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

Kenneth I Ataga,Victor R Gordeuk,Kimberly Gittings,Irene Agodoa,Jennifer A Colby,Isabel E Allen,Philippe Connes

doi:10.1371/journal.pone.0229959

Abstract

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/).

Highlights

Sickle cell disease (SCD) is characterized by deoxygenation–induced polymerization of hemoglobin in red blood cells (RBCs), leading to altered blood rheology, hemolysis and vaso–occlusion
In an effort to report on a robust body of evidence, the current analysis focuses on hemoglobin concentration and 4 key clinical outcomes, namely stroke and silent cerebral infarction, albuminuria, elevated estimated pulmonary artery systolic pressure (PASP; based on tricuspid regurgitant jet velocity [TRV] 2.5 m/s), and mortality
The random effects meta–analysis showed that hemoglobin concentration was significantly lower overall by 0.4 g/dL in patients with a history of stroke (0.4 g/ dL in patients with stroke/silent cerebral infarct and 0.4 g/dL in stroke alone) compared with those who had no history of stroke (Fig 2)

Summary

Introduction

Sickle cell disease (SCD) is characterized by deoxygenation–induced polymerization of hemoglobin in red blood cells (RBCs), leading to altered blood rheology, hemolysis and vaso–occlusion. The chronic hemolytic anemia experienced in varying degrees by patients with SCD leads to reduced oxygen– carrying capacity, tissue hypoxia, and clinical manifestations such as fatigue. Vaso–occlusion, and tissue ischemia, SCD is characterized by progressive end–organ damage of the heart, brain, lungs, spleen, liver, kidneys, and bones [6, 7]. Most patients with SCD in resource–rich countries live beyond childhood, the median life expectancy remains low, and is reduced by 2 to 3 decades [8]. This increased risk of early mortality is, in large part, due to the development of multiple end–organ damage [9,10,11,12]

Methods

Results

Conclusion