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Impact of early transcranial Doppler screening and intensive therapy on cerebral vasculopathy outcome in a newborn sickle cell anemia cohort

Françoise Bernaudin, Suzanne Verlhac, Cécile Arnaud, Annie Kamdem, Sylvie Chevret, Isabelle Hau, Lena Coïc, Emmanuella Leveillé, Elisabeth Lemarchand, Emmanuelle Lesprit, Isabelle Abadie, Nadia Medejel, Fouad Madhi, Sophie Lemerle, Sandra Biscardi, Josiane Bardakdjian, Frédéric Galactéros, Martine Torres, Mathieu Kuentz, Christelle Ferry, Gérard Socié, Philippe Reinert and Christophe Delacourt

Article Figures & Data

Figures

  • Figure 1

    Diagram of the CHIC SCA newborn cohort.

  • Figure 2

    Cumulative risk of overt stroke.

  • Figure 3

    MCA velocities. (A) Right and (B) left TAMMX ( ± SD) MCA velocities at annual check-up.

  • Figure 4

    Cumulative risk. (A) Cumulative risk of abnormal TCD (TAMMX velocities ≥ 200 cm/s). (B) Cumulative risk of abnormal MRA (stenosis). Of the 22 SS/Sβ0-patients with abnormal MRA, 16 had a history of abnormal TCD, 2 had conditional TCD, and 4 had normal TCD (1 had an extracranial cerebral vasculopathy, 1 had inadequate window on one side and normal velocities on the other side, and for the last 2, anomalies might have been related to flow artifact because the repeat MRA was normal). (C) Cumulative risk of silent strokes. Among the 35 SS/Sβ0 patients with silent strokes, 28 had silent strokes on the first MRI, and secondary occurrence of silent strokes was only observed in 7 boys: 1 had a history of abnormal TCD but parents had refused long-term TP, 1 with abnormal TCD still had abnormal velocities despite TP, and 5 nonintensified patients developed silent strokes. (D) Cumulative cerebral vasculopathy risk (strokes, abnormal TCD, stenosis, or silent strokes).

Tables

  • Table 1

    SCA patients: clinical and biological characteristics

    ValuesNo.Percent
    Sex
        F10247
        M11553
    G6PD
        Deficiency2111.5
        Normal16188.5
    Alpha genes
        2158
        36735.8
        410455.6
        510.5
    α-Thalassemia
        Absent10556.1
        Present8243.9
    Beta haplotype
        Car/Car6743.8
        Ben/Ben3623.5
        Sen/Sen117.2
        Others3925.5
    Parameters at baseline, median (Q1-Q3)
        WBC count, ×109/L18314.200 (10.750-17.850)
        Neutrophil count, ×109/L1715.320 (3.855-7.955)
        Platelet count, ×109/L182355.000 (282.500-434.000)
        Hemoglobin level, g/dL1857.8 (7.2-8.7)
        Hematocrit, %17923.4 (21.6-27)
        MCV, flt17880.35 (74.23-85.2)
        Reticulocyte count, ×109/L173286.200 (213.400-359.200)
        HbF, %16913.3 (8.1-20.7)
        SpO2, %6998 (97-100)
        LDH, IU/L163978 (760.5-1210)
    • Average biologic parameters were obtained at baseline after the age of 12 months and before the age of 3 years, a minimum of 3 months away from a transfusion, 1 month from a painful episode, and before any intensive therapy (hydroxyurea, transfusion program, or stem cell transplantation). G6PD activity was assessed by reduction of NADP to NADPH, measured by ultraviolet spectrophotometry. LDH range for the institution: 135-225 IU/L.

    • HbF indicates fetal hemoglobin; LDH, lactate dehydrogenase; MCV, mean corpuscular volume; and SCA, sickle cell anemia.

  • Table 2

    Patients assessed with TCD and MRI/MRA (n = 132): distribution of patients in each category of cerebral vasculopathy

    n
    TCD and MRI/MRA performed132
    Normal TCD and MRA, no stroke, no silent stroke (no cerebral vasculopathy risk)66
        Isolated abnormal TCD17
        Isolated abnormal MRA2
        Isolated silent stroke21
        Abnormal TCD + abnormal MRA9
        Abnormal TCD + silent stroke5
        Abnormal MRA + silent stroke3
        Abnormal TCD + abnormal MRA + silent stroke6
        Abnormal TCD + abnormal MRA + overt stroke1
        Normal TCD + overt stroke1
        Unavailable TCD + abnormal MRA + overt stroke1
    Stroke or abnormal TCD or abnormal MRA or silent stroke (cerebral vasculopathy risk)66
    • MRI/MRA indicates magnetic resonance imaging/magnetic resonance angiography; and TCD, transcranial Doppler.

  • Table 3

    Baseline prognostic factors for abnormal TCD, abnormal MRA, silent strokes, and cerebral vasculopathy risk (strokes, abnormal TCD, abnormal MRA, or silent strokes) by the age of 14 years in SCA participants

    Baseline parametersAbnormal TCDAbnormal MRASilent strokesStroke or abnormal TCD or abnormal MRA or silent stroke
    No. events/HR (95% CI)PNo. events/HR (95% CI)PNo. events/HR (95% CI)PNo. events/HR (95% CI)P
    No. patientsNo. patientsNo. patientsNo. patients
    Univariate analysis
        Sex
            Male25/115 = 22%1.1 (0.6-1.9).8610/71 = 14%0.7 (0.3-1.6).421/67 = 31%1.6 (0.8-3.4).06540/71 = 56%1.3 (0.8-2.2).253
            Female20/102 = 20%112/61 = 20%11/59 = 19%26/61 = 43%
        G6PD
            Normal31/161 = 19%111/100 = 11%24/97 = 25%49/100 = 49%
            Deficiency10/21 = 48%2.0 (1.0-4.0)*.042*8/16 = 50%4.8 (1.9-11.9)*.001*7/13 = 54%2.0 (0.9-4.3).07213/16 = 81%1.8 (0.9-3.3).082
        α-Thalassemia
            Present09/82 = 11%12/51 = 3.9%13/50 = 26%20/51 = 39%
            Absent30/105 = 29%2.8 (1.3-5.8)*.007*16/74 = 22%3.7 (1.1-12.7)*.038*18/69 = 26%1.1 (0.5-2.1).93643/74 = 58%1.6 (0.9-2.6).116
        Leukocyte count per 1 × 109/L increase1.1 (1.0-1.1)*.001*1.1 (1.0-1.2)*.003*1.0 (0.9-1.1).7071.0 (0.9-1.1).061
        Neutrophil count per 1 × 109/L increase1.0 (0.9-1.1).5461.0 (0.9-1.2).7250.9 (0.8-1.1).3361.0 (0.9-1.1).64
        Platelet count per 1 × 109/L increase1.0 (1.0-1.0).2350.9 (0.6-1.4).6431.0 (1.0-1.0).4771.0 (1.0-1.0).38
        Hemoglobin level per 1 g/dL increase0.73(0.54-0.97)*.034*0.47 (0.28-0.79)*.004*0.67 (0.46-0.98)*.048*0.77 (0.60-1.00)*.050*
        MCV per (fL) increase1.04 (0.99-1.08).0531.05 (0.98-1.12).1491.02 (0.98-1.07).2921.03 (0.99-1.07).069
        Reticulocyte count per 1 × 109/L increase1.005 (1.002-1.008).001*1.005 (1.000-1.010).0691.0 (1.0-1.0).6411.003 (1.000-1.005)*.028*
        HbF per 1% increase1.02 (0.98-1.06).2790.98 (0.91-1.06).6880.97 (0.92-1.03).2651.0 (1.0-1.0).94
        LDH per IU/mL increase2.73 (1.14-5.64)*.024*7.31 (1.91-27.92)*.004*2.06 (0.72-5.88).1773.31 (1.61-6.83)*.001*
    Multivariate analysis
        G6PD deficiency2.3 (1.0-5.2)*.046*3.6 (1.2-11.0)*.024*
        Absence of α-thalassemia2.5 (1.04-5.0)*.041*
        Hemoglobin level per 1 g/dL decrease1.7 (1.1-2.8)*.011*
        Reticulocyte count per 1 × 109/L increase1.005* (1.002-1.008)*<.001*1.003 (1.000-1.006)*.04*
        LDH per IU/mL increase4.9 (1.2-19.7)*.027*2.78 (1.33-5.81)*.007*
    • Shown are the results of the Cox regression univariate and multivariate analysis performed in to assess baseline predictive factors associated with abnormal TCD, abnormal MRA (stenosis), silent stroke, and those associated with the cumulative cerebral risk.

    • For this analysis, biologic parameters were (as in the Table 1) the average of those obtained at baseline after the age of 12 months and before the age of 3 years, a minimum of 3 months away from a transfusion, 1 month from a painful episode, and before any intensive therapy (hydroxyurea, transfusion program or stem cell transplantation).

    • CI indicates confidence interval; HbF, fetal hemoglobin; HR, hazard ratio; LDH, lactate dehydrogenase; MCV, mean corpuscular volume; MRA, magnetic resonance angiography; and SCA, sickle cell anemia.

    • * Statistically significant.

  • Table 4

    Blood parameters in 54 patients before and after HU therapy

    Before HU°On HU°°P
    Mean (SD)Mean (SD)
    Age, y6.4 (3.6)9.5 (4.0)
    WBC count, ×109/L14.6 (5.8)9.1 (3.8)<.001
    Neutrophil count, ×109/L7.3 (4.2)4.6 (3.3)<.001
    Platelet count, ×109/L405.6 (118.9)320.1 (99.4)<.001
    Hemoglobin level, g/dL7.5 (0.9)8.7 (1.1)<.001
    Hematocrit, %22.4 (3.0)26.0 (3.5)<.001
    MCV, flt80.4 (9.5)97.6 (13.7)<.001
    Reticulocyte count, ×109/L303.4 (99.9)183.5 (86.8)<.001
    HbF, %8.5 (5.0)16.4 (8.4)<.001
    LDH, IU/L1090 (361)801 (313)<.001
    Total bilirubin, μmol/L53.9 (38.4)42.1 (25.9).068
    • HbF indicates fetal hemoglobin; HR, hazard ratio; LDH, lactate dehydrogenase; MCV, mean corpuscular volume; and WBC, white blood cell count.

  • Table 5

    Comparative stroke risk in different cohorts

    CSSCDJamaicaDallasLondon, United KingdomCréteil, France
    Blood 1998J Pediatr 1992Blood 2004Haematologica 2007Newborn Cohort
    Infant CohortNewborn CohortNewborn CohortNewborn Cohort
    Enrollment period1978-19881983-20021983-20051988-2007
    SS patientsSS patientsSS/Sb0 patientsSS patientsSS/Sb0 patients
    Number of patients included in the cohort2436310448180217
    Patient-years of follow-up1781357115421609
    Number of first strokes before age 20 years51173073
    First stroke incidence/100 patient-years0.61
        Up to 16 years0.3 (95% CI 0.1-0.8)
        Up to 18 years0.850.19 (95% CI 0.04-0.5)
    KM estimate of stroke risk by age
        43.7% (95% CI 1.7%-5.7%)
        50.7% (95% CI 0.1%-5.0%)1.9% (95% CI 0.6%-5.9%).
        65.7% (95% CI 3.3%-8.2%)
        108.4% (95% CI 5.5%-11.6%)2.7% (95% CI 0.9%-8.3%)1.9% (95% CI 0.6%-5.9%).
        147.8%11.5% (95% CI 7.3%-15.7%)1.9% (95% CI 0.6%-5.9%).
        154.3% (95% CI 1.5%-11.4%)
        1811.5% (95% CI 7.3%-15.7%)1.9% (95% CI 0.6%-5.9%).
        2011%12.8% (95% CI 4.8%-31.3%)
    • CI indicates confidence interval; and CSSCD, Cooperative Study of Sickle Cell Disease.