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

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

Voxelotor: alteration of sickle cell disease pathophysiology by a first-in-class polymerization inhibitor

“…In particular, hemolysis is established as a primary driver of disease severity partly as a result of studies associating anemia (as a surrogate marker of hemolysis) with the aforementioned sequelae, as well as with increased mortality. 14 – 19 Similar associations have been found for other markers of hemolysis, in particular lactate dehydrogenase, indirect bilirubin, cell-free plasma hemoglobin, and red blood cell-derived microparticles. 15 Although the degree of chronic hemolysis varies widely from patient to patient, its essential importance to the pathobiology of SCD does not, as the endothelial activation and vascular damage caused by the release of intra-corpuscular elements drive the increased cellular adhesion, inflammation, and disturbed rheology behind the ischemia–reperfusion damage that characterizes the disease.…”

Use of Real‐World Evidence to Drive Drug Development Strategy and Inform Clinical Trial Design

“…57 For example, a systematic literature review analyzed published data from multiple sources (e.g., clinical trials and RWE from registries) to understand how hemoglobin concentration (a biomarker) is related to various clinical endpoints, such as stroke, cerebrovascular disease, kidney disease, pulmonary vasculopathy, and mortality in patients with sickle cell disease. 58 Based on a meta-analysis of these data, researchers concluded that changes in hemoglobin concentration are a validated intermediary measure of disease progression in patients with sickle cell disease.…”

Transcranial doppler as screening method for sickling crises in children with sickle cell anemia: a latin America cohort study

“…The flow rates evaluated by TCD were correlated with severity of anemia [ 10 ]. Similarly, low hematocrit and hemoglobin levels were associated with complications of the disease [ 11 ]. It is therefore interesting to assume that changes in the velocities identified by TCD examination may reflect the severity of SCA.…”