Interleukin-10 haplotypes are not associated with acute cerebral ischemia or high-risk transcranial Doppler in a newborn cohort of 395 children with sickle cell anemia

Introduction: India has been identified as having the second largest number of births with sickle cell anemia (SCA) in the world after Africa, with estimated 44,400 new-borns affected per year. SCD was previously reported to have a milder course in children from India, with less severe disease among aboriginal tribal populations than in non-tribal populations. Recent reports indicate the occurrence of severe manifestations of SCD in both tribal and non-tribal populations in India. Stroke is one of the serious complications of SCD, but there are no data on transcranial Doppler (TCD) screening for evaluating children with SCD in India who may be at high risk for strokes. The objective of this study was to assess the feasibility of using TCD to measure time averaged maximum of the mean velocities (TAMMV) in the intracranial arteries in children attending a tertiary centre in central India. Methods: STUDY DESIGN: A cross sectional study was conducted in consecutively recruited stable children of either sex with homozygous SCA proven by electrophoresis and high performance liquid chromatography in the age group of 1-26 years. Patients who were febrile, acutely ill, hypoxic or asleep were not included in the study as these conditions can falsely elevate the intracranial blood flow velocities. Patients with hemoglobinopathies other than HbSS or S/b0 Thalassemia and those with a history of congenital neurological illness were excluded. DETERMINATION OF TCD VELOCITY: TCD was performed in a tertiary care center in Nagpur using either an imaging machine (Lasiq s8) in the department of radiology or a portable non-imaging TCD (Compumedics); for both a probe of frequency 2Mhz was used. Maximum values for TAMMV in the Middle (MCA) and Anterior (ACA) cerebral arteries were measured in all; for the non-imaging TCD values for posterior cerebral artery (PCA) and basilar artery were also obtained. The results of the first scan performed on these individuals were included in this study. Using values similar to the STOP trial, TAMMV of each of these vessels were categorized as follows: Normal <= 170cm/s; Conditional - between 170 and 199 cm/s; Abnormal >= 200 cm/s; Low <50 cm/s and unobtainable. MEASUREMENT OF HAEMATOLOGICAL VALUES: Laboratory parameters such as Hemoglobin, white blood cell count (WBC), Mean corpuscular volume (MCV) and hemoglobin F (HbF) levels of the patients in the study were also included if the parameters were available on the day of TCD or within 90 days of TCD study. MEASUREMENT OF HEIGHT, WEIGHT AND BMI: The height and weight of each of the patients on the day of TCD or within a period of 60 days from the TCD were measured and the body mass index (BMI) was calculated. Results One hundred and twenty children and youth aged 1-26 (median 7) years, 67 male (56%), were recruited. Of the 120 patients, 106 (88.5%) belonged to the Scheduled Caste category, 3 (2.5%) to the Scheduled Tribe category and 11 (9.1%) to the Other Classes category. Three (2.5%) had had a clinical stroke and 8 (7%) had had seizures, one of whom also had a stroke. Twenty-seven (23%) children had TAMMV outside the normal range. Five had abnormal TAMMV in the MCA (n=4) and/or ACA (n=1), 8 had conditional TAMMV in the MCA (n=7) and/or ACA (n=1) while 14 patients had low (n=12) or unobtainable (n=2) TAMMV in the MCA. One child with stroke had low TAMMV and one had conditional TAMMV while the third had normal TAMMV. Of the 7 with isolated seizures, one had low TAMMV and one had conditional TAMMV while the remaining 5 were normal. BMI was 8.6-25.3 (median 14.1), height/weight was 3.4-10.3 (median 6.5), hemoglobin was 43-134 (median 81) g/L, oxygen saturation 87-100 (median 99)%, HbF was 1.9-60 (median 21) g/dL, MCV was 59.1-96.7 (median 83.2) fl, WBC was 2.3-35.9 (median 10.1)*109. Those with TAMMV outside the normal range were not different from those with normal TAMMV in terms of age, BMI, Height/weight, or recent hemoglobin, oxygen saturation, HbF, MCV, or WBC. Discussion This study demonstrates the feasibility and importance of TCD screening in Indian SCD population. TAMMV on TCD was outside the normal range in nearly a quarter of children with SCD, as has been reported in studies in other populations. The findings of this study may not be representative of stroke risk in tribal populations since they were underrepresented in this study. These data provide the rationale for implementing systematic screening with TCD to reduce the risk of stroke in children affected by SCD in India. Disclosures Darbari: Novartis: Membership on an entity's Board of Directors or advisory committees; Hilton Publishing: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Other: one day advisory board meeting .

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Glucose-6-Phosphate Dehydrogenase Deficiency in Brazilian Children With Sickle Cell Anemia is not Associated With Clinical Ischemic Stroke or High-Risk Transcranial Doppler

Pediatric Blood & Cancer ◽

10.1002/pbc.25924 ◽

2016 ◽

Vol 63 (6) ◽

pp. 1046-1049 ◽

Cited By ~ 8

Author(s):

André Rolim Belisário ◽

Rahyssa Rodrigues Sales ◽

Nayara Evelin Toledo ◽

Cibele Velloso-Rodrigues ◽

Célia Maria Silva ◽

...

Keyword(s):

Ischemic Stroke ◽

High Risk ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Transcranial Doppler ◽

Dehydrogenase Deficiency ◽

Glucose 6 Phosphate Dehydrogenase ◽

Brazilian Children

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Study of transcranial Doppler ultrasound and endothelin-1 in children with sickle cell anemia: a single-center study

Pediatric Hematology/Oncology and Immunopathology ◽

10.24287/1726-1708-2021-20-3-31-35 ◽

2021 ◽

Vol 20 (3) ◽

pp. 31-35

Author(s):

S. Ragab ◽

E. Badr ◽

H. El-Kholy ◽

M. El-Hawy

Keyword(s):

High Risk ◽

Patient Group ◽

Sickle Cell ◽

Serum Ferritin ◽

Sickle Cell Anemia ◽

Transcranial Doppler ◽

Control Group ◽

Healthy Children ◽

Endothelin 1 ◽

The Impact

To assess the impact of our transcranial Doppler (TCD) screening program on the incidence of a first stroke in children with sickle cell anemia and to study the role of elevated serum endothelin-1 (an inflammatory mediator) in these children. Background: stroke is a major complication of sickle cell disease (SCD), even in very young children. About 11% of children with homozygous sickle cell anemia (SS) develop stroke by the end of the second decade of life. The underlying etiology in most cases is an ischemic stroke caused by large-vessel stenosis or occlusion. Transcranial Doppler (TCD) recommended as a routine screening test to identify children at high risk of developing a stroke, measures flow velocities within large intracranial arteries. TCD should be routinely performed in children between 2 and 16 years as this age group is at the highest risk of sickle cerebral vasculopathy. We carried out a prospective case-control study which included 2 groups: a patient group consisted of 30 children with sickle cell anemia and sickle thalassemia and a group of 30 healthy children of matched age and sex. Each group included 11 males (36.5%) and 19 females (63.5%); the age range was 2 to 17 years. Both groups underwent a thorough clinical examination and laboratory tests (CBC, liver and renal function, serum ferritin and endothelin-1). Additionally, TCD was performed in all children included in the patient group. According to the results of TCD, time-averaged mean of the maximum velocity (TAMMX) was < 170 cm/s (normal), 170–200 cm/s (conditional), ≥ 200 cm/s (high risk) in 20 (66.7%), 4 (13.3%) 6 (20%) patients, respectively. The level of endothelin-1 was significantly higher in the patients (57.1 ± 91.3) than in the controls (21.9 ± 14.8). Hemoglobin concentration was significantly lower in the patient group than in the control group, but the levels of reticulocytes, WBCs and serum ferritin were significantly higher in the patients than in the healthy controls. Serum Endotheline-1 level was higher in patients with sickle cell anemia than control group.

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Effects of Chronic Transfusion Therapy on transcranial Doppler Ultrasonography Velocities in Children with Sickle Cell Anemia at Risk for Primary Stroke: Baseline Findings from the Twitch Trial

Blood ◽

10.1182/blood.v124.21.87.87 ◽

2014 ◽

Vol 124 (21) ◽

pp. 87-87 ◽

Cited By ~ 6

Author(s):

Hamayun Imran ◽

Banu Aygun ◽

Barry R. Davis ◽

Sara L. Pressel ◽

William Herbert Schultz ◽

...

Keyword(s):

High Risk ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Transcranial Doppler ◽

Doppler Ultrasonography ◽

Study Entry ◽

Red Cell ◽

Transfusion Therapy ◽

The Mean ◽

Red Cell Transfusion

Abstract Introduction: Transcranial Doppler ultrasonography (TCD) is an established screening modality used to predict stroke in children with sickle cell anemia (SCA). Children with abnormal TCD velocities are at high risk for primary stroke. Based on STOP and STOP 2 data, indefinite chronic red cell transfusion therapy is recommended for children with SCA and abnormal TCD velocity, defined as a maximum time-averaged mean velocity (TAMV) ≥200 cm/sec. The aim of the current analysis was to evaluate the long term effects of transfusion therapy on TCD velocities, in a large cohort of children with SCA who received chronic red cell transfusion therapy for primary stroke prophylaxis. Methods: The TCD With Transfusions Changing to Hydroxyurea (TWiTCH) study is a phase III, randomized, controlled, multicenter non-inferiority trial comparing hydroxyurea to transfusions for primary stroke prevention in children with SCA and abnormal TCD velocities (ClinicalTrials.gov NCT01425307). Children with SCA and a history of abnormal TCD who received at least 12 months of transfusion therapy were eligible to participate. All subjects’ index TCD velocities (the TCD examination that prompted the start of chronic transfusion therapy) were reviewed centrally to confirm study eligibility. At enrollment, study TCD velocities were obtained using the SONARA/tek TCD Module by trained examiners and reviewed centrally. In addition, all children were evaluated with brain magnetic resonance angiography (MRA) scans, which were also reviewed centrally. Associations between demographic, clinical, radiological, and laboratory findings and index/enrollment TCD velocities were examined. Results: One hundred and thirty eight children with complete data were included in this analysis. Mean age for the entire cohort at enrollment was 9.8±2.8 years; 40% were male and 98.8% had HbSS. Mean age at the diagnosis of index TCD was 5.5±2 years. The mean duration of transfusion therapy was 4.3±2.4 years with 63% receiving simple transfusions, 30% receiving partial exchange transfusions, and 7% undergoing erythrocytapheresis. The mean pre-transfusion hemoglobin at study entry was 9.1±0.8 gm/dL and the mean pre-transfusion %HbS for the last 6 months prior to study entry was 29.5±8.3%. The average index TCD TAMV was 217±22 cm/sec (range 147-325). At study entry, the average TAMV was lower at 150±27cm/sec overall (142±27 cm/sec on the left and 140±29 cm/sec on the right). In 77% of the subjects, the TCD velocities had decreased to normal levels (<170 cm/sec), while they remained conditional in 21% and abnormal in 3%. The average decline from index to study entry TCD was 67±31 cm/sec. Nineteen subjects (13.7%) had severe vasculopathy on brain MRA. Higher recent pre-transfusion %HbS (p=.04), fewer years of transfusion therapy (p<.001), and the presence of severe vasculopathy (p<.001) were associated with higher TCD velocities at study entry and with larger declines in velocity from index to study entry. Higher index TCD values were also associated with larger declines in velocity from index to study entry (p<.001). Age and transfusion type did not have an effect on TCD values. Conclusions: Most of the children with SCA at high risk for primary stroke enrolled in the TWiTCH study have normal TCD velocities at study entry, although 21% have conditional and 3% still have abnormal velocities. Longer duration of transfusion therapy was associated with lower TCD velocities, while the presence of severe vasculopathy on brain MRA and recent higher pre-transfusion %HbS values were associated with higher TCD velocities. The TWiTCH trial will serially perform TCD examinations to compare the effects of hydroxyurea versus transfusions. Disclosures Off Label Use: Use of hydroxyurea in children with sickle cell disease.

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Transcranial Doppler Screening in a Current Cohort of Children With Sickle Cell Anemia

Journal of Pediatric Hematology/Oncology ◽

10.1097/mph.0000000000002103 ◽

2021 ◽

Vol Publish Ahead of Print ◽

Author(s):

Julie Kanter ◽

Shannon Phillips ◽

Alyssa M. Schlenz ◽

Martina Mueller ◽

Mary Dooley ◽

...

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Transcranial Doppler ◽

A Current

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Ischemic Stroke in Children and Young Adults with Sickle Cell Disease (SCD) in the Post-STOP Era

Blood ◽

10.1182/blood.v126.23.68.68 ◽

2015 ◽

Vol 126 (23) ◽

pp. 68-68 ◽

Cited By ~ 3

Author(s):

Janet L. Kwiatkowski ◽

Julie Kanter ◽

Heather J. Fullerton ◽

Jenifer Voeks ◽

Ellen Debenham ◽

...

Keyword(s):

Ischemic Stroke ◽

High Risk ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Stroke Prevention ◽

Cell Disease ◽

Clinical Series ◽

The Mean

Abstract Background: The Stroke Prevention Trial in Sickle Cell Anemia (STOP) and Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) established routine transcranial Doppler ultrasound (TCD) screening with indefinite chronic red cell transfusions (CRCT) for children with abnormal TCD as standard of care. To identify children at high-risk of stroke, annual TCD screening is recommended from ages 2 to 16 years, with more frequent monitoring if the result is not normal. A reduction in stroke incidence in children with SCD has been reported in several clinical series and analyses utilizing large hospital databases when comparing rates before and after the publication of the STOP study in 1998. We sought to determine the rate of first ischemic stroke in a multicenter cohort of children who had previously participated in the STOP and/or STOP 2 trials and to determine whether these strokes were screening or treatment failures. Subjects and Methods: Between 1995 and 2005, STOP and STOP 2 (STOP/2) were conducted at 26 sites in the US and Canada. These studies included 3,835 children, ages 2 to 16 y with SCD type SS or S-beta-0-thalassemia. Participation in STOP/2 ranged from a single screening TCD to randomization. STOP 2 also had an observational arm for children on CRCT for abnormal TCD whose TCD had not reverted to normal. The Post-STOP study was designed to follow-up the outcomes of children who participated in one or both trials. 19 of the 26 original study sites participated in Post-STOP, contributing a total of 3,539 (92%) of the STOP/2 subjects. After exit from STOP/2, these children received TCD screening and treatment according to local practices. Data abstractors visited each clinical site and obtained retrospective data from STOP/2 study exit to 2012-2014 (depending on site) including follow-up TCD and brain imaging results, clinical information, and laboratory results. Two vascular neurologists, blinded to STOP/2 status and prior TCD and neuroimaging results, reviewed source records to confirm all ischemic strokes, defined as a symptomatic cerebral infarction; discordant opinions were resolved through discussion. For the first Post-STOP ischemic stroke, prior TCD result and treatment history subsequently were analyzed. Results: Of the 3,539 subjects, follow-up data were available for 2,850 (81%). Twelve children who had a stroke during STOP or STOP2 were excluded from these analyses resulting in data on 2,838 subjects. The mean age at the start of Post-STOP was 10.5 y and mean duration of follow-up after exiting STOP/2 was 9.1 y. A total of 69 first ischemic strokes occurred in the Post-STOP observation period (incidence 0.27 per 100 pt years). The mean age at time of stroke was 14.4±6.2 (median 13.8, range 3.5-28.9) y. Twenty-five of the 69 patients (36%) had documented abnormal TCD (STOP/2 or Post-STOP) prior to the stroke; 15 (60%) were receiving CRCT and 9 (36%) were not (treatment data not available for 1 subject). Among the 44 subjects without documented abnormal TCD, 29 (66%) had not had TCD re-screen in the Post-STOP period prior to the event; 7 of these 29 (24%) were 16 y or older at the start of Post-STOP, which is beyond the recommended screening age. Four of the 44 (9%) patients had inadequate TCD in Post-STOP (1 to 10.7 y prior to event). Six (14%) had normal TCD more than a year before the event (1.2 - 4 y); all but one of these children were younger than 16 y at the time of that TCD. Only 5 (11%) had a documented normal TCD less than 1 year prior to the event. Conclusions: In the Post-STOP era, the rate of first ischemic stroke was substantially lower than that reported in the Cooperative Study of Sickle Cell Disease, prior to implementation of TCD screening. Many (39%) of the Post-STOP ischemic strokes were associated with a failure to re-screen according to current guidelines, while only 11% occurred in children who had had recent low-risk TCD. Among those known to be at high risk prior to stroke, treatment refusal or inadequate treatment may have contributed. While TCD screening and treatment are effective at reducing ischemic stroke in clinical practice, significant gaps in screening and treatment, even at sites experienced in the STOP protocol, remain to be addressed. Closing these gaps should provide yet further reduction of ischemic stroke in SCD. Disclosures No relevant conflicts of interest to declare.

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