Therapy Insight: Stroke Risk and Its Management in Patients With Sickle Cell Disease

Fenella J. Kirkham


Nat Clin Pract Neurol. 2007;3(5):264-278. 

In This Article

Summary and Introduction

Children with sickle cell disease, a chronic hemolytic anemia, present with a wide variety of neurological syndromes, including ischemic and hemorrhagic stroke, transient ischemic attacks, 'soft neurological signs', seizures, headache, coma, visual loss, altered mental status, cognitive difficulties, and covert or 'silent' infarction. Those with ischemic stroke usually have stenosis or occlusion of the distal internal carotid and proximal middle cerebral arteries. Indefinite transfusion prevents recurrence in most patients who have had a stroke, and can prevent first stroke in those with high transcranial Doppler velocities. High white cell count, low hemoglobin and oxyhemoglobin desaturation predict neurological complications. Other risk factors for overt ischemic stroke include hypertension, previous transient ischemic attack, covert infarction and chest crisis. For hemorrhagic stroke, aneurysms are common in adults but not children, who often present with hypertension after transfusion or corticosteroids. Seizures are particularly common in patients with cerebrovascular disease and covert infarction; the latter is also associated with hyposplenism and infrequent pain. Factors associated with cognitive difficulties include thrombocytosis, infarction, large-vessel disease, and perfusion abnormality on neuroimaging. As well as investigating the role of genes and the possibility that hydroxyurea or blood pressure control reduce neurological complications, we should explore the modifiable effects of poor nutrition, chronic infection, hemolysis and oxyhemoglobin desaturation on stroke risk.

Sickle cell disease (SCD) is a group of recessively inherited hemoglobinopathies common among people of Equatorial African, Saudi Arabian and Mediterranean ancestry, and now widespread in the Americas and Europe. The causative mutation is the substitution of valine for glutamic acid at the sixth position of the β globin chain (Glu6Val). Sickle cell hemoglobin (HbS) behaves like normal hemoglobin when fully oxygenated, but at low oxygen tension the hydrophobic valine residues cause the HbS to polymerize, resulting in gel formation and increasing red cell density. The rigid and deformed sickle cell is damaged by mechanical stress during passage through the vasculature, resulting in a chronic hemolytic anemia with red cell destruction, the rate of which is influenced by factors such as infection and drugs.

The homozygous state (HbSS) is known as sickle cell anemia; compound heterozygotes with HbSβ0-thalassemia, who also have a severe reduction in the synthesis of β globin chains, have a similar prevalence of complications, including stroke, although variations in phenotype in these conditions are not fully understood. People with the double heterozygous form of sickle cell disease (HbSC) or HbSβ+-thalassemia usually have less-severe neurological complications in later life, and there is ongoing controversy as to whether stroke is more common in those with sickle cell trait (HbAS) than in the general population. Children with SCD can develop acute neurological symptoms and signs consistent with cerebrovascular accident (CVA), either spontaneously or in the context of an acute illness such as infection.[1] There is a high risk of CVA recurrence—particularly for patients presenting spontaneously—that is reduced but not eliminated by regular blood transfusion.[1,2] In the longitudinal Cooperative Study of Sickle Cell Disease (CSSCD), 25% of patients with HbSS and 10% of those with HbSC disease had a CVA by the age of 45 years.[3] In patients with SCD, cerebral infarction has been reported to be the most common cause of stroke in the first two decades of life and from the fourth decade onwards, whereas hemorrhagic stroke occurs more commonly in the third decade.[3] The reasons for this age distribution and the pathophysiology are poorly understood, however.

The aims of this Review are to document the range of neurological complications of sickle cell disease, to define the known risk factors, to determine the current evidence-based treatment strategies, and to suggest strategies for investigating long-term stroke prevention.


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