Abnormal Transcranial Doppler Velocities Research Articles

Hydroxyurea Improves Intelligence Quotient Scores in Children with Sickle Cell Anemia and Elevated Transcranial Doppler Velocity

Introduction: Structural brain abnormalities resulting from sickle cell disease because of strokes, silent cerebral infarcts (SCI) and other biophysical characteristics of parenchymal damage from repeated sickling affect cognitive functioning. Hydroxyurea therapy reduces transcranial Doppler (TCD) velocities and improves SCI and other neurological outcomes in children with sickle cell anaemia. Hence the objectives of EXpanding Treatment for Existing Neurological Disease (EXTEND, NCT02556099), a phase 2 clinical trial, was to determine whether hydroxyurea titrated to maximum tolerated dose was effective in lowering transcranial Doppler (TCD) velocities and improving cognitive function in Jamaican children with sickle cell anemia (SCA) with increased stroke risk. Methods: Full-Scale Intelligence Quotient (FSIQ), verbal and nonverbal IQ were measured with the Wechsler Abbreviated Scale of Intelligence (WASI-II) at baseline and after 18 months of hydroxyurea treatment in 30 of the 43 enrolled children. Verbal Comprehension Index (VCI) was assessed using the Vocabulary and Similarities subtests. Perceptual Reasoning Index (PRI) was scored with the Block Design and Matrix Reasoning subtests. Members of the team conducting the tests were trained and test results were verified by an experienced member of the Epidemiology Research Unit, Caribbean Institute for Health Research. Participants were enrolled in the EXTEND trial based on a pre-treatment conditional or abnormal TCD velocity. They were assigned to one of three risk categories according to treatment status and stroke history at study enrollment: Group 1 (low stroke risk: no previous stroke, on hydroxyurea treatment n= 12), Group 2 (medium stroke risk: no previous stroke, no hydroxyurea, n=10) and Group 3 (High stroke risk: previous stroke, no hydroxyurea n=8). Anthropometric variables, including height and weight, were recorded as well as oxygen saturation and hematological variables. Differences in post treatment outcome were modelled using mixed linear regression. A p-value of <0.05 was considered statistically significant. Results: There was no difference in mean anthropometric values or gender distribution at baseline by stroke risk category groups (Table 1). The mean(sd) age in years of participants in Group 1 was 8.2(1.7), while for Group 2 the average age was 7.7(2.1) and for Group 3 it was 10.5(2.8). The mean age of Group 3 was significantly greater than Group 1. After 18 months of hydroxyurea treatment, participants were taking an average dose of 25 mg/kg/d, range 13.7 to 34.9 mg/kg/d. On treatment TCD velocities decreased by mean(sd) of 29.5 cm/sec (31.5). Hemoglobin (Hb) concentration was lowest in Group 3 but all groups showed increases during treatment with the rate of increase in Groups 2 and 3 being greater than Group 1 (p<0.001). Absolute neutrophil counts and absolute reticulocyte counts were not different by group, and both decreased significantly post treatment (p<0.001) (Table 1). At both time points, the VCI, PRI and FSIQ mean scores in Group 3 were low [Overall means(sd); 71(11.7), 71(12.6),69(11.6), respectively] and were significantly lower compared with Group 1 (p<0.001) (Table 1). While there was no significant effect of treatment on VCI and PRI scores, the mean FSIQ score increased on average by 2.9 units (95%CI 0.3, 5.4) post treatment among participants. Adjusting for age at enrollment had no effect on the improvement on FSIQ, however adjusting for changes in hemoglobin resulted in an increase in FSIQ by 3.3 units (95%CI -0.4, 7.0) which approached statistical significance (p=0.079). Conclusion: Participants treated with hydroxyurea at maximum tolerated dose for 18 months with or without a previous stroke had significant improvement in hematological variables and neuropsychological scores. Children with sickle cell anemia with high risk of stroke may benefit from routine neuropsychological testing, hydroxyurea treatment in addition to educational interventions.

Genetic Variation and Sickle Cell Disease Severity

Sickle cell disease (SCD) is a monogenic disorder, yet clinical outcomes are influenced by additional genetic factors. Despite decades of research, the genetics of SCD remain poorly understood. To assess all reported genetic modifiers of SCD, evaluate the design of associated studies, and provide guidelines for future analyses according to modern genetic study recommendations. PubMed, Web of Science, and Scopus were searched through May 16, 2023, identifying 5290 publications. At least 2 reviewers identified 571 original, peer-reviewed English-language publications reporting genetic modifiers of human SCD phenotypes, wherein the outcome was not treatment response, and the comparison was not between SCD subtypes or including healthy controls. Data relevant to all genetic modifiers of SCD were extracted, evaluated, and presented following STREGA and PRISMA guidelines. Weighted z score meta-analyses and pathway analyses were conducted. Outcomes were aggregated into 25 categories, grouped as acute complications, chronic conditions, hematologic parameters or biomarkers, and general or mixed measures of SCD severity. The 571 included studies reported on 29 670 unique individuals (50% ≤ 18 years of age) from 43 countries. Of the 17 757 extracted results (4890 significant) in 1552 genes, 3675 results met the study criteria for meta-analysis: reported phenotype and genotype, association size and direction, variability measure, sample size, and statistical test. Only 173 results for 62 associations could be cross-study combined. The remaining associations could not be aggregated because they were only reported once or methods (eg, study design, reporting practice) and genotype or phenotype definitions were insufficiently harmonized. Gene variants regulating fetal hemoglobin and α-thalassemia (important markers for SCD severity) were frequently identified: 19 single-nucleotide variants in BCL11A, HBS1L-MYB, and HBG2 were significantly associated with fetal hemoglobin (absolute value of Z = 4.00 to 20.66; P = 8.63 × 10-95 to 6.19 × 10-5), and α-thalassemia deletions were significantly associated with increased hemoglobin level and reduced risk of albuminuria, abnormal transcranial Doppler velocity, and stroke (absolute value of Z = 3.43 to 5.16; P = 2.42 × 10-7 to 6.00 × 10-4). However, other associations remain unconfirmed. Pathway analyses of significant genes highlighted the importance of cellular adhesion, inflammation, oxidative and toxic stress, and blood vessel regulation in SCD (23 of the top 25 Gene Ontology pathways involve these processes) and suggested future research areas. The findings of this comprehensive systematic review and meta-analysis of all published genetic modifiers of SCD indicated that implementation of standardized phenotypes, statistical methods, and reporting practices should accelerate discovery and validation of genetic modifiers and development of clinically actionable genetic profiles.

Optimizing the Frequency of Transcranial Doppler (TCD) Exams in Children with Sickle Cell Anemia

Background Transcranial Doppler (TCD) screening of the large intracranial arteries can detect elevated blood velocity and is a strong predictor of stroke risk in children with sickle cell anemia (SCA, HbSS and HbSβ0-thalassemia). Initiation of chronic blood transfusion for patients with confirmed abnormal TCD velocities (time-averaged mean velocity, TAMV≥200 cm/sec) is shown to effectively reduce primary stroke. Current guidelines recommend annual TCD screening for children with SCA ages 2-16 years. Screening intervals were developed following evidence from the STOP studies1 (Figure 1). The estimated prevalence of normal TCD velocities is 83%2 and these children will have received 15 TCD exams from ages 2 to 16 if all results remain within normal range. The cumulative incidence of conversion from normal to conditional TCD velocities is dependent on age, whereby the risk is four times lower in children >10 years, compared to those <10 years of age3. Although TCD screening is non-invasive and safe, it consumes time and requires specialized equipment and trained examiners. Identifying sub-populations for whom TCD screening frequency could be safely reduced could lessen time burden on patients and caregivers and could be cost saving. Main objective To estimate the risk of TAMV conversion from normal to conditional or abnormal categories among children with SCA relative to age. Design/Method We included all participants with SCA from the Sickle Cell Clinical Research and Intervention Program, a longitudinal lifetime cohort of patients with SCD with at least one TCD measurement available both before and after age 10 years. We classified participants into two groups based on TCD screening results before 10 years of age; one group with all normal TCDs, and the other group with at least one non-normal TCD. We then compared the time to first non-normal study after ten years of age between the two groups using the log rank test. Time to first conversion was defined as time from age 10, to time of conversion if conversion occurred, or time to last follow up if no conversion occurred. We correlated the number of TCD exams before age 10 with time to first conversion using the Cox proportional regression model. Exposure to chronic transfusion or hydroxyurea before age 10 and age at first TCD measurement were covariates and were correlated with the time to first conversion. Results Of the 614 patients with TCD screening, 297 had SCA and at least 1 screening before and after age 10 (Table 1). Of these, 174 patients had only normal TCD screening before age 10 and the remaining 123 patients had at least 1 non-normal TCD screening before age 10. During the time they were followed,no patients with only normal TCD screenings before age 10, regardless of exposure to hydroxyurea or transfusions, had a conditional or abnormal TCD exam. Conversely, 41.5% of patients with at least one non-normal TCD before age 10 had a conditional or abnormal TCD screening after age 10. Conclusion In a large retrospective cohort study analysis of children with SCA, patients with TCD exams consistently within the normal range under age 10 years were not at risk of conversion to conditional or abnormal TAMV. These results suggest that children with SCA with all normal TCD velocities before age 10 years may not require additional TCD screening exams after age 10. These results translate to 6 fewer TCD exams per each child with SCA over age 10 with all prior normal TCD exams, potentially conserving resources and reducing burden on patients, families, and the health system. De-implementation studies to reduce the use of TCD screening exams in low-risk cases are needed

THE ROLE OF HYDROXYUREA IN INCREASING PULSE OXIMETRY AMONG PATIENTS WITH SICKLE CELL DISEASE

To identify the influence of hydroxyurea (HU) on oxygen saturation levels among patients with Sickle Cell Disease (SCD). A cross-sectional study was carried out that evaluated the use of HU for at least 1 year and the oxygen saturation measured on the oximeter in patients recruited in a SCD cohort in Brazil. A total of 275 patients were evaluated and 132 were included in this study. Inclusion criteria were (i) SS genotype, (ii) age over 18 years, (iii) HU use for more than 1 year (iv) no HU use, (v) active follow-up. Patients who did not use HU were the control group. The HU group had 57 patients with a mean age of 32 (±13.38) years, 50.88% women and 49.12% men. The means of Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Heart Rate (HR) and Oxygen Saturation (SpO 2 ) in this group were, respectively, 117.95 (±15.52) mmHg, 65.39 (±11.22) mmHg, 81.40 (±14.55) bpm and 93.02 (±14.55)%. The Control group consisted of 32 patients, the mean age was 30.50 (±10.92) years, 56.25% were women and 43.75% were men. The means of SBP, DBP, HR and SpO 2 in the control were respectively 114.69 (±12.37) mmHg, 62.44 (±9.37) mmHg, 80.19 (±15.66) bpm and 90.16 (±6.16)%. The difference between SpO 2 in the groups was statistically significant (p = 0.01). In the other variables evaluated there was no statistical significance. Oxygen desaturation is common in SCD and predicts clinical severity. Hypoxemia is associated with risk of stroke, abnormal transcranial Doppler velocities, elevation of tricuspid regurgitation, diastolic dysfunction, increased incidence of vaso-occlusive crises and chest syndrome sharp. Pulse oximetry is a non-invasive method of measuring oxyhemoglobin saturation. Peripheral perfusion, external light sources, and skin color and device quality should be observed. HU is the primary therapy in SCD and is capable of increasing the production of fetal hemoglobin (HbF). Studies have shown a strong correlation between peripheral SpO 2 and HbF level, so treatments that elevate HbF should impact desaturation and be beneficial for complications associated with hypoxia. In the United Kingdom, there is already a recommendation from the HU for the treatment of chronic hypoxemia in SCD. The measurement of SpO 2 is crucial for effective management in SCD. The association between HbF and SpO 2 reaffirms the importance of interventions that are able to increase both, like the HU. This study shows that the patients under use of HU had a significantly higher SpO 2 when compared to patients without it.

Relationships Between Transcranial Doppler Velocity, Von Willebrand Factor, Factor VIII, and Hematological Parameters in Children with Sickle Cell Anemia: A Comparative Cross-Sectional Study

Background and ObjectivesSickle cell anemia (SCA) is associated with recurrent acute inflammatory processes. These inflammatory processes could lead to elevation of Factor VIII and Von Willebrand Factor levels, thereby increasing the risk of stroke in SCA children. This study aims to determine vWF/FVIII levels in children with SCA and their association with abnormal transcranial Doppler (TCD).Subjects and MethodsThis study enrolled 75 children, including 24 SCA cases with normal TCD, 27 SCA cases with abnormal TCD, and 24 Hb AA controls, all aged between 2 and 16 years. Transcranial Doppler (TCD) ultrasound was performed to measure the cerebral blood velocity. Venous blood drawn from each participant was used to determine the levels of von Willebrand Factor Antigen (vWF: Ag) and Factor VIII (FVIII) and the complete blood count (CBC). Relationships among the measured parameters were determined using SPSS version 25. Statistical significance was set at P &lt; .05.ResultsFVIII and vWF levels were significantly higher among children with SCA compared to the Hb AA controls ( P &lt; .001). Although SCA patients with abnormal TCD tended to have higher levels of FVIII and vWF, this result did not attain statistical significance ( P &gt; .05). There was a moderate negative correlation between the left middle cerebral artery and FVIII, (r = −0.332; P = .017). Children with SCA showing an abnormal TCD velocity had significantly higher platelet count compared to those with normal TCD ( P = .018).ConclusionChildren with SCA have elevated levels of FVIII and vWF, and an abnormal TCD velocity is associated with elevated platelet count.

Hydroxyurea for primary stroke prevention in children with sickle cell anaemia in Nigeria (SPRING): a double-blind, multicentre, randomised, phase 3 trial

In high-income countries, standard care for primary stroke prevention in children with sickle cell anaemia and abnormal transcranial Doppler velocities results in a 92% relative risk reduction of strokes but mandates initial monthly blood transfusion. In Africa, where regular blood transfusion is not feasible for most children, we tested the hypothesis that initial moderate-dose compared with low-dose hydroxyurea decreases the incidence of strokes for children with abnormal transcranial Doppler velocities. SPRING is a double-blind, parallel-group, randomised, controlled, phase 3 trial of children aged 5-12 years with sickle cell anaemia with abnormal transcranial Doppler velocities conducted at three teaching hospitals in Nigeria. For randomisation, we used a permuted block allocation scheme with block sizes of four, stratified by sex and site. Allocation was concealed from all but the pharmacists and statisticians. Participants were assigned in a 1:1 ratio to low-dose (10 mg/kg per day) or moderate-dose (20 mg/kg per day) oral hydroxyurea taken once daily with monthly clinical evaluation and laboratory monitoring. The primary outcome was initial stroke or transient ischaemic attack, centrally adjudicated. The secondary outcome was all-cause hospitalisation. We used the intention-to-treat population for data analysis. The trial was stopped early for futility after a planned minimum follow-up of 3·0 years to follow-up for participants. This trial was registered with ClinicalTrials.gov, number NCT02560935. Between Aug 2, 2016, and June 14, 2018, 220 participants (median age 7·2 years [IQR 5·5-8·9]; 114 [52%] female) were randomly allocated and followed for a median of 2·4 years (IQR 2·0-2·8). All participants were Nigerian and were from the following ethnic groups: 179 (82%) people were Hausa, 25 (11%) were Fulani, and 16 (7%) identified as another ethnicity. In the low-dose hydroxyurea group, three (3%) of 109 participants had strokes, with an incidence rate of 1·19 per 100 person-years and in the moderate-dose hydroxyurea group five (5%) of 111 had strokes with an incidence rate of 1·92 per 100 person-years (incidence rate ratio 0·62 [95% CI 0·10-3·20], p=0·77). The incidence rate ratio of hospitalisation for any reason was 1·71 (95% CI 1·15-2·57, p=0·0071), with higher incidence rates per 100 person-years in the low-dose group versus the moderate-dose group (27·43 vs 16·08). No participant had hydroxyurea treatment stopped for myelosuppression. Compared with low-dose hydroxyurea therapy, participants treated with moderate-dose hydroxyurea had no difference in the stroke incidence rate. However, secondary analyses suggest that the moderate-dose group could lower incidence rates for all-cause hospitalisations. These findings provide an evidence-based guideline for the use of low-dose hydroxyurea therapy for children with sickle cell anaemia at risk of stroke. National Institute of Neurological Disorders and Stroke.

Are current interventions for preventing silent cerebral infarcts in people with sickle cell disease effective and safe? A Cochrane Review summary with commentary.

Are current interventions for preventing silent cerebral infarcts in people with sickle cell disease effective and safe? A Cochrane Review summary with commentary.

Blood transfusion for preventing primary and secondary stroke in people with sickle cell disease.

Blood transfusion for preventing primary and secondary stroke in people with sickle cell disease.

Interventions for preventing silent cerebral infarcts in people with sickle cell disease.

Interventions for preventing silent cerebral infarcts in people with sickle cell disease.

Progression of Central Nervous System Vasculopathy in Young Adults with Sickle Cell Anemia

Progression of Central Nervous System Vasculopathy in Young Adults with Sickle Cell Anemia

Did the Outcome of Sicke Cell Disease Babies Screened at Birth Improved from 2000? a Single Center Experience

Newborn sreening (NS) for sickle cell disease (SCD) is effective in reducing early mortality and morbidity through education, prevention of infections and strategies to prevent stroke in children at risk of cerebral vasculopathy. Universal NS was implemented in all Brussels maternity wards since 2000. All identified children with SCD benefited from comprehensive medical care in dedicated centers. This retrospective study included all children with SCD diagnosed through NS and born between January 2000 and December 2005 (Group 1) and between January 2010 and December 2015 (Group 2) followed at Hôpital Universitaire des Enfants Reine Fabiola (Brussels, Belgium). Only patients whose parents consented to be recorded in the Belgian SCD database were eligible for this study. The aim of our study was to compare the outcome of 2 NS cohorts born at 10 years of interval. Demographic data, baseline hematological values and clinical events, occurrence of cerebral vasculopathy and prescription of disease-modifying treatments during the first 5 years of life were compared between both groups. Data were collected until March 1, 2019. 59 patients were identified for this study (35 in Group 1 and 24 in Group 2). Their characteristics are detailed in Table 1. Two patients in Group 2 did not completed the full 5-year evaluation period. Among these 59 patients, 77.9% patients developed at least one SCD clinical event before the age of 5. The number of patients who developed a specific clinical event as well as their age at this first event was the same between the 2 groups (Table 2). The hospitalization number and hospitalization days were not statistically different in the 2 groups (5 vs 4 hospitalizations during 5 years and 19 vs 17 days of hospitalization between Groups 1 and 2 respectively). 3 patients presented an overt stroke (1 in Group 1 and 2 in Group 2) with a global incidence of 1.02 stroke per 100 patient-years. No death was reported in both groups. The proportion of patients with abnormal transcranial doppler velocities decreased slightly in Group 2 (14.3% vs 8.3%, P=0.69) with more conditional velocities (5.7% vs 20.8%, P=0.10) but it was not statistically significant. 60% of patients in Group 1 were treated with hydroxyurea (HU) compared to 75% in Group 2 (P=0.27). HU was introduced at a median age of 2.5 (0.9-4.8) and 2.3 (0.8-4.8) in Groups 1 and 2 respectively (P=0.79). One patient from each group underwent an hematopoietic stem cell transplantation at 4.9 and 3.5 years. Hematological values were not different in the 2 groups excepted for platelets count, which were significantly lower in Group 2 (421 x 10³/µl vs 331 x 10³/µl, P=0.03). Moreover in patients under HU, platelet and reticulocytes count were statistically lower and HbF higher in Group 2 compared to Group 1 (Table 3). Nearly 80% of patients presented a clinical event before the age of 5. This is comparable to what is described in the literature. The Kaplan-Meier survival curves were not statistically different in both groups for the occurrence of a first dactylitis (P=0.52), a first vaso-occlusive crisis (P=0.22) and acute chest syndrome (P=0.37). No more difference was observed for acute anemia (P=0.43), severe infection (P=0.35) or patients under HU (P=0.40). Even if the number of patients on hydroxyurea is not statistically higher in Group 2, a better exposure to hydroxyurea is attested by the significant changes in some biological parameters. The limits of this study are the small size of our single center cohort and the exclusion of patients not recorded in the Belgian Registry because of lack of parental consent. This last point might create a bias by selecting patients whose parents are more prone to participate actively in the comprehensive care program. This periodic evaluation is essential to ensure the quality of care of patients and to measure possible changes in the management. Comprehensive care developed in our tertiary center had been already effective since 2000. Physicians not only tend to prescribe more hydroxyurea in young symptomatic patients, but also routinely adjust the dose to reach the maximal tolerated dose. Moreover adherence to treatment has been achieved through continuous education. Disclosures No relevant conflicts of interest to declare.

Correlating transcranial arterial Doppler velocities with haematologic parameters and haemolytic indices of Nigerian children with sickle cell anaemia.

Cerebral vasculopathy, elevated transcranial Doppler velocities and stroke are linked to excessive intravascular haemolysis in sickle cell anaemia. This study determined the prevalence and pattern of abnormal blood flow velocities in children with sickle cell anaemia from Northern Nigeria using transcranial Doppler and to correlate transcranial Doppler velocities with haematological and biochemical markers of haemolysis. Full blood count, reticulocyte count, fetal haemoglobin and some selected biochemical markers of haemolysis of 100 children with sickle cell anaemia were determined at steady state. The time-averaged mean of maximal velocities in four major intracranial blood vessels was measured using non-imaging transcranial Doppler, which were then classified according to the stroke prevention in sickle cell disease trial protocol. A simple linear correlation between time-averaged mean of maximal velocities in the four major intracranial vessels as the dependent variable and haematological and biochemical markers of haemolysis as independent variables was also determined at the significance level of 0.05. Abnormal transcranial Doppler velocities, classified as high risk, were found in 3% of the studied patients; 11% had intermediate risk while 84% had standard risk. Most high velocities were detected in the middle cerebral artery. The time-averaged mean of maximal velocities of middle cerebral artery positively correlated with total white blood cell count, absolute neutrophil count, platelet count, reticulocyte count, serum lactate dehydrogenase and total bilirubin, while it was negatively correlated with haematocrit and fetal haemoglobin levels. Our study showed low prevalence of abnormal transcranial Doppler velocities and low prevalence is unrelated to low markers of haemolysis in our study population.

Relationship between Hemolytic Index Early in Life with Development of Abnormal Transcranial Doppler Velocities in Pediatric Patients with Sickle Cell Anemia

Introduction: Sickle cell disease is a complex disease process highlighted by a high phenotypic variability associated with a myriad of acute and chronic complications. Cerebrovascular disease is a serious complication in SCD associated with a high degree of morbidity and mortality. The utility of transcranial doppler ultrasound (TCD) to measure velocity within major arteries of the brain has been validated as a way to predict those at increased risk for stroke. Unfortunately, despite the availability of TCD, individuals may develop stroke and/or silent stroke prior to obtaining an abnormal study. Hemolysis via a hemolytic index variable has been shown to be associated with other complications associated with SCD. This study aimed to evaluate an association between a hemolytic index variable obtained in the first two years of life and development of abnormal or conditional TCD velocities later in childhood in patients with sickle cell anemia (SCA) with thoughts this may provide an earlier tool to determine those who may be at increased risk for stroke prior to either obtaining a TCD or developing an abnormal TCD.Methods: This study was a single-center, retrospective chart review of patients with SCA receiving their disease related care at our center over a 17 year period. Laboratory values, including lactate dehydrogenase (LDH), aspartate aminotransferase (AST), total bilirubin (TB), absolute reticulocyte count (ARC), and hemoglobin (HB), obtained in the first two years of life were extracted; these values were utilized to calculate a hemolytic index (HI) via principle component analysis to determine if a relationship existed between HI and development of conditional or abnormal TCD. All TCD results obtained from 2-14 years of age were also extracted from the patient's record. Cox proportional hazards models were then used to determine if the hemolytic index was a risk factor for abnormal or conditional TCD results.Results: A total of 193 patients with SCA between ages 2 - 21 years were reviewed with 109 included in the analysis. Laboratory values were averaged from included patients, then principle component analysis was used to find a linear combination of LDH, AST, TB and ARC to calculate a HI. The HI accounted for 49% of the total variation and had a correlation of 0.58 with mean LDH, 0.38 with mean AST, 0.46 with mean TB and 0.56 with mean ARC. Cox regression hazards model utilizing HI revealed a hazard ratio of 1.33 (95% CI 1.04‐1.70, p = 0.025) for developing a conditional or abnormal TCD velocity.HB was then included along with the other four laboratory values for principle component analysis in creation of a hemoglobin HI (HHI); in this case, the index accounts for 44% of the total variance and it has a correlation of 0.52 with mean LDH, 0.33 with mean AST, 0.38 with mean TB, 0.55 with mean ARC and ‐0.42 with mean HB. Cox regression hazards model utilizing HHI revealed a hazard ratio of 1.31 (95% CI 1.04‐1.66, p = 0.024).Conclusions: This retrospective study noted an increased risk for development of an abnormal or conditional TCD with an increased HI. The addition of hemoglobin to the HI to form HHI showed an elevated risk for abnormal or conditional TCD to the same degree as HI itself. These results could offer an additional tool in the evaluation of the pediatric SCA population, although these results would benefit from a prospective look. Further look into a possible association between HI and other SCD related complications such as stroke and acute chest syndrome could provide further information for the treating team for the overall management of this complex disease. [Display omitted] DisclosuresWoods:Global Blood Therapeutics: Research Funding; Pfizer: Research Funding; Guidepoint: Honoraria; Putman: Honoraria; Children's Mercy Hospital: Employment, Membership on an entity's Board of Directors or advisory committees.

Children with HbSβ0 thalassemia have higher hemoglobin levels and lower incidence rate of acute chest syndrome compared to children with HbSS.

Based on the presumed clinical similarity between the two most severe sickle cell disease (SCD) genotypes, hemoglobin (Hb) Sβ0 thalassemia and HbSS, randomized controlled trials (RCTs) have included both genotypes. Our group has demonstrated that healthcare providers inadequately distinguish the two diagnoses through clinical and laboratory parameters. In a retrospective cohort study utilizing data from the Silent Cerebral Infarct Transfusion trial (NCT00072761), we tested the hypothesis that children with genotypic diagnoses of HbSβ0 thalassemia, when compared to HbSS, have significantly different rates of SCD comorbidities. Exclusion criteria included those with previous overt stroke or treatment with hydroxyurea or regular blood transfusion therapy. Among children with HbSβ0 thalassemia (n=22) and HbSS (n=786), the mean hemoglobin was higher in children with HbSβ0 thalassemia (9.2g/dl) compared to HbSS (8.1g/dl, P<0.001). In children with HbSβ0 thalassemia, when compared to HbSS, the incidence rate of acute chest syndrome (ACS) was 3.0 and 14.4 events per 100 patient-years (P=0.028), and mean transcranial Doppler (TCD) velocities were 112.6 and 135.6cm/sec, respectively (P=0.026). The number of children with HbSβ0 thalassemia and HbSS with conditional TCD velocities were zero (0%) and 26 (4.9%), respectively (P=1.00), and the number with silent cerebral infarcts were five (27.8%) and 209 (30.8%), respectively (P=0.78). We have provided preliminary evidence that clinically relevant differences occur in ACS rates and TCD velocities between children with HbSβ0 thalassemia and HbSS. Future SCD RCTs should consider balanced allocation of these SCD genotypes, particularly when ACS and abnormal TCD velocities are primary outcome measures.

Red blood cell transfusion to treat or prevent complications in sickle cell disease: an overview of Cochrane reviews.

This is the protocol for a review and there is no abstract. The objectives are as follows: To summarize the evidence in Cochrane reviews of the effectiveness and safety of red cell transfusions versus no transfusion, or restrictive (to increase the total haemoglobin) versus liberal (to decrease the haemoglobin S level below a specified percentage) transfusion, for treatment or prevention of complications experienced by people with SCD.

How I manage sickle cell patients with high transcranial doppler results.

Stroke is one of the most severe complications to affect children with sickle cell anaemia (SCA). Transcranial doppler (TCD) is an accurate and non-invasive method to determine stroke risk. Randomised controlled trials have demonstrated the efficacy of chronic transfusion therapy in stroke prevention based on risk stratification determined by TCD velocities. This has led to the regular use of TCD monitoring for children with SCA in order to determine stroke risk. Significant resource allocation is necessary to facilitate training, quality assurance and failsafe arrangements for non-attenders. In a subgroup of patients, chronic transfusions for primary stroke prevention can be replaced by hydroxycarbamide therapy, provided careful monitoring is undertaken; including repeat TCD studies at frequent intervals. The authors propose an evidence-based algorithm for the management of abnormal TCD velocities and discuss the role of this test in other clinical contexts, such as in Haemoglobin SC disease.

Interventions for preventing silent cerebral infarcts in people with sickle cell disease.

Interventions for preventing silent cerebral infarcts in people with sickle cell disease.

Transcranial Doppler in hemoglobin SC disease.

Stroke is a severe clinical disorder in sickle cell disease (SCD), and few studies have evaluated transcranial Doppler (TCD) flow velocities in hemoglobin SC disease (HbSC). The guidelines for stroke risk are based on evaluations in sickle cell anemia (SCA) or HbS/β thalassemia. In this study, we compare cerebral blood flow in patients with SCD stratified by genotypes. A total of 1,664 pediatric patients with SCD underwent TCD velocity screening, and the time-averaged maximum mean velocity (TAMM) was determined in the middle cerebral artery (MCA), anterior cerebral artery (ACA), and distal intracranial internal carotid artery (ICA). Abnormal velocities were not identified in the ACA; therefore, we only use ICA and MCA velocities. TAMM from the left and right in the ICA and MCA was 134.3 ± 32.0 and 134.4 ± 32.6 cm/s in patients with SCA, and 105.2 ± 20.6 and 104.7 ± 20.0 cm/s in the patients with HbSC, respectively. Mean TAMM between right and left ICA/MCA was 134.5 ± 30.5 cm/s in the SCA group, and 104.9 ± 19.3 cm/s in the HbSC group. Notably, our data show that TCD velocities were significantly lower among the patients with HbSC compared to SCA. TAMM was negatively correlated with hemoglobin and hematocrit in both genotypes. These results suggest that a different cut-off value for abnormal TCD velocities could be considered for patients with HbSC. Additional studies are warranted to determine the actual risk of stroke in HbSC genotype associated with this possible TCD risk value.

Cellular Hydration and Oxidation As Phenotype Modifiers in Sickle Cell Anemia

Although Sickle Cell Anemia (SCA) is caused by a single nucleotide mutation in the beta globin gene, there is broad phenotypic variability in affected individuals. It would be highly advantageous to be able to predict which SCA patients are most likely to suffer severe complications and which are likely to benefit from specific treatments. Since two of the major pathologic mechanisms in SCA are erythrocyte dehydration and chronic inflammation, alterations in the expression and/or function of proteins affecting these processes may be responsible for heterogeneity in SCA phenotype. We have developed a 23-gene Next-Generation sequencing panel to identify variants in genes involved in erythrocyte hydration and in reactive oxygen species (ROS) generation and reduction in patients with SCA. We have collected blood samples from an initial cohort of 18 SCA patients with severe phenotype, defined by history of stroke or abnormal transcranial Doppler velocities, and 13 SCA patients with mild phenotype for DNA preparation and for specialized testing to evaluate erythrocyte hydration status and ROS generation.Advia Automated Cell Counter results provided the clearest indications of erythrocyte dehydration in patient blood samples. The ability to examine reticulocyte parameters made it possible to evaluate hydration regardless of the frequency of transfusion. Reticulocyte CHCM, MCV, and percent hyperdense cells were significantly different between the two groups and indicative of a greater degree of dehydration in the severe phenotype group.Osmoscans (using a LoRRca ektacytometer) demonstrated a highly significant left shift indicative of erythrocyte dehydration in both mild and severe groups relative to controls (O min and O hyper values significantly decreased). Both phenotypic groups also demonstrated a significantly lower EI max in relation to controls, indicating decreased deformability of sickle erythrocytes. Deformability scans revealed significant increases in SS ½ and decreases in EI max in both groups in relation to the controls. There were significant differences between mild and severe phenotype groups in osmoscan O min and O hyper values and in deformability assay SS ½ and EI max values. The severe group had values closer to the normal values, most likely due to the contribution of transfused blood in the severe phenotype group. There were no significant differences between the mild and severe SCA phenotype groups in intracellular cation levels (K+ and Na+) measured by flame emission spectroscopy, although both groups had significantly higher intracellular Na+ compared to normal controls.Erythrocyte ROS detection was performed using a flow cytometry DCFDA assay. Both mild and severe phenotype groups demonstrated a highly significant increase in ROS compared to controls. However there was not a significant difference in erythrocyte ROS between the mild and severe phenotype groups.DNA from patient blood samples has been sequenced using the Haloplex target enrichment system and Illumina high-throughput sequencing. We analyzed 23 genes that are likely candidates to be involved in erythrocyte hydration (ABCB6, ABCG5, ABCG8, AQP1, AQP3, ATP2B4, KCNN4, PIEZO1, RHAG, SLC9A1, SLC12A4, SLC12A6, SLC12A7, SLC2A1, SLC4A1, STOM, TRPC6, XK) or in ROS production or reduction (G6PD, NOX1, CYBB, NOX4, NOX5). At least 19 variants classified as possibly damaging have been detected in 10 of the genes. Future study will be directed toward exploring the phenotypic implications of identified variants.Results of this study should further our understanding of the pathogenesis of SCD and help identify biomarkers of disease severity which may ultimately help guide clinical management for individual patients. They may also suggest novel targets for development of new therapies for SCD based on the modulation of erythrocyte hydration and inflammation. DisclosuresQuinn:Amgen: Research Funding; Eli Lilly: Research Funding; Silver Lake Research Corporation: Consultancy. Joiner:Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees.

EXpanding Treatment for Existing Neurological Disease (EXTEND): An Open-Label Phase II Clinical Trial of Hydroxyurea Treatment in Sickle Cell Anemia.

BackgroundCerebral vasculopathy in sickle cell anemia (SCA) begins in childhood and features intracranial arterial stenosis with high risk of ischemic stroke. Stroke risk can be reduced by transcranial doppler (TCD) screening and chronic transfusion therapy; however, this approach is impractical in many developing countries. Accumulating evidence supports the use of hydroxyurea for the prevention and treatment of cerebrovascular disease in children with SCA. Recently we reported that hydroxyurea significantly reduced the conversion from conditional TCD velocities to abnormal velocities; whether hydroxyurea can be used for children with newly diagnosed severe cerebrovascular disease in place of starting transfusion therapy remains unknown.ObjectiveThe primary objective of the EXpanding Treatment for Existing Neurological Disease (EXTEND) trial is to investigate the effect of open label hydroxyurea on the maximum time-averaged mean velocity (TAMV) after 18 months of treatment compared to the pre-treatment value. Secondary objectives include the effects of hydroxyurea on serial TCD velocities, the incidence of neurological and non-neurological events, quality of life (QOL), body composition and metabolism, toxicity and treatment response, changes to brain magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA), genetic and serologic markers of disease severity, and cognitive and pulmonary function.MethodsThis prospective Phase II trial will enroll children with SCA in Jamaica, between the ages of 2 and 17 years, with either conditional (170-199 cm/sec) or abnormal (≥ 200 cm/sec) TCD velocities. Oral hydroxyurea will be administered daily and escalated to the maximum tolerated dose (MTD). Participants will be seen in the Sickle Cell Unit (SCU) in Kingston, Jamaica monthly until achieving MTD, and then every 3 months. TCD will be performed every 6 months.ResultsCurrently, 43 participants have been enrolled out of a projected 50. There was one withdrawal due to immigration, with no permanent screen failures. Of the 43 enrolled, 37 participants have initiated study treatment.ConclusionsThis trial investigates the effects of hydroxyurea treatment at MTD in children with conditional or abnormal TCD velocities before transfusion therapy and may represent an important advance towards establishing a suitable non-transfusion protocol for stroke prevention in children with SCA. The trial outcomes will have profound significance in developing countries where the disease burden is highest.ClinicalTrialClinicalTrials.gov NCT02556099; https://clinicaltrials.gov/ct2/show/NCT02556099 (Archived by WebCite at http://www.webcitation.org/6k1yMAa9G)