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Introduction

Sickle cell disease (SCD) is one of the most common monogenetic diseases in the world. Sickle cell anemia, the most common and most severe form of SCD, occurs in individuals who are homozygous for a single GAG α GTG substitution in the β-globin gene, resulting in the production of hemoglobin S (HbS). Patients with other types of SCD are compound heterozygotes, having one copy of HbS and one copy of another β-globin mutation, such as hemoglobin SC or HbS-β thalassemia.1 The presence of concurrent α-thalassemia, which will reduce the intracellular concentration of hemoglobin, also modulates disease severity and accounts for some of the variability in the clinical presentation of patients with SCD.2 It is estimated that approximately 250,000 children worldwide are born with homozygous sickle cell (HbSS) anemia every year.3 Approximately 0.15% of African Americans are homozygous for SCD, and 8% have sickle cell trait. In sub-Saharan Africa, up to 40% of the population carry sickle cell trait, and up to 1% of children are born with SCD.4

Despite significant improvements in the life expectancy of patients with SCD, estimates of the median age at death range from 42 to 53 years for men and 48 to 58.5 years for women.5,6 Within this context, pulmonary complications of SCD are common and a major threat to the well-being of patients with SCD, accounting for a large proportion of deaths among these patients.5,79 According to the Cooperative Study of Sickle Cell Disease (CSSCD), a prospective multicenter study of 3764 patients, over 20% of adults likely had fatal pulmonary complications of SCD.5 Among the 299 patients enrolled in the long-term follow-up study of patients who participated in the Multicenter Study of Hydroxyurea (MSH) in Sickle Cell Anemia, pulmonary disease was the most common cause of mortality, accounting for 28% of all deaths.10 The numbers likely underestimate the importance of pulmonary disease in risk of death, as pulmonary hypertension (PH) was not diagnosed in these cohorts. Indeed, retrospective evaluation of banked plasma samples from the studies using N-terminal probrain natriuretic peptide (NT-proBNP) as a surrogate for the presence of PH suggested that PH was a major risk factor for death in both the CSSCD and MSH cohorts.11,12

When deoxygenated, HbS is much less soluble than normal hemoglobin (HbA).13,14 Deoxygenated HbS polymerizes and aggregates inside sickle erythrocytes as they traverse the microcirculation. Rigid, dense, and sickled cells can become physically entrapped in the microcirculation, a process that is enhanced by inflammation and integrin molecule expression, causing red cell and leukocyte adhesion to endothelium. Mechanistic studies in transgenic mice expressing exclusively human HbS suggests that microvascular occlusion results in episodic interruption in blood flow, ischemia, and reperfusion injury, with secondary inflammatory, thrombotic, and oxidant stress.1522

In patients, vasoocclusion leads to the frequent episodes of bone pain ...

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