Sickle cell anemia is an autosomal recessive disorder and the most common genetic disease affecting African-Americans. Approximately 0.15% of African-Americans are homozygous for sickle cell disease, and 8% have sickle cell trait. Acute pain crisis, acute chest syndrome (ACS), and secondary pulmonary hypertension are common complications of sickle cell anemia. Pulmonary hypertension has now been identified as a major cause of death in adults with sickle cell disease. Similarly, pulmonary hypertension has been identified as a chronic complication of hemolytic disorders such as thalassemia, hereditary spherocytosis and paroxysmal nocturnal hemoglobinuria. Sildenafil has been proposed as a possible therapy for both primary and secondary pulmonary hypertension and recent phase I/II studies from the intramural NIH suggest it is well tolerated and efficacious in this population. Furthermore, a number of recent studies have suggested that NO based therapies may have a favorable impact on sickle red cells at the molecular level and could improve the abnormal microvascular perfusion that is characteristic of sickle cell anemia. This clinical trial was designed with three major objectives: 1) to assess cardiopulmonary function in patients with sickle cell disease and thalassemia with and without pulmonary hypertension, to better characterize the effects of chronic hydroxyurea therapy on cardiopulmonary function, 2) to determine the relative acute vasodilatory effects of sildenafil, and inhaled NO in patients with hemolysis-associated pulmonary hypertension and 3) to determine the chronic effects of the addition of inhaled NO on pulmonary hemodynamics and functional capacity in patients with hemolysis-associated pulmonary hypertension chronically treated with sildenafil. Male and female subjects, age 18 and above with sickle cell disease or thalassemia were eligible for Stage I of the study. Stage I evaluated 25 subjects and included pulmonary function testing, chest x-rays, VQ scan, 6-minute walk, sleep study, cardiac MRI, MRI assessment of liver iron burden, high resolution CT scan, and blood tests. After the Stage I testing subjects who were found to have mild to severe pulmonary hypertension were asked to breathe nitric oxide for 20 minutes through a facemask while undergoing the right heart catheterization. Then they received one dose of sildenafil and their pressures were monitored for 4 hours followed by another 20 minutes of breathing nitric oxide. Eighteen subjects completed Stage II of the study. Stage III was open to those individuals who had completed Stages I and II and had been on chronic sildenafil therapy for at least 3 months. Stage III consisted of breathing nitric oxide through the INO Pulse device for 6 weeks while continuing to take the oral sildenafil therapy. Three subjects completed this stage. The NHLBI IRB approved this study on 6/6/06. Our first patient was enrolled on 9/11/06. Thirty-one subjects were enrolled in this study. Three subjects completed all three stages;18 additional subjects completed stages I and II only;7 subjects completed stage I only;1 subject completed only part of Stage I, 1 subject did not return for the study after giving informed consent;and 1 subject withdrew for medical reasons. Stages I and II of this protocol provided the necessary work-up needed to determine if a subject had pulmonary hypertension. It also provided the research subjects for Stage III, which evaluated an intervention for this disease. This study is now closed to accrual and is open for data analysis and sample sharing only. Samples have been sent under an MTA to Dr. Mark Gladwin at the University of Pittsburgh for use in the project to examine if the TSP-1 binds to vWF therefore preventing its degradation by ADAMTS13. Protocol hemodynamic, pulmonary function, clinical laboratory and other data are being analyzed in relationship to mortality in preparation for publication. One manuscript has been submitted. These data are also being analyzed to determine relationships to 1) radiology data obtained during the study, in collaboration with CC Radiology Department collaborators led by Dr. Daniel Mollura;2) planned analysis of hemodynamic Witt monitor digital files by calculating right ventricular flow-volume loops, a promising way to determine right ventricular function, in collaboration with University of Pittsburgh cardiologist Hunter Champion.

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Nguyen, Kim-Lien; Tian, Xin; Alam, Shoaib et al. (2016) Elevated transpulmonary gradient and cardiac magnetic resonance-derived right ventricular remodeling predict poor outcomes in sickle cell disease. Haematologica 101:e40-3
Mehari, Alem; Alam, Shoaib; Tian, Xin et al. (2013) Hemodynamic predictors of mortality in adults with sickle cell disease. Am J Respir Crit Care Med 187:840-7
Mehari, Alem; Gladwin, Mark T; Tian, Xin et al. (2012) Mortality in adults with sickle cell disease and pulmonary hypertension. JAMA 307:1254-6
Novelli, Enrico M; Kato, Gregory J; Ragni, Margaret V et al. (2012) Plasma thrombospondin-1 is increased during acute sickle cell vaso-occlusive events and associated with acute chest syndrome, hydroxyurea therapy, and lower hemolytic rates. Am J Hematol 87:326-30
Linguraru, Marius George; Pura, John A; Van Uitert, Robert L et al. (2010) Segmentation and quantification of pulmonary artery for noninvasive CT assessment of sickle cell secondary pulmonary hypertension. Med Phys 37:1522-32