Hydroxyurea reduces cerebral metabolic stress in patients with sickle cell anemia

Abstract

Chronic transfusion therapy (CTT) prevents stroke in selected patients with sickle cell anemia (SCA). We have shown that CTT mitigates signatures of cerebral metabolic stress, reflected by elevated oxygen extraction fraction (OEF), which likely drives stroke risk reduction. The region of highest OEF falls within the border zone, where cerebral blood flow (CBF) nadirs; OEF in this region was reduced after CTT. The neuroprotective efficacy of hydroxyurea (HU) remains unclear. To test our hypothesis that patients receiving HU therapy have lower cerebral metabolic stress compared with patients not receiving disease-modifying therapy, we prospectively obtained brain magnetic resonance imaging scans with voxel-wise measurements of CBF and OEF in 84 participants with SCA who were grouped by therapy: no disease-modifying therapy, HU, or CTT. There was no difference in whole-brain CBF among the 3 cohorts (P = .148). However, whole-brain OEF was significantly different (P < .001): participants without disease-modifying therapy had the highest OEF (median 42.9% [interquartile range (IQR) 39.1%-49.1%]), followed by HU treatment (median 40.7% [IQR 34.9%-43.6%]), whereas CTT treatment had the lowest values (median 35.3% [IQR 32.2%-38.9%]). Moreover, the percentage of white matter at highest risk for ischemia, defined by OEF greater than 40% and 42.5%, was lower in the HU cohort compared with the untreated cohort (P = .025 and P = .034 respectively), but higher compared with the CTT cohort (P = .018 and P = .029 respectively). We conclude that HU may offer neuroprotection by mitigating cerebral metabolic stress in patients with SCA, but not to the same degree as CTT.

Graphical abstract

Figure 1.

Whole-brain and segmented CBF and OEF between cohorts. Although there was no difference in CBF among the 3 cohorts in the whole brain, gray matter, or white matter (A), there was a significant decrease in whole brain, gray matter and white matter OEF in the cohort receiving HU therapy (blue) compared with those not receiving disease-modifying therapy (red), but not to the extent of those receiving CTT (green) (B). *Statistically significant after Benjamini-Hochberg step-up procedure used to correct for multiple comparisons.

Figure 2.

HU decreases the volume of brain tissue with elevated OEF in the border zone. The average white matter OEF map for each cohort was thresholded at 40% (dark teal), 42.5% (light teal), and 45% (white) OEF to identify the brain regions with peak oxygen metabolic stress, as a potential index of elevated stroke risk. The figure shows the average OEF map for each cohort (left), paired with the thresholded regions overlaid on a T1 atlas (right). There is a decrease in thresholded brain tissue in the cohort treated with HU when compared with those not receiving disease-modifying therapy across all thresholds, but the cohort receiving CTT has a significantly lower volume of at risk tissue compared with the HU cohort.

Figure 3.

Percentage of patients with brain tissue experiencing increased metabolic stress decreases with HU. These population heat maps illustrate the percentage of participants within each white matter voxel that has an OEF exceeding the defined threshold overlaid on a T1 atlas (OEF threshold of 40%, left column; 42.5%, middle column; 45%, right column). The highest prevalence of elevated OEF consistently falls within the internal border zone in all 3 cohorts. The percentage of participants exceeding these thresholds is decreased in participants treated with HU compared with those not receiving disease-modifying therapy, but not to the extent of the participants receiving CTT.