Impact of early transcranial Doppler screening and intensive therapy on cerebral vasculopathy outcome in a newborn sickle cell anemia cohort

Article (PDF Available)inBlood 117(4):1130-40; quiz 1436 · November 2010with7 Reads
DOI: 10.1182/blood-2010-06-293514 · Source: PubMed
Abstract
Transcranial Doppler (TCD) is used to detect children with sickle cell anemia (SCA) who are at risk for stroke, and transfusion programs significantly reduce stroke risk in patients with abnormal TCD. We describe the predictive factors and outcomes of cerebral vasculopathy in the Créteil newborn SCA cohort (n = 217 SS/Sβ(0)), who were early and yearly screened with TCD since 1992. Magnetic resonance imaging/magnetic resonance angiography was performed every 2 years after age 5 (or earlier in case of abnormal TCD). A transfusion program was recommended to patients with abnormal TCD and/or stenoses, hydroxyurea to symptomatic patients in absence of macrovasculopathy, and stem cell transplantation to those with human leukocyte antigen-genoidentical donor. Mean follow-up was 7.7 years (1609 patient-years). The cumulative risks by age 18 years were 1.9% (95% confidence interval [95% CI] 0.6%-5.9%) for overt stroke, 29.6% (95% CI 22.8%-38%) for abnormal TCD, which reached a plateau at age 9, whereas they were 22.6% (95% CI 15.0%-33.2%) for stenosis and 37.1% (95% CI 26.3%-50.7%) for silent stroke by age 14. Cumulating all events (stroke, abnormal TCD, stenoses, silent strokes), the cerebral risk by age 14 was 49.9% (95% CI 40.5%-59.3%); the independent predictive factors for cerebral risk were baseline reticulocytes count (hazard ratio 1.003/L × 10(9)/L increase, 95% CI 1.000-1.006; P = .04) and lactate dehydrogenase level (hazard ratio 2.78/1 IU/mL increase, 95% CI1.33-5.81; P = .007). Thus, early TCD screening and intensification therapy allowed the reduction of stroke-risk by age 18 from the previously reported 11% to 1.9%. In contrast, the 50% cumulative cerebral risk suggests the need for more preventive intervention.
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Penn State Milton S. Hershey Medical Center
500 University Drive; HO46
Hershey, PA 17033-0850
Fax: (717) 531-0647
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OF HEMATOLOGY/ONCOLOGY
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Chair, Search Committee
Division of Hematology/Oncology
Penn State Milton S. Hershey Medical Center
500 University Drive; HO46
Hershey, PA 17033-0850
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Fox Chase Cancer Center
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    • "Both the frequency (1Á6%) and incidence (0Á25 per 100 patient-years) of stroke in our cohort were comparable to the most recently published cohorts (Telfer et al, 2007; Bernaudin et al, 2011 ). Stroke prevention requires both systematic early TCD and CT initiation (Adams et al, 1998). "
    [Show abstract] [Hide abstract] ABSTRACT: We conducted a retrospective study on newborns with sickle-cell disease (SCD), born 1995-2009, followed in a multicentre hospital-based network. We assessed patient outcomes, medical care and compliance with the national guidelines published in December 2005. Data from 1033 patients (742 SS/Sβ°-thalassaemia) with 6776 patient-years of follow-up were analysed (mean age 7·1 ± 3·9 years). SCD-related deaths (n = 13) occurred only in SS-genotype patients at a median age of 23·1 months, mainly due to acute anaemia (n = 5, including 2 acute splenic sequestrations) and infection (n = 3). Treatment non-compliance was associated with a 10-fold higher risk of SCD-related death (P = 0·01). Therapeutic intensification was provided for all stroke patients (n = 12), almost all patients with abnormal transcranial Doppler (TCD) (n = 76) or with >1 acute chest syndrome/lifetime (n = 64) and/or ≥3 severe vaso-occlusive crises/year (n = 100). Only 2/3 of patients with baseline haemoglobin <70 g/l received intensification, mainly for other severity criteria. Overall, hydroxycarbamide was under-prescribed, given to 2/3 of severe vaso-occlusive patients and 1/3 of severely anaemic patients. Nevertheless, introduction of the on-line guidelines was concomitant with an improvement in medical care in the 2006-2009 cohort with a trend towards increased survival at 5 years, from 98·3% to 99·2%, significantly increased TCD coverage (P = 0·004) and earlier initiation of intensification of therapy (P ≤ 0·01).
    Full-text · Article · Apr 2016
    • "Consistent with data from other reports that measured G6PD activity [5,8,9], we did not detect any difference in the mean G6PD activity in groups with and without clinical ischemic stroke or high-risk TCD. Reports from Créteil (France) have demonstrated the association between G6PD activity and high-risk TCD and/or vasculopathy on MRA.[6,7] It is difficult to explain these controversial results. Theoretically, the influence of G6PD on stroke risk appears improbable, because one of the most powerful predictors of stroke risk, increased steady-state reticulocyte count,[18][19][20] also elevates G6PD activity, as confirmed in our study. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Stroke is a severe complication of sickle cell anemia (SCA). The role of glucose-6-phosphate dehydrogenase (G6PD) deficiency in the development of stroke in children with SCA is controversial. Procedure: The aim of this study was to investigate the association of clinical ischemic stroke, high-risk transcranial Doppler measurements (TCD), and hematological features with molecular variants usually linked to G6PD deficiency or with the biochemical activity of G6PD in a cohort of 395 Brazilian children with SCA. G6PD activity was quantitatively determined using an enzymatic-colorimetric assay. G6PD mutations were determined by PCR-RFLP and sequencing. Clinical and hematological data were retrieved from the children's records. Results: The prevalence of molecularly defined deficiency (hereafter, molecular deficiency) was 4.3% (95% confidence interval: 2.3-6.3%). The mean G6PD activity was 16.88 U/g hemoglobin (Hb) (standard error of the mean [SEM] 0.28) in the group without G6PD molecular deficiency and 8.43 (SEM 1.01) U/g Hb in the group with G6PD A(-) molecular deficiency. G6PD molecular deficiency was not associated with any hematological features. No effects of G6PD molecular deficiency on clinical ischemic stroke or high-risk TCD were detected. The mean G6PD activity was similar in children who had clinical ischemic stroke and in those without stroke. Similar results were obtained in analyses comparing children who had high-risk TCD and those without high-risk TCD. Conclusions: Our study demonstrated that G6PD molecular deficiency was not associated either with clinical ischemic stroke or high-risk TCD. Similarly, we found no associations between G6PD enzyme activity and stroke or high-risk TCD. Small sample size precludes definitive conclusions.
    Full-text · Article · Feb 2016
    • "A possible alternative explanation is that in HP22 individuals the haem- oxygenase-1 compensatory pathway may be more successfully up-regulated in response to haem exposure, demonstrated to have powerful anti-inflammatory and anti-stasis effects (Jison et al, 2004; Belcher et al, 2006). Conflicting reports of an effect of G6PD on CBFv (Bernaudin et al, 2008Bernaudin et al, , 2011 Rees et al, 2009; Miller et al, 2011; Thangarajh et al, 2012) may result from variations between populations in either the phenotypic expression compared to assessed genotype or from population or methodological differences between in-vivo vs. in-vitro enzyme activity, when this has been measured directly (Johnson et al, 2009). There is little evidence for an association of either low enzyme activity (Miller et al, 2011) or genotype (Flanagan et al, 2011) with stroke. "
    [Show abstract] [Hide abstract] ABSTRACT: Transcranial Doppler ultrasonography measures cerebral blood flow velocity (CBFv) of basal intracranial vessels and is used clinically to detect stroke risk in children with sickle cell anaemia (SCA). Co-inheritance in SCA of alpha-thalassaemia and glucose-6-phosphate dehydrogenase (G6PD) polymorphisms is reported to associate with high CBFv and/or risk of stroke. The effect of a common functional polymorphism of haptoglobin (HP) is unknown. We investigated the effect of co-inheritance of these polymorphisms on CBFv in 601 stroke-free Tanzanian SCA patients aged <24 years. Homozygosity for alpha-thalassaemia 3·7 deletion was significantly associated with reduced mean CBFv compared to wild-type (β-coefficient -16·1 cm/s, P = 0·002) adjusted for age and survey year. Inheritance of 1 or 2 alpha-thalassaemia deletions was associated with decreased risk of abnormally high CBFv, compared to published data from Kenyan healthy control children (Relative risk ratio [RRR] = 0·53 [95% confidence interval (CI):0·35-0·8] & RRR = 0·43 [95% CI:0·23-0·78]), and reduced risk of abnormally low CBFv for 1 deletion only (RRR = 0·38 [95% CI:0·17-0·83]). No effects were observed for G6PD or HP polymorphisms. This is the first report of the effects of co-inheritance of common polymorphisms, including the HP polymorphism, on CBFv in SCA patients resident in Africa and confirms the importance of alpha-thalassaemia in reducing risk of abnormal CBFv.
    Full-text · Article · Feb 2014
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