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  • 1
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    Prevalence of Extracranial Internal Carotid Arteriopathy in Stroke-Free SCA-Children: A New Risk Factor for Silent Strokes
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 88-88
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 88-88
    Abstract: Abstract 88 Background. Strokes are a well-known complication of sickle-cell anemia (SCA), and are largely due to intracranial arteriopathy, detected by routine transcranial Doppler (TCD). Adams et al. showed in the STOP I trial (N Engl J Med, 1998) the efficiency of transfusion programs for primary stroke prevention in patients identified by TCD as being at risk of stroke. We recently reported in the CHIC newborn cohort (Bernaudin et al., Blood, 2011) that early TCD imaging (TCDI) screening significantly reduces the risk of stroke by age 18 from the previously reported 11% to only 1.9%, but has not allowed adequate prevention of silent infarcts, with a risk of 37.1% by age 14, suggesting that TCDI does not distinguish all SCA-patients at risk of silent infarcts. Extracranial internal carotid artery (eICA) vasculopathy is considered rare and has not been routinely assessed; however, several recent cases of stroke with extracranial arteriopathy prompted the inclusion of eICA evaluation in routine screening. The aim of the study was to establish the ranges of eICA velocities in SCA-patients, to determine the cut-off limits of velocities predictive of eICA stenoses by extracranial MRA, to evaluate the prevalence of abnormal eICA velocities and to determine their association with intracranial stenoses and/or silent infarcts by MRI. Methods. Since June-2011, all stroke-free SCA patients from the CHIC and Debre cohorts who had routine yearly TCDI for intracranial arteries were also systematically assessed for eICA using submandibular windows (Gorman et al., Neurology 2009) and the same 2Mhz TCDI transducer probe. Time-averaged mean of maximum velocities (TAMMV) were obtained for intra and extracranial cerebral arteries. By color Doppler mapping, the course of eICA was considered as straight, or as tortuous if the artery changed direction with an angle 〉 120° between adjacent segments. Extracranial cervical MRA was added to routine intracranial MRI/MRA, performed every 2 years or as soon as abnormal velocities were found. Results. Between June 2011 and January 2012, 435 consecutive SCA-children from the two cohorts (202M, 233F) were assessed by Doppler at the median age of 8.5 years (range: 1.3–18.7). MRI/intra and extracranial MRA was performed in 104 patients. At time of Doppler assessment, mean±SD hemoglobin was 9.1±1.6 g/dl. eICA velocities were significantly correlated with middle cerebral arteries (MCA) velocities (r=0.234, p 〈 0.001), and were about 25–30% lower than MCA velocities (mean:95±38 vs 127±32 cm/sec). As for MCA, eICA velocities were maxima between 3–7 years of age. eICA tortuosities were echo-detected in 25% cases (107/435), and were more frequent in boys (65/202; 32%) than in girls (42/233; 18%), p 〈 0.001. Regression logistic analysis showed that tortuosities were not associated with age, but significantly associated with males (OR:2.2, 95%CI:1.4–3.4, p=0.001). Cervical MRA found stenoses in 40/104 patients. ROC curve showed that eICA velocities ≥ 160 cm/sec were highly predictive of stenoses on eMRA (100% specificity, 80% sensitivity). The prevalence of eICA velocities ≥ 160 cm/sec was 10.3% (45/435), and was significantly higher in males (14.9% vs 6.4%; p=0.004). Low hemoglobin (OR:2.6/1g/dl decrease, 95%CI:1.4–4.6; p=0.002) and tortuosities (OR:14.5, 95%CI:4.1–50; p 〈 0.001) were significant and independent risk factors for eICA velocities ≥ 160cm/sec. Intracranial stenoses were detected in 29/104 patients, while 40/104 patients had extracranial stenoses with 31/40 showing no intracranial stenoses. Silent infarcts were detected in 35/104 patients, and were highly associated with the presence of intra and/or extracranial stenoses (30/35: 86%, p 〈 0.001). Intra (OR:5.1,95% CI:1.9–13.8, p=0.002) and extracranial (OR:4.5, 95% CI:1.7–11.6; p=0.002) stenoses were significant and independent risk factors for silent infarcts. Conclusion. This study shows for the first time that in cohorts previously assessed early by TCDI for intracranial arteries, about 10% stroke-free patients have eICA vasculopathy. Moreover, we show that intra and/or extracranial stenoses are significant risk factors for silent infarcts. These data may explain why silent infarcts still occurred in patients early assessed by TCDI exploring only intracranial arteries. Thus, extracranial Doppler assessment should be routinely done with TCD to evaluate the full extent of cerebral vasculopathy in SCA. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.88.88
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 2
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    French National Drepagreffe Trial: Cognitive Performances and Neuroimaging at Enrollment and after 12 Months on Transfusion Program or Transplantation (AP-HP: NCT 01340404)
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 544-544
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 544-544
    Abstract: Background: "Drepagreffe" is a French national prospective trial involving 67 sickle cell anemia (SCA)-children with a history of abnormal cerebral arterial velocities by TCD, and comparing for the first time the outcome of cerebral vasculopathy following transfusion program (TP) or transplantation (HSCT). Inclusion criteria at enrollment were children with SCA (SS/Sb0), younger than 15 years, with a history of abnormal cerebral arterial velocities (TAMMX ≥ 200 cm/sec) and placed on long-term TP, with at least one non-SCA sibling, and with parents accepting HLA-typing and HSCT if a genoidentical donor was available. The 2 arms (TP/HSCT) were defined by the random-availability of a genoidentical donor. Seven of the 67 patients had a history of stroke. Transplanted patients (n=32) received a conditioning regimen of Busilvex-CY 200 mg/kg and 20 mg/kg rabbit Thymoglobulin, with CSA and a short course of MTX or MMF for GvHD prophylaxis. In the TP arm (n=35), HbS% was maintained at 〈 30%, with an Hb at 9-11g/dL. At enrollment and 12 months post-enrollment, blood screening, Doppler, and cerebral MRI/MRA were performed along with cognitive performance testing, the latter being done in parallel in the non-SCA siblings. Preliminary findings on cerebral velocities as the primary endpoint were reported at the last ASH meeting (abstract 67237), and demonstrated that all patients were alive at one year and that the 32 transplanted patients had no chronic GVHD and the same hemoglobin profile as their donor. Velocities were significantly lower post-HSCT than under TP (p 〈 0.001), and were normalized in a greater number of patients (p =0.003). Patients and Methods: We report here the cerebral imaging (MRI/MRA) and cognitive performance data performed at enrollment and after 12 months. The scoring applied for MRI was: 3 = territorial, 2 = borderzone (cortical and subcortical), 1 = white matter or basal ganglia infarcts, 0 to 3 = atrophia, and for MRA: 1 = mild stenosis (25-49%), 2 = moderate stenosis (50-74%), 3 = severe stenosis (75-99%), 4 = occlusion for each artery and 0 to 2 for Moya presence. Cognitive testing using the WPPSI-3 (3-6 yr), WISC-4 (7-16 yr) or WAIS-3 ( 〉 16 yr) scales, depending on the age, was performed in patients and in siblings when possible. Results: MRI/MRA data were available in 66/67 patients. At enrollment (M0), ischemic lesions and stenoses were present in 25 and 35/66 patients, respectively. Cognitive testing was obtained in 64 patients and 56 siblings. Paired analysis with siblings (Table 1) showed significant differences in Verbal Comprehension Index (VCI) with a mean difference of 7.6±14.5(p =0.0004), Processing Speed Index (PSI) 6.3±20.5 (p =0.04), and Full Scale IQ (FSIQ) 7.3±15.0 (p =0.01). After exclusion of the 7 patients with stroke history, significant differences were still observed in VCI (p =0.013) and FSIQ (p =0.019). Patient cognitive performance indexes were correlated negatively and significantly with the MRI and MRA scores (Table 2). At post-enrollment (M12),ischemic lesions and stenoses were present in 26/66 patients. The mean variation in MRI and MRA scores between M12 and M0 was not significantly different between the 2 arms (Table 3). The cognitive tests were performed at M12 in 60 patients (Table 4) and the performance indexes were improved in the TP compared to the HSCT arm, but only significantly for FSIQ. Conclusion This first prospective trial initially showed that HSCT reduces more significantly the cerebral velocities at M12 and in a higher proportion of patients than TP. Here, we show that patients with a history of abnormal cerebral velocities had significantly lower cognitive performances than their siblings, even in the absence of stroke history; however, there was no significant difference between the 2 arms for the outcomes of ischemic lesions and stenosis at M0 and M12. The fact that cognitive performances were improved in the TP compared to the HSCT arm might be explained by the stress of the HSCT procedure and the lack of schooling during this period. Despite the higher ability of HSCT to decrease velocities at M12 compared to TP, a longer follow-up will be required to demonstrate its effect on stenosis and cognitive performances; therefore, patients will be reassessed at 3 years post-HSCT. Disclosures Bernaudin: Novartis: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.544.544
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 3
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    Tuberculosis in children with sickle cell anaemia: a retrospective study in French tertiary care centres
    Springer Science and Business Media LLC ; 2017
    In:  European Journal of Pediatrics Vol. 176, No. 6 ( 2017-6), p. 723-729
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    In: European Journal of Pediatrics, Springer Science and Business Media LLC, Vol. 176, No. 6 ( 2017-6), p. 723-729
    Type of Medium: Online Resource
    ISSN: 0340-6199 , 1432-1076
    URL: Article
    DOI: 10.1007/s00431-017-2905-0
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
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  • 4
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    Stroke without Cerebral Vasculopathy in Sickle Cell Disease Children: Which Causes? Which Treatment?
    American Society of Hematology ; 2021
    In:  Blood Vol. 138, No. Supplement 1 ( 2021-11-05), p. 2041-2041
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    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 2041-2041
    Abstract: Sickle cell disease (SCD) is a severe hemoglobinopathy due to abnormal hemoglobin S (HbS). One of the most serious complications of SCD is cerebral vasculopathy (CV) leading to ischemic stroke in 8% of homozygous SS children without prevention strategy. Typical CV in SCD is a stenosis of one or more intracranial or cervical arteries, including internal carotid arteries, anterior cerebral arteries and middle cerebral arteries. However, several studies have reported the occurrence of stroke in SCD children in the absence of typical cerebral vasculopathy. The aim of the study is to investigate the prevalence of stroke without CV in SCD children, and to compare them to "classical" stroke (i.e in a context of typical CV) in terms of suspected etiologies, triggering events, treatment and risk of recurrence. In a large cohort of about 1500 SCD children living in Paris area, France, we recorded all the strokes occurring between 2007 and 2020, excluding venous thrombosis and PRESS Syndrome. These children were followed in a university hospital, and all benefited from early screening for cerebral vasculopathy and an adapted stroke prevention program. We considered as a "typical" stroke any new ischemic lesion of the cerebral parenchyma associated with an acute neurological syndrome occurring in the territory of a pre-existing and/or non-regressive stenosis. 25 strokes occurred during the study period. 12 of them (48%) did not met the definition of a "typical" stroke related to sickle cell CV. The children with "atypical" stroke were older (9 years old +/- 4.6, vs 6.5 years old +/- 4.3 in the typical group, p = 0.0086) and less frequently of SS genotype (33% non-SS vs 8% non-SS in the typical group). They had lower leukocyte count (11.3 G/L +/- 4.6, vs 15.7 G/L +/- 2.3 in the typical group, p=0. 04) and higher hemoglobin level at the time of the stroke (11 g/dl +/- 3 vs 7.4 g/dl +/- 1.3 in the typical group, p= 0.027). 17% of atypical strokes had posterior ischemic lesions, 33% had anterior lesions and 17% had multiple systematized lesions, in counting junctional lesions. We also found 33% of ischemic lesions of the cerebellum. Considering a potential trigger of the stroke, 58% of atypical events were hospitalized in an anesthesia or intensive care unit at the time of the stroke or less than 7 days before, compared to 8% of children with a "classic" stroke (p= 0.011). The etiologies adopted by clinicians and radiologists for the atypical stroke were reversible cerebral vasoconstriction syndrome (RCVS) (Figure 1), cerebral fat embolism, hyperviscosity and vasculitis in systemic inflammatory context. The evolution in the atypical group was more favorable in terms of recurrence (0% within 2 years vs 42 % in the typical group, p= 0.045), although only 33% (3 children) of atypical strokes were still under exchange transfusion program 24 months after the stroke vs 92% in the group of typical stroke. Overall, in a cohort of SCD children with efficient stroke prevention program, atypical strokes account for nearly half of all acute ischemic neurological events, related to hyperviscosity, RVCS or inflammatory vasculitis. Physicians must be aware of the potential triggers and of the context in which such events occur. Nevertheless, stroke without CV may not require long-term transfusion program contrary to stroke with CV, given the very low risk of recurrence we highlighted. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2021-147757
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
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  • 5
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    Cerebral Arterial Velocities in SCA-Children with Abnormal Doppler Are Reduced and Normalized More Frequently after Transplantation Than after Transfusion Program (French National Trial “Drepagreffe” AP-HP N°: NCT 01340404)
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 561-561
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    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 561-561
    Abstract: Background : Evidence-based practices have shown that transfusion program (TP) is beneficial to SCA-patients with abnormally high velocities by Doppler; however, TP cannot be stopped safely, except following HSCT. No prospective trial has to date compared the extent of cerebral vasculopathy following TP or HSCT. The premise of the French National Trial “Drepagreffe” is that cerebral velocities will be reduced to a greater extent after HSCT than under TP. Patients and Methods : We present here preliminary results from this prospective trial with 2 arms (TP/HSCT), defined by the random-availability of a genoidentical donor. Inclusion criteria were SCA (SS/Sb0) children younger than 15 years with a history of abnormal cerebral arterial velocities (TAMMX ≥ 200 cm/sec), placed on long-term transfusion programs, with at least one non-SCA sibling and parents accepting HLA-typing and HSCT if a genoidentical donor was available. Transplanted patients received as conditioning regimen Busilvex-CY 200 mg/kg and 20 mg/kg rabbit Thymoglobulin with CSA and short MTX or MMF for GVHD prophylaxis. In the TP arm, HbS% was maintained at 〈 30% with Hb 9-11g/dL. At enrollment and 12 months post-enrollment, blood screening, Doppler, cerebral MRI/MRA were performed along with cognitive performance testing, the latter done in parallel in the control sibling. Primary endpoint was the significantly greater reduction of velocities in the HSCT than in the TP arm. Among the various secondary endpoints, Doppler normalization defined by velocities 〈 170 cm/s in all arteries was to occur more often after HSCT than on TP. Results: SCA-children (n=67; 36F-31M) from 10 French SCA-centers were enrolled between 12/2010 and 6/2013 at the mean (SD) age of 7.6 (3.1) years. History of stroke was present in 6 patients (4 in HSCT and 2 in TP) and 1 TIA in HSCT arm. At TP initiation, velocities≥200/cm/sec were found in middle (n=50), anterior (n=11) and internal carotid arteries (n=30) as abnormal velocities were observed in more than one artery in several patients. Mean (SD) maximum velocities were 219 (26) cm/s (range: 200-333). At enrollment all patients were on TP and paired analysis showed that mean(SD) maximum velocities had significantly decreased (p 〈 0.001) under TP:169 (46) cm/s vs 219 (26) cm/s). Following HLA-typing, 35 without genoidentical donor were included in the transfusion arm and 32 with genoidentical donor were transplanted in 6 HSCT-centers. Mean (SD) maximum velocities were not significantly different in both arms at enrollment: 167 (41) in TP vs 170 (51) cm/s in HSCT. During the 12 months follow-up, no stroke was observed but one patient in the TP arm experienced a hyperammonemic reversible coma, without MRI/MRA alteration requiring transfer to intensive care. In the HSCT arm, all patients successfully engrafted, one grade II and two grade III acute GVHD, and no chronic GVHD were observed. Two patients required transfer to intensive care for seizures and pneumonia. Other complications were seizures (n=2), CMV (n=9) or EBV replications (n=1), hemorrhagic cystitis (n=3), aspergillosis (n=1), prolonged but reversible thrombopenia (n=2), transitory hemolytic anemia (n=1). At 12 months, data, available in 63/67 patients, showed that all patients were alive, mean (SD) Hb and HbS% in TP arm were 9.1 (0.9) and 27.5% (11.9), respectively, whereas in the HSCT arm, mean (SD) Hb and % donor chimerism were 12.0 (1.0) g/dL and 86.5% (12.2) respectively (range:60-100%). All transplanted patients had the same Hb electrophoresis than their donor. Mean (SD) maximum velocities were significantly lower post-HSCT (n=31) than under TP (n=32):128 (34) vs 174 (36) cm/s, respectively; (p 〈 0.001), and were decreased more significantly following HSCT than on TP: mean(SD)Δ: -44 (24) vs +6 (3), respectively. The percentage of patients with normal velocities was significantly higher post-HSCT (27/31) than in the TP arm (16/32) (p=0.003). Conclusions: This prospective national trial comparing TP vs. HSCT in SCA-patients with a history of abnormal velocities shows for the first time that HSCT repeatedly and significantly results in a greater decrease in velocities than TP, and has very little toxicity. These preliminary results are encouraging and suggest that suppression of host SCA-erythropoiesis by HSCT is the treatment of choice for SCA-children with abnormal-TCD and genoidentical donor. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Bernaudin: Novartis: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.561.561
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 6
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    Comparative histological analysis of spleens in pediatric patients with hemolytic anemias: Insights into the pathophysiological mechanisms of spleen destruction in sickle cell anemia
    Wiley ; 2024
    In:  American Journal of Hematology Vol. 99, No. 9 ( 2024-09), p. 1670-1679
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    In: American Journal of Hematology, Wiley, Vol. 99, No. 9 ( 2024-09), p. 1670-1679
    Abstract: While sickle cell anemia (SCA) and hereditary spherocytosis (HS) share common features of increased spleen erythrophagocytosis due to increased red blood cell (RBC) turnover, SCA is specifically characterized by susceptibility to infections. In this study, histological lesions in the spleens of pediatric patients with SCA were analyzed, in close correlation with past clinical history and comparatively to HS, healthy and transfused β‐thalassemia patients (TDT). An evaluation of red pulp elementary lesions (red pulp fibrosis, iron deposition, number of Gandy–Gamna, and RBC trapping) combined into a severity score was established, as well as B‐cell follicles analysis. Quantification on digitalized slides of iron deposition, RBC trapping, and red pulp fibrosis was additionally performed. Spleens from 22 children with SCA, eight with HS, eight with TDT, and three healthy controls (HC) were analyzed. Median age at splenectomy was not different between SCA and HS patients, 6.05 years (range: 4.5–16.0) versus 4.75 (range: 2.2–9.5). Marked heterogeneity was found in SCA spleens in contrast to other conditions . Contrary to previous reports, B‐cell follicles were generally preserved in SCA. While RBC trapping was significantly increased in both SCA and HS (compared to TDT and HC), quantitative fibrosis and overall red pulp severity score were significantly increased in SCA spleens compared to other conditions. Moreover, there was an inverse correlation between quantitative fibrosis and number of B‐cell follicles, linking these two compartments as well as spleen fibrosis to infectious susceptibility in SCA, potentially through impaired red pulp macrophage scavenging and B‐cell subpopulations defects.
    Type of Medium: Online Resource
    ISSN: 0361-8609 , 1096-8652
    URL: Issue
    URL: Article
    DOI: 10.1002/ajh.v99.9
    DOI: 10.1002/ajh.27374
    Language: English
    Publisher: Wiley
    Publication Date: 2024
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  • 7
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    Association of Matched Sibling Donor Hematopoietic Stem Cell Transplantation With Transcranial Doppler Velocities in Children With Sickle Cell Anemia
    American Medical Association (AMA) ; 2019
    In:  JAMA Vol. 321, No. 3 ( 2019-01-22), p. 266-
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    In: JAMA, American Medical Association (AMA), Vol. 321, No. 3 ( 2019-01-22), p. 266-
    Type of Medium: Online Resource
    ISSN: 0098-7484
    URL: Article
    DOI: 10.1001/jama.2018.20059
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    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2019
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    detail.hit.zdb_id: 2018410-4
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  • 8
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    Risk Factors For Cerebral Vasculopathy In a Sickle Cell Disease Newborn Cohort
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 4685-4685
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    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 4685-4685
    Abstract: Children with sickle cell disease (SCD) have a significant vascular morbidity responsible of pain and stroke. They are at high risk of cerebral vasculopathy (CV) that can be detected in these children by transcranial Doppler. The aim of this study was to identify risk factors for CV using longitudinal data in the 375 newborn cohort of Robert Debre Pediatric Sickle Cell Referral Center. Among the 59 children presented CV, seven had a stroke. There was a total of 2677 patient-years of follow up. Overall, the incidence rate of CV was 2.20/100 patient-years (95% CI 1.64-2.76) and the incidence rate of stroke was 0.26/100 patient-years (95% CI 0.07-0.46). The cumulative risk of CV by age 14 years was 26.0% (95% CI 20.0%-33.3%).To take into account longitudinal data, risk factors of CV were assessed by a survival Cox model built in two steps. The final Cox multivariable analyze for CV retained five variables. Upper airways obstruction (HR 1.41 95%CI 1.00-1.98), bronchial obstruction (HR 2.13 95%CI 1.77-2.57), acute anemic event (HR 1.15 95%CI 1.01-1.32) and reticulocyte count (HR 1.41 per 20000/mm3 increase 95%CI 1.16-1.71) were independent risk factors whereas hydroxycarbamide therapy (HR 0.03 95%CI 0.01-0.35) was protective. Evaluation and specific treatment for symptoms of asthma or sleep apnea or nocturnal respiratory abnormalities could potentially reduce the risk of CV and stroke after treatment. Our findings suggest that hydroxycarbamide could protect from CV. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.4685.4685
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 9
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    Probability of TCD-Normalization in the "Drepagreffe" Trial Comparing Transplantation to Chronic Transfusion in Sickle Cell Anemia Children with Abnormal-Transcranial Doppler Is Associated with Lower Ang-2 and BDNF Plasma Levels
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 506-506
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 506-506
    Abstract: Sickle cell anemia (SCA) is a chronic illness that causes an increased risk of stroke and progressive brain and cognitive dysfunction. SCA-related cerebral vasculopathy includes vascular remodeling, abnormal arterial velocities and infarction. We studied the relationship between cytokines, velocities, and blood parameters in SCA-children enrolled in the "Drepagreffe" trial, a French prospective, Mendelian-randomized trial with 2 arms (transfusions/transplantation) defined by random-availability of a HLA-matched sibling. This trial enrolled SCA-children younger than 15, regularly transfused for abnormal-TCD history, with at least one non-SCA sibling, and parents agreeing to HLA-typing and transplantation. Between 12/2010 and 6/2013, 67 SCA-children (7 with stroke history) were enrolled. Thirty-two had a matched-sibling donor (MSD) and were transplanted, while 35 (no donor) were included in the transfusion arm. Hypoxia/angiogenesis and brain injury-related factor expression at 1-year was one of the trial secondary outcome. Elevated plasma BDNF and PDGF-AA have been shown to be significantly associated with high cerebral velocities (Hyacinth 2012). Chronic transfusion has been shown to reduce vascular endothelial activation and thrombogenicity in SCA-children with abnormal-TCD (Hyacinth 2014) but no study has been performed in transplanted SCA-children. Plasma samples were obtained at enrollment and 1-year post-enrollment and stored frozen. The expression of the following cytokines (VEGF, Ang-1, Ang-2, FGFb, HGF, PDGF-BB, BDNF) was assessed with a multiplex immunoassay (Bio-Techne). Ang-2, and BDNF levels were confirmed with specific enzyme-linked immunosorbent assays (ELISA, Bio-Techne). Blood parameters, velocities, ischemic lesions and stenoses were assessed at enrollment and 1-year post-enrollment. At 1-year, the percentage of patients with normalized-TCD (velocities 〈 170cm/sec) was significantly higher in transplanted patients than in those maintained on chronic transfusion (27/32 (84%) vs 17/35 (49%), respectively; p=0.001). As shown (Table), leukocytes, neutrophils, platelets, reticulocytes, LDH, bilirubin, ferritin, HbS% were highly significantly lower in transplanted children than in those maintained on chronic transfusion, while hemoglobin and HbA% were highly significantly higher. Ang-2 and HGF were significantly lower in transplanted children than in those on chronic transfusion (p 〈 0.001 and p=0.002, respectively). Velocities recorded in the artery with the highest values were significantly positively correlated with Ang-2 (r=0.385, p=0.015) and BDNF (r=0.444, p=0.005). Logistic regression analysis showed that TCD-normalization was significantly associated with the transplantation arm (OR=5.72 (95%CI:1.79-18.27); p=0.003). High hemoglobin (OR=1.49 per 1g/dL increase; 95%CI: 1.08-2.06; p=0.014) and HbA% (OR=1.05 per1% increase; 95%CI: 1.01-1.10; p=0.014) were significantly positively associated with TCD-normalization, but not independently. Higher levels of Ang-2 (OR=0.51 per 1 pg/mL increase, 95%CI:0.29-0.91; p=0.023) and BDNF (OR=0.69 per 1 pg/mL increase, 95%CI:0.50-0.94; p=0.02) were negatively and independently significantly associated with TCD-normalization. Multivariate analysis, also including the treatment arm, showed that BDNF remained an independent risk factor for a lack of TCD-normalization (OR=0.65, 95%CI:0.45-0.92: p=0.017). This study confirms the association between high levels of BDNF and high velocities, and suggests that transplantation increases the likelihood of TCD-normalization compared to transfusion, and is associated with reduced Ang-2 expression in plasma, which may reflect improved brain oxygenation. Disclosures Thuret: Addmedica: Research Funding; bluebird bio: Research Funding; Novartis: Research Funding. Pondarré:Addmedica: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Blue Bird Bio: Honoraria. Bernaudin:AddMedica: Honoraria; Pierre fabre: Research Funding; Cordons de Vie: Research Funding; BlueBirdBio: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-118091
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
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    Online Resource
    Delayed haemolytic transfusion reaction in paediatric patients with sickle cell disease: A retrospective study in a French national reference centre
    Wiley ; 2023
    In:  British Journal of Haematology Vol. 201, No. 1 ( 2023-04), p. 125-132
    Details
    In: British Journal of Haematology, Wiley, Vol. 201, No. 1 ( 2023-04), p. 125-132
    Abstract: Delayed haemolytic transfusion reaction (DHTR) is a life‐threatening haemolytic anaemia following red blood cell transfusion in patients with sickle cell disease, with only scarce data in children. We retrospectively analysed 41 cases of DHTR in children treated between 2006 and 2020 in a French university hospital. DHTR manifested at a median age of 10.5 years, symptoms occurred a median of 8 days after transfusion performed for an acute event (63%), before surgery (20%) or in a chronic transfusion programme (17%). In all, 93% of patients had painful crisis. Profound anaemia (median 49 g/L), low reticulocyte count (median 140 ×10 9 /L) and increased lactate dehydrogenase (median 2239 IU/L) were observed. Antibody screening was positive in 51% of patients, and more frequent when there was a history of alloimmunisation. Although no deaths were reported, significant complications occurred in 51% of patients: acute chest syndrome (12 patients), cholestasis (five patients), stroke (two patients) and kidney failure (two patients). A further transfusion was required in 23 patients and corticosteroids were used in 21 to reduce the risk of additional haemolysis. In all, 13 patients subsequently received further transfusions with recurrence of DHTR in only two. The study affords a better overview of DHTR and highlights the need to establish guidelines for its management in children.
    Type of Medium: Online Resource
    ISSN: 0007-1048 , 1365-2141
    URL: Issue
    URL: Article
    DOI: 10.1111/bjh.v201.1
    DOI: 10.1111/bjh.18605
    RVK:
    XA 34100
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 1475751-5
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