Advertisement

Pulmonary Hypertension in Children with Sickle Cell Disease: a Review of the Current Literature

  • Jamie K. Harrington
  • Usha S. KrishnanEmail author
Cardiology (W Zuckerman and E Silver, Section Editors)
  • 1 Downloads
Part of the following topical collections:
  1. Cardiology

Abstract

Purpose of Review

Pulmonary hypertension (PH) is a well-recognized complication of sickle cell disease (SCD) and is one of the strongest predictors of increased morbidity and mortality in adult patients. There is evidence that PH can develop in children with SCD and the clinical implications of this finding are an area of active research. We review the current literature examining the association of SCD and PH in childhood.

Recent Findings

The recent literature has focused on elucidating the multifactorial mechanisms for the development of PH in SCD with the goal of developing targeted therapies. In addition, there has been a focus on understanding the significance of echocardiographic evidence of PH in children with SCD, a finding that has recently been associated with adverse clinical factors. While still based on limited evidence, the increased understanding of the important prognostic implications of echocardiographic evidence of PH has led to the development of guidelines that recommend screening echocardiograms beginning in childhood in children with SCD.

Summary

PH can develop in children with SCD and, while the exact clinical implications of this finding are still being elucidated, current guidelines and research are aimed at early identification and treatment to improve outcomes.

Keywords

Sickle cell disease pulmonary hypertension pediatric tricuspid regurgitant jet velocity 

Notes

Compliance with Ethical Standards

Conflict of Interest

Jamie K. Harrington and Usha S. Krishnan declare no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Kato GJ, Piel FB, Reid CD, Gaston MH, Ohene-Frempong K, Krishnamurti L, et al. Sickle cell disease. Nat Rev Dis Prim . 2018;4:18010.Google Scholar
  2. 2.
    Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. 2010 ;376:2018–31.Google Scholar
  3. 3.
    Miller AC, Gladwin MT. Pulmonary Complications of Sickle Cell Disease. Am J Respir Crit Care Med. 2012;185:1154–65.Google Scholar
  4. 4.
    Gladwin MT, Sachdev V. Cardiovascular Abnormalities in Sickle Cell Disease. J Am Coll Cardiol. 2012;59:1123–33.Google Scholar
  5. 5.
    Gladwin MT. Cardiovascular complications in patients with sickle cell disease. Hematol Am Soc Hematol Educ Progr. 2017;2017:423–30.Google Scholar
  6. 6.
    Gladwin MT. Cardiovascular complications and risk of death in sickle-cell disease. Lancet. 2016;387:2565–74.Google Scholar
  7. 7.
    Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF, Minter K, et al. Pulmonary Hypertension as a Risk Factor for Death in Patients with Sickle Cell Disease. N Engl J Med. 2004;350:886–95.Google Scholar
  8. 8.
    Gladwin MT, Barst RJ, Gibbs JSR, Hildesheim M, Sachdev V, Nouraie M, et al. Risk factors for death in 632 patients with sickle cell disease in the United States and United Kingdom. West J, editor. PLoS One. 2014;9:e99489.Google Scholar
  9. 9.
    Mehari A, Gladwin MT, Tian X, Machado RF, Kato GJ. Mortality in Adults With Sickle Cell Disease and Pulmonary Hypertension. JAMA. 2012;307:1254.Google Scholar
  10. 10.
    Mehari A, Alam S, Tian X, Cuttica MJ, Barnett CF, Miles G, et al. Hemodynamic Predictors of Mortality in Adults with Sickle Cell Disease. Am J Respir Crit Care Med. 2013;187:840–7.Google Scholar
  11. 11.
    Damy T, Bodez D, Habibi A, Guellich A, Rappeneau S, Inamo J, et al. Haematological determinants of cardiac involvement in adults with sickle cell disease†. Eur Heart J. 2015;37:1158–67.Google Scholar
  12. 12.
    Castro O, Minniti CP, Nouraie M. Pulmonary Hypertension in Sickle Cell Disease. N Engl J Med. 2011;365:1645–9.Google Scholar
  13. 13.
    McLaughlin V V., Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al. ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension. J Am Coll Cardiol [Internet]. Journal of the American College of Cardiology. 2009;53:1573–619.Google Scholar
  14. 14.
    Galiè N, Humbert M, Vachiery J-L, Gibbs S, Lang I, Torbicki A, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2016;37:67–119.Google Scholar
  15. 15.
    Upadhya B, Stacey RB, Ntim W, Knovich MA, Pu M. Echocardiography-Derived Tricuspid Regurgitant Jet Velocity Is an Important Marker for the Progression of Sickle-Cell Disease. Acta Haematol. 2014;132:152–8.Google Scholar
  16. 16.
    Pashankar FD, Carbonella J, Bazzy-Asaad A, Friedman A. Prevalence and risk factors of elevated pulmonary artery pressures in children with sickle cell disease. Pediatrics. 2008;121:777–82.Google Scholar
  17. 17.
    Ambrusko SJ, Gunawardena S, Sakara A, Windsor B, Lanford L, Michelson P, et al. Elevation of tricuspid regurgitant jet velocity, a marker for pulmonary hypertension in children with sickle cell disease. Pediatr Blood Cancer. 2006;47:907–13.Google Scholar
  18. 18.
    Colombatti R, Maschietto N, Varotto E, Grison A, Grazzina N, Meneghello L, et al. Pulmonary hypertension in sickle cell disease children under 10 years of age. Br J Haematol. 2010;150:601–9.Google Scholar
  19. 19.
    Musa BM, Galadanci NA, Coker M, Bussell S, Aliyu MH. The global burden of pulmonary hypertension in sickle cell disease: a systematic review and meta-analysis. Ann Hematol. 2016;95:1757–64.Google Scholar
  20. 20.
    Caughey MC, Poole C, Ataga KI, Hinderliter AL. Estimated pulmonary artery systolic pressure and sickle cell disease: a meta-analysis and systematic review. Br J Haematol. 2015;170:416–24.Google Scholar
  21. 21.
    •• Abman SH, Hansmann G, Archer SL, Ivy DD, Adatia I, Chung WK, et al. Pediatric Pulmonary Hypertension: Guidelines From the American Heart Association and American Thoracic Society. Circulation. 2015;132:2037–99. This is an executive summary from a committee of experienced clinicians from the American Heart Association and American Thoracic Society summarizing and appraising the relevant literature, and providing evidence-based recommendations for diagnosis and management of pulmonary hypertension in children, including in sickle cell disease. Google Scholar
  22. 22.
    • Abman SH, Ivy DD, Archer SL, Wilson K, AHA/ATS Joint Guidelines for Pediatric Pulmonary Hypertension Committee. Executive Summary of the American Heart Association and American Thoracic Society Joint Guidelines for Pediatric Pulmonary Hypertension. Am J Respir Crit Care Med. 2016;194:898–906. This is an executive summary of the longer official guidelines, reference 21, from the American Heart Association and American Thoracic Society joint committee on recommendations for diagnosis and management of pediatric pulmonary hypertension highlighting the key recommendations. Google Scholar
  23. 23.
    Abman SH. New guidelines for managing pulmonary hypertension. Curr Opin Pediatr. 2016;28:597–606.Google Scholar
  24. 24.
    Klings ES, Machado RF, Barst RJ, Morris CR, Mubarak KK, Gordeuk VR, 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;189:727–40.Google Scholar
  25. 25.
    Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, et al. Management of Sickle Cell Disease. JAMA. 2014;312:1033.Google Scholar
  26. 26.
    Kato GJ, Steinberg MH, Gladwin MT. Intravascular hemolysis and the pathophysiology of sickle cell disease. J Clin Invest [Internet]. American Society for Clinical Investigation. 2017;127:750–60.Google Scholar
  27. 27.
    Gordeuk VR, Castro OL, Machado RF. Pathophysiology and treatment of pulmonary hypertension in sickle cell disease. Blood. 2016;127:820–8.Google Scholar
  28. 28.
    Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, et al. Updated Clinical Classification of Pulmonary Hypertension. J Am Coll Cardiol. 2009;54:S43–54.Google Scholar
  29. 29.
    Hatano S, Strasser T. Primary Pulmonary Hypertension: report on a WHO meeting. Geneva: World Heal Organ.Google Scholar
  30. 30.
    Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, et al. Updated Clinical Classification of Pulmonary Hypertension. J Am Coll Cardiol [Internet]. Journal of the American College of Cardiology. 2013;62:D34–41.Google Scholar
  31. 31.
    Rosenzweig EB, Abman SH, Adatia I, Beghetti M, Bonnet D, Haworth S, Ivy DD, Berger RMF Paediatric pulmonary arterial hypertension: updates on definition, classification, diagnostics and management. Eur Respir J. 2019;53.Google Scholar
  32. 32.
    Graham JK, Mosunjac M, Hanzlick RL, Mosunjac M. Sickle Cell Lung Disease and Sudden Death. Am J Forensic Med Pathol. 2007;28:168–72.Google Scholar
  33. 33.
    Manci EA, Culberson DE, Yang Y-M, Gardner TM, Powell R, Haynes J, et al. Causes of death in sickle cell disease: an autopsy study. Br J Haematol. 2003;123:359–65.Google Scholar
  34. 34.
    Haque AK, Gokhale S, Rampy BA, Adegboyega P, Duarte A, Saldana MJ. Pulmonary hypertension in sickle cell hemoglobinopathy: a clinicopathologic study of 20 cases. Hum Pathol. 2002;33:1037–43.Google Scholar
  35. 35.
    Parent F, Bachir D, Inamo J, Lionnet F, Driss F, Loko G, et al. A Hemodynamic Study of Pulmonary Hypertension in Sickle Cell Disease. N Engl J Med. 2011;365:44–53.Google Scholar
  36. 36.
    Fonseca GHH, Souza R, Salemi VMC, Jardim CVP, Gualandro SFM. Pulmonary hypertension diagnosed by right heart catheterisation in sickle cell disease. Eur Respir J. 2012;39:112–8.Google Scholar
  37. 37.
    Gladwin MT, Machado RF. Pulmonary Hypertension in Sickle Cell Disease. N Engl J Med. 2011;365:1645–9.Google Scholar
  38. 38.
    Machado RF, Barst RJ, Yovetich NA, Hassell KL, Kato GJ, Gordeuk VR, et al. Hospitalization for pain in patients with sickle cell disease treated with sildenafil for elevated TRV and low exercise capacity. Blood. 2011;118:855–64.Google Scholar
  39. 39.
    Barst RJ, Mubarak KK, Machado RF, Ataga KI, Benza RL, Castro O, 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;149:426–35.Google Scholar
  40. 40.
    Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2018;53:1801913.Google Scholar
  41. 41.
    Hoeper MM, Bogaard HJ, Condliffe R, Frantz R, Khanna D, Kurzyna M, et al. Definitions and Diagnosis of Pulmonary Hypertension. J Am Coll Cardiol. 2013;62:D42–50.Google Scholar
  42. 42.
    Galiè N, Hoeper MM, Humbert M, Torbicki A, Vachiery J-L, Barbera JA, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J Off J Eur Soc Clin Respir Physiol. 2009;34:1219–63.Google Scholar
  43. 43.
    Skinner GJ. Echocardiographic Assessment of Pulmonary Arterial Hypertension for Pediatricians and Neonatologists. Front Pediatr [Internet]. Frontiers Media SA. 2017;5:168.Google Scholar
  44. 44.
    Jone P-N, Ivy DD. Echocardiography in pediatric pulmonary hypertension. Front Pediatr [Internet]. Frontiers Media SA. 2014;2:124.Google Scholar
  45. 45.
    Gladwin MT. Revisiting the hyperhemolysis paradigm. Blood. American Society of Hematology. 2015;126:695–6.Google Scholar
  46. 46.
    Gladwin MT, Barst RJ, Castro OL, Gordeuk VR, Hillery CA, Kato GJ, et al. Pulmonary hypertension and NO in sickle cell. Blood [Internet]. American Society of Hematology. 2010;116:852–4.Google Scholar
  47. 47.
    Reiter CD, Wang X, Tanus-Santos JE, Hogg N, Cannon RO, Schechter AN, et al. Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nat Med. 2002;8:1383–9.Google Scholar
  48. 48.
    Hsu LL, Champion HC, Campbell-Lee SA, Bivalacqua TJ, Manci EA, Diwan BA, et al. Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability. Blood [Internet]. American Society of Hematology. 2007;109:3088–98.Google Scholar
  49. 49.
    Rother RP, Bell L, Hillmen P, Gladwin MT. The Clinical Sequelae of Intravascular Hemolysis and Extracellular Plasma Hemoglobin. JAMA. 2005;293:1653.Google Scholar
  50. 50.
    Ballas SK, Kesen MR, Goldberg MF, Lutty GA, Dampier C, Osunkwo I, et al. Beyond the definitions of the phenotypic complications of sickle cell disease: an update on management. ScientificWorldJournal. Hindawi Limited. 2012;2012:949535.Google Scholar
  51. 51.
    Zuckerman WA, Rosenzweig EB. Pulmonary hypertension in children with sickle cell disease. Expert Rev Respir Med. 2011;5:233–43.Google Scholar
  52. 52.
    DeMartino AW, Kim-Shapiro D, Patel RP, Gladwin MT. Nitrite and nitrate chemical biology and signaling. Br J Pharmacol. 2018.Google Scholar
  53. 53.
    Walford G, Loscalzo J. Nitric oxide in vascular biology. J Thromb Haemost. 2003;1:2112–8.Google Scholar
  54. 54.
    Morris CR, Kato GJ, Poljakovic M, Wang X, Blackwelder WC, Sachdev V, et al. Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease. JAMA. 2005;294:81–90.Google Scholar
  55. 55.
    Landburg PP, Teerlink T, Biemond BJ, Brandjes DPM, Muskiet FAJ, Duits AJ, et al. Plasma asymmetric dimethylarginine concentrations in sickle cell disease are related to the hemolytic phenotype. Blood Cells, Mol Dis. 2010;44:229–32.Google Scholar
  56. 56.
    Kalra VK, Zhang S, Malik P, Tahara SM. Placenta growth factor mediated gene regulation in sickle cell disease. Blood Rev. 2018;32:61–70.Google Scholar
  57. 57.
    Bilan VP, Schneider F, Novelli EM, Kelley EE, Shiva S, Gladwin MT, et al. Experimental intravascular hemolysis induces hemodynamic and pathological pulmonary hypertension: association with accelerated purine metabolism. Pulm Circ. 2018;8:204589401879155.Google Scholar
  58. 58.
    Conran N, Belcher JD. Inflammation in sickle cell disease. Connes P, ed. Clin Hemorheol Microcirc. 2018;68:263–99.Google Scholar
  59. 59.
    Figueiredo RT, Fernandez PL, Mourao-Sa DS, Porto BN, Dutra FF, Alves LS, et al. Characterization of heme as activator of Toll-like receptor 4. J Biol Chem [Internet]. American Society for Biochemistry and Molecular Biology. 2007;282:20221–9.Google Scholar
  60. 60.
    Dutra FF, Alves LS, Rodrigues D, Fernandez PL, de Oliveira RB, Golenbock DT, et al. Hemolysis-induced lethality involves inflammasome activation by heme. Proc Natl Acad Sci. 2014;111:E4110–8.Google Scholar
  61. 61.
    Hebbel RP, Key NS. Microparticles in sickle cell anaemia: promise and pitfalls. Br J Haematol. 2016;174:16–29.Google Scholar
  62. 62.
    Camus SM, De Moraes JA, Bonnin P, Abbyad P, Le Jeune S, Lionnet F, et al. Circulating cell membrane microparticles transfer heme to endothelial cells and trigger vasoocclusions in sickle cell disease. Blood. 2015;125:3805–14.Google Scholar
  63. 63.
    Gladwin MT, Ofori-Acquah SF. Erythroid DAMPs drive inflammation in SCD. Blood. 2014;123:3689–90.Google Scholar
  64. 64.
    Mendonça R, Silveira AAA, Conran N. Red cell DAMPs and inflammation. Inflamm Res. 2016;65:665–78.Google Scholar
  65. 65.
    Tantawy AAG, Adly AAM, Ismail EAR, Habeeb NM, Farouk A. Circulating platelet and erythrocyte microparticles in young children and adolescents with sickle cell disease: Relation to cardiovascular complications. Platelets. 2013;24:605–14.Google Scholar
  66. 66.
    Niss O, Quinn CT, Lane A, Daily J, Khoury PR, Bakeer N, et al. Cardiomyopathy With Restrictive Physiology in Sickle Cell Disease. JACC Cardiovasc Imaging. 2016;9:243–52.Google Scholar
  67. 67.
    Desai AA, Patel AR, Ahmad H, Groth J V., Thiruvoipati T, Turner K, et al. Mechanistic Insights and Characterization of Sickle Cell Disease–Associated Cardiomyopathy. Circ Cardiovasc Imaging. 2014;7:430–7.Google Scholar
  68. 68.
    Junqueira FP, Fernandes JL, Cunha GM, TA Kubo T, MAO Lima C, BP Lima D, et al. Right and left ventricular function and myocardial scarring in adult patients with sickle cell disease: a comprehensive magnetic resonance assessment of hepatic and myocardial iron overload. J Cardiovasc Magn Reson. 2013;15:83.Google Scholar
  69. 69.
    Bratis K, Kattamis A, Athanasiou K, Hautemann D, van Wijk K, Reiber H, et al. Abnormal myocardial perfusion–fibrosis pattern in sickle cell disease assessed by cardiac magnetic resonance imaging. Int J Cardiol. 2013;166:e75–6.Google Scholar
  70. 70.
    Milton JN, Rooks H, Drasar E, McCabe EL, Baldwin CT, Melista E, et al. Genetic determinants of haemolysis in sickle cell anaemia. Br J Haematol. 2013;161:270–8.Google Scholar
  71. 71.
    Steinberg MH, Sebastiani P. Genetic modifiers of sickle cell disease. Am J Hematol. 2012;87:795–803.Google Scholar
  72. 72.
    Chang AK, Ginter Summarell CC, Birdie PT, Sheehan VA. Genetic modifiers of severity in sickle cell disease. Connes P, editor. Clin Hemorheol Microcirc. 2018;68:147–64.Google Scholar
  73. 73.
    Renoux C, Joly P, Faes C, Mury P, Eglenen B, Turkay M, et al. Association between Oxidative Stress, Genetic Factors, and Clinical Severity in Children with Sickle Cell Anemia. J Pediatr. 2018;195:228–35.Google Scholar
  74. 74.
    Habara A, Steinberg MH. Minireview: Genetic basis of heterogeneity and severity in sickle cell disease. Exp Biol Med. 2016;241:689–96.Google Scholar
  75. 75.
    Khorshied MM, Mohamed NS, Hamza RS, Ali RM, El-Ghamrawy MK. Protein Z and Endothelin-1 genetic polymorphisms in pediatric Egyptian sickle cell disease patients. J Clin Lab Anal. 2018;32:e22264.Google Scholar
  76. 76.
    Dahoui HA, Hayek MN, Nietert PJ, Arabi MT, Muwakkit SA, Saab RH, et al. Pulmonary hypertension in children and young adults with sickle cell disease: Evidence for familial clustering. Pediatr Blood Cancer. 2010;54:398–402.Google Scholar
  77. 77.
    Sokunbi OJ, Ekure EN, Temiye EO, Anyanwu R, Okoromah CAN. Pulmonary hypertension among 5 to 18 year old children with sickle cell anaemia in Nigeria. Tayo BO, editor. PLoS One. 2017;12:e0184287.Google Scholar
  78. 78.
    Al-Allawi N, Mohammad AM, Jamal S. Doppler-Defined Pulmonary Hypertension in Sickle Cell Anemia in Kurdistan, Iraq. West J, editor. PLoS One. 2016;11:e0162036.Google Scholar
  79. 79.
    Harrington JK, Krishnan U, Jin Z, Mardy C, Kobsa S, Lee MT. Longitudinal Analysis of Echocardiographic Abnormalities in Children With Sickle Cell Disease. J Pediatr Hematol Oncol. 2017;39:500–5.Google Scholar
  80. 80.
    Nelson SC, Adade BB, McDonough EA, Moquist KL, Hennessy JM. High Prevalence of Pulmonary Hypertension in Children With Sickle Cell Disease. J Pediatr Hematol Oncol. 2007;29:334–7.Google Scholar
  81. 81.
    Sedrak A, Rao SP, Miller ST, Hekmat V, Rao M. A Prospective Appraisal of Pulmonary Hypertension in Children With Sickle Cell Disease. J Pediatr Hematol Oncol. 2009;31:97–100.Google Scholar
  82. 82.
    Onyekwere OC, Campbell A, Teshome M, Onyeagoro S, Sylvan C, Akintilo A, et al. Pulmonary Hypertension in Children and Adolescents with Sickle Cell Disease. Pediatr Cardiol. 2008;29:309–12.Google Scholar
  83. 83.
    Minniti CP, Sable C, Campbell A, Rana S, Ensing G, Dham N, et al. Elevated tricuspid regurgitant jet velocity in children and adolescents with sickle cell disease: association with hemolysis and hemoglobin oxygen desaturation. Haematologica. 2009;94:340–7.Google Scholar
  84. 84.
    Agha H, El Tagui M, El Ghamrawy M, Hady MA. The 6-min walk test: an independent correlate of elevated tricuspid regurgitant jet velocity in children and young adult sickle cell patients. Ann Hematol. 2014;93:1131–8.Google Scholar
  85. 85.
    Hebson C, New T, Record E, Oster M, Ehrlich A, Border W, et al. Elevated tricuspid regurgitant velocity as a marker for pulmonary hypertension in children with sickle cell disease: less prevalent and predictive than previously thought? J Pediatr Hematol Oncol. 2015;37:134–9.Google Scholar
  86. 86.
    Lee MT, Small T, Khan MA, Rosenzweig EB, Barst RJ, Brittenham GM. Doppler-defined pulmonary hypertension and the risk of death in children with sickle cell disease followed for a mean of three years. Br J Haematol. 2009;146:437–41.Google Scholar
  87. 87.
    Kato GJ, Onyekwere OC, Gladwin MT. Pulmonary hypertension in sickle cell disease: relevance to Children. Pediatr Hematol Oncol. 2007;24:159–70.Google Scholar
  88. 88.
    Nouraie M, Lee JS, Zhang Y, Kanias T, Zhao X, Xiong Z, et al. The relationship between the severity of hemolysis, clinical manifestations and risk of death in 415 patients with sickle cell anemia in the US and Europe. Haematologica. 2013;98:464–72.Google Scholar
  89. 89.
    Elalfy MS, Youssef OI, Deghedy MMR, Abdel Naby MM. Left Ventricular Structural and Functional Changes in Children With β-Thalassemia and Sickle Cell Disease. J Pediatr Hematol Oncol. 2018;40:171–7.Google Scholar
  90. 90.
    Liem RI, Nevin MA, Prestridge A, Young LT, Thompson AA. Tricuspid regurgitant jet velocity elevation and its relationship to lung function in pediatric sickle cell disease. Pediatr Pulmonol. 2009;44:281–9.Google Scholar
  91. 91.
    Mondal P, Stefek B, Sinharoy A, Sankoorikal B-J, Abu-Hasan M, Aluquin V. The association of nocturnal hypoxia and an echocardiographic measure of pulmonary hypertension in children with sickle cell disease. Pediatr Res. 2018.Google Scholar
  92. 92.
    Newaskar M, Hardy KA, Morris CR. Asthma in Sickle Cell Disease. Sci World J. 2011;11:1138–52.Google Scholar
  93. 93.
    Morris CR. Asthma management: Reinventing the wheel in sickle cell disease. Am J Hematol. 2009;84:234–41.Google Scholar
  94. 94.
    Minniti CP, Taylor JG, Hildesheim M, O’Neal P, Wilson J, Castro O, et al. Laboratory and echocardiography markers in sickle cell patients with leg ulcers. Am J Hematol. 2011;86:705–8.Google Scholar
  95. 95.
    De Castro LM, Jonassaint JC, Graham FL, Ashley-Koch A, Telen MJ. Pulmonary hypertension associated with sickle cell disease: Clinical and laboratory endpoints and disease outcomes. Am J Hematol. 2008;83:19–25.Google Scholar
  96. 96.
    Naik RP, Streiff MB, Haywood C, Nelson JA, Lanzkron S. Venous Thromboembolism in Adults with Sickle Cell Disease: A Serious and Under-recognized Complication. Am J Med. 2013;126:443–9.Google Scholar
  97. 97.
    Leveziel N, Bastuji-Garin S, Lalloum F, Querques G, Benlian P, Binaghi M, et al. Clinical and Laboratory Factors Associated With the Severity of Proliferative Sickle Cell Retinopathy in Patients With Sickle Cell Hemoglobin C (SC) and Homozygous Sickle Cell (SS) Disease. Medicine (Baltimore). 2011;90:372–8.Google Scholar
  98. 98.
    Forrest S, Kim A, Carbonella J, Pashankar F. Proteinuria is associated with elevated tricuspid regurgitant jet velocity in children with sickle cell disease. Pediatr Blood Cancer. 2012;58:937–40.Google Scholar
  99. 99.
    Lorch D, Spevack D, Little J. An Elevated Estimated Pulmonary Arterial Systolic Pressure, Whenever Measured, Is Associated with Excess Mortality in Adults with Sickle Cell Disease. Acta Haematol. 2011;125:225–9.Google Scholar
  100. 100.
    Sachdev V, Kato GJ, Gibbs JSR, Barst RJ, Machado RF, Nouraie M, 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;124:1452–60.Google Scholar
  101. 101.
    Ataga KI, Moore CG, Jones S, Olajide O, Strayhorn D, Hinderliter A, et al. Pulmonary hypertension in patients with sickle cell disease: a longitudinal study. Br J Haematol. 2006;134:109–15.Google Scholar
  102. 102.
    Paul R, Minniti CP, Nouraie M, Luchtman-Jones L, Campbell A, Rana S, et al. Clinical correlates of acute pulmonary events in children and adolescents with sickle cell disease. Eur J Haematol. 2013;91:62–8.Google Scholar
  103. 103.
    Gordeuk VR, Minniti CP, Nouraie M, Campbell AD, Rana SR, Luchtman-Jones L, 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;96:33–40.Google Scholar
  104. 104.
    Dham N, Ensing G, Minniti C, Campbell A, Arteta M, Rana S, et al. Prospective echocardiography assessment of pulmonary hypertension and its potential etiologies in children with sickle cell disease. Am J Cardiol. 2009;104:713–20.Google Scholar
  105. 105.
    Darbari DS, Onyekwere O, Nouraie M, Minniti CP, Luchtman-Jones L, Rana S, et al. Markers of Severe Vaso-Occlusive Painful Episode Frequency in Children and Adolescents with Sickle Cell Anemia. J Pediatr. 2012;160:286–90.Google Scholar
  106. 106.
    Liem RI, Young LT, Lay AS, Pelligra SA, Labotka RJ, Thompson AA. Reproducibility of tricuspid regurgitant jet velocity measurements in children and young adults with sickle cell disease undergoing screening for pulmonary hypertension. Am J Hematol. 2010;85:741–5.Google Scholar
  107. 107.
    • Kato GJ. TRV: a physiological biomarker in sickle cell disease. Pediatr Blood Cancer. 2012;58:831–2. This is a recent article recommending a modified noninvasive echocardiogram screening protocol for children with sickle cell disease with suggested recommendations to consider invasive evaluation based on the tricuspid regurgitant jet velocity. Google Scholar
  108. 108.
    Sachdev V, Machado RF, Shizukuda Y, Rao YN, Sidenko S, Ernst I, et al. Diastolic dysfunction is an independent risk factor for death in patients with sickle cell disease. J Am Coll Cardiol. 2007;49:472–9.Google Scholar
  109. 109.
    Lilje C, Harry J, Gajewski KK, Gardner R V. A modified noninvasive screening protocol for pulmonary hypertension in children with sickle cell disease-Who should be sent for invasive evaluation? Pediatr Blood Cancer. 2017;64:e26606.Google Scholar
  110. 110.
    van der Land V, Peters M, Biemond BJ, Heijboer H, Harteveld CL, Fijnvandraat K. Markers of endothelial dysfunction differ between subphenotypes in children with sickle cell disease. Thromb Res. 2013;132:712–7.Google Scholar
  111. 111.
    El-Shanshory M, Badraia I, Donia A, Abd El-hameed F, Mabrouk M. Asymmetric dimethylarginine levels in children with sickle cell disease and its correlation to tricuspid regurgitant jet velocity. Eur J Haematol. 2013;91:55–61.Google Scholar
  112. 112.
    Elbarbary NS, Ismail EAR, Roushdy A, Fahmy E. Serum apelin as a novel non-invasive marker for subclinical cardiopulmonary complications in children and adolescents with sickle cell disease. Blood Cells, Mol Dis. 2016;57:1–7.Google Scholar
  113. 113.
    Machado RF, Anthi A, Steinberg MH, Bonds D, Sachdev V, Kato GJ, et al. N-Terminal Pro-Brain Natriuretic Peptide Levels and Risk of Death in Sickle Cell Disease. JAMA. 2006;296:310.Google Scholar
  114. 114.
    Voskaridou E, Tsetsos G, Tsoutsias A, Spyropoulou E, Christoulas D, Terpos E. Pulmonary hypertension in patients with sickle cell/beta thalassemia: incidence and correlation with serum N-terminal pro-brain natriuretic peptide concentrations. Haematologica. 2007;92:738–43.Google Scholar
  115. 115.
    Mokhtar GM, Adly AAM, Alfy MS El, Tawfik LM, Khairy AT. N-Terminal Natriuretic Peptide and Ventilation-Perfusion Lung Scan in Sickle Cell Disease and Thalassemia Patients with Pulmonary Hypertension. Hemoglobin. 2010;34:78–94.Google Scholar
  116. 116.
    Tantawy AAG, Adly AAM, Ismail EAR. Soluble CD163 in young sickle cell disease patients and their trait siblings. Blood Coagul Fibrinolysis. 2012;23:640–8.Google Scholar
  117. 117.
    Adly AA, Ismail EA, Andrawes NG, Mahmoud MM, Eladawy R. Soluble Fas/FasL ratio as a marker of vasculopathy in children and adolescents with sickle cell disease. Cytokine. 2016;79:52–8.Google Scholar
  118. 118.
    Saleemi S. Saudi Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Pulmonary hypertension associated with hemolytic anemia. Ann Thorac Med. 2014;9:67.Google Scholar
  119. 119.
    Almeida CB, Souza LEB, Leonardo FC, Costa FTM, Werneck CC, Covas DT, et al. Acute hemolytic vascular inflammatory processes are prevented by nitric oxide replacement or a single dose of hydroxyurea. Blood. 2015;126:711–20.Google Scholar
  120. 120.
    Olnes M, Chi A, Haney C, May R, Minniti C, Taylor J, et al. Improvement in hemolysis and pulmonary arterial systolic pressure in adult patients with sickle cell disease during treatment with hydroxyurea. Am J Hematol [Internet]. NIH Public Access. 2009;84:530–2.Google Scholar
  121. 121.
    Gordeuk VR, Campbell A, Rana S, Nouraie M, Niu X, Minniti CP, et al. Relationship of erythropoietin, fetal hemoglobin, and hydroxyurea treatment to tricuspid regurgitation velocity in children with sickle cell disease. Blood. 2009;114:4639–44.Google Scholar
  122. 122.
    Detterich JA, Kato RM, Rabai M, Meiselman HJ, Coates TD, Wood JC. Chronic transfusion therapy improves but does not normalize systemic and pulmonary vasculopathy in sickle cell disease. Blood. 2015;126:703–10.Google Scholar
  123. 123.
    Covi S, Ravindranath Y, Farooqi A, Savasan S, Chu R, Aggarwal S. Changes in Bi-ventricular Function After Hematopoietic Stem Cell Transplant as Assessed by Speckle Tracking Echocardiography. Pediatr Cardiol. 2018;39:365–74.Google Scholar
  124. 124.
    Dallas MH, Triplett B, Shook DR, Hartford C, Srinivasan A, Laver J, et al. Long-term outcome and evaluation of organ function in pediatric patients undergoing haploidentical and matched related hematopoietic cell transplantation for sickle cell disease. Biol Blood Marrow Transplant. 2013;19:820–30.Google Scholar
  125. 125.
    Quimby KR, Hambleton IR, Landis RC. Intravenous infusion of haptoglobin for the prevention of adverse clinical outcome in Sickle Cell Disease. Med Hypotheses. 2015;85:424–32.Google Scholar
  126. 126.
    Schaer CA, Deuel JW, Schildknecht D, Mahmoudi L, Garcia-Rubio I, Owczarek C, et al. Haptoglobin Preserves Vascular Nitric Oxide Signaling during Hemolysis. Am J Respir Crit Care Med. 2016;193:1111–22.Google Scholar
  127. 127.
    Baek JH, D’Agnillo F, Vallelian F, Pereira CP, Williams MC, Jia Y, et al. Hemoglobin-driven pathophysiology is an in vivo consequence of the red blood cell storage lesion that can be attenuated in guinea pigs by haptoglobin therapy. J Clin Invest. 2012;122:1444–58.Google Scholar
  128. 128.
    Haw A, Palevsky HI. Pulmonary hypertension in chronic hemolytic anemias: Pathophysiology and treatment. Respir Med. 2018;137:191–200.Google Scholar
  129. 129.
    Minniti CP, Machado RF, Coles WA, Sachdev V, Gladwin MT, Kato GJ. Endothelin receptor antagonists for pulmonary hypertension in adult patients with sickle cell disease. Br J Haematol. 2009;147:737–43.Google Scholar
  130. 130.
    Sabaa N, de Franceschi L, Bonnin P, Castier Y, Malpeli G, Debbabi H, et al. Endothelin receptor antagonism prevents hypoxia-induced mortality and morbidity in a mouse model of sickle-cell disease. J Clin Invest. 2008;118:1924–33.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Cardiology, Boston Children’s Hospital; and Department of PediatricsHarvard Medical SchoolBostonUSA
  2. 2.Division of Pediatric Cardiology, Department of Pediatrics, College of Physicians and SurgeonsColumbia University Medical CenterNew YorkUSA

Personalised recommendations