SCKIN Resources
Foundational Articles
Peer-reviewed papers that changed how sickle cell disease is understood and treated, in the order they were published. Written for healthcare professionals.
29 articles
1910
first description
Herrick JB. Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. Arch Intern Med. 1910;6(5):517-521.
What it established: First published description of sickled red cells, in a dental student from Grenada.
- Theme: Biology
- Impact: Changed understanding
- Study type: Case report
- Population: Adults
- Region: Global
1949
a molecular disease
Pauling L, Itano HA, Singer SJ, Wells IC. Sickle cell anemia, a molecular disease. Science. 1949;110(2865):543-548.
What it established: Showed sickle hemoglobin differs physically from normal hemoglobin: the first disease traced to an abnormal protein.
- Theme: Biology
- Impact: Changed understanding
- Study type: Lab/genetics
- Population: All ages
- Region: Global
1949
inheritance
Neel JV. The inheritance of sickle cell anemia. Science. 1949;110(2846):64-66.
What it established: Established sickle cell anemia as a recessive trait: carriers have sickle cell trait, homozygotes have the disease.
- Theme: Biology
- Impact: Changed understanding
- Study type: Lab/genetics
- Population: All ages
- Region: Global
1954
malaria protection
Allison AC. Protection afforded by sickle-cell trait against subtertian malareal infection. Br Med J. 1954;1(4857):290-294.
What it established: Explained why the sickle gene persists: carriers are protected against severe falciparum malaria.
- Theme: Biology
- Impact: Changed understanding
- Study type: Cohort
- Population: All ages
- Region: Sub-Saharan Africa
Free full text: Protection afforded by sickle-cell trait against subtertian malareal infection (opens in a new tab)DOI: Protection afforded by sickle-cell trait against subtertian malareal infection (opens in a new tab)PubMed: Protection afforded by sickle-cell trait against subtertian malareal infection (opens in a new tab)1957
the single substitution
Ingram VM. Gene mutations in human haemoglobin: the chemical difference between normal and sickle cell haemoglobin. Nature. 1957;180(4581):326-328.
What it established: Identified the cause as one amino acid change (glutamic acid to valine) in the beta-globin chain.
- Theme: Biology
- Impact: Changed understanding
- Study type: Lab/genetics
- Population: All ages
- Region: Global
1986
penicillin prophylaxis (PROPS)
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(25):1593-1599.
What it established: Daily penicillin cut pneumococcal sepsis by 84% in young children; the trial was stopped early and led to universal prophylaxis and newborn screening.
- Theme: Disease management
- Impact: Changed practice
- Study type: RCT
- Population: Children
- Region: High-income
1988
newborn screening
Vichinsky E, Hurst D, Earles A, Kleman K, Lubin B. Newborn screening for sickle cell disease: effect on mortality. Pediatrics. 1988;81(6):749-755.
What it established: Children diagnosed at birth and enrolled in comprehensive care had 1.8% mortality versus 8% for those diagnosed later.
- Theme: Epidemiology
- Impact: Changed practice
- Study type: Cohort
- Population: Children
- Region: High-income
1994
life expectancy
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(23):1639-1644.
What it established: Median survival 42 years for men and 48 for women with sickle cell anemia; identified fetal hemoglobin as protective. Still the most cited survival figure.
- Theme: Epidemiology
- Impact: Changed understanding
- Study type: Cohort
- Population: All ages
- Region: High-income
1995
hydroxyurea (MSH)
Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med. 1995;332(20):1317-1322.
What it established: Hydroxyurea roughly halved painful crises, acute chest syndrome and transfusions in adults; the basis for the first FDA-approved sickle cell drug.
- Theme: Drug therapy
- Impact: Changed practice
- Study type: RCT
- Population: Adults
- Region: High-income
1996
bone marrow transplantation
Walters MC, Patience M, Leisenring W, et al. Bone marrow transplantation for sickle cell disease. N Engl J Med. 1996;335(6):369-376.
What it established: First multicenter series showing matched-sibling transplant could cure children with severe disease.
- Theme: Curative therapy
- Impact: Changed practice
- Study type: Cohort
- Population: Children
- Region: High-income
1998
stroke prevention (STOP)
Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med. 1998;339(1):5-11.
What it established: Transcranial Doppler screening plus chronic transfusion cut first stroke by about 90%; stopped early for benefit.
- Theme: Disease management
- Impact: Changed practice
- Study type: RCT
- Population: Children
- Region: High-income
DOI: Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography (opens in a new tab)PubMed: Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography (opens in a new tab)1998
stroke rates (CSSCD)
Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood. 1998;91(1):288-294.
What it established: Quantified stroke risk: about 11% of patients with sickle cell anemia have a stroke by age 20, highest in early childhood.
- Theme: Epidemiology
- Impact: Changed understanding
- Study type: Cohort
- Population: All ages
- Region: High-income
2000
acute chest syndrome
Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group. N Engl J Med. 2000;342(25):1855-1865.
What it established: Defined the causes (infection, fat embolism) and outcomes of acute chest syndrome and established early transfusion and bronchodilator care.
- Theme: Disease management
- Impact: Changed understanding
- Study type: Cohort
- Population: All ages
- Region: High-income
2003
hydroxyurea and mortality
Steinberg MH, Barton F, Castro O, et al. Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment. JAMA. 2003;289(13):1645-1651.
What it established: Nine-year follow-up of MSH: hydroxyurea use was associated with 40% lower mortality.
- Theme: Drug therapy
- Impact: Changed practice
- Study type: Cohort
- Population: Adults
- Region: High-income
DOI: Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment (opens in a new tab)PubMed: Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment (opens in a new tab)2008
BCL11A
Sankaran VG, Menne TF, Xu J, et al. Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science. 2008;322(5909):1839-1842.
What it established: Identified BCL11A as the switch that silences fetal hemoglobin; the target of today's CRISPR therapy.
- Theme: Biology
- Impact: Changed understanding
- Study type: Lab/genetics
- Population: All ages
- Region: Global
2009
transplant in adults
Hsieh MM, Kang EM, Fitzhugh CD, et al. Allogeneic hematopoietic stem-cell transplantation for sickle cell disease. N Engl J Med. 2009;361(24):2309-2317.
What it established: Nonmyeloablative conditioning made transplant feasible for adults with organ damage, not just children.
- Theme: Curative therapy
- Impact: Changed practice
- Study type: Cohort
- Population: Adults
- Region: High-income
Free full text: Allogeneic hematopoietic stem-cell transplantation for sickle cell disease (opens in a new tab)DOI: Allogeneic hematopoietic stem-cell transplantation for sickle cell disease (opens in a new tab)PubMed: Allogeneic hematopoietic stem-cell transplantation for sickle cell disease (opens in a new tab)2011
hydroxyurea in infants (BABY HUG)
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(9778):1663-1672.
What it established: Hydroxyurea was safe and reduced pain, dactylitis and hospitalisation in children aged 9 to 18 months; extended the drug to infancy.
- Theme: Drug therapy
- Impact: Changed practice
- Study type: RCT
- Population: Children
- Region: High-income
Free full text: Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG) (opens in a new tab)DOI: Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG) (opens in a new tab)PubMed: Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG) (opens in a new tab)2013
global burden
Piel FB, Patil AP, Howes RE, et al. Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates. Lancet. 2013;381(9861):142-151.
What it established: Estimated about 300,000 births with sickle cell anemia per year, three quarters in sub-Saharan Africa, with India the next largest burden.
- Theme: Epidemiology
- Impact: Changed understanding
- Study type: Cohort
- Population: All ages
- Region: Sub-Saharan Africa
- Region: India
Free full text: Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates (opens in a new tab)DOI: Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates (opens in a new tab)PubMed: Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates (opens in a new tab)2014
NHLBI guidelines
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(10):1033-1048.
What it established: The reference guideline for day-to-day management: hydroxyurea for all with sickle cell anemia, TCD screening, pain management, transfusion indications.
- Theme: Disease management
- Tag: Guidelines
- Impact: Changed practice
- Study type: Review/guideline
- Population: All ages
- Region: High-income
2014
silent infarcts (SIT)
DeBaun MR, Gordon M, McKinstry RC, et al. Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia. N Engl J Med. 2014;371(8):699-710.
What it established: Chronic transfusion reduced recurrence of silent cerebral infarcts, the most common brain injury in children with the disease.
- Theme: Disease management
- Impact: Changed practice
- Study type: RCT
- Population: Children
- Region: High-income
Free full text: Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia (opens in a new tab)DOI: Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia (opens in a new tab)PubMed: Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia (opens in a new tab)2014
reproductive issues
Smith-Whitley K. Reproductive issues in sickle cell disease. Blood. 2014;124(24):3538-3543.
What it established: Framed fertility, contraception and pregnancy as part of routine sickle cell care as survival into adulthood became the norm.
- Theme: Disease management
- Impact: Changed understanding
- Study type: Review/guideline
- Population: Adults
- Region: High-income
2016
hydroxyurea for TCD (TWiTCH)
Ware RE, Davis BR, Schultz WH, et al. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial. Lancet. 2016;387(10019):661-670.
What it established: Hydroxyurea was non-inferior to transfusion for keeping TCD velocities down; offered a way off lifelong transfusion.
- Theme: Drug therapy
- Tag: Guidelines
- Impact: Changed practice
- Study type: RCT
- Population: Children
- Region: High-income
Free full text: Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia (TWiTCH) (opens in a new tab)DOI: Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia (TWiTCH) (opens in a new tab)PubMed: Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia (TWiTCH) (opens in a new tab)2017
first gene therapy patient
Ribeil JA, Hacein-Bey-Abina S, Payen E, et al. Gene therapy in a patient with sickle cell disease. N Engl J Med. 2017;376(9):848-855.
What it established: First report of lentiviral gene therapy (LentiGlobin) producing anti-sickling hemoglobin and resolving symptoms in a teenager.
- Theme: Curative therapy
- Impact: Changed understanding
- Study type: Case report
- Population: Children
- Region: High-income
2018
L-glutamine
Niihara Y, Miller ST, Kanter J, et al. A phase 3 trial of L-glutamine in sickle cell disease. N Engl J Med. 2018;379(3):226-235.
What it established: L-glutamine reduced pain crises; the second FDA-approved drug for sickle cell disease, 19 years after hydroxyurea.
- Theme: Drug therapy
- Impact: Changed practice
- Study type: RCT
- Population: All ages
- Region: High-income
2019
hydroxyurea in Africa (REACH)
Tshilolo L, Tomlinson G, Williams TN, et al. Hydroxyurea for children with sickle cell anemia in sub-Saharan Africa. N Engl J Med. 2019;380(2):121-131.
What it established: Hydroxyurea was feasible, safe and effective in 606 children across Angola, DRC, Kenya and Uganda, with fewer malaria episodes and deaths.
- Theme: Drug therapy
- Impact: Changed practice
- Study type: Cohort
- Population: Children
- Region: Sub-Saharan Africa
Free full text: Hydroxyurea for children with sickle cell anemia in sub-Saharan Africa (opens in a new tab)DOI: Hydroxyurea for children with sickle cell anemia in sub-Saharan Africa (opens in a new tab)PubMed: Hydroxyurea for children with sickle cell anemia in sub-Saharan Africa (opens in a new tab)2020
hydroxyurea and ovarian reserve
Pecker LH, Hussain S, Christianson MS, Lanzkron S. Hydroxycarbamide exposure and ovarian reserve in women with sickle cell disease in the Multicenter Study of Hydroxycarbamide. Br J Haematol. 2020;191(5):880-887.
What it established: Women with sickle cell anemia show diminished ovarian reserve from their mid-20s, and hydroxyurea exposure was independently associated with it; the evidence behind fertility-preservation counselling.
- Theme: Disease management
- Impact: Changed understanding
- Study type: Cohort
- Population: Adults
- Region: High-income
Free full text: Hydroxycarbamide exposure and ovarian reserve in women with sickle cell disease in the Multicenter Study of Hydroxycarbamide (opens in a new tab)DOI: Hydroxycarbamide exposure and ovarian reserve in women with sickle cell disease in the Multicenter Study of Hydroxycarbamide (opens in a new tab)PubMed: Hydroxycarbamide exposure and ovarian reserve in women with sickle cell disease in the Multicenter Study of Hydroxycarbamide (opens in a new tab)2021
CRISPR, first patients
Frangoul H, Altshuler D, Cappellini MD, et al. CRISPR-Cas9 gene editing for sickle cell disease and beta-thalassemia. N Engl J Med. 2021;384(3):252-260.
What it established: First patients treated with BCL11A-targeted CRISPR editing; both had sustained fetal hemoglobin and no vaso-occlusive events.
- Theme: Curative therapy
- Impact: Changed understanding
- Study type: Case report
- Population: Adults
- Region: High-income
2022
LentiGlobin (lovo-cel)
Kanter J, Walters MC, Krishnamurti L, et al. Biologic and clinical efficacy of LentiGlobin for sickle cell disease. N Engl J Med. 2022;386(7):617-628.
What it established: Pivotal data for lovotibeglogene autotemcel: complete resolution of severe vaso-occlusive events in treated patients; approved as Lyfgenia in December 2023.
- Theme: Curative therapy
- Impact: Changed practice
- Study type: Cohort
- Population: All ages
- Region: High-income
2024
exa-cel pivotal
Frangoul H, Locatelli F, Sharma A, et al. Exagamglogene autotemcel for severe sickle cell disease. N Engl J Med. 2024;390(18):1649-1662.
What it established: Pivotal trial of exa-cel: 97% of evaluable patients free of severe vaso-occlusive crises for at least 12 months; approved as Casgevy in December 2023.
- Theme: Curative therapy
- Impact: Changed practice
- Study type: Cohort
- Population: All ages
- Region: High-income