Blood Reviews 37 (2019) 100580

Contents lists available at ScienceDirect

Blood Reviews
journal homepage: www.elsevier.com/locate/blre

Review

Sickle cell disease: Clinical presentation and management of a global health T

challenge
M.E. Houwinga, P.J. de Pagtera, E.J. van Beersb, B.J. Biemondc, E. Rettenbacherd,
A.W. Rijnevelde, E.M. Scholsf, J.N.J. Philipseng, R.Y.J. Tammingah, K. Fijn van Draati,j, E. Nurc,
M.H. Cnossena, , on behalf of the SCORE Consortium1
⁎

a
Department of Paediatric Haematology, Erasmus University Medical Center – Sophia Children's Hospital, Wytemaweg 80, 3015, CN, Rotterdam, the Netherlands
b
Department of Internal Medicine and Dermatology, Van Creveldkliniek, University Medical Center Utrecht, Internal mail no C.01.412, 3508, GA, Utrecht, the Netherlands
c
Department of Internal Medicine and Clinical Haematology, Amsterdam University Medical Centers, Meibergdreef 9, 1105, AZ, Amsterdam, the Netherlands
d
Department of Paediatric Haematology, Radboud University Medical Center – Amalia Children's Hospital, Geert Grooteplein Zuid 10, 6500, HB, Nijmegen, the
Netherlands
e
Department of Haematology, Erasmus University Medical Center, Wytemaweg 80, 3015, CN, Rotterdam, the Netherlands
f
Department of Haematology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525, GA, Nijmegen, the Netherlands
g
Department of Cell Biology, Erasmus University Medical Center, Wytemaweg 80, 3015, CN, Rotterdam, the Netherlands
h
Department of Paediatric Oncology and Haematology, University Medical Center Groningen – Beatrix Children's Hospital, Postbus 30001, 9700, RB, Groningen, the
Netherlands.
i
Department of Paediatric Haematology, Amsterdam University Medical Centers – Emma Children's Hospital, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
j
Department of Plasma Proteins, Sanquin Research, the Netherlands

ARTICLE INFO ABSTRACT

Keywords: Sickle cell disease is an autosomal recessive, multisystem disorder, characterised by chronic haemolytic anaemia,
Sickle cell disease painful episodes of vaso-occlusion, progressive organ failure and a reduced life expectancy. Sickle cell disease is
Vaso-occlusion the most common monogenetic disease, with millions affected worldwide. In well-resourced countries, com-
Complications prehensive care programs have increased life expectancy of sickle cell disease patients, with almost all infants
Treatment
surviving into adulthood. Therapeutic options for sickle cell disease patients are however, still scarce. Predictors
of sickle cell disease severity and a better understanding of pathophysiology and (epi)genetic modifiers are
warranted and could lead to more precise management and treatment. This review provides an extensive
summary of the pathophysiology and management of sickle cell disease and encompasses the characteristics,
complications and current and future treatment options of the disease.

1. Introduction Saharan Africa. Due to absence of newborn screening, 50 to 90% of

these children will die undiagnosed in the first five years of their life
Sickle cell disease is an autosomal recessive, multisystem disorder, [1–4]. In contrast, in well-resourced countries, comprehensive care
characterised by chronic haemolytic anaemia, painful ischaemic epi- programs have increased life expectancy of sickle cell disease patients,
sodes of vaso-occlusion, and progressive organ failure. Sickle cell dis- with almost all infants surviving into adulthood [5]. Therapeutic op-
ease is the most common monogenetic disease, with millions affected tions for sickle cell disease patients are however, still scarce. The only
worldwide. The vast majority of sickle cell disease births occur in sub- clinically available and notably safe disease-modifying treatment

⁎
Corresponding author at: Department of Paediatric Haematology. Erasmus University Medical Center – Sophia Children's Hospital, Wytemaweg 80, 3015, CN,
Rotterdam, the Netherlands.
E-mail addresses: [email protected] (M.E. Houwing), [email protected] (P.J. de Pagter), [email protected] (E.J. van Beers),
[email protected] (B.J. Biemond), [email protected] (E. Rettenbacher), [email protected] (A.W. Rijneveld),
[email protected] (E.M. Schols), [email protected] (J.N.J. Philipsen), [email protected] (R.Y.J. Tamminga),
[email protected] (K.F. van Draat), [email protected] (E. Nur), [email protected] (M.H. Cnossen).
1
SCORE consortium: E.J. van Beers, B.J. Biemond, M. Beijlevelt, M.H. Cnossen, J.J. Gerritsma, C.L. Harteveld, H.Heijboer, K.M.J. Heitink-Polle, M.E. Houwing,
J.L.H. Kerkhoffs, A.C. Lankester, K. Fijn van Draat, A.B.U. Mäkelburg, H. Mekelenkamp, E. Nur, P.J. de Pagter, M.Peters, E. Rettenbacher, J.N.J. Philipsen, M.A.B.
Rab, A.W. Rijneveld, E.M. Schols, S.A.M.C. Teuben, F.J. Smiers, R.Y.J. Tamminga, C.F.J. van Tuijn, E. Zwagemaker.

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M.E. Houwing, et al. Blood Reviews 37 (2019) 100580

modalities are hydroxyurea and blood (exchange) transfusions. Hae- a single mutation in the β-globin gene. In case of homozygous HbSS
matopoietic stem cell transplantation (HSCT) remains the only curative sickle cell disease, a specific point-mutation is located in exon I on both
treatment option. Unfortunately, its use is limited by the lack of suitable chromosome 11 homologues. This mutation replaces the 17th nucleo-
donors and concerns about toxicity. Early results of gene therapy trials tide thymine (T) for adenine (A), which reverses the T/A pair to A/T
are promising and may form a potential alternative [6]. and produces an abnormal haemoglobin that contains valine instead of
glutamic acid in the sixth codon (HBB p.Glu6Val, rs334) [18]. The loss
2. Classification of the negatively charged glutamic acid results in an altered electro-
phoretic mobility and when deoxygenated, valine favours hydrophobic
Sickle cell disease is a term for a group of conditions resulting from interactions with other HbS molecules. As a consequence, HbS mole-
the inheritance of haemoglobin S (HbS). The most prevalent form is cules adhere in large quantities, forming haemoglobin polymers in the
HbSS with homozygosity for the S allele in the β-globin gene. Variant erythrocyte that deform the structure of the red blood cell, referred to
syndromes include haemoglobinopathies in which the sickle mutation as ‘sickling’. The rate and extent of HbS polymerisation coincides with
in the β-globin gene is inherited in combination with another β-globin the extent and duration of the haemoglobin deoxygenation and the
gene mutation (compound heterozygous sickle cell disease), such as intracellular HbS concentration [19].
haemoglobin C (HbSC) – the second most common form of sickle cell Herrick was the first to describe the characteristic sickle-shaped
disease, haemoglobin D (HbSD), haemoglobin E (HbSE), or various erythrocytes in a West Indian student in 1910 [20]. Sickled erythrocytes
forms with a β-thalassaemia mutation (HbSβ0 or HbSβ+-thalassaemia). are rigid, lysis-prone and interact with leucocytes and the vascular
The inheritance of both HbA (normal adult haemoglobin) and HbS is endothelium. This results in haemolytic anaemia and recurrent occlu-
defined as sickle cell trait or sickle cell carrier status (HbAS). sion of the small vessels. Vaso-occlusion leads to ischaemic damage of
tissues resulting in severe pain and cumulative organ damage. Sub-
3. Epidemiology: Prevalence and burden of disease sequent reperfusion of ischaemic tissues promotes chronic inflamma-
tion by increased reactive oxygen species (ROS) production [21].
The HbS allele was originally distributed throughout sub-Saharan Concomitantly, inflammation amplifies the expression of adhesion
Africa, the Middle East, the Mediterranean area and India. Carrier rates molecules, further increasing adherence of sickled erythrocytes to the
range from 5% to > 40% in these areas [7]. This wide distribution of vascular wall and worsening of vaso-occlusion [22].
the HbS allele is indicative of the natural selection of heterozygous Haemolysis in sickle cell disease is also a direct result of HbS
HbAS individuals by their relative protection against Plasmodium fal- polymerisation which damages the sickle cell erythrocyte membrane.
ciparum malaria. Although the exact mechanism of this protection is yet The lifespan of sickled erythrocytes is at least six times shorter than that
to be fully understood, several studies have verified the abnormal of normal erythrocytes; i.e. 10–20 days versus 120 days. Haemolysis
transportation of malaria parasites and lower parasite densities in HbAS results in the release of haemoglobin and arginase-1 from the ery-
individuals [8–11]. Migration from these malaria-endemic regions to throcyte into plasma, where they scavenge nitric oxide (NO) and its
North America, Western Europe and Australia has subsequently led to precursor L-arginine, causing decreased NO bioavailability [23,24]. NO
spreading of the HbS allele far beyond its origins. In addition, with regulates basal vessel tonus by initiating and maintaining vasodilata-
increasing numbers of migrants from countries with HbS allele fre- tion. In addition, NO inhibits adhesion molecules and platelet activa-
quencies higher than 10%, the number of individuals with sickle cell tion and maintains the haemostatic balance [25–27]. Cell free plasma
disease in new populations is increasing [12]. haemoglobin and haem are referred to as erythrocyte damage-asso-
The prevalence of sickle cell disease is highest in Nigeria, India and ciated molecular pattern molecules, which drive oxidative and in-
the Democratic Republic of Congo, where half of the world's sickle cell flammatory stress. As a consequence persistent intravascular haemo-
disease population lives. Moreover explicitly, 75% of the global burden lysis promotes vasoconstriction, hypercoagulability and the
of sickle cell disease occurs in sub-Saharan Africa [1,13], where the development of vasculopathy [28,29].
majority of children with the disease do not reach their fifth birthday.
Generally, diagnostic facilities are poor and routine neonatal screening 4.2. Phenotypic heterogeneity
is lacking in these regions. Most infants will therefore die undiagnosed
due to acute complications, most notably bacterial sepsis or severe Although a typical Mendelian disease, the clinical expression of
anaemia [14]. In contrast, life expectancy of children with sickle cell sickle cell disease varies significantly. Many studies have investigated
disease in well-resourced countries has significantly improved. This has genotype- phenotype relationships and it is currently generally ac-
been achieved by the introduction of comprehensive care programs cepted that the individual course of disease is influenced by a combi-
which include neonatal screening, penicillin prophylaxis and hydro- nation of genetic, epigenetic and environmental factors and their in-
xyurea treatment [15]. Recent data from an adult cohort (HbSS and teraction.
HbSβ0 genotype) in a high-income setting, even reported a median
survival of patients exceeding 65 years of age [5]. 4.2.1. Genetic modifiers of disease severity
With an estimated 300.000 births annually, sickle cell disease has With the exception of HbSβ0-thalassaemia, the compound hetero-
been recognised as a global public health problem by the World Health zygous genotypes of sickle cell disease are generally less severe than the
Organisation [16], the United Nations and by the American Society of homozygous genotype (HbSS). However, even within identical geno-
Hematology (ASH) [17]. This incidence is rising as population growth types, there is a broad range of disease severity. Besides the causative
rates are high in developing countries (about 3% per year) with the genotype, the clinical phenotype of sickle cell disease is most strongly
highest frequencies of the HbS allele. Additionally, as a consequence of influenced by two key genetic modifiers: foetal haemoglobin (HbF)
overall decrease in infant mortality by public health measures, the expression and co-inheritance of α-thalassaemia [30]. The role of other
global number of children with sickle cell disease is expected to exceed potential genetic modulators is less clear.
14 million in the coming 40 years [1].
4.2.1.1. β-globin genotypes. The likelihood of sickling is highly
4. Pathophysiology dependent on the haemoglobin composition in the erythrocyte, the
concentration of HbS, and concentration and type of non-S
4.1. General haemoglobin [31,32]. Hence, it is not surprising that the major
primary genetic determinant of disease severity is the specific
Sickle cell disease is autosomal recessively inherited and caused by genotype of sickle cell disease. Homozygous and HbSβ0-thalassaemia

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Table 1
Published genome-wide associations studies in sickle cell disease (p-values < 5 × 10−8).
Subphenotype/complication Gene(s) Reference(s)

Acute vaso-occlusive pain KIAA1109 Chaturvedi et al., 2017a

Diabetes mellitus APOB Zhang et al., 2015b
Acute chest syndrome COMMD7 Galarneau et al., 2013c
Bilirubin levels and cholelithiasis UGT1A Milton et al., 2012d
Nephropathy MYH9 - APOL1 Kao et al., 2008e
HbF -levels BCL11A, HBS1L-MYB (HMIP), the 5’HBB region (i.e. Xmn1-HBG2) Thein et al., 2007f; Uda et al., 2008g; Solovieff et al., 2010h

Abbreviations; HbF: foetal haemoglobin.

a
Chaturvedi S, Bhatnagar P, Bean CJ, Steinberg MH, Milton JN, Casella JF, et al. Genome-wide association study to identify variants associated with vaso-
occlusive pain in sickle cell anemia. Blood. 2017;130:686–8.
b
Zhang X, Zhang W, Saraf SL, Nouraie M, Han J, Gowhari M, et al. Genetic polymorphism of APOB is associated with diabetes mellitus in sickle cell disease. Hum
Genet. 2015;134:895–904.
c
Galarneau G, Coady S, Garrett ME, Jeffries N, Puggal M, Paltoo D, et al. Gene-centric association study of acute chest syndrome and painful crisis in sickle cell
disease patients. Blood. 2013;122:434–42.
d
Milton JN, Sebastiani P, Solovieff N, Hartley SW, Bhatnagar P, Arking DE, et al. A genome-wide association study of total bilirubin and cholelithiasis risk in sickle
cell anemia. PLoS One. 2012;7:e34741.
e
Kao WH, Klag MJ, Meoni LA, Reich D, Berthier-Schaad Y, Li M, et al. MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat
Genet. 2008;40:1185–92.
f
Thein SL, Menzel S, Peng X, Best S, Jiang J, Close J, et al. Intergenic variants of HBS1L-MYB are responsible for a major quantitative trait locus on chromosome
6q23 influencing fetal hemoglobin levels in adults. Proc Natl Acad Sci U S A. 2007;104:11346–51.
g
Uda M, Galanello R, Sanna S, Lettre G, Sankaran VG, Chen W, 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.
h
Solovieff N, Milton JN, Hartley SW, Sherva R, Sebastiani P, Dworkis DA, et al. Fetal hemoglobin in sickle cell anemia: genome-wide association studies suggest a
regulatory region in the 5′ olfactory receptor gene cluster. Blood. 2010;115:1815–22.

individuals have a haemoglobin composition almost exclusively HbS. established genetic HbF modifiers and their evidence in cells, mice and
The presence of HbA in HbSβ+-thalassaemia has a diluting effect on the humans.
intracellular concentration of HbS. Furthermore, HbA does not Increased HbF levels reduce total HbS concentration, since HbF is
participate in HbS polymerisation. The clinical severity of HbSβ+- excluded from the HbS polymer thereby inhibiting HbS polymerisation
thalassaemia is thus highly dependent on the mutation and therefore [45]. However, the specific HbF level in each individual erythrocyte
residual β globin production of the β+-thalassaemia allele [32,33]. seems most critical. Patients with high HbF% may exhibit severe dis-
Erythrocytes of patients with HbSC contain equal levels of HbS and ease if HbF is unevenly distributed among F-cells (red blood cells with
HbC. HbC enhances the pathogenic properties of HbS by dehydration of detectable HbF), with a majority of erythrocytes containing insufficient
the erythrocyte, resulting in a synergistic interaction between both HbF concentrations to inhibit HbS polymerisation [46].
haemoglobin types [34]. Furthermore, patients with HbSC usually ex-
hibit a milder anaemia than patients with other sickle cell disease 4.2.1.3. Alpha-thalassaemia. Co-inheritance of α-thalassaemia exists in
genotypes, resulting in higher haematocrit values with more disease up to one third of patients of African origin with sickle cell disease, and
complications related to viscosity. HbSC is less severe than the homo- is present in more than half of the patients in India and Saudi Arabia.
zygous form of sickle cell disease, however some complications are Normally, humans have four α-globin genes two on each copy of
more common in HbSC sickle cell disease such as ophthalmological chromosome 16. The co-inherited α-thalassaemia in sickle cell disease
complications and hearing loss [35]. is almost always a result of heterozygosity (−α/αα) or homozygosity
(−α/−α) for the α-globin gene deletion [47].
4.2.1.2. Foetal haemoglobin. HbF is the major haemoglobin type of the Pathophysiologically, co-inheritance of α-thalassaemia positively
foetus and newborn. By the time a healthy infant reaches the age of influences sickle cell disease phenotype. Due to a decreased presence of
6 months, HbF accounts for < 5% of the total haemoglobin and α-globin chains, the haemoglobin concentration in the erythrocyte is
continues to fall thereafter, reaching adult levels of < 1% by 2 years reduced, which leads to less HbS polymerisation and therefore reduced
of age [36]. As both foetal and adult haemoglobin contain α-globin HbS polymer induced damage. This results in less haemolysis with a
chains, the switch from HbF to HbA is essentially the replacement of γ- higher haematocrit, a lower mean corpuscular volume (MCV) and a
globin with β-globin. However, this switch is not complete as it does not lower reticulocyte count [48]. Therefore, patients with sickle cell dis-
lead to a total extinction of HbF in adult life. Mutations that affect β- ease and concomitant α-thalassaemia have a reduced incidence of
globin functioning and production (e.g. sickle cell disease and β- complications associated with the presence of haemolytic anaemia
thalassaemia) only become clinically apparent as the number of [49]. This reduction is presumably due to preserved NO bioactivity and
erythrocytes that contain measurable HbF declines [37]. In sickle cell reduced chronic inflammation, both as a result of decreased in-
disease patients, persistence of significant HbF levels beyond infancy travascular haemolysis [50]. However, it has also been reported that
can ameliorate the severity of the disease [38], including reduced clinical symptoms associated with microvascular occlusion such as
painful vaso-occlusive crises and increased life expectancy [5,39]. painful vaso-occlusive events, acute chest syndrome and osteonecrosis,
The degree of persistent HbF varies greatly between sickle cell may be more common in patients with co-inherited α-thalassaemia, due
disease patients (from 1% up to > 25%) and is largely genetically to increases in haematocrit and therefore blood viscosity [48].
controlled [40]. The BLC11A gene and ZBTB7A gene (LRF protein) are
responsible for the physiological decrease in HbF expression and the 4.2.1.4. Other. Before the development of genome-wide genotyping
switch to adult haemoglobin production [41]. Depending on the po- arrays, molecular genetic research in sickle cell disease was performed
pulation, genetic variations of BLC11A, HBS1L-MYB and HBB loci ex- with combinations of linkage- and candidate-gene-based approaches
plain up to 50% of HbF variance in individuals with sickle cell disease [51]. These strategies are complex, since many prior supposed
[42–44]. See Supplementary Table S1 for an overview of the best associations between sickle cell disease complications and genetic

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M.E. Houwing, et al. Blood Reviews 37 (2019) 100580

aberrations could not be reproduced by genome-wide association 5. Diagnosis and neonatal screening
studies (GWAS) [52].
Association studies with GWAS-level significance in sickle cell dis- Diagnosis of haemoglobinopathies is based on the detection of HbS
ease are summarised in Table 1. in relation to HbA and HbF. The most commonly used methods are
electrophoresis (gel- or capillary- based), high-pressure liquid chro-
matography (HPLC), isoelectric focusing and molecular approaches
4.2.1.5. Environmental factors. Environmental factors are likely to play
such as PCR [74]. These are relatively cheap techniques and available
an important role in the phenotypic variability of sickle cell disease.
worldwide. However, all techniques require well-trained staff, reason-
However, studies are limited and results are often inconsistent.
able laboratory facilities with special equipment and systems for sto-
Nongenetic factors include socio-economic factors as well as
rage of reagents. As over 80% of the population at risk for sickle cell
meteorological factors and air quality. Identification of environmental
disease reside in low-and middle-income countries, diagnostic facilities
factors that trigger or provoke clinical complications is important.
for sickle cell disease remain poor globally [75]. In many African set-
Alteration may lead to improvements in patient care, better quality of
tings, the sickle solubility test (Sickledex) is the only available tech-
life and reduction of hospital admissions and healthcare costs.
nique, but this test cannot distinguish sickle cell disease from sickle cell
trait (HbAS) [76]. Recently, however, promising diagnostic methods for
4.2.1.6. Socioeconomic factors. Socioeconomic factors are important rapid and reliable point-of-care determination of haemoglobin fractions
determinants of health in all individuals. Poverty is associated with in low-resource settings have been developed, such as HemoTypeSC™
higher rates of illness, shorter life expectancy, high stress levels, low and Sickle SCAN™ [77,78].
birth weight and many other negative health outcomes in general [53]. A prompt diagnosis is the first step in improving outcomes of in-
The ‘Cooperative Study of Sickle Cell Disease (CSSCD)’ suggests that dividuals with sickle cell disease. Pre-emptive diagnosis allows for
socioeconomic status differs in families with sickle cell disease when parental education on pathophysiology of disease and recognition of
compared to matched families in the same country. The study also specific signs to seek immediate medical care. Moreover, preventive
found a higher percentage of single female heads-of-household within interventions including vaccinations, prophylactic antibiotics and anti-
the sickle cell disease population. Moreover, male sickle cell disease malarial drugs can be discussed and implemented [75]. In developed
patients had a lower median income compare to healthy black males countries, such as the United States and many European countries,
[54,55]. In addition, low socio-economic status has been reported to be neonatal screening programmes for haemoglobinopathies and sub-
associated with poor academic performance [56]. Another study found sequent treatment have been established and have decreased childhood
lower admission rates for children during weekends, particularly for mortality significantly [79,80].
vaso-occlusive crises. This may arise from the fact that parents are able In addition to rapid diagnosis followed by adequate prophylactic
to stay at home and look after their children at the weekends, whereas treatment, an accurate and inexpensive method of determining sickle
this is much more difficult during working days [57]. cell disease carrier status can lead to informed parental choices [77].
Knowledge of sickle cell trait allows for a range of options, including
limiting of family size, ensuring that at-risk infants are tested at birth,
4.2.1.7. Geography. Geographic location also plays a role in sickle cell
and consideration of prenatal diagnosis [1]. However, sickle cell disease
disease outcomes. Use of healthcare services is lower in patients living
and its carrier status are still associated with a considerable stigma in
in rural areas, even though they have lower physical functioning and
many affected communities.
higher socioeconomic distress levels [58,59]. In addition, distance to
care has been associated with increases in patient hospitalisations [60].
6. Clinical presentation and disease management
It has been well documented that exposure to altitude leads to an
increased risk of vaso-occlusive crises in children and adults with sickle
6.1. Symptoms of disease
cell disease [61,62]. Atmospheric pressure and inspired oxygen pres-
sure fall roughly linearly with altitude [63]. Reduced oxygen tension
Overall, complications of sickle cell disease can be divided into two
may lead to increased HbS polymerisation and erythrocyte sickling.
main groups: those mainly due to haemolytic disease and functional
Therefore, patients living at high, and even moderate altitude, have
nitric oxide deficiency which cause large vessel vasculopathy (cere-
increased sickle cell-related complication rates [64].
brovascular disease, pulmonary hypertension, nephropathy, priapism
and leg ulcers) and those caused by vaso-occlusive ischaemic events
4.2.1.8. Weather and air pollution. An association between acute leading to painful episodes and progressive organ damage (hypos-
painful vaso-occlusive events and weather conditions has been plenism, osteonecrosis, retinopathy and liver damage) [28,69].
recognised for > 80 years, with special note of an increase in vaso-
occlusive crises in presence of cold weather [65–68]. Interestingly, a 6.1.1. Acute complications
large study in London and Paris recently investigated these associations 6.1.1.1. Vaso-occlusive crises. Acute recurrent painful sickle cell crises
in young patients with sickle cell disease. The study confirmed previous are caused by vaso-occlusion and ischaemic damage due to obstruction
reports of higher risk of admission in presence of wind and rainfall of post-capillary venules, but also due to ischaemia-reperfusion injury
[57,69]. High wind speed is likely to accelerate skin cooling and to [81]. Hypoxia, ischaemia and ultimately tissue damage, leads to the
promote vaso-occlusion, possibly as a result of impaired control of release of inflammatory mediators with concomitant mast cell
vascular tonus [70–72]. However, no associations were found with activation [82,83].
temperature, which may reflect available access to warm clothes and The occurrence of acute vaso-occlusive pain is unpredictable and
heated building facilities in these countries [57,69]. may be precipitated by triggers such as dehydration, infection and/or
Patients with sickle cell disease in high-income countries in Europe fever, cold, stress, acidosis, hypoxia and pain itself [84]. Pain episodes
and the United States predominantly live in capital cities and large in sickle cell disease are intense and involve peripheral afferent noci-
urban centres with high concentrations of air pollutants [55]. Air ceptor activation and hyperalgesia [85]. Overall, most episodes can be
quality is hypothetically an important determinant of complications in successfully managed at home [86]. Treatment is supportive with
patients with sickle cell disease. However, studies have yielded con- adequate pain medication (paracetamol, non-steroidal anti-in-
flicting results. Most pollutants are closely intertwined and correlated flammatory drugs and opiate analgesia administered at standard time
with weather conditions, making it difficult to establish the primary points), adequate hydration, warmth and rest. Aborting the acute
cause [55,73]. painful crisis at its onset may potentially prevent or minimise tissue

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damage [82]. As acute painful vaso-occlusive crises are associated with attacks and causing motor, cognitive and psychological deficits.
severe complications, such as acute chest syndrome and multiorgan Generally, a sudden onset of neurological symptoms should be
failure [87], patients and parents/caregivers should be educated as to presumed as stroke, warranting immediate brain MRI and MRA [110].
when to seek medical help. Patients presenting to the emergency de- Although the underlying pathophysiological mechanisms for CVA
partment with acute vaso-occlusive pain require rapid triage, evalua- remain uncertain, most cases are associated with vasculopathy affecting
tion and stringent administration of analgesics. In cases of severe pain the distal internal carotid and middle cerebral arteries. Vasculopathy
unresponsive to standard care, treatment with other medication such as seems to start in infancy and contributing factors include anaemia,
ketamine or clonidine may be necessary [88–90]. leucocytosis, hypoxaemia, endothelial dysfunction, functional NO de-
Nearly all patients with sickle cell disease will experience vaso-oc- ficiency, decreased cerebral vascular reserve and impaired regulation of
clusive episodes during their lifetime. The first episode may occur in blood flow causing hyperaemia [111–113]. The aetiology of silent
infancy, often presenting as dactylitis. Classical localisations for vaso- cerebral infarcts is less clear [114]. In contrast to overt strokes, they
occlusive crises in both children and adults are legs and arms, chest, typically occur in the territory of small penetrating arteries [111].
and back [91,92]. Acute pain is the most important complication from In absence of primary transcranial Doppler (TCD) screening, arterial
patient's perspective [93,94]. It is also the most common reason for ischaemic stroke occurs in 5–10% of children with sickle cell disease
emergency room visits and hospitalisation for both adults and children [115,116]. The cumulative risk for overt stroke is 11% by age 20 years.
with sickle cell disease, although it is more prevalent in adolescents and By age 30 and 45 years, 15% and 24% respectively will have experi-
young adults than in young children. enced an overt stroke [111,115]. Silent cerebral infarcts occur in ap-
proximately one-quarter of children before their sixth birthday and
6.1.1.2. Infectious disease. Although comprehensive care programs approximately one-third before their 14th birthday [117,118]. Silent
have dramatically reduced childhood mortality and improved life infarcts are associated with significant cognitive and academic mor-
expectancy [5,15,95], infection remains a significant contributor to bidity [56,119,120], and their presence predicts development of both
morbidity and mortality in sickle cell disease [1,96]. The increased new silent cerebral infarcts as well as overt strokes [121,122]. Re-
susceptibility to bacterial infections is mainly a result of functional current (secondary) strokes occur in half to two thirds of untreated
asplenia which is already present at a very young age. individuals and are associated with increasing morbidity and mortality
Autosplenectomy, but also other factors such as impaired fixation of [123].
complement, reduced oxidative burst capacity of chronically activated When an acute stroke is diagnosed, immediate exchange transfusion
neutrophils, dysfunctional IgM and IgG antibody responses and should be performed, followed by regular transfusion therapy to pre-
defective opsonisation contribute to the increased susceptibility for vent stroke recurrence [124]. During chronic transfusion therapy it is
infectious complications [97–100]. recommended to keep the HbS level below 30% of total haemoglobin
In addition, hyposplenic and asplenic individuals lack IgM memory [125,126]. The randomised Stroke Prevention Trial in Sickle Cell
B cells and therefore cannot mount a rapid specific response to en- Anaemia (STOP I trial), showed that long-term blood transfusion
capsulated organisms. The main pathogen of concern is Streptococcus therapy given to children with high cerebral artery blood flow velo-
pneumoniae, though severe and systemic infections with Haemophilus cities reduces the occurrence of a first stroke by 90% [127]. In the STOP
influenzae, Neisseria meningitidis, and salmonellae also occur. II trial, attempts to discontinue transfusions after three years resulted in
Overwhelming sepsis can develop rapidly with no obvious primary an increased risk of conversion to abnormal TCD velocities and adverse
source of infection, resulting in shock, disseminated intravascular neurologic events [128,129], suggesting that indefinite therapy is
coagulation, adrenal haemorrhage, and death within 24 to 48 h [101]. needed for primary stroke prevention. However, chronic transfusion
Promptly identifying and treating suspected bacterial infections is im- therapy places an intense burden on the patient and their family as
perative [88]. monthly transfusions are required. In addition, various medical com-
Next to being at risk for bacteraemia/sepsis, meningitis and pneu- plications may occur such as alloimmunisation and iron overload
monia, patients with sickle cell disease are predisposed to osteomyelitis. [130,131].
The bone marrow is expanded to accommodate for the increased hae- The multicentre TCD With Transfusion Changing to Hydroxyurea
matopoiesis and oxygen demand is high. At the same time circulation is trial (TWiTCH) demonstrated that for a subset of patients with sickle
sluggish. These factors make bone tissue vulnerable to vaso-occlusive cell disease who have received at least 1 year of transfusions, and have
episodes and infarction. Areas of necrotic bone act as foci for infection, no MRA-defined severe vasculopathy, hydroxyurea is an effective al-
which a high chance of systemic involvement duo to haematogenous ternative to transfusions [132]. However, long-term follow-up data are
spread [102,103]. Salmonella is the predominant pathogen in sickle cell needed to define the long-term benefits of hydroxyurea therapy
disease osteomyelitis [104,105]. This may be a consequence of [133,134].
ischaemia and infarction of the bowel secondary to microvascular oc-
clusion, which in turn allows gut bacteria to invade the intestinal wall 6.1.1.4. Acute chest syndrome. Acute chest syndrome is the second most
and enter the bloodstream [103]. common cause of hospital admissions in patients with sickle cell disease
In contrast to the relative resistance of carriers against malaria, [39]. It is a form of acute lung injury and is defined as a new pulmonary
patients with sickle cell disease are highly susceptible to the lethal ef- infiltrate involving at least one lung segment on chest radiograph
fect of malaria. Co-existence of the two is associated with increased accompanied by fever and/or respiratory symptoms [87]. Rapid
mortality and morbidity [106], and malaria is the most common pre- respiratory decline can be life threatening, commonly within 24 h of
cipitating cause of vaso-occlusive pain in endemic countries [107]. onset [135].
Patients travelling to endemic countries should therefore be treated The underlying cause of acute chest syndrome is unclear, however it
with malaria prophylaxis [108]. is thought to be a combination of infection, fat embolism, hypoventi-
lation and vaso-occlusion of the pulmonary vasculature [87]. Clinical
6.1.1.3. Cerebrovascular accidents. Cerebrovascular accident (CVA) is a risk factors include higher baseline haemoglobin concentration, leuco-
devastating complication of sickle cell disease. Complications vary from cytosis and lower HbF concentration [136,137]. Furthermore, several
overt stroke with abrupt onset of neurological deficit to silent cerebral studies have shown that children with sickle cell disease and asthma
infarcts, which are not clinically apparent but may be associated with have a higher rate of acute chest syndrome events than those with sickle
cognitive impairment [56,109]. CVA in patients with sickle cell disease cell disease without asthma [135,137–140].
often has similar presenting signs and symptoms as in persons without The incidence of acute chest syndrome is lower in older adults
sickle cell disease, including being preceded by transient ischaemic compared to children (8.8 events/100 patients' years in older adults

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M.E. Houwing, et al. Blood Reviews 37 (2019) 100580

versus 24.5 events/100 patient years in young children) [136,141]. sequestration of erythrocytes in the spleen classically causes abdominal
Severity varies, although acute chest syndrome in children is rarely the pain and distension, with serious haemodynamic symptoms. Severe
primary cause of death (< 1% of episodes); whereas in adults it is a episodes may lead to hypovolemic shock and death from cardiovascular
significant cause of mortality. The higher incidence of bone marrow and collapse. Acute splenic sequestration is usually seen in infants and
fat emboli in adults with acute chest syndrome suggests a different young children with a median age at first episode of 1.4 years [164] and
aetiology [87,142]. is rarely observed after 6 years of age [165]. To date, no solid predictor
The management of acute chest syndrome is largely similar in of acute splenic sequestration has been identified [161], however a
children and adults with sickle cell disease and typically includes sup- relapse is frequent with 50%–75% of patients experiencing more than
portive measures (oxygen, fluids, bronchodilators, pain control). Initial one episode [164].
treatment involves antibiotics effective against Streptococcus pneumo- Mild splenomegaly alone warrants no specific management, how-
niae combined with a macrolide for treatment of Mycoplasma pneumo- ever along with poor growth, bone marrow hyperplasia or reduced
niae or Chlamydia pneumoniae and should be adjusted according to transfusion efficiency, a splenectomy is indicated if age allows [161].
bacterial cultures [143]. If haemoglobin concentrations decrease or the Acute splenic sequestration requires the immediate restoration of blood
patient's clinical condition deteriorates e.g. increasing respiratory rate, volume by fluids and blood transfusion. Treatment options to prevent
increasing oxygen requirement, an erythrocyte transfusion is given to recurrence include watchful waiting, chronic transfusion and sple-
raise the haemoglobin concentration up to 10–11 g/dL (6.2–6.8 mmol/ nectomy. There is no clear evidence in favour of splenectomy versus
L) [135,144]. In general, it is better to initiate transfusion early as acute conservative management [166].
respiratory failure can develop rapidly. Exchange transfusion to reduce
the HbS level down to 30% should be performed if acute chest syn- 6.1.1.7. Hepatobiliary complications. The hepatobiliary system is one of
drome progresses despite simple transfusion, if there are severe clinical the most common intra-abdominal organs involved in sickle cell disease
features, or if the patient has multi-lobar disease [145]. Lastly, in- [167]. Sickle hepatopathy is a term used to describe a wide variety of
centive spirometry helps to reduce the risk of acute chest syndrome in both acute and chronic causes of liver abnormalities in patients with
patients with chest or rib pain, but has only been proven to be effective sickle cell disease, including cholelithiasis, vaso occlusive hypoxic liver
in children [146–148]. injury, hepatic sequestration, venous outflow obstruction, viral
hepatitis, sickle cell intrahepatic cholestasis and biliary cirrhosis. The
6.1.1.5. Acute kidney injury. Acute kidney injury, formerly called acute significant clinical heterogeneity and overlap in terms of presentation,
renal failure, is defined as an acute decline in renal function, leading to investigation and natural history make the use of one descriptive term
a rise in serum creatinine and/or a fall in urine output. The aetiology of insufficient [168,169].
acute kidney injury in sickle cell disease is not fully known [149]. Vaso- Hepatobiliary complications in sickle cell disease occur either di-
occlusion causes ischaemia in the renal medulla. Contributing factors rectly from the sickling process -which causes microvascular occlusion
include volume depletion due to hyposthenuria, frequent and chronic and ischaemia- or indirectly as a result of chronic haemolysis or iron
use of non-steroidal anti-inflammatory drugs (NSAIDS), infections, overload due to multiple blood transfusions. Clinically, diagnosis is
massive haemolysis and rhabdomyolysis [150–152]. Recent studies confounded by difficulties differentiating abnormal liver enzymes due
have established an association between episodes of acute kidney injury to intrinsic liver disease from those resulting from haemolysis. In ad-
and progression to chronic kidney disease [153–157]. dition, it is important to realise that a spectrum of clinical manifesta-
Acute kidney injury occurs in 4–10% of hospitalised adult patients tions may be observed for the same underlying pathophysiology.
with sickle cell disease, and is more frequent in patients with acute Sickle cell intrahepatic cholestasis is a rare, but potentially fatal
chest syndrome (13.6%) [149,158]. In paediatric patients, the in- complication of sickle cell disease. It is characterised by severe right
cidence may be as high as 17% in children presenting to the hospital upper quadrant pain, progressive hepatomegaly, extreme hyperbilir-
emergency room with vaso-occlusive crisis [159]. ubinemia, but mild elevation of liver enzymes, and coagulopathy [170].
Management of acute kidney injury involves daily monitoring of The role of liver biopsy in the diagnosis of sickle cell intrahepatic
renal function, fluid intake and output, and haemodynamic parameters cholestasis is uncertain, due to problems obtaining liver tissue for his-
(blood pressure) to avoid hypoperfusion of the kidneys. Potential ne- tologic analysis as this is often contraindicated in the acute setting of
phrotoxic drugs and imaging agents should be avoided. The patient critically ill sickle cell disease patients [171].
should be evaluated for all potential aetiologies [88]. The management of sickle hepatopathy relies on accurate identifi-
cation and treatment of any coexisting cause(s) and still remains mainly
6.1.1.6. Splenic complications. The spleen is one of the first organs to be supportive. Unfortunately, medical management is limited and the role
damaged in sickle cell disease patients, as hyposplenism presents in the of hydroxyurea or prophylactic cholecystectomy in preventing hepa-
majority of children before 12 months of age [160]. The structure and tobiliary manifestations has not been defined [172,173]. Acute hepatic
function of the spleen predisposes for ischaemic infarctions as it is sequestration may lead to hypovolemic shock and therefore prompt
characterised by low flow and an open microcirculation leading to treatment with fluids and (exchange) transfusion is warranted [174].
deoxygenation and sickling of HbS erythrocytes [161]. These vaso- Sickle cell intrahepatic cholestasis in the acute stage requires early and
occlusive events are not painful and clinically silent, but lead to fibrosis vigorous exchange transfusion to prevent fulminant liver failure. It is
and functional asplenia. not clear which patients will progress to end-stage liver disease and the
There are different manifestations of splenic injury in patients with role of liver transplantation therefore remains controversial [169].
sickle cell disease which are not mutually exclusive and may coexist.
There is no correlation between spleen size and function. Although 6.1.1.8. Priapism. Priapism is defined as a painful or painless,
most spleens rapidly decrease in size, functional hyposplenism and undesirable and persistent state of penile erection, which may follow
splenomegaly are often combined in young children with sickle cell in the absence of a sexual stimulus [175]. There are three types of
disease [162]. This is explained by progressive yet moderate trapping of priapism: ischaemic priapism (veno-occlusive, low flow), stuttering
sickled erythrocytes in the red pulp. priapism (recurrent ischaemic) and non-ischaemic priapism (arterial,
Hypersplenism is defined as splenomegaly in combination with high flow). The vast majority of cases in sickle cell disease are
anaemia, leucopenia and/or thrombocytopenia. Diagnosis can be dif- ischaemic [176]. Ischaemic priapism is defined by reduced or absent
ficult as splenomegaly is frequent and anaemia pre-exists. Acute splenic intracorporal blood flow and is characterised by painful rigidity of the
sequestration is defined as an acute splenic enlargement with a ≥ 20% corpora cavernosa due to blood stagnation within these structures. This
fall in haemoglobin level from baseline level [163]. The rapid subsequently leads to hypoxia, acidosis and tissue ischaemia. If

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M.E. Houwing, et al. Blood Reviews 37 (2019) 100580

priapism persists, it can lead to permanent local tissue damage with psychological disturbances caused by sickle cell disease [207]. Because
cavernosal fibrosis and permanent erectile dysfunction [177]. Most of the complexity of managing sickle cell related pain -and the need to
priapism episodes begin during sleep [178–180] and occurrence is differentiate between acute and chronic pain- ideally a pain manage-
associated with higher HbS levels and inversely correlated to foetal ment specialist is a member in each sickle cell team.
haemoglobin levels [181,182]. The exact pathophysiology of priapism
is unclear, however decreased bioavailability of NO most likely plays an 6.1.2.2. Pulmonary hypertension. Pulmonary hypertension is defined as
important role [183]. a mean pulmonary artery pressure of 25 mmHg or more, with a left
The mean age of onset of priapism is 15 years. The calculated ac- ventricular end-diastolic pressure of 15 mmHg or lower measured
tuarial probability of experiencing priapism is 25% by 10 years of age, during right heart catheterization [208]. The pathophysiology of
and 75% by 20 years of age [184]. Medical management is warranted pulmonary hypertension in sickle cell disease patients is
and includes urgent relief of pain with opioids, hydration, and multifactorial. There is a prominent role for intravascular haemolysis
achievement of prompt penile detumescence [185]. Standard treatment inducing a state of vascular dysfunction, with pulmonary vasculopathy
involves an oral dose of a vasoactive agent, such as pseudoephedrine to as well as pulmonary hypertension through decreased NO
induce smooth muscle contraction and thereby reduce congestion bioavailability and vasoconstriction [209]. In addition, the
[186]. Corporeal aspiration and phenylephrine intracavernosal injec- physiologic response to severe anaemia is a compensatory increase in
tion should only be performed by an urologist and induces rapid de- cardiac output in order to maintain adequate oxygen delivery. This
tumescence and thus allows oxygenated blood to re-enter the cavernosa increased cardiac output is generated by increases in blood volume,
[176]. In addition, sickle cell disease patients with priapism may also preload, heart rate, and stroke volume, along with a decrease in
benefit from hydroxyurea therapy and erythrocyte or exchange trans- afterload [210].
fusions. However these strategies alone cannot be recommended as a Patients with sickle cell disease develop a high pulse pressure in
standard of care for patients with acute attacks of priapism and in fact, both the systemic and the pulmonary circulation. About half of sickle
may cause harm by deleterious delaying of timely interventions. Only if cell disease patients with related pulmonary hypertension have pre-
conservative measures fail to produce detumescence, penile shunt capillary pulmonary hypertension with different potential aetiologies,
surgery should be performed [187,188]. the other half have post capillary pulmonary hypertension secondary to
Stuttering priapism, also called recurrent priapism, is characterised left ventricular and mitral valve dysfunction [211]. It is recognised that
by multiple self-limited episodes of ischaemic priapism and affects as the elevation in cardiac output and reduced blood viscosity associated
many as 35% of males with sickle cell disease [189]. Although self- with sickle cell disease results in a lower baseline pulmonary vascular
limiting, stuttering priapism may also lead to impotence. Current pre- resistance than among healthy individuals. Therefore, the pulmonary
ventive treatments include the 5α-reductase inhibitor finasteride or artery pressure in sickle cell disease patients is subsequently only
short- and long-acting phosphodiesterase type 5 (PDE5) inhibitors, such moderately elevated [212].
as sildenafil and tadalafil [190,191]. In addition, hormonal analogues Pulmonary hypertension is associated with increased morbidity and
might reduce symptoms, although there is no evidence regarding im- mortality in adult sickle cell disease patients [208,213,214]. Left and
provement in functional outcomes [192]. right ventricle dilation, diastolic dysfunction, and elevated pulmonary
arterial pressures are commonly reported findings. Current interven-
6.1.2. Chronic complications tions include hydroxyurea therapy, and in some cases, chronic trans-
6.1.2.1. Chronic pain. In addition to intermittent acute vaso-occlusive fusions, anticoagulation and oxygen therapy. Specific drugs used in
pain, sickle cell disease patients also experience chronic pain. The pulmonary hypertension for patients without sickle cell disease may be
aetiology of chronic pain is not clearly understood. Chronic pain in considered, but these therapies do not have clear evidence of efficacy in
sickle cell disease patients occurs irrespective of a vaso-occlusive crisis sickle cell disease [208,211].
and although chronic pain is sometimes secondary to avascular necrosis
at various joints, most patients with chronic pain do not have an 6.1.2.3. Renal dysfunction. Renal dysfunction is almost inevitable in
obvious anatomic source. A number of factors ranging from genetic to sickle cell disease and starts very early in life with impaired urine
behavioural are associated with pain response and are further concentrating ability and glomerular hyperfiltration [215,216]. There
influenced by interactions between the nervous, endocrine, and is a strong tendency for HbS to polymerise in the renal medulla, due to
immune systems. Patients describe chronic pain using both low partial pressure of oxygen, low pH, and high osmolality. This
nociceptive and neuropathic descriptors and sensory testing reveals subsequently causes erythrocyte dehydration and vaso-occlusion [24].
both peripheral and central nervous system abnormalities [193–197]. The pathophysiology of glomerular hyperfiltration is mostly
Between 17 and 30% of adults with sickle cell disease experience attributable to the haemolysis associated vasculopathy [217]. Sickle
daily pain [86,198]. In addition, 40% of children and adolescents aged cell nephropathy is characterised by proteinuria with
8–18 years have chronic pain with 35% reporting daily pain [199]. The glomerulosclerosis, decreased glomerular filtration rate and eventual
‘Cooperative Study of Sickle Cell Disease (CSSCD)’ demonstrated that renal failure [218].
chronic pain impairs health status and quality-of-life more than any A large proportion of children with sickle cell disease have glo-
other sickle cell disease-related complication [200]. Chronic pain is merular hyper filtration. The glomerular filtration rate (GFR) seems to
associated with psychosocial morbidity (e.g., depression, anxiety, des- start declining after 16 years of age [219]. Proteinuria is age-dependent
pair, loneliness, helplessness), as well as unemployment and school in sickle cell disease, and occurs in up to 27% of patients in the first
dropout [199,201–204]. The current literature focuses on prevention three decades and in up to 68% of older patients [220–223]. It can
and management of acute painful episodes, with few data or guidelines progress to nephrotic proteinuria, with > 3.5 g protein loss in 24 h
on the management of chronic pain. However, early and aggressive [224]. Renal involvement contributes substantially to the diminished
treatment of acute sickle cell pain may reduce the development of life expectancy of patients with sickle cell disease, accounting for
chronic pain [82]. The purpose of pain control is to maximize quality of 5–18% of mortality [39,96,225].
life. It is recommended to combine interventions and to include both Treatment focusses on screening for microalbuminuria and the early
pharmacological (e.g., acetaminophen, NSAIDs, anticonvulsants, tri- use of hydroxyurea to prevent renal dysfunction [226–231]. In addi-
cyclic antidepressants, judicious use of opioids) and non- tion, angiotensin converting enzyme (ACE) inhibitors reduce protei-
pharmacological treatments (e.g., heat, physiotherapy, massage, re- nuria and delay the progression of chronic kidney disease [232,233]. In
laxation therapies, meditation) [205,206]. Cognitive behaviour therapy end-stage kidney-failure, renal transplantation has reasonable survival
helps the patient to develop strategies for pain coping and other outcomes, comparable with transplant outcomes in patients with

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M.E. Houwing, et al. Blood Reviews 37 (2019) 100580

diabetic kidney failure [234]. geographically, with rates as high as 75% in Jamaica and 25% in the
United States [259,260]. However, in the CSSCD, the overall pre-
6.1.2.4. Avascular necrosis. Avascular necrosis, also known as valence was 2,5% in persons 10 years of age and older and was higher
osteonecrosis, ischaemic necrosis or aseptic necrosis, is one of the in patients with HbSS (5%) and HbSβ0 (4%) genotype compared to
most devastating musculoskeletal manifestations of sickle cell disease. patients with other genotypes [259]. Regardless, leg ulcers occur ten
It occurs when vaso-occlusion results in the infarction of the articular times more frequently in sickle cell disease than in the general popu-
surfaces and head of the long bones. Although the exact lation [261].
pathophysiology of this condition in patients with sickle cell disease The major challenges in management of leg ulcers in patients with
is unknown, it is suggested that repetitive vaso-occlusion may be sickle cell disease are the prolonged course to recovery and the high
associated with tissue hypoxia, reperfusion injury, inflammation, and recurrence rate of healed or grafted ulcers [262]. The treatment is
subsequent bone necrosis and collapse. The most common site of multidisciplinary with adequate control of sickle cell disease and pain
avascular necrosis is the femoral head followed by the head of the as well as aggressive local therapy including wound care and surgery
humerus, knee and small joints of the hands and feet [104,235,236]. [263]. The role of hydroxyurea and exchange transfusion is presently
Avascular necrosis affects 50% of the patients by 35 years of age unclear, however, there are many potential benefits such as increase in
[237,238], and bilateral hip involvement is seen in 40 to 91% of pa- haemoglobin, decrease in haemolysis, increase in oxygen carrying ca-
tients [239–242]. Clinical symptoms peak during adolescence, how- pacity, and improved red blood cell rheology. Lastly, it is crucial to
ever, patients are frequently asymptomatic during the early stages, address both the immediate consequences of pain, infection and dis-
delaying diagnosis until it has progressed to advanced stages [243]. ability, and long term effects on quality of life, employment and stigma
Symptomatic patients complain of painful and limited motion of the associated with chronic ulceration [264].
affected joint, occasionally with pain at rest. Early disease is best di-
agnosed by MRI, as plain X-rays my not detect early disease [237,244]. 6.2. Comprehensive care
If left untreated, osteonecrosis can be extremely debilitating and may
lead to severe pain, loss of function, and degenerative joint changes 6.2.1. Immunisations and infection prophylaxis
[245,246]. Although several conservative management approaches Prior to the initiation of neonatal screening for sickle cell disease,
exist, total joint arthroplasty seems to be the most effective treatment infection due to invasive pneumococcal disease was the leading cause
intervention. of death in afflicted children [265]. Particularly very young children
are at risk, with a reported incidence of invasive pneumococcal disease
6.1.2.5. Ophthalmologic complications. Chronic ophthalmological of 10 per 100 in children aged < 3 years and a 30% fatality rate
complications of sickle cell disease include proliferative retinopathy [266,267]. The risk decreases to 1.1 per 100 in those aged 5–9 years,
and vitreous haemorrhage. Proliferative retinopathy develops due to and 0.6 per 100 in those aged over 10 years [268].
peripheral retinal arteriolar occlusions. Local ischaemia from repeated The ‘Prophylaxis with Oral Penicillin in Children with Sickle Cell
episodes of arteriolar closure triggers angiogenesis through the Anaemia’ (PROPS) trial in 1986 demonstrated the significant reduction
production of vascular endothelial growth factors [247]. Goldberg on morbidity and mortality by penicillin prophylaxis [269]. It was also
defined five stages of proliferative retinopathy, with stage I only noted that early initiation of penicillin prophylaxis is most effective as
consisting of arteriolar occlusion and stage V defined by the presence the risk of infection is inversely related to age. Accordingly, most ad-
of retinal detachment with or without hole formation in the retina visory health committees have recommended early diagnosis by neo-
[248]. natal screening in order to commence penicillin prophylaxis in early
The prevalence of proliferative retinopathy is higher in the HbSC infancy [270].
genotype compared to homozygous sickle cell disease, with reported To determine the age at which it is safe to stop penicillin prophy-
incidences of 33% and 14% respectively [249–251]. Current research laxis, PROPS II was conducted [271]. Infection rate was shown to de-
has not yet been able to explain the reason for this profound dis- crease significantly after the age of five years, whether or not the child
crepancy. The peak prevalence of proliferative retinopathy in HbSS received penicillin. Therefore, it was concluded that prophylaxis could
patients occurs between 25 and 39 years, whereas in the HbSC genotype be discontinued at five years of age without a clinically important in-
it occurs from 15 to 24 years in men and 20–39 years in women creased risk of infection [271]. However, globally guidelines differ with
[251,252]. Neither gender nor the presence of systemic manifestations regard to age at which penicillin prophylaxis is stopped [272].
is predictive for prevalence or age of onset of retinopathy [253]. Additional research has extensively documented the benefit of
Therapeutic intervention is usually recommended in cases of bi- pneumococcal vaccines next to daily penicillin prophylaxis. There are
lateral proliferative disease, spontaneous haemorrhage, large elevated three main vaccine schedules: polyvalent polysaccharide vaccines
neovascular fronds, and rapid growth of neovascularization. Laser (PPV), polysaccharide conjugate vaccines (PCV), and a combination of
photocoagulation helps in avoiding haemorrhage and sight loss, how- both. The conventional unconjugated 23-valent PPV (PPV-23) can only
ever it does not significantly lead to the regression of advanced pro- be given to children after 23 months of age. Before this age, which is the
liferative retinopathy. Innovative therapy includes intravitreal injection period of highest pneumococcal infection risk [273–275], the more
of an anti-vascular endothelial growth factor which appears compara- recently developed conjugated vaccines in which polysaccharides are
tively safe and efficient [254]. covalently linked to protein carriers, should be administered. Two large
studies both showed a marked reduction in invasive pneumococcal
6.1.2.6. Leg ulcers. Leg ulcers occur in areas with less subcutaneous fat disease in sickle cell disease patients following PCV introduction
and with decreased blood flow [255]. The skin around both side of the [272,276,277].
ankle is most often affected, less common sites are the anterior tibia Finally, it is important to highlight the use of routine courses of
area and the dorsum of the foot [256]. The pathogenesis of chronic immunisations in the care of children with sickle cell disease. These
ulcers in sickle cell disease is complex. Venographic studies have shown should be administered according to their chronological age regardless
that venous insufficiency is not a primary cause of sickle cell of prematurity. In addition children and adult patients should be of-
ulcerations. Instead, the arteriovenous shunting is recognised as a fered vaccination against influenza annually from the age of six months.
decisive factor in ulcer formation. This shunting deprives the skin of
oxygen, promoting ulceration [257]. High haemolytic rate and low 6.2.2. Screening for complications
haemoglobin concentrations have been recognised as risk factors [258]. 6.2.2.1. Risk of stroke. Sickle cell disease has a high incidence of
The prevalence of leg ulcers in sickle cell disease varies cerebral infarction, primarily occurring in childhood, with a second

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M.E. Houwing, et al. Blood Reviews 37 (2019) 100580

peak in adults over the age of 29 years [115]. In children, overt stroke is cardiomyocyte stretching. High levels reflect cardiac chamber volume
related to stenosis and occlusion of large cerebral arteries of the Circle and pressure overload. NT-proBNP gives systemic vasodilation, inhibits
of Willis which can be detected by TCD ultrasonography. High maximal the sympathetic nervous system and the renin-angiotensin-aldosterone
mean velocity cerebral artery flow identifies children at high risk of system while promoting natriuresis [291,292]. Elevated plasma con-
stroke [278,279]. The stroke risk increases in proportion to increasing centrations of NT-proBNP (> 160 pg/mL) are an independent risk
time-averaged mean of the maximum velocity (TAMV) in the distal factor for mortality in sickle cell disease [214,293–296]. The pre-
internal carotid artery or proximal middle cerebral artery. High flow valence of a high NT-proBNP level increases with age in adults. This is
velocity is an indirect indicator of either increased volume flow or not the case for paediatric patients given the physiologically higher
stenosis in the large vessels [280]. normal NT-proBNP levels in children, especially during the first year of
Current standard of care includes annual or biannual TCD screening life [292].
between the ages of 2 and 16 years [88]. Repeated measurements are To screen for pulmonary hypertension, the American Thoracic
performed dependent on the result of the prior examination i.e. yearly if Society recommends annual echocardiography and NT-proBNP con-
the initial TCD is normal (TAMV < 170 cm/s), every 6 months if low centrations for adult patients [212]. The prevalence and consequences
conditional (TAMV 170–184 cm/s), every 3 months if high conditional of increased TRV and signs of pulmonary hypertension in children with
(TAMV 185–199 cm/s), and within 1 month if abnormal (TAMV sickle cell disease are less clear as there are no large data sets of chil-
≥200 cm/s) [125,126]. If the second TCD is in the abnormal range, dren with this condition. Neither have reports been published in chil-
MRI/ MRA imaging is recommended and subsequent transfusion dren on associations of elevated TRV with increased mortality
therapy, if cerebral stenosis is confirmed. [297–300]. This may be due to the overall low mortality rate in chil-
Currently, there are no validated methods to screen for increased dren with sickle cell disease in high income countries [15]. Routine
risk of stroke in adults with sickle cell disease. The velocity criteria used echocardiograpical screening for paediatric patients is therefore not
in children cannot been used to stratify risk of stroke in adults, due to recommended [88]. Given the lack of data, it may be possible that
an age related decline in TCD velocities and an absence of reference patients are underdiagnosed and therefore under treated [297,301]. See
TCD values for adults [281]. Table 2 for rationale for (not) screening for pulmonary hypertension in
adult and paediatric patients with sickle cell disease according to the
6.2.2.2. Retinopathy. Almost all ocular structures can be affected by principles for screening proposed by Wilson and Junger [302]. These
microvascular occlusions caused by sickle cell disease[282], but the principles give guidance in the selection of conditions that would be
most common complication is proliferative retinopathy. This is suitable for screening.
characterised by lesions in the areas at the border between the
vascular and avascular retina with abnormal arteriovenous 6.2.3. Treatment
communications [251,283,284]. Proliferative retinopathy can lead to 6.2.3.1. Hydroxyurea. The primary benefits of hydroxyurea for sickle
visual loss from vitreous haemorrhage, macular lesions and retinal cell disease relate to its ability to increase HbF levels, first described in
detachment. Until such complications arise, patients are often the 1980s [303]. The exact mechanisms by which hydroxyurea induces
asymptomatic. HbF remain incompletely understood [304]. In addition, the full
Vision loss from proliferative retinopathy is largely preventable benefits of hydroxyurea therapy in sickle cell disease are
when detected early and if careful follow-up and treatment is initiated. multifactorial, extending beyond HbF induction. Other mechanisms of
Although the peak prevalence occurs earlier in the HbSC genotype, it is action include decreased neutrophil and reticulocyte counts due to
recommended to screen for retinopathy in all sickle cell disease geno- cytotoxic effects of hydroxyurea, a reduced expression of surface
types from the age of 10 years by an ophthalmologist performing di- molecules that adhere to the endothelium and increased levels of NO
lated fundus examination. Serial examinations may be done biennially as a consequence of hydroxyurea metabolism that may contribute to
for eyes with normal findings, and fluorescein angiography on eyes local vasodilatation [305,306].
with abnormal examinations, with follow-up when indicated [88,253]. Several prospective clinical trials have consistently shown both
clinical efficacy (e.g. less frequent vaso-occlusive pain- and acute chest
6.2.2.3. Cardiopulmonary complications. Regular screening for episodes, fewer hospitalisations and blood transfusions) as well as ef-
pulmonary and cardiac complications in sickle cell patients is fects on laboratory values (e.g. increased total haemoglobin and foetal
controversial due to the lack of evidence regarding efficacy on haemoglobin, decreased lactate dehydrogenase and bilirubin) of hy-
clinical outcomes in asymptomatic individuals [88]. However, droxyurea in both paediatric and adult sickle cell disease patients
cardiopulmonary complications are the most common causes of death [307–310]. Importantly, the BABY HUG trial allowed the enrolment of
in adults with sickle cell disease [208,214,285]. In addition, early clinically asymptomatic infants, and proved the benefits of hydroxyurea
interventions might reduce severe cardiac disease development. treatment in both children with and without sickle cell disease-related
A non-invasive method for screening of patients to determine the symptoms and complications [311]. Additional effects of hydroxyurea
presence of pulmonary hypertension uses Doppler echocardiography to on organ function also included decreases in urine albumin to creati-
measure tricuspid valve regurgitation velocity (TRV). Approximately nine ratio (ACR) and decreased glomerular hyperfiltration
one-third of adult patients with sickle cell disease have an elevated [229,231,312], normalised microvascular blood flow [313], less airway
tricuspid valve regurgitant jet velocity (TRV) of 2.5 m/s or higher, a hyper-reactivity [314], higher oxygen saturations [315–317], improved
threshold that is associated with an increased risk of having a mean cognitive functioning [318] and lower transcranial Doppler (TCD) ve-
artery systolic pressure of at least 30 mmHg measured with right heart locities [231,319–322]. In addition, observational studies have con-
catheterisation [214,286,287]. Although pulmonary hypertension is firmed safety and long-term clinical efficacy and reduction of mortality
only found in about 10% of patients with elevated TRV [288], patients in both adults and children on hydroxyurea treatment [323–328].
with a TRV above 2.5 m/s have a 9- to 10-fold higher risk for early Side effects of hydroxyurea are usually mild and include dose-de-
mortality than those with a lower TRV [214,286,289]. Abnormal pendent myelosuppression, cutaneous effects including nail- and skin
echocardiography should therefore instigate referral to a cardiologist or hyperpigmentation and gastrointestinal symptoms [307]. Conse-
pulmonologist with expertise in pulmonary hypertension. Regardless of quently, recent National Heart, Lung, and Blood Institute (NHLBI)
the echocardiographic findings, right heart catheterization is the golden guidelines and the British Society for Haematology Guideline re-
standard for diagnosis of pulmonary hypertension [290]. commend offering hydroxyurea to all children of 9 months of age and
NT-proBNP (N-terminal prohormone brain natriuretic peptide) is a older with sickle cell disease (HbSS or HbSß0 genotype), regardless of
hormone released from the cardiac ventricles in response to their symptoms in order to reduce and prevent complications [88,329].

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M.E. Houwing, et al. Blood Reviews 37 (2019) 100580

Table 2
Rationale for (not) screening for pulmonary hypertension (echocardiography) in patients with sickle cell disease.
Characteristic of disease appropriate for Supporting evidence in adults Supporting evidence in children (< 18 y)
screening*

Disease is relatively common. Prevalence elevated TRV: 24.4% (95% CI 18.4–30.4) a, of which Prevalence elevated TRV: 20.7% (95% CI 15.7–-25.6) a, no data
6–11% have PH confirmed on RHCb,c,d,e. on prevalence PH.
Disease has a significant negative impact Both elevated TRV and PH are associated with an increased No association between TRV, mortality and clinically relevant
on health. mortalityb,c,d,e,f morbidityf,g,h,i.
Disease has an identifiable Patients with PH are frequently asymptomatic early on; cases of No data.
asymptomatic period. PH are often identified late in the course of disease j, k.
Treatment before symptoms occur is No data, however highly plausible as a number of studies on PH in Different clinical associations with PH in adults vs. children with
more effective than if treatment is the general population indicate that early therapeutic sickle cell disease suggests alternative mechanisms of disease
delayed. intervention positively influences disease progression when pathogenesis. So far there are no data if paediatric PH persists into
compared to delayed treatment l. adulthood f.
Consequences of false negative or false The positive predictive value of echocardiography for detection of No data, however patients with elevated TRV should undergo a
positive test are modest. PH in SCD is 25% b. RHC. RHC is associated with a low risk of complications, but is
invasive.
Screening test is easy to administer, not Doppler echocardiography is simple and non-invasive. Doppler echocardiography is simple and non-invasive.
harmful and reliable.

Abbreviations; y: year, TRV: tricuspid valve regurgitant jet velocity, pH: pulmonary hypertension, RHC: right heart catheterisation, vs: versus, SCD: sickle cell disease
* According to the principles for screening proposed by Wilson and Jungerm.
a
Musa BM, Galadanci NA, Coker M, Bussell S, Aliyu MH. The global burden of pulmonary hypertension in sickle cell disease: a systematic review and meta-
analysis. Ann Hematol. 2016;95:1757–64.
b
Parent F, Bachir D, Inamo J, Lionnet F, Driss F, Loko G, et al. A hemodynamic study of pulmonary hypertension in sickle cell disease. N Engl J Med.
2011;365:44–53.
c
Fonseca GH, Souza R, Salemi VM, Jardim CV, Gualandro SF. Pulmonary hypertension diagnosed by right heart catheterisation in sickle cell disease. Eur Respir J.
2012;39:112–8.
d
Mehari A, Gladwin MT, Tian X, Machado RF, Kato GJ. Mortality in adults with sickle cell disease and pulmonary hypertension. JAMA. 2012;307:1254–6.
e
Gladwin MT, Barst RJ, Gibbs JS, Hildesheim M, Sachdev V, Nouraie M, et al. Risk factors for death in 632 patients with sickle cell disease in the United States and
United Kingdom. PLoS One. 2014;9:e99489.
f
Hagar RW, Michlitsch JG, Gardner J, Vichinsky EP, Morris CR. Clinical differences between children and adults with pulmonary hypertension and sickle cell
disease. Br J Haematol. 2008;140:104–12.
g
Dham N, Ensing G, Minniti C, Campbell A, Arteta M, Rana S, et al. Prospective echocardiography assessment of pulmonary hypertension and its potential
etiologies in children with sickle cell disease. Am J Cardiol. 2009;104:713–20.
h
Lee MT, Small T, Khan MA, Rosenzweig EB, Barst RJ, Brittenham GM. Doppler-defined pulmonary hypertension and the risk of death in children with sickle cell
disease followed for a mean of three years. Br J Haematol. 2009;146:437–41.
i
Gordeuk VR, Minniti CP, Nouraie M, Campbell AD, Rana SR, Luchtman-Jones L, et al. Elevated tricuspid regurgitation velocity and decline in exercise capacity
over 22 months of follow up in children and adolescents with sickle cell anemia. Haematologica. 2011;96:33–40.
j
Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF, Minter K, et al. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N
Engl J Med. 2004;350:886–95.
k
Galie N, Manes A, Branzi A. The endothelin system in pulmonary arterial hypertension. Cardiovasc Res. 2004;61:227–37.
l
Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary
arterial hypertension in the modern management era. Circulation. 2010;122:156–63.
m
World Health Organization; Wilson JMGJ, G. The principles and practice of screening for disease. 1966.

Despite the accumulating evidence on the safety, efficacy and cost- overloading. However, its use is limited by difficulties with venous
effectiveness, hydroxyurea in sickle cell disease patients is still under- access and the need for increased volumes of donor red blood cells
utilised in clinical practice [330]. This is partly due to concerns about [337].
side effects and uncertainties about long term effects of hydroxyurea. As The main indication for an emergency top-up red blood cell trans-
treatment duration currently approaches 15 to 20 years in some chil- fusion is severe anaemia in particular due to red cell aplasia caused by
dren and cumulative exposure years worldwide are estimated hundreds parvovirus B19 infection or acute splenic sequestration. The aim is to
of thousands, hydroxyurea used in therapeutic doses in young patients correct the anaemia and to improve the oxygen carrying capacity of
with sickle cell disease does not confer an increased risk of malignancy blood. The main indications for an acute exchange transfusion are
[323,331–333]. Regarding fertility, there are insufficient data to con- clinical complications which require an immediate and significant de-
clude whether or not there is an independent association between crease in HbS percentage, i.e. acute stroke, acute multiorgan failure,
sperm quality and hydroxyurea use in male patients with sickle cell acute chest syndrome, severe sepsis and intrahepatic cholestasis
disease other than effects of the disease itself on male spermatogenesis [338,339]. Indications for chronic (exchange) transfusion most often
[334–336]. relate to stroke prevention, either to prevent secondary stroke or as
primary prevention in children with a raised TCD velocity over 200 cm/
6.2.3.2. Blood and exchange transfusion. Red blood cell transfusions s [88]. Preoperatively, transfusions are administered to prevent post-
have an important role in the treatment and prevention of both acute operative complications related to sickle cell disease [339]. There is
and chronic disease complications. Transfusions raise haemoglobin insufficient evidence to determine whether simple top-up preoperative
level, but more importantly decrease the percentage of HbS transfusion is as effective as exchange transfusion [340].
erythrocytes, suppress HbS synthesis and reduce haemolysis, all of Red blood cell transfusions are associated with severe side effects
which reduce the risk of vaso-occlusion and ischaemia. Blood and patients must therefore be carefully monitored. Main risks are red
transfusions can be administered as a simple top-up transfusion or as blood cell alloimmunization, delayed haemolytic transfusion reactions,
an exchange transfusion where there is the simultaneous removal and hyperhaemolysis, iron overload and risk of transmission of infectious
replacement of blood. Exchange transfusions decrease the percentage of diseases [341,342]. In addition, transfusions raise the haematocrit of
HbS erythrocytes more efficiently and lower the risk of iron circulating blood, resulting in an increased viscosity which may

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M.E. Houwing, et al. Blood Reviews 37 (2019) 100580

promote sickling and trigger vaso-occlusion [343]. Red blood cell al- and HSCT, identification of (bio) markers may be helpful to predict
loimmunisation occurs in approximately 30% of transfused sickle cell disease severity and risk of complications in HSCT [366]. Meanwhile,
disease patients compared to 2–5% of all transfusion recipients [344]. patients and families should be educated on disease severity, the like-
This is partly due to the differences in non-ABO red blood cell antigen lihood of reduced life expectancy and the advantages, limitations and
expression frequencies between Caucasian blood donors and the mostly adverse events associated with HSCT, so that they are able to make an
African-American recipients with sickle cell disease [345]. Although informed decision together with treating physicians [367].
antibody titres may be low or even undetectable, alloantibodies are
known to persist for many years and can result in clinically significant 6.2.3.4. Emerging therapies
delayed haemolytic transfusion reactions. Alloimmunisation therefore 6.2.3.4.1. Gene therapy. Gene therapy studies to modify or cure
limits the ability to identify compatible blood units for transfusions sickle cell disease have been ongoing for many years [368]. Gene
when life threatening situations occur [346]. Lastly, iron overload due therapy involves the therapeutic ex vivo modification of autologous
to frequent transfusions can cause cardiac, liver and endocrine dys- haematopoietic stem cells to treat -and hopefully cure- sickle cell
function. Chelation therapy should be initiated to remove excess iron in disease. As gene therapy does not necessitate the identification of a
patients with secondary iron overload [342]. HLA-matched donor and avoids the risk of GvHD and graft rejection,
Although red blood cell transfusions can help ameliorate many this is potentially a valuable alternative to allogeneic HSCT [369].
sickle cell disease complications, more research is indicated, and risks Various gene therapy approaches have been developed. In gene
and benefits of transfusion should be fully discussed with patients and modification, the most commonly used method, a lentiviral vector is
their families before a (long-term) transfusion program is commenced used to transfer a modified gene into haematopoietic stem cells [370].
[347]. The rationale behind γ-globin gene addition is based on the observation
that high levels of foetal haemoglobin (α2γ2) positively influence sickle
6.2.3.3. Haematopoietic stem cell transplantation. At this moment, HSCT cell disease phenotype (α2β2).
is the only curative treatment for patients with sickle cell disease. Recently, a 13 year old boy with HbSS genotype was reported who
Worldwide, over 1000 patients with sickle cell disease have received received treatment with a self-inactivating lentiviral vector. Once the
HSCT [348,349]. Most HSCTs in sickle cell disease patients have been transduced stem cells had engrafted, normal blood cell counts were
performed in children with human leucocyte antigen (HLA)-compatible attained in all lineages, haemolysis was corrected as well as other
sibling donors. HSCT is effective in preventing clinical complications, hallmark clinical features [6]. So far, five clinical trials are ongoing to
such as vaso-occlusive crises, acute chest syndrome, stroke and evaluate gene therapy for sickle cell disease (Table 3) [371,372]. In
progression of cerebrovascular disease [350,351]. With declining addition, one study focusses on the long-term safety and efficacy for
incidences of rejection, graft-versus-host disease (GvHD) and individuals with haemoglobinopathies (including sickle cell disease)
transplant-related mortality, overall survival and disease free survival who have been treated with gene therapy in clinical studies [373].
in paediatric patients are now approaching 90% [349,350,352–354]. In It is important to consider however, that although gene therapy is
adult patients, remarkable data have recently been published showing certainly a potential therapy for sickle cell disease in well-developed
that reduced intensity conditioning in HLA-matched siblings parts of the world, it will not be available for several decades for mil-
transplantations results in a successful engraftment in > 85% of the lions of patients in sub-Saharan Africa and elsewhere [14].
patients [353,355,356]. 6.2.3.4.2. Other. After a lack of drug development trials in the last
Unfortunately, overall only 10–20% sickle cell disease patients have 20 years, new pharmacotherapeutic approaches to sickle cell disease
an HLA-identical sibling [357]. The outcomes of unrelated donor HSCT are being explored as indicated by a large number of clinical trials
are often complicated by delayed engraftment and/or GvHD. Especially [374,375]. The most promising interventions are the oral
chronic GvHD is associated with an unacceptable morbidity and mor- pharmaceutical-grade L-glutamine treatment, the intravenously
tality, especially in a non-malignant disease such as sickle cell disease antiadhesive agent's crizanlizumab and rivipansel, and the oral
[354,358]. Substantial efforts are ongoing to increase availability of haemoglobin modifier voxelotor. A L-glutamine treatment has
HSCT by expansion of the donor pool. These include alternative stem recently been approved by the FDA for preventing acute painful
cell sources such as HSCT with HLA-haploidentical donors, use of cord crises in children and adults with sickle cell disease [376]. Although
blood cells and CD34+ selection [359,360]. To date, however, the the mechanism of action of the drug is not fully understood, it is
outcome of patients with sickle cell disease undergoing unrelated donor thought to be effective by its antioxidant characteristics.
HSCT has shown disappointing results [361–363]. Rivipansel is a pan-selectin antagonist that inhibits selectin medi-
Although HSCT is potentially curative, there is much debate about ated vaso-occlusion and has demonstrated to reduce the use of opioid
the eligibility criteria for HSCT as substantial concerns remain with analgesics during vaso-occlusive crises [377]. Crizanlizumab is a
regard to the transplant-related mortality and long-term toxicities, monoclonal antibody against P-selectin. In the SUSTAIN study, which
particularly infertility [326,360]. In a recent review, Fitzhugh et al. compared two different doses of crizanlizumab with placebo, crizanli-
suggested that HSCT should be considered for all patients with HbSS or zumab significantly reduced the frequency of sickle cell pain crises
HbSβ0 patients who have a HLA-matched sibling donor, regardless of versus placebo [378]. However, more definitive answers are required
symptomatology [364]. In contrast, DeBaun argued that HSCT should regarding short and long term benefits as well as potential risks of this
only be offered in multicentre peer-reviewed clinical trials to children novel therapy [379].
with sickle cell disease that have progressive decline in organ function Voxelotor (previously called GBT440) is an anti-polymerisation
[365]. With current supportive care and increasing data on long-term agent which increases haemoglobin oxygen affinity. A recent rando-
hydroxyurea therapy, which appears to be safe and effective, survival is mised phase 1/2 placebo-controlled trial in patients with sickle cell
likely to increase significantly. A Belgium cohort study showed that disease demonstrated haematologic improvements including increased
patients treated with hydroxyurea had a better 15-year survival rate haemoglobin levels and a reduction in haemolysis and HbS levels
than those treated with HSCT [326]. Similarly, the most recent NHLBI [380].
guidelines do not offer recommendations regarding HSCT in sickle cell Other non-genetic approaches currently being assessed mostly aim
disease, claiming that more research is needed to implement it widely to ameliorate the downstream sequelae of HbS polymerisation. Given
in this population [88]. the wide phenotypic variety of sickle cell disease, it is likely that the
The challenges faced by patients, parents, and health care providers most optimal therapy will only be achieved by a multitargeted ap-
considering HSCT for sickle cell disease will likely evolve over time. proach in which hydroxyurea and new pharmacotherapeutic ap-
Besides improvements in the clinical management of sickle cell disease proaches will be combined.

11

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M.E. Houwing, et al. Blood Reviews 37 (2019) 100580

6.2.4. Reproductive care

Active, not recruiting

6.2.4.1. Contraception. Contraceptive use is an important strategy for
reducing the risk of unintended pregnancy. However, provision of
Recruiting various contraceptive options, especially those containing hormones, is

Recruiting

Recruiting

Recruiting
controversial in women with sickle cell disease due to lack of compiled
Status

evidence on safety. The principal concern is the potential for an

increased risk of venous thromboembolism (VTE), due to a
chronically activated coagulation system in sickle cell disease patients
[381–383]. However, there is no clear evidence to suggest that
hormonal contraceptive use is associated with an increased risk of
Sickle cell disease, β-

complications in women with sickle cell disease [384,385]. Therefore,

Sickle cell disease

Sickle cell disease

Sickle cell disease

Sickle cell disease

the WHO currently classifies sickle cell disease as a Category 2 for

thalassaemia

combined oral contraceptives, meaning that the benefits of combined

oral contraceptives use among women with this condition generally
Disease

outweigh the theoretical or proven risks [386].

Not available

6.2.4.2. Preconceptional care. Premarital and preconceptional

Conditioning

Melphalan

screening programs have been established in some high income

Busulfan

Busulfan

Busulfan

countries and programs are starting to be developed in areas with a

very high prevalence of sickle cell disease, including India and some
African countries [69]. However, voluntary premarital screening relies
upon recognition of the high risk groups and a proper organisation to
10, 18–35
29, > 18

screen patients. [387]. Especially in Western countries, where the sickle

6, > 18
7, 5–35

7, 3–40
N, ages
(years)

cell gene is less common, awareness of carriership of the disease is

relatively low.
In countries with comprehensive sickle cell care, the majority of
Autologous BM CD34+ cells transduced by the βA-T87Q

Autologous BM CD34+ cells transduced by the βA-T87Q

Autologous BM CD34+ cells transduced by the βAS3-

women with the disease are seen regularly in a haematology outpatient

Autologous BM CD34+ cells transduced by the γ-

Autologous BM CD34+ cells transduced by the γ-

clinic where they are monitored for chronic complications, many of

these having implications in pregnancy. Conception and contraception
should be discussed during regular outpatient visits once the woman
reaches child bearing age [388]. Education of women regarding the
inheritance of sickle cell disease, including genetic screening of partners
and the possibility of preimplantation genetic diagnosis, is an essential
part of preconceptional care. In addition, couples should be aware of
-globin lentiviral vector

-globin lentiviral vector

globin lentiviral vector

globin lentiviral vector

the risks of pregnancy in sickle cell disease.

FB lentiviral vector

Women on chronic blood transfusion regimes should be fully as-

Cellular product

sessed for the complications of iron overload before embarking on

pregnancy. This includes a cardiac and hepatic MRI scan. Patients
should undergo aggressive iron chelation in case of iron overload before
trying to conceive [388]. In addition, it is advised to stop taking hy-
droxyurea before conceiving due to teratogenic effects in animals
[389,390]. However, ‘the Multicenter Study of Hydroxyurea in Sickle Cell
University of Southern California

University of Cincinnati Medical

Bluebird Bio, Necker Children's

Anemia (MSH)’ trial followed parents who, although advised to use

Boston Children's Hospital

contraceptives, became pregnant during hydroxyurea use and they

found no teratogenic changes in those pregnancies, indicating that
pregnancy termination because of the use of hydroxyurea during
pregnancy is not needed [391].
Hospital Paris
Bluebird Bio

6.2.4.3. Pregnancy. Pregnancy in women with sickle cell disease is

Center
Group

complicated by the maternal condition characterised by years of

chronic organ damage, as well as by the physiologic changes and
ClinicalTrials.gov identifier or European clinical trials

adaptations that are inherent to pregnancy. For example, plasma

volume begins to expand between 6 and 8 weeks of gestation,
ultimately achieving a 45% increase over non-pregnancy volume
[392]. Adaptation required by the haematologic, cardiovascular,
Current sickle cell gene therapy trials.

respiratory and renal systems are problematic in patients with sickle

Abbreviations; BM: bone marrow.

cell disease [393], while those physiologic changes are generally well
tolerated in healthy pregnant women [394].
Pregnancy in women with sickle cell disease is associated with an
increased risk of adverse perinatal outcomes, including spontaneous
abortion, intra uterine growth retardation (IUGR), pre-eclampsia, se-
database number

vere foetal anaemia, stillbirth, the risk of caesarean delivery and neo-
NCT02140554

NCT02151526

NCT02247843

NCT02186418

NCT03282656

natal mortality [395–398]. Those increased risks are regardless whether

these women live in low-or high-income countries. However, the risk of
Table 3

maternal mortality is significantly higher for low income countries

[399].

12

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M.E. Houwing, et al. Blood Reviews 37 (2019) 100580

Antenatal care is provided by a multidisciplinary team, including an Conflict of interest statement

obstetrician with experience in high risk antenatal care and a sickle cell
disease specialised haematologist [398]. Screening of the partner for Drs. M.E. Houwing, Dr. P.J. de Pagter, Dr. E. Nur, Drs. E.
carrier status is important if this has not been done preconceptually. If Rettenbacher, Dr. E.M. Schols, and Dr. R.Y.J. Tamminga have no con-
both parents are carrier of, or affected by, sickle cell disease the couple flicts of interest. Dr. E.J. van Beers has received grants from the
should receive appropriate counselling regarding the risk of having Netherlands Organisation for Health Research and Development
affected offspring. In addition, they should be informed about the (ZonMw), Novartis, Agios, Bayer, RR Mechatronics, Novartis,
methods and risk of prenatal diagnosis and termination of pregnancy, Eurostars-2 Programme, the Dutch “Innovatiefonds Zorgverzekeraars”
ideally by ten weeks gestation [388]. and National Institutes of Health. Prof. B.J. Biemond has received
grants from the Netherlands Organisation for Health Research and
7. Conclusion and future considerations Development (ZonMw), Fonds Nuts-Ohra, Janivo Stichting, the Egberts
Stichting, and the NIH. Dr. A.W. Rijneveld is a member of Novartis
There has been a significant increase in our understanding of the honorarium for advisory board. Prof. J.N.J. Philipsen has received
pathophysiology and factors contributing to the severity of sickle cell grants from the Netherlands Organisation for Health Research and
disease over the past decade. Comprehensive care programs including Development (ZonMw), European Union 7th framework programme,
neonatal screening, infection prophylaxis, prevention of neurological and the Landsteiner Foundation for Blood Transfusion Research (LSBR).
complications and early hydroxyurea therapy will hopefully further Prof. K. Fijn van draat has received grants from CSL Behring, Novo
increase life expectancy and quality of life of sickle cell disease patients. Nordisk and Bayer. Ass. Prof. M.H. Cnossen has received investigator-
Allogeneic stem cell transplantation is becoming more safe and more initiated research and travel grants from The Netherlands Organisation
widely available, although its use is limited to developed countries. In for Scientific Research (NWO)- the Netherlands Organisation for Health
the near future HSCT may be superseded by the gene addition and Research and Development (ZonMw), the Dutch “Innovatiefonds
editing approaches with the first patients having received gene therapy Zorgverzekeraars”, Pfizer, Bayer, Takedo, Novo Nordisk, Nordic
now showing complete clinical remission. Pharma, Novartis, CSL Behring, Sobi and Biogen Idec and is a member
Establishing national, and ultimately international, databases for of the advisory boards of Bayer and Roche.
sickle cell disease will be of great importance to understand the natural
history and diverse heterogeneity of the disease and to improve Appendix A. Supplementary data
symptom management. However, many healthcare providers do not
have the comprehensive knowledge and expertise to care for people Supplementary data to this article can be found online at https://
with sickle cell disease. Therefore, ensuring implementation of existing doi.org/10.1016/j.blre.2019.05.004.
standard-of-care guidelines and best practices is essential.
The global burden of sickle cell disease is enormous and there is a References
lack of knowledge and information among the wider population re-
garding sickle cell disease, indicating the need for more awareness in- [1] Piel FB, Hay SI, Gupta S, Weatherall DJ, Williams TN. Global burden of sickle cell
itiatives for the public. In countries with poor public health systems, anaemia in children under five, 2010-2050: modelling based on demographics,
excess mortality, and interventions. PLoS Med 2013;10:e1001484.
sickle cell disease remains a major killer of infants and children, similar [2] Grosse SD, Odame I, Atrash HK, Amendah DD, Piel FB, Williams TN. Sickle cell
to other diseases like malaria and HIV/AIDS. Governments and phi- disease in Africa: a neglected cause of early childhood mortality. Am J Prev Med
lanthropic groups should be educated about the importance of 2011;41:S398–405.
[3] Williams TN, Uyoga S, Macharia A, Ndila C, McAuley CF, Opi DH, et al.
screening and caring for people with this disease. Hopefully, with Bacteraemia in Kenyan children with sickle-cell anaemia: a retrospective cohort
growing public and governmental awareness together with global and case-control study. Lancet 2009;374:1364–70.
multidisciplinary partnerships, sickle cell disease can emerge from its [4] Makani J, Cox SE, Soka D, Komba AN, Oruo J, Mwamtemi H, et al. Mortality in
sickle cell anemia in Africa: a prospective cohort study in Tanzania. PLoS One
neglected stage. 2011;6:e14699.
[5] Gardner K, Douiri A, Drasar E, Allman M, Mwirigi A, Awogbade M, et al. Survival
Practice Points in adults with sickle cell disease in a high-income setting. Blood 2016;128:1436–8.
[6] Ribeil JA, Hacein-Bey-Abina S, Payen E, Magnani A, Semeraro M, Magrin E, et al.
Gene therapy in a patient with sickle cell disease. N Engl J Med 2017;376:848–55.
- Sickle cell disease is the most common monogenetic disorder [7] Weatherall DJ, Clegg JB. Inherited haemoglobin disorders: an increasing global
worldwide and has been declared a global health problem by the health problem. Bull World Health Organ 2001;79:704–12.
World Health Organisation. [8] Lederberg JJBS. Haldane (1949) on infectious disease and evolution. Genetics
1999;153:1–3.
- High quality evidence is limited in most areas of sickle cell disease [9] Flint J, Harding RM, Boyce AJ, Clegg JB. The population genetics of the hae-
management; most recommendations are solely expert-opinions. moglobinopathies. Baillieres Clin Haematol 1998;11:1–51.
- Patients with sickle cell disease should be treated in a multi-dis- [10] May J, Evans JA, Timmann C, Ehmen C, Busch W, Thye T, et al. Hemoglobin
variants and disease manifestations in severe falciparum malaria. JAMA
ciplinary setting before they develop chronic, irreversible and ulti- 2007;297:2220–6.
mately fatal organ damage. [11] Piel FB, Patil AP, Howes RE, Nyangiri OA, Gething PW, Williams TN, et al. Global
- Patient and family support is crucial in order to practice optimal distribution of the sickle cell gene and geographical confirmation of the malaria
hypothesis. Nat Commun 2010;1:104.
comprehensive care. [12] Piel FB, Tatem AJ, Huang Z, Gupta S, Williams TN, Weatherall DJ. Global mi-
gration and the changing distribution of sickle haemoglobin: a quantitative study
Research Agenda of temporal trends between 1960 and 2000. Lancet Glob Health 2014;2:e80–9.
[13] Piel FB, Patil AP, Howes RE, Nyangiri OA, Gething PW, Dewi M, et al. Global
epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical
- Establishment of international databases to determine the natural model-based map and population estimates. Lancet 2013;381:142–51.
course of sickle cell disease and to identify disease modifying fac- [14] McGann PT, Hernandez AG, Ware RE. Sickle cell anemia in sub-Saharan Africa:
advancing the clinical paradigm through partnerships and research. Blood
tors.
2017;129:155–61.
- Insight into the genetic modifiers and non-genetic risk factors of [15] Quinn CT, Rogers ZR, McCavit TL, Buchanan GR. Improved survival of children
sickle cell disease and treatment outcome. and adolescents with sickle cell disease. Blood 2010;115:3447–52.
- Prospective, ethical research focussing on improvement of survival [16] Africa WHOROf. Sickle-cell disease: A strategy for the WHO African region. 2010.
[17] Hematology ASo. State of sickle cell disease. 2016.
and quality of life for individuals with sickle cell disease in low- [18] Marotta CA, Forget BG, Cohne-Solal M, Wilson JT, Weissman SM. Human beta-
resource settings. globin messenger RNA. I. Nucleotide sequences derived from complementary RNA.
- Development of new, affordable pharmacological therapies. J Biol Chem 1977;252:5019–31.

13

Downloaded for Anonymous User (n/a) at R4L.Senegal from ClinicalKey.com by Elsevier on July 02, 2023. For
personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.
M.E. Houwing, et al. Blood Reviews 37 (2019) 100580

[19] Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med Silent cerebral infarction, income, and grade retention among students with sickle
1997;337:762–9. cell anemia. Am J Hematol 2014;89:E188–92.
[20] Herrick CJ. The evolution of intelligence and its organs. Science 1910;31:7–18. [57] Piel FB, Tewari S, Brousse V, Analitis A, Font A, Menzel S, et al. Associations
[21] Nur E, Biemond BJ, Otten HM, Brandjes DP, Schnog JJ, Group CS. Oxidative stress between environmental factors and hospital admissions for sickle cell disease.
in sickle cell disease; pathophysiology and potential implications for disease Haematologica 2017;102:666–75.
management. Am J Hematol 2011;86:484–9. [58] Haque A, Telfair J. Socioeconomic distress and health status: the urban-rural di-
[22] Manwani D, Frenette PS. Vaso-occlusion in sickle cell disease: pathophysiology chotomy of services utilization for people with sickle cell disorder in North
and novel targeted therapies. Blood 2013;122:3892–8. Carolina. J Rural Health 2000;16:43–55.
[23] Morris CR, Kato GJ, Poljakovic M, Wang X, Blackwelder WC, Sachdev V, et al. [59] Telfair J, Haque A, Etienne M, Tang S, Strasser S. Rural/urban differences in access
Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, to and utilization of services among people in Alabama with sickle cell disease.
and mortality in sickle cell disease. JAMA 2005;294:81–90. Public Health Rep 2003;118:27–36.
[24] Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet 2010;376:2018–31. [60] Shankar SM, Arbogast PG, Mitchel E, Ding H, Wang WC, Griffin MR. Impact of
[25] Mack AK, Kato GJ. Sickle cell disease and nitric oxide: a paradigm shift? Int J proximity to comprehensive sickle cell center on utilization of healthcare services
Biochem Cell Biol 2006;38:1237–43. among children with sickle cell disease. Pediatr Blood Cancer 2008;50:66–71.
[26] Ataga KI, Moore CG, Hillery CA, Jones S, Whinna HC, Strayhorn D, et al. [61] Claster S, Godwin MJ, Embury SH. Risk of altitude exposure in sickle cell disease.
Coagulation activation and inflammation in sickle cell disease-associated pul- West J Med 1981;135:364–7.
monary hypertension. Haematologica 2008;93:20–6. [62] Green RL, Huntsman RG, Serjeant GR. The sickle-cell and altitude. Br Med J
[27] Ataga KI, Brittain JE, Desai P, May R, Jones S, Delaney J, et al. Association of 1971;4:593–5.
coagulation activation with clinical complications in sickle cell disease. PLoS One [63] Peacock AJ. Oxygen at high altitude. Bmj 1998;317:1063–6.
2012;7:e29786. [64] Stokes CL, McKinney CM, Silliman CC. Complication rates in patients with sickle
[28] Kato GJ, Steinberg MH, Gladwin MT. Intravascular hemolysis and the pathophy- cell disease living chronically at moderate altitude. Blood 2014;124:4095.
siology of sickle cell disease. J Clin Invest 2017;127:750–60. [65] Graham GS. A case of sickle cell anemia with necropsy. Arch Intern Med
[29] Potoka KP, Gladwin MT. Vasculopathy and pulmonary hypertension in sickle cell 1924;34:778–800.
disease. Am J Physiol Lung Cell Mol Physiol 2015;308:L314–24. [66] Konotey-Ahulu FI. Sicklaemic human hygrometers. Lancet 1965;1:1003–4.
[30] Serjeant G, Serjeant B, Stephens A, Roper D, Higgs D, Beckford M, et al. [67] Redwood AM, Williams EM, Desal P, Serjeant GR. Climate and painful crisis of
Determinants of haemoglobin level in steady-state homozygous sickle cell disease. sickle-cell disease in Jamaica. Br Med J 1976;1:66–8.
Br J Haematol 1996;92:143–9. [68] Rogovik AL, Persaud J, Friedman JN, Kirby MA, Goldman RD. Pediatric vasooc-
[31] Noguchi CT, Schechter AN, Rodgers GP. Sickle cell disease pathophysiology. clusive crisis and weather conditions. J Emerg Med 2011;41:559–65.
Baillieres Clin Haematol 1993;6:57–91. [69] Piel FB, Steinberg MH, Rees DC. Sickle cell disease. N Engl J Med
[32] Thein SL. Genetic modifiers of the beta-haemoglobinopathies. Br J Haematol 2017;376:1561–73.
2008;141:357–66. [70] Resar LM, Oski FA. Cold water exposure and vaso-occlusive crises in sickle cell
[33] Steinberg MH. Genetic etiologies for phenotypic diversity in sickle cell anemia. anemia. J Pediatr 1991;118:407–9.
ScientificWorldJournal 2009;9:46–67. [71] Mohan J, Marshall JM, Reid HL, Thomas PW, Hambleton I, Serjeant GR. Peripheral
[34] Nagel RL, Fabry ME, Steinberg MH. The paradox of hemoglobin SC disease. Blood vascular response to mild indirect cooling in patients with homozygous sickle cell
Rev 2003;17:167–78. (SS) disease and the frequency of painful crisis. Clin Sci (Lond) 1998;94:111–20.
[35] Gualandro SF, Fonseca GH, Yokomizo IK, Gualandro DM, Suganuma LM. Cohort [72] Mohan JS, Marshall JM, Reid HL, Thomas PW, Hambleton I, Serjeant GR.
study of adult patients with haemoglobin SC disease: clinical characteristics and Comparison of responses evoked by mild indirect cooling and by sound in the
predictors of mortality. Br J Haematol 2015;171:631–7. forearm vasculature in patients with homozygous sickle cell disease and in normal
[36] Maier-Redelsperger M, Noguchi CT, de Montalembert M, Rodgers GP, Schechter subjects. Clin Auton Res 1998;8:25–30.
AN, Gourbil A, et al. Variation in fetal hemoglobin parameters and predicted he- [73] Mekontso Dessap A, Contou D, Dandine-Roulland C, Hemery F, Habibi A, Charles-
moglobin S polymerization in sickle cell children in the first two years of life: Nelson A, et al. Environmental influences on daily emergency admissions in sickle-
Parisian prospective study on sickle cell disease. Blood 1994;84:3182–8. cell disease patients. Medicine (Baltimore) 2014;93:e280.
[37] Thein SL, Menzel S. Discovering the genetics underlying foetal haemoglobin pro- [74] Ryan K, Bain BJ, Worthington D, James J, Plews D, Mason A, et al. Significant
duction in adults. Br J Haematol 2009;145:455–67. haemoglobinopathies: guidelines for screening and diagnosis. Br J Haematol
[38] Watson J. A study of sickling of young erythrocytes in sickle cell anemia. Blood 2010;149:35–49.
1948;3:465–9. [75] Williams TN. An accurate and affordable test for the rapid diagnosis of sickle cell
[39] Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, et al. disease could revolutionize the outlook for affected children born in resource-
Mortality in sickle cell disease. Life expectancy and risk factors for early death. N limited settings. BMC Med 2015;13:238.
Engl J Med 1994;330:1639–44. [76] McGann PT, Hernandez AG, Ware RE. Sickle cell anemia in sub-Saharan Africa:
[40] Dzierzak E, Philipsen S. Erythropoiesis: development and differentiation. Cold advancing the clinical paradigm through partnerships and research. Blood
Spring Harb Perspect Med 2013;3:a011601. 2017;129:155–61.
[41] Masuda T, Wang X, Maeda M, Canver MC, Sher F, Funnell AP, et al. Transcription [77] Quinn CT, Paniagua MC, DiNello RK, Panchal A, Geisberg M. A rapid, inexpensive
factors LRF and BCL11A independently repress expression of fetal hemoglobin. and disposable point-of-care blood test for sickle cell disease using novel, highly
Science 2016;351:285–9. specific monoclonal antibodies. Br J Haematol 2016;175:724–32.
[42] Bae HT, Baldwin CT, Sebastiani P, Telen MJ, Ashley-Koch A, Garrett M, et al. Meta- [78] Kanter J, Telen MJ, Hoppe C, Roberts CL, Kim JS, Yang X. Validation of a novel
analysis of 2040 sickle cell anemia patients: BCL11A and HBS1L-MYB are the point of care testing device for sickle cell disease. BMC Med 2015;13:225.
major modifiers of HbF in African Americans. Blood 2012;120:1961–2. [79] Vichinsky E, Hurst D, Earles A, Kleman K, Lubin B. Newborn screening for sickle
[43] Bauer DE, Kamran SC, Lessard S, Xu J, Fujiwara Y, Lin C, et al. An erythroid cell disease: effect on mortality. Pediatrics 1988;81:749–55.
enhancer of BCL11A subject to genetic variation determines fetal hemoglobin [80] Le PQ, Ferster A, Dedeken L, Vermylen C, Vanderfaeillie A, Rozen L, et al. Neonatal
level. Science 2013;342:253–7. screening improves sickle cell disease clinical outcome in Belgium. J Med Screen
[44] Lettre G, Bauer DE. Fetal haemoglobin in sickle-cell disease: from genetic epide- 2018;25:57–63.
miology to new therapeutic strategies. Lancet 2016;387:2554–64. [81] Eltzschig HK, Eckle T. Ischemia and reperfusion–from mechanism to translation.
[45] Akinsheye I, Alsultan A, Solovieff N, Ngo D, Baldwin CT, Sebastiani P, et al. Fetal Nat Med 2011;17:1391–401.
hemoglobin in sickle cell anemia. Blood 2011;118:19–27. [82] Ballas SK, Gupta K, Adams-Graves P. Sickle cell pain: a critical reappraisal. Blood
[46] Steinberg MH, Chui DH, Dover GJ, Sebastiani P, Alsultan A. Fetal hemoglobin in 2012;120:3647–56.
sickle cell anemia: a glass half full? Blood 2014;123:481–5. [83] Vincent L, Vang D, Nguyen J, Gupta M, Luk K, Ericson ME, et al. Mast cell acti-
[47] Steinberg MH, Embury SH. Alpha-thalassemia in blacks: genetic and clinical as- vation contributes to sickle cell pathobiology and pain in mice. Blood
pects and interactions with the sickle hemoglobin gene. Blood 1986;68:985–90. 2013;122:1853–62.
[48] JGt Taylor, Nolan VG, Mendelsohn L, Kato GJ, Gladwin MT, Steinberg MH. [84] Ballas SK. Sickle cell disease: clinical management. Baillieres Clin Haematol
Chronic hyper-hemolysis in sickle cell anemia: association of vascular complica- 1998;11:185–214.
tions and mortality with less frequent vasoocclusive pain. PLoS One 2008;3:e2095. [85] Cataldo G, Rajput S, Gupta K, Simone DA. Sensitization of nociceptive spinal
[49] Steinberg MH, Sebastiani P. Genetic modifiers of sickle cell disease. Am J Hematol neurons contributes to pain in a transgenic model of sickle cell disease. Pain
2012;87:795–803. 2015;156:722–30.
[50] Kato GJ. Defective nitric oxide metabolism in sickle cell disease. Pediatr Blood [86] van Tuijn CF, Sins JW, Fijnvandraat K, Biemond BJ. Daily pain in adults with sickle
Cancer 2015;62:373–4. cell disease-a different perspective. Am J Hematol 2017;92:179–86.
[51] Risch N, Merikangas K. The future of genetic studies of complex human diseases. [87] Vichinsky EP, Neumayr LD, Earles AN, Williams R, Lennette ET, Dean D, et al.
Science 1996;273:1516–7. Causes and outcomes of the acute chest syndrome in sickle cell disease. National
[52] Lettre G. The search for genetic modifiers of disease severity in the beta-he- Acute Chest Syndrome Study Group. N Engl J Med 2000;342:1855–65.
moglobinopathies. Cold Spring Harb Perspect Med 2012;2. [88] Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, et al.
[53] Marmot M. Social determinants of health inequalities. Lancet 2005;365:1099–104. Management of sickle cell disease: summary of the 2014 evidence-based report by
[54] Farber MD, Koshy M, Kinney TR. Cooperative study of sickle cell disease: demo- expert panel members. JAMA 2014;312:1033–48.
graphic and socioeconomic characteristics of patients and families with sickle cell [89] Schwenk ES, Viscusi ER, Buvanendran A, Hurley RW, Wasan AD, Narouze S, et al.
disease. J Chronic Dis 1985;38:495–505. Consensus guidelines on the use of intravenous ketamine infusions for acute pain
[55] Tewari S, Brousse V, Piel FB, Menzel S, Rees DC. Environmental determinants of management from the American Society of Regional Anesthesia and Pain
severity in sickle cell disease. Haematologica 2015;100:1108–16. Medicine, the American Academy of pain medicine, and the American Society of
[56] King AA, Rodeghier MJ, Panepinto JA, Strouse JJ, Casella JF, Quinn CT, et al. Anesthesiologists. Reg Anesth Pain Med 2018;43:456–66.

14

Downloaded for Anonymous User (n/a) at R4L.Senegal from ClinicalKey.com by Elsevier on July 02, 2023. For
personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.
M.E. Houwing, et al. Blood Reviews 37 (2019) 100580

[90] Uprety D, Baber A, Foy M. Ketamine infusion for sickle cell pain crisis refractory to modified transfusion program for prevention of stroke in sickle cell disease. Blood
opioids: a case report and review of literature. Ann Hematol 2014;93:769–71. 1992;79:1657–61.
[91] Benjamin LJ, Swinson GI, Nagel RL. Sickle cell anemia day hospital: an approach [124] Brousse V, Kossorotoff M, de Montalembert M. How I manage cerebral vasculo-
for the management of uncomplicated painful crises. Blood 2000;95:1130–6. pathy in children with sickle cell disease. Br J Haematol 2015;170:615–25.
[92] Jacob E, Beyer JE, Miaskowski C, Savedra M, Treadwell M, Styles L. Are there [125] Adams RJ, Brambilla DJ, Granger S, Gallagher D, Vichinsky E, Abboud MR, et al.
phases to the vaso-occlusive painful episode in sickle cell disease? J Pain Symptom Stroke and conversion to high risk in children screened with transcranial Doppler
Manage 2005;29:392–400. ultrasound during the STOP study. Blood 2004;103:3689–94.
[93] Platt OS, Thorington BD, Brambilla DJ, Milner PF, Rosse WF, Vichinsky E, et al. [126] Hankins JS, Fortner GL, McCarville MB, Smeltzer MP, Wang WC, Li CS, et al. The
Pain in sickle cell disease. Rates and risk factors. N Engl J Med 1991;325:11–6. natural history of conditional transcranial Doppler flow velocities in children with
[94] van Tuijn CF, van Beers EJ, Schnog JJ, Biemond BJ. Pain rate and social cir- sickle cell anaemia. Br J Haematol 2008;142:94–9.
cumstances rather than cumulative organ damage determine the quality of life in [127] Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, et al. Prevention of a
adults with sickle cell disease. Am J Hematol 2010;85:532–5. first stroke by transfusions in children with sickle cell anemia and abnormal results
[95] Hassell KL. Population estimates of sickle cell disease in the U.S. Am J Prev Med on transcranial Doppler ultrasonography. N Engl J Med 1998;339:5–11.
2010;38:S512–21. [128] Adams RJ, Brambilla D. Optimizing primary stroke prevention in sickle cell
[96] Manci EA, Culberson DE, Yang YM, Gardner TM, Powell R, Haynes Jr. J, et al. Anemia trial I. discontinuing prophylactic transfusions used to prevent stroke in
Causes of death in sickle cell disease: an autopsy study. Br J Haematol sickle cell disease. N Engl J Med 2005;353:2769–78.
2003;123:359–65. [129] Lee MT, Piomelli S, Granger S, Miller ST, Harkness S, Brambilla DJ, et al. Stroke
[97] Raghupathy R, Haider MZ, Azizieh F, Abdelsalam R, D'Souza TM, Adekile AD. Th1 prevention trial in sickle cell Anemia (STOP): extended follow-up and final results.
and Th2 cytokine profiles in sickle cell disease. Acta Haematol 2000;103:197–202. Blood 2006;108:847–52.
[98] Serjeant BE, Hambleton IR, Kerr S, Kilty CG, Serjeant GR. Haematological response [130] Campbell-Lee SA, Liu J, Velliquette RW, Halverson GR, Shirey RS, Chaudhuri A,
to parvovirus B19 infection in homozygous sickle-cell disease. Lancet et al. The production of red blood cell alloantibodies in mice transfused with blood
2001;358:1779–80. from transgenic Fyb-expressing mice. Transfusion 2006;46:1682–8.
[99] Battersby AJ, Knox-Macaulay HH, Carrol ED. Susceptibility to invasive bacterial [131] Wood JC, Cohen AR, Pressel SL, Aygun B, Imran H, Luchtman-Jones L, et al. Organ
infections in children with sickle cell disease. Pediatr Blood Cancer iron accumulation in chronically transfused children with sickle cell anaemia:
2010;55:401–6. baseline results from the TWiTCH trial. Br J Haematol 2016;172:122–30.
[100] Evans C, Orf K, Horvath E, Levin M, De La Fuente J, Chakravorty S, et al. [132] Ware RE, Davis BR, Schultz WH, Brown RC, Aygun B, Sarnaik S, et al.
Impairment of neutrophil oxidative burst in children with sickle cell disease is Hydroxycarbamide versus chronic transfusion for maintenance of transcranial
associated with heme oxygenase-1. Haematologica 2015;100:1508–16. doppler flow velocities in children with sickle cell anaemia-TCD with transfusions
[101] William BM, Corazza GR. Hyposplenism: a comprehensive review. Part I: basic changing to hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-in-
concepts and causes. Hematology 2007;12:1–13. feriority trial. Lancet 2016;387:661–70.
[102] Atkins BL, Price EH, Tillyer L, Novelli V, Evans J. Salmonella osteomyelitis in [133] DeBaun MR, Kirkham FJ. New option for primary stroke prevention in sickle cell
sickle cell disease children in the east end of London. J Infect 1997;34:133–8. anaemia. Lancet 2016;387:626–7.
[103] Booth C, Inusa B, Obaro SK. Infection in sickle cell disease: a review. Int J Infect [134] Bernaudin F, Verlhac S, Arnaud C, Kamdem A, Hau I, Leveille E, et al. Long-term
Dis 2010;14:e2–12. treatment follow-up of children with sickle cell disease monitored with abnormal
[104] Almeida A, Roberts I. Bone involvement in sickle cell disease. Br J Haematol transcranial Doppler velocities. Blood 2016;127:1814–22.
2005;129:482–90. [135] DeBaun MR, Strunk RC. The intersection between asthma and acute chest syn-
[105] Workman MR, Philpott-Howard JN, Casewell MW, Bellingham AJ. Salmonella drome in children with sickle-cell anaemia. Lancet 2016;387:2545–53.
bacteraemia in sickle cell disease at King's college hospital: 1976-1991. J Hosp [136] Castro O, Brambilla DJ, Thorington B, Reindorf CA, Scott RB, Gillette P, et al. The
Infect 1994;27:195–9. acute chest syndrome in sickle cell disease: incidence and risk factors. The co-
[106] Aidoo M, Terlouw DJ, Kolczak MS, McElroy PD, ter Kuile FO, Kariuki S, et al. operative study of sickle cell disease. Blood 1994;84:643–9.
Protective effects of the sickle cell gene against malaria morbidity and mortality. [137] DeBaun MR, Rodeghier M, Cohen R, Kirkham FJ, Rosen CL, Roberts I, et al. Factors
Lancet 2002;359:1311–2. predicting future ACS episodes in children with sickle cell anemia. Am J Hematol
[107] Makani J, Williams TN, Marsh K. Sickle cell disease in Africa: burden and research 2014;89:E212–7.
priorities. Ann Trop Med Parasitol 2007;101:3–14. [138] Knight-Madden JM, Forrester TS, Lewis NA, Greenough A. Asthma in children
[108] Willen SM, Thornburg CD, Lantos PM. The traveler with sickle cell disease. J with sickle cell disease and its association with acute chest syndrome. Thorax
Travel Med 2014;21:332–9. 2005;60:206–10.
[109] van der Land V, Hijmans CT, de Ruiter M, Mutsaerts HJ, Cnossen MH, Engelen M, [139] Boyd JH, Macklin EA, Strunk RC, DeBaun MR. Asthma is associated with acute
et al. Volume of white matter hyperintensities is an independent predictor of in- chest syndrome and pain in children with sickle cell anemia. Blood
telligence quotient and processing speed in children with sickle cell disease. Br J 2006;108:2923–7.
Haematol 2015;168:553–6. [140] Sylvester KP, Patey RA, Broughton S, Rafferty GF, Rees D, Thein SL, et al.
[110] Ware RE, de Montalembert M, Tshilolo L, Abboud MR. Sickle cell disease. Lancet Temporal relationship of asthma to acute chest syndrome in sickle cell disease.
2017;390:311–23. Pediatr Pulmonol 2007;42:103–6.
[111] Switzer JA, Hess DC, Nichols FT, Adams RJ. Pathophysiology and treatment of [141] Vichinsky EP, Styles LA, Colangelo LH, Wright EC, Castro O, Nickerson B. Acute
stroke in sickle-cell disease: present and future. Lancet Neurol 2006;5:501–12. chest syndrome in sickle cell disease: clinical presentation and course. Cooperative
[112] Prohovnik I, Hurlet-Jensen A, Adams R, De Vivo D, Pavlakis SG. Hemodynamic study of sickle cell disease. Blood 1997;89:1787–92.
etiology of elevated flow velocity and stroke in sickle-cell disease. J Cereb Blood [142] Dang NC, Johnson C, Eslami-Farsani M, Haywood LJ. Bone marrow embolism in
Flow Metab 2009;29:803–10. sickle cell disease: a review. Am J Hematol 2005;79:61–7.
[113] Nur E, Kim YS, Truijen J, van Beers EJ, Davis SC, Brandjes DP, et al. [143] Dean D, Neumayr L, Kelly DM, Ballas SK, Kleman K, Robertson S, et al. Chlamydia
Cerebrovascular reserve capacity is impaired in patients with sickle cell disease. pneumoniae and acute chest syndrome in patients with sickle cell disease. J
Blood 2009;114:3473–8. Pediatr Hematol Oncol 2003;25:46–55.
[114] DeBaun MR, Kirkham FJ. Central nervous system complications and management [144] Claster S, Vichinsky EP. Managing sickle cell disease. BMJ 2003;327:1151–5.
in sickle cell disease. Blood 2016;127:829–38. [145] Velasquez MP, Mariscalco MM, Goldstein SL, Airewele GE. Erythrocytapheresis in
[115] Ohene-Frempong K, Weiner SJ, Sleeper LA, Miller ST, Embury S, Moohr JW, et al. children with sickle cell disease and acute chest syndrome. Pediatr Blood Cancer
Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood 2009;53:1060–3.
1998;91:288–94. [146] Bellet PS, Kalinyak KA, Shukla R, Gelfand MJ, Rucknagel DL. Incentive spirometry
[116] Verduzco LA, Nathan DG. Sickle cell disease and stroke. Blood 2009;114:5117–25. to prevent acute pulmonary complications in sickle cell diseases. N Engl J Med
[117] Kwiatkowski JL, Zimmerman RA, Pollock AN, Seto W, Smith-Whitley K, Shults J, 1995;333:699–703.
et al. Silent infarcts in young children with sickle cell disease. Br J Haematol [147] Ahmad FA, Macias CG, Allen JY. The use of incentive spirometry in pediatric
2009;146:300–5. patients with sickle cell disease to reduce the incidence of acute chest syndrome. J
[118] Bernaudin F, Verlhac S, Arnaud C, Kamdem A, Chevret S, Hau I, et al. Impact of Pediatr Hematol Oncol 2011;33:415–20.
early transcranial Doppler screening and intensive therapy on cerebral vasculo- [148] Howard J, Hart N, Roberts-Harewood M, Cummins M, Awogbade M, Davis B, et al.
pathy outcome in a newborn sickle cell anemia cohort. Blood 2011;117:1130–40. Guideline on the management of acute chest syndrome in sickle cell disease. Br J
[quiz 436]. Haematol 2015;169:492–505.
[119] Schatz J, Brown RT, Pascual JM, Hsu L, DeBaun MR. Poor school and cognitive [149] Sklar AH, Perez JC, Harp RJ, Caruana RJ. Acute renal failure in sickle cell anemia.
functioning with silent cerebral infarcts and sickle cell disease. Neurology Int J Artif Organs 1990;13:347–51.
2001;56:1109–11. [150] Pham PT, Pham PC, Wilkinson AH, Lew SQ. Renal abnormalities in sickle cell
[120] Bernaudin F, Verlhac S, Freard F, Roudot-Thoraval F, Benkerrou M, Thuret I, et al. disease. Kidney Int 2000;57:1–8.
Multicenter prospective study of children with sickle cell disease: radiographic and [151] Ataga KI, Orringer EP. Renal abnormalities in sickle cell disease. Am J Hematol
psychometric correlation. J Child Neurol 2000;15:333–43. 2000;63:205–11.
[121] Kugler S, Anderson B, Cross D, Sharif Z, Sano M, Haggerty R, et al. Abnormal [152] Statius van Eps LW, Pinedo-Veels C, de Vries GH, de Koning J. Nature of con-
cranial magnetic resonance imaging scans in sickle-cell disease. Neurological centrating defect in sickle-cell nephropathy. Microradioangiographic studies
correlates and clinical implications. Arch Neurol 1993;50:629–35. Lancet 1970;1:450–2.
[122] Pegelow CH, Wang W, Granger S, Hsu LL, Vichinsky E, Moser FG, et al. Silent [153] Basile DP, Donohoe D, Roethe K, Osborn JL. Renal ischemic injury results in
infarcts in children with sickle cell anemia and abnormal cerebral artery velocity. permanent damage to peritubular capillaries and influences long-term function.
Arch Neurol 2001;58:2017–21. Am J Physiol Renal Physiol 2001;281:F887–99.
[123] Cohen AR, Martin MB, Silber JH, Kim HC, Ohene-Frempong K, Schwartz E. A [154] Basile DP. The endothelial cell in ischemic acute kidney injury: implications for

15

Downloaded for Anonymous User (n/a) at R4L.Senegal from ClinicalKey.com by Elsevier on July 02, 2023. For
personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.
M.E. Houwing, et al. Blood Reviews 37 (2019) 100580

acute and chronic function. Kidney Int 2007;72:151–6. cell disease. South Med J 1966;59:1393–6.
[155] Cohen SD, Kimmel PL. Long-term sequelae of acute kidney injury in the ICU. Curr [188] Chakrabarty A, Upadhyay J, Dhabuwala CB, Sarnaik S, Perlmutter AD, Connor JP.
Opin Crit Care 2012;18:623–8. Priapism associated with sickle cell hemoglobinopathy in children: long-term ef-
[156] Mammen C, Al Abbas A, Skippen P, Nadel H, Levine D, Collet JP, et al. Long-term fects on potency. J Urol 1996;155:1419–23.
risk of CKD in children surviving episodes of acute kidney injury in the intensive [189] Olujohungbe AB, Adeyoju A, Yardumian A, Akinyanju O, Morris J, Westerdale N,
care unit: a prospective cohort study. Am J Kidney Dis 2012;59:523–30. et al. A prospective diary study of stuttering priapism in adolescents and young
[157] Chawla LS, Eggers PW, Star RA, Kimmel PL. Acute kidney injury and chronic men with sickle cell anemia: report of an international randomized control trial–
kidney disease as interconnected syndromes. N Engl J Med 2014;371:58–66. the priapism in sickle cell study. J Androl 2011;32:375–82.
[158] Audard V, Homs S, Habibi A, Galacteros F, Bartolucci P, Godeau B, et al. Acute [190] Bivalacqua TJ, Musicki B, Kutlu O, Burnett AL. New insights into the pathophy-
kidney injury in sickle patients with painful crisis or acute chest syndrome and its siology of sickle cell disease-associated priapism. J Sex Med 2012;9:79–87.
relation to pulmonary hypertension. Nephrol Dial Transplant 2010;25:2524–9. [191] Little JA, Hauser KP, Martyr SE, Harris A, Maric I, Morris CR, et al. Hematologic,
[159] Baddam S, Aban I, Hilliard L, Howard T, Askenazi D, Lebensburger JD. Acute biochemical, and cardiopulmonary effects of L-arginine supplementation or
kidney injury during a pediatric sickle cell vaso-occlusive pain crisis. Pediatr phosphodiesterase 5 inhibition in patients with sickle cell disease who are on
Nephrol 2017;32:1451–6. hydroxyurea therapy. Eur J Haematol 2009;82:315–21.
[160] Rogers ZR, Wang WC, Luo Z, Iyer RV, Shalaby-Rana E, Dertinger SD, et al. [192] Kheirandish P, Chinegwundoh F, Kulkarni S. Treating stuttering priapism. BJU Int
Biomarkers of splenic function in infants with sickle cell anemia: baseline data 2011;108:1068–72.
from the BABY HUG trial. Blood 2011;117:2614–7. [193] Franck LS, Treadwell M, Jacob E, Vichinsky E. Assessment of sickle cell pain in
[161] Brousse V, Buffet P, Rees D. The spleen and sickle cell disease: the sick(led) spleen. children and young adults using the adolescent pediatric pain tool. J Pain
Br J Haematol 2014;166:165–76. Symptom Manage 2002;23:114–20.
[162] Serjeant GR. The emerging understanding of sickle cell disease. Br J Haematol [194] Wilkie DJ, Molokie R, Boyd-Seal D, Suarez ML, Kim YO, Zong S, et al. Patient-
2001;112:3–18. reported outcomes: descriptors of nociceptive and neuropathic pain and barriers to
[163] Topley JM, Rogers DW, Stevens MC, Serjeant GR. Acute splenic sequestration and effective pain management in adult outpatients with sickle cell disease. J Natl Med
hypersplenism in the first five years in homozygous sickle cell disease. Arch Dis Assoc 2010;102:18–27.
Child 1981;56:765–9. [195] Brandow AM, Farley RA, Panepinto JA. Early insights into the neurobiology of
[164] Brousse V, Elie C, Benkerrou M, Odievre MH, Lesprit E, Bernaudin F, et al. Acute pain in sickle cell disease: a systematic review of the literature. Pediatr Blood
splenic sequestration crisis in sickle cell disease: cohort study of 190 paediatric Cancer 2015;62:1501–11.
patients. Br J Haematol 2012;156:643–8. [196] Ezenwa MO, Yao Y, Engeland CG, Molokie RE, Wang ZJ, Suarez ML, et al. A
[165] Emond AM, Collis R, Darvill D, Higgs DR, Maude GH, Serjeant GR. Acute splenic randomized controlled pilot study feasibility of a tablet-based guided audio-visual
sequestration in homozygous sickle cell disease: natural history and management. relaxation intervention for reducing stress and pain in adults with sickle cell dis-
J Pediatr 1985;107:201–6. ease. J Adv Nurs 2016;72:1452–63.
[166] Owusu-Ofori S, Hirst C. Splenectomy versus conservative management for acute [197] Jacob E, Chan VW, Hodge C, Zeltzer L, Zurakowski D, Sethna NF. Sensory and
sequestration crises in people with sickle cell disease. Cochrane Database Syst Rev thermal quantitative testing in children with sickle cell disease. J Pediatr Hematol
2013:CD003425. Oncol 2015;37:185–9.
[167] Shah R, Taborda C, Chawla S. Acute and chronic hepatobiliary manifestations of [198] Smith WR, Penberthy LT, Bovbjerg VE, McClish DK, Roberts JD, Dahman B, et al.
sickle cell disease: a review. World J Gastrointest Pathophysiol 2017;8:108–16. Daily assessment of pain in adults with sickle cell disease. Ann Intern Med
[168] Berry PA, Cross TJ, Thein SL, Portmann BC, Wendon JA, Karani JB, et al. Hepatic 2008;148:94–101.
dysfunction in sickle cell disease: a new system of classification based on global [199] Sil S, Cohen LL, Dampier C. Psychosocial and functional outcomes in youth with
assessment. Clin Gastroenterol Hepatol 2007;5:1469–76. [quiz 369]. chronic sickle cell pain. Clin J Pain 2016;32:527–33.
[169] Gardner K, Suddle A, Kane P, O'Grady J, Heaton N, Bomford A, et al. How we treat [200] Dampier C, LeBeau P, Rhee S, Lieff S, Kesler K, Ballas S, et al. Health-related
sickle hepatopathy and liver transplantation in adults. Blood 2014;123:2302–7. quality of life in adults with sickle cell disease (SCD): a report from the compre-
[170] Ahn H, Li CS, Wang W. Sickle cell hepatopathy: clinical presentation, treatment, hensive sickle cell centers clinical trial consortium. Am J Hematol 2011;86:203–5.
and outcome in pediatric and adult patients. Pediatr Blood Cancer [201] Cohen LL, Vowles KE, Eccleston C. The impact of adolescent chronic pain on
2005;45:184–90. functioning: disentangling the complex role of anxiety. J Pain 2010;11:1039–46.
[171] Zakaria N, Knisely A, Portmann B, Mieli-Vergani G, Wendon J, Arya R, et al. Acute [202] Ballas SK. New era dawns on sickle cell pain. Blood 2010;116:311–2.
sickle cell hepatopathy represents a potential contraindication for percutaneous [203] Bediako SM. Predictors of employment status among African Americans with
liver biopsy. Blood 2003;101:101–3. sickle cell disease. J Health Care Poor Underserved 2010;21:1124–37.
[172] Suell MN, Horton TM, Dishop MK, Mahoney DH, Olutoye OO, Mueller BU. [204] Sogutlu A, Levenson JL, McClish DK, Rosef SD, Smith WR. Somatic symptom
Outcomes for children with gallbladder abnormalities and sickle cell disease. J burden in adults with sickle cell disease predicts pain, depression, anxiety, health
Pediatr 2004;145:617–21. care utilization, and quality of life: the PiSCES project. Psychosomatics
[173] Haberkern CM, Neumayr LD, Orringer EP, Earles AN, Robertson SM, Black D, et al. 2011;52:272–9.
Cholecystectomy in sickle cell anemia patients: perioperative outcome of 364 [205] Elander J, Beach MC, Haywood Jr. C. Respect, trust, and the management of sickle
cases from the National Preoperative Transfusion Study. Preoperative transfusion cell disease pain in hospital: comparative analysis of concern-raising behaviors,
in sickle cell disease study Group. Blood 1997;89:1533–42. preliminary model, and agenda for international collaborative research to inform
[174] Olivieri NF. Progression of iron overload in sickle cell disease. Semin Hematol practice. Ethn Health 2011;16:405–21.
2001;38:57–62. [206] Taylor LE, Stotts NA, Humphreys J, Treadwell MJ, Miaskowski C. A review of the
[175] Montague DK, Jarow J, Broderick GA, Dmochowski RR, Heaton JP, Lue TF, et al. literature on the multiple dimensions of chronic pain in adults with sickle cell
American urological association guideline on the management of priapism. J Urol disease. J Pain Symptom Manage 2010;40:416–35.
2003;170:1318–24. [207] Thomas V. Cognitive behavioural therapy in pain management for sickle cell
[176] Broderick GA, Kadioglu A, Bivalacqua TJ, Ghanem H, Nehra A, Shamloul R. disease. Int J Palliat Nurs 2000;6:434–42.
Priapism: pathogenesis, epidemiology, and management. J Sex Med [208] Gladwin MT. Cardiovascular complications and risk of death in sickle-cell disease.
2010;7:476–500. Lancet 2016;387:2565–74.
[177] Morrison BF, Burnett AL. Priapism in hematological and coagulative disorders: an [209] Adjagba PM, Habib G, Robitaille N, Pastore Y, Raboisson MJ, Curnier D, et al.
update. Nat Rev Urol 2011;8:223–30. Impact of sickle cell anaemia on cardiac chamber size in the paediatric population.
[178] Mantadakis E, Cavender JD, Rogers ZR, Ewalt DH, Buchanan GR. Prevalence of Cardiol Young 2017;27:918–24.
priapism in children and adolescents with sickle cell anemia. J Pediatr Hematol [210] Pereira AA, Sarnak MJ. Anemia as a risk factor for cardiovascular disease. Kidney
Oncol 1999;21:518–22. Int Suppl 2003:S32–9.
[179] Hamre MR, Harmon EP, Kirkpatrick DV, Stern MJ, Humbert JR. Priapism as a [211] Gordeuk VR, Castro OL, Machado RF. Pathophysiology and treatment of pul-
complication of sickle cell disease. J Urol 1991;145:1–5. monary hypertension in sickle cell disease. Blood 2016;127:820–8.
[180] Virag R, Bachir D, Lee K, Galacteros F. Preventive treatment of priapism in sickle [212] Klings ES, Machado RF, Barst RJ, Morris CR, Mubarak KK, Gordeuk VR, et al. An
cell disease with oral and self-administered intracavernous injection of etilefrine. official American Thoracic Society clinical practice guideline: diagnosis, risk
Urology 1996;47:777–81. [discussion 81]. stratification, and management of pulmonary hypertension of sickle cell disease.
[181] Adedeji MO, Onuora VC, Ukoli FA. Haematological parameters associated with Am J Respir Crit Care Med 2014;189:727–40.
priapism in Nigerian patients with homozygous sickle cell disease. J Trop Med Hyg [213] Sachdev V, Machado RF, Shizukuda Y, Rao YN, Sidenko S, Ernst I, et al. Diastolic
1988;91:157–9. dysfunction is an independent risk factor for death in patients with sickle cell
[182] Al-Awamy B, Taha SA, Naeem MA. Priapism in association with sickle cell anemia disease. J Am Coll Cardiol 2007;49:472–9.
in Saudi Arabia. Acta Haematol 1985;73:181–2. [214] Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF, Minter K, et al.
[183] Burnett AL, Lowenstein CJ, Bredt DS, Chang TS, Snyder SH. Nitric oxide: a phy- Pulmonary hypertension as a risk factor for death in patients with sickle cell
siologic mediator of penile erection. Science 1992;257:401–3. disease. N Engl J Med 2004;350:886–95.
[184] Adeyoju AB, Olujohungbe AB, Morris J, Yardumian A, Bareford D, Akenova A, [215] Ware RE, Rees RC, Sarnaik SA, Iyer RV, Alvarez OA, Casella JF, et al. Renal
et al. Priapism in sickle-cell disease; incidence, risk factors and complications - an function in infants with sickle cell anemia: baseline data from the BABY HUG trial.
international multicentre study. BJU Int 2002;90:898–902. J Pediatr 2010;156. [66-70 e1].
[185] Olujohungbe A, Burnett AL. How I manage priapism due to sickle cell disease. Br J [216] Wolf RB, Kassim AA, Goodpaster RL, DeBaun MR. Nocturnal enuresis in sickle cell
Haematol 2013;160:754–65. disease. Expert Rev Hematol 2014;7:245–54.
[186] Bosch RJ, Benard F, Aboseif SR, Stief CG, Lue TF, Tanagho EA. Penile detumes- [217] Aygun B, Mortier NA, Smeltzer MP, Hankins JS, Ware RE. Glomerular hyperfil-
cence: characterization of three phases. J Urol 1991;146:867–71. tration and albuminuria in children with sickle cell anemia. Pediatr Nephrol
[187] Snyder GB, Wilson CA. Surgical management of priapism and its sequelae in sickle 2011;26:1285–90.

16

Downloaded for Anonymous User (n/a) at R4L.Senegal from ClinicalKey.com by Elsevier on July 02, 2023. For
personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.
M.E. Houwing, et al. Blood Reviews 37 (2019) 100580

[218] Nath KA, Hebbel RP. Sickle cell disease: renal manifestations and mechanisms. Nat [250] Condon PI, Serjeant GR. Ocular findings in homozygous sickle cell anemia in
Rev Nephrol 2015;11:161–71. Jamaica. Am J Ophthalmol 1972;73:533–43.
[219] Haymann JP, Stankovic K, Levy P, Avellino V, Tharaux PL, Letavernier E, et al. [251] Downes SM, Hambleton IR, Chuang EL, Lois N, Serjeant GR, Bird AC. Incidence
Glomerular hyperfiltration in adult sickle cell anemia: a frequent hemolysis as- and natural history of proliferative sickle cell retinopathy: observations from a
sociated feature. Clin J Am Soc Nephrol 2010;5:756–61. cohort study. Ophthalmology 2005;112:1869–75.
[220] Ataga KI, Derebail VK, Archer DR. The glomerulopathy of sickle cell disease. Am J [252] Fox PD, Dunn DT, Morris JS, Serjeant GR. Risk factors for proliferative sickle re-
Hematol 2014;89:907–14. tinopathy. Br J Ophthalmol 1990;74:172–6.
[221] Dharnidharka VR, Dabbagh S, Atiyeh B, Simpson P, Sarnaik S. Prevalence of mi- [253] Gill HS, Lam WC. A screening strategy for the detection of sickle cell retinopathy
croalbuminuria in children with sickle cell disease. Pediatr Nephrol in pediatric patients. Can J Ophthalmol 2008;43:188–91.
1998;12:475–8. [254] Menaa F, Khan BA, Uzair B, Menaa A. Sickle cell retinopathy: improving care with
[222] Guasch A, Navarrete J, Nass K, Zayas CF. Glomerular involvement in adults with a multidisciplinary approach. J Multidiscip Healthc 2017;10:335–46.
sickle cell hemoglobinopathies: prevalence and clinical correlates of progressive [255] Trent JT, Kirsner RS. Leg ulcers in sickle cell disease. Adv Skin Wound Care
renal failure. J Am Soc Nephrol 2006;17:2228–35. 2004;17:410–6.
[223] van Tuijn CFJ, Schimmel M, van Beers EJ, Nur E, Biemond BJ. Prospective eva- [256] Serjeant GR, Serjeant BE, Mohan JS, Clare A. Leg ulceration in sickle cell disease:
luation of chronic organ damage in adult sickle cell patients: a seven-year follow- medieval medicine in a modern world. Hematol Oncol Clin North Am
up study. Am J Hematol 2017;92. (E584-E90). 2005;19:943–56. [viii-ix].
[224] McPherson Yee M, Jabbar SF, Osunkwo I, Clement L, Lane PA, Eckman JR, et al. [257] Minniti CP, Eckman J, Sebastiani P, Steinberg MH, Ballas SK. Leg ulcers in sickle
Chronic kidney disease and albuminuria in children with sickle cell disease. Clin J cell disease. Am J Hematol 2010;85:831–3.
Am Soc Nephrol 2011;6:2628–33. [258] Nolan VG, Adewoye A, Baldwin C, Wang L, Ma Q, Wyszynski DF, et al. Sickle cell
[225] Hamideh D, Alvarez O. Sickle cell disease related mortality in the United States leg ulcers: associations with Haemolysis and SNPs in klotho, TEK and genes of the
(1999-2009). Pediatr Blood Cancer 2013;60:1482–6. TGF-β/BMP pathway: —sickle cell leg ulcers, genetics and Haemolysis. Br J
[226] Alvarez O, Miller ST, Wang WC, Luo Z, McCarville MB, Schwartz GJ, et al. Effect of Haematol 2006;133:570–8.
hydroxyurea treatment on renal function parameters: results from the multi-center [259] Koshy M, Entsuah R, Koranda A, Kraus AP, Johnson R, Bellvue R, et al. Leg ulcers
placebo-controlled BABY HUG clinical trial for infants with sickle cell anemia. in patients with sickle cell disease. Blood 1989;74:1403–8.
Pediatr Blood Cancer 2012;59:668–74. [260] Serjeant GR. Leg ulceration in sickle cell anemia. Arch Intern Med
[227] Aygun B, Mortier NA, Smeltzer MP, Shulkin BL, Hankins JS, Ware RE. 1974;133:690–4.
Hydroxyurea treatment decreases glomerular hyperfiltration in children with [261] Sen CK. Wound healing essentials: let there be oxygen. Wound Repair Regen
sickle cell anemia. Am J Hematol 2013;88:116–9. 2009;17:1–18.
[228] Laurin LP, Nachman PH, Desai PC, Ataga KI, Derebail VK. Hydroxyurea is asso- [262] EKAMH SN. Leg ulcers in sickle cell patients: management challenges. Chronic
ciated with lower prevalence of albuminuria in adults with sickle cell disease. Wound Care Management and Research 2016;3:157–61.
Nephrol Dial Transplant 2014;29:1211–8. [263] Singh APM, C.P. leg ulceration in sickle cell disease: an early and visible sign of
[229] Fitzhugh CD, Wigfall DR, Ware RE. Enalapril and hydroxyurea therapy for chil- end-organ disease. 2016.
dren with sickle nephropathy. Pediatr Blood Cancer 2005;45:982–5. [264] Minniti CP, Kato GJ. Critical reviews: how we treat sickle cell patients with leg
[230] Bartolucci P, Habibi A, Stehle T, Di Liberto G, Rakotoson MG, Gellen-Dautremer J, ulcers. Am J Hematol 2016;91:22–30.
et al. Six months of hydroxyurea reduces albuminuria in patients with sickle cell [265] Onwubalili JK. Sickle cell disease and infection. J Infect 1983;7:2–20.
disease. J Am Soc Nephrol 2016;27:1847–53. [266] Leikin SL, Gallagher D, Kinney TR, Sloane D, Klug P, Rida W. Mortality in children
[231] Thornburg CD, Dixon N, Burgett S, Mortier NA, Schultz WH, Zimmerman SA, et al. and adolescents with sickle cell disease. Cooperative study of sickle cell disease.
A pilot study of hydroxyurea to prevent chronic organ damage in young children Pediatrics 1989;84:500–8.
with sickle cell anemia. Pediatr Blood Cancer 2009;52:609–15. [267] Zarkowsky HS, Gallagher D, Gill FM, Wang WC, Falletta JM, Lande WM, et al.
[232] Foucan L, Bourhis V, Bangou J, Merault L, Etienne-Julan M, Salmi RL. A rando- Bacteremia in sickle hemoglobinopathies. J Pediatr 1986;109:579–85.
mized trial of captopril for microalbuminuria in normotensive adults with sickle [268] Overturf GD. Prevention of invasive pneumococcal infection in sickle cell disease:
cell anemia. Am J Med 1998;104:339–42. on the threshold of a new era of successes? J Pediatr 2003;143:423–5.
[233] Falk RJ, Scheinman J, Phillips G, Orringer E, Johnson A, Jennette JC. Prevalence [269] Gaston MH, Verter JI, Woods G, Pegelow C, Kelleher J, Presbury G, et al.
and pathologic features of sickle cell nephropathy and response to inhibition of Prophylaxis with oral penicillin in children with sickle cell anemia. A randomized
angiotensin-converting enzyme. N Engl J Med 1992;326:910–5. trial. N Engl J Med 1986;314:1593–9.
[234] Huang E, Parke C, Mehrnia A, Kamgar M, Pham PT, Danovitch G, et al. Improved [270] Hirst C, Owusu-Ofori S. Prophylactic antibiotics for preventing pneumococcal
survival among sickle cell kidney transplant recipients in the recent era. Nephrol infection in children with sickle cell disease. Cochrane Database Syst Rev
Dial Transplant 2013;28:1039–46. 2014:CD003427.
[235] Lonergan GJ, Cline DB, Abbondanzo SL. Sickle cell anemia. Radiographics [271] Falletta JM, Woods GM, Verter JI, Buchanan GR, Pegelow CH, Iyer RV, et al.
2001;21:971–94. Discontinuing penicillin prophylaxis in children with sickle cell anemia.
[236] Jean-Baptiste G, De Ceulaer K. Osteoarticular disorders of haematological origin. Prophylactic penicillin study II. J Pediatr 1995;127:685–90.
Baillieres Best Pract Res Clin Rheumatol 2000;14:307–23. [272] Rankine-Mullings AE, Owusu-Ofori S. Prophylactic antibiotics for preventing
[237] Milner PF, Kraus AP, Sebes JI, Sleeper LA, Dukes KA, Embury SH, et al. Sickle cell pneumococcal infection in children with sickle cell disease. Cochrane Database
disease as a cause of osteonecrosis of the femoral head. N Engl J Med Syst Rev 2017;10:CD003427.
1991;325:1476–81. [273] Kaplan J, Frost H, Sarnaik S, Schiffman G. Type-specific antibodies in children
[238] Mahadeo KM, Oyeku S, Taragin B, Rajpathak SN, Moody K, Santizo R, et al. with sickle cell anemia given polyvalent pneumococcal vaccine. J Pediatr
Increased prevalence of osteonecrosis of the femoral head in children and ado- 1982;100:404–6.
lescents with sickle-cell disease. Am J Hematol 2011;86:806–8. [274] Overturf GD, Rigau-Perez JG, Selzer J, Field RJ, Powars D, Pang EJ, et al.
[239] Athanassiou-Metaxa M, Kirkos J, Koussi A, Hatzipantelis E, Tsatra I, Economou M. Pneumococcal polysaccharide immunization of children with sickle cell disease. I.
Avascular necrosis of the femoral head among children and adolescents with sickle Clinical reactions to immunization and relationship to preimmunization antibody.
cell disease in Greece. Haematologica 2002;87:771–2. Am J Pediatr Hematol Oncol 1982;4:19–23.
[240] Lavernia CJ, Sierra RJ. Core decompression in atraumatic osteonecrosis of the hip. [275] Anderson EL, Kennedy DJ, Geldmacher KM, Donnelly J, Mendelman PM.
J Arthroplasty 2000;15:171–8. Immunogenicity of heptavalent pneumococcal conjugate vaccine in infants. J
[241] Clarke HJ, Jinnah RH, Brooker AF, Michaelson JD. Total replacement of the hip Pediatr 1996;128:649–53.
for avascular necrosis in sickle cell disease. J Bone Joint Surg Br 1989;71:465–70. [276] Halasa NB, Shankar SM, Talbot TR, Arbogast PG, Mitchel EF, Wang WC, et al.
[242] Hernigou P, Galacteros F, Bachir D, Goutallier D. Deformities of the hip in adults Incidence of invasive pneumococcal disease among individuals with sickle cell
who have sickle-cell disease and had avascular necrosis in childhood. A natural disease before and after the introduction of the pneumococcal conjugate vaccine.
history of fifty-two patients. J Bone Joint Surg Am 1991;73:81–92. Clin Infect Dis 2007;44:1428–33.
[243] Ware HE, Brooks AP, Toye R, Berney SI. Sickle cell disease and silent avascular [277] Adamkiewicz TV, Silk BJ, Howgate J, Baughman W, Strayhorn G, Sullivan K, et al.
necrosis of the hip. J Bone Joint Surg Br 1991;73:947–9. Effectiveness of the 7-valent pneumococcal conjugate vaccine in children with
[244] Gupta R, Adekile AD. MRI follow-up and natural history of avascular necrosis of sickle cell disease in the first decade of life. Pediatrics 2008;121:562–9.
the femoral head in Kuwaiti children with sickle cell disease. J Pediatr Hematol [278] Adams R, McKie V, Nichols F, Carl E, Zhang DL, McKie K, et al. The use of tran-
Oncol 2004;26:351–3. scranial ultrasonography to predict stroke in sickle cell disease. N Engl J Med
[245] Hernigou P, Habibi A, Bachir D, Galacteros F. The natural history of asymptomatic 1992;326:605–10.
osteonecrosis of the femoral head in adults with sickle cell disease. J Bone Joint [279] Adams RJ, McKie VC, Carl EM, Nichols FT, Perry R, Brock K, et al. Long-term
Surg Am 2006;88:2565–72. stroke risk in children with sickle cell disease screened with transcranial Doppler.
[246] Ilyas I, Moreau P. Simultaneous bilateral total hip arthroplasty in sickle cell dis- Ann Neurol 1997;42:699–704.
ease. J Arthroplasty 2002;17:441–5. [280] Adams RJ, Nichols FT, Figueroa R, McKie V, Lott T. Transcranial Doppler corre-
[247] Cao J, Mathews MK, McLeod DS, Merges C, Hjelmeland LM, Lutty GA. Angiogenic lation with cerebral angiography in sickle cell disease. Stroke 1992;23:1073–7.
factors in human proliferative sickle cell retinopathy. Br J Ophthalmol [281] Strouse JJ, Lanzkron S, Urrutia V. The epidemiology, evaluation and treatment of
1999;83:838–46. stroke in adults with sickle cell disease. Expert Rev Hematol 2011;4:597–606.
[248] Penman AD, Talbot JF, Chuang EL, Thomas P, Serjeant GR, Bird AC. New classi- [282] Nagpal KC, Goldberg MF, Rabb MF. Ocular manifestations of sickle hemoglobi-
fication of peripheral retinal vascular changes in sickle cell disease. Br J nopathies. Surv Ophthalmol 1977;21:391–411.
Ophthalmol 1994;78:681–9. [283] Goldberg MF. Natural history of untreated proliferative sickle retinopathy. Arch
[249] Condon PI, Serjeant GR. Ocular findings in hemoglobin SC disease in Jamaica. Am Ophthalmol 1971;85:428–37.
J Ophthalmol 1972;74:921–31. [284] Goldberg MF. Classification and pathogenesis of proliferative sickle retinopathy.

17

Downloaded for Anonymous User (n/a) at R4L.Senegal from ClinicalKey.com by Elsevier on July 02, 2023. For
personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.
M.E. Houwing, et al. Blood Reviews 37 (2019) 100580

Am J Ophthalmol 1971;71:649–65. sickle cell patients after treatment with hydroxyurea. Pediatr Blood Cancer
[285] Fitzhugh CD, Lauder N, Jonassaint JC, Telen MJ, Zhao X, Wright EC, et al. 2008;50:1258–60.
Cardiopulmonary complications leading to premature deaths in adult patients [316] Narang I, Kadmon G, Lai D, Dhanju S, Kirby-Allen M, Odame I, et al. Higher
with sickle cell disease. Am J Hematol 2010;85:36–40. nocturnal and awake oxygen saturations in children with sickle cell disease re-
[286] Ataga KI, Sood N, De Gent G, Kelly E, Henderson AG, Jones S, et al. Pulmonary ceiving hydroxyurea therapy. Ann Am Thorac Soc 2015;12:1044–9.
hypertension in sickle cell disease. Am J Med 2004;117:665–9. [317] Pashankar FD, Manwani D, Lee MT, Green NS. Hydroxyurea improves oxygen
[287] De Castro LM, Jonassaint JC, Graham FL, Ashley-Koch A, Telen MJ. Pulmonary saturation in children with sickle cell disease. J Pediatr Hematol Oncol
hypertension associated with sickle cell disease: clinical and laboratory endpoints 2015;37:242–3.
and disease outcomes. Am J Hematol 2008;83:19–25. [318] Puffer E, Schatz J, Roberts CW. The association of oral hydroxyurea therapy with
[288] Musa BM, Galadanci NA, Coker M, Bussell S, Aliyu MH. The global burden of improved cognitive functioning in sickle cell disease. Child Neuropsychol
pulmonary hypertension in sickle cell disease: a systematic review and meta- 2007;13:142–54.
analysis. Ann Hematol 2016;95:1757–64. [319] Kratovil T, Bulas D, Driscoll MC, Speller-Brown B, McCarter R, Minniti CP.
[289] Kato GJ, Onyekwere OC, Gladwin MT. Pulmonary hypertension in sickle cell Hydroxyurea therapy lowers TCD velocities in children with sickle cell disease.
disease: relevance to children. Pediatr Hematol Oncol 2007;24:159–70. Pediatr Blood Cancer 2006;47:894–900.
[290] Ataga KI, Klings ES. Pulmonary hypertension in sickle cell disease: diagnosis and [320] Zimmerman SA, Schultz WH, Burgett S, Mortier NA, Ware RE. Hydroxyurea
management. Hematology Am Soc Hematol Educ Program 2014;2014:425–31. therapy lowers transcranial Doppler flow velocities in children with sickle cell
[291] Hall C. Essential biochemistry and physiology of (NT-pro)BNP. Eur J Heart Fail anemia. Blood 2007;110:1043–7.
2004;6:257–60. [321] Lagunju I, Brown BJ, Sodeinde O. Hydroxyurea lowers transcranial Doppler flow
[292] Machado RF, Hildesheim M, Mendelsohn L, Remaley AT, Kato GJ, Gladwin MT. velocities in children with sickle cell anaemia in a Nigerian cohort. Pediatr Blood
NT-pro brain natriuretic peptide levels and the risk of death in the cooperative Cancer 2015;62:1587–91.
study of sickle cell disease. Br J Haematol 2011;154:512–20. [322] Ghafuri DL, Chaturvedi S, Rodeghier M, Stimpson SJ, McClain B, Byrd J, et al.
[293] Parent F, Bachir D, Inamo J, Lionnet F, Driss F, Loko G, et al. A hemodynamic Secondary benefit of maintaining normal transcranial Doppler velocities when
study of pulmonary hypertension in sickle cell disease. N Engl J Med using hydroxyurea for prevention of severe sickle cell anemia. Pediatr Blood
2011;365:44–53. Cancer 2017;64.
[294] Fonseca GH, Souza R, Salemi VM, Jardim CV, Gualandro SF. Pulmonary hy- [323] Steinberg MH, Barton F, Castro O, Pegelow CH, Ballas SK, Kutlar A, et al. Effect of
pertension diagnosed by right heart catheterisation in sickle cell disease. Eur hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and
Respir J 2012;39:112–8. benefits up to 9 years of treatment. JAMA 2003;289:1645–51.
[295] Mehari A, Gladwin MT, Tian X, Machado RF, Kato GJ. Mortality in adults with [324] Voskaridou E, Christoulas D, Bilalis A, Plata E, Varvagiannis K, Stamatopoulos G,
sickle cell disease and pulmonary hypertension. JAMA 2012;307:1254–6. et al. The effect of prolonged administration of hydroxyurea on morbidity and
[296] Schimmel M, van Beers EJ, van Tuijn CF, Nur E, Rijneveld AW, Mac Gillavry MR, mortality in adult patients with sickle cell syndromes: results of a 17-year, single-
et al. N-terminal pro-B-type natriuretic peptide, tricuspid jet flow velocity, and center trial (LaSHS). Blood 2010;115:2354–63.
death in adults with sickle cell disease. Am J Hematol 2015;90:E75–6. [325] Lobo CL, Pinto JF, Nascimento EM, Moura PG, Cardoso GP, Hankins JS. The effect
[297] Hagar RW, Michlitsch JG, Gardner J, Vichinsky EP, Morris CR. Clinical differences of hydroxcarbamide therapy on survival of children with sickle cell disease. Br J
between children and adults with pulmonary hypertension and sickle cell disease. Haematol 2013;161:852–60.
Br J Haematol 2008;140:104–12. [326] Le PQ, Gulbis B, Dedeken L, Dupont S, Vanderfaeillie A, Heijmans C, et al. Survival
[298] Dham N, Ensing G, Minniti C, Campbell A, Arteta M, Rana S, et al. Prospective among children and adults with sickle cell disease in Belgium: benefit from hy-
echocardiography assessment of pulmonary hypertension and its potential etiol- droxyurea treatment. Pediatr Blood Cancer 2015;62:1956–61.
ogies in children with sickle cell disease. Am J Cardiol 2009;104:713–20. [327] Karacaoglu PK, Asma S, Korur A, Solmaz S, Buyukkurt NT, Gereklioglu C, et al.
[299] Lee MT, Small T, Khan MA, Rosenzweig EB, Barst RJ, Brittenham GM. Doppler- East Mediterranean region sickle cell disease mortality trial: retrospective multi-
defined pulmonary hypertension and the risk of death in children with sickle cell center cohort analysis of 735 patients. Ann Hematol 2016;95:993–1000.
disease followed for a mean of three years. Br J Haematol 2009;146:437–41. [328] Steinberg MH, McCarthy WF, Castro O, Ballas SK, Armstrong FD, Smith W, et al.
[300] Gordeuk VR, Minniti CP, Nouraie M, Campbell AD, Rana SR, Luchtman-Jones L, The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: a 17.5
et al. Elevated tricuspid regurgitation velocity and decline in exercise capacity year follow-up. Am J Hematol 2010;85:403–8.
over 22 months of follow up in children and adolescents with sickle cell anemia. [329] Qureshi A, Kaya B, Pancham S, Keenan R, Anderson J, Akanni M, et al. Guidelines
Haematologica 2011;96:33–40. for the use of hydroxycarbamide in children and adults with sickle cell disease: a
[301] Morris CR. New strategies for the treatment of pulmonary hypertension in sickle British Society for Haematology guideline. Br J Haematol 2018;181:460–75.
cell disease : the rationale for arginine therapy. Treat Respir Med 2006;5:31–45. [330] Stettler N, McKiernan CM, Melin CQ, Adejoro OO, Walczak NB. Proportion of
[302] World Health Organization; Wilson JMGJ, G. The principles and practice of adults with sickle cell anemia and pain crises receiving hydroxyurea. JAMA
screening for disease. 1966. 2015;313:1671–2.
[303] Platt OS, Orkin SH, Dover G, Beardsley GP, Miller B, Nathan DG. Hydroxyurea [331] Zimmerman SA, Schultz WH, Davis JS, Pickens CV, Mortier NA, Howard TA, et al.
enhances fetal hemoglobin production in sickle cell anemia. J Clin Invest Sustained long-term hematologic efficacy of hydroxyurea at maximum tolerated
1984;74:652–6. dose in children with sickle cell disease. Blood 2004;103:2039–45.
[304] Pule GD, Mowla S, Novitzky N, Wiysonge CS, Wonkam A. A systematic review of [332] McGann PT, Howard TA, Flanagan JM, Lahti JM, Ware RE. Chromosome damage
known mechanisms of hydroxyurea-induced fetal hemoglobin for treatment of and repair in children with sickle cell anaemia and long-term hydroxycarbamide
sickle cell disease. Expert Rev Hematol 2015;8:669–79. exposure. Br J Haematol 2011;154:134–40.
[305] Cokic VP, Smith RD, Beleslin-Cokic BB, Njoroge JM, Miller JL, Gladwin MT, et al. [333] Ware RE. How I use hydroxyurea to treat young patients with sickle cell anemia.
Hydroxyurea induces fetal hemoglobin by the nitric oxide-dependent activation of Blood 2010;115:5300–11.
soluble guanylyl cyclase. J Clin Invest 2003;111:231–9. [334] McGann PT, Flanagan JM, Howard TA, Dertinger SD, He J, Kulharya AS, et al.
[306] King SB. Nitric oxide production from hydroxyurea. Free Radic Biol Med Genotoxicity associated with hydroxyurea exposure in infants with sickle cell
2004;37:737–44. anemia: results from the BABY-HUG phase III clinical trial. Pediatr Blood Cancer
[307] Kinney TR, Helms RW, O'Branski EE, Ohene-Frempong K, Wang W, Daeschner C, 2012;59:254–7.
et al. Safety of hydroxyurea in children with sickle cell anemia: results of the HUG- [335] DeBaun MR. Hydroxyurea therapy contributes to infertility in adult men with
KIDS study, a phase I/II trial. Pediatric hydroxyurea Group. Blood sickle cell disease: a review. Expert Rev Hematol 2014;7:767–73.
1999;94:1550–4. [336] Berthaut I, Bachir D, Kotti S, Chalas C, Stankovic K, Eustache F, et al. Adverse
[308] Hoppe C, Vichinsky E, Quirolo K, van Warmerdam J, Allen K, Styles L. Use of effect of hydroxyurea on spermatogenesis in patients with sickle cell anemia after
hydroxyurea in children ages 2 to 5 years with sickle cell disease. J Pediatr 6 months of treatment. Blood 2017;130:2354–6.
Hematol Oncol 2000;22:330–4. [337] Danielson CF. The role of red blood cell exchange transfusion in the treatment and
[309] Ferster A, Tahriri P, Vermylen C, Sturbois G, Corazza F, Fondu P, et al. Five years prevention of complications of sickle cell disease. Ther Apher 2002;6:24–31.
of experience with hydroxyurea in children and young adults with sickle cell [338] Styles LA, Abboud M, Larkin S, Lo M, Kuypers FA. Transfusion prevents acute
disease. Blood 2001;97:3628–32. chest syndrome predicted by elevated secretory phospholipase A2. Br J Haematol
[310] de Montalembert M, Brousse V, Elie C, Bernaudin F, Shi J, Landais P, et al. Long- 2007;136:343–4.
term hydroxyurea treatment in children with sickle cell disease: tolerance and [339] Howard J, Malfroy M, Llewelyn C, Choo L, Hodge R, Johnson T, et al. The
clinical outcomes. Haematologica 2006;91:125–8. transfusion alternatives preoperatively in sickle cell disease (TAPS) study: a ran-
[311] Thornburg CD, Files BA, Luo Z, Miller ST, Kalpatthi R, Iyer R, et al. Impact of domised, controlled, multicentre clinical trial. Lancet 2013;381:930–8.
hydroxyurea on clinical events in the BABY HUG trial. Blood 2012;120:4304–10. [340] Estcourt LJ, Fortin PM, Trivella M, Hopewell S. Preoperative blood transfusions for
[quiz 448]. sickle cell disease. Cochrane Database Syst Rev 2016;4:CD003149.
[312] Lebensburger J, Johnson SM, Askenazi DJ, Rozario NL, Howard TH, Hilliard LM. [341] Files B, Brambilla D, Kutlar A, Miller S, Vichinsky E, Wang W, et al. Longitudinal
Protective role of hemoglobin and fetal hemoglobin in early kidney disease for changes in ferritin during chronic transfusion: a report from the stroke prevention
children with sickle cell anemia. Am J Hematol 2011;86:430–2. trial in sickle cell Anemia (STOP). J Pediatr Hematol Oncol 2002;24:284–90.
[313] Sachdev V, Sidenko S, Wu MD, Minniti CP, Hannoush H, Brenneman CL, et al. [342] Chou ST, Jackson T, Vege S, Smith-Whitley K, Friedman DF, Westhoff CM. High
Skeletal and myocardial microvascular blood flow in hydroxycarbamide-treated prevalence of red blood cell alloimmunization in sickle cell disease despite
patients with sickle cell disease. Br J Haematol 2017;179:648–56. transfusion from Rh-matched minority donors. Blood 2013;122:1062–71.
[314] Shilo NR, Alawadi A, Allard-Coutu A, Robitaille N, Pastore Y, Berube D, et al. [343] Schmalzer EA, Lee JO, Brown AK, Usami S, Chien S. Viscosity of mixtures of sickle
Airway hyperreactivity is frequent in non-asthmatic children with sickle cell dis- and normal red cells at varying hematocrit levels. Implications for transfusion.
ease. Pediatr Pulmonol 2016;51:950–7. Transfusion 1987;27:228–33.
[315] Singh SA, Koumbourlis AC, Aygun B. Resolution of chronic hypoxemia in pediatric [344] Sins JW, Biemond BJ, van den Bersselaar SM, Heijboer H, Rijneveld AW, Cnossen

18

Downloaded for Anonymous User (n/a) at R4L.Senegal from ClinicalKey.com by Elsevier on July 02, 2023. For
personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.
M.E. Houwing, et al. Blood Reviews 37 (2019) 100580

MH, et al. Early occurrence of red blood cell alloimmunization in patients with [370] Olowoyeye A, Okwundu CI. Gene therapy for sickle cell disease. Cochrane
sickle cell disease. Am J Hematol 2016;91:763–9. Database Syst Rev 2016;11:CD007652.
[345] Aygun B, Padmanabhan S, Paley C, Chandrasekaran V. Clinical significance of RBC [371] Hoban MD, Lumaquin D, Kuo CY, Romero Z, Long J, Ho M, et al. CRISPR/Cas9-
alloantibodies and autoantibodies in sickle cell patients who received transfusions. mediated correction of the sickle mutation in human CD34+ cells. Mol Ther
Transfusion 2002;42:37–43. 2016;24:1561–9.
[346] Wahl S, Quirolo KC. Current issues in blood transfusion for sickle cell disease. Curr [372] Hoban MD, Orkin SH, Bauer DE. Genetic treatment of a molecular disorder: gene
Opin Pediatr 2009;21:15–21. therapy approaches to sickle cell disease. Blood 2016;127:839–48.
[347] Howard J. Sickle cell disease: when and how to transfuse. Hematology Am Soc [373] Bluebird bio I. bluebird bio's LentiGlobin™ gene therapy granted accelerated as-
Hematol Educ Program 2016;2016:625–31. sessment by European medicines Agency for the Treatment of transfusion-de-
[348] Pasquini M, Wang Z, Horowitz MM, Gale RP. 2013 report from the Center for pendent β-thalassemia. Cambridge: Business wire. 2018.
International Blood and Marrow Transplant Research (CIBMTR): current uses and [374] Telen MJ. Beyond hydroxyurea: new and old drugs in the pipeline for sickle cell
outcomes of hematopoietic cell transplants for blood and bone marrow disorders. disease. Blood 2016;127:810–9.
Clin Transpl 2013:187–97. [375] Ware RE. Technological advances in sickle cell disease. Blood Cells Mol Dis
[349] Gluckman E, Cappelli B, Bernaudin F, Labopin M, Volt F, Carreras J, et al. Sickle 2017;67:102–3.
cell disease: an international survey of results of HLA-identical sibling hemato- [376] Niihara Y, Miller ST, Kanter J, Lanzkron S, Smith WR, Hsu LL, et al. A phase 3 trial
poietic stem cell transplantation. Blood 2017;129:1548–56. of l-glutamine in sickle cell disease. N Engl J Med 2018;379:226–35.
[350] Bernaudin F, Socie G, Kuentz M, Chevret S, Duval M, Bertrand Y, et al. Long-term [377] Telen MJ, Wun T, McCavit TL, De Castro LM, Krishnamurti L, Lanzkron S, et al.
results of related myeloablative stem-cell transplantation to cure sickle cell dis- Randomized phase 2 study of GMI-1070 in SCD: reduction in time to resolution of
ease. Blood 2007;110:2749–56. vaso-occlusive events and decreased opioid use. Blood 2015;125:2656–64.
[351] Walters MC, De Castro LM, Sullivan KM, Krishnamurti L, Kamani N, Bredeson C, [378] Ataga KI, Kutlar A, Kanter J, Liles D, Cancado R, Friedrisch J, et al. Crizanlizumab
et al. Indications and results of HLA-identical sibling hematopoietic cell trans- for the prevention of pain crises in sickle cell disease. N Engl J Med
plantation for sickle cell disease. Biol Blood Marrow Transplant 2016;22:207–11. 2017;376:429–39.
[352] McPherson ME, Hutcherson D, Olson E, Haight AE, Horan J, Chiang KY. Safety and [379] Debaun MR. A new phase II agent holds promise for first FDA approved therapy
efficacy of targeted busulfan therapy in children undergoing myeloablative mat- for treatment of acute Vaso-occlusive pain events in SCD. DC: The Hamatologist
ched sibling donor BMT for sickle cell disease. Bone Marrow Transplant ASH News and Reports Washington; 2017.
2011;46:27–33. [380] Howard J, Hemmaway CJ, Telfer P, Layton DM, Porter J, Awogbade M, et al. A
[353] Hsieh MM, Fitzhugh CD, Weitzel RP, Link ME, Coles WA, Zhao X, et al. phase 1/2 ascending dose study and open-label extension study of voxelotor in
Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell patients with sickle cell disease. Blood 2019;133:1865–75.
transplantation for severe sickle cell phenotype. JAMA 2014;312:48–56. [381] Rickles FR, O'Leary DS. Role of coagulation system in pathophysiology of sickle
[354] Arnold SD, Bhatia M, Horan J, Krishnamurti L. Haematopoietic stem cell trans- cell disease. Arch Intern Med 1974;133:635–41.
plantation for sickle cell disease - current practice and new approaches. Br J [382] Ataga KI. Hypercoagulability and thrombotic complications in hemolytic anemias.
Haematol 2016;174:515–25. Haematologica 2009;94:1481–4.
[355] Hsieh MM, Kang EM, Fitzhugh CD, Link MB, Bolan CD, Kurlander R, et al. [383] Austin H, Lally C, Benson JM, Whitsett C, Hooper WC, Key NS. Hormonal con-
Allogeneic hematopoietic stem-cell transplantation for sickle cell disease. N Engl J traception, sickle cell trait, and risk for venous thromboembolism among African
Med 2009;361:2309–17. American women. Am J Obstet Gynecol 2009;200(620). [e1-3].
[356] Saraf SL, Oh AL, Patel PR, Jalundhwala Y, Sweiss K, Koshy M, et al. [384] Haddad LB, Curtis KM, Legardy-Williams JK, Cwiak C, Jamieson DJ.
Nonmyeloablative stem cell transplantation with Alemtuzumab/low-dose irra- Contraception for individuals with sickle cell disease: a systematic review of the
diation to cure and improve the quality of life of adults with sickle cell disease. literature. Contraception 2012;85:527–37.
Biol Blood Marrow Transplant 2016;22:441–8. [385] Qureshi AI, Malik AA, Adil MM, Suri MF. Oral contraceptive use and incident
[357] Walters MC, Patience M, Leisenring W, Eckman JR, Buchanan GR, Rogers ZR, et al. stroke in women with sickle cell disease. Thromb Res 2015;136:315–8.
Barriers to bone marrow transplantation for sickle cell anemia. Biol Blood Marrow [386] Altshuler AL, Gaffield ME, Kiarie JN. The WHO's medical eligibility criteria for
Transplant 1996;2:100–4. contraceptive use: 20 years of global guidance. Curr Opin Obstet Gynecol
[358] Filipovich AH. Diagnosis and manifestations of chronic graft-versus-host disease. 2015;27:451–9.
Best Pract Res Clin Haematol 2008;21:251–7. [387] Serjeant GR, Serjeant BE, Mason KP, Gibson F, Gardner R, Warren L, et al.
[359] Bolanos-Meade J, Fuchs EJ, Luznik L, Lanzkron SM, Gamper CJ, Jones RJ, et al. Voluntary premarital screening to prevent sickle cell disease in Jamaica: does it
HLA-haploidentical bone marrow transplantation with posttransplant cyclopho- work? J Community Genet 2017;8:133–9.
sphamide expands the donor pool for patients with sickle cell disease. Blood [388] Howard J, Oteng-Ntim E. The obstetric management of sickle cell disease. Best
2012;120:4285–91. Pract Res Clin Obstet Gynaecol 2012;26:25–36.
[360] Dallas MH, Triplett B, Shook DR, Hartford C, Srinivasan A, Laver J, et al. Long- [389] Brawley OW, Cornelius LJ, Edwards LR, Gamble VN, Green BL, Inturrisi C, et al.
term outcome and evaluation of organ function in pediatric patients undergoing National Institutes of Health consensus development conference statement: hy-
haploidentical and matched related hematopoietic cell transplantation for sickle droxyurea treatment for sickle cell disease. Ann Intern Med 2008;148:932–8.
cell disease. Biol Blood Marrow Transplant 2013;19:820–30. [390] National Toxicology P. NTP-CERHR monograph on the potential human re-
[361] Shenoy S, Eapen M, Panepinto JA, Logan BR, Wu J, Abraham A, et al. A trial of productive and developmental effects of hydroxyurea. NTP CERHR MON
unrelated donor marrow transplantation for children with severe sickle cell dis- 2008:vii–. [v, ix-III1].
ease. Blood 2016;128:2561–7. [391] Savage WJ, Buchanan GR, Yawn BP, Afenyi-Annan AN, Ballas SK, Goldsmith JC,
[362] Abraham A, Cluster A, Jacobsohn D, Delgado D, Hulbert ML, Kukadiya D, et al. et al. Evidence gaps in the management of sickle cell disease: a summary of needed
Unrelated umbilical cord blood transplantation for sickle cell disease following research. Am J Hematol 2015;90:273–5.
reduced-intensity conditioning: results of a phase I trial. Biol Blood Marrow [392] Gabbe SG, Melville J, Mandel L, Walker E. Burnout in chairs of obstetrics and
Transplant 2017;23:1587–92. gynecology: diagnosis, treatment, and prevention. Am J Obstet Gynecol
[363] Radhakrishnan K, Bhatia M, Geyer MB, Del Toro G, Jin Z, Baker C, et al. Busulfan, 2002;186:601–12.
fludarabine, and alemtuzumab conditioning and unrelated cord blood transplan- [393] Rogers DT, Molokie R. Sickle cell disease in pregnancy. Obstet Gynecol Clin North
tation in children with sickle cell disease. Biol Blood Marrow Transplant Am 2010;37:223–37.
2013;19:676–7. [394] Hoyert DL. Maternal mortality and related concepts. Vital Health Stat
[364] Fitzhugh CD, Walters MC. The case for HLA-identical sibling hematopoietic stem 2007;3:1–13.
cell transplantation in children with symptomatic sickle cell anemia. Blood Adv [395] Barfield WD, Barradas DT, Manning SE, Kotelchuck M, Shapiro-Mendoza CK.
2017;1:2563–7. Sickle cell disease and pregnancy outcomes: women of African descent. Am J Prev
[365] DeBaun MR, Clayton EW. Primum non nocere: the case against transplant for Med 2010;38:S542–9.
children with sickle cell anemia without progressive end-organ disease. Blood Adv [396] Hassell K. Pregnancy and sickle cell disease. Hematol Oncol Clin North Am
2017;1:2568–71. 2005;19:903–16. [vii-viii].
[366] Nickel RS, Kamani NR. Ethical challenges in hematopoietic cell transplantation for [397] Chakravarty EF, Khanna D, Chung L. Pregnancy outcomes in systemic sclerosis,
sickle cell disease. Biol Blood Marrow Transplant 2018;24:219–27. primary pulmonary hypertension, and sickle cell disease. Obstet Gynecol
[367] Bhatia M, Sheth S. Hematopoietic stem cell transplantation in sickle cell disease: 2008;111:927–34.
patient selection and special considerations. J Blood Med 2015;6:229–38. [398] Villers MS, Jamison MG, De Castro LM, James AH. Morbidity associated with
[368] Bank A, Markowitz D, Lerner N. Gene transfer. A potential approach to gene sickle cell disease in pregnancy. Am J Obstet Gynecol 2008;199(125). [e1-5].
therapy for sickle cell disease. Ann N Y Acad Sci 1989;565:37–43. [399] Boafor TK, Olayemi E, Galadanci N, Hayfron-Benjamin C, Dei-Adomakoh Y,
[369] Romero Z, Urbinati F, Geiger S, Cooper AR, Wherley J, Kaufman ML, et al. Beta- Segbefia C, et al. Pregnancy outcomes in women with sickle-cell disease in low and
globin gene transfer to human bone marrow for sickle cell disease. J Clin Invest high income countries: a systematic review and meta-analysis. BJOG
2013;123(8):3317–30. 2016;123:691–8.

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