Stroke Risk in Sickle Cell Disease: Screening and Preventing a Devastating Complication

Stroke is a devastating complication of sickle cell disease. In children, haemorrhagic strokes are actually more common than ischaemic strokes. Risk factors for ischaemic stroke include the conventional cardiovascular risk factors (hypertension, diabetes, dyslipidaemia, atrial fibrillation and renal disease), which contribute through CNS vasculopathy; any situation that reduces oxygen saturation or increases oxygen demand, such as acute chest syndrome, fever or seizures; a sudden fall in haemoglobin, as happens in an aplastic crisis from parvovirus B19 infection; and increased cerebral blood flow that reduces cerebrovascular reserve.

How Common Is Stroke, and Who Is at Risk

In a cohort of children born and followed for 18 years in sub-Saharan Africa and India, where primary stroke prevention was not routinely practised, 11% went on to have an overt stroke and 39% had silent cerebral infarcts. Looking at age of first cerebrovascular accident by genotype, patients with sickle cell anaemia (HbSS) had a 24% chance, and patients with HbSC disease a 10% chance, of having a stroke by the age of 45. Beyond genotype, the specific risk factors for stroke are abnormal transcranial doppler velocities, increasing age, hypertension, a previous transient ischaemic attack, a silent cerebral infarct, and chronically low haemoglobin.

Transcranial Doppler Screening and Primary Prevention

Transcranial doppler ultrasound predicts stroke risk by detecting stenosis or occlusion of the internal carotid or middle cerebral artery. Velocities under 200 are considered safe and keep a child stroke-free for roughly 36 to 40 months. Two landmark trials, STOP in 1998 and STOP 2 in 2005, established that maintaining haemoglobin S below 30% with regular red cell transfusions reduces the risk of a first overt stroke by 92%; STOP 2 also showed that stopping prophylactic transfusions after 30 months led to a renewed high risk of stroke, so regular transfusion needs to continue for primary prevention rather than being time-limited. Building on this evidence, the American Society of Hematology's 2020 guidelines recommend annual transcranial doppler screening from age two to sixteen in patients with HbSS or HbS-beta-zero disease; if the scan is abnormal, regular transfusions should keep haemoglobin S below 30% or haemoglobin above 9 g for at least a year, after which hydroxyurea at the maximum tolerated dose can be considered, an approach supported by the 2016 TWiTCH trial.

Secondary Prevention and Silent Cerebral Infarcts

Secondary stroke prevention again relies on a chronic transfusion programme, with the same goals of keeping haemoglobin S below 30% and haemoglobin above 9 g. Even with a chronic transfusion programme in place, 23% of children unfortunately go on to have a second stroke. Silent cerebral infarcts are also common and become more frequent with age, affecting around 40% of children and 50% of adults; they are linked to cognitive impairment, poor school performance and a higher chance of future cerebral infarcts. Current guidance recommends a one-time MRI for all school-age children and adults, and managing any silent infarcts found with regular transfusions and regular cognitive evaluation.

This article is based on a Jivo Masterclass session conducted by Dr. Divya Doval, Senior Consultant, Bone Marrow Transplant & Haemato-Oncology, BLK-Max Super Speciality Hospital, New Delhi. The article has been summarised with the assistance of an AI tool from the original masterclass recording. Watch the full Masterclass recording