Median life expectancy of patients with sickle cell disease has increased to up to 55 years but there are still frequent cases of premature death, mostly in patients with pre-existing organ failure ...such as pulmonary hypertension, kidney injury, and cerebral vasculopathy. Most organ injuries remain asymptomatic for a long time and can only be detected through early systematic screening. Protocols combining assessment of velocities on transcranial Doppler and regular transfusions in patients with abnormal velocities have been demonstrated to dramatically reduce the risk of stroke. In contrast, no consensus has been reached on systematic screening or therapy for silent cerebral infarcts. The prognostic significance of increased tricuspid regurgitant jet velocity on echocardiography has not yet been identified in children, whereas increased albuminuria is a good predictor of kidney injury. Finally, screening for hip and eye disorder is recommended; however, different countries adopt different screening strategies. Hydroxyurea is probably of potential benefit in preventing chronic organ damage but this requires further study in order to be fully demonstrated. Efficacy and safety of the other new drugs available are also under investigation.
Sickle cell disease Ware, Russell E, Dr Prof; de Montalembert, Mariane, MD PhD; Tshilolo, Léon, Prof ...
The Lancet (British edition),
07/2017, Letnik:
390, Številka:
10091
Journal Article
Recenzirano
Summary Sickle cell disease is a common and life-threatening haematological disorder that affects millions of people worldwide. Abnormal sickle-shaped erythrocytes disrupt blood flow in small ...vessels, and this vaso-occlusion leads to distal tissue ischaemia and inflammation, with symptoms defining the acute painful sickle-cell crisis. Repeated sickling and ongoing haemolytic anaemia, even when subclinical, lead to parenchymal injury and chronic organ damage, causing substantial morbidity and early mortality. Currently available treatments are limited to transfusions and hydroxycarbamide, although stem cell transplantation might be a potentially curative therapy. Several new therapeutic options are in development, including gene therapy and gene editing. Recent advances include systematic universal screening for stroke risk, improved management of iron overload using oral chelators and non-invasive MRI measurements, and point-of-care diagnostic devices. Controversies include the role of haemolysis in sickle cell disease pathophysiology, optimal management of pregnancy, and strategies to prevent cerebrovascular disease.
Summary
Advances achieved over the last three decades have transformed sickle cell disease (SCD) from a fatal childhood disease to a long‐term chronic condition. Consequently, patients must ...transition from paediatric to adult care. The transition is a high‐risk period associated with increases in hospital admissions and death. The factors underlying this increased risk include not only characteristics of the disease itself, with the accumulation of disabilities and progression of organ damage, but also psychological factors and a frequent paucity of adult‐care resources for SCD. Leaving the familiar paediatric team causes marked anxiety in many patients. The transition of care coincides with the many other transitions that characterize the emotional, social and academic development of adolescents. The shift from protection by parents and physicians to independent self‐management may be difficult. Finally, young adults may have limited access to health insurance. In recent years, many medical groups have suggested the development of transitioning programmes combining transition schedules, printed and web‐based materials, and, in some cases, transition‐dedicated physicians, nurses and psychologists. Transition must begin early, involve both the paediatric and the adult team, direct appropriate attention to the parents and occur over a period of several years. Evaluations of these programmes are urgently needed.
The Liver in Sickle Cell Disease Lacaille, Florence; Allali, Slimane; Montalembert, Mariane
Journal of pediatric gastroenterology and nutrition,
January 2021, Letnik:
72, Številka:
1
Journal Article
Recenzirano
ABSTRACT
Liver involvement is found in nearly 40% of children with sickle cell disease. The most frequent complication is cholelithiasis. The most severe complication is acute hepatic crisis, with ...symptoms ranging from increasing jaundice to multiple organ failure and death. The emergency and mostly efficient treatment is exchange transfusion. Chronic cholangiopathy is increasingly recognized, with autoimmune features in most cases, worsened by chronic ischemia. Transfusion‐related iron overload is not yet a concern in children, and hepatotoxicity of iron chelators is rare. We propose recommendations to prevent, explore, and treat these complications. We emphasize the close collaboration required between hepatologists and specialists of sickle cell disease.
Two patients, one with transfusion-dependent β-thalassemia and the other with sickle cell disease, received autologous CD34+ cells edited with CRISPR-Cas9 targeting of
BCL11A
. Their clinical course ...over the following 16 to 18 months supports further experimental testing of CRISPR-Cas9 gene editing to treat these diseases.
Gene Therapy in a Patient with Sickle Cell Disease Ribeil, Jean-Antoine; Hacein-Bey-Abina, Salima; Payen, Emmanuel ...
The New England journal of medicine,
03/2017, Letnik:
376, Številka:
9
Journal Article
Recenzirano
Odprti dostop
A boy with hydroxyurea-refractory sickle cell anemia underwent bone marrow transplantation with autologous hematopoietic stem cells transduced by a lentivirus to express an antisickling β-globin ...variant. No sickle cell crises occurred in the following 15 months.
Sickle cell disease is among the most prevalent inherited monogenic disorders. Approximately 90,000 people in the United States have sickle cell disease, and worldwide more than 275,000 infants are born with the disease annually.
1
,
2
Sickle cell disease was the first disease for which the molecular basis was identified: a single amino acid substitution in “adult” βA-globin (Glu6Val) stemming from a single base substitution (A→T) in the first exon of the human βA-globin gene (
HBB
) was discovered in 1956.
3
Sickle hemoglobin (HbS) polymerizes on deoxygenation, reducing the deformability of red cells. Patients have intensely painful vaso-occlusive . . .
Summary
Sickle cell disease induces specific brain alterations that involve both the macrocirculation and the microcirculation. The main overt neurovascular complications in children are infarctive ...stroke, transient ischaemic attack and cerebral haemorrhage. Silent cerebral infarction, cognitive dysfunction and recurrent headache are also common. Cerebrovascular disease selectively affects children with the HbSS or HbS‐β0 genotypes (i.e. sickle cell anaemia). The incidence of stroke peaks between 2 and 5 years of age (1·02/100 patient‐years) and increases with the severity of the anaemia. Most strokes can be prevented by annual transcranial Doppler screening from 2 to 16 years of age and providing chronic blood transfusion when this investigation shows elevated blood‐flow velocities. The role for hydroxycarbamide in children with abnormal transcranial Doppler findings is under investigation. After a stroke, chronic blood transfusion is very strongly recommended, unless haematopoietic stem cell transplantation can be performed. Routine magnetic resonance imaging shows that more than one‐third of children have silent cerebral infarction, which is associated with cognitive impairments. Screening for silent infarcts seems legitimate, since their presence may lead to supportive treatments. The role for more aggressive interventions such as hydroxycarbamide or chronic blood transfusion is debated.
Hereditary hemolytic anemias are a group of disorders with a variety of causes, including red cell membrane defects, red blood cell enzyme disorders, congenital dyserythropoietic anemias, thalassemia ...syndromes and hemoglobinopathies. As damaged red blood cells passing through the red pulp of the spleen are removed by splenic macrophages, splenectomy is one possible therapeutic approach to the management of severely affected patients. However, except for hereditary spherocytosis for which the effectiveness of splenectomy has been well documented, the efficacy of splenectomy in other anemias within this group has yet to be determined and there are concerns regarding short- and long-term infectious and thrombotic complications. In light of the priorities identified by the European Hematology Association Roadmap we generated specific recommendations for each disorder, except thalassemia syndromes for which there are other, recent guidelines. Our recommendations are intended to enable clinicians to achieve better informed decisions on disease management by splenectomy, on the type of splenectomy and the possible consequences. As no randomized clinical trials, case control or cohort studies regarding splenectomy in these disorders were found in the literature, recommendations for each disease were based on expert opinion and were subsequently critically revised and modified by the Splenectomy in Rare Anemias Study Group, which includes hematologists caring for both adults and children.
Several controlled studies have evidenced good efficacy and short‐term and mid‐term safety profiles for hydroxyurea (HU), which has become the cornerstone for prevention of sickle‐cell disease ...(SCD)‐related vaso‐occlusive crises. However, there are few large‐scale reports on its long‐term use and certain caregivers and patients have concerns about its safety. Following the licensing of HU in Europe for children and adults with severe forms of SCD, ESCORT‐HU was designed as a Phase IV observational cohort study. It included 1906 participants, of whom 55% were adults. The most common hemoglobin (Hb) genotypes were HbSS (84.7%) and HbSβ+ (7.0%). The median duration of follow‐up was 45 months, for a total of 7309 patient‐years of observation. The dose of HU after 1 year was 20.6 mg/kg/d for children and 16.3 mg/kg/d for adults. There was a statistically significant decrease in the number of vaso‐occlusive episodes lasting >48 h, acute chest syndrome episodes, hospitalizations, and the percentage of patients requiring blood transfusions within the first 12 months relative to the year before enrolment. Neutropenia and thrombocytopenia were the most commonly reported adverse effects. No new HU toxicity was identified. Overall, 125 pregnancies were reported in 101 women and no malformations were observed in the neonates. There were 12 pregnancies for partners of male patients treated with HU. One case of fatal myelodysplastic syndrome was reported, for which a causal association with HU could not be excluded. This cohort study of patients with SCD highlights the positive benefit‐to‐risk ratio of HU in children and adults.
Despite its high prevalence in children with sickle cell anemia (SCA), the pathophysiology of silent cerebral infarcts (SCI) remains elusive. The main objective of this study was to explore the ...respective roles of major determinants of brain perfusion in SCA children with no past or current history of intracranial or extracranial vasculopathy. We used a multimodal approach based notably on perfusion imaging arterial spin labeling (ASL) magnetic resonance imaging (MRI) and near infra-red spectroscopy (NIRS), as well as biomarkers reflecting blood rheology and endothelial activation. Out of 59 SCA patients (mean age 11.4±3.9 yrs), eight (13%) had a total of 12 SCI. Children with SCI had a distinctive profile characterized by decreased blood pressure, impaired blood rheology, increased P-selectin levels, and marked anemia. Although ASL perfusion and oximetry values did not differ between groups, comparison of biological and clinical parameters according to the level of perfusion categorized in terciles showed an independent association between high perfusion and increased sP-selectin, decreased red blood cell deformability, low hemoglobin F level, increased blood viscosity and no a-thalassemia deletion. NIRS measurements did not yield additional novel results. Altogether, these findings argue for early MRI detection of SCI in children with no identified vasculopathy and suggest a potential role for ASL as an additional screening tool. Early treatment targeting hemolysis, anemia and endothelial dysfunction should reduce the risk of this under diagnosed and serious complication.
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