, Volume 186, Issue 4, pp 247–254

Pulmonary Hypertension Associated with Sickle Cell Disease: Pathophysiology and Rationale for Treatment



Approximately one third of patients with sickle cell disease (SCD) have pulmonary hypertension (PH), which increases their risk of death. Endothelin (ET)-1 is elevated in SCD and appears to play a key role in many of the pathologic processes in this disease, including PH, suggesting that endothelin receptor antagonists such as bosentan may be effective in treating patients with SCD, particularly those with PH. Other possible treatments include sildenafil, epoprostenol, and oral arginine. Data from controlled clinical trials are needed to establish the most effective treatment of patients with PH associated with SCD.


Pulmonary hypertension Sickle cell disease Endothelin receptor antagonist 


  1. 1.
    Simonneau G, Galie N, Rubin LJ, Langleben D, Seeger W, Domenighetti G, Gibbs S, Lebrec D, Speich R, Beghetti M, Rich S, Fishman A (2004) Clinical classification of pulmonary hypertension. J Am Coll Cardiol 43:5S–12SCrossRefPubMedGoogle Scholar
  2. 2.
    Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, Klug PP (1994) Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 330:1639–1644CrossRefPubMedGoogle Scholar
  3. 3.
    Graham LM (2004) The effect of sickle cell disease on the lung. Clin Pulm Med 11:369–378CrossRefGoogle Scholar
  4. 4.
    Bossone E, Bodini BD, Mazza A, Allegra L (2005) Pulmonary arterial hypertension: the key role of echocardiography. Chest 127:1836–1843CrossRefPubMedGoogle Scholar
  5. 5.
    Castro O, Hoque M, Brown BD (2003) Pulmonary hypertension in sickle cell disease: cardiac catheterization results and survival. Blood 101:1257–1261CrossRefPubMedGoogle Scholar
  6. 6.
    Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF, Minter K, Brown B, Coles WA, Nichols JS, Ernst I, Hunter LA, Blackwelder WC, Schechter AN, Rodgers GP, Castro O, Ognibene FP (2004) Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med 350:886–895CrossRefPubMedGoogle Scholar
  7. 7.
    Minter KR, Gladwin MT (2001) Pulmonary complications of sickle cell anemia. A need for increased recognition, treatment, and research. Am J Respir Crit Care Med 164:2016–2019CrossRefPubMedGoogle Scholar
  8. 8.
    McGoon M, Gutterman D, Steen V, Barst R, McCrory DC, Fortin TA, Loyd JE, American College of Chest Physicians (2004) Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 126:14S–34SCrossRefPubMedGoogle Scholar
  9. 9.
    Graham JK, Mosunjac M, Hanzlick RL (2007) Sickle cell lung disease and sudden death: a retrospective/prospective study of 21 autopsy cases and literature review. Am J Forensic Med Pathol 28:168–172CrossRefPubMedGoogle Scholar
  10. 10.
    Hillery CA, Panepinto JA (2004) Pathophysiology of stroke in sickle cell disease. Microcirculation 11:195–208CrossRefPubMedGoogle Scholar
  11. 11.
    Ataga KI, Sood N, De Gent G, Kelly E, Henderson AG, Jones S, Strayhorn D, Lail A, Lieff S, Orringer EP (2004) Pulmonary hypertension in sickle cell disease. Am J Med 117:665–669CrossRefPubMedGoogle Scholar
  12. 12.
    Machado RF, Gladwin MT (2005) Chronic sickle cell lung disease: new insights into the diagnosis, pathogenesis and treatment of pulmonary hypertension. Br J Haematol 129:449–464CrossRefPubMedGoogle Scholar
  13. 13.
    Anthi A, Machado RF, Jison ML, Taveira-Dasilva AM, Rubin LJ, Hunter L, Hunter CJ, Coles W, Nichols J, Avila NA, Sachdev V, Chen CC, Gladwin MT (2007) Hemodynamic and functional assessment of patients with sickle cell disease and pulmonary hypertension. Am J Respir Crit Care Med 175:1272–1279CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Sachdev V, Machado RF, Shizukuda Y, Rao YN, Sidenko S, Ernst I, St Peter M, Coles WA, Rosing DR, Blackwelder WC, Castro O, Kato GJ, Gladwin MT (2007) Diastolic dysfunction is an independent risk factor for death in patients with sickle cell disease. J Am Coll Cardiol 49:472–479CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Ataga KI, Moore CG, Jones S, Olajide O, Strayhorn D, Hinderliter A, Orringer EP (2006) Pulmonary hypertension in patients with sickle cell disease: a longitudinal study. Br J Haematol 134:109–115CrossRefPubMedGoogle Scholar
  16. 16.
    Liem RI, Young LT, Thompson AA (2007) Tricuspid regurgitant jet velocity is associated with hemolysis in children and young adults with sickle cell disease evaluated for pulmonary hypertension. Haematologica 92:1549–1552CrossRefPubMedGoogle Scholar
  17. 17.
    Nelson SC, Adade BB, McDonough EA, Moquist KL, Hennessy JM (2007) High prevalence of pulmonary hypertension in children with sickle cell disease. J Pediatr Hematol Oncol 29:334–337CrossRefPubMedGoogle Scholar
  18. 18.
    El-Beshlawy A, Abd El Raouf E, Mostafa F, Talaat M, Isma’eel H, Aoun E, Hoffbrand AV, Taher A (2006) Diastolic dysfunction and pulmonary hypertension in sickle cell anemia: is there a role for L-carnitine treatment? Acta Haematol 115:91–96CrossRefPubMedGoogle Scholar
  19. 19.
    Suell MN, Bezold LI, Okcu MF, Mahoney DH Jr, Shardonofsky F, Mueller BU (2005) Increased pulmonary artery pressures among adolescents with sickle cell disease. J Pediatr Hematol Oncol 27:654–658CrossRefPubMedGoogle Scholar
  20. 20.
    Hagar RW, Michlitsch JG, Gardner J, Vichinsky EP, Morris CR (2008) Clinical differences between children and adults with pulmonary hypertension and sickle cell disease. Br J Haematol 140:104–112PubMedGoogle Scholar
  21. 21.
    Morris CR, Singer ST, Walters MC (2006) Clinical hemoglobinopathies: iron, lungs and new blood. Curr Opin Hematol 13:407–418PubMedGoogle Scholar
  22. 22.
    Aessopos A, Kati M, Farmakis D (2007) Heart disease in thalassemia intermedia: a review of the underlying pathophysiology. Haematologica 92:658–665CrossRefPubMedGoogle Scholar
  23. 23.
    Voskaridou E, Tsetsos G, Tsoutsias A, Spyropoulou E, Christoulas D, Terpos E (2007) Pulmonary hypertension in patients with sickle cell/beta thalassemia: incidence and correlation with serum N-terminal pro-brain natriuretic peptide concentrations. Haematologica 92:738–743CrossRefPubMedGoogle Scholar
  24. 24.
    De Castro LM, Jonassaint JC, Graham FL, Ashley-Koch A, Telen MJ (2008) Pulmonary hypertension associated with sickle cell disease: clinical and laboratory endpoints and disease outcomes. Am J Hematol 83:19–25CrossRefPubMedGoogle Scholar
  25. 25.
    Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Omland T, Wolf PA, Vasan RS (2004) Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med 350:655–663CrossRefPubMedGoogle Scholar
  26. 26.
    Kragelund C, Gronning B, Kober L, Hildebrandt P, Steffensen R (2005) N-terminal pro-B-type natriuretic peptide and long-term mortality in stable coronary heart disease. N Engl J Med 352:666–675CrossRefPubMedGoogle Scholar
  27. 27.
    Yap LB, Ashrafian H, Mukerjee D, Coghlan JG, Timms PM (2004) The natriuretic peptides and their role in disorders of right heart dysfunction and pulmonary hypertension. Clin Biochem 37:847–856CrossRefPubMedGoogle Scholar
  28. 28.
    Machado RF, Anthi A, Steinberg MH, Bonds D, Sachdev V, Kato GJ, Taveira-DaSilva AM, Ballas SK, Blackwelder W, Xu X, Hunter L, Barton B, Waclawiw M, Castro O, Gladwin MT, MSH Investigators (2006) N-terminal pro-brain natriuretic peptide levels and risk of death in sickle cell disease. JAMA 296:310–318CrossRefPubMedGoogle Scholar
  29. 29.
    Lin EE, Gladwin MT, Machado RF (2005) Pulmonary hypertension in patients with hemoglobinopathies: could a mechanism for dysfunction provide an avenue for novel therapeutics? Haematologica 90:441–444PubMedGoogle Scholar
  30. 30.
    Galie N, Manes A, Branzi A (2004) The endothelin system in pulmonary arterial hypertension. Cardiovasc Res 61:227–237CrossRefPubMedGoogle Scholar
  31. 31.
    Levin ER (1995) Endothelins. N Engl J Med 333:356–363CrossRefPubMedGoogle Scholar
  32. 32.
    Davenport AP (2002) International Union of Pharmacology. XXIX. Update on endothelin receptor nomenclature. Pharmacol Rev 54:219–226CrossRefPubMedGoogle Scholar
  33. 33.
    Dupuis J (2001) Endothelin-receptor antagonists in pulmonary hypertension. Lancet 358:1113–1114CrossRefPubMedGoogle Scholar
  34. 34.
    Seo B, Oemar BS, Siebenmann R, von Segesser L, Lüscher TF (1994) Both ETA and ETB receptors mediate contraction to endothelin-1 in human blood vessels. Circulation 89:1203–1208CrossRefPubMedGoogle Scholar
  35. 35.
    Cacoub P, Dorent R, Nataf P, Carayon A (1993) Endothelin-1 in pulmonary hypertension. N Engl J Med 329:1967–1968CrossRefPubMedGoogle Scholar
  36. 36.
    Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, Kimura S, Masaki T, Duguid WP, Stewart DJ (1993) Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 328:1732–1739CrossRefPubMedGoogle Scholar
  37. 37.
    Rubens C, Ewert R, Halank M, Wensel R, Orzechowski HD, Schultheiss HP, Hoeffken G (2001) Big endothelin-1 and endothelin-1 plasma levels are correlated with the severity of primary pulmonary hypertension. Chest 120:1562–1569CrossRefPubMedGoogle Scholar
  38. 38.
    Yoshibayashi M, Nishioka K, Nakao K, Saito Y, Matsumura M, Ueda T, Temma S, Shirakami G, Imura H, Mikawa H (1991) Plasma endothelin concentrations in patients with pulmonary hypertension associated with congenital heart defects. Evidence for increased production of endothelin in pulmonary circulation. Circulation 84:2280–2285CrossRefPubMedGoogle Scholar
  39. 39.
    Graido-Gonzalez E, Doherty JC, Bergreen EW, Organ G, Telfer M, McMillen MA (1998) Plasma endothelin-1, cytokine, and prostaglandin E2 levels in sickle cell disease and acute vaso-occlusive sickle crisis. Blood 92:2551–2555PubMedGoogle Scholar
  40. 40.
    Rybicki AC, Benjamin LJ (1998) Increased levels of endothelin-1 in plasma of sickle cell anemia patients. Blood 92:2594–2596PubMedGoogle Scholar
  41. 41.
    Shiu YT, McIntire LV, Udden MM (2002) Sickle erythrocytes increase prostacyclin and endothelin-1 production by cultured human endothelial cells under flow conditions. Eur J Haematol 68:163–169CrossRefPubMedGoogle Scholar
  42. 42.
    Werdehoff SG, Moore RB, Hoff CJ, Fillingim E, Hackman AM (1998) Elevated plasma endothelin-1 levels in sickle cell anemia: relationships to oxygen saturation and left ventricular hypertrophy. Am J Hematol 58:195–199CrossRefPubMedGoogle Scholar
  43. 43.
    Rivera A, Jarolim P, Brugnara C (2002) Modulation of Gardos channel activity by cytokines in sickle erythrocytes. Blood 99:357–603CrossRefPubMedGoogle Scholar
  44. 44.
    Cines DB, Pollak ES, Buck CA, Loscalzo J, Zimmerman GA, McEver RP, Pober JS, Wick TM, Konkle BA, Schwartz BS, Barnathan ES, McCrae KR, Hug BA, Schmidt AM, Stern DM (1998) Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 91:3527–3561PubMedGoogle Scholar
  45. 45.
    Lin G, Macdonald RL, Marton LS, Kowalczuk A, Solenski NJ, Weir BK (2001) Hemoglobin increases endothelin-1 in endothelial cells by decreasing nitric oxide. Biochem Biophys Res Commun 280:824–830CrossRefPubMedGoogle Scholar
  46. 46.
    Hammerman SI, Kourembanas S, Conca TJ, Tucci M, Brauer M, Farber HW (1997) Endothelin-1 production during the acute chest syndrome in sickle cell disease. Am J Respir Crit Care Med 156:280–285CrossRefPubMedGoogle Scholar
  47. 47.
    Sabaa N, de Franceschi L, Bonnin P, Malpeli G, Germain S, Vandermeersch S, Maier-Redelsperger M, Scarpa A, Janin A, Levy B, Girot R, Beuzard Y, Leboeuf C, Henri A, Dussaule J-C, Tharaux P-L (2006) The dual endothelin receptor antagonist bosentan prevents the acute sickle cell-related hypoxic lung and kidney injury in transgenic SAD mice. Blood 108:Abstract 687Google Scholar
  48. 48.
    Morris CR (2006) New strategies for the treatment of pulmonary hypertension in sickle cell disease: the rationale for arginine therapy. Treat Respir Med 5:31–45CrossRefPubMedGoogle Scholar
  49. 49.
    Morris CR, Morris SM Jr, Hagar W, Van Warmerdam J, Claster S, Kepka-Lenhart D, Machado L, Kuypers FA, Vichinsky EP (2003) Arginine therapy: a new treatment for pulmonary hypertension in sickle cell disease? Am J Respir Crit Care Med 168:63–69CrossRefPubMedGoogle Scholar
  50. 50.
    Gladwin MT, Schechter AN (2001) Nitric oxide therapy in sickle cell disease. Semin Hematol 38:333–342CrossRefPubMedGoogle Scholar
  51. 51.
    Sullivan KJ, Goodwin SR, Evangelist J, Moore RD, Mehta P (1999) Nitric oxide successfully used to treat acute chest syndrome of sickle cell disease in a young adolescent. Crit Care Med 27:2563–2568CrossRefPubMedGoogle Scholar
  52. 52.
    Machado RF, Martyr S, Kato GJ, Barst RJ, Anthi A, Robinson MR, Hunter L, Coles W, Nichols J, Hunter C, Sachdev V, Castro O, Gladwin MT (2005) Sildenafil therapy in patients with sickle cell disease and pulmonary hypertension. Br J Haematol 130:445–453CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Derchi G, Forni GL, Formisano F, Cappellini MD, Galanello R, D’Ascola G, Bina P, Magnano C, Lamagna M (2005) Efficacy and safety of sildenafil in the treatment of severe pulmonary hypertension in patients with hemoglobinopathies. Haematologica 90:452–458PubMedGoogle Scholar
  54. 54.
    Kato GJ, Onyekwere OC, Gladwin MT (2007) Pulmonary hypertension in sickle cell disease: relevance to children. Pediatr Hematol Oncol 24:159–170CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Badesch DB, Abman SH, Simonneau G, Rubin LJ, McLaughlin VV (2007) Medical therapy for pulmonary arterial hypertension: updated ACCP evidence-based clinical practice guidelines. Chest 131:1917–1928CrossRefPubMedGoogle Scholar
  56. 56.
    Reiter CD, Wang X, Tanus-Santos JE, Hogg N, Cannon RO 3rd, Schechter AN, Gladwin MT (2002) Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nat Med 8:1383–1389CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.University of Alabama at BirminghamBirminghamUSA

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