Abstract

Sickle cell disease (SCD) is a group of inherited disorders caused by mutations in HBB, which encodes haemoglobin subunit β. The incidence is estimated to be between 300,000 and 400,000 neonates globally each year, the majority in sub-Saharan Africa. Haemoglobin molecules that include mutant sickle β-globin subunits can polymerize; erythrocytes that contain mostly haemoglobin polymers assume a sickled form and are prone to haemolysis. Other pathophysiological mechanisms that contribute to the SCD phenotype are vaso-occlusion and activation of the immune system. SCD is characterized by a remarkable phenotypic complexity. Common acute complications are acute pain events, acute chest syndrome and stroke; chronic complications (including chronic kidney disease) can damage all organs. Hydroxycarbamide, blood transfusions and haematopoietic stem cell transplantation can reduce the severity of the disease. Early diagnosis is crucial to improve survival, and universal newborn screening programmes have been implemented in some countries but are challenging in low-income, high-burden settings.

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References

  1. 1.

    The inheritance of sickle cell anemia. Science 110, 64–66 (1949).

  2. 2.

    & Genetic modifiers of sickle cell disease. Am. J. Hematol. 87, 795–803 (2012).

  3. 3.

    et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N. Engl. J. Med. 330, 1639–1644 (1994). This landmark natural history study established life expectancy and risk factors for mortality for SCD in the United States.

  4. 4.

    , & Sickle cell disease. N. Engl. J. Med. 376, 1561–1573 (2017).

  5. 5.

    , , & Sickle cell disease. Lancet 390, 311–323 (2017).

  6. 6.

    & Management of sickle cell disease; lessons from the Jamaican Cohort Study. Blood Rev. 7, 137–145 (1993).

  7. 7.

    Three decades of innovation in the management of sickle cell disease: the road to understanding the sickle cell disease clinical phenotype. Blood Rev. 19, 99–110 (2005).

  8. 8.

    , , & Improved survival of children and adolescents with sickle cell disease. Blood 115, 3447–3452 (2010).

  9. 9.

    et al. Survival in adults with sickle cell disease in a high-income setting. Blood 128, 1436–1438 (2016).

  10. 10.

    et al. Sickle cell disease in Africa: a neglected cause of early childhood mortality. Am. J. Prev. Med. 41, S398–405 (2011).

  11. 11.

    Protection afforded by sickle-cell trait against subtertian malarial infection. BMJ 1, 290–294 (1954).

  12. 12.

    Sickle cell anaemia and malaria. Mediterr. J. Hematol. Infect. Dis. 4, e2012065 (2012).

  13. 13.

    et al. Global distribution of the sickle cell gene and geographical confirmation of the malaria hypothesis. Nat. Commun. 1, 104 (2010).

  14. 14.

    et al. Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates. Lancet 381, 142–151 (2013).

  15. 15.

    The importance of micromapping the gene frequencies for the common inherited disorders of haemoglobin. Br. J. Haematol. 149, 635–637 (2010).

  16. 16.

    et al. The distribution of haemoglobin C and its prevalence in newborns in Africa. Sci. Rep. 3, 1671 (2013).

  17. 17.

    , , , & Global burden of sickle cell anaemia in children under five, 2010-2050: modelling based on demographics, excess mortality, and interventions. PLoS Med. 10, e1001484 (2013). This study places the disease burden of SCA into a global perspective.

  18. 18.

    & Sickle cell disease in sub-Saharan Africa: stakes and strategies for control of the disease. Curr. Opin. Hematol. 21, 210–214 (2014).

  19. 19.

    , , & Newborn screening for sickle cell diseases in the United States: a review of data spanning 2 decades. Semin. Perinatol. 39, 238–251 (2015).

  20. 20.

    NHS Sickle Cell and Thalassaemia Screening Programme Data Report 2015/16: Trends and Performance Analysis (Public Health England, 2017).

  21. 21.

    & History and current status of newborn screening for hemoglobinopathies. Semin. Perinatol. 34, 134–144 (2010).

  22. 22.

    , , , & Birth prevalence of disorders detectable through newborn screening by race/ethnicity. Genet. Med. 14, 937–945 (2012).

  23. 23.

    et al. Incidence of sickle cell trait — United States, 2010. MMWR Morb. Mortal. Wkly Rep. 63, 1155–1158 (2014).

  24. 24.

    et al. Sickle cell disease incidence among newborns in New York State by maternal race/ethnicity and nativity. Genet. Med. 15, 222–228 (2013).

  25. 25.

    Ministry of Health Brazil. Sickle Cell disease: what you should know about genetic inheritance, 2014 [Portuguese]. Ministério da Saúde (2014).

  26. 26.

    et al. Screening for structural hemoglobin variants in Bahia, Brazil. Int. J. Environ. Res. Publ. Health 13, 225 (2016).

  27. 27.

    et al. Newborn screening program for hemoglobinopathies in Rio de Janeiro, Brazil. Pediatr. Blood Cancer 61, 34–39 (2014).

  28. 28.

    , , , & Guidelines on neonatal screening and painful vaso-occlusive crisis in sickle cell disease: Associacao Brasileira de Hematologia, Hemoterapia e Terapia Celular: Project guidelines: Associacao Medica Brasileira - 2016. Rev. Bras. Hematol. Hemoter. 38, 147–157 (2016).

  29. 29.

    et al. Prevalence of sickle cell disease and sickle cell trait in national neonatal screening studies. Rev. Bras. Hematol. Hemoter. 33, 49–54 (2011).

  30. 30.

    et al. Newborn screening for sickle cell disease in Brazil: the Campinas experience. Clin. Lab. Haematol. 26, 15–19 (2004).

  31. 31.

    Predicting clinical severity in sickle cell anaemia. Br. J. Haematol. 129, 465–481 (2005).

  32. 32.

    et al. Fetal hemoglobin in sickle cell anemia: genetic studies of the Arab-Indian haplotype. Blood Cells Mol. Dis. 51, 22–26 (2013).

  33. 33.

    et al. Variable phenotypes of sickle cell disease in India with the Arab-Indian haplotype. Br. J. Haematol. 168, 156–159 (2015).

  34. 34.

    et al. Clinical, hematologic and molecular variability of sickle cell-beta thalassemia in western India. Indian J. Hum. Genet. 16, 154–158 (2010).

  35. 35.

    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. 131, 530–533 (2005).

  36. 36.

    , , , & Environmental determinants of severity in sickle cell disease. Haematologica 100, 1108–1116 (2015).

  37. 37.

    , , , & Leg ulcers in sickle cell disease. Am. J. Hematol. 85, 831–833 (2010).

  38. 38.

    & Priapism is rare in sickle cell disease in India. J. Assoc. Physicians India 48, 255 (2000).

  39. 39.

    et al. High mortality from Plasmodium falciparum malaria in children living with sickle cell anemia on the coast of Kenya. Blood 116, 1663–1668 (2010).

  40. 40.

    et al. Bacteraemia in Kenyan children with sickle-cell anaemia: a retrospective cohort and case-control study. Lancet 374, 1364–1370 (2009).

  41. 41.

    The inherited diseases of hemoglobin are an emerging global health burden. Blood 115, 4331–4336 (2010).

  42. 42.

    Pathophysiology of sickle cell disease. Baillieres Clin. Haematol. 11, 163–184 (1998).

  43. 43.

    et al. Correction of sickle cell disease in transgenic mouse models by gene therapy. Science 294, 2368–2371 (2001).

  44. 44.

    Sickle-cell haemoglobin polymerization: is it the primary pathogenic event of sickle-cell anaemia? Br. J. Haematol. 139, 173–184 (2007).

  45. 45.

    , , & Erythrocyte Hb-S concentration. An important factor in the low oxygen affinity of blood in sickle cell anemia. J. Clin. Invest. 52, 422–432 (1973).

  46. 46.

    et al. Sickle hemoglobin disturbs normal coupling among erythrocyte O2 content, glycolysis, and antioxidant capacity. Blood 121, 1651–1662 (2013).

  47. 47.

    et al. Elevated sphingosine-1-phosphate promotes sickling and sickle cell disease progression. J. Clin. Invest. 124, 2750–2761 (2014).

  48. 48.

    et al. Sphingosine-1-phosphate promotes erythrocyte glycolysis and oxygen release for adaptation to high-altitude hypoxia. Nat. Commun. 7, 12086 (2016).

  49. 49.

    et al. Elevated adenosine signaling via adenosine A2B receptor induces normal and sickle erythrocyte sphingosine kinase 1 activity. Blood 125, 1643–1652 (2015).

  50. 50.

    & Sickle haemoglobin polymerization in solution and in cells. Annu. Rev. Biophys. Biophys. Chem. 14, 239–263 (1985)

  51. 51.

    et al. The role of blood rheology in sickle cell disease. Blood Rev. 30, 111–118 (2016).

  52. 52.

    , & The irreversibly sickled cell. Am. J. Pediatr. Hematol. Oncol. 4, 307–315 (1982).

  53. 53.

    & Membrane-associated sickle hemoglobin: a major determinant of sickle erythrocyte rigidity. Blood 70, 1443–1449 (1987).

  54. 54.

    , & Rheologic impairment of sickle RBCs induced by repetitive cycles of deoxygenation-reoxygenation. Blood 72, 539–545 (1988).

  55. 55.

    Hemoglobin s polymerization and red cell membrane changes. Hematol. Oncol. Clin. North Am. 28, 155–179 (2014).

  56. 56.

    & Some morphological consequences of uncoupling the lipid bilayer from the plasma membrane skeleton in intact erythrocytes. Biomed. Biochim. Acta 42, S11–16 (1983).

  57. 57.

    , , , & Transmembrane mobility of phospholipids in sickle erythrocytes: effect of deoxygenation on diffusion and asymmetry. Blood 77, 849–854 (1991).

  58. 58.

    , , , & Loss of phospholipid asymmetry and surface exposure of phosphatidylserine is required for phagocytosis of apoptotic cells by macrophages and fibroblasts. J. Biol. Chem. 276, 1071–1077 (2001).

  59. 59.

    Membrane lipid alterations in hemoglobinopathies. Hematol. Am. Soc. Hematol. Educ. Program 2007, 68–73 (2007).

  60. 60.

    & The role of phosphatidylserine in recognition and removal of erythrocytes. Cell. Mol. Biol. 50, 147–158 (2004).

  61. 61.

    , & Circulating microparticles: pathophysiology and clinical implications. Blood Rev. 21, 157–171 (2007).

  62. 62.

    et al. Microvesicles in haemoglobinopathies offer insights into mechanisms of hypercoagulability, haemolysis and the effects of therapy. Br. J. Haematol. 142, 126–135 (2008).

  63. 63.

    & Red blood cell-derived microparticles: an overview. Blood Cells Mol. Dis. 59, 134–139 (2016).

  64. 64.

    & Microparticles in sickle cell anaemia: promise and pitfalls. Br. J. Haematol. 174, 16–29 (2016).

  65. 65.

    Oxidative pathways in the sickle cell and beyond. Blood Cells Mol. Dis. (2017).

  66. 66.

    , & Shedding light on the cell biology of extracellular vesicles. Nat. Rev. Mol. Cell Biol. (2018).

  67. 67.

    et al. Biochemical surrogate markers of hemolysis do not correlate with directly measured erythrocyte survival in sickle cell anemia. Am. J. Hematol. 91, 1195–1201 (2016).

  68. 68.

    The metabolism of hemoglobin and bile pigment in hemolytic disease. Am. J. Med. 18, 112–122 (1955).

  69. 69.

    et al. Pulmonary hypertension and nitric oxide depletion in sickle cell disease. Blood 116, 687–692 (2010).

  70. 70.

    , & Intravascular hemolysis and the pathophysiology of sickle cell disease. J. Clin. Invest. 127, 750–760 (2017). This is a comprehensive review of the contribution of haemolysis to SCD pathophysiology.

  71. 71.

    & Sickle cell disease: role of reactive oxygen and nitrogen metabolites. Clin. Exp. Pharmacol. Physiol. 34, 926–932 (2007).

  72. 72.

    & Redox-dependent impairment of vascular function in sickle cell disease. Free Radic. Biol. Med. 43, 1469–1483 (2007).

  73. 73.

    et al. Hydroxyurea-induced expression of glutathione peroxidase 1 in red blood cells of individuals with sickle cell anemia. Antioxid. Redox Signal. 13, 1–11 (2010).

  74. 74.

    et al. Erythrocyte glutamine depletion, altered redox environment, and pulmonary hypertension in sickle cell disease. Blood 111, 402–410 (2008).

  75. 75.

    et al. Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nat. Med. 8, 1383–1389 (2002).

  76. 76.

    et al. Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease. JAMA 294, 81–90 (2005).

  77. 77.

    , , & Remaining mysteries of molecular biology: the role of polyamines in the cell. J. Mol. Biol. 427, 3389–3406 (2015).

  78. 78.

    et al. Plasma asymmetric dimethylarginine concentrations in sickle cell disease are related to the hemolytic phenotype. Blood Cells Mol. Dis. 44, 229–232 (2010).

  79. 79.

    et al. Association of plasma asymmetrical dimethylarginine (ADMA) with elevated vascular superoxide production and endothelial nitric oxide synthase uncoupling: implications for endothelial function in human atherosclerosis. Eur. Heart J. 30, 1142–1150 (2009).

  80. 80.

    , , & Molecular mechanisms of endothelial NO synthase uncoupling. Curr. Pharm. Des. 20, 3548–3553 (2014).

  81. 81.

    et al. Lipid levels in sickle-cell disease associated with haemolytic severity, vascular dysfunction and pulmonary hypertension. Br. J. Haematol. 149, 436–445 (2010).

  82. 82.

    et al. Apolipoprotein A-I and serum amyloid A plasma levels are biomarkers of acute painful episodes in patients with sickle cell disease. Haematologica 95, 1467–1472 (2010).

  83. 83.

    et al. APOL1, alpha-thalassemia, and BCL11A variants as a genetic risk profile for progression of chronic kidney disease in sickle cell anemia. Haematologica 102, e1–e6 (2017).

  84. 84.

    & Erythroid DAMPs drive inflammation in SCD. Blood 123, 3689–3690 (2014).

  85. 85.

    et al. Heme-bound iron activates placenta growth factor in erythroid cells via erythroid Kruppel-like factor. Blood 124, 946–954 (2014).

  86. 86.

    et al. Iron, inflammation, and early death in adults with sickle cell disease. Circ. Res. 116, 298–306 (2015).

  87. 87.

    Adhesive interactions of sickle erythrocytes with endothelium. J. Clin. Invest. 100, S83–86 (1997).

  88. 88.

    et al. Monoclonal antibodies to alphaVbeta3 (7E3 and LM609) inhibit sickle red blood cell-endothelium interactions induced by platelet-activating factor. Blood 95, 368–374 (2000).

  89. 89.

    & Vascular cell adhesion molecule-1 is involved in mediating hypoxia-induced sickle red blood cell adherence to endothelium: potential role in sickle cell disease. Blood 88, 2311–2320 (1996).

  90. 90.

    et al. Novel epinephrine and cyclic AMP-mediated activation of BCAM/Lu-dependent sickle (SS) RBC adhesion. Blood 101, 3281–3287 (2003).

  91. 91.

    , & Sickle cell adhesion depends on hemodynamics and endothelial activation. J. Lab Clin. Med. 144, 260–268 (2004).

  92. 92.

    et al. Role of Rap1 in promoting sickle red blood cell adhesion to laminin via BCAM/LU. Blood 105, 3322–3329 (2005).

  93. 93.

    , , & Thrombospondin mediates adherence of CD36+ sickle reticulocytes to endothelial cells. Blood 80, 2634–2642 (1992).

  94. 94.

    et al. Prediction of adverse outcomes in children with sickle cell disease. N. Engl. J. Med. 342, 83–89 (2000).

  95. 95.

    et al. Factors associated with survival in a contemporary adult sickle cell disease cohort. Am. J. Hematol. 89, 530–535 (2014).

  96. 96.

    , , & Neutrophils, platelets, and inflammatory pathways at the nexus of sickle cell disease pathophysiology. Blood 127, 801–809 (2016). This is an updated review of the principal adhesive pathways involved in SCD vaso-occlusion.

  97. 97.

    et al. Participation of Mac-1, LFA-1 and VLA-4 integrins in the in vitro adhesion of sickle cell disease neutrophils to endothelial layers, and reversal of adhesion by simvastatin. Haematologica 96, 526–533 (2011).

  98. 98.

    et al. Prominent role of platelets in the formation of circulating neutrophil-red cell heterocellular aggregates in sickle cell anemia. Haematologica 99, e214–e217 (2014).

  99. 99.

    et al. A novel inflammatory role for platelets in sickle cell disease. Platelets 26, 726–729 (2015).

  100. 100.

    Prenatal and newborn screening for hemoglobinopathies. Int. J. Lab. Hematol. 35, 297–305 (2013).

  101. 101.

    Pre-implantation genetic diagnosis. Best Pract. Res. Clin. Obstet. Gynaecol. 39, 74–88 (2017).

  102. 102.

    , & Newborn screening for sickle cell disease: A 1988–2003 Quebec experience. Paediatr. Child Health 11, 223–227 (2006).

  103. 103.

    , , , & Newborn screening for sickle cell disease: effect on mortality. Pediatrics 81, 749–755 (1988).

  104. 104.

    et al. Prophylaxis with oral penicillin in children with sickle cell anemia. A randomized trial. N. Engl. J. Med. 314, 1593–1599 (1986). This study provides proof that penicillin prophylaxis reduces mortality, which marked a turning point for life expectancy in SCA.

  105. 105.

    & Epidemiology of sickle cell disorder in the state of Maharashtra. Int. J. Hum. Genet. 2, 161–167 (2002).

  106. 106.

    , , & The Chhattisgarh state screening programme for the sickle cell gene: a cost-effective approach to a public health problem. J. Commun. Genet. 6, 361–368 (2015).

  107. 107.

    & Sickle cell trait diagnosis: clinical and social implications. Hematol. Am. Soc. Hematol. Educ. Program 2015, 160–167 (2015).

  108. 108.

    et al. Sickle cell trait, rhabdomyolysis, and mortality among U. S. army soldiers. N. Engl. J. Med. 375, 435–442 (2016).

  109. 109.

    , & Negative health implications of sickle cell trait in high income countries: from the football field to the laboratory. Br. J. Haematol. 170, 5–14 (2015).

  110. 110.

    , & Positive screening and carrier results for the England-wide universal newborn sickle cell screening programme by ethnicity and area for 2005–2007. J. Clin. Pathol. 63, 626–629 (2010).

  111. 111.

    et al. Neonatal screening for sickle cell disease in France: evaluation of the selective process. J. Clin. Pathol. 63, 548–551 (2010).

  112. 112.

    & Neonatal haemoglobinopathy screening in Spain. J. Clin. Pathol. 62, 22–25 (2009).

  113. 113.

    et al. Organizing national responses for rare blood disorders: the Italian experience with sickle cell disease in childhood. Orphanet J. Rare Dis. 8, 169 (2013).

  114. 114.

    et al. Significant prevalence of sickle cell disease in Southwest Germany: results from a birth cohort study indicate the necessity for newborn screening. Ann. Hematol. 95, 397–402 (2016).

  115. 115.

    , , & Newborn screening programs and sickle cell disease: a public health services and systems approach. Am. J. Prev. Med. 51, S39–S47 (2016).

  116. 116.

    , , & Sickle cell disease in tribal populations in India. Indian J. Med. Res. 141, 509–515 (2015).

  117. 117.

    & Hemoglobin disorders in South India. ISRN Hematol. 2011, 748939 (2011).

  118. 118.

    et al. Hydroxyurea in sickle cell disease — a study of clinico-pharmacological efficacy in the Indian haplotype. Blood Cells Mol. Dis. 42, 25–31 (2009).

  119. 119.

    & Epidemiology of sickle cell disease in a rural hospital of central India. Indian Pediatr. 37, 391–396 (2000).

  120. 120.

    & Sickle-cell trait in Central India. Lancet 1, 297–298 (1958).

  121. 121.

    et al. Current status of newborn screening worldwide: 2015. Semin. Perinatol. 39, 171–187 (2015).

  122. 122.

    , , & Screening newborns for sickle cell disease in Ghana. Pediatrics 121 (Suppl. 2), S120–S121(2008).

  123. 123.

    et al. A prospective newborn screening and treatment program for sickle cell anemia in Luanda, Angola. Am. J. Hematol. 88, 984–989 (2013).

  124. 124.

    , , & Newborn screening for sickle cell disease in the Republic of Benin. J. Clin. Pathol. 62, 46–48 (2009).

  125. 125.

    et al. Neonatal haemoglobinopathy screening in Burkina Faso. J. Clin. Pathol. 62, 39–41 (2009).

  126. 126.

    et al. Neonatal screening for sickle cell disease in Central Africa: a study of 1825 newborns with a new enzyme-linked immunosorbent assay test. J. Med. Screen. 14, 113–116 (2007).

  127. 127.

    et al. Neonatal screening for sickle cell anaemia in the Democratic Republic of the Congo: experience from a pioneer project on 31 204 newborns. J. Clin. Pathol. 62, 35–38 (2009).

  128. 128.

    , & Newborn screening for sickle cell disease in a Nigerian hospital. Publ. Health 122, 1111–1116 (2008).

  129. 129.

    et al. Sickle cell disease neonatal screening. First evaluation [French]. Dakar Med. 48, 202–205 (2003).

  130. 130.

    et al. Health policy for sickle cell disease in Africa: experience from Tanzania on interventions to reduce under-five mortality. Trop. Med. Int. Health 20, 184–187 (2015).

  131. 131.

    et al. Burden of sickle cell trait and disease in the Uganda Sickle Surveillance Study (US3): a cross-sectional study. Lancet Global Health 4, e195–e200 (2016).

  132. 132.

    The natural history of sickle cell disease. Cold Spring Harb. Perspect. Med. 3, a011783 (2013).

  133. 133.

    & Genomic polymorphisms in sickle cell disease: implications for clinical diversity and treatment. Expert Rev. Hematol. 3, 443–458 (2010).

  134. 134.

    , & Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Rev. 21, 37–47 (2007).

  135. 135.

    & Fetal haemoglobin in sickle-cell disease: from genetic epidemiology to new therapeutic strategies. Lancet 387, 2554–2564 (2016).

  136. 136.

    , , , & Fetal hemoglobin in sickle cell anemia: a glass half full? Blood 123, 481–485 (2014).

  137. 137.

    et al. A GCH1 haplotype confers sex-specific susceptibility to pain crises and altered endothelial function in adults with sickle cell anemia. Am. J. Hematol. 89, 187–193 (2014).

  138. 138.

    , , , & Patients with sickle cell disease have increased sensitivity to cold and heat. Am. J. Hematol. 88, 37–43 (2013).

  139. 139.

    , & Survival of children with sickle cell disease. Blood 103, 4023–4027 (2004).

  140. 140.

    Psychological complications in sickle cell disease. Br. J. Haematol. 129, 723–729 (2005).

  141. 141.

    The challenge of haemoglobinopathies in resource-poor countries. Br. J. Haematol. 154, 736–744 (2011).

  142. 142.

    & The case for and against initiating either hydroxyurea therapy, blood transfusion therapy or hematopoietic stem cell transplant in asymptomatic children with sickle cell disease. Expert Opin. Pharmacother. 15, 325–336 (2014).

  143. 143.

    & Hydroxyurea therapy for sickle cell anemia. Expert Opin. Drug Saf. 14, 1749–1758 (2015).

  144. 144.

    et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N. Engl. J. Med. 332, 1317–1322 (1995). This landmark trial proved that hydroxycarbamide reduces the frequency of pain episodes in SCA, leading to the approval of this drug.

  145. 145.

    et al. Medication adherence among pediatric patients with sickle cell disease: a systematic review. Pediatrics 134, 1175–1183 (2014).

  146. 146.

    , & Pharmacogenomics of sickle cell disease: steps toward personalized medicine. Pharmgenom. Pers. Med. 10, 261–265 (2017).

  147. 147.

    , , & Update on the use of hydroxyurea therapy in sickle cell disease. Blood 124, 3850–3857 (2014).

  148. 148.

    Hydroxyurea therapy contributes to infertility in adult men with sickle cell disease: a review. Expert Rev. Hematol. 7, 767–773 (2014).

  149. 149.

    et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N. Engl. J. Med. 376, 429–439 (2017).

  150. 150.

    et al. Hydroxyurea therapy for children with sickle cell anemia in sub-Saharan Africa: rationale and design of the REACH trial. Pediatr. Blood Cancer 63, 98–104 (2016).

  151. 151.

    et al. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet 377, 1663–1672 (2011). This article presents evidence that hydroxycarbamide is effective in infants and toddlers with SCA.

  152. 152.

    et al. A multinational trial of Prasugrel for sickle cell vaso-occlusive events. N. Engl. J. Med. 374, 625–635 (2016).

  153. 153.

    et al. Evidence review of hydroxyurea for the prevention of sickle cell complications in low-income countries. Arch. Dis. Child. 98, 908–914 (2013).

  154. 154.

    , , , & Frequent red cell transfusions reduced vascular endothelial activation and thrombogenicity in children with sickle cell anemia and high stroke risk. Am. J. Hematol. 89, 47–51 (2014).

  155. 155.

    et al. Effect of chronic blood transfusion on biomarkers of coagulation activation and thrombin generation in sickle cell patients at risk for stroke. PLoS ONE 10, e0134193 (2015).

  156. 156.

    & in Rossi's Principles of Transfusion Medicine (eds Simon T. L. et al.) (Wiley-Blackwell, 2016).

  157. 157.

    & Red blood cell antigen genotyping for sickle cell disease, thalassemia, and other transfusion complications. Transfus. Med. Rev. 30, 197–201 (2016).

  158. 158.

    et al. Indications and results of HLA-identical sibling hematopoietic cell transplantation for sickle cell disease. Biol. Blood Marrow Transplant. 22, 207–211 (2016).

  159. 159.

    et al. Sickle cell disease: an international survey of results of HLA-identical sibling hematopoietic stem cell transplantation. Blood 129, 1548–1556 (2017).

  160. 160.

    et al. Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype. JAMA 312, 48–56 (2014).

  161. 161.

    et al. Nonmyeloablative stem cell transplantation with alemtuzumab/low-dose irradiation to cure and improve the quality of life of adults with sickle cell disease. Biol. Blood Marrow Transplant. 22, 441–448 (2016).

  162. 162.

    Allogeneic transplantation strategies including haploidentical transplantation in sickle cell disease. Hematol. Am. Soc. Hematol. Educ. Program 2013, 370–376 (2013).

  163. 163.

    , & Sickle cell pain: a critical reappraisal. Blood 120, 3647–3656 (2012).

  164. 164.

    et al. A quality improvement initiative to improve emergency department care for pediatric patients with sickle cell disease. J. Clin. Outcomes Manag. 21, 62–70 (2014).

  165. 165.

    et al. Improving the management of vaso-occlusive episodes in the pediatric emergency department. Pediatrics 136, e1016–1025 (2015).

  166. 166.

    et al. A randomized controlled trial comparing two vaso-occlusive episode (VOE) protocols in sickle cell disease (SCD). Am. J. Hematol. 93, 159–168 (2018).

  167. 167.

    et al. Impact of a dedicated infusion clinic for acute management of adults with sickle cell pain crisis. Am. J. Hematol. 90, 376–380 (2015).

  168. 168.

    et al. The impact of race and disease on sickle cell patient wait times in the emergency department. Am. J. Emerg. Med. 31, 651–656 (2013).

  169. 169.

    et al. Patient-controlled analgesia versus continuous infusion of morphine during vaso-occlusive crisis in sickle cell disease, a randomized controlled trial. Am. J. Hematol. 82, 955–960 (2007).

  170. 170.

    , , , & Sickle cell disease: new opportunities and challenges in Africa. Sci. World J. 2013, 193252 (2013).

  171. 171.

    et al. Causes of death in sickle cell disease: an autopsy study. Br. J. Haematol. 123, 359–365 (2003).

  172. 172.

    & Crises in sickle cell disease. Chest 149, 1082–1093 (2016).

  173. 173.

    et al. Acute chest syndrome in sickle cell disease: clinical presentation and course. Blood 89, 1787–1792 (1997).

  174. 174.

    et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. N. Engl. J. Med. 342, 1855–1865 (2000). This study comprehensively establishes the causes and outcomes of acute chest syndrome.

  175. 175.

    & The intersection between asthma and acute chest syndrome in children with sickle-cell anaemia. Lancet 387, 2545–2553 (2016).

  176. 176.

    et al. Guideline on the management of acute chest syndrome in sickle cell disease. Br. J. Haematol. 169, 492–505 (2015).

  177. 177.

    et al. Beneficial effect of intravenous dexamethasone in children with mild to moderately severe acute chest syndrome complicating sickle cell disease. Blood 92, 3082–3089 (1998).

  178. 178.

    , , & How I treat and manage strokes in sickle cell disease. Blood 125, 3401–3410 (2015).

  179. 179.

    , , & How we treat delayed haemolytic transfusion reactions in patients with sickle cell disease. Br. J. Haematol. 170, 745–756 (2015).

  180. 180.

    , & Systemic corticosteroids in acute chest syndrome: friend or foe? Paediatr. Respir. Rev. 15, 24–27 (2014).

  181. 181.

    et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood 91, 288–294 (1998).

  182. 182.

    et al. Neuropsychological dysfunction and neuroimaging abnormalities in neurologically intact adults with sickle cell anemia. JAMA 303, 1823–1831 (2010).

  183. 183.

    et al. Silent cerebral infarcts: a review on a prevalent and progressive cause of neurologic injury in sickle cell anemia. Blood 119, 4587–4596 (2012).

  184. 184.

    & Stroke With Transfusions Changing to Hydroxyurea (SWiTCH). Blood 119, 3925–3932 (2012).

  185. 185.

    , , , & Primary hemorrhagic stroke in children with sickle cell disease is associated with recent transfusion and use of corticosteroids. Pediatrics 118, 1916–1924 (2006).

  186. 186.

    & Moyamoya disease and moyamoya syndrome. N. Engl. J. Med. 360, 1226–1237 (2009).

  187. 187.

    et al. Pial synangiosis for moyamoya syndrome in children with sickle cell anemia: a comprehensive review of reported cases. Neurosurg. Focus 36, E12 (2014).

  188. 188.

    et al. Acute splenic sequestration crisis in sickle cell disease: cohort study of 190 paediatric patients. Br. J. Haematol. 156, 643–648 (2012).

  189. 189.

    et al. The linear effects of alpha-thalassaemia, the UGT1A1 and HMOX1 polymorphisms on cholelithiasis in sickle cell disease. Br. J. Haematol. 138, 263–270 (2007).

  190. 190.

    , & A case series of cholecystectomy in Jamaican sickle cell disease patients — the need for a new strategy. Ann. Med. Surg. 15, 37–42 (2017).

  191. 191.

    , , , & Outcome of sickle cell anemia: a 4-decade observational study of 1056 patients. Medicine 84, 363–376 (2005).

  192. 192.

    et al. Pain site frequency and location in sickle cell disease: the PiSCES project. Pain 145, 246–251 (2009).

  193. 193.

    Update on pain management in sickle cell disease. Hemoglobin 35, 520–529 (2011).

  194. 194.

    et al. Frequency of hospitalizations for pain and association with altered brain network connectivity in sickle cell disease. J. Pain 16, 1077–1086 (2015).

  195. 195.

    et al. Physical therapy alone compared with core decompression and physical therapy for femoral head osteonecrosis in sickle cell disease. Results of a multicenter study at a mean of three years after treatment. J. Bone Joint Surg. Am. 88, 2573–2582 (2006).

  196. 196.

    et al. High one year mortality in adults with sickle cell disease and end-stage renal disease. Br. J. Haematol. 159, 360–367 (2012).

  197. 197.

    , & Sickle cell nephropathy at end-stage renal disease in the United States: patient characteristics and survival. Clin. Nephrol. 58, 9–15 (2002).

  198. 198.

    et al. Improved survival among sickle cell kidney transplant recipients in the recent era. Nephrol. Dial. Transplant. 28, 1039–1046 (2013).

  199. 199.

    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. 86, 203–205 (2011).

  200. 200.

    & 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. 91, 5–14 (2016).

  201. 201.

    et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA 312, 1033–1048 (2014).

  202. 202.

    et al. Evidence-Based Management of Sickle Cell Disease: Expert Panel Report 2014 (National Heart Lung and Blood Institute, 2014). This article presents detailed evidence-based guidelines for the clinical management of individuals with SCD.

  203. 203.

    et al. An official American Thoracic Society clinical practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease. Am. J. Respir. Crit. Care Med. 189, 727–740 (2014).

  204. 204.

    , , , & Serotype distribution of Streptococcus pneumoniae infections among preschool children in the United States, 1978-1994: implications for development of a conjugate vaccine. J. Infect. Dis. 171, 885–889 (1995).

  205. 205.

    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. 44, 1428–1433 (2007).

  206. 206.

    & Penicillin prophylaxis in children with sickle cell disease. J. Pediatr. Pharmacol. Ther. 15, 152–159 (2010).

  207. 207.

    & Preventing infections in sickle cell disease: the unfinished business. Pediatr. Blood Cancer 63, 781–785 (2016).

  208. 208.

    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. 339, 5–11 (1998). This study shows that ischaemic stroke can be prevented by chronic transfusion in children identified at high risk by non-invasive ultrasonography screening.

  209. 209.

    , & Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. N. Engl. J. Med. 353, 2769–2778 (2005).

  210. 210.

    , , , & Hydroxyurea therapy lowers transcranial Doppler flow velocities in children with sickle cell anemia. Blood 110, 1043–1047 (2007).

  211. 211.

    et al. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial. Lancet 387, 661–670 (2016).

  212. 212.

    et al. Primary stroke prevention in Nigerian children with sickle cell disease (SPIN): challenges of conducting a feasibility trial. Pediatr. Blood Cancer 62, 395–401 (2015).

  213. 213.

    et al. Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia. N. Engl. J. Med. 371, 699–710 (2014).

  214. 214.

    et al. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N. Engl. J. Med. 350, 886–895 (2004).

  215. 215.

    , , & Asthma is associated with Increased mortality in individuals with sickle cell anemia. Haematologica 92, 1115–1118 (2007).

  216. 216.

    et al. Wheezing and asthma are independent risk factors for increased sickle cell disease morbidity. Br. J. Haematol. 159, 472–479 (2012).

  217. 217.

    , , , & Sickle cell chronic lung disease: prior morbidity and the risk of pulmonary failure. Medicine 67, 66–76 (1988).

  218. 218.

    et al. Prevalence and pathologic features of sickle cell nephropathy and response to inhibition of angiotensin-converting enzyme. N. Engl. J. Med. 326, 910–915 (1992).

  219. 219.

    et al. Relative systemic hypertension in patients with sickle cell disease is associated with risk of pulmonary hypertension and renal insufficiency. Am. J. Hematol. 83, 15–18 (2008).

  220. 220.

    et al. Natural history of blood pressure in sickle cell disease: risks for stroke and death associated with relative hypertension in sickle cell anemia. Am. J. Med. 102, 171–177 (1997).

  221. 221.

    , & Is “relative” hypertension a risk factor for vaso-occlusive complications in sickle cell disease? Am. J. Med. Sci. 305, 150–156 (1993).

  222. 222.

    et al. Incidence and natural history of proliferative sickle cell retinopathy: observations from a cohort study. Ophthalmology 112, 1869–1875 (2005).

  223. 223.

    , , & Patterns of visual loss in untreated sickle cell retinopathy. Eye 2, 330–335 (1988).

  224. 224.

    et al. Depression, quality of life, and medical resource utilization in sickle cell disease. Blood Adv. 1, 1983–1992 (2017).

  225. 225.

    et al. Comorbidity, pain, utilization, and psychosocial outcomes in older versus younger sickle cell adults: the PiSCES project. Biomed. Res. Int. 2017, 4070547 (2017).

  226. 226.

    , , , & Psychological characteristics and pain frequency are associated with experimental pain sensitivity in pediatric patients with sickle cell disease. J. Pain 18, 1216–1228 (2017).

  227. 227.

    , , & A systematic review of the association between depression and health care utilization in children and adults with sickle cell disease. Br. J. Haematol. 174, 136–147 (2016).

  228. 228.

    et al. Sleep disturbance, depression and pain in adults with sickle cell disease. BMC Psychiatry 14, 207 (2014).

  229. 229.

    , & Coagulation abnormalities of sickle cell disease: relationship with clinical outcomes and the effect of disease modifying therapies. Blood Rev. 30, 245–256 (2016).

  230. 230.

    & The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med. Care 30, 473–483 (1992).

  231. 231.

    The PedsQLTM 4.0 Measurement Model for the Pediatric Quality of Life InventoryTM Version 4.0: Administration Guidelines. PedsQLTM (2004).

  232. 232.

    et al. Determining the longitudinal validity and meaningful differences in HRQL of the PedsQL Sickle Cell Disease Module. Health Qual. Life Outcomes 15, 124 (2017).

  233. 233.

    & Health-related quality of life in sickle cell disease: past, present, and future. Pediatr. Blood Cancer 59, 377–385 (2012).

  234. 234.

    , , , & Patient reports of health outcome for adults living with sickle cell disease: development and testing of the ASCQ-Me item banks. Health Qual. Life Outcomes 12, 125 (2014).

  235. 235.

    et al. PedsQL sickle cell disease module: feasibility, reliability, and validity. Pediatr. Blood Cancer 60, 1338–1344 (2013).

  236. 236.

    , & Fatigue in adolescents and young adults with sickle cell disease: biological and behavioral correlates and health-related quality of life. J. Pediatr. Oncol. Nurs. 31, 6–17 (2014).

  237. 237.

    et al. Health related quality of life in sickle cell patients: the PiSCES project. Health Qual. Life Outcomes 3, 50 (2005).

  238. 238.

    , , & Vaso-occlusive painful events in sickle cell disease: impact on child well-being. Pediatr. Blood Cancer 54, 92–97 (2010).

  239. 239.

    , & Postdischarge pain, functional limitations and impact on caregivers of children with sickle cell disease treated for painful events. Br. J. Haematol. 144, 782–788 (2009).

  240. 240.

    , , & Home management of pain in sickle cell disease: a daily diary study in children and adolescents. J. Pediatr. Hematol. Oncol. 24, 643–647 (2002).

  241. 241.

    et al. Daily assessment of pain in adults with sickle cell disease. Ann. Intern. Med. 148, 94–101 (2008).

  242. 242.

    et al. Understanding pain and improving management of sickle cell disease: the PiSCES study. J. Natl Med. Assoc. 97, 183–193 (2005).

  243. 243.

    et al. Hydroxyurea and sickle cell anemia: effect on quality of life. Health Qual. Life Outcomes 4, 59 (2006).

  244. 244.

    , & Differences in health-related quality of life in children with sickle cell disease receiving hydroxyurea. J. Pediatr. Hematol. Oncol. 33, 251–254 (2011).

  245. 245.

    et al. Health-related quality of life in children with sickle cell anemia: impact of blood transfusion therapy. Am. J. Hematol. 90, 139–143 (2015).

  246. 246.

    et al. Validation of a novel point of care testing device for sickle cell disease. BMC Med. 13, 225 (2015).

  247. 247.

    , & Clinically meaningful interpretation of pediatric health-related quality of life in sickle cell disease. J. Pediatr. Hematol. Oncol. 37, 128–133 (2015).

  248. 248.

    , & Genetic treatment of a molecular disorder: gene therapy approaches to sickle cell disease. Blood 127, 839–848 (2016).

  249. 249.

    et al. Gene therapy in a patient with sickle cell disease. N. Engl. J. Med. 376, 848–855 (2017).

  250. 250.

    , & Use of genome-editing tools to treat sickle cell disease. Hum. Genet. 135, 1011–1028 (2016).

  251. 251.

    et al. A genome-editing strategy to treat beta-hemoglobinopathies that recapitulates a mutation associated with a benign genetic condition. Nat. Med. 22, 987–990 (2016).

  252. 252.

    et al. CRISPR/Cas9 beta-globin gene targeting in human haematopoietic stem cells. Nature 539, 384–389 (2016).

  253. 253.

    Beyond hydroxyurea: new and old drugs in the pipeline for sickle cell disease. Blood 127, 810–819 (2016).

  254. 254.

    et al. Randomized phase 2 study of GMI-1070 in SCD: reduction in time to resolution of vaso-occlusive events and decreased opioid use. Blood 125, 2656–2664 (2015).

  255. 255.

    et al. Systematic review of interventional sickle cell trials registered in ClinicalTrials.gov. Clin. Trials 12, 575–583 (2015).

  256. 256.

    et al. Phase 3 study of L-glutamine therapy in sickle cell anemia and sickle β0-thalassemia subgroup analyses show consistent clinical improvement. Blood 128, 1318–1318 (2016).

  257. 257.

    Renaissance of Sickle Cell Disease Research in the Genome Era (Imperial College Press, 2007).

  258. 258.

    , , & Survival of children with sickle cell disease in the comprehensive newborn screening programme in Minas Gerais, Brazil. Paediatr. Int. Child Health 35, 329–332 (2015).

  259. 259.

    , , , & Cohort study of adult patients with haemoglobin SC disease: clinical characteristics and predictors of mortality. Br. J. Haematol. 171, 631–637 (2015).

  260. 260.

    The compound state: Hb S/beta-thalassemia. Rev. Bras. Hematol. Hemoter. 37, 150–152 (2015).

  261. 261.

    in Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management (eds Steinberg, M. H., Forget, B. G., Higgs, D. R. & Weatherall, D. J.) 786–810 (Cambridge Univ. Press, 2009).

  262. 262.

    , & The high resolution crystal structure of deoxyhemoglobin S. J. Mol. Biol. 272, 398–407 (1997).

  263. 263.

    & Sickle cell hemoglobin polymerization. Adv. Protein Chem. 40, 63–279 (1990).

  264. 264.

    & Effects of pH, 2,3-diphosphoglycerate and salts on gelation of sickle cell deoxyhemoglobin. J. Mol. Biol. 80, 445–458 (1973).

  265. 265.

    , & Determinants of red cell sickling. Effects of varying pH and of increasing intracellular hemoglobin concentration by osmotic shrinkage. J. Lab Clin. Med. 87, 597–616 (1976).

  266. 266.

    , & Editorial: Delay time of gelation: a possible determinant of clinical severity in sickle cell disease. Blood 47, 621–627 (1976).

  267. 267.

    The delay time in sickle cell disease after 40 years: a paradigm assessed. Am. J. Hematol. 90, 438–445 (2015).

  268. 268.

    , , & Free heme and the polymerization of sickle cell hemoglobin. Biophys. J. 99, 1976–1985 (2010).

  269. 269.

    , , & Erythrocyte adherence to endothelium in sickle-cell anemia. A possible determinant of disease severity. N. Engl. J. Med. 302, 992–995 (1980).

  270. 270.

    , & Inhibition of Ca2+-dependent K+ transport and cell dehydration in sickle erythrocytes by clotrimazole and other imidazole derivatives. J. Clin. Invest. 92, 520–526 (1993).

  271. 271.

    Centers for Disease Control and Prevention. Registry and Surveillance System for Hemoglobinopathies (RuSH). CDC (2017).

  272. 272.

    , , & The performance of the PedsQL generic core scales in children with sickle cell disease. J. Pediatr. Hematol. Oncol. 30, 666–673 (2008).

  273. 273.

    [No authors listed.] FDA Briefing Document, Oncologic Drugs Advisory Committee Meeting, NDA 208587, L-glutamine, Applicant: Emmaus Medical, Inc. U.S. Food and Drug Administration (2017).

  274. 274.

    et al. Design of the DOVE (Determining Effects of Platelet Inhibition on Vaso-Occlusive Events) trial: a global phase 3 double-blind, randomized, placebo-controlled, multicenter study of the efficacy and safety of prasugrel in pediatric patients with sickle cell anemia utilizing a dose titration strategy. Pediatr. Blood Cancer 63, 299–305 (2016).

  275. 275.

    & Purified poloxamer 188 for sickle cell vaso-occlusive crisis. Ann. Pharmacother. 38, 320–324 (2004).

  276. 276.

    et al. A randomized, placebo-controlled trial of arginine therapy for the treatment of children with sickle cell disease hospitalized with vaso-occlusive pain episodes. Haematologica 98, 1375–1382 (2013).

  277. 277.

    , , , & Quantification of anti-sickling effect of Aes-103 in sickle cell disease using an in vitro microfluidic assay. Blood 124, 2699–2699 (2014).

  278. 278.

    et al. Effect of N-acetylcysteine on pain in daily life in patients with sickle cell disease: a randomised clinical trial. Br. J. Haematol. (2017).

  279. 279.

    et al. A multicenter randomized controlled trial of intravenous magnesium for sickle cell pain crisis in children. Blood 126, 1651–1657 (2015).

  280. 280.

    , & Stroke With Transfusions Changing to Hydroxyurea (SWiTCH). Blood 119, 3925–3932 (2012).

  281. 281.

    et al. Discovery of GBT440, an orally bioavailable R-state stabilizer of sickle cell hemoglobin. ACS Med. Chem. Lett. 8, 321–326 (2017).

  282. 282.

    et al. Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis: a randomized controlled trial. JAMA 305, 893–902 (2011).

  283. 283.

    et al. Hospitalization for pain in patients with sickle cell disease treated with sildenafil for elevated TRV and low exercise capacity. Blood 118, 855–864 (2011).

  284. 284.

    et al. A Phase Ib open label, randomized, safety study of SANGUINATE in patients with sickle cell anemia. Rev. Bras. Hematol. Hemoter 39, 20–27 (2017).

  285. 285.

    et al. Sevuparin binds to multiple adhesive ligands and reduces sickle red blood cell-induced vaso-occlusion. Br. J. Haematol. 175, 935–948 (2016).

  286. 286.

    et al. Pomalidomide and lenalidomide regulate erythropoiesis and fetal hemoglobin production in human CD34+ cells. J. Clin. Invest. 118, 248–258 (2008).

  287. 287.

    et al. A novel, highly potent and selective PDE9 inhibitor for the treatment of sickle cell disease. Blood 128, 268–268 (2016).

  288. 288.

    et al. Double-blind, placebo-controlled, randomised cross-over clinical trial of NIPRISAN in patients with Sickle Cell Disorder. Phytomedicine 8, 252–261 (2001).

  289. 289.

    Prospects for early investigational therapies for sickle cell disease. Expert Opin. Investig. Drugs 24, 595–602 (2015).

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Affiliations

  1. Heart, Lung and Blood Vascular Medicine Institute and the Division of Hematology–Oncology, Department of Medicine, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15261, USA.

    • Gregory J. Kato
  2. MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London, UK.

    • Frédéric B. Piel
  3. Sickle Cell Disease Branch, National Heart, Lung and Blood Institute, NIH, Bethesda, MD, USA.

    • Clarice D. Reid
  4. The Gaston and Porter Health Improvement Center, Potomac, MD, USA.

    • Marilyn H. Gaston
  5. Sickle Cell Foundation of Ghana, Kumasi, Ghana.

    • Kwaku Ohene-Frempong
  6. Division of Pediatric Hematology–Oncology–BMT, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.

    • Lakshmanan Krishnamurti
  7. Division of General Internal Medicine, Department of Medicine, Virginia Commonwealth University, Richmond, VA, USA.

    • Wally R. Smith
  8. Department of Pediatrics, Hematology–Oncology–Bone Marrow Transplantation, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI, USA.

    • Julie A. Panepinto
  9. MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, UK.

    • David J. Weatherall
  10. INCT de Sangue, Haematology and Haemotherapy Centre, School of Medicine, University of Campinas — UNICAMP, Campinas, São Paulo, Brazil.

    • Fernando F. Costa
  11. Hematology and Oncology, UCSF Benioff Children's Hospital, Oakland, University of California, San Francisco, CA, USA.

    • Elliott P. Vichinsky

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Contributions

Introduction (M.H.G. and C.D.R.); Epidemiology (D.J.W. and F.B.P.); Mechanisms/pathophysiology (G.J.K. and F.F.C.); Diagnosis, screening and prevention (K.O.-F., E.P.V. and L.K.); Management (G.J.K., E.P.V. and F.B.P.); Quality of life (W.R.S. and J.A.P.); Outlook (G.J.K., F.B.P. and E.P.V.); Overview of Primer (G.J.K., F.B.P. and E.P.V.).

Competing interests

G.J.K. is listed as a co-inventor on a patent application by the US NIH for the formulation of topical sodium nitrite (PCT/US2015/060015), receives research support from Bayer Pharmaceuticals and has received research support from AesRx and personal consulting fees (honoraria) from Novartis and Bioverativ outside the submitted work. The University of Pittsburgh received support for G.J.K.'s salary to serve on the steering committee for a clinical trial by Mast Therapeutics. F.B.P. reports personal fees (honoraria) from Novartis outside the submitted work. L.K., W.R.S., J.A.P., D.J.W., F.F.C. and E.V.P. declare no competing interests. Editor's note: all other authors have chosen not to declare any competing interests.

Corresponding author

Correspondence to Gregory J. Kato.

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DOI

https://doi.org/10.1038/nrdp.2018.10