Hydroxyurea reduces cerebral metabolic stress in patients with sickle cell anemia

Melanie E. Fields, Kristin P. Guilliams, Dustin Ragan, Michael M. Binkley, Amy Mirro, Slim Fellah, Monica L. Hulbert, Morey Blinder, Cihat Eldeniz, Katie Vo, Joshua S. Shimony, Yasheng Chen, Robert C. McKinstry, Hongyu An, Jin-Moo Lee and Andria L. Ford

Key points

  • Cerebral metabolic stress is reduced in SCA patients on HU compared to untreated patients, but remains higher than patients on CTT.

  • HU reduces the volume of tissue with maximal metabolic stress in the internal border zone, a region at high risk of stroke.


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, and 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 to patients not receiving disease-modifying therapy, we prospectively obtained brain MRIs 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 between the 3 cohorts (p = 0.148). However, whole brain OEF was significantly different (p < 0.001): participants without disease-modifying therapy had the highest OEF (42.9 [39.1-49.1]%), followed by HU treatment (40.7 [34.9-43.6]%), while CTT treatment had the lowest values (35.3 [32.2-38.9] %). Moreover, the percent of white matter at highest risk for ischemia, defined by OEF greater than 40 and 42.5%, was lower in the HU cohort compared to the untreated cohort (p = 0.025 and p = 0.034 respectively), but higher compared to the CTT cohort (p = 0.018 and p = 0.029 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.

  • Submitted September 20, 2018.
  • Accepted March 2, 2019.