Sickle Cell Disease (SCD) is a genetic blood disorder caused by a mutation in the hemoglobin protein. This mutation causes red blood cells to deform into a rigid, crescent shape under certain conditions. These misshapen cells do not flow smoothly, leading to blockages and damage throughout the body’s vascular system.
SCD significantly increases the risk of stroke, making it one of the most devastating complications of the disease, particularly in children. Approximately 11% of individuals with the most severe forms of SCD experience an overt stroke by the age of 20.
The Pathophysiology of Blood Flow Restriction
The mechanism linking SCD to stroke begins with the sickled red blood cells, which are stiff and sticky. These abnormal cells clog small blood vessels, impeding the flow of oxygenated blood to the brain tissue. This process is known as vaso-occlusion. The sickled cells also adhere abnormally to the inner lining of blood vessels, called the endothelium, initiating a cycle of damage and inflammation.
Chronic hemolysis, the premature destruction of red blood cells, releases cell-free hemoglobin into the bloodstream, which is a potent factor in promoting inflammation and endothelial dysfunction. This inflammatory state contributes to cerebral vasculopathy, where the walls of the brain’s blood vessels become thickened, narrowed, and damaged. Narrowing of major intracranial arteries, such as the internal carotid and middle cerebral arteries, reduces the space for blood flow. This combination sets the stage for an obstruction to completely block blood supply, resulting in an ischemic stroke.
Identifying High-Risk Individuals and Stroke Types
Stroke in SCD patients presents primarily as two types: ischemic and hemorrhagic. The risk profile shifts across the lifespan. Ischemic stroke, caused by a blockage, is the most common type seen in children, typically peaking between the ages of two and five years.
Hemorrhagic stroke, caused by a blood vessel rupture, is less common overall but becomes the predominant type in adulthood. The risk of hemorrhagic stroke increases significantly with age, showing a 13-fold rise between the ages of 20 and 60. Individuals with the most severe genotype, Hemoglobin SS, have the highest risk for both stroke types. Other risk factors include a history of severe anemia, prior episodes of acute chest syndrome, and a higher white blood cell count.
Clinical Strategies for Stroke Prevention
Preventing a first stroke in children with SCD relies on routine screening using Transcranial Doppler (TCD) ultrasound. This non-invasive tool measures the speed of blood flow in the major cerebral arteries, primarily the middle cerebral and internal carotid arteries. An elevated blood flow velocity indicates vessel narrowing, which is a strong predictor of stroke risk.
A mean maximum velocity of 200 centimeters per second (cm/s) or greater is considered an abnormal, high-risk result in children. For children identified as high-risk by TCD, the established preventative therapy is chronic blood transfusion therapy. This treatment involves regular transfusions of healthy blood, which dilutes the concentration of sickled cells and reduces the risk of a first stroke by over 90%.
Hydroxyurea is another disease-modifying therapy used for stroke prevention, often as an alternative or alongside transfusion therapy. This medication works by increasing the production of fetal hemoglobin, which interferes with the sickling process and improves the flexibility of red blood cells. Hydroxyurea has been shown to reduce blood flow velocities in the cerebral arteries, making it an effective strategy for children with conditionally high TCD velocities (170–199 cm/s).