A new study indicates the incidence of stroke continues to increase for adults and children living with sickle cell disease (SCD). Prior studies had shown rates of stroke had decreased in children after publication of the landmark Stroke Prevention Trial in Sickle Cell Anemia (STOP) study.

STOP was a landmark clinical trial published in 1998. The study demonstrated that chronic red blood cell transfusions decreased the incidence of events like strokes in high-risk children with SCD. These children were identified by abnormal blood flow as measured by a Transcranial Doppler testing (TCD), a type of brain ultrasound.

The new study determined more recent trends in rates of stroke amongst Californians living with SCD. It was led by Ted Wun, associate dean for clinical and translational research at the UC Davis School of Medicine, and was published today in Blood.

Individuals living with SCD, the most common inherited red blood cell disorder in the United States, are especially susceptible to cerebrovascular events. This includes ischemic or hemorrhagic strokes, when a blood vessel leading to the brain is either blocked or bursts. It also includes transient ischemic attacks, when blood flow temporarily stops in a blood vessel supplying the brain but does not cause long-term damage.

In a population-based study, Wun’s team found that the risk of stroke increased with age, doubling for every 20 years of age.

“As hematologists, our training emphasizes that the risk of stroke is highest in young children, but I think that has resulted in far less attention being paid to adult patients,” said Wun, the study’s senior author. “There’s very little data on [stroke in adults living with sickle cell disease], so we just extrapolate what happens in children to adults, but we don’t know if that’s appropriate or not.”

The researchers accessed databases from California’s Emergency Department Utilization (2005 - 2019) and Patient Discharge Data hospitalization (1991 - 2019). They identified 7,636 patients with a diagnosis of SCD.

Of these patients, 9.6% had experienced at least one cerebrovascular event. This included:

• Ischemic stroke (5.9%)
• Hemorrhagic stroke (3%) or
• Transient ischemic attack (2.7%)

These events were more common in women and patients hospitalized three or more times per year.

The cumulative incidence of hemorrhagic stroke increased 13-fold from age 20 to age 60. Additionally, despite a two-year decline in cerebrovascular events following the publication of the STOP study, the highest rates occurred across all age groups in the most recent decade, 2010 - 2019.

“Even in children, who probably get the best care for patients with sickle cell disease in this country, these trends are opposite what we would hope,” Wun said. “Based on these results, it appears that STOP guidelines haven’t been effectively implemented.”

As hematologists, our training emphasizes that the risk of stroke is highest in young children, but I think that has resulted in far less attention being paid to adult patients.” —Ted Wun

An increase in strokes post-STOP

Wun and his team hypothesized that the increase in strokes post-STOP could be due to several factors, such as:

• A decreased adherence to the TCD screening guidelines
• Improved technology to diagnose ischemic strokes
• Low rates of blood transfusion therapy
• Low usage of hydroxyurea, a drug commonly used to decrease the likelihood of blood cells developing a sickle shape, that also reduces the risk of stroke

The researchers also looked at modifiable risk factors for stroke. They found that factors that increase risk of ischemic stroke included frequent hospitalization, high blood pressure, high cholesterol, and a prior transient ischemic attack.

However, patients that had complications of SCD, such as acute chest syndrome, liver failure, and prior ischemic stroke, were more likely to suffer a hemorrhagic stroke.

These updated data on modifiable risk factors of stroke “emphasize the need to pay attention to screenings for high cholesterol, high blood pressure, and other risk factors in adults,” said Olubusola Oluwole, assistant professor at the University of Pittsburgh School of Medicine and the study’s first author.

“The steps that we know help prevent stroke in the general population are just as important for people living with sickle cell disease,” added Wun, especially as people with this condition live longer and are at greater risk of stroke.

The study noted several limitations, including a lack of reliable data on tobacco use, which increases the risk of stroke, and a lack of documentation of the sub-type of SCD. Additionally, the authors did not have access to imaging reports and could not radiographically confirm a stroke diagnosis. Furthermore, the rate of cerebrovascular events in patients in California may be underestimated if they had a stroke outside of the state, died of stroke prior to hospitalization, or if transient ischemic attack symptoms were managed at home.

The researchers hope this study will stimulate more studies on stroke and SCD in adults.