Low hemoglobin increases risk for cerebrovascular disease, kidney disease, pulmonary vasculopathy, and mortality in sickle cell disease: A systematic literature review and meta-analysis.

Sickle cell disease (SCD) is characterized by deoxygenation-induced polymerization of hemoglobin in red blood cells, leading to hemolytic anemia, vaso-occlusion, and the development of multiple clinical complications. To characterize the clinical burden associated with differences in hemoglobin concentration and hemolysis measures, a systematic literature review of MEDLINE, EMBASE, and related meta-analyses was undertaken. For quantitative analyses related to hemoglobin concentration, pooled results were analyzed using random effects models to control for within-and between-study variability. To derive risk ratios associated with hemoglobin concentration change, we combined ratios of means from select studies, which reported hazard and odds ratios in meta-analyses for hemoglobin concentration-related outcomes and changes between groups. Forty-one studies were identified for inclusion based on relating hemoglobin concentration to clinical outcomes. Meta-analyses demonstrated that mean hemoglobin concentration was significantly lower in patients with cerebrovascular disease (0.4 g/dL), increased transcranial Doppler velocity in cerebral arteries (0.6 g/dL), albuminuria (0.6 g/dL), elevated estimated pulmonary artery systolic pressure (0.9 g/dL), and in patients that subsequently died (0.6 g/dL). In a risk reduction meta-analysis, modeled increased hemoglobin concentrations of 1 g/dL or greater resulted in decreased risk of negative clinical outcomes of 41% to 64%. In conclusion, chronic anemia is associated with worse clinical outcomes in individuals with SCD and even modest increases in hemoglobin concentration may be beneficial in this patient population. This systematic review has been registered on Prospero (Registration number CRD42018096860; https://www.crd.york.ac.uk/prospero/).
Competing Interests: K.I.A. is an advisory board member for GBT, Novartis, and Bioverativ and has served as a consultant for Modus Therapeutics. V.R.G. has served as a consultant for GBT and CSL Behring. I.A. is a current employee and stockholder of GBT. J.A.C. and K.G. are current employees of Xcenda, LLC, an AmerisourceBergen company. I.E.A. is a current employee of University of California, San Francisco and has served as a consultant for GBT. This does not alter our adherence to PLOS ONE policies on sharing data and materials.