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Background: In adults with sickle cell disease (SCD), an increased tricuspid regurgitant velocity (TRV) measured by Doppler echocardiography, an increased serum N-terminal pro-brain natriuretic peptide (NT-pro-BNP) level, and pulmonary hypertension (PH) diagnosed by right heart catheterization (RHC) are independent risk factors for mortality. Methods: A multidisciplinary committee was formed by clinicianinvestigators experienced in the management of patients with PH and/or SCD. Clinically important questions were posed, related evidence was appraised, and questions were answered with evidencebased recommendations. Target audiences include all clinicians who take care of patients with SCD. Results: Mortality risk stratification guides decision making. An increased risk for mortality is defined as a TRV equal to or greater than 2.5 m/second, an NT-pro-BNP level equal to or greater than 160 pg/ml, or RHC-confirmed PH. For patients identified as having increased mortality risk, we make a strong recommendation for hydroxyurea as first-line therapy and a weak recommendation for chronic transfusions as an alternative therapy. For all patients with SCD with elevated TRV alone or elevated NT-pro-BNP alone, and for patients with SCD with RHC-confirmed PH with elevated pulmonary artery wedge pressure and low pulmonary vascular resistance, we make a strong recommendation against PAH-specific therapy. However, for select patients with SCD with RHC-confirmed PH who have elevated pulmonary vascular resistance and normal pulmonary capillary wedge pressure, we make a weak recommendation for either prostacyclin agonist or endothelin receptor antagonist therapy and a strong recommendation against phosphodiesterase-5 inhibitor therapy.Conclusions: Evidence-based recommendations for the management of patients with SCD with increased mortality risk are provided, but will require frequent reassessment and updating.

Rationale: Pulmonary complications of sickle cell anemia (Hb-SS) commonly cause morbidity, yet few large studies of pulmonary function tests (PFTs) in this population have been reported. Objectives: PFTs (spirometry, lung volumes, and diffusion capacity for carbon monoxide [DL CO ]) from 310 adults with Hb-SS were analyzed to determine the pattern of pulmonary dysfunction and their association with other systemic complications of sickle cell disease. Methods: Raw PFT data were compared with predicted values. Each subject was subclassified into one of five groups: obstructive physiology, restrictive physiology, mixed obstructive/restrictive physiology, isolated low DL CO , or normal. The association between laboratory data of patients with decreased DL CO Sickle cell anemia (Hb-SS) results from homozygosity for a point mutation in the ␤-globin gene (HBB; Glu6Val) causing the resultant sickle hemoglobin (Hb S) to be less soluble when deoxygenated than normal hemoglobin (1). Even with improved treatment, including the early use of prophylactic antibiotic regimens, judicious transfusions, and the administration of hydroxyurea in selected patients, mortality remains high for this population. The median age at death is 42 yr for males and 48 yr for females with Hb-SS. Pulmonary complications, including acute chest syndrome (ACS), pulmonary hypertension (PH), and pulmonary fibrosis, account for 20-30% of deaths in the Hb-SS population and are often underrecognized by the health care community (2, 3).Dyspnea is a frequent complaint amongst patients with sickle cell disease, the etiology of which is unclear and likely multifacto- 5). Studies of lung function to date in this population have been of modest size, often involving fewer than 50 patients (4, 6-11) and largely inconclusive. Their results have yielded a spectrum of abnormalities, including restrictive lung disease, abnormal diffusion capacity for carbon monoxide (Dl CO ), obstructive disease, and hypoxemia (4,6,7,9,12). No definitive profile for pulmonary function in sickle cell disease has emerged. As a result, clinicians find pulmonary function tests (PFTs) difficult to interpret in this population and their clinical utility for directing further investigation and therapy has not been well evaluated.Of growing concern is the link between obstructive lung disease and ACS, particularly in children (7,13,14). The few published studies suggest that obstructive lung disease, in some cases, plays a role in the pathogenesis of ACS (7,13,15). Moreover, obstructive lung disease could be a long-term sequela of recurrent episodes of ACS (6, 9). Larger scale studies are necessary to elucidate more clearly the interaction between lung function and ACS. In addition, certain findings on PFTs might be a marker of other complications of sickle vasculopathy. For example, isolated decreased Dl CO is a well-established finding associated with PH (16, 17). However, its role as a marker or predictor of PH in the Hb-SS population is unknown. The purpose of this study is to evalua...

Erythrocyte glutathione depletion has been linked to hemolysis and oxidative stress. Glutamine plays an additional antioxidant role through preservation of intracellular nicotinamide adenine dinucleotide phosphate (NADPH) levels, required for glutathione recycling. Decreased nitric oxide (NO) bioavailability, which occurs in the setting of increased hemolysis and oxidative stress, contributes to the pathogenesis of pulmonary hypertension (PH) in sickle cell disease (SCD). We hypothesized that altered glutathione and glutamine metabolism play a role in this process. Total glutathione (and its precursors) and glutamine were assayed in plasma and erythrocytes of 40 SCD patients and 9 healthy volunteers. Erythrocyte total glutathione and glutamine levels were significantly lower in SCD patients than in healthy volunteers. Glutamine depletion was independently associated with PH, defined as a tricuspid regurgitant jet velocity (TRV) of at least 2.5 m/s. The ratio of erythrocyte glutamine:glutamate correlated inversely to TRV (r ‫؍‬ ؊0.62, P < .001), plasma arginase concentration (r ‫؍‬ ؊0.45, P ‫؍‬ .002), and plasma-free hemoglobin level (r ‫؍‬ ؊0.41, P ‫؍‬ .01), linking erythrocyte glutamine depletion to dysregulation of the arginine-NO pathway and increased hemolytic rate. Decreased erythrocyte glutathione and glutamine levels contribute to alterations in the erythrocyte redox environment, which may compromise erythrocyte integrity, contribute to hemolysis, and play a role in the pathogenesis of PH of SCD. IntroductionThe erythrocyte redox environment may contribute to the increased oxidative stress, hemolysis, and decreased nitric oxide (NO) bioavailability observed in pulmonary hypertension (PH), a common complication of hemolytic disorders. Reduced glutathione (gamma-glutamyl-cysteinyl-glycine; GSH) is the most abundant low-molecular weight thiol 1 and the principal thiol redox buffer in erythrocytes. 2,3 The red blood cell contributes up to 10% of whole-body GSH synthesis in humans. [4][5][6] In addition to its role as a critical antioxidant, GSH possesses diverse biological functions involved in detoxification, cell proliferation and apoptosis, redox signaling, gene expression, protein glutathionylation, cytokine production, the immune response, mitochondrial function, and integrity as well as NO metabolism. 7,8 Glutathione is synthesized from glutamate, cysteine, and glycine via reactions catalyzed by 2 cytosolic enzymes, gammaglutamylcysteine ligase and GSH synthetase. The intracellular GSH concentration is the final result of a dynamic balance between the rate of GSH synthesis and the combined rate of intracellular GSH consumption and efflux. GSH is readily oxidized to glutathione disulfide (GSSG) by free radicals and reactive oxygen and nitrogen species. GSSG efflux from cells contributes to a net loss of intracellular GSH. 1 Due to its high intracellular concentrations, GSH variations in oxidation states can significantly modify the redox environment of red blood cells. Within the erythrocyte, GSH may...

In a genome-wide association study of 848 blacks with sickle cell anemia, we identified single nucleotide polymorphisms (SNPs) associated with fetal hemoglobin concentration. The most significant SNPs in a discovery sample were tested in a replication set of 305 blacks with sickle cell anemia and in subjects with hemoglobin E or beta thalassemia trait from Thailand and Hong Kong. A novel region on chromosome 11 containing olfactory receptor genes OR51B5 and OR51B6 was identified by 6 SNPs (lowest P = 4.7E-08) and validated in the replication set. An additional olfactory receptor gene, OR51B2, was identified by a novel SNP set enrichment analysis. Genome-wide association studies also validated a previously identified SNP (rs766432) in BCL11A, a gene known to affect fetal hemoglobin levels (P = 2.6E-21) and in Thailand and Hong Kong subjects. Elements within the olfactory receptor gene cluster might play a regulatory role in gamma-globin gene expression.