The goal of this study is to determine the effectiveness of blood transfusion therapy for prevention of silent cerebral infarct (stroke) in children with sickle cell anemia.

Silent cerebral infarct (stroke) is the most common cause of severe cognitive impairments and related neurological functions in children with sickle cell anemia. Currently there exists no systemic strategy to identify or treat children with silent strokes.

The primary aim of this trial is to determine the effectiveness of blood transfusion therapy for the prevention of silent strokes in children with sickle cell anemia. This trial will also determine if blood transfusion therapy will prevent further cerebral injury and if the measured benefits of the therapy outweigh the risks associated with it.

Participants in this multi-center trial will be randomly assigned to one of 2 groups-the blood transfusion group or the observation group. Those in the blood transfusion group will receive at least monthly blood transfusion therapy. All participants will have history and physical examinations every 3 months, and magnetic resonance imaging (MRI) at the beginning of their entry into the study and at study exit.

Advances in the understanding and treatment of silent strokes will likely lead to a decrease in the burden associated with cerebral injury in children with sickle cell anemia and change the standard care for these children.

Statistical Analyses: The original statistical analysis plan suggested a simple difference in proportions between the proportion of individuals with an endpoint in the transfusion group and the proportion of individuals with an endpoint in the usual care group using a traditional chi squared test. The data should be analyzed according to an intent to treat principal. Because of various logistical concerns in SIT, some individuals were not imaged within the 36-month window (30-42 months). We propose using all available information by changing the primary analysis from a dichotomous (yes/no) endpoint to a traditional epidemiological endpoint of an incidence rate in the group randomized to transfusion to the incidence rate in the group randomized to usual care. We will compute the incidence ratio:

(a/ta)/(b/tb)

Where "a" is the number of endpoints in the transfusion group, "ta" is the sum of the individual times at risk of the individuals randomized to the transfusion group, "b" is the number of endpoints in the observation group and "tb" is the sum of the individual times at risk of the individuals randomized to the observation group.

Since the standard statistical test for it being different than 1.0 involves the assumption of a Poisson distribution, we will compute an "exact" 95% confidence interval using a bootstrap with a large number of replications.

INCLUSION:

• Patient must have sickle cell anemia (hemoglobin SS) or sickle beta thalassemia (hemoglobin SB) as confirmed at the local institution.
• Participating institutions must submit documentation of the diagnostic hemoglobin analysis to the Statistical and Clinical Coordinating Centers to confirm the diagnosis of sickle cell anemia prior to randomization.
• Patient must be 5 through 14 years of age.
• Patient must have a cerebral infarct documented by MRI scan as read by the neuroradiology panel.
• Informed consent with assent in accordance with the institutional policies (institutional Institutional Review Board approval) and Federal guidelines (approved by the United States Department of Health and Human Services) must be signed by the patient's legally authorized guardian acknowledging written consent to join the study. When suitable, patients will be requested to give their assent to join the study.

EXCLUSION:

• Patient with a history of a focal neurologic event lasting more than 24 hours with medical documentation or a history of prior overt stroke.
• Patients with a transcranial doppler (TCD) study with a time-averaged mean velocity greater than 200 cm/sec verified by the study radiologist.
• Patients with other neurological problems, such as neurofibromatosis, lead poisoning, or tuberous sclerosis.
• Patients with HIV infection.
• Pregnancy.
• Patients who received treatment with anti-sickling drugs or hydroxyurea within 3 months or anticipate receiving anti-sickling drugs or hydroxyurea during the course of the study.
• Abnormal kidney function (creatinine > 2x upper limit of normal).
• Patients on chronic blood transfusion therapy for other reasons.
• Patients judged not likely to be compliant by his/her hematologist and local nurse coordinator based on previous compliance in clinic appointments and following advice. Specifically, families that have missed at least two appointments without notification within 12 months prior to the trial or parents of potential patients that have been reported for medical or education neglect are not eligible for this trial.
• Patients unable to receive blood transfusion because of alloimmunization.
• Patients with permanent or semi-permanent metallic (braces on teeth) structures attached to their body. Such patients cannot obtain a MRI of the head to assess the presence of silent cerebral infarcts.
• Siblings randomized in the trial.

The SIT Trial results are not directly applicable to all children with SCA. Those who were on hydroxyurea therapy for severe disease, had abnormally elevated TCDs, were receiving blood transfusion for stroke prevention or had epilepsy were excluded.