Sickle Cell Disease Related Vasculopathies and Early Evaluation in a Pediatric Population

Abstract

Background/aim: Cardiovascular pathologies are ubiquitous in sickle cell disease (SCD). A targeted literature review was conducted to compare the overall epidemiology of selected vasculopathies seen in SCD (SCDVs) compared to the general population. Since many SCDV may originate in childhood, the study also focused on the retrospective investigation of SCDVs in a pediatric cohort at the Harbor-UCLA Medical Center.

Patients and methods: SCDVs were studied along patient age, β-globin genotypes, and fetal hemoglobin (HbF). Urine microalbumin/creatinine ratios (UM/Cr), trans-cranial doppler (TCD) and tricuspid regurgitant jet velocities (TRJV) were analyzed as well. Retinographies and overt vasculopathies were presented descriptively.

Results: Among 20 females and 20 males [average 8.3 years (2.3-19 years)], 70% had HbSS/Sβ0, 22.5% HbSC and 7.5%-HbSβ+. The mean(±SD) HbF% was 17.4±12.7% (30% higher in <10 vs. ≥10 y/o, and 3 times higher in SS/Sβ0). Twenty-six patients received hydroxyurea and 13/26, L-glutamine. Thirty-six patients had TCDs within 1.4±0.9 years and all laboratory values were obtained within the last 12 months. TCDs showed low-normal velocities, but 2 were higher for HbSS/Sβ0 vs. HbSC/Sβ+ (MCA-96 vs. 86 cm/s, p=0.03; and PCA-50 vs. 41, p<0.001). Nineteen of 28 patients with echocardiograms had measurable TRJV (2.46±0.19 m/s); 9 had TRJV ≥2.5-2.8 m/s, but BNP ≤80 pg/ml. SS/Sβ0 was associated with higher UM/Cr. There were 2 cases with silent infarcts, 1-Moyamoya, 2-persistent macroalbuminuria, and 1-hematuria/renal papillary necrosis. Most ≥9 y/o patients had retinographies without SCD-related changes. There was no correlation among TCD (MCA), TRJV, and UM/Cr (n=17); thus, in this subpopulation, pathologies of cerebral, cardiopulmonary, and renal vasculatures evolved independently. Patients with higher TRJV and/or overt vasculopathy (n=14) were older than ones without (12.5±4.7 vs. 6.1±3.1 y/o, p<0.001), and had lower HbF (11.4±7.6 vs. 20.6±13.8%, p=0.026).

Conclusion: While overt SCDVs are less frequent in children, age-dependent trends/surrogate markers suggest their early origination in youth, justifying intense screening to prevent their progression with disease-modifying measures.

Keywords: Sickle cell disease; early evaluation; pediatric population; vasculopathies.

Figure 1. Cardiopulmonary and renal vasculopathies in SCD. Chronic hemolysis, anemia and vaso-occlusion cause ongoing vascular and endorgan damage including lungs, heart, and kidneys. SCD: Sickle cell disease.

Figure 2. Study design.

Figure 3. Increased occurrence of selected CV complications in SCD. Prevalence in SCD and in the General population are shown in the table as percentages for all complications except for sudden death, which was depicted as an incidence-percentage of overall mortality in SCD or “natural deaths” in the general population. CV: Cardiovascular; SCD: sickle cell disease; ePASP: elevated pulmonary artery systolic pressure; PH: pulmonary hypertension; HFpEF: heart failure with preserved ejection fraction; CKD: chronic kidney disease.

Figure 4. Transcranial doppler velocities for 3 vessels: ACA, MCA and PCA. ACE: Anterior cerebral artery; MCA: middle cerebral artery; PCA: posterior cerebral artery.

Figure 5. No correlation was found between TRJV, MCA velocities and UM/Cr ratios in 17 patients. Slightly upward trending dotted tread line between MCA velocities (X-axis) vs. TRJV (Y-axis) shows an R2 value that does not support a strong correlation between the two. The size of each dot/bubble corresponds to the amount of albuminuria for each patient, and the absence of clustering of the similar size bubbles demonstrates no association between the UM/Cr ratios and TRJV or MCA velocities. TRJV: Tricuspid regurgitant jet velocity; MCA: middle cerebral artery; UM/Cr: urine microalbumin/creatinine ratio.