Improved stenosis outcome in stroke-free sickle cell anemia children after transplantation compared to chronic transfusion.

We report here the 3-year stenosis outcome in 60 stroke-free children with sickle cell anaemia (SCA) and an abnormal transcranial Doppler history, enrolled in the DREPAGREFFE trial, which compared stem cell transplantation (SCT) with standard-care (chronic transfusion for 1-year minimum). Twenty-eight patients with matched sibling donors were transplanted, while 32 remained on standard-care. Stenosis scores were calculated after performing cerebral/cervical 3D time-of-flight magnetic resonance angiography. Fourteen patients had stenosis at enrollment, but only five SCT versus 10 standard-care patients still had stenosis at 3 years. Stenosis scores remained stable on standard-care, but significantly improved after SCT (P = 0·006). No patient developed stenosis after SCT, while two on standard-care did, indicating better stenosis prevention and improved outcome after SCT.

Association of Matched Sibling Donor Hematopoietic Stem Cell Transplantation With Transcranial Doppler Velocities in Children With Sickle Cell Anemia.

Importance: In children with sickle cell anemia (SCA), high transcranial Doppler (TCD) velocities are associated with stroke risk, which is reduced by chronic transfusion. Whether matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) can reduce velocities in patients with SCA is unknown. Objective: To determine the association of MSD-HSCT with TCD velocities as a surrogate for the occurrence of ischemic stroke in children with SCA. Design, Setting, and Participants: Nonrandomized controlled intervention study conducted at 9 French centers. Patients with SCA were enrolled between December 2010 and June 2013, with 3-year follow-up ending in January 2017. Children with SCA were eligible if younger than 15 years, required chronic transfusions for persistently elevated TCD velocities, and had at least 1 sibling without SCA from the same 2 parents. Families agreed to HLA antigen typing and transplantation if a matched sibling donor was identified or to standard care in the absence of a matched sibling donor. Exposures: MSD-HSCT (n = 32), compared with standard care (n = 35) (transfusions for ≥1 year with potential switch to hydroxyurea thereafter), using propensity score matching. Main Outcomes and Measures: The primary outcome was the highest time-averaged mean of maximum velocities in 8 cerebral arteries, measured by TCD (TCD velocity) at 1 year. Twenty-five of 29 secondary outcomes were analyzed, including the highest TCD velocity at 3 years and normalization of velocities (<170 cm/s) and ferritin levels at 1 and 3 years. Results: Sixty-seven children with SCA (median age, 7.6 years; 35 girls [52%]) were enrolled (7 with stroke history). In the matched sample, highest TCD velocities at 1 year were significantly lower on average in the transplantation group (129.6 cm/s) vs the standard care group (170.4 cm/s; difference, -40.8 cm/s [95% CI, -62.9 to -18.6]; P < .001). Of the 25 analyzed secondary end points, 4 showed significant differences, including the highest TCD velocity at 3 years (112.4 cm/s in the transplantation group vs 156.7 cm/s in the standard care group; difference, -44.3 [95% CI, -71.9 to -21.1]; P = .001); normalization rate at 1 year (80.0% in the transplantation group vs 48.0% in the standard care group; difference, 32.0% [95% CI, 0.2% to 58.6%]; P = .045); and ferritin levels at 1 year (905 ng/mL in the transplantation group vs 2529 ng/mL in the standard care group; difference, -1624 [95% CI, -2370 to -879]; P < .001) and 3 years (382 ng/mL in the transplantation group vs 2170 ng/mL in the standard care group; difference, -1788 [95% CI, -2570 to -1006]; P < .001). Conclusions and Relevance: Among children with SCA requiring chronic transfusion because of persistently elevated TCD velocities, MSD-HSCT was significantly associated with lower TCD velocities at 1 year compared with standard care. Further research is warranted to assess the effects of MSD-HSCT on clinical outcomes and over longer follow-up. Trial Registration: ClinicalTrials.gov Identifier: NCT01340404.

Association between oxidative stress and vascular reactivity in children with sickle cell anaemia and sickle haemoglobin C disease.

Oxidative stress and haemolysis-associated nitric oxide (NO) depletion plays a crucial role in the development of vasculopathy in sickle cell anaemia (SS). However it remains unknown whether oxidative stress and haemolysis levels influence vascular function in patients with sickle haemoglobin C disease (SC). Microvascular response to heat (using Laser Doppler flowmetry on finger), oxidative stress biomarkers, NO metabolites, endothelin-1 and haematological parameters were compared between patients with SS and SC. Vascular function, oxidative and nitrosative markers were also measured in healthy (AA) children. SS and SC had increased plasma advanced oxidation protein products (AOPP), malondialdehyde, plasma antioxidant activities and NO end products, compared to AA. SC had lower catalase activity compared to AA and SS. Haemolytic rate, glutathione peroxidase and nitrotyrosine concentrations were significantly increased in children with SS compared to SC and AA. SS and SC had impaired microvascular reactivity compared to AA. In SS, the plateau phase of the response to local thermal heating was negatively associated with nitrotyrosine and AOPP. No association between vascular function parameters and oxidative stress markers was observed in SC. Mild haemolysis in SC, compared to SS, may limit oxidative and nitrosative stress and could explain the better preserved microvascular function in this group.

Cerebral and muscle microvascular oxygenation in children with sickle cell disease: Influence of hematology, hemorheology and vasomotion.

The present study investigated cerebral and muscle hemoglobin oxygen saturation (tissue oxygen index, TOI) in children with sickle cell anemia (SS), sickle cell hemoglobin C disease (SC) and healthy children (AA). TOI was measured by near-infrared spectroscopy (NIRS) and spectral analysis of the TOI variability was used to assess flowmotion and vasomotion. Arterial oxyhemoglobin saturation (SpO2), hemorheological and hematological parameters were also measured in SS and SC children. Both TOI were lower in SS compared to both AA and SC children, with SC exhibiting lower values than AA children. Cerebral vasomotion expressed in absolute values was enhanced in SS compared to AA and SC children. Muscle vasomotion did not differ between the three groups. Hematocrit, SpO2 and red blood cell deformability were positively associated with cerebral TOI in SS children. We demonstrated that 1) cerebral and muscle TOI were markedly decreased in SS children while the decrease of TOI was milder in SC children, 2) cerebral TOI level was associated with several biological markers in SS children only and 3) cerebral vasomotion was enhanced in SS, possibly to counterbalance the effects of chronic cerebral hypoxia.

Micro- and macrovascular function in children with sickle cell anaemia and sickle cell haemoglobin C disease.

It is unclear whether vascular function is affected similarly in children with sickle cell anaemia (SS) and children with sickle haemoglobin C (SC) disease. Therefore, we compared micro and macrovascular functions in healthy (AA) children, children with SS and SC disease, and assessed their association with physical activity. Participants (24 SS, 22 SC and 16 AA), were compared in terms of 1) thermal hyperaemic response (finger pad warming to 42°C) measured by Laser Doppler techniques, 2) arterial stiffness determined by pulse wave velocity, 3) daily energy expenditure related to moderate and intense physical activities estimated by questionnaire and 4) fitness level, evaluated by the six-minute walk test. Response to heating differed between SS, SC and controls. Peripheral microvascular reactivity was lower and pulse wave velocity higher in SS compared to AA. SC had blunted microvascular reactivity in response to heating compared to AA but pulse wave velocity was not different within the two groups. Physical activity and fitness levels were markedly lower in sickle cell patients compared to healthy controls but no association was observed with vascular function. Microvasodilatory reserve is decreased in both SS and SC patients but only SS patients were also characterised by impaired macrovascular function.

Alpha-thalassaemia promotes frequent vaso-occlusive crises in children with sickle cell anaemia through haemorheological changes.

BACKGROUND: Sickle cell anaemia (SCA) is a severe hereditary haemoglobinopathy characterised by haemorheological abnormalities, which play a role in the occurrence of several acute and chronic clinical complications. While ßS -haplotypes and alpha-thalassaemia modulate SCA clinical severity, their effects on blood rheology have been incompletely described. The aim of this study was to test the effects of these genetic modifiers on the haemorheological properties and clinical complication of children with SCA. PROCEDURE: Steady-state haemorheological profile, biological parameters, ßS -haplotypes, alpha-globin status, vaso-occlusive crisis (VOC) and acute chest syndrome frequencies were analysed in 128 children (aged 5 to 18 years) with SCA. RESULTS: Patients with alpha-thalassaemia showed increased red blood cell (RBC) deformability and aggregation compared to those without. Median VOC rate was higher in patients with homozygous alpha-thalassaemia compared to those with a normal alpha genotype. Conversely, the haemorheological profile and clinical complications were not influenced by the ßS -haplotypes in our study. CONCLUSION: Our results demonstrate that alpha-thalassaemia is associated with higher risk for VOC events in children with SCA, which may be due in part to its effects on RBC deformability and aggregation.

Which side of the balance determines the frequency of vaso-occlusive crises in children with sickle cell anemia: Blood viscosity or microvascular dysfunction?

Vascular resistance and tissue perfusion may be both affected by impaired vascular function and increased blood viscosity. Little is known about the effects of vascular function on the occurrence of painful vaso-occlusive crises (VOC) in children with sickle cell anemia (SCA). The aim of the present study was to determine which side of the balance (blood viscosity or vascular function) is the most deleterious in SCA and increases the risk for frequent hospitalized VOC. Microvascular function, microcirculatory oxygenation and blood viscosity were determined in a group of 22 SCA children/adolescents at steady state and a group of 13 healthy children/adolescents. Univariate analyses demonstrated blunted microvascular reactivity during local thermal heating test and decreased microcirculatory oxygenation in SCA children compared to controls. Multivariate analysis revealed that increased blood viscosity and decreased microcirculatory oxygenation were independent risk factors of frequent VOC in SCA. In contrast, the level of microvascular dysfunction does not predict VOC rate. In conclusion, increased blood viscosity is usually well supported in healthy individuals where vascular function is not impaired. However, in the context of SCA, microvascular function is impaired and any increase of blood viscosity or decrease in microcirculatory oxygenation would increase the risks for frequent VOC.

Physical activity level is not a determinant of autonomic nervous system activity and clinical severity in children/adolescents with sickle cell anemia: A pilot study.

BACKGROUND: Autonomic nervous system (ANS) activity has been suggested to modulate the clinical severity of sickle cell anemia (SCA) by increasing the risk for vaso-occlusive events. Regular physical activity (PA) is known to improve ANS activity and health status in several cardiovascular and metabolic diseases. Whether regular PA improves the health status of SCA patients remains unknown. PROCEDURE: Twenty-two patients with SCA and 15 healthy (AA) children/adolescents participated to the study. Heart rate variability was measured in supine position and after a tilt-test to quantify the ANS activity. PA energy expenditure (PAEE) was assessed with questionnaire. RESULTS: 1) PAEE was lower in SCA compared to AA (190 ± 152 vs. 432 ± 277 kcal · d(-1), respectively, P < 0.01), 2) overall ANS activity was lower in SCA compared to AA, 3) parasympathetic withdrawal was observed in SCA with aging, 4) ANS reactivity was slightly impaired in SCA compared to AA (reduction in HFnu: -38 ± 27 vs. -58 ± 14%, respectively, P < 0.05), 5) ANS indices, PAEE, and rates of clinical events were not correlated. CONCLUSION: Both the level of PA and ANS activity are reduced in SCA compared to AA children/adolescents, particularly in those older than 15 years. Neither PAEE, nor ANS activity seem to influence the clinical severity of children/adolescents with SCA.

Hematologic and hemorheological determinants of resting and exercise-induced hemoglobin oxygen desaturation in children with sickle cell disease.

The aim of the study was to determine the factors associated with resting and exercise-induced hemoglobin oxygen desaturation. The well-established six-minute walk test was conducted in 107 sickle cell children (50 with sickle hemoglobin C disease and 57 with sickle cell anemia) at steady state. Hemoglobin oxygen saturation was measured before and immediately after the six-minute walk test. Blood samples were obtained on the same day to measure hematologic and hemorheological parameters. Exercise-induced hemoglobin oxygen desaturation was defined as a drop in hemoglobin oxygen saturation of 3% or more at the end of the six-minute walk test compared to resting levels. No children with sickle hemoglobin C disease, but approximately 50% of children with sickle cell anemia showed mild or moderate oxygen desaturation at rest, which was independently associated with the percentage of reticulocytes. Exercise-induced hemoglobin oxygen desaturation was observed in 18% of children with sickle hemoglobin C disease and 34% of children with sickle cell anemia, and was independently associated with the six-minute walk test, acute chest syndrome rate and the strength of red blood cell aggregates in children with sickle cell anemia. No association was found in children with sickle hemoglobin C disease between exercise-induced hemoglobin oxygen desaturation and the measured parameters. Hemoglobin oxygen desaturation at rest was common in children with sickle cell anemia but not in children with sickle hemoglobin C disease, and was mainly associated with greater hemolysis. Physiological strain during exercise and red blood cell aggregation properties may predict the occurrence of exercise-induced hemoglobin oxygen desaturation in children with sickle cell anemia.

Hemorheological risk factors of acute chest syndrome and painful vaso-occlusive crisis in children with sickle cell disease.

BACKGROUND: Little is known about the effects of blood rheology on the occurrence of acute chest syndrome and painful vaso-occlusive crises in children with sickle cell anemia and hemoglobin SC disease. DESIGN AND METHODS: To address this issue, steady-state hemorheological profiles (blood viscosity, red blood cell deformability, aggregation properties) and hematologic parameters were assessed in 44 children with sickle cell anemia and 49 children with hemoglobin SC disease (8-16 years old) followed since birth. Clinical charts were retrospectively reviewed to determine prior acute chest syndrome or vaso-occlusive episodes, and rates of these complications were calculated. RESULTS: Multivariate analysis revealed that: 1) a higher steady-state blood viscosity was associated with a higher rate of vaso-occlusive crises in children with sickle cell anemia, but not in children with hemoglobin SC disease; 2) a higher steady-state red blood cell disaggregation threshold was associated with previous history of acute chest syndrome in children with hemoglobin SC disease and boys with sickle cell anemia. CONCLUSIONS: Our results indicate for the first time that the red blood cell aggregation properties may play a role in the pathophysiology of acute chest syndrome in children with hemoglobin SC disease and boys with sickle cell anemia. In addition, whereas greater blood viscosity is associated with a higher rate of vaso-occlusive crises in children with sickle cell anemia, no association was found in children with hemoglobin SC disease, underscoring differences in the etiology of vaso-occlusive crises between sickle cell anemia and hemoglobin SC disease.

Dengue in hospitalized children with sickle cell disease: A retrospective cohort study in the French departments of America.

BACKGROUND: To describe the characteristics of dengue in sickle cell children and try to identify risk factors of severity. METHODS: In this retrospective study, we describe the evolution according to genotype (SS or SC and controls) and severity. RESULTS AND CONCLUSIONS: From 2005 to 2013, 106 hospitalizations for dengue fever were recorded, 35 SS genotype, 35 SC and 36 without SCD or any other chronic disease. The clinical evolution was quite different. During hospitalization, SC patients were more likely to develop multiorgan failure (31.4% versus 25.7% for SS, and 0% for controls, p=0.001), or acute pulmonary complications than patients without SC sickle cell disease (14.3% versus 8.6% for SS, and 0% for controls, p=0.03). Level 3 analgesic treatment was more frequent in SC patients (22.9% versus 3% for SS, and 0% for controls, p<0.001). Patients with SC sickle cell disease had a higher proportion of severe forms of dengue (57.1% versus 37.1% for SS, and 0% for controls, p<0.001) than patients without SC sickle cell disease. Transfer in intensive care unit was required for most SC patients (22.9% versus 3% for SS, and 0% for controls, p=0.005).Fatal episodes were more frequent in SC patients than in patients without SC sickle cell disease (5 deaths versus 1 for SS and 0 for controls, p=0.02). Thirty-three patients (47.1%) were diagnosed as having severe dengue (13 SS and 20 SC). On univariate analysis, age >10 years, acute pulmonary complications, multiorgan failure, severe anemia requiring transfusion, use of antibiotic treatment, need for treatment with morphine, and longer hospital stay were statistically more frequent in severe dengue-associated cases. Multiple logistic regression analysis showed that HbSC genotype and acute pulmonary complications, were significantly associated with severe dengue. In the multivariate model, the area of the ROC curve was 0.831. Children with SC genotype, typically thought to have less severe disease, actually had a higher rate of severe dengue and death than those with SS genotype.

Effect of Age on Blood Rheology in Sickle Cell Anaemia and Sickle Cell Haemoglobin C Disease: A Cross-Sectional Study.

OBJECTIVES: Blood rheology plays a key role in the pathophysiology of sickle cell anaemia (SS) and sickle cell haemoglobin C disease (SC), but its evolution over the lifespan is unknown. MATERIALS AND METHODS: Blood viscosity, red blood cell (RBC) deformability and aggregation, foetal haemoglobin (HbF) and haematocrit were measured in 114 healthy individuals (AA), 267 SS (161 children + 106 adults) and 138 SC (74 children + 64 adults) patients. RESULTS: Our results showed that 1) RBC deformability is at its maximal value during the early years of life in SS and SC populations, mainly because HbF level is also at its peak, 2) during childhood and adulthood, hydroxycarbamide treatment, HbF level and gender modulated RBC deformability in SS patients, independently of age, 3) blood viscosity is higher in older SS and SC patients compared to younger ones and 4) haematocrit decreases as SS patients age. CONCLUSION: The hemorheological changes detected in older patients could play a role in the progressive development of several chronic disorders in sickle cell disease, whose prevalence increases with age. Retarding these age-related haemorheological impairments, by using suitable drugs, may minimize the risks of vaso-occlusive events and chronic disorders.

Universal newborn screening for haemoglobinopathies in Guadeloupe (French West Indies): a 27-year experience.

OBJECTIVES: In Guadeloupe, an island in the French West Indies, a universal newborn screening programme for sickle cell disease and other abnormal haemoglobins was initiated in 1984. In 1990, a comprehensive sickle cell centre was established to carry on the management programme. We here report the main results from the newborn screening programme from 1984 to 2010, and consider how the establishment of the sickle cell centre affected the programme. METHODS: All blood samples were screened for the haemoglobinopathies using two reference methods in a single reference diagnosis laboratory. DNA analyses were also performed for confirmatory tests and analysis of the globin gene status. RESULTS: Between 1 January 1984 and 31 December 2010, 178,428 newborns were screened at birth, and 585 children were diagnosed with major sickle cell syndromes (ie. an overall incidence of 1 in 304 births). Sickle cell anaemia (haemoglobin SS disease) was the most frequently observed (1 in 575 births), followed by haemoglobin SC disease (1 in 771 births) and haemoglobin Sß-thalassemia disease (1 in 4,243 births). Some other rare haemoglobin variants were also detected, the most common being HbD(Punjab). The establishment of a comprehensive sickle cell centre resulted in a significant improvement in the screening coverage (p < 0.001) and a significant reduction of the delay between diagnosis and the first medical visit (p < 0.001). CONCLUSION: The universal screening programme has made it possible to establish the incidence of the major sickle cell syndromes in Guadeloupe, and the management centre has improved its efficiency.

Hematological and hemorheological determinants of the six-minute walk test performance in children with sickle cell anemia.

The six-minute walk test is a well-established submaximal exercise reflecting the functional status and the clinical severity of sickle cell patients. The aim of the present cross-sectional study was to investigate the biological determinants of the six-minute walk test performance in children with sickle cell anemia. Hematological and hemorheological parameters, pulmonary function and the six-minute walk test performance were determined in 42 children with sickle cell anemia at steady state. The performance during the six-minute walk test was normalized for age, sex and height and expressed as percentage of the predicted six-minute walk distance. We showed that a high level of anemia, a low fetal hemoglobin expression and low red blood cell deformability were independent predictors of a low six-minute walk test performance. This study describes for the first time the impact of blood rheology in the six-minute walk test performance in children with sickle cell anemia.