Introduction
The heterozygous condition for β‐thalassemia mutation associated with an extra functional α‐globin gene can produce a Thalassemia Intermedia (TI) phenotype. This genotype is the second ...in frequency in the French Thalassemia Registry NaThalY that prospectively collects laboratory and clinical data.
Materials and Methods
The present report analyses transfusion needs, iron overload (ferritin, hepatic and cardiac iron concentrations), and complication rates in 45 patients included in NaThalY and presenting a heterozygous β0 or β+‐thalassemia mutation associated with a triplication at HBA locus. This cohort was compared to a cohort of patients with TI due to mutations in the beta‐globin gene only and included in the French registry.
Results
Patients with an extra functional α‐globin gene showed a less severe anemia, lower transfusion needs and lower complication rates than those with TI related to the β‐globin gene only. Nevertheless, some of them displayed complications such as cholelithiasis or extramedullary hematopoiesis. In addition, one third of the cohort needed transfusions and another third was under iron chelation.
Conclusion
The genotype associating a heterozygous β0 or β+‐thalassemia mutation with a triplication at HBA locus should be accurately diagnosed as it could lead to symptomatic anemia and to potential iron overload and iron‐related complications even in patients with no transfusion need.
The aim of the present study was to compare blood rheological parameters between children with homozygous sickle cell disease (SS), sickle cell SC disease or S/β+-thalassemia syndrome, and healthy ...children (AA) and to test the associations between blood rheology and the clinical severity in S/β+-thalassemia. Sixty-two SS, 14 SC, 11 S/β+-thalassemia and 12 healthy children participated in this study. Blood viscosity was measured with a cone-plate viscometer at 225 s-1. Red blood cell (RBC) deformability was measured by ektacytometry and RBC aggregation, by syllectometry. Nitric oxide and nitrotyrosine levels were determined for each child. While most of the hematological parameters were not different between SC and S/β+-thalassemia children, we demonstrated that SC patients had lower RBC deformability and aggregation than S/β+ individuals. Nitrotyrosine level, which indicates peroxynitrite production, was similar and lower in both healthy and S/β+ compared to SS children. However, S/β+-thalassemia children who experienced vaso-occlusive crises (VOC) in the 2 previous years had lower NOx and higher nitrotyrosine levels than those who never had VOC within the same period. These findings suggest that vascular function could be impaired in the most severe S/β+-thalassemia children compared to the less severe one.
Échanges érythrocytaires chez les enfants de faible poids Hequet, Olivier; Gauthier, Alexandra; Revesz, Daniela ...
Transfusion clinique et biologique : journal de la Société française de transfusion sanguine,
September 2019, 2019-09-00, Volume:
26, Issue:
3
Journal Article
Peer reviewed
Les Échanges Érythrocytaires (EE) sont utilisés pour traiter et prévenir les complications vasculaires graves des patients drépanocytaires. Cependant, le faible poids des jeunes enfants nécessite des ...précautions et une adaptation pour éviter une mauvaise tolérance clinique lors de ces séances. En effet, le volume extracorporel peut représenter un pourcentage non négligeable du volume sanguin de l’enfant lors des EE. Nous avons analysé la tolérance clinique lors des séances d’EE en pédiatrie en adaptant nos pratiques au poids de l’enfant et avons mis en évidence les périodes critiques lors de ces échanges. Chez les enfants de poids inférieur à 20kg (n=5), un amorçage du kit avec un concentré de globules rouges et une perfusion continue d’albumine 4 % (10mL/kg) permettent d’éviter une diminution significative de la tension artérielle (TA) au début et pendant toute la durée de l’EE (25 séances analysées). Chez les enfants pesant entre 20 et 40kg (n=17), la perfusion d’une macromolécule ou d’albumine 4 % (15mL/kg) lors de l’EE permet d’éviter une diminution de la TA uniquement si elle est réalisée de manière strictement continue (217 séances analysées). L’existence d’une anémie (hématocrite inférieur à 23 %) nécessite une perfusion initiale (de volume variable selon le poids de l’enfant) par albumine et une surveillance clinique particulière. De plus, l’échange d’une quantité trop importante de globules rouges prédispose à la survenue de malaises et de baisse de TA chez l’enfant. Au total, la réalisation d’EE est possible chez les enfants de faible poids (>10kg) sans conséquence clinique délétère, à condition de prévoir une stratégie thérapeutique et une surveillance adaptées.
Une enfant de 17 mois est amenée aux urgences pour asthénie progressive et syncopes répétées. Le bilan biologique d’entrée révèle :
– une anémie sévère à 31g/L ;
– un test direct à l’anti globuline ...fortement positif de type IgG ;
– la présence d’anticorps anti-érythrocytaires libres dans le plasma de spécificité anti-publique, d’une composante anti-RH5 puissante et de témoins autologues positifs.
Son phénotype est RH :1, 2,−3, 4, 5. Des pathologies dysimmunitaires ont été diagnostiquées dans sa fratrie. Devant ce profil classique d’anémie hémolytique auto-immune (AHAI) à auto-anticorps chauds, un traitement immunosuppresseur est entrepris et l’enfant est transfusée avec des unités RH :-3. Des échanges plasmatiques s’avèrent nécessaires devant la constatation d’une hémoglobinurie et de mauvais rendements transfusionnels. Des échantillons sont adressés au CNRGS qui identifie un anticorps anti-RH17 (absence de réactivité sur hématies D− –) de titre 16 et une puissante réactivité anti-RH5 (titre 1000). Ce profil est fréquent dans les AHAI. L’étude du gène RHCE, en ne révélant aucune mutation, conforte l’origine auto-immune des anticorps. L’instabilité clinique de l’enfant justifie la décision de recourir à 2 fractions d’une unité rare de phénotype D− –. Le rendement transfusionnel est excellent, avec amélioration spectaculaire de l’état clinique et sortie d’unité de soins continus. Malgré une nouvelle poussée d’hémolyse survenue quelques jours plus tard, aucune autre unité rare D− – n’a été nécessaire. Cette observation peu fréquente illustre l’intérêt d’un recours ponctuel, mais avec un net bénéfice, d’unités de sang rare compatibles avec des auto-anticorps de spécificité anti-publique.
Erythrocyte deformability is impaired in sickle cell disease (SCD). The regulation of cytoskeletal protein organization plays a key role in erythrocyte deformability. The activation of adenylyl ...cyclase (AC)/cAMP/Protein kinase A (PKA) signaling pathway was associated with increased deformability in healthy erythrocytes, however the role of this pathway in SCD is unknown.
We evaluated mechanical responses of sickle red blood cells under physiological levels of shear stress and the possible link between their deformability and AC/cAMP/PKA signaling pathway.
The shearing of sickle red blood cells at physiological level (5 Pa) and the measurement of deformability were performed by a laser assisted optical rotational cell analyzer (LORRCA).
Red blood cell deformability increased of 2.5-6.5% by blocking the activity of phosphodiesterase with Pentoxifylline (10μM) (p < 0.05). The inhibition of AC with SQ22536 (100μM) produced more significant rise in deformability (+4.8-12%, p < 0.01). No significant change was observed by the inhibition of PKA with H89 (10μM).
Pentoxifylline and SQ22536 increased the deformability of sickle red blood cells under fluid shear stress. Modulation of the AC/cAMP/PKA pathway could have the potential to be an effective therapeutic approach for SCD through shear-induced improvements of RBC deformability.
Abstract
Objectives
Because of the increased hemolytic rate, a significant proportion of patients with sickle cell disease (
SCD
) are prone to develop cholelithiasis. The present study investigated ...the role of several genetic factors (
UGT
1A1
promoter (
TA
)
n
repeat polymorphism, alpha‐globin status), hematological parameters, clinical severity, and hydroxyurea (
HU
) therapy on the occurrence of cholelithiasis in
SCD
.
Methods
One hundred and fifty‐eight children (2–18 yr old) regularly followed at the University Hospital of Lyon (France) were included. A multivariate Cox model was used to test the associations between cholelithiasis and the different parameters analyzed.
Results
We confirmed that alpha‐thalassemia and low basal reticulocyte (
RET
) count were independent protective factors for cholelithiasis while 7/7, 8/8 and 7/8
UGT
1A1
(
TA
)
n
genotypes were independent predisposing factors for this complication. We also showed for the first time that
HU
treatment decreased the risk for cholelithiasis while frequent vaso‐occlusive crises and acute chest syndrome events increased that risk.
Conclusions
Our findings demonstrate that
UGT
1A1
(
TA
)
n
polymorphism is not the only factor triggering gallstone formation in
SCD
. Cholelithiasis is also modulated by
RET
count, the number of deleted alpha‐genes,
HU
therapy and the frequency of vaso‐occlusive events.
DREPADO is a randomized controlled trial (RCT) assessing the impact of a pediatric-adult transition program, on the health status of adolescents with sickle cell disease. Using a biopsychosocial ...approach with three main facets (educational, psychological and social interactions), it constitutes a complex transition program, which is quite difficult to implement. To facilitate the implementation of this complex program, the aim of this ancillary study is to explore barriers and facilitators at the early stages of this implementation.
A qualitative study with semi-structured interviews was conducted, according to COREQ quality criteria, in patients with sickle cell disease who had already experienced the transition to adult care before DREPADO, and healthcare professionals working on the DREPADO RCT.
Semi-structured interviews were conducted with patients (n = 12) and healthcare professionals (n = 12) from November 2019 to May 2020. The main barriers identified by patients were time and implication required by this transition program. Healthcare professionals involved in the coordinating center mentioned changes in their working habits and also elements about the RCT regulatory procedures. Main facilitators reported by both patients and healthcare professionals were the positive perception of the transition program design, and especially the home setting for therapeutic education sessions.
This study led to the identification of main barriers and facilitators to the implementation of both the DREPADO intervention and RCT. These propositions could also be used to promote other complex public health interventions or/and other randomized controlled trials.
Objectives
Because of the increased hemolytic rate, a significant proportion of patients with sickle cell disease (SCD) are prone to develop cholelithiasis. The present study investigated the role of ...several genetic factors (UGT1A1 promoter (TA)n repeat polymorphism, alpha‐globin status), hematological parameters, clinical severity, and hydroxyurea (HU) therapy on the occurrence of cholelithiasis in SCD.
Methods
One hundred and fifty‐eight children (2–18 yr old) regularly followed at the University Hospital of Lyon (France) were included. A multivariate Cox model was used to test the associations between cholelithiasis and the different parameters analyzed.
Results
We confirmed that alpha‐thalassemia and low basal reticulocyte (RET) count were independent protective factors for cholelithiasis while 7/7, 8/8 and 7/8 UGT1A1 (TA)n genotypes were independent predisposing factors for this complication. We also showed for the first time that HU treatment decreased the risk for cholelithiasis while frequent vaso‐occlusive crises and acute chest syndrome events increased that risk.
Conclusions
Our findings demonstrate that UGT1A1 (TA)n polymorphism is not the only factor triggering gallstone formation in SCD. Cholelithiasis is also modulated by RET count, the number of deleted alpha‐genes, HU therapy and the frequency of vaso‐occlusive events.
Purpose: DREPADO is a randomized controlled trial (RCT) assessing the impact of a pediatric-adult transition program, on the health status of adolescents with sickle cell disease. Using a ...biopsychosocial approach with three main facets (educational, psychological and social interactions), it constitutes a complex transition program, which is quite difficult to implement. To facilitate the implementation of this complex program, the aim of this ancillary study is to explore barriers and facilitators at the early stages of this implementation.Methods: A qualitative study with semi-structured interviews was conducted, according to COREQ quality criteria, in patients with sickle cell disease who had already experienced the transition to adult care before DREPADO, and healthcare professionals working on the DREPADO RCT.Results: Semi-structured interviews were conducted with patients (n = 12) and healthcare professionals (n = 12) from November 2019 to May 2020. The main barriers identified by patients were time and implication required by this transition program. Healthcare professionals involved in the coordinating center mentioned changes in their working habits and also elements about the RCT regulatory procedures. Main facilitators reported by both patients and healthcare professionals were the positive perception of the transition program design, and especially the home setting for therapeutic education sessions.Conclusion: This study led to the identification of main barriers and facilitators to the implementation of both the DREPADO intervention and RCT. These propositions could also be used to promote other complex public health interventions or/and other randomized controlled trials.
Arterial stiffness and calcification are nontraditional cardiovascular risk factors in chronic kidney disease (CKD). Using a rat model of CKD with mineral imbalance, medial vascular calcification has ...been associated with inflammation and increased endothelin-1 (ET-1) production. We therefore hypothesized that ET-1, through the endothelin type A (ETA) receptor, induces vascular inflammation, calcification and stiffness in CKD.
CKD was induced in Wistar rats by renal mass ablation. To induce medial vascular calcification, mineral imbalance was established with a identified as calcium-rich/phosphate-rich diet and vitamin D supplementation (Ca/P/VitD). One group of CKD + Ca/P/VitD rats was given the ETA receptor antagonist atrasentan (10 mg/kg/day) for 6 weeks. Hemodynamic parameters including SBP, pulse pressure (PP) and pulse wave velocity (PWV) were determined. Vascular calcification, smooth muscle cells osteoblastic differentiation and expression of inflammatory markers such as inflammatory cytokines and calgranulins S100A8 and S100A9 were assessed in the thoracic aorta.
As compared with CKD control rats, CKD + Ca/P/VitD rats developed medal vascular calcification that was associated with increased SBP, PP and PWV. These changes were also associated with increased macrophage infiltration and expression of IL-6, calgranulins and osteoblastic markers. Treatment of CKD + Ca/P/VitD rats with atrasentan reduced vascular calcification, SBP, PP and PWV, macrophage infiltration and expression of IL-1β, IL-6, tumor necrosis factor, calgranulins and osteoblastic markers.
This study shows that ETA receptor blockade reduced vascular inflammation, smooth muscle cells differentiation, calcification and stiffness indicating a pivotal role for ET-1 in medial vascular calcification in this rat remnant kidney model of CKD with mineral imbalance. Therefore, the endothelin system may be a potential therapeutic target for improving cardiovascular morbidity in patients with CKD.
