Sickle cell disease is a disorder in which red blood cells (RBCs) are abnormally shaped. This can result in painful episodes, serious infections, chronic anemia (a decrease in the number of red blood cells), and damage to body organs. Hydroxyurea therapy offers significant benefits for infants, children, and adolescents with sickle cell anemia. These include a reduction in the frequency of pain crises and acute chest syndrome (inflammation of the lungs) and an increase in hemoglobin (the oxygen-carrying protein) in the blood. Patients on hydroxyurea who receive a maximum tolerated dose (MTD) that is specific for them have greater clinical benefit than those who receive a standard lower dose. There is, however, no way currently to predict the MTD for individual patients. As such, MTD for each patient is currently determined by gradual increases in the dose over several months. This process is time-consuming, requires monthly clinic visits, and delays the benefits of hydroxyurea therapy.

Our research group has come up with an equation that could be used to predict each patient's MTD using baseline clinical and laboratory measures before starting hydroxyurea treatment. The purpose of this research study is to compare the use of our equation for predicting MTD to the current standard practice of gradually increasing the hydroxyurea dose until MTD is reached. We want to see if the use of our predictive equation will allow us to achieve MTD faster and with no more side effects than with the standard practice.

To be eligible to participate in this study, patients must have decided that they want to begin hydroxyurea therapy. Patients choosing to participate in this study will be assigned randomly (like flipping a coin) to one of two hydroxyurea treatment groups. Both groups of patients will receive hydroxyurea treatment, but the determination of the starting hydroxyurea dose will be different between the two groups:

1. Group 1: The standard (dose increase) group: Patients assigned to this group will be treated following the method that is currently standard for all patients starting hydroxyurea at our institution. All patients will be started at a dose of 20 milligrams per kilogram of body weight. Dose changes will be made every eight weeks until the patient is judged to be at his or her MTD.
2. Group 2: The alternative (dose-prediction) group: Patients assigned to this group will have their predicted MTD determined using our dose-prediction equation and will be started directly at this dose.

Patients in both groups will be assessed monthly to see if they are having any side effects to hydroxyurea. We will also check to see if the MTD has been reached. Once it is decided that the patient has reached their maximum dose, they will continue to be monitored for two additional clinic visits (approximately eight additional weeks) to complete collection of end-of-study biological blood and urine samples and to ensure that there is no late harmful effects from hydroxyurea. The maximum time the patient will be on the study is 12 months after starting hydroxyurea therapy.

Patients will also be asked to participate in optional associated studies.

Biologic studies: The purpose of these studies is to determine the effect of hydroxyurea therapy on blood and urine markers that may be increased or decreased because of sickle cell disease. Patients participating in these studies will have one blood sample of 2 teaspoons (10 milliliters) and a urine sample collected before starting hydroxyurea therapy. Another blood and urine sample will be collected when they complete the study. These samples will be used to analyze markers associated with the following disease processes in sickle cell disease:

1. inflammation, blood vessel damage and oxidative stress.
2. blood viscosity.
3. early kidney disease.
4. early brain disease.
5. altered function of white blood cells, red blood cells, and platelets.

Inclusion Criteria:

1. A severe form of sickle cell disease (HbSS or HbS beta-zero thalassemia)
2. Age range of 1.0-15.99 years, inclusive, at the time of enrollment
3. A decision by the subject's family and primary clinician to initiate hydroxyurea therapy, made independently of recruitment for the study (not applicable for the biological arm patients)
4. Informed consent and assent (as applicable) obtained from parent/guardian and child.
5. Ability to comply with all study related treatments, evaluations, and follow-up/study exit

Exclusion Criteria:

1. Documented clinical stroke or transient ischemic attack (TIA).
2. Known severe vasculopathy or moya-moya disease on brain imaging studies
3. Asparagine aminotransferase (AST) or alanine aminotransferase (ALT) greater than three times upper limit of normal or serum creatinine greater than 0.8 mg/dl
4. Current participation in other interventional trials. Subjects must have been off any alternative therapy for at least three months prior to enrollment in this study
5. Erythrocyte transfusion within the prior 2 months
6. Any condition or chronic illness that in the opinion of the primary clinician makes participation in the trial ill advised
7. Inability or unwillingness to complete required studies
8. Pregnancy or unwillingness to use a medically acceptable form of contraception if sexually active (male OR female)

Patients excluded from participation due to laboratory abnormalities, participation in other interventional trials, or recent transfusions may be re-screened at a later date