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

464haematologica | 2013; 98(3)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). 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

Hematologic and hemorheological determinants of resting and exercise-induced hemoglobin oxygen desaturation in children with sickle cell disease

“…The reasons for this lack of independent association are unknown, but Quinn et al observed that the level of anemia explained only 5% of the arterial oxygen desaturation variability in SS/Sb 0 thalassemia children, and suggested that anemia was not the main factor explaining the presence of hemoglobin oxygen desaturation at rest. 5 Nevertheless, further studies using primary markers of hemolysis, such as life span, 40 or the recent integrated hemolytic marker validated by Nouraie et al, 44 are needed to definitively exclude a role of anemia in resting hemoglobin oxygen desaturation in SS patients.…”

Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel

“…64,65 However, mortality is still significant once patients reach adulthood. 61,66 SCD-associated morbidity and mortality in young adults is largely due to as yet unpreventable complications such as priapism, avascular necrosis, chronic pulmonary impairment, hypertension, stroke and recurrent venoocclusive crises. 58,[67][68][69][70] The only curative approach for SCD is HSCT.…”

Cellular, Pharmacological, and Biophysical Evaluation of Explanted Lungs from a Patient with Sickle Cell Disease and Severe Pulmonary Arterial Hypertension

“…14 PAH is epidemiologically linked to a high baseline rate of intravascular hemolysis in SCD. 15 Preclinical and human vascular studies have confirmed that hemolytic anemia leads to vasculopathy through decreased NO bioavailability due to NO scavenging by cell-free plasma hemoglobin, increased arginase 1 levels in plasma, and increased xanthine oxidase-mediated superoxide production. [16][17][18] Similar to patients with SCD, sickle cell mice with high baseline hemolysis have diminished responses to NO and NO donors and develop PAH as they age.…”