Cerebrovascular Reserve and White Matter Disease in Patients With Chronic Anemia

This is primarily an observational trial in patients with chronic anemia syndromes (sickle
cell disease and thalassemia) and control subjects. The key purpose is to understand how
brain blood flow reserve (the ability of the brain to increase its flow in response to
stress) is altered in patients with chronic anemia. Since this parameter may depend on anemia
severity, we will perform the MRI monitoring prior to and following clinically indicated
transfusions in a subset of patients. Most patients will already be prescribed hydroxyurea as
part of their standard of care. Since hydroxyurea could impact brain blood flow, there is
also a small pilot study (20 patients, nonrandomized, open label) where MRI imaging will be
performed prior to and following administration of hydroxyurea up to maximum tolerated dose.
The study will enroll 90 adult subjects with transfusion independent sickle cell disease (70
SS, 10 SC, 10 Sβ0) and 60 patients with transfusion-dependent sickle cell disease. It will
also include 10 transfusion independent thalassemia patients and 20 transfusion dependent
thalassemia patients as well as 40 control subjects recruited from first degree relatives of
the sickle cell disease population. All eligible subjects will be asked to provide informed
consent before participating in the study.

Treatment:

All patients will undergo baseline phlebotomy, brain MRI, and neurocognitive testing. The MRI
will include measurements of brain blood flow prior to and following administration of 16
mg/kg of acetazolamide to maximally vasodilate the cerebral vasculature. All transfusion
dependent patients will have their MRI performed immediately prior to a routinely scheduled
transfusion at their hemoglobin nadir. 20 sickle cell disease patients on chronic simple
transfusions and 10 thalassemia patients on chronic simple transfusions will undergo repeat
MRI assessment of cerebral blood flow and reactivity following their clinically indicated
blood transfusion. 10 sickle cell disease patients on exchange transfusions will undergo
repeat MRI assessment of cerebral blood flow and reactivity following their clinically
indicated exchange transfusion; this transfusion will be performed to lower their hemoglobin
S percentage by 25% points while keeping the total hemoglobin unchanged (isocrit exchange).
20 non transfusion dependent sickle cell disease patients not already receiving hydroxyurea
will be placed on hydroxyurea following their baseline exam and titrated to maximal tolerated
dose. They will then undergo a repeat MRI within two months of reaching that dose and be
given the option to continue on hydroxyurea or stop.

Safety Assessment:

All patients will have a physician present during the MRI examination to monitor vital signs
and response to acetazolamide. Patients placed onto hydroxyurea will have monthly study
visits with monitoring of complete blood count, vital signs, complete metabolic panel, and
hemoglobin electrophoresis. Adverse events will be assessed at every study visit after the
first dose through to the last subject visit.

Efficacy Assessments:

Baseline cerebrovascular reserve (CVR) predictors will be assessed by multivariate regression
after appropriate transformations. Potential independent predictors include oxygen content,
hemoglobin subtype, as well as markers of hemolysis, inflammation, and iron overload.

- Inclusion Criteria:

1. Diagnosis of sickle cell disease (genotype SS, SC, or SB0), thalassemia
(transfusion dependent or transfusion independent), or normal control subject
that are ≥18yrs, ethnicity, and sex matched to the sickle cell disease
population.

2. Ability to tolerate a one hour MRI examination.

3. Age equal to or greater than 7 years old for Anemia groups.

4. Agreeable to use an approved method of contraception for the entire duration of
hydroxyurea usage if accepted onto the hydroxyurea substudy (male or female of
childbearing potential)

Exclusion Criteria:

1. Hospitalization within one month

2. Contraindication to acetazolamide use (seizures)

3. Severe claustrophobia.

4. Pregnancy or nursing (a negative HCG (pregnancy) test must be obtained prior to MRI)

5. As a result of medical review, physical examination or screening investigations, the
Principal Investigator (PI) considers the subject unfit for the study

6. No fixed address

7. In control subjects, chronic hepatitis, diabetes, hypertension, coronary artery
disease, cognitively impaired or developmental delay