Blood Transfusions Lower Risks for Children With Sickle Cell

Diedtra Henderson

August 20, 2014

Children with sickle cell anemia and asymptomatic neurologic injury were 58% less likely to suffer a repeat cerebral infarction while undergoing regular blood transfusions, according to a small study.

Michael R. DeBaun, MD, MPH, from the Department of Pediatrics, Division of Hematology-Oncology, Vanderbilt-Meharry Center of Excellence in Sickle Cell Disease, Vanderbilt University School of Medicine, Nashville, Tennessee, and 37 coauthors published the results of their randomized, single-blind clinical trial in the August 21 issue of the New England Journal of Medicine.

One in 396 black newborns and about 100,000 people in the United States suffer from sickle cell anemia. The disorder takes its name from the abnormal "sickle" hemoglobin, or hemoglobin S, which transforms blood cells into crescent shapes that gum up blood's otherwise smooth movement through vessels.

Dr. DeBaun and colleagues write that 33% of children with sickle cell anemia experience silent cerebral infarcts, with most occurring by 6 years of age. These children are at higher risk of suffering stroke and IQ reduction.

The authors hypothesize that children undergoing regular blood transfusions, which replace abnormally shaped blood cells with typical disc-shaped cells, would have a lower chance of suffering a repeat infarct. They screened 1074 children aged 5 to 15 years at 29 clinical centers in the United States, Canada, France, and the United Kingdom between December 2004 and May 2010, using magnetic resonance imaging scans to pinpoint telltale signs of the neurologic injury. Of those, 196 children were enrolled in the study, with 1 child assigned to the observation group for every child assigned to the treatment group.

Ninety-nine children assigned to the transfusion group received transfusions monthly to maintain a target hemoglobin concentration greater than 9.0 g/dL and hemoglobin S concentrations at 30% or less of total hemoglobin. Nine children declined transfusions.

Researchers followed the children for a median of 3 years, with 185 (94%) participants undergoing exit scans, for a total of 304 patient-years of follow-up data. Fourteen (14%) of 97 children in the observation group suffered a recurrence of an infarct, which the authors defined as a stroke or a new or enlarged silent cerebral infarct, compared with 6 (6%) of 99 participants in the treatment group.

"The primary results of our study indicate that children with sickle cell anemia, silent cerebral infarcts, and normal transcranial Doppler measurements will have a 58% relative risk reduction in the recurrence of infarcts while they are receiving regular blood-transfusion therapy," Dr. DeBaun and coauthors write.

The authors argue that the new results support stepped-up surveillance, with a magnetic resonance imaging scan performed on children with sickle cell anemia as they enter school.

"Detecting silent cerebral infarcts in children is particularly important owing to the predicted effects on cognition and now the evidence from this trial that infarct recurrence can be prevented in most children," the authors write. "IQ scores in children with silent cerebral infarcts are 5 points lower than those in children without silent cerebral infarcts, which corresponds to a 5 to 9% reduction in annual income as adults. If silent cerebral infarcts are detected at the time children begin elementary school, cognitive difficulties may be identified and academic support initiated."

In an accompanying editorial, Martin H. Steinberg, MD, from the Departments of Medicine, Pediatrics, and Pathology and Laboratory Medicine, Boston University School of Medicine, Massachusetts, took a longer view. The study gives food for thought for pediatricians and internists, he said. These clinicians see children for many years when adverse effects from chronic transfusions might become apparent, such as inability to maintain intravenous access, "inevitable" iron overload, and alloimmunization, he writes.

"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?" Dr. Steinberg notes.

Transfusion therapy is suggested for at least 3 years by the finding, but abruptly halting it raises the risks of children suffering strokes. "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," he writes, adding that an approved therapy is available and is a more feasible treatment in the developing world, where sickle cell anemia is more common.

Financial support for the study was provided by the National Institute of Neurological Disorders and Stroke; National Center for Research Resources; the National Center for Advancing Translational Sciences, Clinical and Translational Research; National Institutes of Health; and Research and Development in the National Health Service. Six study authors disclosed relevant financial relationships, including 3 who reported receiving grant support, honoraria, travel support, consulting fees, or payments from Mast Therapeutics for serving on a data and safety monitoring board. One coauthor also disclosed receiving honoraria and lecture fees from Siemens Healthcare and consulting fees from Guerbet. Another coauthor also disclosed receiving grant support from ClinDatrix and Novartis. Another coauthor disclosed being paid to serve on an advisory board for Shire Pharmaceuticals, receiving consulting fees from Shire Pharmaceuticals and Sideris Pharmaceuticals, and receiving a grant from Resonance Health. Another coauthor disclosed receiving lecture fees from Novartis. A coauthor also disclosed receiving grant support from Eli Lilly. Another coauthor, an inventor, also disclosed being a named party on a patent and licensing agreement for an assay panel of brain biomarkers to detect brain injury, licensed to ImmunArray, with pending royalties. The other authors disclosed no relevant financial relationships. Dr. Steinberg reports receiving grant support, personal fees, and nonfinancial support from the following companies and groups: Emmaus, Selexsys, Biogen Idec, Mast Therapeutics, Advances in Hematology, GLG Group, Tufts Medical Center, Tufts Floating Hospital for Children, the American Board of Internal Medicine, the Sickle Cell Meeting, Albert Einstein College of Medicine, Thomas Jefferson University, Sickle Cell in Focus, UpToDate, Cambridge University Press, Methodist Hospital, University of Dammam, Cervella Hospital, and AABB (formerly known as the American Association of Blood Banks).

N Engl J Med. Published online August 20, 2014.

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