagnòstic d'hemoglobinopatia tant del pacient com d'un dels seus familiars més propers. Comentari:. Cal conèixer les limitacions d'una eina tan utilitzada en la pràctica diària habitual com és el pulsioxímetre, així com considerar les variants de l'hemoglobina dintre del diagnòstic diferencial de la hipoxèmia, sobretot en el pacient asimptomàtic

Introducción: Hoy en día existen más de mil variantes de la hemoglobina conocidas y probablemente hay muchas más que están aún por conocer. En ocasiones, éstas pueden dar lugar a hemoglobinas inestables que producen hemólisis, alteraciones en la afinidad por el oxígeno, o pueden no alterar la función de la molécula, pero sí ser causa de lecturas anómalas por pulsioximetría, una herramienta muy extendida hoy en día en nuestros servicios de urgencias. Caso clínico: Presentamos el caso de un paciente asintomático y sin antecedentes del cual, a partir de una falsa baja saturación de oxígeno detectada en el servicio de urgencias, llegamos al diagnós-tico de variante de la hemoglobina, tanto en el paciente como en uno de sus familiares más cercanos. Comentarios: A raíz de este caso, el objetivo es hacer hincapié en la importancia de conocer las limitaciones de una herramienta tan extendida como el pulsioxímetro, así como en el hecho de considerar las hemoglobinopatías dentro del diagnóstico diferencial de la hipoxemia

Introduction: Currently, there are more than 1,000 known hemog-lobin variants and probably more variants that have yet to be identified. Some variants can result in unstable hemoglobin causing hemolysis and alterations in the oxygen affinity, or can also result in abnormal readings by pulse oximetry without any alteration in their function. Case report: We present the case of an asymptomatic patient and with no relevant personal or family medical history who was diagnosed with a hemoglobin variant after an abnormal reading in a pulse oximeter. Comments: This case highlights the importance of acknowledging the limitations of pulse oximetry, as well as the need to consider hemoglobinopathies in the differential diagnosis of hypoxemia, particularly in the asymptomatic patient

Capillarys 2 Flex Piercing Detected a Rare Case of Hb Broomhill.

We report a case of an extremely rare hemoglobin (Hb) variant-Hb Broomhill, which has been only reported once in the literature. Hemoglobin fractions were determined by capillary electrophoresis (Sebia Capillarys 2 Flex piercing) and high performance liquid chromatography (HPLC) (Bio-Rad Variant™ II Hemoglobin Testing System), respectively. Complete blood count and DNA sequencing were also performed. The capillary electrophoregram revealed a tiny shoulder peak before the HbA peak and a subtle abnormal HbA2 peak (slightly wider and lower), even though the percentage of each hemoglobin fraction was within the reference range (HbA, 97.4%; HbA2, 2.6%). On HPLC, not only the percentage but also the peak shape of each hemoglobin fraction was normal (HbA 88.2%, HbA2 2.5%, HbF 0.6%). Eventually, sequencing analysis of α genes confirmed a missense mutation (CCC>GCC at codon 114 in alpha1 gene) which caused Hb Broomhill variant. Our report suggest that capillary electrophoresis may be an accurate tool for screening and diagnosis of Hb disorders.

Heart failure in haemoglobinopathies: pathophysiology, clinical phenotypes, and management.

Hereditary haemoglobinopathies, mainly beta-thalassemia and sickle cell disease, constitute the most common monogenic disorders in humans, and although once geographically confined, they are currently globally distributed. They are demanding clinical entities that require multidisciplinary medical management. Despite their genotypic and phenotypic heterogeneity, the haemoglobinopathies share several similarities in pathophysiology, clinical manifestations, therapeutic requirements, and complications, among which heart failure (HF) represents a leading cause of mortality and morbidity. However, haemoglobinopathies have generally been addressed in a rather fragmentary manner. A unifying approach focusing on the underlying similarities of HF attributes in the two main entities might contribute to their better understanding, characterization, and management. In the present review, we attempt such an approach to the pathophysiology, clinical phenotypes, and management of HF in haemoglobinopathies.

HbE/ß-Thalassemia and Oxidative Stress: The Key to Pathophysiological Mechanisms and Novel Therapeutics.

SIGNIFICANCE: Oxidative stress and generation of free radicals are fundamental in initiating pathophysiological mechanisms leading to an inflammatory cascade resulting in high rates of morbidity and death from many inherited point mutation-derived hemoglobinopathies. Hemoglobin (Hb)E is the most common point mutation worldwide. The ßE-globin gene is found in greatest frequency in Southeast Asia, including Thailand, Malaysia, Indonesia, Vietnam, Cambodia, and Laos. With the wave of worldwide migration, it is entering the gene pool of diverse populations with greater consequences than expected. CRITICAL ISSUES: While HbE by itself presents as a mild anemia and a single gene for ß-thalassemia is not serious, it remains unexplained why HbE/ß-thalassemia (HbE/ß-thal) is a grave disease with high morbidity and mortality. Patients often exhibit defective physical development, severe chronic anemia, and often die of cardiovascular disease and severe infections. Recent Advances: This article presents an overview of HbE/ß-thal disease with an emphasis on new findings pointing to pathophysiological mechanisms derived from and initiated by the dysfunctional property of HbE as a reduced nitrite reductase concomitant with excess α-chains exacerbating unstable HbE, leading to a combination of nitric oxide imbalance, oxidative stress, and proinflammatory events. FUTURE DIRECTIONS: Additionally, we present new therapeutic strategies that are based on the emerging molecular-level understanding of the pathophysiology of this and other hemoglobinopathies. These strategies are designed to short-circuit the inflammatory cascade leading to devastating chronic morbidity and fatal consequences. Antioxid. Redox Signal. 26, 794-813.

Hemoglobinopathies and sleep--The road less traveled.

Sickle cell disease and thalassemia are common hereditary blood disorders associated with increased systemic inflammation, tissue hypoxia, endothelial dysfunction and end-organ damage, the latter accounting for the substantial morbidity and abbreviated lifespan associated with these conditions. Sleep perturbations in general, and sleep-disordered breathing in particular are also highly prevalent conditions and the mechanisms underlying their widespread end-organ morbidities markedly and intriguingly overlap with the very same pathways implicated in the hemoglobinopathies. However, little attention has been given to date to the potential contributing role of sleep disorders to sickle cell disease manifestations. Here, we comprehensively review the pathophysiological mechanisms and clinical manifestations linking disturbed sleep and hemoglobinopathies, with special emphasis on sickle cell disease. In addition to a broad summary of the available evidence, we identify many of the research gaps that require attention and future investigation, and provide the scientific contextual setting that should enable opportunities to investigate the intertwined pathophysiological mechanisms and clinical outcomes of sleep disorders and hemoglobinopathies.

Hb Burgos (α 1 CD64(E13)(Asp→Asn)): una nueva variante de hemoglobina detectada durante la monitorización de pacientes con diabetes / Hb Burgos (α 1 CD64(E13)(Asp→Asn)): A new hemoglobin variant detected during follow-up of diabetic patients

Fundamento y objetivo: El control de la diabetes mellitus se realiza mediante la determinación de hemoglobina glucosilada (HbA1c) por cromatografía líquida de alta resolución. Algunas variantes estructurales de la hemoglobina (Hb) son conocidas por causar interferencia analítica en la medición de la HbA1c. Pacientes y métodos: En este estudio se ha caracterizado una nueva variante de Hb en 4 pacientes, que se detectó al realizarse un control de HbA1c. Resultados: La secuenciación selectiva del gen α1 mostró una mutación responsable del cambio de ácido aspártico (Asp) por asparagina (Asn) en el codón 64. El cambio de Asp por Asn no produce ninguna alteración funcional de la Hb y se comporta como una hemoglobinopatía silente. Conclusión: Las variantes estructurales de la Hb se pueden detectar durante la medición de la HbA1c y pueden alterar sus valores. Estos casos, aunque poco frecuentes, requieren examinar a fondo los cromatogramas para detectar posibles interferencias (AU)

Background and objective: The glycated hemoglobin (HbA1c) test by high performance liquid chromatography is a useful tool for the follow-up of diabetes mellitus patients. Some structural hemoglobin (Hb) variants are known to cause interference in the analytical measurement of HbA1c. Patients and methods: In this study, it has been characterized a new Hb variant in 4 patients during their regular control of HbA1c. Results: Selective α1 gene sequencing showed a mutation GAC > AAC at codon 64 within exon 2. This produces a change of aspartic acid (Asp) by asparagine (Asn) that does not produce any functional alteration so the resultant molecule behaves as a silent hemoglobinopathy. Conclusion: The structural Hb variants can be detected during the analysis of HbA1c and may alter its values. Though rare, this occurrence signals the need to being aware when measuring HbA1 (AU)

Impaired oxygen uptake kinetics in the first high-level athlete with Hb Hope: a case study.

Hemoglobin (Hb) Hope is a beta-globin chain variant with reduced oxygen (O2) affinity, known to induce anemia. This usually leads to limitations in O2uptake (VO2) and exercise tolerance. We studied the case of a high-level female athlete with Hb Hope. She had been selected for cross-country races from 13 yrs onward, then was a national junior champion in 400-m race, and finally failed to win any cross-country races as an adult. Hematological analysis revealed normal red blood cell indices and Hb level (12.3 g.dL⁻¹). Incremental exercise showed peak work rate (WR), VO(2max) and gas exchange threshold (GET) within normal ranges for healthy females. Constant WR testing at 90% of GET showed that kinetics of pulmonary VO2included the presence of a slow component. This was in disagreement with the data on VO2kinetics response to exercise intensities below GET. Phase 2 parameters, time constant (τ2, 31 s), time delay (TD2, 39 s), amplitude (A2, 780 ml.min⁻¹), and gain in VO2(ΔVO2 .ΔWR-1, 9.2 ml.min-1.W⁻¹) were within normal ranges. Phase 3 showed a slow component similar to that reported in severe exercise. The absence of anemia and the normality of phase 2 suggested normal O2delivery and oxidative metabolism in exercising muscles. In contrast, phase 3 suggested poor aerobic capacity and limited exercise tolerance. However, the lack of symptoms during testing also suggested that the slow component was due to the specific recruitment of fast-twitch fibers in this former champion athlete with Hb Hope in races requiring mainly anaerobic metabolism.

Prevalence of hemoglobin variants in a diabetic population at high risk of hemoglobinopathies and optimization of HbA1c monitoring by incorporating HPLC in the laboratory workup.

BACKGROUND: In Tunisia, diabetes mellitus and hemoglobinopathies are major public health problems. Glycated hemoglobin (HbA1c) is recommended for long-term monitoring of diabetes mellitus, but the presence of hemoglobin variants may interfere with HbA1c measurement. The aim was to determine the prevalence of hemoglobin variants in Tunisian diabetics and optimize the monitoring of diabetics using HbA1c. METHODS: The study enrolled 9,792 Tunisian diabetic patients. HbA1c was measured by cation-exchange high-pressure liquid chromatography (HPLC). All the chromatograms were analyzed for the presence of Hb variants. RESULTS: We identified 228 cases (2.33%) of Hb variants with D-10 HPLC (Bio-Rad): 191 with HbA/S trait, 27 with HbA/C trait, and 10 hemoglobin variants with the mention 'Variant-Window' on the chromatograms and subsequently identified as HbA/S on Variant I HPLC (Bio-Rad). Thus, the prevalence of HbS was 2.05%. We did not find any homozygous variant. All HbA1c results were reported to the treating physician. CONCLUSIONS: To evaluate glycated hemoglobin in populations with a high prevalence of hemoglobinopathies, we should use the HPLC method, which is easy, economical, and reliable. Based on an algorithm, hemoglobin variants visualized on HPLC should be reported to the physician to improve the management of patients.

Two new γ chain variants: Hb F-Augusta GA [(G)γ59(E3)Lys → Arg; HBG2: c.179A > G] and Hb F-Port Royal-II [(A)γ125(H3)Glu → Ala; HBG1: c.377A > C].

The total number of hemoglobin (Hb) variants so far reported to the HbVar database is 1598 (April 9 2014) and 130 of them are fetal Hb variants. Fetal Hb are categorized as two different subunits, (G)γ- and (A)γ-globin chains, and γ chain variants can be observed in both subunits. There are 72 (G)γ- and 58 (A)γ-globin chain variants. Most of them are clinically silent and detected during newborn screening programs in the USA and outside the USA. In this report, we discuss the molecular characteristics and diagnostic difficulties of two new γ-globin chain variants found in an African American baby with no clinical symptoms. One is a new (G)γ-globin chain variant, Hb F-Augusta GA [(G)γ59(E3)Lys → Arg; HBG2: c.179A > G] and the other one is Hb F-Port Royal-II [(A)γ125(H3)Glu → Ala; HBG1: c.377A > C].

[Pathophysiological aspects of K+: Cl- cotransporters]. / Aspectos fisiopatologicos de los cotransportaores de K+ :CI- .

The K+:Cl- cotransporters or KCCs are membrane proteins that move K+ and Cl- ions across the membrane without changing the transmembrane potential. KCCs belong to the SLC12 (Solute Carrier Family 12) family of electroneutral cation-chloride cotransporters (CCC), and they are secondary active ion transporters because use the established gradients from the primary active transporter through the Na+/K+- ATPase. Although there are nine members identify in this family, up today only seven genes had been characterized. Among them are two loop diuretics-sensitive Na+:K+:2Clcotransporters (NKCC1/NKCC2), the thiazide-sensitive Na+:Cl- cotransporter (NCC), and finally the K+:Cl- cotransporters (KCC), encoded for at least four homologous genes (KCC1-KCC4), and from which there are many isoforms due to alternative splicing. KCC1 is a ubiquitous isoform, KCC3 and KCC4 isoforms are widely expressed, particularly in epithelial cells, while KCC2 is restricted to the central nervous system (CNS). All these cotransporters play an essential role in many physiological processes such as cell volume regulation, transepithelial salt transport and regulation of the intraneuronal chloride concentration. This review has the purpose to show briefly the molecular characteristics as well as the physiological importance and roles of the KCCs in several pathologies.

Physiology and pathophysiology of iron in hemoglobin-associated diseases.

Iron overload and iron toxicity, whether because of increased absorption or iron loading from repeated transfusions, can be major causes of morbidity and mortality in a number of chronic anemias. Significant advances have been made in our understanding of iron homeostasis over the past decade. At the same time, advances in magnetic resonance imaging have allowed clinicians to monitor and quantify iron concentrations noninvasively in specific organs. Furthermore, effective iron chelators are now available, including preparations that can be taken orally. This has resulted in substantial improvement in mortality and morbidity for patients with severe chronic iron overload. This paper reviews the key points of iron homeostasis and attempts to place clinical observations in patients with transfusional iron overload in context with the current understanding of iron homeostasis in humans.

Modulators of erythropoiesis: emerging therapies for hemoglobinopathies and disorders of red cell production.

Use of new compound such as inhibitors of JAK2 or transforming growth factor ß-like molecules might soon revolutionize the treatment of ß-thalassemia and related disorders. However, this situation requires careful optimization, noting the potential for off-target immune suppression for JAK2 inhibitors and the lack of mechanistic insights for the use of the ligand trap soluble molecules that sequester ligands of activin receptor IIA and B.

Online biomedical resources for malaria-related red cell disorders.

Warnings about the expected increase of the global public health burden of malaria-related red cell disorders are accruing. Past and present epidemiological data are necessary to track spatial and temporal changes in the frequencies of these genetic disorders. A number of open access biomedical databases including data on malaria-related red cell disorders have been launched over the last two decades. Here, we review the content of these databases, most of which focus on genetic diversity, and we describe a new epidemiological resource developed by the Malaria Atlas Project. To tackle upcoming public health challenges, the integration of epidemiological and genetic data is important. As many countries are considering implementing national screening programs, strategies to make such data more accessible are also needed.