Case-Based Review

Sickle Cell Disease

Hospital Physician: Hematology/Oncology. 2017 January;12(1):2-15

References

Weatherall D, Hofman K, Rodgers G, Ruffin J, Hrynkow S. A case for developing North-South partnerships for research in sickle cell disease. Blood 2005;105:921–3.
Flint J, Harding RM, Boyce AJ, Clegg JB. The population genetics of the haemoglobinopathies. Baillieres Clin Haematol 1998;11:1–51.
Allison AC. The distribution of the sickle-cell trait in East Africa and elsewhere, and its apparent relationship to the incidence of subtertian malaria. Trans R Soc Trop Med Hyg 1954;48:312–8.
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;330:1639–44.
Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet 2010;376:2018–31.
Serjeant GR, Serjeant BE. Sickle cell disease. 3rd ed. New York: Oxford University Press; 2001.
Moo-Penn W, Bechtel K, Jue D, et al. The presence of hemoglobin S and C Harlem in an individual in the United States. Blood 1975;46:363–7.
Monplaisir N, Merault G, Poyart C, et al. Hemoglobin S Antilles: a variant with lower solubility than hemoglobin S and producing sickle cell disease in heterozygotes. Proc Natl Acad Sci U S A 1986;83:9363–7.
Nagel RL, Fabry ME, Steinberg MH. The paradox of hemoglobin SC disease. Blood Rev 2003;17:167–78.
Nagel RL, Daar S, Romero JR, et al. HbS-oman heterozygote: a new dominant sickle syndrome. Blood 1998;92:4375–82.
Masiello D, Heeney MM, Adewoye AH, et al. Hemoglobin SE disease: a concise review. Am J Hematol 2007;82:643–9.
Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med 1997;337:762–9.
Brittenham GM, Schechter AN, Noguchi CT. Hemoglobin S polymerization: primary determinant of the hemolytic and clinical severity of the sickling syndromes. Blood 1985;65:183–9.
.Nagel RL, Bookchin RM, Johnson J, et al. Structural bases of the inhibitory effects of hemoglobin F and hemoglobin A2 on the polymerization of hemoglobin S. Proc Natl Acad Sci U S A 1979;76:670–2.
.Ballas SK, Dover GJ, Charache S. Effect of hydroxyurea on the rheological properties of sickle erythrocytes in vivo. Am J Hematol 1989;32:104–11.
Frenette PS. Sickle cell vaso-occlusion: multistep and multicellular paradigm. Curr Opin Hematol 2002;9:101–6.
Reiter CD, Wang X, Tanus-Santos JE, et al. Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nature Med 2002;8:1383–9.
Nouraie M, Lee JS, Zhang Y, 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.
Serjeant GR. The natural history of sickle cell disease. Cold Spring Harb Perspect Med 2013;3:a011783.
Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA 2014;312:1033–48.
Serjeant GR. Natural history and determinants of clinical severity of sickle cell disease. Curr Opin Hematol 1995;2:103–8.
Odenheimer DJ, Sarnaik SA, Whitten CF, et al. The relationship between fetal hemoglobin and disease severity in children with sickle cell anemia. Am J Med Genet 1987;27:525–35.
Platt OS, Thorington BD, Brambilla DJ, et al. Pain in sickle cell disease. Rates and risk factors. N Engl J Med 1991;325:11–6.
Falusi AG, Olatunji PO. Effects of alpha thalassaemia and haemoglobin F (HbF) level on the clinical severity of sickle-cell anaemia. Eur J Haematol 1994;52:13–5.
Watson J. The significance of the paucity of sickle cells in newborn Negro infants. Am J Med Sci 1948;215:419–23.
Marcus SJ, Ware RE. Physiologic decline in fetal hemoglobin parameters in infants with sickle cell disease: implications for pharmacological intervention. J Pediatr Hematol Oncol 1999;21:407–11.
Schroeder WA, Powars DR, Kay LM, et al. Beta-cluster haplotypes, alpha-gene status, and hematological data from SS, SC, and S-beta-thalassemia patients in southern California. Hemoglobin 1989;13:325–53.
Steinberg MH, Voskaridou E, Kutlar A, et al. Concordant fetal hemoglobin response to hydroxyurea in siblings with sickle cell disease. Am J Hematol 2003;72:121–6.
Ngo D, Bae H, Steinberg MH, et al. Fetal hemoglobin in sickle cell anemia: genetic studies of the Arab-Indian haplotype. Blood Cells Mol Dis 2013;51:22–6.
Galarneau G, Palmer CD, Sankaran VG, et al. Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation. Nat Genet 2010;42:1049–51.
Lettre G, Sankaran VG, Bezerra MA, et al. DNA polymorphisms at the BCL11A, HBS1L-MYB, and beta-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease. Proc Natl Acad Sci U S A 2008;105:11869–74.
Sankaran VG, Menne TF, Xu J, et al. Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science 2008;322:1839–42.
Uda M, Galanello R, Sanna S, et al. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia. Proc Natl Acad Sci U S A 2008;105:1620–5.
Adams RJ, Kutlar A, McKie V, et al. Alpha thalassemia and stroke risk in sickle cell anemia. Am J Hematol 1994;45:279–82.
Ballas SK. Effect of alpha-globin genotype on the pathophysiology of sickle cell disease. Pediatr Pathol Mol Med 2001;20:107–21.
Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral penicillin in children with sickle cell anemia. A randomized trial. N Engl J Med 1986;314:1593–9.
Ballas SK, Talacki CA, Rao VM, Steiner RM. The prevalence of avascular necrosis in sickle cell anemia: correlation with alpha-thalassemia. Hemoglobin 1989;13:649–55.
.Kato GJ, Gladwin MT, Steinberg MH. Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Rev 2007;21:37–47.
Murphy JR, Wengard M, Brereton W. Rheological studies of Hb SS blood: influence of hematocrit, hypertonicity, separation of cells, deoxygenation, and mixture with normal cells. J Lab Clin Med 1976;87:475–86.
Fabry ME, Kaul DK, Raventos-Suarez C, Chang H, Nagel RL. SC erythrocytes have an abnormally high intracellular hemoglobin concentration. Pathophysiological consequences. J Clin Invest 1982;70:1315–9.
Stuart J, Johnson CS. Rheology of the sickle cell disorders. Baillieres Clin Haematol 1987;1:747–75.
Lionnet F, Hammoudi N, Stojanovic KS, et al. Hemoglobin sickle cell disease complications: a clinical study of 179 cases. Haematologica 2012;97:1136-41.
Adamkiewicz TV, Sarnaik S, Buchanan GR, et al. Invasive pneumococcal infections in children with sickle cell disease in the era of penicillin prophylaxis, antibiotic resistance, and 23-valent pneumococcal polysaccharide vaccination. J Pediatr 2003;143:438–44.
Abboud MR, Yim E, Musallam KM, Adams RJ, Investigators SIS. Discontinuing prophylactic transfusions increases the risk of silent brain infarction in children with sickle cell disease: data from STOP II. Blood 2011;118:894–8.
Adams RJ. Lessons from the Stroke Prevention Trial in Sickle Cell Anemia (STOP) study. J Child Neurol 2000;15:344–9.
Adams RJ, Brambilla DJ, Granger S, et al. Stroke and conversion to high risk in children screened with transcranial Doppler ultrasound during the STOP study. Blood 2004;103:3689–94.
Lee MT, Piomelli S, Granger S, et al. Stroke Prevention Trial in Sickle Cell Anemia (STOP): extended follow-up and final results. Blood 2006;108:847–52.
Charache S, Dover GJ, Moore RD, et al. Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia. Blood 1992;79:2555–65.
Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med 1995;332:1317–22.
Charache S. Mechanism of action of hydroxyurea in the management of sickle cell anemia in adults. Semin Hematol 1997;34:15–21.
Steinberg MH, McCarthy WF, Castro O, et al. The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: A 17.5 year follow-up. Am J Hematol 2010;85:403–8.
Noguchi CT, Rodgers GP, Serjeant G, Schechter AN. Levels of fetal hemoglobin necessary for treatment of sickle cell disease. N Engl J Med 1988;318:96–9.
Powars DR, Weiss JN, Chan LS, Schroeder WA. Is there a threshold level of fetal hemoglobin that ameliorates morbidity in sickle cell anemia? Blood 1984;63:921–6.
Maier-Redelsperger M, de Montalembert M, Flahault A, et al. Fetal hemoglobin and F-cell responses to long-term hydroxyurea treatment in young sickle cell patients. The French Study Group on Sickle Cell Disease. Blood 1998;91:4472–9.
Steinberg MH, Chui DH, Dover GJ, et al. Fetal hemoglobin in sickle cell anemia: a glass half full? Blood 2014;123:481–5.
Adragna NC, Fonseca P, Lauf PK. Hydroxyurea affects cell morphology, cation transport, and red blood cell adhesion in cultured vascular endothelial cells. Blood 1994;83:553–60.
Bridges KR, Barabino GD, Brugnara C, et al. A multiparameter analysis of sickle erythrocytes in patients undergoing hydroxyurea therapy. Blood 1996;88:4701–10.
Jiang J, Jordan SJ, Barr DP, et al. In vivo production of nitric oxide in rats after administration of hydroxyurea. Mol Pharmacol 1997;52:1081–6.
Ware RE. How I use hydroxyurea to treat young patients with sickle cell anemia. Blood 2010;115:5300–11.
Yates AM, Dedeken L, Smeltzer MP, et al. Hydroxyurea treatment of children with hemoglobin SC disease. Pediatr Blood Cancer 2013;60:323–5.
Barbosa CG, Aleluia AC, Pacheco AP, et al. Genetic modulation of HbF in Brazilians with HbSC disease and sickle cell anemia. Am J Hematol 2013;88:923–4.
Hsieh MM, Kang EM, Fitzhugh CD, et al. Allogeneic hematopoietic stem-cell transplantation for sickle cell disease. N Engl J Med 2009;361:2309–17.
King A, Shenoy S. Evidence-based focused review of the status of hematopoietic stem cell transplantation as treatment of sickle cell disease and thalassemia. Blood 2014;123:3089–94.
Oringanje C, Nemecek E, Oniyangi O. Hematopoietic stem cell transplantation for people with sickle cell disease. Cochrane Database Syst Rev 2013;5:CD007001.
Freed J, Talano J, Small T, et al. Allogeneic cellular and autologous stem cell therapy for sickle cell disease: ‘whom, when and how’. Bone Marrow Transplant 2012;47:1489–98.
Urbinati F, Hargrove PW, Geiger S, et al. Potentially therapeutic levels of anti-sickling globin gene expression following lentivirus-mediated gene transfer in sickle cell disease bone marrow CD34 cells. Exp Hematol 2015;43:346–51.
Brugnara C, Mohandas N. Red cell indices in classification and treatment of anemias: from M.M. Wintrobes’s original 1934 classification to the third millennium. Curr Opin Hematol 2013;20:222–30.
Key NS, Derebail VK. Sickle-cell trait: novel clinical significance. Hematology Am Soc Hematol Educ Program 2010;2010:418–22.
Kark JA, Posey DM, Schumacher HR, Ruehle CJ. Sickle-cell trait as a risk factor for sudden death in physical training. N Engl J Med 1987;317:781–7.
Goldsmith JC, Bonham VL, Joiner CH, et al. Framing the research agenda for sickle cell trait: building on the current understanding of clinical events and their potential implications. Am J Hematol 2012;87:340–6.
Grant AM, Parker CS, Jordan LB, et al. Public health implications of sickle cell trait: a report of the CDC meeting. Am J Prev Med 2011;41:S435–9.
Ballas SK, Lusardi M. Hospital readmission for adult acute sickle cell painful episodes: frequency, etiology, and prognostic significance. Am J Hematol 2005;79:17–25.
Serjeant GR, Ceulaer CD, Lethbridge R, et al. The painful crisis of homozygous sickle cell disease: clinical features. Br J Haematol 1994;87:586–91.
Vichinsky EP, Johnson R, Lubin BH. Multidisciplinary approach to pain management in sickle cell disease. Am J Pediatr Hematol Oncol 1982;4:328–33.
Gil KM, Carson JW, Porter LS, et al. Daily mood and stress predict pain, health care use, and work activity in African American adults with sickle-cell disease. Health Psychol 2004;23:267–74.
Amjad H, Bannerman RM, Judisch JM. Letter: Sickling pain and season. Br Med J 1974;2:54.
Ibrahim AS. Relationship between meteorological changes and occurrence of painful sickle cell crises in Kuwait. Trans R Soc Trop Med Hyg 1980;74:159–61.
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;131:530–3.
Resar LM, Oski FA. Cold water exposure and vaso-occlusive crises in sickle cell anemia. J Pediatr 1991;118:407–9.
Darbari DS, Ballas SK, Clauw DJ. Thinking beyond sickling to better understand pain in sickle cell disease. Eur J Haematol 2014;93:89–95.
Darbari DS, Onyekwere O, Nouraie M, et al. Markers of severe vaso-occlusive painful episode frequency in children and adolescents with sickle cell anemia. J Pediatr 2011;160:286–90.
Hollins M, Stonerock GL, Kisaalita NR, et al. Detecting the emergence of chronic pain in sickle cell disease. J Pain Symptom Manage 2012;43:1082–93.
Ballas SK, Darbari DS. Neuropathy, neuropathic pain, and sickle cell disease. Am J Hematol 2013;88:927–9.
Brandow AM, Farley RA, Panepinto JA. Early insights into the neurobiology of pain in sickle cell disease: A systematic review of the literature. Pediatr Blood Cancer 2015 May 13. doi: 10.1002/pbc.25574. [Epub ahead of print].
Brandow AM, Farley RA, Panepinto JA. Neuropathic pain in patients with sickle cell disease. Pediatr Blood Cancer 2014;61:512–7.
Brandow AM, Farley RA, Dasgupta M, et al. The use of neuropathic pain drugs in children with sickle cell disease is associated with older age, female sex, and longer length of hospital stay. J Pediatr Hematol Oncol 2015;37:10–5.
Walker TM, Hambleton IR, Serjeant GR. Gallstones in sickle cell disease: observations from The Jamaican Cohort study. J Pediatr 2000;136:80–5.
Penner E, Mayr WR, Djawan S, et al. [The genetics of Gilbert syndrome]. Schweiz Med Wochenschr 1976;106:860–2. [German]
Powell RW, Levine GL, Yang YM, Mankad VN. Acute splenic sequestration crisis in sickle cell disease: early detection and treatment. J Pediatr Surg 1992;27:215–8.
Al Salem AH, Qaisaruddin S, Nasserullah Z, et al. Splenectomy and acute splenic sequestration crises in sickle cell disease. Pediatr Surg Int 1996;11:26–8.
Pearson HA, Spencer RP, Cornelius EA. Functional asplenia in sickle-cell anemia. N Engl J Med 1969;281:923–6.
Wang WC, Ware RE, Miller ST, et al. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet 2011;377:1663–72.
Brousse V, Buffet P, Rees D. The spleen and sickle cell disease: the sick(led) spleen. Br J Haematol 2014;166:165–76.
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;302:374–9.
Michel JB, Hernandez JA, Buchanan GR. A fatal case of acute splenic sequestration in a 53–year-old woman with sickle-hemoglobin C disease. Am J Med 1992;92:97–100.
Hatton CS, Bunch C, Weatherall DJ. Hepatic sequestration in sickle cell anaemia. Br Med J (Clin Res Ed) 1985;290:744–5.
Castro O, Brambilla DJ, Thorington B, et al. The acute chest syndrome in sickle cell disease: incidence and risk factors. The Cooperative Study of Sickle Cell Disease. Blood 1994;84:643–9.
Gill FM, Sleeper LA, Weiner SJ, et al. Clinical events in the first decade in a cohort of infants with sickle cell disease. Cooperative Study of Sickle Cell Disease. Blood 1995;86:776–83.
Owusu-Ofori S, Hirst C. Splenectomy versus conservative management for acute sequestration crises in people with sickle cell disease. Cochrane Database Syst Rev 2013;5:CD003425.
00.Al-Salem AH. Splenic complications of sickle cell anemia and the role of splenectomy. ISRN Hematol 2011;2011:864257.
Sabarense AP, Lima GO, Silva LM, Viana MB. Characterization of mortality in children with sickle cell disease diagnosed through the Newborn Screening Program. J Pediatr (Rio J) 2015;91:242–7.
Aslam AF, Aslam AK, Dipillo F. Fatal splenic sequestration crisis with multiorgan failure in an adult woman with sickle cell-beta+ thalassemia. Am J Med Sci 2005;329:141–3.
Berry RA, Odumakinde EA, Lewis JP. Massive splenic infarction in doubly abnormal heterozygous sickling disorders. A new complication of acute splenic sequestration syndrome. The West J Med 1991;155:531–2.
Bonanomi MT, Lavezzo MM. Sickle cell retinopathy: diagnosis and treatment. Arq Bras de Oftalmol 2013;76:320–7.
Chen RW, Flynn HW Jr, Lee WH, et al. Vitreoretinal management and surgical outcomes in proliferative sickle retinopathy: a case series. Am J Ophthalmol 2014;157:870–5 e1.
Howard J, Malfroy M, Llewelyn C, et al. The Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) study: a randomised, controlled, multicentre clinical trial. Lancet 2013;381:930–8.
Neumayr L, Koshy M, Haberkern C, et al. Surgery in patients with hemoglobin SC disease. Preoperative Transfusion in Sickle Cell Disease Study Group. Am J Hematol 1998;57:101–8.
08. Savage WJ, Buchanan GR, Yawn BP, et al. Evidence gaps in the management of sickle cell disease: A summary of needed research. Am J Hematol 2015;90:273–5.
Charache S, Barton FB, Moore RD, et al. Hydroxyurea and sickle cell anemia. Clinical utility of a myelosuppressive “switching” agent. The Multicenter Study of Hydroxyurea in Sickle Cell Anemia. Medicine (Baltimore) 1996;75:300–26.
Steinberg MH, Nagel RL, Brugnara C. Cellular effects of hydroxyurea in Hb SC disease. Br J Haematol 1997;98:838–44.
Wang W, Brugnara C, Snyder C, et al. The effects of hydroxycarbamide and magnesium on haemoglobin SC disease: results of the multi-centre CHAMPS trial. Br J Haematol 2011;152:771–6.
Jungst C, Kullak-Ublick GA, Jungst D. Gallstone disease: Microlithiasis and sludge. Best Pract Res Clin Gastroenterol 2006;20:1053–62.
Walker TM, Serjeant GR. Biliary sludge in sickle cell disease. J Pediatr 1996;129:443–5.
Bauer TW, Moore GW, Hutchins GM. The liver in sickle cell disease. A clinicopathologic study of 70 patients. Am J Med 1980;69:833–7.
Ebert EC, Nagar M, Hagspiel KD. Gastrointestinal and hepatic complications of sickle cell disease. Clin Gastroenterol Hepatol 2010;8:483–9.
Hiran S. Multiorgan dysfunction syndrome in sickle cell disease. J Assoc Physicians India 2005;53:19–22.
Shao SH, Orringer EP. Case report: splenic sequestration and multiorgan failure as the presenting manifestation of hemoglobin SC disease. Am J Med Sci 1996;311:139–41.
Hassell KL, Eckman JR, Lane PA. Acute multiorgan failure syndrome: a potentially catastrophic complication of severe sickle cell pain episodes. Am J Med 1994;96:155–62.

INTRODUCTION

Sickle cell disease is the most common inherited blood disorder in the world. It affects more than 100,000 individuals in the United States, and millions more worldwide.¹ Sickle cell disease is most commonly found in individuals of African heritage, but the disease also occurs in Hispanics and people of Middle Eastern and subcontinent Indian heritage.² The distribution of the sickle hemoglobin (hemoglobin S [HbS]) allele overlaps with the distribution of malaria; HbS carriers, or individuals with sickle cell trait, have protection against malaria,³ and are not considered to have sickle cell disease.

Sickle cell disease is a severe monogenic disorder marked by significant morbidity and mortality, affecting every organ in the body.⁴ The term sickle cell disease refers to all genotypes that cause sickling; the most common are the homozygous hemoglobin SS (HbSS) and compound heterozygotes hemoglobin SC (HbSC), hemoglobin S–β⁰-thalassemia (HbSβ⁰),and hemoglobin S–β⁺-thalassemia(HbSβ⁺), although HbS and several rarer hemoglobin variants such as HbSO(Arab) and HbSD(Punjab) can also cause sickle cell disease.The term sickle cell anemia refers exclusively to the most severe genotypes, HbSS and HbSβ⁰.⁵ Common sickling genotypes along with their relative clinical severity are shown in Table 1.^6–11

Table 1. Genotypes of Sickling Syndromes and Their Relative Severities
Genotype	Severity	Characteristics
HbSS	Severe	Most common form
HbSβ⁰	Severe	Clinically indistinguishable from HbSS⁶
HbSO-Arab	Severe	Relatively rare⁶
HbSD-Punjab	Severe	Mostly in northern India⁶
HbSC-Harlem	Severe	Migrates like HbSC, but rare double β-globin mutation⁷
HbCS-Antilles	Severe	Rare double β-globin mutation⁸
HbSC	Moderate	25% of SCD⁹
HbSβ+, Mediterranean	Moderate	5%–16% HbA⁶
HbAS-Oman	Moderate	Dominant rare double β-globin mutation¹⁰
HbSβ+, African	Mild	16%–30% HbA⁶
HbSE	Mild	HbE found mostly in Southeast Asia¹¹
HbS-HPFH	Very mild	Large deletions in β-globin gene complex; > 30% HbF⁶
HbA = hemoglobin A; HbE = hemoglobin E; HbF = fetal hemoglobin; HbS-HPFH = HbS and gene deletion HPFH; HbSC = heterozygous hemoglobin SC; HbSS = homozygous hemoglobin SS; HbSβ⁰ = hemoglobin S-β thalassemia⁰; HbSβ+ = hemoglobin S-β thalassemia+; SCD = sickle cell disease.

This article reviews the pathophysiology of sickle cell disease, common clinical complications, and available therapies. A complex case which illustrates diagnostic and management challenges is presented as well.

PATHOPHYSIOLOGY

HbS is the result of a substitution of valine for glutamic acid in the sixth amino acid of the β-globin chain.¹² The change from a hydrophilic to a hydrophobic amino acid causes the hemoglobin molecules to stack, or polymerize, when deoxygenated. This rigid rod of hemoglobin distorts the cell, producing the characteristic crescent or sickle shape that gives the disease its name.¹³ Polymerization of hemoglobin within the cell is promoted by dehydration, which increases the concentration of HbS.^13,14 Polymerization occurs when hemoglobin is in the deoxygenated state.¹³

The sickle red blood cell is abnormal; it is rigid and dense, and lacks the deformability needed to navigate the microvasculature.¹⁵ Blockages of blood flow result in painful vaso-occlusion that is the hallmark of the disease, and that also can cause damage to the spleen, kidneys, and liver.¹⁶ The sickle red cell is also fragile, with a lifespan of only 20 days compared to the 120-day lifespan of a normal red blood cell.¹³ Frequent hemolysis results in anemia and the release of free hemoglobin, which both scavenges nitric oxide and impairs the production of more nitric oxide, which is essential for vasodilatation.¹⁷ This contributes to vascular dysfunction and an increased risk for stroke.¹⁸ If untreated, the natural course of sickle cell anemia is mortality in early childhood in most cases.¹⁹ Common chronic and acute sickle cell disease–related complications and recommended therapies, based on 2014 National Institutes of Health guidelines, are shown in Table 2 and Table 3.²⁰

Table 2. Common Adult Sickle Cell Disease Chronic Complications and Recommended Therapies
Chronic Complication	Recommended Therapy	Strength of Recommendation
Chronic pain	Opioids	Consensus
Avascular necrosis	Analgesics and physical therapy	Consensus
Proliferative sickle retinopathy	Laser photocoagulation	Strong
Leg ulcers	Standard wound care	Moderate
Recurrent priapism	Consult urology	Moderate
Data from Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA 2014;312:1033–48.

Table 3. Common Adult Sickle Cell Disease Acute Complications and Recommended Therapies
Acute Complication	Recommended Therapy	Strength of Recommendation
Vaso-occlusive crisis	NSAIDs, opioids for severe pain	Moderate-consensus
ACS	Antibiotics, oxygen	Strong
	Simple transfusion^a	Weak
	Urgent exchange transfusion^b	Strong
Acute stroke	Exchange transfusion	Strong
Priapism ≥ 4 hr	Aggressive hydration, pain control, and urology consult	Strong-consensus
Gallstones, symptomatic	Cholecystectomy, laparoscopic	Strong
Splenic sequestration	Intravenous fluids, transfuse cautiously, discuss surgical splenectomy	Strong-moderate
Acute renal failure	Consult nephrology^c	Consensus
ACS = acute chest syndrome; NSAIDs = nonsteroidal anti-inflammatory drugs. a For symptomatic ACS with hemoglobin > 1 g/dL below baseline but > 9.0 g/dL. b When there is progression of ACS (SpO₂ < 90% despite supplemental oxygen, increasing respiratory distress, progressive pulmonary infiltrates despite simple transfusion). c For acute rise in creatinine ≥ 0.3 mg/dL; do not give transfusions unless there are other indications. Data from Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA 2014;312:1033–48.

References

Weatherall D, Hofman K, Rodgers G, Ruffin J, Hrynkow S. A case for developing North-South partnerships for research in sickle cell disease. Blood 2005;105:921–3.
Flint J, Harding RM, Boyce AJ, Clegg JB. The population genetics of the haemoglobinopathies. Baillieres Clin Haematol 1998;11:1–51.
Allison AC. The distribution of the sickle-cell trait in East Africa and elsewhere, and its apparent relationship to the incidence of subtertian malaria. Trans R Soc Trop Med Hyg 1954;48:312–8.
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;330:1639–44.
Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet 2010;376:2018–31.
Serjeant GR, Serjeant BE. Sickle cell disease. 3rd ed. New York: Oxford University Press; 2001.
Moo-Penn W, Bechtel K, Jue D, et al. The presence of hemoglobin S and C Harlem in an individual in the United States. Blood 1975;46:363–7.
Monplaisir N, Merault G, Poyart C, et al. Hemoglobin S Antilles: a variant with lower solubility than hemoglobin S and producing sickle cell disease in heterozygotes. Proc Natl Acad Sci U S A 1986;83:9363–7.
Nagel RL, Fabry ME, Steinberg MH. The paradox of hemoglobin SC disease. Blood Rev 2003;17:167–78.
Nagel RL, Daar S, Romero JR, et al. HbS-oman heterozygote: a new dominant sickle syndrome. Blood 1998;92:4375–82.
Masiello D, Heeney MM, Adewoye AH, et al. Hemoglobin SE disease: a concise review. Am J Hematol 2007;82:643–9.
Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med 1997;337:762–9.
Brittenham GM, Schechter AN, Noguchi CT. Hemoglobin S polymerization: primary determinant of the hemolytic and clinical severity of the sickling syndromes. Blood 1985;65:183–9.
.Nagel RL, Bookchin RM, Johnson J, et al. Structural bases of the inhibitory effects of hemoglobin F and hemoglobin A2 on the polymerization of hemoglobin S. Proc Natl Acad Sci U S A 1979;76:670–2.
.Ballas SK, Dover GJ, Charache S. Effect of hydroxyurea on the rheological properties of sickle erythrocytes in vivo. Am J Hematol 1989;32:104–11.
Frenette PS. Sickle cell vaso-occlusion: multistep and multicellular paradigm. Curr Opin Hematol 2002;9:101–6.
Reiter CD, Wang X, Tanus-Santos JE, et al. Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nature Med 2002;8:1383–9.
Nouraie M, Lee JS, Zhang Y, 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.
Serjeant GR. The natural history of sickle cell disease. Cold Spring Harb Perspect Med 2013;3:a011783.
Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA 2014;312:1033–48.
Serjeant GR. Natural history and determinants of clinical severity of sickle cell disease. Curr Opin Hematol 1995;2:103–8.
Odenheimer DJ, Sarnaik SA, Whitten CF, et al. The relationship between fetal hemoglobin and disease severity in children with sickle cell anemia. Am J Med Genet 1987;27:525–35.
Platt OS, Thorington BD, Brambilla DJ, et al. Pain in sickle cell disease. Rates and risk factors. N Engl J Med 1991;325:11–6.
Falusi AG, Olatunji PO. Effects of alpha thalassaemia and haemoglobin F (HbF) level on the clinical severity of sickle-cell anaemia. Eur J Haematol 1994;52:13–5.
Watson J. The significance of the paucity of sickle cells in newborn Negro infants. Am J Med Sci 1948;215:419–23.
Marcus SJ, Ware RE. Physiologic decline in fetal hemoglobin parameters in infants with sickle cell disease: implications for pharmacological intervention. J Pediatr Hematol Oncol 1999;21:407–11.
Schroeder WA, Powars DR, Kay LM, et al. Beta-cluster haplotypes, alpha-gene status, and hematological data from SS, SC, and S-beta-thalassemia patients in southern California. Hemoglobin 1989;13:325–53.
Steinberg MH, Voskaridou E, Kutlar A, et al. Concordant fetal hemoglobin response to hydroxyurea in siblings with sickle cell disease. Am J Hematol 2003;72:121–6.
Ngo D, Bae H, Steinberg MH, et al. Fetal hemoglobin in sickle cell anemia: genetic studies of the Arab-Indian haplotype. Blood Cells Mol Dis 2013;51:22–6.
Galarneau G, Palmer CD, Sankaran VG, et al. Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation. Nat Genet 2010;42:1049–51.
Lettre G, Sankaran VG, Bezerra MA, et al. DNA polymorphisms at the BCL11A, HBS1L-MYB, and beta-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease. Proc Natl Acad Sci U S A 2008;105:11869–74.
Sankaran VG, Menne TF, Xu J, et al. Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science 2008;322:1839–42.
Uda M, Galanello R, Sanna S, et al. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia. Proc Natl Acad Sci U S A 2008;105:1620–5.
Adams RJ, Kutlar A, McKie V, et al. Alpha thalassemia and stroke risk in sickle cell anemia. Am J Hematol 1994;45:279–82.
Ballas SK. Effect of alpha-globin genotype on the pathophysiology of sickle cell disease. Pediatr Pathol Mol Med 2001;20:107–21.
Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral penicillin in children with sickle cell anemia. A randomized trial. N Engl J Med 1986;314:1593–9.
Ballas SK, Talacki CA, Rao VM, Steiner RM. The prevalence of avascular necrosis in sickle cell anemia: correlation with alpha-thalassemia. Hemoglobin 1989;13:649–55.
.Kato GJ, Gladwin MT, Steinberg MH. Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Rev 2007;21:37–47.
Murphy JR, Wengard M, Brereton W. Rheological studies of Hb SS blood: influence of hematocrit, hypertonicity, separation of cells, deoxygenation, and mixture with normal cells. J Lab Clin Med 1976;87:475–86.
Fabry ME, Kaul DK, Raventos-Suarez C, Chang H, Nagel RL. SC erythrocytes have an abnormally high intracellular hemoglobin concentration. Pathophysiological consequences. J Clin Invest 1982;70:1315–9.
Stuart J, Johnson CS. Rheology of the sickle cell disorders. Baillieres Clin Haematol 1987;1:747–75.
Lionnet F, Hammoudi N, Stojanovic KS, et al. Hemoglobin sickle cell disease complications: a clinical study of 179 cases. Haematologica 2012;97:1136-41.
Adamkiewicz TV, Sarnaik S, Buchanan GR, et al. Invasive pneumococcal infections in children with sickle cell disease in the era of penicillin prophylaxis, antibiotic resistance, and 23-valent pneumococcal polysaccharide vaccination. J Pediatr 2003;143:438–44.
Abboud MR, Yim E, Musallam KM, Adams RJ, Investigators SIS. Discontinuing prophylactic transfusions increases the risk of silent brain infarction in children with sickle cell disease: data from STOP II. Blood 2011;118:894–8.
Adams RJ. Lessons from the Stroke Prevention Trial in Sickle Cell Anemia (STOP) study. J Child Neurol 2000;15:344–9.
Adams RJ, Brambilla DJ, Granger S, et al. Stroke and conversion to high risk in children screened with transcranial Doppler ultrasound during the STOP study. Blood 2004;103:3689–94.
Lee MT, Piomelli S, Granger S, et al. Stroke Prevention Trial in Sickle Cell Anemia (STOP): extended follow-up and final results. Blood 2006;108:847–52.
Charache S, Dover GJ, Moore RD, et al. Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia. Blood 1992;79:2555–65.
Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med 1995;332:1317–22.
Charache S. Mechanism of action of hydroxyurea in the management of sickle cell anemia in adults. Semin Hematol 1997;34:15–21.
Steinberg MH, McCarthy WF, Castro O, et al. The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: A 17.5 year follow-up. Am J Hematol 2010;85:403–8.
Noguchi CT, Rodgers GP, Serjeant G, Schechter AN. Levels of fetal hemoglobin necessary for treatment of sickle cell disease. N Engl J Med 1988;318:96–9.
Powars DR, Weiss JN, Chan LS, Schroeder WA. Is there a threshold level of fetal hemoglobin that ameliorates morbidity in sickle cell anemia? Blood 1984;63:921–6.
Maier-Redelsperger M, de Montalembert M, Flahault A, et al. Fetal hemoglobin and F-cell responses to long-term hydroxyurea treatment in young sickle cell patients. The French Study Group on Sickle Cell Disease. Blood 1998;91:4472–9.
Steinberg MH, Chui DH, Dover GJ, et al. Fetal hemoglobin in sickle cell anemia: a glass half full? Blood 2014;123:481–5.
Adragna NC, Fonseca P, Lauf PK. Hydroxyurea affects cell morphology, cation transport, and red blood cell adhesion in cultured vascular endothelial cells. Blood 1994;83:553–60.
Bridges KR, Barabino GD, Brugnara C, et al. A multiparameter analysis of sickle erythrocytes in patients undergoing hydroxyurea therapy. Blood 1996;88:4701–10.
Jiang J, Jordan SJ, Barr DP, et al. In vivo production of nitric oxide in rats after administration of hydroxyurea. Mol Pharmacol 1997;52:1081–6.
Ware RE. How I use hydroxyurea to treat young patients with sickle cell anemia. Blood 2010;115:5300–11.
Yates AM, Dedeken L, Smeltzer MP, et al. Hydroxyurea treatment of children with hemoglobin SC disease. Pediatr Blood Cancer 2013;60:323–5.
Barbosa CG, Aleluia AC, Pacheco AP, et al. Genetic modulation of HbF in Brazilians with HbSC disease and sickle cell anemia. Am J Hematol 2013;88:923–4.
Hsieh MM, Kang EM, Fitzhugh CD, et al. Allogeneic hematopoietic stem-cell transplantation for sickle cell disease. N Engl J Med 2009;361:2309–17.
King A, Shenoy S. Evidence-based focused review of the status of hematopoietic stem cell transplantation as treatment of sickle cell disease and thalassemia. Blood 2014;123:3089–94.
Oringanje C, Nemecek E, Oniyangi O. Hematopoietic stem cell transplantation for people with sickle cell disease. Cochrane Database Syst Rev 2013;5:CD007001.
Freed J, Talano J, Small T, et al. Allogeneic cellular and autologous stem cell therapy for sickle cell disease: ‘whom, when and how’. Bone Marrow Transplant 2012;47:1489–98.
Urbinati F, Hargrove PW, Geiger S, et al. Potentially therapeutic levels of anti-sickling globin gene expression following lentivirus-mediated gene transfer in sickle cell disease bone marrow CD34 cells. Exp Hematol 2015;43:346–51.
Brugnara C, Mohandas N. Red cell indices in classification and treatment of anemias: from M.M. Wintrobes’s original 1934 classification to the third millennium. Curr Opin Hematol 2013;20:222–30.
Key NS, Derebail VK. Sickle-cell trait: novel clinical significance. Hematology Am Soc Hematol Educ Program 2010;2010:418–22.
Kark JA, Posey DM, Schumacher HR, Ruehle CJ. Sickle-cell trait as a risk factor for sudden death in physical training. N Engl J Med 1987;317:781–7.
Goldsmith JC, Bonham VL, Joiner CH, et al. Framing the research agenda for sickle cell trait: building on the current understanding of clinical events and their potential implications. Am J Hematol 2012;87:340–6.
Grant AM, Parker CS, Jordan LB, et al. Public health implications of sickle cell trait: a report of the CDC meeting. Am J Prev Med 2011;41:S435–9.
Ballas SK, Lusardi M. Hospital readmission for adult acute sickle cell painful episodes: frequency, etiology, and prognostic significance. Am J Hematol 2005;79:17–25.
Serjeant GR, Ceulaer CD, Lethbridge R, et al. The painful crisis of homozygous sickle cell disease: clinical features. Br J Haematol 1994;87:586–91.
Vichinsky EP, Johnson R, Lubin BH. Multidisciplinary approach to pain management in sickle cell disease. Am J Pediatr Hematol Oncol 1982;4:328–33.
Gil KM, Carson JW, Porter LS, et al. Daily mood and stress predict pain, health care use, and work activity in African American adults with sickle-cell disease. Health Psychol 2004;23:267–74.
Amjad H, Bannerman RM, Judisch JM. Letter: Sickling pain and season. Br Med J 1974;2:54.
Ibrahim AS. Relationship between meteorological changes and occurrence of painful sickle cell crises in Kuwait. Trans R Soc Trop Med Hyg 1980;74:159–61.
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;131:530–3.
Resar LM, Oski FA. Cold water exposure and vaso-occlusive crises in sickle cell anemia. J Pediatr 1991;118:407–9.
Darbari DS, Ballas SK, Clauw DJ. Thinking beyond sickling to better understand pain in sickle cell disease. Eur J Haematol 2014;93:89–95.
Darbari DS, Onyekwere O, Nouraie M, et al. Markers of severe vaso-occlusive painful episode frequency in children and adolescents with sickle cell anemia. J Pediatr 2011;160:286–90.
Hollins M, Stonerock GL, Kisaalita NR, et al. Detecting the emergence of chronic pain in sickle cell disease. J Pain Symptom Manage 2012;43:1082–93.
Ballas SK, Darbari DS. Neuropathy, neuropathic pain, and sickle cell disease. Am J Hematol 2013;88:927–9.
Brandow AM, Farley RA, Panepinto JA. Early insights into the neurobiology of pain in sickle cell disease: A systematic review of the literature. Pediatr Blood Cancer 2015 May 13. doi: 10.1002/pbc.25574. [Epub ahead of print].
Brandow AM, Farley RA, Panepinto JA. Neuropathic pain in patients with sickle cell disease. Pediatr Blood Cancer 2014;61:512–7.
Brandow AM, Farley RA, Dasgupta M, et al. The use of neuropathic pain drugs in children with sickle cell disease is associated with older age, female sex, and longer length of hospital stay. J Pediatr Hematol Oncol 2015;37:10–5.
Walker TM, Hambleton IR, Serjeant GR. Gallstones in sickle cell disease: observations from The Jamaican Cohort study. J Pediatr 2000;136:80–5.
Penner E, Mayr WR, Djawan S, et al. [The genetics of Gilbert syndrome]. Schweiz Med Wochenschr 1976;106:860–2. [German]
Powell RW, Levine GL, Yang YM, Mankad VN. Acute splenic sequestration crisis in sickle cell disease: early detection and treatment. J Pediatr Surg 1992;27:215–8.
Al Salem AH, Qaisaruddin S, Nasserullah Z, et al. Splenectomy and acute splenic sequestration crises in sickle cell disease. Pediatr Surg Int 1996;11:26–8.
Pearson HA, Spencer RP, Cornelius EA. Functional asplenia in sickle-cell anemia. N Engl J Med 1969;281:923–6.
Wang WC, Ware RE, Miller ST, et al. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet 2011;377:1663–72.
Brousse V, Buffet P, Rees D. The spleen and sickle cell disease: the sick(led) spleen. Br J Haematol 2014;166:165–76.
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;302:374–9.
Michel JB, Hernandez JA, Buchanan GR. A fatal case of acute splenic sequestration in a 53–year-old woman with sickle-hemoglobin C disease. Am J Med 1992;92:97–100.
Hatton CS, Bunch C, Weatherall DJ. Hepatic sequestration in sickle cell anaemia. Br Med J (Clin Res Ed) 1985;290:744–5.
Castro O, Brambilla DJ, Thorington B, et al. The acute chest syndrome in sickle cell disease: incidence and risk factors. The Cooperative Study of Sickle Cell Disease. Blood 1994;84:643–9.
Gill FM, Sleeper LA, Weiner SJ, et al. Clinical events in the first decade in a cohort of infants with sickle cell disease. Cooperative Study of Sickle Cell Disease. Blood 1995;86:776–83.
Owusu-Ofori S, Hirst C. Splenectomy versus conservative management for acute sequestration crises in people with sickle cell disease. Cochrane Database Syst Rev 2013;5:CD003425.
00.Al-Salem AH. Splenic complications of sickle cell anemia and the role of splenectomy. ISRN Hematol 2011;2011:864257.
Sabarense AP, Lima GO, Silva LM, Viana MB. Characterization of mortality in children with sickle cell disease diagnosed through the Newborn Screening Program. J Pediatr (Rio J) 2015;91:242–7.
Aslam AF, Aslam AK, Dipillo F. Fatal splenic sequestration crisis with multiorgan failure in an adult woman with sickle cell-beta+ thalassemia. Am J Med Sci 2005;329:141–3.
Berry RA, Odumakinde EA, Lewis JP. Massive splenic infarction in doubly abnormal heterozygous sickling disorders. A new complication of acute splenic sequestration syndrome. The West J Med 1991;155:531–2.
Bonanomi MT, Lavezzo MM. Sickle cell retinopathy: diagnosis and treatment. Arq Bras de Oftalmol 2013;76:320–7.
Chen RW, Flynn HW Jr, Lee WH, et al. Vitreoretinal management and surgical outcomes in proliferative sickle retinopathy: a case series. Am J Ophthalmol 2014;157:870–5 e1.
Howard J, Malfroy M, Llewelyn C, et al. The Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) study: a randomised, controlled, multicentre clinical trial. Lancet 2013;381:930–8.
Neumayr L, Koshy M, Haberkern C, et al. Surgery in patients with hemoglobin SC disease. Preoperative Transfusion in Sickle Cell Disease Study Group. Am J Hematol 1998;57:101–8.
08. Savage WJ, Buchanan GR, Yawn BP, et al. Evidence gaps in the management of sickle cell disease: A summary of needed research. Am J Hematol 2015;90:273–5.
Charache S, Barton FB, Moore RD, et al. Hydroxyurea and sickle cell anemia. Clinical utility of a myelosuppressive “switching” agent. The Multicenter Study of Hydroxyurea in Sickle Cell Anemia. Medicine (Baltimore) 1996;75:300–26.
Steinberg MH, Nagel RL, Brugnara C. Cellular effects of hydroxyurea in Hb SC disease. Br J Haematol 1997;98:838–44.
Wang W, Brugnara C, Snyder C, et al. The effects of hydroxycarbamide and magnesium on haemoglobin SC disease: results of the multi-centre CHAMPS trial. Br J Haematol 2011;152:771–6.
Jungst C, Kullak-Ublick GA, Jungst D. Gallstone disease: Microlithiasis and sludge. Best Pract Res Clin Gastroenterol 2006;20:1053–62.
Walker TM, Serjeant GR. Biliary sludge in sickle cell disease. J Pediatr 1996;129:443–5.
Bauer TW, Moore GW, Hutchins GM. The liver in sickle cell disease. A clinicopathologic study of 70 patients. Am J Med 1980;69:833–7.
Ebert EC, Nagar M, Hagspiel KD. Gastrointestinal and hepatic complications of sickle cell disease. Clin Gastroenterol Hepatol 2010;8:483–9.
Hiran S. Multiorgan dysfunction syndrome in sickle cell disease. J Assoc Physicians India 2005;53:19–22.
Shao SH, Orringer EP. Case report: splenic sequestration and multiorgan failure as the presenting manifestation of hemoglobin SC disease. Am J Med Sci 1996;311:139–41.
Hassell KL, Eckman JR, Lane PA. Acute multiorgan failure syndrome: a potentially catastrophic complication of severe sickle cell pain episodes. Am J Med 1994;96:155–62.

Sickle Cell Disease

References

INTRODUCTION

PATHOPHYSIOLOGY

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