Sickle cell anemia and vascular dysfunction: The nitric oxide connection

Abstract

Endothelial dysfunction and impaired nitric oxide bioavailability have been implicated in the pathogenesis of sickle cell anemia. Nitric oxide is a diatomic gas with a role in vascular homeostasis. Hemoglobin polymerization resulting from the HbS mutation produces erythrocyte deformation and hemolysis. Free hemoglobin, released into plasma by hemolysis scavenges on nitric oxide, and leads to reduced nitric oxide bioavailability. Pulmonary hypertension is a known consequence of sickle cell anemia. It occurs in 30-40% of patients with sickle cell anemia, and is associated with increased mortality. Several studies have implicated intravascular hemolysis, and impaired nitric oxide bioavailability in the pathogenesis of pulmonary hypertension. In this review, we summarize the mechanisms of altered nitric oxide bioavailability in sickle cell anemia and its possible role in the pathogenesis of pulmonary hypertension.

Hydroxyurea therapy for priapism prevention and erectile function recovery in sickle cell disease: a case report and review of the literature

“…During hemolysis, free hemoglobin is released, which avidly scavenges intravascular NO, decreasing normal levels [11, 12]. Additionally, hemolysis releases the enzyme arginase into the plasma resulting in the degradation of l -arginine, a precursor to NO, and subsequently a decrease in NO bioavailability [11].…”

“…Additionally, hemolysis releases the enzyme arginase into the plasma resulting in the degradation of l -arginine, a precursor to NO, and subsequently a decrease in NO bioavailability [11]. Chronically decreased NO bioavailability has been shown to promote disruptions in downstream molecular signaling in the penis as associated with priapism [3, 10].…”

Acute Chest Syndrome of Sickle Cell Disease

“…The cause of temporary pulmonary vasoconstriction is likely multifactorial and in part due to nitric oxide (NO) consumption. 11 Pulmonary artery vasoconstriction may occur in a patient with no evidence of underlying pulmonary hypertension. In the acute and chronic settings, PA pressures in patients with SCA and confirmed pulmonary hypertension are generally not as high as in patients with idiopathic pulmonary hypertension.…”

“…However, patients are often symptomatic despite overall lower PA pressures. 11 No randomized controlled trial (RCT) data exist to guide the treatment of pulmonary hypertension in patients with SCA. 6 The most recent guidelines on pulmonary hypertension from the American College of Cardiology classify pulmonary hypertension in SCA as a World Health Organization group 1 diagnosis and suggest aggressive management according to severity classification.…”

Pulmonary Hypertension, Tricuspid Regurgitant Velocity Screening, and the Nitric Oxide Pathway

“…Short-term administration of arginine, the substrate for NO, leads to improvement in NO levels and metabolites in NO pathway, potentially enhanced by coadministration of hydroxyurea. 3,17,20,21 Intravenous administration of arginine resulted in a 50% reduction in opioid use in a randomized, controlled pediatric inpatient SCA study. 22 After a promising pilot study, however, inhaled NO failed to improve the time to crisis resolution in a multicenter study of hospitalized children and adults with SCD.…”