Research from ASH ’ s newest peer-reviewed journal , Blood Advances in a Different Vein
Low Fetal Hemoglobin May Predict Silent Brain Lesions in Patients With Sickle Cell Disease
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
“ [ Our results ] highlight the potential utility of therapeutic strategies inducing fetal hemoglobin expression in SCD patients with silent white-matter damage .”
— DAVID CALVET , MD , PhD
( 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 steadystate 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 singlecenter 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 .
REFERENCE
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 .
56 ASH Clinical News November 2017