Hydroxyurea for the Prevention of Stroke in Sickle Cell Anaemia: Mechanisms, Clinical Trial Evidence, and Global Implementation

Abstract

Background: Stroke is among the most serious complications of sickle cell anemia (SCA), affecting a substantial proportion of children and historically carrying a recurrence risk exceeding 50% after a first overt event. Transcranial Doppler (TCD) screening followed by chronic red-cell transfusion reduces first-stroke risk by more than 90%, but transfusion must be continued indefinitely and is constrained by iron overload, all immunization, venous access, and, most critically, limited feasibility in the low- and middle-income countries where the majority of affected children live.

Mechanisms: Hydroxyurea, the first disease-modifying therapy for SCA, is an oral, inexpensive agent. By inducing fetal hemoglobin and exerting pleiotropic effects on erythrocyte hydration, leukocyte and reticulocyte counts, cellular adhesion, inflammation, and nitric oxide–dependent vascular tone, it reduces HbS polymerization, sickling, and vaso-occlusion, thereby lowering cerebral arterial flow velocities.

Clinical evidence: This review synthesizes the mechanistic rationale and randomized-trial evidence for hydroxyurea in stroke prevention, distinguishing primary from secondary prevention. For primary prevention, the TWiTCH trial established non-inferiority of hydroxyurea to transfusion for maintaining TCD velocities, and trials in sub-Saharan Africa (SPIN, SPHERE, SPRING) confirmed effectiveness even at low fixed doses. For secondary prevention, chronic transfusion remains standard where available; the SPRINT trial and observational data support hydroxyurea as an alternative when transfusion is not feasible. The REACH trial additionally linked hydroxyurea to a significant reduction in all-cause mortality.

Conclusions: Hydroxyurea has a favorable safety profile, and because recently approved gene therapies exclude patients with cerebrovascular disease and remain globally inaccessible, it is the practical foundation of stroke prevention in SCA worldwide. Questions about optimal dosing, treatment duration, and long-term neurocognitive outcomes warrant continued investigation.