Pulmonary hypertension associated with sickle cell disease
- Elizabeth S Klings, MD
Elizabeth S Klings, MD
- Associate Professor of Medicine
- Boston University School of Medicine
- Harrison W Farber, MD
Harrison W Farber, MD
- Professor of Medicine
- Boston University School of Medicine
- Section Editors
- Stanley L Schrier, MD
Stanley L Schrier, MD
- Editor-in-Chief — Hematology
- Section Editor — Myeloproliferative Disorders; Red Cell Disorders
- Professor of Medicine
- Stanford University School of Medicine
- Jess Mandel, MD
Jess Mandel, MD
- Section Editor — Pulmonary Vascular Disease
- Professor of Medicine
- University of California, San Diego
Sickle cell disease (SCD) encompasses a group of hemoglobinopathies characterized by amino acid substitutions in the beta globin chain. The most frequently occurring form of SCD is caused by homozygous presence of hemoglobin S (HbSS).
Pulmonary hypertension (PH) is a relatively frequent and severe complication of SCD and an independent risk factor for mortality [1-3]. The prevalence, pathogenesis, screening, and treatment of PH associated with SCD are discussed here. A discussion of other aspects of SCD and overviews of the pulmonary complications of SCD and of pulmonary hypertension are provided separately. (See "Overview of the clinical manifestations of sickle cell disease" and "Overview of the management and prognosis of sickle cell disease" and "Overview of the pulmonary complications of sickle cell disease" and "Overview of pulmonary hypertension in adults".)
The World Health Organization (WHO) classifies patients with pulmonary hypertension into five groups based upon etiology (table 1). Patients in the first group are considered to have pulmonary arterial hypertension (group 1 PAH), while patients in the remaining four groups are considered to have pulmonary hypertension (groups 2, 3, 4, and 5). When all five groups are discussed collectively, the term PH is used. SCD is placed in group 5, as there are some patients with hemodynamics consistent with PAH, while others have features of PH related to left-sided heart disease or thromboembolic disease. (See "Overview of pulmonary hypertension in adults", section on 'Classification'.)
●Group 1 – PAH
●Group 2 – PH due to left heart disease
- Gladwin MT, Vichinsky E. Pulmonary complications of sickle cell disease. N Engl J Med 2008; 359:2254.
- Klings ES, Machado RF, Barst RJ, et al. An official American Thoracic Society clinical practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease. Am J Respir Crit Care Med 2014; 189:727.
- Gordeuk VR, Castro OL, Machado RF. Pathophysiology and treatment of pulmonary hypertension in sickle cell disease. Blood 2016; 127:820.
- Ataga KI, Moore CG, Jones S, et al. Pulmonary hypertension in patients with sickle cell disease: a longitudinal study. Br J Haematol 2006; 134:109.
- Gladwin MT, Sachdev V, Jison ML, et al. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med 2004; 350:886.
- Parent F, Bachir D, Inamo J, et al. A hemodynamic study of pulmonary hypertension in sickle cell disease. N Engl J Med 2011; 365:44.
- Klings ES, Anton Bland D, Rosenman D, et al. Pulmonary arterial hypertension and left-sided heart disease in sickle cell disease: clinical characteristics and association with soluble adhesion molecule expression. Am J Hematol 2008; 83:547.
- Gordeuk VR, Minniti CP, Nouraie M, et al. Elevated tricuspid regurgitation velocity and decline in exercise capacity over 22 months of follow up in children and adolescents with sickle cell anemia. Haematologica 2011; 96:33.
- Colombatti R, Maschietto N, Varotto E, et al. Pulmonary hypertension in sickle cell disease children under 10 years of age. Br J Haematol 2010; 150:601.
- Mehari A, Gladwin MT, Tian X, et al. Mortality in adults with sickle cell disease and pulmonary hypertension. JAMA 2012; 307:1254.
- Fonseca GH, Souza R, Salemi VM, et al. Pulmonary hypertension diagnosed by right heart catheterisation in sickle cell disease. Eur Respir J 2012; 39:112.
- Machado RF, Anthi A, Steinberg MH, et al. N-terminal pro-brain natriuretic peptide levels and risk of death in sickle cell disease. JAMA 2006; 296:310.
- Kato GJ, McGowan V, Machado RF, et al. Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease. Blood 2006; 107:2279.
- Machado RF, Mack AK, Martyr S, et al. Severity of pulmonary hypertension during vaso-occlusive pain crisis and exercise in patients with sickle cell disease. Br J Haematol 2007; 136:319.
- Hsu LL, Champion HC, Campbell-Lee SA, et al. Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability. Blood 2007; 109:3088.
- Bunn HF, Nathan DG, Dover GJ, et al. Pulmonary hypertension and nitric oxide depletion in sickle cell disease. Blood 2010; 116:687.
- Niss O, Quinn CT, Lane A, et al. Cardiomyopathy With Restrictive Physiology in Sickle Cell Disease. JACC Cardiovasc Imaging 2016; 9:243.
- Gladwin MT, Barst RJ, Castro OL, et al. Pulmonary hypertension and NO in sickle cell. Blood 2010; 116:852.
- Hebbel RP. Reconstructing sickle cell disease: a data-based analysis of the "hyperhemolysis paradigm" for pulmonary hypertension from the perspective of evidence-based medicine. Am J Hematol 2011; 86:123.
- Rother RP, Bell L, Hillmen P, Gladwin MT. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA 2005; 293:1653.
- Mori M, Gotoh T. Regulation of nitric oxide production by arginine metabolic enzymes. Biochem Biophys Res Commun 2000; 275:715.
- Boucher JL, Moali C, Tenu JP. Nitric oxide biosynthesis, nitric oxide synthase inhibitors and arginase competition for L-arginine utilization. Cell Mol Life Sci 1999; 55:1015.
- Jison ML, Gladwin MT. Hemolytic anemia-associated pulmonary hypertension of sickle cell disease and the nitric oxide/arginine pathway. Am J Respir Crit Care Med 2003; 168:3.
- Morris CR, Kato GJ, Poljakovic M, et al. Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease. JAMA 2005; 294:81.
- Kato GJ, Wang Z, Machado RF, et al. Endogenous nitric oxide synthase inhibitors in sickle cell disease: abnormal levels and correlations with pulmonary hypertension, desaturation, haemolysis, organ dysfunction and death. Br J Haematol 2009; 145:506.
- Stamler JS, Singel DJ, Loscalzo J. Biochemistry of nitric oxide and its redox-activated forms. Science 1992; 258:1898.
- Hebbel RP, Eaton JW, Balasingam M, Steinberg MH. Spontaneous oxygen radical generation by sickle erythrocytes. J Clin Invest 1982; 70:1253.
- Amer J, Ghoti H, Rachmilewitz E, et al. Red blood cells, platelets and polymorphonuclear neutrophils of patients with sickle cell disease exhibit oxidative stress that can be ameliorated by antioxidants. Br J Haematol 2006; 132:108.
- Akinsheye I, Klings ES. Sickle cell anemia and vascular dysfunction: the nitric oxide connection. J Cell Physiol 2010; 224:620.
- De Castro LM, Jonassaint JC, Graham FL, et al. Pulmonary hypertension associated with sickle cell disease: clinical and laboratory endpoints and disease outcomes. Am J Hematol 2008; 83:19.
- Sachdev V, Kato GJ, Gibbs JS, et al. Echocardiographic markers of elevated pulmonary pressure and left ventricular diastolic dysfunction are associated with exercise intolerance in adults and adolescents with homozygous sickle cell anemia in the United States and United Kingdom. Circulation 2011; 124:1452.
- Benza RL. Pulmonary hypertension associated with sickle cell disease: pathophysiology and rationale for treatment. Lung 2008; 186:247.
- Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA 2014; 312:1033.
- http://www.nhlbi.nih.gov/health-pro/guidelines/sickle-cell-disease-guidelines/index.htm (Accessed on September 30, 2014).
- http://www.nhlbi.nih.gov/health-pro/guidelines/current/management-sickle-cell-disease.htm (Accessed on September 30, 2014).
- Anthi A, Machado RF, Jison ML, et al. Hemodynamic and functional assessment of patients with sickle cell disease and pulmonary hypertension. Am J Respir Crit Care Med 2007; 175:1272.
- Aliyu ZY, Suleiman A, Attah E, et al. NT-proBNP as a marker of cardiopulmonary status in sickle cell anaemia in Africa. Br J Haematol 2010; 150:102.
- Machado RF, Hildesheim M, Mendelsohn L, et al. NT-pro brain natriuretic peptide levels and the risk of death in the cooperative study of sickle cell disease. Br J Haematol 2011; 154:512.
- Minniti CP, Sable C, Campbell A, et al. Elevated tricuspid regurgitant jet velocity in children and adolescents with sickle cell disease: association with hemolysis and hemoglobin oxygen desaturation. Haematologica 2009; 94:340.
- Gladwin MT, Machado RF. Pulmonary hypertension in sickle cell disease. N Engl J Med 2011; 365:1646.
- McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation 2009; 119:2250.
- Mehari A, Alam S, Tian X, et al. Hemodynamic predictors of mortality in adults with sickle cell disease. Am J Respir Crit Care Med 2013; 187:840.
- Ambrusko SJ, Gunawardena S, Sakara A, et al. Elevation of tricuspid regurgitant jet velocity, a marker for pulmonary hypertension in children with sickle cell disease. Pediatr Blood Cancer 2006; 47:907.
- Falk RJ, Scheinman J, Phillips G, et al. Prevalence and pathologic features of sickle cell nephropathy and response to inhibition of angiotensin-converting enzyme. N Engl J Med 1992; 326:910.
- Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med 1995; 332:1317.
- Steinberg MH, McCarthy WF, Castro O, et al. The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: A 17.5 year follow-up. Am J Hematol 2010; 85:403.
- Cho G, Hambleton IR. Regular long-term red blood cell transfusions for managing chronic chest complications in sickle cell disease. Cochrane Database Syst Rev 2014; :CD008360.
- Tsitsikas DA, Seligman H, Sirigireddy B, et al. Regular automated red cell exchange transfusion in the management of pulmonary hypertension in sickle cell disease. Br J Haematol 2014; 167:707.
- Naik RP, Streiff MB, Haywood C Jr, et al. Venous thromboembolism in adults with sickle cell disease: a serious and under-recognized complication. Am J Med 2013; 126:443.
- Barst RJ, Mubarak KK, Machado RF, et al. Exercise capacity and haemodynamics in patients with sickle cell disease with pulmonary hypertension treated with bosentan: results of the ASSET studies. Br J Haematol 2010; 149:426.
- Minniti CP, Machado RF, Coles WA, et al. Endothelin receptor antagonists for pulmonary hypertension in adult patients with sickle cell disease. Br J Haematol 2009; 147:737.
- Machado RF, Barst RJ, Yovetich NA, et al. Hospitalization for pain in patients with sickle cell disease treated with sildenafil for elevated TRV and low exercise capacity. Blood 2011; 118:855.
- Machado RF, Martyr S, Kato GJ, et al. Sildenafil therapy in patients with sickle cell disease and pulmonary hypertension. Br J Haematol 2005; 130:445.
- Derchi G, Forni GL, Formisano F, et al. Efficacy and safety of sildenafil in the treatment of severe pulmonary hypertension in patients with hemoglobinopathies. Haematologica 2005; 90:452.
- Gladwin MT. Prevalence, risk factors and mortality of pulmonary hypertension defined by right heart catheterization in patients with sickle cell disease. Expert Rev Hematol 2011; 4:593.
- CLINICAL PRESENTATION
- SCREENING AND RISK STRATIFICATION
- EVALUATION FOR PH
- Supportive care and treatment of comorbidities
- SCD-specific treatments
- Long-term anticoagulation
- Pulmonary vasodilator therapy
- SUMMARY AND RECOMMENDATIONS