Sickle Cell Disease and CardiovAscular Risk - Red Cell Exchange Trial (SCD-CARRE)

Inclusion Criteria: * Age 18 years or older * Diagnosis of SCD: homozygous sickle cell disease, hemoglobin-SC, Sβ-thalassemia, hemoglobin-SO or hemoglobin-SD. * Patients not on a chronic exchange transfusion program for at least 60 days. * If patients are on a SCD drug (e.g. hydroxyurea, glutamine, or P-selectin inhibitors), the doses must be stable for at least 60 days prior to randomization. At the time of randomization, participants must be off Oxbryta for at least 30 days. * Any one of the following vasculopathy biomarker clinical results (a, b, c, d or e) measured in the last 24 months before randomization that indicates a high-risk patient: 1. Both a TRV 2.5- \<3.0 m/sec and NT-proBNP plasma level ≥ 160 pg/mL, 2. TRV ≥ 3.0 m/sec, 3. Both a mean pulmonary artery pressure (PAP) by right heart catheterization 20-24 mmHg and NT-proBNP plasma level ≥ 160 pg/mL, 4. Mean PAP by right heart catheterization ≥ 25 mmHg, 5. Chronic kidney disease (CKD) due to SCD with abnormal measures on 2 separate occasions as defined by: macroalbuminuria (albumin to creatinine ratio (ACR) \>300 mg/g) or proteinuria (protein to creatinine ratio \>30 mg/mmol), or estimated glomerular filtration rate (eGFR) \< 60 mL/min/1.73 m2. (It is recommended that local laboratories use Chronic Kidney Disease Epidemiology Collaboration \[CKD-EPI\] equation without ethnic factors when estimating and reporting GFR). Clinical results of these biomarkers measured locally at sites within 24 months prior to randomization are acceptable to determine eligibility. TRV, PAP, NT-proBNP, albumin to creatinine ratio, protein to creatinine ratio, or eGFR values must be measured in a steady state (defined as measured ≥ 14 days since an acute care pain event) on different days. vi. Written informed consent obtained from patient to participate in the trial. Exclusion Criteria: * RBC alloimmunization resulting in inability of blood bank to obtain compatible components for chronic exchange transfusions * Previous history of hyper-hemolysis syndrome * Previous history of severe transfusion reaction resulting in renal failure or due to serious complications such as hypotension or respiratory distress * More than 10 vaso-occlusive episodes in the past 12 months requiring admission to a hospital to receive treatment. * Religious objection to receiving blood transfusion * Diagnosis of ischemic stroke within the past 6 months * Clinical evidence of liver failure or advanced cirrhosis or any co-existing medical condition that in the Investigator's judgement will substantially increase the risk associated with the patient's participation in the trial * Women of childbearing potential who have a positive pregnancy test at baseline