Prévention des maladies génétiques. Le retour du médecin de famille ?

International audienceBackground: Information to kin is one of the major ethical problems of the new genetics. In France, the revised bioethics law in 2011 created the possibility for patients to authorize professionals, under certain conditions, to directly contact their relatives at risk. Beyond this, other actors, such as GPs, could however play a role in this process.Methods: Our article is based on an ethnographic-type sociological study by observations and semi-structured interviews with patients (n=59) and genetic professionals (n=16) that took place from 2014 to 2016 in three genetic hospital wards in France and Canada. It focuses particularly on genetic predispositions to breast and ovarian cancers as well as genetic hemochromatosis.Results: Because of its position as a primary care specialist, the general practitioner can play a decisive role in the process of informing relatives about genetic disorders. Upstream of the genetic test, the generalist, thanks to his knowledge of the family context of his patients, can play a referral role towards a specialized consultation. Downstream, it can also ensure a more effective follow-up of the information procedures undertaken by its patients thanks to the medical follow-up that it carries out.Conclusion: The data collected during our study highlight the unprecedented place that could be that of the general practitioner in the field of prevention in genetics. At the articulation between primary care and highly specialized care, it is the figure of the "family" doctor who seems to be called here to be renewed by genetics

Prévention des maladies génétiques. Le retour du médecin de famille ?

International audienceBackground.-Information to kin is one of the major ethical problems of the new genetics. In France, the revised bioethics law in 2011 created the possibility for patients to authorize professionals, under certain conditions, to directly contact their relatives at risk. Beyond this, other actors, such as GPs, could however play a role in this process. Methods.-Our article is based on an ethnographic-type sociological study by observations and semi-structured interviews with patients (n = 59) and genetic professionals (n = 16) that took place from 2014 to 2016 in three genetic hospital wards in France and Canada. It focuses particularly on genetic predispositions to breast and ovarian cancers as well as genetic hemochromatosis. Results.-Because of its position as a primary care specialist, the general practitioner can play a decisive role in the process of informing relatives about genetic disorders. Upstream of the genetic test, the generalist, thanks to his knowledge of the family context of his patients, can play a referral role towards a specialized consultation. Downstream, it can also ensure a more effective follow-up of the information procedures undertaken by its patients thanks to the medical follow-up that it carries out. Conclusion.-The data collected during our study highlight the unprecedented place that could be that of the general practitioner in the field of prevention in genetics. At the articulation between primary care and highly specialized care, it is the figure of the ''family'' doctor who seems to be called here to be renewed by genetics

Prévention des maladies génétiques. Le retour du médecin de famille ?

International audienc

Étude d’une cohorte de 206 patients drépanocytaires adultes transfusés : immunisation, risque transfusionnel et ressources en concentrés globulaires

International audienceBackground: Prevention of hemolytic transfusion reactions depends upon our capacity to prevent allo-immunization and conflicts between antigens of transfused red blood cells and antibodies produced by the recipient. In this study, we show that to secure transfusion of sickle cell disease patients, it is necessary to take into account their immunohematologic characteristics in the organization of transfusion.Methods and results: Immunohematological data of 206 chronically transfused patients have been collected as well as phenotypes of transfused units. In order to prevent allo-immunization against C and E antigens for patients typed D+C-E-c+e+ (56%), 26% of the transfused units were D-C-E-c+e+. We found that 47% of the patients had a history of allo-immunization, whereas only 15% produced an antibody the day of inclusion in the study. The non-detectable antibodies were frequently known as dangerous for transfusion. Finally, this study shows the frequency of anti-D in D+ patients and anti-C in C+ patients, pointing out the question of partial antigens.Conclusion: To insure optimal transfusion safety for sickle cell disease patients, three points have to be improved: blood donation within the Afro-Caribbean community living in France, access to history of immuno-hematological data, detection of variant antigens, especially within the RH blood system.But de l’étude. – La prévention des hémolyses post-transfusionnelles chez les drépanocytaires est conditionnée par notre capacité à prévenir l’allo-immunisation et les conflits antigène–anticorps. Cette étude montre l’importance de mettre en place une organisation transfusionnelle adaptée au profil immunohématologique particulier des drépanocytaires pour leur garantir une sécurité transfusionnelle optimale.Méthodes et résultats. – Les données immunohématologiques de 206 adultes drépanocytaires transfusés en dehors de l’urgence ont été analysées, ainsi que le phénotype des concentrés globulaires (CGR) délivrés. Cinquante-quatre pour cent des patients ont un phénotype D+CEc+e+. Pour prévenir l’allo-immunisation anti-C et anti-E, 26 % de CGR DCEc+e+ ont été transfusés à ces patients D+. Quarante-sept pour cent des patients ont un historique d’allo-immunisation, alors que seulement 15 % ont une recherche d’agglutinines irrégulières positive le jour de l’inclusion, les anticorps non décelables étant souvent dangereux. Enfin, cette étude montre la fréquence importante d’anti-D chez les sujets D+ et d’anti-C chez les sujets C+, posant la question du caractère partiel des antigènes D et C.Conclusion. – Pour une sécurité transfusionnelle optimale des patients drépanocytaires et une meilleure adéquation entre phénotypes des receveurs et phénotypes des CGR disponibles, trois points dans l’organisation transfusionnelle doivent être améliorés : la promotion du don au sein des populations afro-antillaises doit être renforcée pour disposer de CGR D+CEc+e+ et éviter d’utiliser la ressource limitée de CGR DCEc+e+ ; les données immunohématologiques des patients doivent être accessibles aux prescripteurs et transfuseurs, afin d’éviter les accidents immuno-hémolytiques par restimulation ; enfin, la recherche par biologie moléculaire des antigènes variants d’intérêt transfusionnel doit être mise en place chez les donneurs et receveurs afro-antillais

The use of rituximab to prevent severe delayed haemolytic transfusion reaction in immunized patients with sickle cell disease

International audienceBackground: Delayed haemolytic transfusion reaction (DHTR) is mainly caused by an immune response to transfused red blood cells (RBCs). Immunized patients have a high risk of producing antibodies in response to further transfusion. Controlling the immune response to RBCs is therefore a major goal in sickle cell disease (SCD).Study design: We report an observational study of eight alloimmunized SCD patients with history of severe DHTR who were treated with rituximab before a new transfusion to prevent further immunization and DHTR.Results: Five patients showed a good clinical outcome following transfusion preceded by preemptive treatment with rituximab. The remaining patients presented mild DHTR. In all patients, the results of post-transfusion screening tests were identical to those of pretransfusion tests; no newly formed antibodies were detected.Conclusion: These cases suggest that rituximab prevents at least occurrence of newly formed antibodies in high responders and minimizes the risk of severe DHTR. This study confirms that DHTR is complex in SCD and does not rely only on the classical antigens/antibodies conflict. Considering potentially serious adverse effect of rituximab, this treatment should be considered cautiously, and only when transfusion is absolutely necessary in patients with history of severe DHTR linked to immunization

Aggregation of mononuclear and red blood cells through an α4β1-Lu/basal cell adhesion molecule interaction in sickle cell disease

Background Abnormal interactions between red blood cells, leukocytes and endothelial cells play a critical role in the occurrence of the painful vaso-occlusive crises associated with sickle cell disease. We investigated the interaction between circulating leukocytes and red blood cells which could lead to aggregate formation, enhancing the incidence of vaso-occlusive crises. Design and Methods Blood samples from patients with sickle cell disease (n=25) and healthy subjects (n=5) were analyzed by imaging and classical flow cytometry after density gradient separation. The identity of the cells in the peripheral blood mononuclear cell layer was determined using antibodies directed specifically against white (anti-CD45) or red (anti-glycophorin A) blood cells. Results Aggregates between red blood cells and peripheral blood mononuclear cells were visualized in whole blood from patients with sickle cell disease. The aggregation rate was 10-fold higher in these patients than in control subjects. Both mature red blood cells and reticulocytes were involved in these aggregates through their interaction with mononuclear cells, mainly with monocytes. The size of the aggregates was variable, with one mononuclear cell binding to one, two or several red blood cells. Erythroid Lu/basal cell adhesion molecule and α4β1 integrin were involved in aggregate formation. The aggregation rate was lower in patients treated with hydroxycarbamide than in untreated patients. Conclusions Our study gives visual evidence of the existence of circulating red blood cell-peripheral blood mononuclear cell aggregates in patients with sickle cell disease and shows that these aggregates are decreased during hydroxycarbamide treatment. Our results strongly suggest that erythroid Lu/basal cell adhesion molecule proteins are implicated in these aggregates through their interaction with α4β1 integrin on peripheral blood mononuclear cells. Key words: α4β1, Lu/BCAM, sickle cell disease, aggregates. disease. Haematologica 2010;95(11):1841-1848. doi:10.3324/haematol.2010 This is an open-access paper. Citation: Chaar V, Picot J, Renaud O, Bartolucci P, Nzouakou R, Bachir D, Galactéros F, Colin Y, Le Van Kim C, and El Nemer W. Aggregation of mononuclear and red blood cells through an α4β1-Lu/basal cell adhesion molecule interaction in sickle cell Aggregation of mononuclear and red blood cells through an α4β1-Lu/basal cell adhesion molecule interaction in sickle cell diseas

Mitapivat in adult patients with pyruvate kinase deficiency receiving regular transfusions (ACTIVATE-T): a multicentre, open-label, single-arm, phase 3 trial.

Mitapivat, an oral activator of pyruvate kinase (PK) in red blood cells (RBCs), has shown significant improvements in haemoglobin and haemolysis among patients with pyruvate kinase deficiency who were not receiving regular transfusions. We aimed to evaluate the efficacy and safety of mitapivat in adults with pyruvate kinase deficiency receiving regular transfusions. ACTIVATE-T was an open-label, single-arm, phase 3 trial conducted in 20 centres across Europe, North America, and Asia. Eligible participants were adults (aged ≥18 years) with a clinical laboratory confirmation of pyruvate kinase deficiency receiving regular transfusions (at least six episodes in the previous year). Participants received oral mitapivat during a 16-week dose-optimisation period (5 mg, 20 mg, 50 mg twice daily) and 24-week fixed-dose period. The primary endpoint was a reduction in transfusion burden (≥33% reduction in number of RBC units transfused during the fixed-dose period, compared with the participant's individual historical transfusion burden, standardised to 24 weeks). Efficacy and safety were assessed in all participants who received at least one dose of mitapivat. This trial is registered with ClinicalTrials.gov, NCT03559699, and is complete. Between June 26, 2018, and Feb 4, 2020, 27 participants (20 [74%] female and seven [26%] male; 20 [74%] White, three [11%] Asian, and four [15%] not reported) were enrolled and received at least one dose of mitapivat. Median duration of exposure to mitapivat was 40·3 weeks (IQR 40·0-41·3). A reduction in transfusion burden by at least 33% was found in ten (37%) participants (95% CI 19-58; p=0·0002). The most common treatment-emergent adverse events were increase in alanine aminotransferase (ten [37%] participants), headache (ten [37%]), increase in aspartate aminotransferase (five [19%]), fatigue (five [19%]), and nausea (five [19%]). Two grade 3 treatment-emergent adverse events were related to study treatment: joint swelling (one participant [4%]) and an increase in aspartate aminotransferase (one participant [4%]). Three participants had serious treatment-emergent adverse events, none related to the study treatment: increased blood triglycerides, ovarian cyst, and renal colic (each in one participant [4%]). No treatment-related deaths were observed. Mitapivat represents a novel therapy that can reduce transfusion burden in some adults with pyruvate kinase deficiency receiving regular transfusions, and is the first disease-modifying agent approved in this disease. Agios Pharmaceuticals