The clinical features of sickle cell anemia are caused by polymerization of deoxygenated sickle hemoglobin (hemoglobin S), the predominant hemoglobin type found in this genetic disease. Sickle polymer damages the red cell, shortens its life span, and triggers vascular occlusive disease. Among the vascular complications of sickle cell anemia is stroke, which affects about 10% of children who do not undergo long-term blood-transfusion therapy after transcranial Doppler screening. Stroke is accompanied by high cerebral blood-flow velocity, which is associated with endothelial damage, intracranial and extracranial cerebral vascular occlusion, and intracerebral hemorrhage. Blood transfusion reduces the velocity of cerebral blood flow and decreases the percentage of circulating sickle cells.
Approximately 35% of children with sickle cell anemia have cerebrovascular disease, including silent infarction and stroke. In the Silent Cerebral Infarct Transfusion (SIT) trial, the results of which are reported by DeBaun et al.1 in this issue of the Journal, neurologically intact children in whom a silent infarct was detected by magnetic resonance imaging and who were not at high risk for a stroke were randomly assigned to receive standard care (observation group) or a regimen of monthly transfusions to maintain a total hemoglobin level of more than 9 g per deciliter and a target hemoglobin S concentration of 30% or less (transfusion group). After 3 years, the relative risk reduction for new silent infarcts among patients in the transfusion group as compared with those in the observation group was 56%. Cognitive improvement was not observed with the transfusion regimen, as compared with observation, although the cognitive testing and the observation period were limited.
Transfusions can prevent clinically apparent stroke in children with sickle cell anemia while decreasing the incidence of other complications, such as acute episodes of pain and the acute chest syndrome.1,2 Therefore, the results of this trial are not unexpected. Because neurologically intact adults with sickle cell disease can have decreased neurocognitive function, do the observations of DeBaun et al. present an opportunity for decreasing the long-term burden of cerebrovascular disease associated with sickle cell anemia?3 The study raises important questions for pediatricians and especially for internists who see these patients after many years of treatment, when untoward consequences of chronic transfusion can be present.
Up to one third of children with sickle cell anemia have silent cerebral infarction by 6 years of age; should screening and treatment begin earlier? Can screening and transfusion be effective when used in practice, not just efficacious when studied in a clinical trial? The trial consortium was very successful at meeting the targeted goals of transfusion. Is this goal achievable outside the setting of a clinical trial? In a community setting, can alloimmunization be prevented?4,5 Inability to maintain intravenous access is a major problem as patients age; can intravenous access be maintained for the long term? Can the inevitable iron overload be successfully managed? These expected complications of long-term transfusion were already appearing among the patients in the transfusion group of the study. Even if transfusion therapy is proven to be effective, are the benefits sustainable? Is cognitive function improved and does this benefit outweigh the costs of the many negative effects of transfusion? On the basis of the median follow-up period, 3 years is the suggested minimum duration of transfusion therapy. The consequences of stopping transfusions after 3 years among patients who are receiving transfusions because of their high risk for stroke are likely to be poor. In the Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) trial, even when transcranial Doppler flow rates were normalized, stopping transfusions led to reversion of high flow and recurrence of stroke.6 Since the incidence of cerebrovascular disease increases throughout life, it seems unlikely that a relatively brief period of transfusion will afford long-term protection of the brain.
Are there other approaches to reducing the burden of cerebrovascular disease in persons with sickle cell anemia? A single approved drug, hydroxyurea, is available for treating sickle cell anemia. By inducing increased levels of fetal hemoglobin, hydroxyurea inhibits the tendency of hemoglobin S to form a polymer, thereby protecting the erythrocyte. It might also have other beneficial properties. Hydroxyurea reduces the morbidity and mortality associated with the disease in adults.7,8 In children, its hematologic effects are similar, but the long-term risks and benefits are unknown.9When hydroxyurea is started in later childhood or in adulthood, it is unlikely to prevent stroke. Will beginning this treatment very early in life maintain sufficiently high fetal hemoglobin levels in enough sickle cells to retard vascular disease?10 Epidemiologic studies suggest that stroke is less affected by fetal hemoglobin than are many other disease complications. Perhaps treatments that interfere with red-cell–endothelium interactions and blunt the abnormal inflammatory process that contributes to the pathophysiology of disease will be useful adjuncts to fetal hemoglobin induction and will further retard the advance of vascular disease. Screening and long-term transfusion are not options in the parts of the world in which sickle cell anemia is most common, making drug treatment a more feasible approach.
DeBaun et al. showed that in the short term, screening and transfusion therapy decreased the advance of cerebrovascular disease associated with sickle cell anemia. Additional research is required to see whether these results can be effectively translated to medical practice, whether the benefits can be sustained over time, and whether the intended goal of preserving cognitive function without the problems of iron overload is achievable.
Disclosure forms provided by the author are available with the full text of this article at NEJM.org.
From the Departments of Medicine, Pediatrics, and Pathology and Laboratory Medicine, Boston University School of Medicine, Boston.
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