Annals of Hematology

, Volume 95, Issue 11, pp 1757–1764 | Cite as

The global burden of pulmonary hypertension in sickle cell disease: a systematic review and meta-analysis

  • B. M. MusaEmail author
  • N. A. Galadanci
  • M. Coker
  • S. Bussell
  • M. H. Aliyu
Review Article


Elevated tricuspid regurgitant jet velocity (TRJV) is a surrogate measure of pulmonary hypertension (PH) in persons with sickle cell disease (SCD). We sought to estimate the burden of PH in people living with sickle cell disease based on TRJV. From 2000 to 2015, we searched electronic databases for eligible publications and included 29 studies (n = 5358 persons). We used random effects modeling to determine the pooled estimate of elevated TRJV. The overall pooled prevalence of elevated TRJV was 23.5 %(95 % CI 19.5–27.4) in persons with SCD. The pooled prevalence of elevated TRJV in children and adults with SCD was 20.7 % (95 % CI 15.7–-25.6) and 24.4 % (95 % CI 18.4–30.4), respectively. TRJV is prevalent among adults and children with SCD. Our finding support international recommendations that call for screening for PH in SCD patients.


Africa Pulmonary hypertension Tricuspid velocity Sickle cell disease Meta-analysis 



We wish to acknowledge the Vanderbilt Institute for Global Health, for Training on Research Ethics.

Authors’ contributions

Concept and design of study (BMM).

Acquisition of data, (BMM, NAG, CM) analysis and interpretation of data (BMM, SB, AMH).

Revision and intellectual contribution (BMM, NAG, CMSB, AMH).

All authors approved the final version.

Drafting the article or revising it critically for important intellectual (BMM, NAG, CM SB, AMH).

Final approval of the version to be published, (BMM, NAG, CM SB, AMH).

The manuscript has been read and approved by all the authors that the requirements for authorship as stated earlier in this document have been met, and each of us believes that the manuscript represents honest work.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Source(s) of support

This study is not supported by any grant.

Funding sources

Scottie Bussell contributed to this work during his fellowship, which was supported by National Institutes of Health (NIH) Research Training Grant R25 TW009337, funded by Fogarty International Center, the NIH Office of the Director, and the National institute of Mental Health.


  1. 1.
    Aessopos A, Farmakis D, Karagiorga M et al (2001) Cardiac involvement in thalassemia intermedia: a multicenter study. Blood 97:3411–3416CrossRefPubMedGoogle Scholar
  2. 2.
    WHO | Sickle-cell disease and other haemoglobin disorders. In: WHO. Accessed 6 Jan 2016
  3. 3.
    Yater W, Hansmann G (1936) Sickle cell anemia: a new cause of cor pulmonale: report of two cases with numerous disseminated occlusions of the small pulmonary arteries. Am J Med Sci 191:474–484CrossRefGoogle Scholar
  4. 4.
    Gladwin MT (2008) Current and future therapies of sickle cell anemia: an historical perspective. Hematology Am Soc Hematol Educ Program 176. doi:  10.1182/asheducation-2008.1.176
  5. 5.
    Haque AK, Gokhale S, Rampy BA et al (2002) Pulmonary hypertension in sickle cell hemoglobinopathy: a clinicopathologic study of 20 cases. Hum Pathol 33:1037–1043CrossRefPubMedGoogle Scholar
  6. 6.
    Rother RP, Bell L, Hillmen P, Gladwin MT (2005) The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA 293:1653–1662. doi: 10.1001/jama.293.13.1653 CrossRefPubMedGoogle Scholar
  7. 7.
    Reiter CD, Wang X, Tanus-Santos JE et al (2002) Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nat Med 8:1383–1389. doi: 10.1038/nm799 CrossRefPubMedGoogle Scholar
  8. 8.
    Powars D, Weidman JA, Odom-Maryon T et al (1988) Sickle cell chronic lung disease: prior morbidity and the risk of pulmonary failure. Medicine (Baltimore) 67:66–76CrossRefGoogle Scholar
  9. 9.
    Mehari A, Gladwin MT, Tian X et al (2012) Mortality in adults with sickle cell disease and pulmonary hypertension. JAMA 307:1254–1256. doi: 10.1001/jama.2012.358 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Rubin LJ (1997) Primary pulmonary hypertension. N Engl J Med 336:111–117. doi: 10.1056/NEJM199701093360207 CrossRefPubMedGoogle Scholar
  11. 11.
    Simmons BE, Santhanam V, Castaner A et al (1988) Sickle cell heart disease. Two-dimensional echo and Doppler ultrasonographic findings in the hearts of adult patients with sickle cell anemia. Arch Intern Med 148:1526–1528CrossRefPubMedGoogle Scholar
  12. 12.
    Gladwin MT, Sachdev V, Jison ML et al (2004) Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med 350:886–895. doi: 10.1056/NEJMoa035477 CrossRefPubMedGoogle Scholar
  13. 13.
    Ataga KI, Moore CG, Jones S et al (2006) Pulmonary hypertension in patients with sickle cell disease: a longitudinal study. Br J Haematol 134:109–115. doi: 10.1111/j.1365-2141.2006.06110.x CrossRefPubMedGoogle Scholar
  14. 14.
    Castro O, Gladwin MT (2005) Pulmonary hypertension in sickle cell disease: mechanisms, diagnosis, and management. Hematol Oncol Clin North Am 19:881–896. doi: 10.1016/j.hoc.2005.07.007, ViiCrossRefPubMedGoogle Scholar
  15. 15.
    Fonseca GHH, Souza R, Salemi VMC et al (2012) Pulmonary hypertension diagnosed by right heart catheterisation in sickle cell disease. Eur Respir J 39:112–118. doi: 10.1183/09031936.00134410 CrossRefPubMedGoogle Scholar
  16. 16.
    Suell MN, Bezold LI, Okcu MF et al (2005) Increased pulmonary artery pressures among adolescents with sickle cell disease. J Pediatr Hematol Oncol 27:654–658CrossRefPubMedGoogle Scholar
  17. 17.
    Ambrusko SJ, Gunawardena S, Sakara A et al (2006) Elevation of tricuspid regurgitant jet velocity, a marker for pulmonary hypertension in children with sickle cell disease. Pediatr Blood Cancer 47:907–913. doi: 10.1002/pbc.20791 CrossRefPubMedGoogle Scholar
  18. 18.
    Sedrak A, Rao SP, Miller ST et al (2009) A prospective appraisal of pulmonary hypertension in children with sickle cell disease. J Pediatr Hematol Oncol 31:97–100. doi: 10.1097/MPH.0b013e31818e5343 CrossRefPubMedGoogle Scholar
  19. 19.
    Desai AA, Zhou T, Ahmad H et al (2012) A novel molecular signature for elevated tricuspid regurgitation velocity in sickle cell disease. Am J Respir Crit Care Med 186:359–368. doi: 10.1164/rccm.201201-0057OC CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Cabrita IZ, Mohammed A, Layton M et al (2013) The association between tricuspid regurgitation velocity and 5-year survival in a North West London population of patients with sickle cell disease in the United Kingdom. Br J Haematol 162:400–408. doi: 10.1111/bjh.12391 CrossRefPubMedGoogle Scholar
  21. 21.
    Enakpene EO, Adebiyi AA, Ogah OS et al (2014) Non-invasive estimation of pulmonary artery pressures in patients with sickle cell anaemia in Ibadan, Nigeria: an echocardiographic study. Acta Cardiol 69:505–511PubMedGoogle Scholar
  22. 22.
    Soh MC, Sankaran S, Nelson-Piercy C, Oteng-Ntim E (2014) The prevalence of raised tricuspid regurgitation velocity in pregnant women with sickle cell disease and its association with obstetric outcomes-an observational study. Societies of Obstetric Medicine combined 2014 meeting in New Orleans, Louisiana, USA: Obstetric Medicine: The Medicine of Pregnancy 8:28–50. doi: 10.1177/1753495X14566755
  23. 23.
    Pashankar FD, Carbonella J, Bazzy-Asaad A, Friedman A (2008) Prevalence and risk factors of elevated pulmonary artery pressures in children with sickle cell disease. Pediatrics 121:777–782. doi: 10.1542/peds.2007-0730 CrossRefPubMedGoogle Scholar
  24. 24.
    Aliyu ZY, Gordeuk V, Sachdev V et al (2008) Prevalence and risk factors for pulmonary artery systolic hypertension among sickle cell disease patients in Nigeria. Am J Hematol 83:485–490. doi: 10.1002/ajh.21162 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Onyekwere OC, Campbell A, Teshome M et al (2008) Pulmonary hypertension in children and adolescents with sickle cell disease. Pediatr Cardiol 29:309–312. doi: 10.1007/s00246-007-9018-x CrossRefPubMedGoogle Scholar
  26. 26.
    Liem RI, Nevin MA, Prestridge A et al (2009) Tricuspid regurgitant jet velocity elevation and its relationship to lung function in pediatric sickle cell disease. Pediatr Pulmonol 44:281–289. doi: 10.1002/ppul.20996 CrossRefPubMedGoogle Scholar
  27. 27.
    Minniti CP, Sable C, Campbell A et al (2009) Elevated tricuspid regurgitant jet velocity in children and adolescents with sickle cell disease: association with hemolysis and hemoglobin oxygen desaturation. Haematologica 94:340–347. doi: 10.3324/haematol.13812 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Naoman SG, Nouraie M, Castro OL et al (2010) Echocardiographic findings in patients with sickle cell disease. Ann Hematol 89:61–66. doi: 10.1007/s00277-009-0764-0 CrossRefPubMedGoogle Scholar
  29. 29.
    Parent F, Bachir D, Inamo J et al (2011) A hemodynamic study of pulmonary hypertension in sickle cell disease. N Engl J Med 365:44–53. doi: 10.1056/NEJMoa1005565 CrossRefPubMedGoogle Scholar
  30. 30.
    Gordeuk VR, Minniti CP, Nouraie M et al (2011) Elevated tricuspid regurgitation velocity and decline in exercise capacity over 22 months of follow up in children and adolescents with sickle cell anemia. Haematologica 96:33–40. doi: 10.3324/haematol.2010.030767 CrossRefPubMedGoogle Scholar
  31. 31.
    Sachdev V, Kato GJ, Gibbs JSR et al (2011) 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 124:1452–1460. doi: 10.1161/CIRCULATIONAHA.111.032920 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Al-Khoufi EAS (2013) Prevalence of pulmonary arterial hypertension among sickle cell disease patients in Al Hassa. Glob J Health Sci 5:174–180. doi: 10.5539/gjhs.v5n5p174 PubMedPubMedCentralGoogle Scholar
  33. 33.
    Sharma S, Efird J, Kadali R et al (2013) Pulmonary artery occlusion pressure may overdiagnose pulmonary artery hypertension in sickle cell disease. Clin Cardiol 36:524–530. doi: 10.1002/clc.22153 CrossRefPubMedGoogle Scholar
  34. 34.
    Cox SE, Soka D, Kirkham FJ et al (2014) Tricuspid regurgitant jet velocity and hospitalization in Tanzanian children with sickle cell anemia. Haematologica 99:e1–4. doi: 10.3324/haematol.2013.089235 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Gladwin MT, Barst RJ, Gibbs JSR et al (2014) Risk factors for death in 632 patients with sickle cell disease in the United States and United Kingdom. PLoS ONE 9:e99489. doi: 10.1371/journal.pone.0099489 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Marouf R, Behbehani N, Zubaid M et al (2014) Transthoracic echocardiography and 6-minute walk test in Kuwaiti sickle cell disease patients. Med Princ Pract 23:212–217. doi: 10.1159/000362126 CrossRefPubMedGoogle Scholar
  37. 37.
    Upadhya B, Stacey RB, Ntim W et al (2014) Echocardiography-derived tricuspid regurgitant jet velocity is an important marker for the progression of sickle-cell disease. Acta Haematol 132:152–158. doi: 10.1159/000357393 CrossRefPubMedGoogle Scholar
  38. 38.
    Agha H, El Tagui M, El Ghamrawy M, Abdel Hady M (2014) The 6-min walk test: an independent correlate of elevated tricuspid regurgitant jet velocity in children and young adult sickle cell patients. Ann Hematol 93:1131–1138. doi: 10.1007/s00277-014-2030-3 PubMedGoogle Scholar
  39. 39.
    Molavi MA, Rajaei S, Elahi Z, et al (2015) Evaluation of tricuspid regurgitation jet velocity in children with sickle cell disease in Iran 2012-2013. Advances in Bioresearch 6(5);211Google Scholar
  40. 40.
    Mushemi-Blake S, Melikian N, Drasar E, et al (2015) Pulmonary haemodynamics in sickle cell disease are driven predominantly by a high-output state rather than elevated pulmonary vascular resistance: a prospective 3-dimensional echocardiography/doppler study. PLoS One. doi:  10.1371/journal.pone.0135472
  41. 41.
    Hebson C, New T, Record E et al (2015) 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 37:134–139. doi: 10.1097/MPH.0000000000000184 CrossRefPubMedGoogle Scholar
  42. 42.
    Barth RE, Huijgen Q, Taljaard J, Hoepelman AIM (2010) Hepatitis B/C and HIV in sub-Saharan Africa: an association between highly prevalent infectious diseases. A systematic review and meta-analysis. Int J Infect Dis 14:e1024–1031. doi: 10.1016/j.ijid.2010.06.013 CrossRefPubMedGoogle Scholar
  43. 43.
    DerSimonian R, Kacker R (2007) Random-effects model for meta-analysis of clinical trials: an update. Contemp Clin Trials 28:105–114. doi: 10.1016/j.cct.2006.04.004 CrossRefPubMedGoogle Scholar
  44. 44.
    Cohn LD, Becker BJ (2003) How meta-analysis increases statistical power. Psychol Methods 8:243–253. doi: 10.1037/1082-989X.8.3.243 CrossRefPubMedGoogle Scholar
  45. 45.
    Stroup DF, Berlin JA, Morton SC et al (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 283:2008–2012CrossRefPubMedGoogle Scholar
  46. 46.
    Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101CrossRefPubMedGoogle Scholar
  47. 47.
    Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Sutton LL, Castro O, Cross DJ et al (1994) Pulmonary hypertension in sickle cell disease. Am J Cardiol 74:626–628CrossRefPubMedGoogle Scholar
  49. 49.
    Castro O (1996) Systemic fat embolism and pulmonary hypertension in sickle cell disease. Hematol Oncol Clin North Am 10:1289–1303CrossRefPubMedGoogle Scholar
  50. 50.
    Hagar RW, Michlitsch JG, Gardner J et al (2008) Clinical differences between children and adults with pulmonary hypertension and sickle cell disease. Br J Haematol 140:104–112. doi: 10.1111/j.1365-2141.2007.06822.x PubMedGoogle Scholar
  51. 51.
    Rhodes CJ, Wharton J, Wilkins MR (2013) Pulmonary hypertension: biomarkers. Handb Exp Pharmacol 218:77–103. doi: 10.1007/978-3-642-38664-0_4 CrossRefPubMedGoogle Scholar
  52. 52.
    Janda S, Shahidi N, Gin K, Swiston J (2011) Diagnostic accuracy of echocardiography for pulmonary hypertension: a systematic review and meta-analysis. Heart 97:612–622. doi: 10.1136/hrt.2010.212084 CrossRefPubMedGoogle Scholar
  53. 53.
    Klings ES, Machado RF, Barst RJ et al (2014) 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 189:727–740. doi: 10.1164/rccm.201401-0065ST CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Machado RF, Barst RJ, Yovetich NA et al (2011) Hospitalization for pain in patients with sickle cell disease treated with sildenafil for elevated TRV and low exercise capacity. Blood 118:855–864. doi: 10.1182/blood-2010-09-306167 CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Bunn HF, Nathan DG, Dover GJ et al (2010) Pulmonary hypertension and nitric oxide depletion in sickle cell disease. Blood 116:687–692. doi: 10.1182/blood-2010-02-268193 CrossRefPubMedGoogle Scholar
  56. 56.
    Machado R, Barst R, Yovetich N, et al (2009) Safety and efficacy of sildenafil therapy for Doppler-defined pulmonary hypertension in patients with sickle cell disease: preliminary results of the Walk- PHaSST clinical trial. American Society of Hematology. In: Top 10 clinically oriented abstracts in sickle cell disease. American Journal of Hematology, n New Orleans, Louisiana, USA, pp 204–205Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • B. M. Musa
    • 1
    Email author
  • N. A. Galadanci
    • 2
  • M. Coker
    • 3
  • S. Bussell
    • 4
    • 5
  • M. H. Aliyu
    • 4
    • 5
    • 6
  1. 1.Department of MedicineBayero University/Aminu Kano Teaching HospitalKanoNigeria
  2. 2.Department of HematologyBayero University/Aminu Kano Teaching HospitalKanoNigeria
  3. 3.Institute of Human VirologyUniversity of MarylandBaltimoreUSA
  4. 4.Vanderbilt Institute for Global HealthVanderbilt University School of MedicineNashvilleUSA
  5. 5.Department of Preventive MedicineVanderbilt University School of MedicineNashvilleUSA
  6. 6.Departments of Family and Community MedicineMeharry Medical CollegeNashvilleUSA

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