Page 58 - Haematologica July

Haematologica 2018 Volume 103(7):1136-1142
1Red Cell Biology Unit, King’s College Hospital, King’s College London, UK; 2Proteomics Laboratory, Institute of Psychiatry, King’s College London, UK; 3Department of Neurosciences, Institute of Child Health, University College Hospital, London, UK; 4Evelina Children’s Hospital, Guy’s and St Thomas’ Hospital, London, UK; 5Division of Health & Social Care Research, King's College London, UK; 6Sickle Cell Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
Ferrata Storti Foundation
Red Cell Biology & its Disorders
Proteomic analysis of plasma from children with sickle cell anemia and silent cerebral infarction
Sanjay Tewari,1 George Renney,2 John Brewin,1 Kate Gardner,1 Fenella Kirkham,3 Baba Inusa,4 James E Barrett,5 Stephan Menzel,1 Swee Lay Thein,6 Malcolm Ward2 and David C. Rees1
ABSTRACT
Silent cerebral infarction is the most common neurological abnormal- ity in children with sickle cell anemia, affecting 30-40% of 14 year olds. There are no known biomarkers to identify children with silent cerebral infarcts, and the pathological basis is also unknown. We used an unbiased proteomic discovery approach to identify plasma pro- teins differing in concentration between children with and without silent cerebral infarcts. Clinical parameters and plasma samples were analysed from 51 children (mean age 11.8 years, range 6-18) with sickle cell anemia (HbSS). A total of 19 children had silent cerebral infarcts and 32 normal MRI; the children with silent infarcts had lower HbF levels (8.6 vs. 16.1%, P=0.049) and higher systolic blood pressures (115 vs. 108.6, P=0.027). Plasma proteomic analysis showed 13 proteins increased more than 1.3 fold in the SCI patients, including proteins involved in hypercoagulability (α2-antiplasmin, fibrinogen−g chain, thrombospondin-4), inflammation (α2-macroglobulin, complement C1s and C3), and atherosclerosis (apolipoprotein B-100). Higher levels of gelsolin and retinol-binding pro- tein 4 were also found in the population with silent infarcts, both of which have been linked to stroke. We investigated the genetic basis of these differences by studying 359 adults with sickle cell disease (199 with silent cerebral infarcts, 160 normal MRIs), who had previously undergone a genome-wide genotyping array. None of the genes coding for the dif- ferentially expressed proteins were significantly associated with silent infarction. Our study suggests that silent cerebral infarcts in sickle cell anemia may be associated with higher systolic blood pressure, lower HbF levels, hypercoagulability, inflammation and atherosclerotic lipopro- teins.
Introduction
Sickle cell anemia (SCA) is the most common cause of stroke in childhood.1 The abnormal sickle hemoglobin (HbS) polymerizes when deoxygenated, damaging red cells, causing vaso-occlusion and vascular endothelial dysfunction.2 A cascade of pathological processes follows, including inflammation, hemolysis, anemia, oxidative stress, reperfusion injury, hypercoagulability, and nitric oxide deficiency.3 Survival is reduced by 20-30 years4,5 and vasculopathic complications include pul- monary hypertension, priapism, and cerebrovascular disease.6 The latter is the major cause of morbidity in children and takes two forms: overt stroke often asso- ciated with large vessel disease,7 and silent cerebral infarcts (SCI) of less certain pathology.8 Without intervention, overt stroke has a peak incidence of 1.02/100 patient years between 2 and 5 years,9 although primary prevention using transcra-
Correspondence:
david.rees2@nhs.net.
Received: January 10, 2018. Accepted: March 14, 2018. Pre-published: March 15, 2018.
doi:10.3324/haematol.2018.187815
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/7/1136
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