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
Authors: Imran Hamayun , Aygun Banu , Davis Barry R. , Pressel Sara L. , Schultz William Herbert , Jackson Sherron M. , Singh Sharon A. , Sarnaik Sharada A. , Gauger Cynthia A. , Fuh Beng , Helton Kathleen J. , Roberts Donna , Adams Robert J. , Ware Russell E. 
Published: October 2019

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.