Powars et al., 1991101101 Powars DR. Sickle cell anemia: beta s-gene-cluster haplotypes as prognostic indicators of vital organ failure. Semin Hematol. 1991;28(3):202-8.
|
Cohort |
Stroke |
785 |
SS |
Cases: 13.1 (0.6–47.1) |
|
βS CAR haplotype |
Alpha-thalassemia |
Balkaran et al., 1992135135 Balkaran B, Char G, Morris JS, Thomas PW, Serjeant BE, Serjeant GR. Stroke in a cohort of patients with homozygous sickle cell disease. J Pediatr. 1992;120(3):360-6.
|
Cohort |
Stroke |
310 |
SS |
9–17 |
|
↑Hb A2, ↑WBC |
|
Adams et al., 1992136136 Adams R, McKie V, Nichols F, Carl E, Zhang DL, McKie K, et al. The use of transcranial ultrasonography to predict stroke in sickle cell disease. N Engl J Med. 1992;326(9):605-10.
|
Cohort |
Cerebral infarction |
190 |
SS |
8.9 ± 4.2 (3–18) |
|
High velocity of cerebral blood flow |
|
|
|
Positive ultrasonography (≥170 cm/s) |
|
|
|
|
Cerebral infarction |
|
Rodgers et al., 1993137137 Rodgers GP, Walker EC, Podgor MJ. Is “relative” hypertension a risk factor for vaso-occlusive complications in sickle cell disease? Am J Med Sci. 1993;305(3):150-6.
|
Cohort |
Stroke |
89 |
SS |
7–44 |
|
↑systolic blood pressure, ↑diastolic blood pressure |
|
de Montalembert et al., 1993105105 de Montalembert M, Beauvais P, Bachir D, Galacteros F, Girot R. Cerebrovascular accidents in sickle cell disease. Risk factors and blood transfusion influence. French Study Group on Sickle Cell Disease. Eur J Pediatr. 1993;152(3):201-4.
|
Cohort |
Cerebrovascular accident |
444 |
SS or SC |
1–43 |
|
Past history of bacterial meningitis |
|
Adams et al., 1994138138 Adams RJ, Kutlar A, McKie V, Carl E, Nichols FT, Liu JC, et al. Alpha thalassemia and stroke risk in sickle cell anemia. Am J Hematol. 1994;45(4):279-82.
|
Cohort |
Stroke |
300 |
SS |
Stroke: 7.5 ± 3.5 No stroke: 7.7 ± 4.7 |
|
Absence of alpha-thalassemia, ↓RBC, ↓Hct, ↑MCH, ↑MCHC, ↑reticulocytes, ↓Hb F |
|
Gill el al., 19957575 Gill FM, Sleeper LA, Weiner SJ, Brown AK, Bellevue R, Grover R, et al. Clinical events in the first decade in a cohort of infants with sickle cell disease. Cooperative study of sickle cell disease. Blood. 1995;86(2):776-83.
|
Cohort |
Cerebrovascular accident |
310 |
SS |
Entry age: 3.0 ± 1.4 (Follow-up 4.2 ± 2.6) |
|
|
Alpha-thalassemia |
Tam 19975757 Tam DA. Protein C and protein S activity in sickle cell disease and stroke. J Child Neurol. 1997;12(1):19-21.
|
Cross-sectional |
Stroke |
13 |
SS |
12.6 ± 2.9 |
|
↓Protein C activity, ↓ protein S activity |
|
Houston et al., 1997139139 Houston PE, Rana S, Sekhsaria S, Perlin E, Kim KS, Castro OL. Homocysteine in sickle cell disease: relationship to stroke. Am J Med. 1997;103(3):192-6.
|
Cross-sectional |
Ischemic stroke |
99 |
SS or Sβ0-thal |
19 (1–58) |
|
↑Homocysteine |
|
Adams et al., 19971313 Adams RJ, McKie VC, Carl EM, Nichols FT, Perry R, Brock K, et al. Long-term stroke risk in children with sickle cell disease screened with transcranial Doppler. Ann Neurol. 1997;42(5):699-704.
|
Cohort |
Stroke |
315 |
SS or Sβ0-thal |
8.8 ± 4.2 (3–18.8) |
|
TAMMV (MCA/ICA) ≥ 200 cm/s |
|
|
|
TAMMV ≥ 200 cm/s |
|
|
|
|
↓age, ↓Hct, ↑WBC, ↑reticulocytes |
|
Pegelow et al., 1997140140 Pegelow CH, Colangelo L, Steinberg M, Wright EC, Smith J, Phillips G, et al. Natural history of blood pressure in sickle cell disease: risks for stroke and death associated with relative hypertension in sickle cell anemia. Am J Med. 1997;102(2):171-7.
|
Cohort |
Occlusive strokes |
3317 |
SS or SC |
2–44 |
|
↑systolic blood pressure |
|
Kahn et al., 1997141141 Kahn MJ, Scher C, Rozans M, Michaels RK, Leissinger C, Krause J. Factor V Leiden is not responsible for stroke in patients with sickling disorders and is uncommon in African Americans with sickle cell disease. Am J Hematol. 1997;54(1):12-5.
|
Cohort |
History of stroke |
82 |
SS, SC or Sβ+-thal |
10.5 (48 days to 31 years) |
|
↑age, SS genotype |
SC genotype |
Ohene-Frempong et al., 199888 Ohene-Frempong K, Weiner SJ, Sleeper LA, Miller ST, Embury S, Moohr JW, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood. 1998;91(1):288-94.
|
Cohort |
Infarctive stroke |
3.943 |
SS, SC, Sβ+, or Sβ0
|
14.2 ± 12.7 |
|
Prior TIA, ↓steady-state Hb, ACS, ↑systolic blood pressure |
Alpha-thalassemia |
Neonato et al., 20008181 Neonato MG, Guilloud-Bataille M, Beauvais P, Begue P, Belloy M, Benkerrou M, et al. Acute clinical events in 299 homozygous sickle cell patients living in France. French Study Group on Sickle Cell Disease. Eur J Haematol. 2000;65(3):155-164.
|
Cohort |
Stroke (occlusion or hemorrhage) |
299 |
SS |
10.1 ± 5.8 |
|
|
Alpha-thalassemia |
Styles et al., 2000142142 Styles LA, Hoppe C, Klitz W, Vichinsky E, Lubin B, Trachtenberg E. Evidence for HLA-related susceptibility for stroke in children with sickle cell disease. Blood. 2000;95(11):3562-7.
|
Case–control |
Cerebral infarction |
53 |
SS |
12.9 ± 5.6 |
|
HLA B*5301, DRB1*0301, DRB1*0302, DQB1*0201 alleles |
HLA B*4501, DRB1*1501, DRB1*1503, DQB1*0602 alleles |
Hoppe et al., 2001100100 Hoppe C, Cheng S, Grow M, Silbergleit A, Klitz W, Trachtenberg E, et al. A novel multilocus genotyping assay to identify genetic predictors of stroke in sickle cell anaemia. Br J Haematol. 2001;114(3):718-20.
|
Case–control |
Cerebral infarction |
69 |
SS |
Cases: 7.1 ± 3.5 Controls: 16.5 ± 8.7 |
|
|
CBS 278thr |
Kirkham et al., 2001126126 Kirkham FJ, Hewes DK, Prengler M, Wade A, Lane R, Evans JP. Nocturnal hypoxaemia and central-nervous-system events in sickle-cell disease. Lancet. 2001;357(9269):1656-9.
|
Cohort |
Central nervous system events (stroke, TIA or seizure) |
149 |
SS, SC or Sβ-thal |
Median 7.7 (1–23.1) |
|
↑right or left ICA or MCA velocity at time of sleep study, SS genotype, ↑Hb, ↓ nocturnal SaO2 |
↑Mean oxygen |
Tang et al., 2001143143 Tang DC, Prauner R, Liu W, Kim KH, Hirsch RP, Driscoll MC, et al. Polymorphisms within the angiotensinogen gene (GT-repeat) and the risk of stroke in pediatric patients with sickle cell disease: a case–control study. Am J Hematol. 2001;68(3):164-9.
|
Case–control |
Cerebrovascular accident |
63 |
Not informed |
2–21 |
|
sz22 and/or sz24 angiotensinogen GT-repeat allele |
|
Sarnaik et al., 2001102102 Sarnaik SA, Ballas SK. Molecular characteristics of pediatric patients with sickle cell anemia and stroke. Am J Hematol. 2001;67(3):179-82.
|
Case series |
Cerebrovascular accident |
41 |
SS |
5.6 ± 3.2 |
|
Female gender; βS Ben/CAR, atypical, CAR/CAR haplotypes |
Alpha-thalassemia |
Miller et al., 2001127127 Miller ST, Macklin EA, Pegelow CH, Kinney TR, Sleeper LA, Bello JA, et al. Silent infarction as a risk factor for overt stroke in children with sickle cell anemia: a report from the Cooperative Study of Sickle Cell Disease. J Pediatr. 2001;139(3):385-90.
|
Cohort |
Stroke |
248 |
SS |
8.3 ± 1.9 |
|
Silent infarcts, prior TIA (marginal association), bacterial meningitis (marginal association), ↑Hct, ↑aspartate aminotransferase |
|
Taylor et al., 2002144144 Taylor JG, Tang DC, Savage SA, Leitman SF, Heller SI, Serjeant GR, et al. Variants in the VCAM1 gene and risk for symptomatic stroke in sickle cell disease. Blood. 2002;100(13):4303-9.
|
Case–control |
Clinical stroke |
102 |
SS |
17.1 ± 7.4 (cases) |
|
|
VCAM-1 G1238C |
Taylor et al., 20024444 Taylor JG, Tang D, Foster CB, Serjeant GR, Rodgers GP, Chanock SJ. Patterns of low-affinity immunoglobulin receptor polymorphisms in stroke and homozygous sickle cell disease. Am J Hematol. 2002;69(2):109-14.
|
Case–control |
Clinical stroke |
102 |
SS |
17.1 ± 7.4 (cases) |
|
↑WBC |
|
Hoppe et al., 20037373 Hoppe C, Klitz W, Noble J, Vigil L, Vichinsky E, Styles L. Distinct HLA associations by stroke subtype in children with sickle cell anemia. Blood. 2003;101(7):2865-9.
|
Cohort |
Small vessel stroke |
231 |
SS |
13.1 ± 2.9 |
|
HLA HLA-A*0102 and HLA-A*2612 alleles |
HLA HLA-A*3301 alleles |
|
|
Large vessel stroke |
|
|
|
|
HLA DPB1*0401 alleles |
HLA DPB1*1701 alleles |
Hsu et al., 20037676 Hsu LL, Miller ST, Wright E, Kutlar A, McKie V, Wang W, et al. Alpha Thalassemia is associated with decreased risk of abnormal transcranial Doppler ultrasonography in children with sickle cell anemia. J Pediatr Hematol Oncol. 2003;25(8):622-8.
|
STOP study data |
Abnormal TCD (≥200 cm/s) |
225 |
SS or Sβ0-thal |
2–16 |
|
↓Age, ↓Hb |
Alpha-thalassemia-2, ↓MCV |
Driscoll et al., 20037171 Driscoll MC, Hurlet A, Styles L, McKie V, Files B, Olivieri N, et al. Stroke risk in siblings with sickle cell anemia. Blood. 2003;101(6):2401-4.
|
Cohort |
Clinical stroke |
2353 |
SS |
≤21 |
|
Siblings with stroke |
|
Kwiatkowski et al., 20037272 Kwiatkowski JL, Hunter JV, Smith-Whitley K, Katz ML, Shults J, Ohene-Frempong K. Transcranial Doppler ultrasonography in siblings with sickle cell disease. Br J Haematol. 2003;121(6):932-7.
|
Cohort |
‘Positive’ TCD (≥170 cm/s) |
249 |
SS or Sβ0-thal |
10.1 ± 4.9 (1.9–20.9) |
|
Sibling with a positive TCD |
↑Hb |
Hoppe el al., 20049696 Hoppe C, Klitz W, Cheng S, Apple R, Steiner L, Robles L, et al. Gene interactions and stroke risk in children with sickle cell anemia. Blood. 2004;103(6):2391-6.
|
Cohort |
Large vessel stroke |
230 |
SS |
8.4 ± 1.7 |
|
IL4R 503P, HLA-A |
ADRB2 27E, TNF-α -308A |
|
|
Small vessel stroke |
|
|
|
|
VCAM1 (-1594)C, HLA locus homozygosity |
LDLR (exon18) Ncol- |
Romana et al., 2004145145 Romana M, Diara JP, Doumbo L, Muralitharan S, Ramasawmy R, Keclard L, et al. Angiotensinogen gene associated polymorphisms and risk of stroke in sickle cell anemia: additional data supporting an association. Am J Hematol. 2004;76(3):310-1.
|
Cohort |
Cerebrovascular accident |
156 |
SS |
2–18 |
|
Allele sz28 of the angiotensinogen gene |
|
Sebastiani et al., 20058989 Sebastiani P, Ramoni MF, Nolan V, Baldwin CT, Steinberg MH. Genetic dissection and prognostic modeling of overt stroke in sickle cell anemia. Nat Genet. 2005;37(4):435-40.
|
Cohort |
Stroke |
1398 |
SS |
|
|
A Bayesian network describing the joint association of 69 SNPs in 20 genes with stroke was established. Of these, 25 SNPs in 11 genes were directly associated with stroke. |
|
Kwiatkowski et al., 2006146146 Kwiatkowski JL, Granger S, Brambilla DJ, Brown RC, Miller ST, Adams RJ. Elevated blood flow velocity in the anterior cerebral artery and stroke risk in sickle cell disease: extended analysis from the STOP trial. Br J Haematol. 2006;134(3):333-9.
|
STOP study data |
Stroke |
1975 |
SS or Sβ0-thal |
8.1 |
|
ACA ≥ 170 cm/s |
|
Hoppe et al., 20079797 Hoppe C, Klitz W, D’Harlingue K, Cheng S, Grow M, Steiner L, et al. Confirmation of an association between the TNF(-308) promoter polymorphism and stroke risk in children with sickle cell anemia. Stroke. 2007;38(8):2241-6.
|
STOP study data plus local institution subjects |
Large vessel subtype of stroke |
96 |
SS |
9.5 ± 4.2 (1.8–17.7) |
|
IL4R 503P allele |
TNF(-308)A and LTC4S(-444)C alleles |
Bernaudin et al., 20087777 Bernaudin F, Verlhac S, Chevret S, Torres M, Coic L, Arnaud C, et al. G6PD deficiency, absence of alpha-thalassemia, and hemolytic rate at baseline are significant independent risk factors for abnormally high cerebral velocities in patients with sickle cell anemia. Blood. 2008;112(10):4314-7.
|
Cohort |
Abnormal TCD (≥200 cm/s) |
373 |
SS |
Median at TCD examination: 3.1 (1.5–8.3) |
|
Absence of alpha-thalassemia, G6PD deficiency, ↑LDH |
↑Hb |
Rees et al., 20081919 Rees DC, Dick MC, Height SE, O’Driscoll S, Pohl KR, Goss DE, et al. A simple index using age, hemoglobin, and aspartate transaminase predicts increased intracerebral blood velocity as measured by transcranial Doppler scanning in children with sickle cell anemia. Pediatrics. 2008;121(6):e1628-32.
|
Cohort |
TAMMV |
96 |
SS |
2–16 |
|
Positive correlation: AST Negative correlation: Hb, age |
|
Quinn et al., 2008129129 Quinn CT, Sargent JW. Daytime steady-state haemoglobin desaturation is a risk factor for overt stroke in children with sickle cell anaemia. Br J Haematol. 2008;140(3):336-9.
|
Nested case–control |
Clinically overt stroke |
412 |
SS or Sβ0-thal |
Cases: 8.5 Controls: 9.5 |
|
↓daytime SpO2, ↓age |
|
Chang Milbauer et al., 20087474 Chang Milbauer L, Wei P, Enenstein J, Jiang A, Hillery CA, Scott JP, et al. Genetic endothelial systems biology of sickle stroke risk. Blood. 2008;111(7):3872-9.
|
Experimental |
Abnormal TCD (≥200 cm/s), abnormal MRA or clinical stroke |
20 |
SS or Sβ0-thal |
4–19 |
|
Inflammation biological system |
|
Hellani et al., 2009147147 Hellani A, Al-Akoum S, Abu-Amero KK. G6PD Mediterranean S188F codon mutation is common among Saudi sickle cell patients and increases the risk of stroke. Genet Test Mol Biomarkers. 2009;13(4):449-52.
|
Case–control |
Abnormal TCD |
48 |
SS |
37.6 |
|
G6PD deficiency |
|
Rees et al., 2009108108 Rees DC, Lambert C, Cooper E, Bartram J, Goss D, Deane C, et al. Glucose 6 phosphate dehydrogenase deficiency is not associated with cerebrovascular disease in children with sickle cell anemia. Blood. 2009;114(3):742-3, author reply 743-4.
|
Cohort |
Cerebrovascular disease (abnormal TCD, conditional TCD or stroke and stenosed vessels on MRA). |
218 |
SS |
Children |
|
↑MCH, ↑LDH |
|
Quinn et al., 2009131131 Quinn CT, Variste J, Dowling MM. Haemoglobin oxygen saturation is a determinant of cerebral artery blood flow velocity in children with sickle cell anaemia. Br J Haematol. 2009;145(4):500-5.
|
Cross-sectional |
TAMMV |
181 |
SS or Sβ0-thal |
8.0 (3.2–13.5) |
|
Positive correlation: proxy measure for degree of stenosis Negative correlation: SpO2, age, Hct |
|
|
|
Abnormal TCD |
|
|
|
|
↓SpO2
|
|
Makani et al., 2009130130 Makani J, Kirkham FJ, Komba A, Ajala-Agbo T, Otieno G, Fegan G, et al. Risk factors for high cerebral blood flow velocity and death in Kenyan children with Sickle Cell Anaemia: role of haemoglobin oxygen saturation and febrile illness. Br J Haematol. 2009;145(4):529-32.
|
Cross-sectional |
“High cerebral blood flow velocity” (≥150 cm/s) |
105 |
SS |
7.4 ± 4.0 |
|
SpO2 ≤95% and history of fever (3 or more episodes of fever in past year) |
|
Belisario et al., 20105151 Belisario AR, Rodrigues CV, Martins ML, Silva CM, Viana MB. Coinheritance of alpha-thalassemia decreases the risk of cerebrovascular disease in a cohort of children with sickle cell anemia. Hemoglobin. 2010;34(6):516-29.
|
Cohort |
Cerebrovascular disease (ischemic stroke or TCD ≥ 170 cm/s) |
208 |
SS |
6.5 ± 2.3 (2.5–10.4) |
|
Absence of alpha-thalassemia |
|
Pavlakis et al., 2010148148 Pavlakis SG, Rees RC, Huang X, Brown RC, Casella JF, Iyer RV, et al. TCD velocities transcranial doppler ultrasonography (TCD) in infants with sickle cell anemia: baseline data from the BABY HUG trial. Pediatr Blood Cancer. 2010;54(2):256-9.
|
BABY HUG data |
TAMMV |
192 |
SS or Sβ0-thal |
12.6 months (7–17) |
|
Positive correlation: age, reticulocytes Negative correlation: Hb |
|
Deane et al., 2010149149 Deane CR, Goss D, Bartram J, Pohl KR, Height SE, Sibtain N, et al. Extracranial internal carotid arterial disease in children with sickle cell anemia. Haematologica. 2010;95(8):1287-92.
|
Cohort |
Extracranial internal carotid artery velocities |
236 |
SS |
2–16 |
|
Positive correlation: LDH Negative correlation: age |
|
|
|
Clinical stroke |
|
|
|
|
Extracranial stenosis |
|
Silva et al., 20118383 Silva CM, Giovani P, Viana MB. High reticulocyte count is an independent risk factor for cerebrovascular disease in children with sickle cell anemia. Pediatr Blood Cancer. 2011;56(1):116-21.
|
Cross-sectional |
Cerebrovascular disease (abnormal TCD or ischemic stroke) |
262 |
SS or Sβ0-thal |
Median 6.2 (2–11.2) |
|
↑reticulocytes |
|
Flanagan et al., 20117878 Flanagan JM, Frohlich DM, Howard TA, Schultz WH, Driscoll C, Nagasubramanian R, et al. Genetic predictors for stroke in children with sickle cell anemia. Blood. 2011;117(24):6681-4.
|
Case–control |
Ischemic stroke |
233 |
SS |
Cases: 5.8 ± 2.8 Controls: 10.2 ± 3.5 |
|
ANXA2 (rs11853426), TEK (rs489347), TGFBR3 (rs284875) |
Alpha-thalassemia, ADCY9 (rs2238432) |
Filho et al., 2011103103 Filho IL, Leite AC, Moura PG, Ribeiro GS, Cavalcante AC, Azevedo FC, et al. Genetic polymorphisms and cerebrovascular disease in children with sickle cell anemia from Rio de Janeiro, Brazil. Arq Neuropsiquiatr. 2011;69(3):431-5.
|
Case–control |
Cerebrovascular disease (abnormal TCD, TIA or ischemic stroke) |
94 |
SS |
6.6 (3.2–15) |
|
Car/Atp βS haplotype |
|
Bernaudin et al., 201177 Bernaudin F, Verlhac S, Arnaud C, Kamdem A, Chevret S, Hau I, et al. Impact of early transcranial Doppler screening and intensive therapy on cerebral vasculopathy outcome in a newborn sickle cell anemia cohort. Blood. 2011;117(4):1130-40, quiz 1436.
|
Cohort |
Abnormal TCD |
217 |
SS, Sβ0, or SD-Punjab |
Mean follow-up: 7.7 ± 5.0 |
|
G6PD deficiency, absence of alpha-thalassemia, ↑reticulocytes |
|
|
|
Abnormal MRA |
132 |
|
|
|
G6PD deficiency, ↑LDH |
|
|
|
Cerebral vasculopathy (stroke or abnormal TCD or abnormal MRA or silent stroke) |
217 |
|
|
|
↑ reticulocytes, ↑LDH |
|
Vicari et al., 20119999 Vicari P, Silva GS, Nogutti MA, Neto FM, dos Santos NJ, Massaro AR, et al. Absence of association between TNF-alpha polymorphism and cerebral large-vessel abnormalities in adults with sickle cell anemia. Acta Haematol. 2011;125(3):141-4.
|
Cross-sectional |
|
49 |
SS |
Median 23 (13–55) |
|
|
|
|
|
Abnormal MRA |
|
|
|
|
↓Hb, ↑LDH |
|
Hyacinth et al., 2012109109 Hyacinth HI, Gee BE, Adamkiewicz TV, Adams RJ, Kutlar A, Stiles JK, et al. Plasma BDNF and PDGF-AA levels are associated with high TCD velocity and stroke in children with sickle cell anemia. Cytokine. 2012;60(1):302-8.
|
Cross-sectional, nested prospective study |
Abnormal DTC |
40 |
Cases: SS or Sβ0 Controls: SS and health controls |
Controls: 9.6 ± 1.7 SS with normal TCD: 8.8 ± 2.3 SS with abnormal TCD: 8.1 ± 3.1 |
|
↑BDNF, ↑PDGF-AA, ↑ reticulocytes, ↓Hb |
|
|
|
Stroke |
|
|
|
|
↑PDGF-AA, ↑WBC |
|
Ataga et al., 20125858 Ataga KI, Brittain JE, Desai P, May R, Jones S, Delaney J, et al. Association of coagulation activation with clinical complications in sickle cell disease. PLoS ONE. 2012;7(1):e29786.
|
Cohort |
History of stroke |
52 |
SS, Sβ0 or SD |
37.5 (26.75–46.25) |
|
↑D-dimer |
|
Thangarajh et al., 2012122122 Thangarajh M, Yang G, Fuchs D, Ponisio MR, McKinstry RC, Jaju A, et al. Magnetic resonance angiography-defined intracranial vasculopathy is associated with silent cerebral infarcts and glucose-6-phosphate dehydrogenase mutation in children with sickle cell anaemia. Br J Haematol. 2012;159(3):352-9.
|
SIT trial data |
Magnetic resonance angiography-defined intracranial vasculopathy |
516 (genetic analysis: 191 male participants) |
SS or Sβ0-thal |
9.1 (5–15) |
|
Silent infarct, G6PD deficiency |
|
Leite et al., 2012150150 Leite AC, de Oliveira RV, de Moura PG, Silva CM, Lobo C. Abnormal transcranial Doppler ultrasonography in children with sickle cell disease. Rev Bras Hematol Hemoter. 2012;34(4):307-10.
|
Cross-sectional |
Conditional or abnormal TCD |
773 |
SS, SC or Sβ0-thal |
6.5 (1.8–15.8) |
|
SS genotype, “complications of SCD”, “laboratory abnormalities”, “TCD as a screening test” |
Coexisting thalassemia |
Flanagan et al., 20139090 Flanagan JM, Sheehan V, Linder H, Howard TA, Wang YD, Hoppe CC, et al. Genetic mapping and exome sequencing identify 2 mutations associated with stroke protection in pediatric patients with sickle cell anemia. Blood. 2013;121(16):3237-45.
|
GWAS and WES |
Clinical stroke |
677 |
SS |
Stroke group: 12.1 ± 4.1 Non-stroke group: 12.9 ± 3.7 |
|
|
22 non-synonymous variants were identified; GOLGB1 Y1212C and ENPP1 K173Q were validated. |
Domingos et al., 20147979 Domingos IF, Falcao DA, Hatzlhofer BL, Cunha AF, Santos MN, Albuquerque DM, et al. Influence of the beta haplotype and alpha-thalassemia on stroke development in a Brazilian population with sickle cell anaemia. Ann Hematol. 2014;93(7):1123-9.
|
Cohort |
|
261 |
SS |
Age at stroke: 12.4 (1–44) |
|
|
|
|
|
Stroke susceptibility (stroke or TCD velocities ≥170 cm/s) |
|
|
|
|
Female gender, ↓RBC, ↓Hb, ↑ reticulocytes, ↓ indirect bilirubin, ↑LDH, ↓Hb F |
|
|
|
Stroke |
|
|
|
|
βS haplotype CAR/CAR |
Hb F, Alpha-thalassemia |
Cox et al., 20148080 Cox SE, Makani J, Soka D, L’Esperence VS, Kija E, Dominguez-Salas P, et al. Haptoglobin, alpha-thalassaemia and glucose-6-phosphate dehydrogenase polymorphisms and risk of abnormal transcranial Doppler among patients with sickle cell anaemia in Tanzania. Br J Haematol. 2014;165(5):699-706.
|
Cohort |
Cerebral blood flow velocity |
601 |
SS |
9.76 ± 3.86 (0.6–22.6) |
|
Negative correlation: age, Hb |
Alpha-thalassemia |
Meier et al., 2014111111 Meier ER, Wright EC, Miller JL. Reticulocytosis and anemia are associated with an increased risk of death and stroke in the newborn cohort of the Cooperative Study of Sickle Cell Disease. Am J Hematol. 2014;89(9):904-6.
|
Cohort |
Stroke |
354 |
SS |
145 ± 33 days at entry |
|
↑reticulocytes |
|
Lagunju et al., 20142121 Lagunju I, Sodeinde O, Brown B, Akinbami F, Adedokun B. Transcranial Doppler ultrasonography in children with sickle cell anemia: clinical and laboratory correlates for elevated blood flow velocities. J Clin Ultrasound. 2014;42(2):89-95.
|
Cohort |
Elevated TAMMV |
237 |
SS |
101.8 ± 47.9 months |
|
↓age, ↓Hb, ↓Hct, ↓SpO2
|
|
Belisário et al., 20159898 Belisario AR, Nogueira FL, Rodrigues RS, Toledo NE, Cattabriga AL, Velloso-Rodrigues C, et al. Association of alpha-thalassemia TNF-alpha (-308G>A) and VCAM-1 (c.1238G>C) gene polymorphisms with cerebrovascular disease in a newborn cohort of 411 children with sickle cell anemia. Blood Cells Mol Dis. 2015;54(1):44-50.
|
Cohort |
Ischemic stroke |
386 |
SS |
9.63 ± 2.99 |
|
TNF-α −308G>A |
Alpha-thalassemia |
|
|
Cerebrovascular disease |
|
|
|
|
|
Alpha-thalassemia |
Joly et al., 2015151151 Joly P, Garnier N, Kebaili K, Renoux C, Dony A, Cheikh N, et al. G6PD deficiency and absence of alpha-thalassemia increase the risk for cerebral vasculopathy in children with sickle cell anemia. Eur J Haematol. 2016;96(4):404-8.
|
Cohort |
Cerebral vasculopathy (stroke, silent infarct or abnormal TCD) |
121 |
SS |
Group without cerebral vasculopathy: 8.6 ± 4.3 Group without cerebral vasculopathy: 9.1 ± 4.5 |
|
Absence of alpha-thalassemia |
Absence of G6PD deficiency |
Meier et al., 2015110110 Meier ER, Fasano RM, Estrada M, He J, Luban NL, McCarter R. Early reticulocytosis and anemia are associated with abnormal and conditional transcranial doppler velocities in children with sickle cell anemia. J Pediatr. 2016;169, 227–31 e221.
|
Cohort |
Conditional or abnormal TCD |
121 |
SS |
5.8 ± 3.0 |
|
↑reticulocytes, ↓Hb |
|
Belisário et al., 20159191 Belisario AR, Sales RR, Toledo NE, Velloso-Rodrigues C, Silva CM, Viana MB. Association between ENPP1 K173Q and stroke in a newborn cohort of 395 Brazilian children with sickle cell anemia. Blood. 2015;126(10):1259-60.
|
Cohort |
Stroke |
395 |
SS |
6–16 |
|
ENPP1 K173Q |
|
Sommet et al., 2016112112 Sommet J, Alberti C, Couque N, Verlhac S, Haouari Z, Mohamed D, et al. Clinical and haematological risk factors for cerebral macrovasculopathy in a sickle cell disease newborn cohort: a prospective study. Br J Haematol. 2016;172(6):966-77.
|
Cohort |
Cerebral macrovasculopathy (abnormal TCD, two high conditional TCDs with abnormal MRA or overt stroke) |
375 |
SS or Sβ0-thal |
Median follow-up: 6.8 |
|
Upper-airway obstruction, Bronchial obstruction and ↑reticulocytes |
↑Hb F |
Belisário et al., 20168282 Belisário AR, Sales RR, Toledo NE, Muniz MBdSR, Velloso-Rodrigues C, Silva CM, et al. Reticulocyte count is the most important predictor of acute cerebral ischemia and high-risk transcranial Doppler in a newborn cohort of 395 children with sickle cell anemia. Ann Hematol. 2016;95(11):1869-80.
|
Cohort |
Abnormal TCD |
395 |
SS |
Mean follow-up period: 9.04 ± 0.17 |
|
↑reticulocytes, TEK rs489347 and TGFBR3 rs284875 |
|
|
|
Acute cerebral ischemia (Ischemic stroke or TIA) |
|
|
|
|
↑reticulocytes, ↑WBC, ↑ACS rate, TEK rs489347 and TNF-α rs1800629 |
|