Assessment of Algorithm-Based Hydroxyurea Dosing on Fetal Hemoglobin Response, Acute Complications, and Organ Function in People With Sickle Cell Disease

Background: \- Sickle cell disease (SCD) is a blood disease. The drug hydroxyurea (HU) is approved to prevent pain crises in people with SCD. Researchers want to see how higher doses of HU affect the blood. This will help them learn about the right dosage of HU to give to people with SCD. Objective: \- To improve hydroxyurea dosing in people with SCD. Eligibility: \- People age 15 or older with homozygous SCD (HbSS). Design: * Participants will be screened with medical history, physical exam, medication review, and blood and urine tests. * Participants will be in the study for about 15 months. * First 3 months: monthly study visits with blood and urine tests. * After 3 months: participants will take HU as a capsule by mouth. If you are already taking HU, your dose will be increased. * Within a month of starting or increasing HU: participants will keep a daily pain diary for 2 weeks. They will have an echocardiogram (ultrasound) of the heart, a 6-minute walk test. They will complete a quality-of-life questionnaire. * Participants will visit every month until they reach their highest tolerated dose of HU. They may need to come as often as every week sometimes to closely monitor their blood counts. Then they will alternate a phone call one month and a visit the next. At the visits, participants will bring their pill bottle, answer questions about side effects, and have blood tests. * Every 2 months, participants will have a medical history, physical exam, and blood tests. * Every 4 months, participants will have blood and urine tests. They will also complete another 2-week pain diary and quality-of-life questionnaire. * About 12 months after starting or increasing HU, participants will have blood tests, an echocardiogram, and a 6-minute walk test.