Pulmonary hypertension in patients with hemoglobinopathies: could a mechanism for dysfunction provide an avenue for novel therapeutics?

Advances in the care of patients with thalassemia, sickle cell disease, and other hemolytic disorders through early detection, education, improvements in red cell transfusion and iron chelation therapy, penicillin prophylaxis, vaccination, and hydroxyurea therapy have led to a significant prolongation of the life expectancy of such patients. As this patient population ages, new chronic complications of these hemoglobinopathies develop. In this context, pulmonary hypertension is emerging as one of the leading causes of morbidity and mortality in adult sickle cell and thalassemia patients. Retrospective and prospective studies estimate a pulmonary hypertension prevalence of 20-40% in patients with sickle cell disease, 40-50% in patients with thalassemia intermedia, and 10-75% in patients with thalassemia major. In addition, post-mortem studies in patients with sickle cell disease have revealed obliterative pulmonary vasculopathy with medial and intimal hyperplasia and plexogenic dilations of pulmonary vessels in one-third of patients. A study by Derchi and colleagues, published in this issue of the journal (see page 450) adds important new data on the use of sildenafil in this at risk population. In Derchi’s case series, seven patients with thalassemia intermedia (n=4), thalassemia major (n=2), and sickle thalassemia (n=1) and severe pulmonary hypertension were treated with 50 mg of sildenafil twice daily for a period ranging from 4 weeks to 48 months. Pulmonary pressures decreased in all patients and functional status and six-minute walked distance improved. We will now attempt to frame these therapeutically provocative findings in the context of emerging data on the prognosis, pathophysiology, and therapy of pulmonary hypertension in patients with chronic hemolytic anemias.