Transcranial Doppler (TCD) With Transfusions Changing to Hydroxyurea

Inclusion Criteria:

1. Pediatric subjects with severe forms of sickle cell anemia (HbSS, HbSβ0thalassemia,HbSOArab)

2. Age range of 4.0-15.99 years, inclusive, at the time of enrollment

3. Documented index (pre-treatment) abnormally high TCD Velocity by Transcranial Dopplerultrasonography. An abnormally high index TCD is defined as TCD V greater than orequal to 200 cm/sec, or abnormally high TCDi V greater than or equal to185cm/sec, orTCD maximum V greater than or equal to 250 cm/sec.

4. At least 12 months of chronic monthly erythrocyte transfusions since the indexabnormal TCD examination

5. Adequate monthly erythrocyte transfusions with average HbS less than or equal to 45% (the upper limit of the established academic community standard) for the past 6 monthsbefore enrollment

6. Parent or guardian willing and able to provide informed consent with verbal or writtenassent from the child

7. Ability to comply with study related treatments, evaluations, and follow-up

Exclusion Criteria:

1. Completed overt clinical stroke or TIA

2. Inability to obtain TCD velocities due to anatomical abnormalities such as a)Inadequate bone windows b) Previous revascularization procedures (e.g., EDAS)

3. Known severe vasculopathy or moya-moya disease on brain MRA

4. Inability to receive or tolerate chronic red blood cell (RBC) transfusion therapy, dueto any of the following: a) Multiple RBC alloantibodies making cross-matchingdifficult or impossible b) RBC autoantibodies making cross-matching difficult orimpossible c) Religious objection to transfusions that preclude their chronic use d)Non-compliance with transfusions over the past 6 months before enrollment (temporaryexclusion)

5. Inability to take or tolerate daily oral hydroxyurea, including a) Known allergy tohydroxyurea therapy b) Positive serology to HIV infection c) Malignancy d) Currentlactation e) Previous stem cell transplant or other myelosuppressive therapy

6. Clinical and laboratory evidence of hypersplenism (temporary exclusions): a) Palpablesplenomegaly greater than 5cm below the left costal margin AND b) Transfusionrequirement greater than 250 mL/kg over the previous 12 months

7. Abnormal laboratory values at initial evaluation (temporary exclusions): a)Pre-transfusion hemoglobin concentration less than 8.0 gm/dL b) WBC count less than 3.0 x 10^9/L c) Absolute neutrophil count (ANC) less than 1.5 x 10^9/L d) Plateletcount less than 100 x 10^9/L e) Serum creatinine more than twice the upper limit forage OR greater than or equal to 1.0 mg/dL

8. Current participation in other therapeutic clinical trials

9. Current use of other therapeutic agents for sickle cell disease (e.g., arginine,decitabine, magnesium). Subjects must have been off hydroxyurea for at least 3- monthsprior to enrollment.

10. Any condition or chronic illness, such as a positive tuberculin (PPD) test, which inthe opinion of the CI makes participation ill-advised.

11. Inability or unwillingness to complete required screening and exit studies, includingTCD ultrasonography, brain MRI/MRA, liver MRI and blood tests.

12. A sibling enrolled in TWiTCH

13. Pregnancy or unwillingness to use a medically acceptable form of contraception ifsexually active (male OR female).