Sickle Cell Stroke Prevention and Chronic Organ Damage

Sickle cell stroke prevention starts with an annual transcranial Doppler scan for every child with HbSS or HbS beta-zero thalassaemia from age 2 to 16. An abnormal result triggers regular transfusions to hold haemoglobin S below 30%, which cut the risk of a first overt stroke by 92% in the landmark STOP trial. Without screening, roughly one child in nine has a stroke.

Stroke is the most devastating complication of sickle cell disease, but it is only one part of a wider pattern of slow organ injury. This article follows Dr. Divya Doval, Principal Consultant - Haemato Oncology & BMT, BLK-Max Super Speciality Hospital, New Delhi, India, through the evidence on stroke and silent cerebral infarcts and then through the chronic damage the disease does to the lungs, heart, kidneys, liver, eyes and bones. The disease's biology and the full treatment framework are in the complete guide to diagnosis and management of sickle cell disease.

Why stroke happens in sickle cell disease

Stroke in sickle cell disease is usually caused by narrowing or blockage of the large arteries at the base of the brain, the internal carotid and the middle cerebral arteries. In children, ischaemic stroke (caused by blocked blood flow) is the dominant type; haemorrhagic stroke (caused by bleeding) becomes relatively more common in young adults.

Dr. Doval grouped the drivers of ischaemic injury into four categories:

• Conventional vascular risk factors. Hypertension, diabetes, dyslipidaemia, atrial fibrillation and kidney disease contribute to cerebral vasculopathy (damage to the brain's blood vessels).
• Falling oxygen delivery with rising demand. Acute chest syndrome, fever and seizures all lower oxygen saturation or raise the brain's oxygen requirement.
• Sudden anaemia. An abrupt fall in haemoglobin, such as an aplastic crisis from parvovirus B19 infection, can precipitate ischaemic injury.
• Exhausted cerebrovascular reserve. In chronic anaemia, cerebral blood flow is already increased to compensate, leaving little reserve when demand rises further.

This is why blood pressure control appears in Dr. Doval's general care checklist: the conventional risk factors are modifiable.

How common is stroke in sickle cell disease?

Without screening, stroke is common. In children followed from birth for 18 years in settings where primary prevention was not routinely practised, 11% had an overt stroke and 39% developed silent cerebral infarcts. These are the numbers Dr. Doval presented to show why screening is non-negotiable.

Risk also depends on genotype. By the age of 45, people with sickle cell anaemia (HbSS) have a 24% chance of having had a stroke, against 10% for those with HbSC disease.

Who is at highest risk

The risk factors for stroke she listed are:

• an abnormal transcranial Doppler result;
• increasing age;
• hypertension;
• a previous transient ischaemic attack (TIA);
• a silent cerebral infarct;
• chronically low haemoglobin;
• HbSS genotype.

Transcranial Doppler screening for stroke risk

Transcranial Doppler (TCD) is a non-invasive ultrasound scan that measures the speed of blood flow in the major brain arteries. Narrowed arteries produce higher velocities, so TCD identifies children at high risk before a stroke occurs.

Dr. Doval described the ASH 2020 recommendation: children with HbSS and HbS beta-zero thalassaemia should have an annual TCD from the age of 2 up to 16.

Velocities are interpreted against standard thresholds, based on the time-averaged mean maximum velocity:

Sickle cell stroke prevention: three trials that set the standard

The modern approach to primary stroke prevention rests on three trials, which Dr. Doval walked through in sequence.

STOP (1998). Children with abnormal TCD velocities were given regular packed red cell transfusions to keep HbS below 30%. This reduced the risk of a first overt stroke by 92%.

STOP II (2005). This trial tested whether prophylactic transfusions could be stopped after 30 months. They could not: stopping led to a return of high stroke risk. The conclusion was that regular transfusions must be continued for primary prevention.

TWiTCH (2016). This trial showed that, after at least a year of transfusion, selected children can switch to hydroxyurea at the maximum tolerated dose.

Together these trials underpin the ASH 2020 guidance as Dr. Doval set it out. If TCD is abnormal, regular transfusions should keep HbS below 30%, or haemoglobin above 9 g/dL, for at least one year. After that year, if the decision is made to stop transfusions, hydroxyurea can be started at the maximum tolerated dose.

Secondary prevention after a first stroke

After a stroke has occurred, the cornerstone is a chronic transfusion programme. The targets are the same: HbS below 30% and haemoglobin above 9 g/dL.

Even this is not fully protective. Dr. Doval noted that 23% of children have a second stroke despite a chronic transfusion programme. Her centre now regards a single stroke as an indication for stem cell transplant in a child, a pathway explored in Dr. Dharma Choudhary's article on when to refer for sickle cell transplant.

Silent cerebral infarcts: the hidden injury

Silent cerebral infarcts are small areas of brain injury that cause no obvious stroke symptoms. They are common and become more frequent with age: Dr. Doval put the prevalence at around 40% in children and 50% in adults.

They are not harmless. They are associated with:

• cognitive impairment;
• poor school performance;
• future cerebral infarcts.

ASH recommends a one-time MRI screen of the brain in school-age children and in adults. Management combines regular transfusions with regular cognitive evaluation of children.

In the discussion, Dr. Doval returned to this point when explaining why she favours transplant. Even when everything is done well, ischaemic events continue in the background. Cognitive and behavioural effects may not look like a problem while the child is young, but they take a toll on brain function over time.

Chronic organ damage in sickle cell disease

Beyond the brain, sickle cell disease causes cumulative damage to the lungs, heart, kidneys, liver, eyes, bones and spleen. Each has a defined management approach.

Lungs and heart

Pulmonary arterial hypertension is a recognised chronic complication. Cardiomegaly (an enlarged heart) can develop and lead eventually to diastolic heart failure. Pulmonary hypertension is also among the conditions in which hydroxyurea can be considered, and an elevated tricuspid regurgitant jet velocity (TRV) on echocardiography, a marker of raised pulmonary pressure, is one of the published indications for transplant.

Kidneys

Chronic kidney disease in sickle cell disease begins with albuminuria and proteinuria. Ongoing protein loss reflects a progressive nephropathy that reduces the glomerular filtration rate and can end in end-stage kidney failure needing dialysis or other renal replacement therapy. Sickle nephropathy is itself an indication for transplant.

Renal medullary carcinoma, a rare kidney cancer associated with sickle cell trait, carries a poor prognosis.

Liver

Chronic hepatopathy has the same causes as acute liver involvement: the sickling process itself, and the consequences of multiple transfusions, including hepatitis B and C infection and iron overload. Sickle hepatopathy is also a published indication for transplant.

Eyes

Sickle retinopathy can develop over time. An annual screening examination of the retina is recommended, and treatment, when needed, is laser photocoagulation or vitrectomy (surgery on the gel inside the eye).

Bones: avascular necrosis

Avascular necrosis (bone death from lost blood supply) is a very important chronic complication. It does not only affect the hip: it can also involve the shoulders, knees, feet and spine. MRI has very high sensitivity and specificity for detecting it. Management starts with pain control and, if symptoms do not settle, orthopaedic intervention.

Asked how avascular necrosis can be prevented, Dr. Doval was candid. Repeated pain crises cause the bone infarcts, and sometimes they cannot be prevented. The measures that help are fluids, hydroxyurea and prompt supportive care every time a pain crisis occurs.

Spleen, growth and skin

Functional asplenia develops by 2 to 3 years of age as repeated infarcts destroy the spleen, leaving a lifelong vulnerability to infection. Other chronic effects include delayed puberty, erectile dysfunction (often after priapism), chronic skin ulcers and chronic pain.

Iron overload monitoring: ferritin and MRI thresholds

Chronic transfusion protects the brain but loads the body with iron. Dr. Doval's monitoring protocol is threshold-driven:

1. Check serum ferritin every 3 months.
2. If ferritin exceeds 1,000 ng/mL, measure liver iron content by liver MRI.
3. If liver iron exceeds 7 mg per gram of dry liver weight, start iron chelation (drugs that bind and remove iron).
4. If it exceeds 15 mg per gram, perform a cardiac T2* MRI to look for iron in the heart and assess cardiac function.

Transfusion technique, alloimmunisation and the other risks of transfusion are covered in the guide to hydroxyurea, transfusion and newer sickle cell therapies.

Long-term monitoring checklist for sickle cell disease

Pulling these threads together, the long-term surveillance Dr. Doval described for a patient with sickle cell disease includes:

• annual TCD from age 2 to 16 for HbSS and HbS beta-zero thalassaemia;
• a one-time brain MRI in school-age children and adults;
• regular cognitive evaluation of children;
• an annual eye examination;
• blood pressure control;
• ferritin every 3 months for patients on chronic transfusion.

Surveillance prevents the slow damage that ultimately decides whether a patient remains eligible for cure. As Dr. Doval explained when asked about the age limit for transplant, there is none, but with age the risk of stroke rises and the liver and kidneys become affected, reducing eligibility. Acute crises are covered in the guide to managing sickle cell crises and acute emergencies. Clinicians' questions on avascular necrosis, transplant success rates and the age limit for transplant, with Dr. Doval's full answers, are on the Live Discussion page.