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Overview of the clinical manifestations of sickle cell disease

Elliott P Vichinsky, MD
Section Editor
Stanley L Schrier, MD
Deputy Editor
Jennifer S Tirnauer, MD


Vasoocclusive phenomena and hemolysis are the clinical hallmarks of sickle cell disease (SCD), an inherited disorder due to homozygosity for the abnormal hemoglobin, hemoglobin S (HbS). Vasoocclusion results in recurrent painful episodes (previously called sickle cell crisis) and a variety of serious organ system complications that can lead to life-long disabilities and/or early death.

Hemoglobin S (HbS), results from the substitution of a valine for glutamic acid as the sixth amino acid of the beta globin chain, which produces a hemoglobin tetramer (alpha2/beta S2) that is poorly soluble when deoxygenated [1]. The polymerization of deoxy HbS is essential to vasoocclusive phenomena [1]. The polymer assumes the form of an elongated rope-like fiber, which usually aligns with other fibers, resulting in distortion into the classic crescent or sickle shape (diagnostic image 1) and a marked decrease in red cell deformability. (See "Sickle hemoglobin polymer: Structure and functional properties".)

This polymerization process is altered by several factors. Fetal hemoglobin (HbF) is a major modulator of polymerization in that the higher the HbF levels, the more benign the clinical and hematologic features of sickle cell anemia [2]. However, polymerization alone does not account for the pathophysiology of SCD. Subsequent changes in red cell membrane structure and function, disordered cell volume control, and increased adherence to vascular endothelium also play an important role [1,3].

An overview of the clinical manifestations of homozygous SCD will be presented here, with more complete discussions of the major clinical manifestations presented separately (eg, pulmonary, renal, bone and joint, cerebrovascular disease) [4]. The diagnosis and treatment of SCD and the management of pregnancy in SCD are also discussed separately. (See "Diagnosis of sickle cell disorders" and "Overview of the management and prognosis of sickle cell disease" and "Hydroxyurea and other disease-modifying therapies in sickle cell disease" and "Pregnancy in women with sickle cell disease".)


The clinical manifestations of sickle cell disease vary markedly among the major genotypes. The following general principles apply to the major sickle cell subtypes. However, within each subtype, there can be a marked variability in disease severity. (See "Overview of variant sickle cell syndromes".)


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  1. Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med 1997; 337:762.
  2. Akinsheye I, Alsultan A, Solovieff N, et al. Fetal hemoglobin in sickle cell anemia. Blood 2011; 118:19.
  3. Kaul DK, Fabry ME, Costantini F, et al. In vivo demonstration of red cell-endothelial interaction, sickling and altered microvascular response to oxygen in the sickle transgenic mouse. J Clin Invest 1995; 96:2845.
  4. Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet 2010; 376:2018.
  5. Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood 1998; 91:288.
  6. Platt OS, Thorington BD, Brambilla DJ, et al. Pain in sickle cell disease. Rates and risk factors. N Engl J Med 1991; 325:11.
  7. Bainbridge R, Higgs DR, Maude GH, Serjeant GR. Clinical presentation of homozygous sickle cell disease. J Pediatr 1985; 106:881.
  8. Brozović M, Anionwu E. Sickle cell disease in Britain. J Clin Pathol 1984; 37:1321.
  9. Brozović M, Davies SC, Brownell AI. Acute admissions of patients with sickle cell disease who live in Britain. Br Med J (Clin Res Ed) 1987; 294:1206.
  10. Dampier C, Setty BN, Eggleston B, et al. Vaso-occlusion in children with sickle cell disease: clinical characteristics and biologic correlates. J Pediatr Hematol Oncol 2004; 26:785.
  11. Smith WR, Penberthy LT, Bovbjerg VE, et al. Daily assessment of pain in adults with sickle cell disease. Ann Intern Med 2008; 148:94.
  12. Alexander N, Higgs D, Dover G, Serjeant GR. Are there clinical phenotypes of homozygous sickle cell disease? Br J Haematol 2004; 126:606.
  13. Powars DR. Natural history of sickle cell disease--the first ten years. Semin Hematol 1975; 12:267.
  14. Houston-Yu P, Rana SR, Beyer B, Castro O. Frequent and prolonged hospitalizations: a risk factor for early mortality in sickle cell disease patients. Am J Hematol 2003; 72:201.
  15. Baum KF, Dunn DT, Maude GH, Serjeant GR. The painful crisis of homozygous sickle cell disease. A study of the risk factors. Arch Intern Med 1987; 147:1231.
  16. Jones S, Duncan ER, Thomas N, et al. Windy weather and low humidity are associated with an increased number of hospital admissions for acute pain and sickle cell disease in an urban environment with a maritime temperate climate. Br J Haematol 2005; 131:530.
  17. Yallop D, Duncan ER, Norris E, et al. The associations between air quality and the number of hospital admissions for acute pain and sickle-cell disease in an urban environment. Br J Haematol 2007; 136:844.
  18. Nolan VG, Zhang Y, Lash T, et al. Association between wind speed and the occurrence of sickle cell acute painful episodes: results of a case-crossover study. Br J Haematol 2008; 143:433.
  19. Hargrave DR, Wade A, Evans JP, et al. Nocturnal oxygen saturation and painful sickle cell crises in children. Blood 2003; 101:846.
  20. Setty BN, Stuart MJ, Dampier C, et al. Hypoxaemia in sickle cell disease: biomarker modulation and relevance to pathophysiology. Lancet 2003; 362:1450.
  21. Sidman JD, Fry TL. Exacerbation of sickle cell disease by obstructive sleep apnea. Arch Otolaryngol Head Neck Surg 1988; 114:916.
  22. Jacob E, Beyer JE, Miaskowski C, et al. Are there phases to the vaso-occlusive painful episode in sickle cell disease? J Pain Symptom Manage 2005; 29:392.
  23. Darbari DS, Neely M, van den Anker J, Rana S. Increased clearance of morphine in sickle cell disease: implications for pain management. J Pain 2011; 12:531.
  24. Ballas SK, Larner J, Smith ED, et al. Rheologic predictors of the severity of the painful sickle cell crisis. Blood 1988; 72:1216.
  25. Ballas SK, Smith ED. Red blood cell changes during the evolution of the sickle cell painful crisis. Blood 1992; 79:2154.
  26. Akinola NO, Stevens SM, Franklin IM, et al. Rheological changes in the prodromal and established phases of sickle cell vaso-occlusive crisis. Br J Haematol 1992; 81:598.
  27. Akinola NO, Stevens SM, Franklin IM, et al. Subclinical ischaemic episodes during the steady state of sickle cell anaemia. J Clin Pathol 1992; 45:902.
  28. Neely CL, Wajima T, Kraus AP, et al. Lactic acid dehydrogenase activity and plasma hemoglobin elevations in sickle cell disease. Am J Clin Pathol 1969; 52:167.
  29. Richardson SG, Matthews KB, Stuart J, et al. Serial changes in coagulation and viscosity during sickle-cell crisis. Br J Haematol 1979; 41:95.
  30. Vichinsky EP, Neumayr LD, Gold JI, et al. Neuropsychological dysfunction and neuroimaging abnormalities in neurologically intact adults with sickle cell anemia. JAMA 2010; 303:1823.
  31. Ware RE, Helms RW. Stroke with transfusions changing to hydroxyurea (SWiTCH): a phase 3 randomized clinical trial for treatment of children with sickle cell anemia, previous stroke, and iron overload. Blood (ASH Annual Meeting Abstracts) 2010; 116:844.
  32. Ruggeri A, Eapen M, Scaravadou A, et al. Umbilical cord blood transplantation for children with thalassemia and sickle cell disease. Biol Blood Marrow Transplant 2011; 17:1375.
  33. Ali SB, Reid M, Fraser R, et al. Seizures in the Jamaica cohort study of sickle cell disease. Br J Haematol 2010; 151:265.
  34. Hassell KL, Eckman JR, Lane PA. Acute multiorgan failure syndrome: a potentially catastrophic complication of severe sickle cell pain episodes. Am J Med 1994; 96:155.
  35. Green M, Hall RJ, Huntsman RG, et al. Sickle cell crisis treated by exchange transfusion. Treatment of two patients with heterozygous sickle cell syndrome. JAMA 1975; 231:948.
  36. Kumar S, Powars D, Allen J, Haywood LJ. Anxiety, self-concept, and personal and social adjustments in children with sickle cell anemia. J Pediatr 1976; 88:859.
  37. Conyard S, Krishnamurthy M, Dosik H. Psychosocial aspects of sickle-cell anemia in adolescents. Health Soc Work 1980; 5:20.
  38. Barrett DH, Wisotzek IE, Abel GG, et al. Assessment of psychosocial functioning of patients with sickle cell disease. South Med J 1988; 81:745.
  39. Anie KA. Psychological complications in sickle cell disease. Br J Haematol 2005; 129:723.
  40. Panepinto JA, O'Mahar KM, DeBaun MR, et al. Health-related quality of life in children with sickle cell disease: child and parent perception. Br J Haematol 2005; 130:437.
  41. Dampier C, LeBeau P, Rhee S, et al. Health-related quality of life in adults with sickle cell disease (SCD): a report from the comprehensive sickle cell centers clinical trial consortium. Am J Hematol 2011; 86:203.
  42. Gil KM, Abrams MR, Phillips G, Williams DA. Sickle cell disease pain: 2. Predicting health care use and activity level at 9-month follow-up. J Consult Clin Psychol 1992; 60:267.
  43. Thompson RJ Jr, Gil KM, Abrams MR, Phillips G. Stress, coping, and psychological adjustment of adults with sickle cell disease. J Consult Clin Psychol 1992; 60:433.
  44. Dilworth-Anderson P. The importance of grandparents in extended-kin caregiving to black children with sickle cell disease. J Health Soc Policy 1994; 5:185.
  45. Brandow AM, Brousseau DC, Panepinto JA. Postdischarge pain, functional limitations and impact on caregivers of children with sickle cell disease treated for painful events. Br J Haematol 2009; 144:782.
  46. Platt OS, Rosenstock W, Espeland MA. Influence of sickle hemoglobinopathies on growth and development. N Engl J Med 1984; 311:7.
  47. Hogan AM, Kirkham FJ, Prengler M, et al. An exploratory study of physiological correlates of neurodevelopmental delay in infants with sickle cell anaemia. Br J Haematol 2006; 132:99.
  48. Stevens MC, Maude GH, Cupidore L, et al. Prepubertal growth and skeletal maturation in children with sickle cell disease. Pediatrics 1986; 78:124.
  49. Olambiwonnu NO, Penny R, Frasier SD. Sexual maturation in subjects with sickle cell anemia: studies of serum gonadotropin concentration, height, weight, and skeletal age. J Pediatr 1975; 87:459.
  50. Alleyne SI, Rauseo RD, Serjeant GR. Sexual development and fertility of Jamaican female patients with homozygous sickle cell disease. Arch Intern Med 1981; 141:1295.
  51. Singhal A, Gabay L, Serjeant GR. Testosterone deficiency and extreme retardation of puberty in homozygous sickle-cell disease. West Indian Med J 1995; 44:20.
  52. Abbasi AA, Prasad AS, Ortega J, et al. Gonadal function abnormalities in sickle cell anemia. Studies in adult male patients. Ann Intern Med 1976; 85:601.
  53. Dada OA, Nduka EU. Endocrine function and haemoglobinopathies: relation between the sickle cell gene and circulating plasma levels of testosterone, luteinising hormone (LH) and follicle stimulating hormone (FSH) in adult males. Clin Chim Acta 1980; 105:269.
  54. Landefeld CS, Schambelan M, Kaplan SL, Embury SH. Clomiphene-responsive hypogonadism in sickle cell anemia. Ann Intern Med 1983; 99:480.
  55. Rogers ZR, Wang WC, Luo Z, et al. Biomarkers of splenic function in infants with sickle cell anemia: baseline data from the BABY HUG Trial. Blood 2011; 117:2614.
  56. Bjornson AB, Lobel JS. Direct evidence that decreased serum opsonization of Streptococcus pneumoniae via the alternative complement pathway in sickle cell disease is related to antibody deficiency. J Clin Invest 1987; 79:388.
  57. Overturf GD. Infections and immunizations of children with sickle cell disease. Adv Pediatr Infect Dis 1999; 14:191.
  58. Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group. N Engl J Med 2000; 342:1855.
  59. Jacobs JE, Quirolo K, Vichinsky E. Novel influenza A (H1N1) viral infection in pediatric patients with sickle-cell disease. Pediatr Blood Cancer 2011; 56:95.
  60. Strouse JJ, Reller ME, Bundy DG, et al. Severe pandemic H1N1 and seasonal influenza in children and young adults with sickle cell disease. Blood 2010; 116:3431.
  61. McAuley CF, Webb C, Makani J, et al. High mortality from Plasmodium falciparum malaria in children living with sickle cell anemia on the coast of Kenya. Blood 2010; 116:1663.
  62. Wong WY, Powars DR, Chan L, et al. Polysaccharide encapsulated bacterial infection in sickle cell anemia: a thirty year epidemiologic experience. Am J Hematol 1992; 39:176.
  63. Overturf GD, Powars D, Baraff LJ. Bacterial meningitis and septicemia in sickle cell disease. Am J Dis Child 1977; 131:784.
  64. Williams TN, Uyoga S, Macharia A, et al. Bacteraemia in Kenyan children with sickle-cell anaemia: a retrospective cohort and case-control study. Lancet 2009; 374:1364.
  65. Hankins J, Ware RE. Sickle-cell disease: an ounce of prevention, a pound of cure. Lancet 2009; 374:1308.
  66. Halasa NB, Shankar SM, Talbot TR, et al. Incidence of invasive pneumococcal disease among individuals with sickle cell disease before and after the introduction of the pneumococcal conjugate vaccine. Clin Infect Dis 2007; 44:1428.
  67. Greene JR, Polk OD, Castro O. Fulminant pneumococcal sepsis in an adult with sickle-cell anemia. N Engl J Med 1984; 311:674.
  68. Olopoenia L, Frederick W, Greaves W, et al. Pneumococcal sepsis and meningitis in adults with sickle cell disease. South Med J 1990; 83:1002.
  69. Zarrouk V, Habibi A, Zahar JR, et al. Bloodstream infection in adults with sickle cell disease: association with venous catheters, Staphylococcus aureus, and bone-joint infections. Medicine (Baltimore) 2006; 85:43.
  70. Vichinsky EP, Styles LA, Colangelo LH, et al. Acute chest syndrome in sickle cell disease: clinical presentation and course. Cooperative Study of Sickle Cell Disease. Blood 1997; 89:1787.
  71. McCavit TL, Quinn CT, Techasaensiri C, Rogers ZR. Increase in invasive Streptococcus pneumoniae infections in children with sickle cell disease since pneumococcal conjugate vaccine licensure. J Pediatr 2011; 158:505.
  72. Cundell DR, Gerard NP, Gerard C, et al. Streptococcus pneumoniae anchor to activated human cells by the receptor for platelet-activating factor. Nature 1995; 377:435.
  73. Miller ML, Gao G, Pestina T, et al. Hypersusceptibility to invasive pneumococcal infection in experimental sickle cell disease involves platelet-activating factor receptor. J Infect Dis 2007; 195:581.
  74. Vichinsky E, Hurst D, Earles A, et al. Newborn screening for sickle cell disease: effect on mortality. Pediatrics 1988; 81:749.
  75. Ward J, Smith AL. Hemophilus influenzae bacteremia in children with sickle cell disease. J Pediatr 1976; 88:261.
  76. Powars D, Overturf G, Turner E. Is there an increased risk of Haemophilus influenzae septicemia in children with sickle cell anemia? Pediatrics 1983; 71:927.
  77. Barrett-Connor E. Bacterial infection and sickle cell anemia. An analysis of 250 infections in 166 patients and a review of the literature. Medicine (Baltimore) 1971; 50:97.
  78. Robinson MG, Watson RJ. Pneumococcal meningitis in sickle-cell anemia. N Engl J Med 1966; 274:1006.
  79. Poncz M, Kane E, Gill FM. Acute chest syndrome in sickle cell disease: etiology and clinical correlates. J Pediatr 1985; 107:861.
  80. Moser FG, Miller ST, Bello JA, et al. The spectrum of brain MR abnormalities in sickle-cell disease: a report from the Cooperative Study of Sickle Cell Disease. AJNR Am J Neuroradiol 1996; 17:965.
  81. Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998; 339:5.
  82. Lal A, Fung EB, Pakbaz Z, et al. Bone mineral density in children with sickle cell anemia. Pediatr Blood Cancer 2006; 47:901.
  83. Fitzhugh CD, Lauder N, Jonassaint JC, et al. Cardiopulmonary complications leading to premature deaths in adult patients with sickle cell disease. Am J Hematol 2010; 85:36.
  84. Gladwin MT, Sachdev V. Cardiovascular abnormalities in sickle cell disease. J Am Coll Cardiol 2012; 59:1123.
  85. Voskaridou E, Christoulas D, Terpos E. Sickle-cell disease and the heart: review of the current literature. Br J Haematol 2012; 157:664.
  86. Covitz W, Espeland M, Gallagher D, et al. The heart in sickle cell anemia. The Cooperative Study of Sickle Cell Disease (CSSCD). Chest 1995; 108:1214.
  87. Varat MA, Adolph RJ, Fowler NO. Cardiovascular effects of anemia. Am Heart J 1972; 83:415.
  88. Gerry JL, Bulkley BH, Hutchins GM. Clinicopathologic analysis of cardiac dysfunction in 52 patients with sickle cell anemia. Am J Cardiol 1978; 42:211.
  89. Zilberman MV, Du W, Das S, Sarnaik SA. Evaluation of left ventricular diastolic function in pediatric sickle cell disease patients. Am J Hematol 2007; 82:433.
  90. Johnson MC, Kirkham FJ, Redline S, et al. Left ventricular hypertrophy and diastolic dysfunction in children with sickle cell disease are related to asleep and waking oxygen desaturation. Blood 2010; 116:16.
  91. Eddine AC, Alvarez O, Lipshultz SE, et al. Ventricular structure and function in children with sickle cell disease using conventional and tissue Doppler echocardiography. Am J Cardiol 2012; 109:1358.
  92. Ng ML, Liebman J, Anslovar J, Gross S. Cardiovascular findings in children with sickle cell anemia. Dis Chest 1967; 52:788.
  93. Mueller BU, Martin KJ, Dreyer W, et al. Prolonged QT interval in pediatric sickle cell disease. Pediatr Blood Cancer 2006; 47:831.
  94. Liem RI, Young LT, Thompson AA. Prolonged QTc interval in children and young adults with sickle cell disease at steady state. Pediatr Blood Cancer 2009; 52:842.
  95. Klings ES, Wyszynski DF, Nolan VG, Steinberg MH. Abnormal pulmonary function in adults with sickle cell anemia. Am J Respir Crit Care Med 2006; 173:1264.
  96. Westwood MA, Shah F, Anderson LJ, et al. Myocardial tissue characterization and the role of chronic anemia in sickle cell cardiomyopathy. J Magn Reson Imaging 2007; 26:564.
  97. Aessopos A, Farmakis D, Trompoukis C, et al. Cardiac involvement in sickle beta-thalassemia. Ann Hematol 2009; 88:557.
  98. Balfour IC, Covitz W, Arensman FW, et al. Left ventricular filling in sickle cell anemia. Am J Cardiol 1988; 61:395.
  99. Karayalcin G, Rosner F, Kim KY, et al. Sickle cell anemia- clinical manifestations in 100 patients and review of the literature. Am J Med Sci 1975; 269:51.
  100. Val-Mejias J, Lee WK, Weisse AB, Regan TJ. Left ventricular performance during and after sickle cell crisis. Am Heart J 1979; 97:585.
  101. Miller DM, Winslow RM, Klein HG, et al. Improved exercise performance after exchange transfusion in subjects with sickle cell anemia. Blood 1980; 56:1127.
  102. Martin CR, Cobb C, Tatter D, et al. Acute myocardial infarction in sickle cell anemia. Arch Intern Med 1983; 143:830.
  103. Martin CR, Johnson CS, Cobb C, et al. Myocardial infarction in sickle cell disease. J Natl Med Assoc 1996; 88:428.
  104. Pannu R, Zhang J, Andraws R, et al. Acute myocardial infarction in sickle cell disease: a systematic review. Crit Pathw Cardiol 2008; 7:133.
  105. Eckman JR. Leg ulcers in sickle cell disease. Hematol Oncol Clin North Am 1996; 10:1333.
  106. Koshy M, Entsuah R, Koranda A, et al. Leg ulcers in patients with sickle cell disease. Blood 1989; 74:1403.
  107. Serjeant GR. Leg ulceration in sickle cell anemia. Arch Intern Med 1974; 133:690.
  108. 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.
  109. Nolan VG, Adewoye A, Baldwin C, et al. Sickle cell leg ulcers: associations with haemolysis and SNPs in Klotho, TEK and genes of the TGF-beta/BMP pathway. Br J Haematol 2006; 133:570.
  110. Cumming V, King L, Fraser R, et al. Venous incompetence, poverty and lactate dehydrogenase in Jamaica are important predictors of leg ulceration in sickle cell anaemia. Br J Haematol 2008; 142:119.
  111. Sehgal SC, Arunkumar BK. Microbial flora and its significance in pathology of sickle cell disease leg ulcers. Infection 1992; 20:86.
  112. Ankra-Badu GA. Sickle cell leg ulcers in Ghana. East Afr Med J 1992; 69:366.
  113. Clare A, FitzHenley M, Harris J, et al. Chronic leg ulceration in homozygous sickle cell disease: the role of venous incompetence. Br J Haematol 2002; 119:567.
  114. Keidan AJ, Stuart J. Rheological effects of bed rest in sickle cell disease. J Clin Pathol 1987; 40:1187.
  115. Mohan JS, Marshall JM, Reid HL, et al. Postural vasoconstriction and leg ulceration in homozygous sickle cell disease. Clin Sci (Lond) 1997; 92:153.
  116. Baum KF, MacFarlane DE, Maude GH, Serjeant GR. Topical antibiotics in chronic sickle cell leg ulcers. Trans R Soc Trop Med Hyg 1987; 81:847.
  117. Weinzweig N, Schuler J, Vitello J. Simultaneous reconstruction of extensive soft-tissue defects of both lower limbs with free hemiflaps harvested from the omentum. Plast Reconstr Surg 1997; 99:757.
  118. Leg ulcers. In: The management of sickle cell disease, 4th ed, National Institutes of Health publication 02-2117, June 2002. p.139.
  119. Wun T, Hassell K. Best practices for transfusion for patients with sickle cell disease. Hematology Reports 2009; 1:e22.
  120. McMahon L, Tamary H, Askin M, et al. A randomized phase II trial of Arginine Butyrate with standard local therapy in refractory sickle cell leg ulcers. Br J Haematol 2010; 151:516.
  121. Méry L, Girot R, Aractingi S. Topical effectiveness of molgramostim (GM-CSF) in sickle cell leg ulcers. Dermatology 2004; 208:135.
  122. Alikhan MA, Carter G, Mehta P. Topical GM-CSF hastens healing of leg ulcers in sickle cell disease. Am J Hematol 2004; 76:192.
  123. Lionnet F, Bachmeyer C, Stankovic K, et al. Efficacy of the endothelin receptor blocker bosentan for refractory sickle cell leg ulcers. Br J Haematol 2008; 142:991.
  124. Ballas SK. Treatment of painful sickle cell leg ulcers with topical opioids. Blood 2002; 99:1096.
  125. Anuforo J, Nguyen J, Luk K, et al. Association of non-healing wounds, pain and neurochemical alterations in sickle cell disease. Blood (ASH Annual Meeting Abstracts) 2010; 116:842.
  126. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 1994; 330:1639.
  127. Gray A, Anionwu EN, Davies SC, Brozovic M. Patterns of mortality in sickle cell disease in the United Kingdom. J Clin Pathol 1991; 44:459.
  128. Powars D, Weidman JA, Odom-Maryon T, et al. Sickle cell chronic lung disease: prior morbidity and the risk of pulmonary failure. Medicine (Baltimore) 1988; 67:66.
  129. Mekontso Dessap A, Leon R, Habibi A, et al. Pulmonary hypertension and cor pulmonale during severe acute chest syndrome in sickle cell disease. Am J Respir Crit Care Med 2008; 177:646.
  130. Alam S, Mehari A, Kato GJ, et al. Study of clinical characteristics of sickle cell disease patients developing cor-pulmonale during acute hospitalization. Am J Respir Crit Care Med 2011; 183:A5945.
  131. Uong EC, Boyd JH, DeBaun MR. Daytime pulse oximeter measurements do not predict incidence of pain and acute chest syndrome episodes in sickle cell anemia. J Pediatr 2006; 149:707.
  132. Rackoff WR, Kunkel N, Silber JH, et al. Pulse oximetry and factors associated with hemoglobin oxygen desaturation in children with sickle cell disease. Blood 1993; 81:3422.
  133. Quinn CT, Ahmad N. Clinical correlates of steady-state oxyhaemoglobin desaturation in children who have sickle cell disease. Br J Haematol 2005; 131:129.
  134. Campbell A, Minniti CP, Nouraie M, et al. Prospective evaluation of haemoglobin oxygen saturation at rest and after exercise in paediatric sickle cell disease patients. Br J Haematol 2009; 147:352.
  135. Gladwin MT, Vichinsky E. Pulmonary complications of sickle cell disease. N Engl J Med 2008; 359:2254.
  136. Paul RN, Castro OL, Aggarwal A, Oneal PA. Acute chest syndrome: sickle cell disease. Eur J Haematol 2011; 87:191.
  137. Sundaram N, Bennett M, Wilhelm J, et al. Biomarkers for early detection of sickle nephropathy. Am J Hematol 2011; 86:559.
  138. McPherson Yee M, Jabbar SF, Osunkwo I, et al. Chronic kidney disease and albuminuria in children with sickle cell disease. Clin J Am Soc Nephrol 2011; 6:2628.
  139. Pham PT, Pham PC, Wilkinson AH, Lew SQ. Renal abnormalities in sickle cell disease. Kidney Int 2000; 57:1.
  140. Campbell KL, Hud LM, Adams S, et al. Safety of iodinated intravenous contrast medium administration in sickle cell disease. Am J Med 2012; 125:100.e11.
  141. Hayes RJ, Condon PI, Serjeant GR. Haematological factors associated with proliferative retinopathy in homozygous sickle cell disease. Br J Ophthalmol 1981; 65:29.
  142. Nagpal KC, Goldberg MF, Rabb MF. Ocular manifestations of sickle hemoglobinopathies. Surv Ophthalmol 1977; 21:391.
  143. McLeod DS, Merges C, Fukushima A, et al. Histopathologic features of neovascularization in sickle cell retinopathy. Am J Ophthalmol 1997; 124:455.
  144. Cao J, Mathews MK, McLeod DS, et al. Angiogenic factors in human proliferative sickle cell retinopathy. Br J Ophthalmol 1999; 83:838.
  145. Friberg TR, Young CM, Milner PF. Incidence of ocular abnormalities in patients with sickle hemoglobinopathies. Ann Ophthalmol 1986; 18:150.
  146. Hayes RJ, Condon PI, Serjeant GR. Haematological factors associated with proliferative retinopathy in sickle cell-haemoglobin C disease. Br J Ophthalmol 1981; 65:712.
  147. van Meurs JC. Ocular findings in sickle cell patients on Curaçao. Int Ophthalmol 1991; 15:53.
  148. Downes SM, Hambleton IR, Chuang EL, et al. Incidence and natural history of proliferative sickle cell retinopathy: observations from a cohort study. Ophthalmology 2005; 112:1869.
  149. Hingorani M, Bentley CR, Jackson H, et al. Retinopathy in haemoglobin C trait. Eye (Lond) 1996; 10 ( Pt 3):338.
  150. Moriarty BJ, Acheson RW, Condon PI, Serjeant GR. Patterns of visual loss in untreated sickle cell retinopathy. Eye (Lond) 1988; 2 ( Pt 3):330.
  151. Clarkson JG. The ocular manifestations of sickle-cell disease: a prevalence and natural history study. Trans Am Ophthalmol Soc 1992; 90:481.
  152. Dover GJ, Boyer SH, Charache S, Heintzelman K. Individual variation in the production and survival of F cells in sickle-cell disease. N Engl J Med 1978; 299:1428.
  153. Nagel RL, Ranney HM. Genetic epidemiology of structural mutations of the beta-globin gene. Semin Hematol 1990; 27:342.
  154. Oner C, Dimovski AJ, Altay C, et al. Sequence variations in the 5' hypersensitive site-2 of the locus control region of beta S chromosomes are associated with different levels of fetal globin in hemoglobin S homozygotes. Blood 1992; 79:813.
  155. Diop S, Thiam D, Cisse M, et al. New results in clinical severity of homozygous sickle cell anemia, in Dakar, Senegal. Hematol Cell Ther 1999; 41:217.
  156. Wilber A, Nienhuis AW, Persons DA. Transcriptional regulation of fetal to adult hemoglobin switching: new therapeutic opportunities. Blood 2011; 117:3945.
  157. West MS, Wethers D, Smith J, Steinberg M. Laboratory profile of sickle cell disease: a cross-sectional analysis. The Cooperative Study of Sickle Cell Disease. J Clin Epidemiol 1992; 45:893.
  158. Tassel C, Arnaud C, Kulpa M, et al. Leukocytosis is a risk factor for lung function deterioration in children with sickle cell disease. Respir Med 2011; 105:788.
  159. Embury SH, Dozy AM, Miller J, et al. Concurrent sickle-cell anemia and alpha-thalassemia: effect on severity of anemia. N Engl J Med 1982; 306:270.
  160. McCurdy PR. 32-DFP and 51-Cr for measurement of red cell life span in abnormal hemoglobin syndromes. Blood 1969; 33:214.
  161. Sherwood JB, Goldwasser E, Chilcote R, et al. Sickle cell anemia patients have low erythropoietin levels for their degree of anemia. Blood 1986; 67:46.
  162. Saraf S, Farooqui M, Infusino G, et al. Standard clinical practice underestimates the role and significance of erythropoietin deficiency in sickle cell disease. Br J Haematol 2011; 153:386.
  163. Singh A, Eckardt KU, Zimmermann A, et al. Increased plasma viscosity as a reason for inappropriate erythropoietin formation. J Clin Invest 1993; 91:251.
  164. JONSSON U, ROATH OS, KIRKPATRICK CI. Nutritional megaloblastic anemia associated with sickle cell states. Blood 1959; 14:535.
  165. Lopez R, Shimizu N, Cooperman JM. Recurrent folic acid deficiency in sickle cell disease. Am J Dis Child 1973; 125:544.
  166. Lanzkowsky P. Iron deficiency anemia. Pediatr Ann 1974; 3:6.
  167. Vichinsky E, Kleman K, Embury S, Lubin B. The diagnosis of iron deficiency anemia in sickle cell disease. Blood 1981; 58:963.
  168. Topley JM, Rogers DW, Stevens MC, Serjeant GR. Acute splenic sequestration and hypersplenism in the first five years in homozygous sickle cell disease. Arch Dis Child 1981; 56:765.
  169. Emond AM, Collis R, Darvill D, et al. Acute splenic sequestration in homozygous sickle cell disease: natural history and management. J Pediatr 1985; 107:201.
  170. Orringer EP, Fowler VG Jr, Owens CM, et al. Case report: splenic infarction and acute splenic sequestration in adults with hemoglobin SC disease. Am J Med Sci 1991; 302:374.
  171. Smith-Whitley K, Zhao H, Hodinka RL, et al. Epidemiology of human parvovirus B19 in children with sickle cell disease. Blood 2004; 103:422.
  172. Pappo A, Buchanan GR. Acute splenic sequestration in a 2-month-old infant with sickle cell anemia. Pediatrics 1989; 84:578.
  173. Airede AI. Acute splenic sequestration in a five-week-old infant with sickle cell disease. J Pediatr 1992; 120:160.
  174. Lane PA, Rogers ZR, Woods GM, et al. Fatal pneumococcal septicemia in hemoglobin SC disease. J Pediatr 1994; 124:859.
  175. Piccin A, Smith OP, Murphy C, et al. Splenectomy in sickle cell anaemia: a cause of further crises? Br J Haematol 2009; 145:144.
  176. Wright JG, Hambleton IR, Thomas PW, et al. Postsplenectomy course in homozygous sickle cell disease. J Pediatr 1999; 134:304.
  177. Rao SP, Miller ST, Cohen BJ. Transient aplastic crisis in patients with sickle cell disease. B19 parvovirus studies during a 7-year period. Am J Dis Child 1992; 146:1328.
  178. Serjeant BE, Hambleton IR, Kerr S, et al. Haematological response to parvovirus B19 infection in homozygous sickle-cell disease. Lancet 2001; 358:1779.
  179. Saarinen UM, Chorba TL, Tattersall P, et al. Human parvovirus B19-induced epidemic acute red cell aplasia in patients with hereditary hemolytic anemia. Blood 1986; 67:1411.
  181. CHERNOFF AI, JOSEPHSON AM. Acute erythroblastopenia in sickle-cell anemia and infectious mononucleosis. AMA Am J Dis Child 1951; 82:310.
  182. Petz LD, Calhoun L, Shulman IA, et al. The sickle cell hemolytic transfusion reaction syndrome. Transfusion 1997; 37:382.
  183. Talano JA, Hillery CA, Gottschall JL, et al. Delayed hemolytic transfusion reaction/hyperhemolysis syndrome in children with sickle cell disease. Pediatrics 2003; 111:e661.
  184. King KE, Shirey RS, Lankiewicz MW, et al. Delayed hemolytic transfusion reactions in sickle cell disease: simultaneous destruction of recipients' red cells. Transfusion 1997; 37:376.
  185. Cullis JO, Win N, Dudley JM, Kaye T. Post-transfusion hyperhaemolysis in a patient with sickle cell disease: use of steroids and intravenous immunoglobulin to prevent further red cell destruction. Vox Sang 1995; 69:355.
  186. Win N, New H, Lee E, de la Fuente J. Hyperhemolysis syndrome in sickle cell disease: case report (recurrent episode) and literature review. Transfusion 2008; 48:1231.
  187. Chadebech P, Habibi A, Nzouakou R, et al. Delayed hemolytic transfusion reaction in sickle cell disease patients: evidence of an emerging syndrome with suicidal red blood cell death. Transfusion 2009; 49:1785.
  188. Zimring JC, Spitalnik SL. To RBC or not to RBC: the role of suicidal death in hemolytic transfusion reactions. Transfusion 2009; 49:1776.
  189. de Montalembert M, Dumont MD, Heilbronner C, et al. Delayed hemolytic transfusion reaction in children with sickle cell disease. Haematologica 2011; 96:801.
  190. Yazdanbakhsh K, Ware RE, Noizat-Pirenne F. Red blood cell alloimmunization in sickle cell disease: pathophysiology, risk factors, and transfusion management. Blood 2012; 120:528.
  191. Mota MA, Sakashita AM, Hammerschlak N, et al. Post-transfusion hyperhemolysis after haemolytic transfusion reaction in a patient with severe anemia: case report (abstract). Vox Sang 2006; 91:233.
  192. Win N, Sinha S, Lee E, Mills W. Treatment with intravenous immunoglobulin and steroids may correct severe anemia in hyperhemolytic transfusion reactions: case report and literature review. Transfus Med Rev 2010; 24:64.
  193. Bachmeyer C, Maury J, Parrot A, et al. Rituximab as an effective treatment of hyperhemolysis syndrome in sickle cell anemia. Am J Hematol 2010; 85:91.
  194. Ballas SK, Marcolina MJ. Hyperhemolysis during the evolution of uncomplicated acute painful episodes in patients with sickle cell anemia. Transfusion 2006; 46:105.
  195. Smits HL, Oski FA, Brody JI. The hemolytic crisis of sickle cell disease: the role of glucose-6-phosphate dehydrogenase deficiency. J Pediatr 1969; 74:544.
  196. www.cdc.gov/ncbddd/sicklecell/index.html (Accessed on October 03, 2011).