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Medical advances in the management of patients with sickle cell disease, thalassemia, and other hemolytic anemias have led to significant increases in life expectancy. Improved public health, neonatal screening, parental and patient education, advances in red cell transfusion medicine, iron chelation therapy, penicillin prophylaxis for children, pneumococcal immunization, and hydroxyurea therapy have all likely contributed to this effect on longevity. Importantly, as a generation of patients with sickle cell disease and thalassemia ages, new chronic complications of these hemoglobinopathies emerge. In this context, pulmonary hypertension is emerging as one of the leading causes of morbidity and mortality in adult sickle cell and thalassemia patients, and likely in patients with other hemolytic anemias.

A common feature of both sickle cell disease and thalassemia is intravascular hemolysis and chronic anemia. Recent data suggests that chronic intravascular hemolysis is associated with a state of endothelial dysfunction characterized by reduced nitric oxide (NO) bioavailability, pro-oxidant and pro-inflammatory stress and coagulopathy, leading to vasomotor instability and ultimately producing a proliferative vasculopathy, a hallmark of which is the development of pulmonary hypertension in adulthood.

This presentation will briefly review the role of NO in homeostatic endothelial and vasomotor function and the specific mechanisms of endothelial dysfunction in sickle cell disease. The putative mechanisms responsible for the development of pulmonary hypertension in hemolytic diseases and role of pulmonary hypertension as a risk factor for death in patients with sickle cell anemia will then be discussed. Finally, a case will be made that hemolytic anemia produces a clinical subphenotype in patients with sickle cell disease that is shared by other hemolytic disorders, a phenotype characterized by pulmonary hypertension, priapism, cutaneous leg ulceration, sudden death, and possibly stroke.



Learning objectives

1. Understand the role of intravascular hemolysis in the development of impaired nitric oxide bioavailability.
2. Understand the contribution of impaired nitric oxide bioavailability to pulmonary hypertension in sickle cell disease and thalassemia.
3. Understand the epidemiologic and pathophysiologic linkages between pulmonary hypertension, cutaneous leg ulceration and priapism in patients with sickle cell disease and other hemolytic disorders.

Kato GJ, Gladwin MT. Hemolysis-associated pulmonary hypertension in sickle cell disease and thalassemia. Hematology Education: the education program for the annual congress of the European Hematology Association, 2007;1(1):134-139.

Kato GJ, Gladwin MT, Steinberg MH. Deconstructing Sickle Cell Disease: Reappraisal of the Role of Hemolysis in the Development of Clinical Subphenotypes. Blood Reviews, 2007; 21:37-47.

Kato GJ, Onyekwere OC, Gladwin MT. Pulmonary Hypertension in Sickle Cell Disease: Relevance to Children. Pediatr Hematol Oncol, 2007; 24:159-170.