Silent white-matter changes (WMC) – permanent neurologic injuries that can cause cognitive deficits and intellectual decline – are common in patients with sickle cell disease (SCD) and are associated with low fetal hemoglobin (HbF) percentage, according to a study of adults with homozygous SCD without a history of stroke or vasculopathy. The results “highlight the potential utility of therapeutic strategies inducing HbF expression in SCD patients with silent white-matter damage,” the authors wrote in an article published in Blood Advances.
David Calvet, MD, PhD, from the Centre Hospitalier Sainte-Anne in Paris, France, and co-authors assessed the prevalence of WMC in a cohort of adults treated at a sickle cell referral center between January 2007 and December 2013. Eligible patients had normal neurologic examination results and steady-state biologic results recorded before hydroxyurea treatment or transfusion and had undergone brain magnetic resonance imaging (MRI) for screening purposes. Two investigators were blind to clinical and biologic data and rated all MRIs for WMCs on the age-related WMC (ARWMC) score, in which the extent of white-matter disease in brain regions was graded on a four-point scale (with a score of 4 representing involvement of the entire region). The scores for each region were added together for a total possible ARWMC score of 30.
The study included 83 patients (mean age = 43.3 years; range not provided), nearly half of whom (49%; n=41) had WMC on MRI.
Fifteen patients had an ARWMC score of 1 (out of a possible 30), 12 had a score of two to four, and 12 others had a score of five or more. Most of the lesions were focal (n=20/41), and the remaining patients had lesions in several distinct brain areas or several lesions in a single area beginning to become confluent.
In multivariable analyses, the following factors were associated with WMC, although, other than HbF percentage, the associations were not statistically significant:
- age (odds ratio [OR] per 10-year increase = 1.40; 95% CI 0.84-2.24; p=0.31)
- hypertension (OR=8.24; 95% CI 0.63-107.75; p=0.11)
- mean corpuscular volume (MCV; OR=0.97; 95% CI 0.90-1.04; p=0.34)
- platelet count (OR per 1-point increase = 1.00; 95% CI 0.99-1.00; p=0.29)
- HbF percentage (OR per 1-point increase = 0.84; 95% CI 0.72-0.97; p=0.02)
Median HbF percentage was 10 percent (range = 4.6-16.2%) in patients with the Senegal β-globin haplotype and 6 percent (range = 2.9-11.1%) in patients with the Bantu “CAR” β-globin haplotype.
“Haplotypes are of interest more because of their geographic origin than as a causal explanation,” the authors noted. “It is possible that deleterious polymorphisms of other genes in people from Senegal offset the beneficial effects of HbF, accounting for this paradoxical result.”
In a post-hoc sensitivity analysis conducted after exclusion of the 14 patients (17%) who started hydroxyurea therapy after steady-state measurement of biologic parameters but before MRI, “the association between a lower HbF percentage and the presence of WMC was similar,” the authors reported.
Lower HbF percentage also was associated with WMC burden; for every one percentage point increase in HbF, the likelihood of WMC decreased by 13 percent (OR=0.87; 95% CI 0.79-0.96; p=0.006).
This association remained significant after adjustment for age, hypertension, and MCV (OR=0.89; 95% CI 0.79-0.99; p=0.039).
“Many studies have shown HbF percentage levels to be associated with clinical and/or biological protective effects, [and] increasing HbF levels through drug treatments or gene therapy is one of the current goals of SCD research,” the authors wrote. “Further studies are required to confirm this association before hydroxyurea can be considered as a suitable treatment for increasing HbF levels to protect against WMC burden and associated cognitive disorders.”
The study is limited by its single-center design, small sample size, and potential for selection bias that may have affected the prevalence of silent WMC reported in the patient population.
The authors report no financial conflicts.
Calvet D, Tuillier T, Mélé N, et al. Low fetal hemoglobin percentage is associated with silent brain lesions in adults with homozygous sickle cell disease. Blood Advances. 2017.