Pulmonary hypertension in sickle cell disease: relevance to children

Abstract

Pulmonary arterial hypertension (PAH), once considered a rare complication of sickle cell disease (SCD) and thalassemia, appears to be more common in adults with hemoglobinopathy than previously appreciated. On prospective screening of adults with SCD, approximately one-third of adults are found on echocardiography to have a tricuspid regurgitant jet velocity (TRV) of 2.5 m/s or higher, many of whom are asymptomatic. Dyspnea on exertion is the most common presenting symptom. This TRV abnormality is a marker for approximately 40% 3-year mortality in adults, and it is associated with laboratory values suggestive of more severe intravascular hemolysis. Release of hemoglobin and arginase from lysed red cells causes scavenging of nitric oxide (NO) and catabolism of L-arginine, the obligate substrate for NO synthase. The resulting impairment in NO bioavailability is associated with pulmonary vasoconstriction, endothelial dysfunction, thrombosis, and eventual development of plexogenic arterial lesions, the histological hallmark of all forms of PAH. Undoubtedly, additional pathophysiological mechanisms will also play a role in its multifactorial pathogenesis. Early data from children with SCD indicate a similar prevalence of elevated TRV, but the prognostic implications of this remain to be established. Individual patient diagnosis of PAH requires confirmation by right heart catheterization studies and individualized management. Hemolysis-associated PAH with impairments in NO bioavailability is being identified in thalassemia and other hemolytic disorders, and may be a general consequence of long-standing, severe intravascular hemolytic anemia.

FIGURE 1

Hypothetical model of the progression of pulmonary arterial hypertension during childhood and adulthood in patients with SCD. In this model, impaired NO bioavailability related to chronic hemolysis results in chronic pulmonary vasoconstriction, mildly elevating pulmonary vascular resistance and pulmonary arterial pressures. As this becomes more long-standing, vascular smooth muscle hyperplasia begins to create a relatively fixed lesion, compounded in later stages by irregular, activated endothelium with expression of adhesion molecules. In situ thrombosis further occludes the vessel lumen, and results in plexogenic changes, further accelerating the progression of the pulmonary arterial hypertension.