• Prevalence of Elevated TCD [ Time Frame: Baseline ]
  Determine the prevalence of elevated (conditional or abnormal) transcranial Doppler (TCD) velocities in a cross-sectional analysis of children with Sickle Cell Anemia (SCA) living in Tanzania
• Change in Primary Stroke Risk [ Time Frame: Up to 12 Months at Month 12 ]
  Transcranial Doppler ultrasound (TCD) will be used to measure the change in the TAMV of arterial blood flow in the 4 major intracranial arteries bilaterally from study enrollment to 12 months after study enrollment.

• Laboratory and Clinical Correlates [ Time Frame: Up to 24 Months ]
  Identify laboratory and clinical correlates of elevated TCD velocities such as age, haemoglobin concentration, foetal haemoglobin, oxygen saturation, splenomegaly, history of acute chest syndrome, and previous malaria infection
• Change in Hemoglobin Concentration [ Time Frame: 6 Months ]
  For those receiving hydroxyurea, the change in hemoglobin between baseline hemoglobin and follow up hemoglobin when a participant has reached maximum tolerated dose of hydroxyurea.
• Effect of Splenomegaly and Malaria Infections [ Time Frame: Up to 24 Months ]
  Incidence of splenomegaly and malaria infection with rapid or laboratory malaria testing will be performed for any child presenting with fever. Incidence will be reported in the number of cases per 100 patient years. Abdominal ultrasound with splenic volume will be performed annually for all study participants. Quantify the degree of hypersplenism or autoinfarction and any association with malaria complications of SCA will be analyzed.
• Prevalence of Co-inherited G6PD and Alpha Thalassemia [ Time Frame: One time at Baseline ]
  DNA will be collected at baseline to determine the prevalence of co-inherited hematologic diseases such as G6PD and alpha thalassemia.
• Hydroxyurea Area Under the Curve (AUC) [ Time Frame: One time at 24 Months (Study Exit) ]
  For those receiving hydroxyurea, the AUC will be assessed after the patient has reached MTD.
• Single Nucleotide Polymorphisms Associated with Change in Percent Hemoglobin F on Hydroxyurea [ Time Frame: One Time at 24 Months (Study Exit) ]
  For those receiving hydroxyurea, we will identify single nucleotide polymorphisms that are associated with a greater change in hemoglobin F percent in response to hydroyxurea therapy.

• Drug: Hydroxyurea
  Hydroxyurea treatment will be provided to reduce stroke risk. Hydroxyurea treatment will be started at a fixed dose of 20.0 ± 5.0 mg/kg/day, followed by escalation to maximum tolerated dose (MTD).
• Diagnostic Test: Elevated Arm TCD Examination

  TCD examination on children with SCA between ages 2 and 16 years of age will be completed to evaluate their risk of stroke.

  For children with elevated velocities at initial screening or at 1 Year who receive hydroxyurea therapy, TCD examinations will occur every 6 ± 2 months.

• Diagnostic Test: Normal Arm TCD Examination
  TCD examination on children with SCA between ages 2 and 16 years of age will be completed to evaluate their risk of stroke. TCD examination for all participants will occur at initial screening, at Year 1 (12 ± 3 months), and Year 2 (24 ± 3 months). Children with normal TCD velocities at initial screening will undergo repeat TCD 12 months after enrolment. If the TCD at 12 months has changed to an elevated velocity (conditional or abnormal), the child can begin study treatment (Hydroxyurea).

• Experimental: Elevated Initial Screening TCD
  Those who have an elevated initial screening TCD (either conditional or abnormal TAMV) and will be a treatment cohort that receives open-label hydroxyurea therapy as per the dosing and administration schedule.
  Interventions:

  • Drug: Hydroxyurea
  • Diagnostic Test: Elevated Arm TCD Examination
• Experimental: Normal Initial Screening TCD
  Those who are found to have a normal TCD at enrolment are a part of the observation/control cohort and will undergo repeat TCD every 12 months after enrolment. If the TCD at 12 months has changed to an elevated velocity (conditional or abnormal), the study participant will be reassigned to the elevated initial screening TCD arm and can begin study treatment (hydroxyurea), but will not be included in the primary endpoint analysis.
  Intervention: Diagnostic Test: Normal Arm TCD Examination

Inclusion Criteria:

• Willingness to sign informed consent
• Willingness to follow all study procedures
• Available for study visits for the duration of the study and no plans to move away from study center.
• Confirmed diagnosis of Sickle Cell Anemia (SCA) by haemoglobin electrophoresis.
• Able to take oral medication and follow hydroxyurea treatment schedule.

Exclusion Criteria:

There are no permanent exclusion criteria for participants to enroll in the screening TCD portion of SPHERE. Temporary, time-limited exclusion criteria for the screening TCD portion include the following:

• Febrile illness within the past two weeks. (Temporary Exclusion)
• Hospitalized within the past two weeks. (Temporary Exclusion)
• Transfusion within the past two weeks. (Temporary Exclusion)

Patients who enroll in the screening portion, have a conditional or abnormal TCD, and are eligible to start hydroxyurea will be excluded from receiving study treatment if they meet any of the following criteria:

• Abnormal pre-enrolment laboratory values (Temporary Exclusion)
• Known medical condition making participation ill-advised.
• Known allergic reactions to components of hydroxyurea.
• Previous history of stroke.
• Currently pregnant or lactating.

• Bugando Medical Centre
• The American Society of Hematology