Annals of Hematology

, Volume 95, Issue 6, pp 993–1000 | Cite as

East Mediterranean region sickle cell disease mortality trial: retrospective multicenter cohort analysis of 735 patients

  • Pelin Kardaş Karacaoglu
  • Suheyl Asma
  • Aslı Korur
  • Soner Solmaz
  • Nurhilal Turgut Buyukkurt
  • Cigdem Gereklioglu
  • Mutlu Kasar
  • Demircan Ozbalcı
  • Selma Unal
  • Hasan Kaya
  • Emel Gurkan
  • Mahmut Yeral
  • Çagla Sariturk
  • Can Boga
  • Hakan Ozdogu
Original Article


Sickle cell disease (SCD), one of the most common genetic disorders worldwide, is characterized by hemolytic anemia and tissue damage from the rigid red blood cells. Although hydroxyurea and transfusion therapy are administered to treat the accompanying tissue injury, whether either one prolongs the lifespan of patients with SCD is unknown. SCD-related mortality data are available, but there are few studies on mortality-related factors based on evaluations of surviving patients. In addition, ethnic variability in patient registries has complicated detailed analyses. The aim of this study was to investigate mortality and mortality-related factors among an ethnically homogeneous population of patients with SCD. The 735 patients (102 children and 633 adults) included in this retrospective cohort study were of Eti-Turk origin and selected from 1367 patients seen at 5 regional hospitals. A central population management system was used to control for records of patient mortality. Data reliability was checked by a data supervision group. Mortality-related factors and predictors were identified in univariate and multivariate analyses using a Cox regression model with stepwise forward selection. The study group included patients with homozygous hemoglobin S (Hgb S) disease (67 %), Hb S-β0 thalassemia (17 %), Hgb S-β+ thalassemia (15 %), and Hb S-α thalassemia (1 %). They were followed for a median of 66 ± 44 (3–148) months. Overall mortality at 5 years was 6.1 %. Of the 45 patients who died, 44 (6 %) were adults and 1 (0.1 %) was a child. The mean age at death was 34.1 ± 10 (18–54) years for males, 40.1 ± 15 (17–64) years for females, and 36.6 ± 13 (17–64) years overall. Hydroxyurea was found to have a notable positive effect on mortality (p = 0.009). Mortality was also significantly related to hypertension and renal damage in a univariate analysis (p = 0.015 and p = 0.000, respectively). Acute chest syndrome, splenic sequestration, and prolonged painful-crisis-related multiorgan failure were the most common causes of mortality. In a multivariate analysis of laboratory values, only an elevated white blood cell count was related to mortality (p = 0.009). These data show that despite recent progress in the treatment of SCD, disease-related factors continue to result in mortality in young adult patients. Our results highlight the importance of evaluating curative treatment options for patients who have an appropriate stem cell donor in addition to improving patient care and patient education.


Sickle cell disease Mortality Painful crisis Acute chest syndrome Hemoglobinopathy 


Compliance with ethical standard

This study was approved by the Institutional Medical and Health Sciences Experimental/Clinical Research Principles and Research Committee (project number: KA15/07). The required approvals for the collaborations in the study were obtained from the concerned departments and hospitals.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Piel FB, Patil AP, Howes RE, Nyangiri OA, Gething PW, Dewi DW et al (2013) Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates. Lancet 381(9861):142–151CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Canatan D, Kose MR, Ustundag M, Haznedaroglu D, Ozbas S (2006) Hemoglobinopathy control program in Turkey. Community Genet 9:124–126CrossRefPubMedGoogle Scholar
  3. 3.
    Archer N, Galacteros F, Brugnara C (2015) Clinical trials update in sickle cell anemia. Am J Hematol. doi: 10.1002/ajh.24116 PubMedGoogle Scholar
  4. 4.
    Kutlar A (2007) Sickle cell disease: a multigenic perspective of a single gene disorder. Hemoglobin 31(2):209–224CrossRefPubMedGoogle Scholar
  5. 5.
    Chaturvedi S, DeBaun MR (2015) Evolution of sickle cell disease from a life threatening disease of children to a chronic disease of adults: the last 40 years. Am J Hematol doi. doi: 10.1002/ajh.24235 Google Scholar
  6. 6.
    Bhatia M, Sheth S (2015) Hematopoietic stem cell transplantation in sickle cell disease: patient selection and special considerations. Journal of Blood Medicine 6:229–238PubMedPubMedCentralGoogle Scholar
  7. 7.
    Sheth S, Licursi M, Bhatia M (2013) Sickle cell disease: time for a closer look at treatment options? Br J Haematol 162(4):455–464CrossRefPubMedGoogle Scholar
  8. 8.
    Lanzkron S, Carroll P, Haywood C Jr (2013) Mortality rates and age at death from sickle cell disease: U.S. 1979–2005. Public Health Rep 128:110–116PubMedPubMedCentralGoogle Scholar
  9. 9.
    Anthony AT, Catherıne P, Graham S (1982) Causes of death in sickle-cell disease in Jamaica. Brıtısh Medıcal Journal 285:633–635Google Scholar
  10. 10.
    Steinberg MH, McCarthy WF, Castro O et al (2010) The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: a 17.5 year follow-up. Am J Hematol 85:403–408PubMedPubMedCentralGoogle Scholar
  11. 11.
    Ozdogu H, Sozer O, Boga C, Kozanoglu L, Maytalman E, Guzey M (2007) Flow cytometric evaluation of circulating endothelial cells: a new protocol for identifying endothelial cells at several stages of differentiation. Am J Hematol 82(8):706–711CrossRefPubMedGoogle Scholar
  12. 12.
    Beutler E (2006) Disorders of hemoglobin structure: sickle cell anemia and related abnormalities. Williams Hematology (Lichtman MA, Beutler E, Kıpps TJ, Seligsohn U, Ed.), Seventhth edn. Mcgraw Hill, New York, pp 667–700Google Scholar
  13. 13.
    Mary EE (2000) Hereditary hemolytic anemias. Emergency Medicine, A comprehensive Study Guide (Tintinally JE, Kelen GD, Stapczynski JS Ed), Fifthth edn. Mc Graw Hill Co. Inc, North Carolina, pp 1382–1387Google Scholar
  14. 14.
    Indications of stem cell transplantation in sickle cell disease, Social Security Institution of Turkey 2015 (Tur),ı_DUYURU
  15. 15.
    Denbow CE, Chung EE, Serjeant GR (1993) Pulmonary artery pressure and the acute chest syndrome in homozygous sickle cell disease. Br Heart J 69:536–538CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Platt OS, Brambilla DJ, Rosse WF (1994) Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 330:1639–1644CrossRefPubMedGoogle Scholar
  17. 17.
    Galarneau G, Coady S, Garrett ME, Jeffries N, Puggal M, Paltoo D et al (2013) Gene-centric association study of acute chest syndrome and painful crisis in sickle cell disease patients. Blood 122(3):434–442CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Hassell KL (2010) Population estimates of sickle cell disease in the U.S. Am J Prev Med 38(4 Suppl):S512–521CrossRefPubMedGoogle Scholar
  19. 19.
    Elmariah H, Garrett ME, De Castro LM et al (2014) Factors associated with survival in a contemporary adult sickle cell disease cohort. Am J Hematol 89:530–535CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Wierenga KH, Hambleton IR, Lewis NA (2001) Survival estimates for patients with homozygous sickle-cell disease in Jamaica: a clinic-based population study. Lancet 357(9257):680–683CrossRefPubMedGoogle Scholar
  21. 21.
    Dover G, Platt O (2003) Sickle cell disease. In: Nathan D, Orkin SH, Ginsburg D, Look AT (eds) Hematology of Infancy and Childhood, sixthth edn. WB Saunders Company, Philadelphia, pp 790–841Google Scholar
  22. 22.
    Sandhu MK, Cohen A (2015) Aging in sickle cell disease: co-morbidities and ew issues in management. Hemoglobin 39(4):221–224CrossRefPubMedGoogle Scholar
  23. 23.
    Hyacinth HI, Gee BE, Hibbert JM (2010) The role of nutrition in sickle cell disease. Nutr Metab Insights 3:57–67CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Kawchak DA, Schall JI, Zemel BS, Ohene-Frempong K, Stallings VA (2007) Adequacy of dietary intake declines with age in children with sickle cell disease. J Am Diet Assoc 107:843–848CrossRefPubMedGoogle Scholar
  25. 25.
    Kozanoglu I, Boga C, Ozdogu H, Sezgin N, Kizilkilic E, Kural M (2007) Automated red cell exchange procedures in patients with sickle cell disease. Transfus Apher Sci 36:305–312CrossRefPubMedGoogle Scholar
  26. 26.
    Platt OS, Thorington BD, Brambilla DJ, Milner PF, Rosse WF, Vichinsky E, Kinney TR et al (1991) Pain in sickle cell disease. Rates and risk factors. N Engl J Med 325(1):11–16CrossRefPubMedGoogle Scholar
  27. 27.
    Charache S, Terrin ML, Moore RD, Dover GJ, McMahon RP, Barton FB et al (1995) Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med 332:1317–1322CrossRefPubMedGoogle Scholar
  28. 28.
    McLaughlin JF, Ballas SK (2015) High mortality among children with sickle cell anemia and overt stroke who discontinue blood transfusion after transition to an adult program. Transfusion. doi: 10.1111/trf.13418 PubMedGoogle Scholar
  29. 29.
    Ware RE (2015) Optimizing hydroxyurea therapy for sickle cell anemia. Hematology Am Soc Hematol Educ Program 2015(1):436–443PubMedGoogle Scholar
  30. 30.
    Hulbert ML, Scothorn DJ, Panepinto JA, Scott JP, Buchanan GR, Sarnaik S (2006) Exchange blood transfusion compared with simple transfusion for first overt stroke is associated with a lower risk of subsequent stroke: a retrospective cohort study of 137 children with sickle cell anemia. J Pediatr 149:710CrossRefPubMedGoogle Scholar
  31. 31.
    Galloway-Blake K, Ried M, Walters C, Jaggon J, Lee MG (2014) Clinical factors associated with morbidity and mortality in patients admitted with sickle cell disease. West Indian Med J 63(7):711–716PubMedPubMedCentralGoogle Scholar
  32. 32.
    Asma S, Kozanoglu I, Tarım E, Sariturk C, Gereklioglu C, Akdeniz A et al (2015) Prophylactic red blood cell exchange may be beneficial in the management of sickle cell disease in pregnancy. Transfusion 55(1):36–44CrossRefPubMedGoogle Scholar
  33. 33.
    Oteng-Ntim E, Meeks D, Seed PT, Webster L, Howard J, Doyle P et al (2015) Adverse maternal and perinatal outcomes in pregnant women with sickle cell disease: systematic review and meta-analysis. Blood 125(21):3316–3325CrossRefPubMedGoogle Scholar
  34. 34.
    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
  35. 35.
    Kato GJ, Onyekwere OC, Gladwin MT (2007) Pulmonary hypertension in sickle cell disease: relevance to children. Pediatr Hematol Oncol 24:159–170CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Mundel P, Reiser J (2010) Proteinuria: an enzymatic disease of the podocyte? Kidney Int 77:571–580CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Castro O, Brambilla DJ, Thorington B, Reindorf CA, Scott RB, Gilette P, Vera JC, Levy PS et al (1994) The acute chest syndrome in sickle cell disease: incidence and risk factors. The Cooperative Study of Sickle Cell Disease. Blood 15:643–649Google Scholar
  38. 38.
    Sebastiani P, Nolan VG, Baldvin CT (2007) A network model to predict the risk of death in sickle cell disease. Blood 110:2727CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Darbari DS, Kple-Faget P, Kwagyan J, Rana S, Gordeuk VR, Castro O (2006) Circumstances of death in adult sickle cell disease patients. Am J Hematol 81:858–863CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Pelin Kardaş Karacaoglu
    • 1
  • Suheyl Asma
    • 2
  • Aslı Korur
    • 2
  • Soner Solmaz
    • 3
  • Nurhilal Turgut Buyukkurt
    • 3
  • Cigdem Gereklioglu
    • 2
  • Mutlu Kasar
    • 3
  • Demircan Ozbalcı
    • 4
  • Selma Unal
    • 5
  • Hasan Kaya
    • 6
  • Emel Gurkan
    • 7
  • Mahmut Yeral
    • 3
  • Çagla Sariturk
    • 8
  • Can Boga
    • 3
  • Hakan Ozdogu
    • 3
  1. 1.Department of Internal MedicineBaskent University Faculty of MedicineAnkaraTurkey
  2. 2.Department of Internal Medicine, Family Medicine DivisionBaskent University Faculty of MedicineAnkaraTurkey
  3. 3.Department of Internal Medicine, Hematology DivisionBaskent University Faculty of MedicineAnkaraTurkey
  4. 4.Mersin State Hospital, Hematology DivisionMersinTurkey
  5. 5.Department of Internal Medicine, Pediatric Hematology DivisionMersin University Faculty of MedicineMersinTurkey
  6. 6.Department of Internal Medicine, Hematology DivisionMustafa Kemal University Faculty of MedicineAntakyaTurkey
  7. 7.Department of Internal Medicine, Hematology DivisionCukurova University Faculty of MedicineAdanaTurkey
  8. 8.Medical statisticsBaskent University Faculty of MedicineAdanaTurkey

Personalised recommendations