Epidemiology of Silent and Overt Strokes in Sickle Cell Disease

Sickle Cell Disease (SCD) is a rare disease occurring in an estimated 100,000 individuals, often poor and underserved, in the US. Silent and overt strokes contribute significantly to morbidity in adults with SCD, resulting in functional impairment, challenges with school and job performance, and premature death. Five NIH-funded randomized controlled trials have identified therapies to prevent silent and overt strokes in children with SCD, including monthly blood transfusion therapy (for preventing initial and recurrent strokes) and hydroxyurea (for preventing initial strokes). Despite the observation that at least 99% of children with SCD in high-income countries reach adulthood, and approximately 60% of adults will experience one or more strokes (\~50% with silent strokes and \~10% with overt strokes), no stroke trials have established therapeutic approaches for adults with SCD. For adults with SCD, inadequate evidence-based guidelines exist for secondary stroke prevention strategies. Applying stroke prevention strategies in children may not be effective for stroke prevention in adults with SCD, particularly given the high rate of co-morbidities. Identifying subgroups of adults with SCD and higher incidence coupled with the contribution of established stroke risk factors in the general population (smoking, diabetes, obesity, renal disease) will provide the requisite data required for the first-ever phase III clinical trials focused on secondary stroke prevention in adults.

In three adult SCD centers, we will conduct a prospective cohort study to test the primary hypothesis that the incidence of infarct recurrence (stroke or silent stroke) or new strokes in adults with silent strokes treated with hydroxyurea will be greater than in those without strokes treated with hydroxyurea. We will test two secondary hypotheses: 1) adults with SCD and silent strokes have cognitive morbidity when compared to adults with SCD without silent strokes, and 2) adults with SCD and strokes receiving regular blood transfusion will have a higher incidence of infarct recurrence than those with SCD without strokes. The aims include Aim 1: Compare the incidence of new overt and silent strokes in adults with SCD and silent strokes to a comparison group of adults without silent strokes or overt strokes. Aim 2: Compare the cognitive morbidity of those with silent strokes and overt strokes to those without strokes. Aim 3: Compare the incidence of new overt and silent stroke in adults with SCD and overt strokes receiving transfusion to adults with SCD without silent or overt strokes treated with hydroxyurea. All clinical information and neuroimaging will be centrally adjudicated with masked and experienced neurology and neuroradiology committees. Data generated after completion of this proposal are critical for developing the first-ever phase III trials for secondary stroke prevention therapies in adults with SCD.

Eligibility Criteria:
Inclusion Criteria:

1. Participants with sickle cell disease on hemoglobin analysis and/or other confirmatory documentation of phenotype
2. Patients ≥ 18 years of age
3. Patients followed regularly (at least two visits per year) in the hematology clinics
4. Patients who have demonstrated adherence with follow-up visits for ≥ 3 years
5. Patients willing to be followed prospectively for a minimum of 3.5 years and agree to a standard care exit MRI/MRA of the brain, as well as MRI/MRA every 12 to 18 months or participation in VUMC AHA trial with Dr. Jordan as PI. These are adults with SCA aged 18-40 years at study entry, enrolled with any infarct status (none, SCI or overt stroke) and followed prospectively.
6. Willingness to comply with study protocol, routine clinic visits

Exclusion criteria:

1. Participants judged to be non-compliant by the hematologist based on previous experience in terms of clinic appointments and following advice
2. Participants with contraindications to MRI, including individuals with MRI-incompatible foreign metal objects