title: The relationship between the severity of hemolysis, clinical manifestations and risk of death in 415 patients with sickle cell anemia in the US and Europe.
abstract: The intensity of hemolytic anemia has been proposed as an independent risk factor for the development of certain clinical complications of sickle cell disease, such as pulmonary hypertension, hypoxemia and cutaneous leg ulceration. A composite variable derived from several individual markers of hemolysis could facilitate studies of the underlying mechanisms of hemolysis. In this study, we assessed the association of hemolysis with outcomes in sickle cell anemia. A hemolytic component was calculated by principal component analysis from reticulocyte count, serum lactate dehydrogenase, aspartate aminotransferase and total bilirubin concentrations in 415 hemoglobin SS patients. Association of this component with direct markers of hemolysis and clinical outcomes was assessed. As primary validation, both plasma red blood cell microparticles and cell-free hemoglobin concentration were higher in the highest hemolytic component quartile compared to the lowest quartile (P≤0.0001 for both analyses). The hemolytic component was lower with hydroxyurea therapy, higher hemoglobin F, and alpha-thalassemia (P≤0.0005); it was higher with higher systemic pulse pressure, lower oxygen saturation, and greater values for tricuspid regurgitation velocity, left ventricular diastolic dimension and left ventricular mass (all P<0.0001). Two-year follow-up analysis showed that a high hemolytic component was associated with an increased risk of death (hazard ratio, HR 3.44; 95% confidence interval, CI: 1.2-9.5; P=0.02). The hemolytic component reflects direct markers of intravascular hemolysis in patients with sickle cell disease and allows for adjusted analysis of associations between hemolytic severity and clinical outcomes. These results confirm associations between hemolytic rate and pulse pressure, oxygen saturation, increases in Doppler-estimated pulmonary systolic pressures and mortality (Clinicaltrials.gov identifier: NCT00492531).
authors.affiliation: Howard University, Washington, USA.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Nouraie
authors.forename: Janet S
authors.initials: JS
authors.lastname: Lee
authors.forename: Yingze
authors.initials: Y
authors.lastname: Zhang
authors.forename: Tamir
authors.initials: T
authors.lastname: Kanias
authors.forename: Xuejun
authors.initials: X
authors.lastname: Zhao
authors.forename: Zeyu
authors.initials: Z
authors.lastname: Xiong
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Oriss
authors.forename: Qilu
authors.initials: Q
authors.lastname: Zeng
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Kato
authors.forename: J Simon R
authors.initials: JS
authors.lastname: Gibbs
authors.forename: Mariana E
authors.initials: ME
authors.lastname: Hildesheim
authors.forename: Vandana
authors.initials: V
authors.lastname: Sachdev
authors.forename: Robyn J
authors.initials: RJ
authors.lastname: Barst
authors.forename: Roberto F
authors.initials: RF
authors.lastname: Machado
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Hassell
authors.forename: Jane A
authors.initials: JA
authors.lastname: Little
authors.forename: Dean E
authors.initials: DE
authors.lastname: Schraufnagel
authors.forename: Lakshmanan
authors.initials: L
authors.lastname: Krishnamurti
authors.forename: Enrico
authors.initials: E
authors.lastname: Novelli
authors.forename: Reda E
authors.initials: RE
authors.lastname: Girgis
authors.forename: Claudia R
authors.initials: CR
authors.lastname: Morris
authors.forename: Erika Berman
authors.initials: EB
authors.lastname: Rosenzweig
authors.forename: David B
authors.initials: DB
authors.lastname: Badesch
authors.forename: Sophie
authors.initials: S
authors.lastname: Lanzkron
authors.forename: Oswaldo L
authors.initials: OL
authors.lastname: Castro
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Goldsmith
authors.forename: Victor R
authors.initials: VR
authors.lastname: Gordeuk
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
mesh_terms: D000755:Anemia, Sickle Cell / Q000453:epidemiology*; D015415:Biomarkers / Q000097:blood; D055252:Cell-Derived Microparticles; D015897:Comorbidity; D004909:Erythrocyte Indices; D005060:Europe / Q000453:epidemiology; D006461:Hemolysis; D006801:Humans; D009026:Mortality; D012307:Risk Factors; D014481:United States / Q000453:epidemiology
chemical_list: D015415:Biomarkers