Hydroxyurea-Increased Fetal Hemoglobin Is Associated with Less Organ Damage and Longer Survival in Adults with Sickle Cell Anemia

PLoS One. 2015 Nov 17;10(11):e0141706. doi: 10.1371/journal.pone.0141706. eCollection 2015.


Background: Adults with sickle cell anemia (HbSS) are inconsistently treated with hydroxyurea.

Objectives: We retrospectively evaluated the effects of elevating fetal hemoglobin with hydroxyurea on organ damage and survival in patients enrolled in our screening study between 2001 and 2010.

Methods: An electronic medical record facilitated development of a database for comparison of study parameters based on hydroxyurea exposure and dose. This study is registered with ClinicalTrials.gov, number NCT00011648.

Results: Three hundred eighty-three adults with homozygous sickle cell disease were analyzed with 59 deaths during study follow-up. Cox regression analysis revealed deceased subjects had more hepatic dysfunction (elevated alkaline phosphatase, Hazard Ratio = 1.005, 95% CI 1.003-1.006, p<0.0.0001), kidney dysfunction (elevated creatinine, Hazard Ratio = 1.13, 95% CI 1.00-1.27, p = 0.043), and cardiopulmonary dysfunction (elevated tricuspid jet velocity on echocardiogram, Hazard Ratio = 2.22, 1.23-4.02, p = 0.0082). Sixty-six percent of subjects were treated with hydroxyurea, although only 66% of those received a dose within the recommended therapeutic range. Hydroxyurea use was associated with improved survival (Hazard Ratio = 0.58, 95% CI 0.34-0.97, p = 0.040). This effect was most pronounced in those taking the recommended dose of 15-35 mg/kg/day (Hazard Ratio 0.36, 95% CI 0.17-0.73, p = 0.0050). Hydroxyurea use was not associated with changes in organ function over time. Further, subjects with higher fetal hemoglobin responses to hydroxyurea were more likely to survive (p = 0.0004). While alkaline phosphatase was lowest in patients with the best fetal hemoglobin response (95.4 versus 123.6, p = 0.0065 and 96.1 versus 113.6U/L, p = 0.041 at first and last visits, respectively), other markers of organ damage were not consistently improved over time in patients with the highest fetal hemoglobin levels.

Conclusions: Our data suggest that adults should be treated with the maximum tolerated hydroxyurea dose, ideally before organ damage occurs. Prospective studies are indicated to validate these findings.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Anemia, Sickle Cell / blood
  • Anemia, Sickle Cell / drug therapy*
  • Anemia, Sickle Cell / mortality
  • Antisickling Agents / pharmacology
  • Antisickling Agents / therapeutic use*
  • Female
  • Fetal Hemoglobin / metabolism
  • Humans
  • Hydroxyurea / pharmacology
  • Hydroxyurea / therapeutic use*
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Proportional Hazards Models
  • Retrospective Studies
  • Treatment Outcome
  • Young Adult


  • Antisickling Agents
  • Fetal Hemoglobin
  • Hydroxyurea

Associated data

  • ClinicalTrials.gov/NCT00011648