Download The spleen and sickle cell disease: the sick(led) spleen - Labex GR-Ex

review
The spleen and sickle cell disease: the sick(led) spleen
Valentine Brousse,1,2,3 Pierre Buffet3,4,5 and David Rees6
1
Department of Paediatrics, Reference Centre for Sickle Cell Disease, H^opital Universitaire Necker-Enfants Malades, APHP, 2Universite Paris Descartes, 3Laboratory of Excellence GR-Ex, 4Centre d’Immunologie et des Maladies Infectieuses de Paris, CIMI-PARIS, U
1135 INSERM/UPMC Universite Paris VI, 5Service de Parasitologie, AP-HP, H^opital Pitie-Salp^etriere, Paris, France and 6Department
of Paediatric Haematology, King’s College Hospital NHS Foundation Trust, King’s Health Partners, Denmark Hill, London, UK
Summary
The spleen has a combined function of immune defence and
quality control of senescent or altered red cells. It is the first
organ injured in sickle cell anaemia (SCA) with evidence of
hyposplenism present before 12 months in the majority of
children. Repeated splenic vaso-occlusion leads to fibrosis
and progressive atrophy of the organ (autosplenectomy),
which is generally complete by 5 years in SCA. The precise
sequence of pathogenic events leading to hyposplenism is
unknown. Splenic injury is generally silent and progressive. It
can be clinically overt with acute splenic sequestration of red
cells, an unpredictable and life-threatening complication in
infants. Splenomegaly, with or without hypersplenism, can
also occur and can coexist with loss of function. Hyposplenism increases the susceptibility of SCA children to infection
with encapsulated bacteria, which is notably reduced by penicillin prophylaxis and immunization. Whether hyposplenism
indirectly increases the risk of vaso-occlusion or other circulatory complications remains to be determined.
Keywords: spleen, sickle cell disease, hyposplenism, acute
splenic sequestration, childhood.
Over the years, the human spleen has received attention in
the literature, mostly from poets and philosophers as the seat
of melancholy and bad temper (Baudelaire, 1869). In English
‘spleen’ is still used to refer to anger, and in French, the
same word means sadness. In physiology, the spleen has been
described as early as Galen’s era and, despite further insight
in the 1970s into its sophisticated ultra structural microanatomy (Chen & Weiss, 1972), the spleen continues to remain
a mysterious organ, often considered as an unnecessary
reservoir. Progressive evidence is pointing, however, to the
Correspondence: Valentine Brousse, Department of Paediatrics,
Reference Centre for Sickle Cell Disease, Hôpital Universitaire
Necker-Enfants Malades, APHP, 149 rue de Sèvres, 75015 Paris,
France.
E-mail: [email protected]
ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
role of the spleen as a major contributor to immune, vascular and blood homeostasis. Hyposplenism, therefore, is
increasingly recognized as a pathological condition with
potentially major consequences, such as vascular complications and immune dysfunction, in addition to the long identified susceptibility to encapsulated bacteria. In sickling
disorders, the spleen is prone to early injury and hyposplenism is consequently a major feature of the disease, and a
constant one in homozygous and S-beta°thalassaemia
patients. This review summarizes the up to date knowledge
on the physiological role of the spleen and its dysfunction in
sickling disorders. The main consequences related to spleen
dysfunction, susceptibility to infections, disease expression
and vascular risk are highlighted. Principles of management
in sickle cell disease (SCD) are discussed.
Functions of the spleen
The spleen is a uniquely adapted lymphoid organ dedicated
to the clearance of blood cells, microorganisms and bloodborne antigens. It is a major filter of the blood, which initiates and links innate and adaptive immune responses against
pathogens. The spleen is histologically divided in three functional interconnected compartments: the white pulp, essentially dedicated to adaptive immunity, the red pulp, which is
essentially dedicated to a filtering function and the marginal
zone (or perifollicular zone) lying in-between, connecting
both functions. Due to its location on the blood mainstream,
as opposed to other secondary lymphoid organs, the spleen
filters approximately 5% of the cardiac output every minute
(William & Corazza, 2007). Blood entering the spleen
through the splenic artery is distributed through the trabecular arteries that branch throughout the parenchyma to a terminating arteriole called the central arteriole, surrounded by
lymphoid cells. The arteriole can either drain directly into
the venous sinuses, which are vascular channels lined by
endothelial cells, or alternatively terminate within the parenchyma and discharge its blood content into the cords of the
red pulp. In this latter case, blood cells and blood-borne bacteria are in close and prolonged contact with specialized
macrophages and resident spleen cells. This interaction triggers phagocytosis of pathogens or red blood cells (RBC)
doi:10.1111/bjh.12950
Review
whenever activating signals are present on the cell surface.
Farther in their progression along this un-endothelialized
space, the remaining cells will re-enter into the venous system after squeezing through narrow (1–3-lm wide), interendothelial slits in the wall of venous sinuses. At this ultimate checkpoint, red cells may be retained upstream from
the sinus wall if they are not deformable enough. They can
also be ‘pitted’ if they contain abnormal material like nuclear
remnants or altered parasites (Buffet et al, 2006; Safeukui
et al, 2008). During this pitting process, the red cell is
groomed of its unwanted material by squeezing through
inter-endothelial slits. If this pitting capacity is altered, red
cells containing abnormal material are found in the circulation. Ten per cent of the blood circulating in the spleen
flows with reduced velocity and high haematocrit in the open
and slow pathway, whilst 90% flows through in the fast
closed pathway, bypassing the filtration beds. Red cell velocity in the slow pathway is in the range of 7 lm/s vs. 100
times greater in the sinus. Additional resistance due to the
dynamic properties of both the endothelial cells and specialized fibroblasts (Donald & Aarhus, 1974) may play an
important role in regulating blood filtration and possibly be
dysfunctional in pathological conditions like SCD.
The white pulp selectively clears lymphocytes and accessory cells from the blood and allows the spleen to initiate an
adaptive immune response. It is divided into T lymphocyte
zones around the artery (periarteriolar lymphocyte sheath,
PALS) and follicles composed of B cells, in addition to
dendritic cells and macrophages.
The spleen contains distinct B cell lineages: follicular and
marginal zone B cells. Follicular B cells recirculate as plasmocytes, producing high affinity antibodies and participate
mainly in T cell-dependent immune responses upon re-infection or immunization. Marginal zone B cells and dendritic
cells capture antigens and promote both T cell-independent
and -dependent immune responses. Marginal zone B cells
[immunonoglobulin (Ig)M memory B cells] express the
memory cell marker CD27, high surface IgM and low levels
of IgD (Weller et al, 2004). These cells can provide early T
cell independent responses by producing natural anti polysaccharide IgMs, which are essential to the phagocytosis of
otherwise poorly opsonised encapsulated bacteria, such as
Streptococcus pneumoniae, Nesseiria meningitidis and Haemophilus influenza type b (Hib). The splenic marginal zone is
central to the generation and the maintenance of IgM
memory B cells.
Macrophages exerting discrete functions are present in all
compartments. Marginal zone macrophages express unique
pattern-recognition receptors and contribute to the clearance
of blood-borne bacteria and regulate tolerance to antigens.
Macrophages in the filtration beds are specialized in erythrophagocytosis, scavenging blood-borne debris and recycling
iron (den Haan & Kraal, 2012).
The main clinical consequences of defective spleen function derive from the alteration of both the filtering and
2
immune functions, leading to increased susceptibility to
bacterial infection, increased risks of vascular complications
and autoimmunity, all of which are further discussed in the
section Consequences of hyposplenism in SCA.
Measuring splenic function
Unlike tests of renal function for instance, there is no direct
way of assessing splenic output, and both biological and
imaging tools are imperfectly suited for functional evaluation.
Blood markers, such as Howell–Jolly bodies (HJB) or
pitted cells (PIT) (Figs 1 and 2, respectively) have been used
to assess the filtering function of the spleen whereas counts
of specific B cell subsets or measures of immune response
following vaccination have been used to assess its immunological function.
Howell–Jolly bodies are nuclear remnants in circulating
mature red cells, which are, in physiological conditions,
groomed or pitted by the spleen. The circulating number of
HJB can be counted on blood smears or by flow cytometry
(Harrod et al, 2007) and has therefore been used as a marker
of splenic dysfunction. A HJB count of ≥665/106 RBC is con-
Fig 1. Howell–Jolly bodies (black arrows) on blood smear stained by
May–Grunwald Giemsa, original magnification 91000, light microscopy.
ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
Review
to their rigidity, allows quantitative determination of the
spleen uptake and anatomy (Gotthardt et al, 2007).
Altogether, these investigational tools have limited application in sickling disorders as hyposplenism is expected and
does not need to be demonstrated nor followed up. Measuring spleen function may occasionally be useful when splenectomy is discussed in very young children in order to assess
the residual function or, possibly, following haematopoietic
stem cell transplantation (HSCT) in order to safely stop antibiotic prophylaxis.
Spleen dysfunction in sickle cell anaemia (SCA):
SS and S beta° genotypes
Fig 2. Pitted cells on blood smear (black arrows) by differential contrast interference (Normarski optics), original magnification 91000.
sidered diagnostic of asplenia in SCA patients (Rogers et al,
2011). Similarly, PIT or pocked RBC observed with interference light microscopy (Normarsky optics) have been used to
measure splenic hypofunction. Pitted, referring to circulating
cells, is a misnomer since ‘pits’ are vesicles underlying the
membrane generated during the process of erythrocyte ageing
(Holroyde et al, 1969). The percentage of PIT has been
found to be <12% in SCA patients with normal splenic
function vs. ≥45% in asplenic patients (Rogers et al, 2011).
Measurement of circulating IgM memory B cells after
splenectomy has also been evaluated as a biomarker of hyposplenism. In a subset of 209 adult asplenic or hyposplenic
subjects compared to normal controls (n = 140), memory B
cells, IgM memory B cells and switched B cells were significantly reduced. The decrease in IgM memory B cells following splenectomy was gradual, reaching a stable level within
6 months. IgM memory B cells, as a proportion of B cells,
were the best discriminator between splenectomized patients
and normal controls. However, the clinical utility of this
marker remains to be determined as no discriminating
threshold was associated with high sensitivity and specificity
(Cameron et al, 2011).
Radio isotopic scanning of the spleen enables morphological and functional evaluation of the organ. This method of
spleen evaluation is however invasive, costly and technically
difficult (Di Sabatino et al, 2011). Spleen scintigraphy with
99m
Tc-labelled colloids allows measurement of the phagocytic
function of the spleen and liver and gives a spleen/liver
uptake ratio. However, only 10% of injected sulphur colloids
accumulate in the spleen, as they are mainly phagocytosed in
the liver. Preferably, spleen scanning with 99mTc-labelled
heated autologous RBC, which are trapped in the spleen due
ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
Sickle cell anaemia is a condition where splenic hypofunction
is constant. However, unlike other conditions, such as coeliac
disease or inflammatory bowel disease in which hyposplenism results from splenic atrophy (Di Sabatino et al, 2011),
SCA may combine, notably in infancy, functional hyposplenism and splenomegaly. At birth, the spleen in SCA is morphologically and functionally normal. Progressive injury
occurs when the haemoglobin switch initiates the multiple
changes in the sickle RBC’ adherence, plastic and signalling
properties.
The first histological description of the spleen in SCA was
published in 1935 (Diggs, 1935) and describes ‘Splenic cords
stuffed with entangled masses of greatly elongated, pointed,
curved and bizarre shaped erythrocytes (. . .). The lesions do
not all progress at the same rate.’ Granuloma-like nodules,
known as Gamna–Gandy bodies, are characteristic, resulting
from periarteriolar haemorrhage followed by fibrosis and
impregnation of iron pigments (Piccin et al, 2012). The precise sequence of pathogenic events leading to splenic alterations in SCA patients is however still hypothetical and is
thought to be a randomly located sequence of vaso-occlusion
followed by ischaemia, leading to progressive fibrosis and
atrophy (Fig 3), resulting in ‘autosplenectomy’.
The spleen is indeed prone to injury in SCA: the specific
slow and open microcirculation favours in vivo deoxygenation and therefore sickling, which in turn favours RBC
adhesion to the spleen matrix or macrophages due to
increased expression of adhesion molecules and activation of
usually quiescent proteins. Several sickle red cell adhesion
molecules have been identified (Wandersee et al, 2005). The
interaction of sickle red cells with laminin via the B-CAM/
LU receptor is the best characterized adhesion phenomenon
(El Nemer et al, 1998). Non-receptor mechanisms include
proadhesive roles for red cell sulphated glycolipids and phosphatidyl serine promoting direct clearance through phagocytosis (death signal). This enhanced clearance contributes to
the shortened life span of sickle RBC. In addition, impaired
deformability of sickled RBC promotes their trapping
upstream by the narrow inter endothelial slits (Fig 4).
The concept of functional asplenia based on the finding of
a palpable spleen without scintigraphic uptake was first iden3
Review
scintigraphy. Out of 44 infants aged 15–18 months, only four
had normal splenic uptake (Rogers et al, 2011).
In the majority of patients, vaso-occlusive events in the
spleen are clinically silent and result in progressive atrophy
of the organ. Autosplenectomy is thought to be complete by
3–5 years of age in SS or S beta° patients (Brown et al,
1994). In a small fraction of children, acute splenic sequestration may precipitate hyposplenism, although the nature of
the causal relationship between these conditions remains to
be determined. Of note splenomegaly, hypersplenism and
functional hyposplenism are not mutually exclusive and may
coexist. Enhanced retention of altered red cells may indeed
lead to splenomegaly and anaemia (hypersplenism), while
impairing the filtering function of the spleen, an effect leading to an increased risk of infection and reduced pitting rates
(hyposplenism).
Fig 3. Haematin-eosin-saffron stained spleen sample following splenectomy in a 3-year-old child with sickle cell anaemia, showing congestion and fibrosis of the red pulp. Original magnification 9100.
Clinical manifestations of splenic injury in SCA
In children with SCA, the spleen can either be clinically palpable or not, functional or not, with no correlation between
size and function.
Splenomegaly
Fig 4. Haematin-eosin-saffron stained spleen sample following splenectomy for acute splenic sequestration in a 5-year-old girl with
sickle cell anaemia, showing sickled red cells retained upstream of
the sinus inter endothelial slits. Original magnification 91000.
tified by Pearson et al (1969).The pathophysiology of functional hyposplenism is hypothetical but two non-mutually
exclusive mechanisms have been proposed resulting from the
congestion of the red pulp: one is the haemodynamic diversion of blood flow to the closed pathway, thus shunting
blood away from the filtration beds, and the other is due to
the limitation of erythrophagocytosis by red pulp macrophages overwhelmed by sickled red cells.
Whatever the precise mechanism, spleen injury occurs very
early in SCA with a sharp rise in PIT counts after 6 months
of age (Brown et al, 1994). In a recent study, loss of splenic
function was found to begin before 12 months of age in 86%
of SCA infants assessed by 99mTc sulphur-colloid liver spleen
4
Moderate splenomegaly (1–2 cm below the left costal margin) with no haematological consequence is classically
described early in life before atrophy occurs. It is hypothesized that splenomegaly results from the progressive yet
moderate trapping of sickled red cells in the red pulp. In a
large Jamaican cohort, the spleen was palpable in 93% of
infants by the age of 1 year decreasing to 16% at 10 years
(Serjeant, 2001). In a North American setting, the mean
spleen volume, assessed by sonography in 199 SCA infants
aged 75–18 months, was 105 ml vs. 18 ml in 18 heightmatched healthy children. Spleen volume was significantly
associated with palpated spleen size (McCarville et al, 2011).
The prevalence of splenomegaly in SCA is however difficult
to interpret because it may depend on interfering genetic or
infectious factors. Persistent high fetal haemoglobin (HbF)
levels promote persistent splenomegaly, as illustrated by a
study in Saudi Arabia that assessed 363 patients (mean age
16 years) by ultrasound. Only 24 (66%) patients had autosplenectomy i.e. no visible spleen. HbF levels were higher in
patients with marked or massive splenomegaly than in those
with autosplenectomy. In this cohort, estimated splenic volume increased with age until about 40 years and then gradually decreased (Al-Salem et al, 1998). Co-inheritance of alpha
thalassaemia may also prolong the function of the spleen
(Higgs et al, 1982). Infectious agents may further interfere
with spleen size, notably in malaria-endemic countries. In
Kenya, for instance, in a total of 124 SCA children, splenomegaly was present in 41 (33%) subjects at a median age of
63 years (Sadarangani et al, 2009).
ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
Review
Hypersplenism
Hypersplenism classically refers to splenomegaly and any
combination of anaemia, leucopenia and/or thrombocytopenia, with compensatory bone marrow hyperplasia for a sustained period, and improvement after splenectomy. In SCA
patients, diagnosis is difficult because splenomegaly is frequent, anaemia pre-exists and defining a drop from baseline
level of haemoglobin at young age is sometimes hazardous.
Thrombocytopenia and ‘abnormally normal’ leucocyte count
are therefore the main haematological signs. The prevalence
of hypersplenism is unknown. It may occur in the absence of
any identified triggering event or follow acute splenic sequestration. Excessive destruction of red cells in SCA children
with prolonged hypersplenism may lead to subsequent
growth impairment and bone marrow hyperplasia. Transfusion efficiency is usually reduced in SCA patients with
hypersplenism.
Acute splenic sequestration
Acute splenic sequestration is defined as an acute splenic
enlargement with a fall in the haemoglobin level of at least
20 g/l (or 20%) from baseline level and a normal or
increased basal reticulocyte count (Topley et al, 1981). It
occurs when RBCs are acutely trapped in the spleen resulting
in abdominal pain and distension, pallor and haemodynamic
symptoms (tachycardia, hypotension, lethargy). Severe episodes may lead to hypovolaemic shock and death from cardiovascular collapse, within a few hours. The diagnosis is
based on clinical signs. Imaging is therefore not essential
and, if performed, should be planned only after treatment
has started. The precise sequence of pathogenic events leading to acute splenic sequestration is unknown. A precipitating event, such as fever or infection may trigger or amplify
red cell sickling in the splenic red pulp. Upon random accumulation of sickle cells in a zone close to a draining vein,
mechanical obstruction of blood flow would induce a drop
in oxygen concentration leading to amplification and extension of sickling. This acute event may be self-limited and
transient or lead to extensive irreversible infarction.
Acute splenic sequestration is the earliest life-threatening
complication seen in SCA patients, with the first occurrence
described as early as 5 weeks of age (Airede, 1992). The median age at first episode was 14 years (01–7) in a retrospective study of 190 cases (Brousse et al, 2012), with 75% of
first cases occurring before 2 years. Acute splenic sequestration is rarely observed after 6 years (Emond et al, 1985)
albeit in patients with high HbF levels or in those on regular
blood transfusion (see Reversal of hyposplenism section).
The life-long prevalence of acute splenic sequestration
ranges from 7 to 30% according to studies (Topley et al,
1981; Powell et al, 1992; Brousse et al, 2012). An associated
clinical event is found in more than 50% of episodes:
isolated fever, upper respiratory tract or gastro intestinal
ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
infection, vaso occlusive crisis. Whether these events are triggering or concomitant factors is unknown but this brings to
light the need for medical and parental awareness of acute
splenic sequestration occurrence in case of fever in SCA
infants.
To date, no solid predictor of acute splenic sequestration
has been identified. As for many other SCA complications,
the time of occurrence of acute splenic sequestration is partly
linked to the kinetics of the haemoglobin switch in infants
and to the HbF level.
Relapse of acute splenic sequestration is frequent with 50–
75% of patients experiencing more than one episode (Emond
et al, 1985; Brousse et al, 2012). In the French cohort, age at
the first episode was the only factor predicting recurrence:
the risk was lower when the first episode occurred after
2 years than before 1 year of age (hazard ratio, 060; 95%
confidence interval, 041–088; P = 0025).
Since the implementation of neonatal SCA screening programmes and subsequent parental education on the risk of
acute splenic sequestration, related mortality rate has
decreased sharply, as illustrated in a study showing a fall in
mortality in the period spanning from June 1973 to December 1981 (Lee et al, 1995). In countries where SCA is diagnosed at birth and comprehensive care is available, mortality
from acute splenic sequestration has now become very infrequent (Telfer et al, 2007; Quinn et al, 2010; van der Plas
et al, 2011).
Consequences of hyposplenism in SCA
Infectious susceptibility
The spleen plays a major role in the defence against infection
by combining the elimination of blood-borne bacteria by red
pulp macrophages through direct recognition and phagocytosis, by the generation and maintenance of IgM memory B
cells which produce natural IgM antibodies, and by allowing
efficient T-dependent immune response which produce high
affinity antibodies. Importantly, infants physiologically lack
IgM memory B cells and consequently are not able to produce natural antibidodies against poorly-opsonized encapsulated bacteria, such as Streptococcus pneumoniae, Nesseiria
meningitidis and Hib. This feature, which may be viewed as
physiological splenic immaturity, explains the early susceptibility to pneumococcal infections in infants. Immunization
against encapsulated bacteria in infants <2 years of age relies
therefore on conjugated vaccines, which allow a T-dependent
response that does not require IgM memory B cells and, consequently, an intact spleen to be efficient (Rosado et al,
2013).
In infants with SCA, early injury of the spleen decreases
the trapping of blood-borne bacteria, further impairs the
generation or maintenance of IgM memory B cells and dramatically increases the risk of life-threatening infections with
encapsulated bacteria. Before pneumococcal immunization
5
Review
and prophylactic antibiotics were implemented, the relative
risk of infection with Streptococcus pneumoniae in young SCA
children compared to normal controls was about 300, with a
15% mortality rate. Similarly, the relative risk of invasive
infection with Haemophilus influenza was 20–100, with a
mortality rate of about 20% (Barrett-Connor, 1971).The wide
spread use of the conjugated vaccine over the past two
decades has virtually eliminated invasive H. influenzae type b
disease where it is used (Ram et al, 2010).
About 10% of healthy humans carry meningococci in their
nasopharynges. About 50% of carriage isolates are unencapsulated, while almost every strain recovered from the blood
stream or the cerebrospinal fluid is encapsulated. Most
invasive isolates of meningococcal disease belong to the
serogroups A, B, C, W-135 and Y (Ram et al, 2010) for
which a conjugated vaccine is now available.
In influenza infection, pneumococcal carriage increases
and upper respiratory tract viral infection favours bacterial
invasion (Rice et al, 2012), warranting annual immunization
against influenza.
Vascular complications
Vascular complications, defined as any condition causing
narrowing or occlusion of a blood vessel, have been associated with asplenia, notably following surgical splenectomy
(Crary & Buchanan, 2009). An absent splenic filter allows
particulate matter, damaged, adherent or sickled cells and
procoagulant cell-derived microparticles to circulate (Fontana
et al, 2008), resulting in injury and activation of the endothelium. In SCA, which combines asplenia, chronic haemolysis and sickling, the risk of vascular complications is,
therefore, expected to be greatly increased. Additional endothelial dysfunction caused by the haemolysis-related nitric
oxide depletion (Kato et al, 2009) and the basal hypercoagulable state further contribute to the pathogenesis of vascular
complications.
The specific contribution of hyposplenism to arteriothrombotic complication in SCA is difficult to assess: cerebrovascular stroke is a major multifactorial complication in
SCA with an overall prevalence rate of 401% (Ohene-Frempong et al, 1998). However, other arteriosclerotic events,
such as myocardial infarction and coronary artery disease are
infrequent.
Studies on the prevalence of venous thromboembolic
complications in SCD have yielded conflicting results. The
prevalence of deep venous thrombosis in SCD was not found
to differ from aged-matched African Americans in a study
based on National Hospital Discharge Survey Data (Stein
et al, 2006). In contrast, this same study demonstrated a
higher incidence of pulmonary embolism, suggesting a
spleen-independent in situ thrombosis mechanism. In a retrospective cross-sectional study of 404 adult SCD patients
(Naik et al, 2013), however, 25% of patients had a history of
venous thromboembolism. Of note, the prevalence of non6
catheter-related venous thromboembolism was significantly
higher in patients with variant genotypes other than SS and
Sbeta°. Whether thromboembolic complications in SCD are
specifically related to spleen dysfunction is therefore difficult
to determine.
Pulmonary arterial hypertension (PAH) is considered a
potential complication of asplenia. In SCA, the prevalence of
PAH is controversial, ranging from 30% (Gladwin et al,
2004) to 6% (Parent et al, 2011), depending on the investigational technique. Altogether, contradictory or limited data
concerning hyposplenism-related vascular complications in
SCA plead for further exploration of the role of the spleen in
vascular homeostasis.
Autoimmunity
The spleen contributes to tolerance to antigens by trapping
particulate matter and circulating apoptotic cells. Tolerance
to apoptotic cells is essential to prevent inflammatory pathology and development of autoimmunity. Antinuclear antibody
positivity has been shown to be more common in SCD (Baethge et al, 1990). Clinical manifestations of immune disorders may have common features with clinical manifestations
of SCD resulting in delayed diagnosis. A higher than
expected incidence of connective tissue disease in SCD
patients compared to the general population has been
reported (Alkindi et al, 2012). Whether this higher incidence
is related to spleen dysfunction remains speculative at this
time.
Reversal of hyposplenism
Interestingly, hyposplenism has been demonstrated to be
reversible, to a certain extent, in patients benefiting from
transfusion therapy, hydroxycarbamide or HSCT. Transfusion therapy resulted in both reduction in PIT counts and
increased scintigraphic uptake on 99Tc sulphur colloid scans
in patients as old as 34 years in whom irreversible splenic
atrophy would have been expected (Pearson et al, 1970; Barrios et al, 1993; Campbell et al, 1997). Along the same lines,
HSCT in three SCA children aged 10–14 years, was associated with restoration of splenic filtering function as evidenced by revisualization of splenic uptake on 99Tc scans
and disappearance of HJB (Ferster et al, 1993).
Anti-sickling agents, such as hydroxycarbamide, may also
contribute to the preservation of splenic function. In a pilot
trial evaluating the effect of hydroxycarbamide in 21 SCA
infants (median age upon treatment initiation 15 months),
splenic radionuclide uptake was observed in 53% of children
while a 20% rate would have been predicted from historical
data (Wang et al, 2001). However, in a subsequent randomized controlled trial of hydroxycarbamide versus placebo in
179 SCA infants (mean age at enrolment 136 months), hydroxycarbamide did not prevent the decline in splenic function as assessed by qualitative spleen scan uptake: 19 of 70
ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
Review
patients presented decreased spleen function at exit in the
hydroxycarbamide group vs. 28 of 74 patients in the placebo
group, P = 021. Interestingly, episodes of splenic sequestration were equal in the two groups (Wang et al, 2011).
Because the duration of the study was relatively short
(2 years) these results do not rule out the possibility that
hydroxycarbamide may also increase the risk of acute
splenic sequestration in older children, by preserving splenic
function.
Altogether, reversal of hyposplenism or preservation of
spleen function following such treatments should be considered as potential beneficial effects, notably in terms of infectious protection. Hyposplenism, however, is not considered
an indication for such interventions.
Polyvalent polysaccharide S. pneumoniae vaccine (PPV23)
protects against additional serotypes and reduces the
incidence of invasive pneumococcal infections in asplenic
and SCD children over 2 years and adult patients (Ammann
et al, 1977). Current recommendations include sequential
13-valent PCV, three doses before 2 years followed by
immunization with PPV23 after 2 years. The interval at
which booster injections of PPV23 should be performed
(3–5 years) is uncertain.
The residual incidence of invasive pneumococcal infection
caused by nonvaccine serotypes is potentially important
(McCavit et al, 2011), supporting the recommendation to
urgently refer all SCA patients with fever to the hospital and
promptly administer broad-spectrum antibiotics.
Principles of management
SCA and Malaria
Hyposplenism and infectious risk
The reduction of infectious risk, particularly to encapsulated
bacteria, is pivotal and based on antibiotic prophylaxis, vaccination and patient and/or parental education to seek
prompt medical evaluation of febrile illness.
Daily oral penicillin has been shown to significantly reduce
morbidity and mortality associated with pneumococcal infection in SCA infants with an 84% reduction in pneumococcal
septicaemia (Gaston et al, 1986). Discontinuation of antibiotic prophylaxis is controversial and no evidence-based recommendation is available. (Hirst & Owusu-Ofori, 2012).
The immunization programme (Table I) should include
pneumococcal, Hib, meningococcal and influenza vaccines.
Immunization by protein conjugated vaccines, which are
immunogenic in infants before 2 years of age, is completed
by polysaccharidic vaccines after 2 years and in adults.
The introduction of a heptavalent pneumococcal conjugate
vaccine (PCV) demonstrated a 65% decrease in the mean
annual rate of hospitalization for invasive pneumococcal
infection among children with SCA (Payne et al, 2013).
The prevalence and density of malarial parasitaemia were
lower in children with SCA than in patients without SCA in
Kenya, with a trend toward a lower incidence of severe forms
(Komba et al, 2009). In a large case-control study in Kenya
there was no strong positive association between SCA and
admission to hospital with either uncomplicated or severe
P. falciparum malaria. However, protection was not complete, and P. falciparum carriage was significantly associated
with severe malarial anaemia and death in SCA patients in
Kenya (McAuley et al, 2010) and Tanzania (Makani et al,
2010). Malaria chemoprophylaxis is thus recommended in
SCA patients living in malaria endemic regions (World
Health Organization (WHO), 2010) despite limited evidence
of a beneficial effect on sickle cell-related events. Reductions
of blood transfusion requirements and, possibly, severe
malarial anaemia have nevertheless been demonstrated (Aneni et al, 2013). Antimalarial chemoprophylaxis is also indicated for SCA patients from non-endemic countries
travelling to endemic countries.
Interestingly, the prevalence of parasitaemia is generally
identical or slightly greater in HbSS than in HbAS subjects,
Table I. Examples of vaccination schedules for adults and children with sickle cell disease, reflecting hyposplenism. All routine vaccinations
should also be given.
Vaccination
Age given
Notes
Haemophilus influenza B
13-valent pneumococcal
conjugated vaccine
Meningitis C conjugated vaccine
23-valent polysaccharide
pneumococcal vaccine
Meningococcal ACWY
conjugated vaccine
Influenza
Hepatitis B
2, 3 and 4 months
2, 4 and 13 months
Routine vaccination for all children in many countries
Routine vaccination for all children in many countries
3 and 13 months
2 years, repeated every 3–5 years, life-long
Routine vaccination for all children in many countries
Hepatitis A
5 months
1 year, repeated annually
12, 13 and 18 months with booster
depending on antibody levels
12, 13 and 18 months
ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
New vaccine produced each year
If likely to travel to countries with endemic Hepatitis B, and
in regularly transfused cases
If significant liver disease, travel, or regular transfusions
7
Review
when a stronger protection of HbSS subjects might be
expected. Higher concentration of HbS should lead to stronger
protection through impaired parasite growth, cytoadherence
or enhanced adaptive response. SCD-induced hyposplenism
may explain why protection is weaker than expected (Deplaine
et al, 2011) but markers of hyposplenism have not been analysed yet in SCA patients with and without malaria.
Management of splenomegaly and hypersplenism:
Isolated mild splenomegaly warrants no specific management
apart from parental education on the risk of acute splenic
sequestration. When the spleen is markedly enlarged with
biological signs of hypersplenism, along with poor growth,
bone marrow hyperplasia and abdominal distension, a supportive transfusion programme can be initiated or splenectomy performed if age allows. Violent sports should be
restricted in order to avoid traumatic splenic rupture (Imbert
et al, 2009).
Management of acute splenic sequestration
Early detection and parental education on the occurrence of
acute splenic sequestration has had a major impact on the
related mortality (Serjeant, 2001). It is a medical emergency
that requires the immediate restoration of blood volume by
fluids and, generally, blood transfusion. Blood transfusion
usually releases the trapped RBC resulting in higher transfusion yields than expected, warranting caution on the amount
of blood transfused in order to avoid a post-transfusional
haematocrit above 35%. Management of acute splenic
sequestration also includes treating an associated infectious
cause.
A major concern following a first episode is preventing
the risk of recurrence. Parental education about the importance of fever, spleen palpation, acute pallor and referral to
hospital is pivotal.
Management of recurrent acute splenic sequestration
Possible strategies to manage recurrent episodes include
watchful waiting, chronic transfusion and splenectomy. Indications are neither clearly defined nor evidence-based and
should be individualized. Factors influencing the decision
process include age, severity of episode, and medical and
parental environment. A recent updated Cochrane review
found no evidence in favour of splenectomy versus conservative management to improve survival and decrease morbidity
from acute splenic sequestration, calling for randomized
studies in order to define the best strategy (Owusu-Ofori &
Hirst, 2013). An algorithm is proposed in Fig 5.
Prophylactic transfusion programmes may be started following the first episode or the first recurrence of acute splenic sequestration. The rationale is to allow permanent
elevation of the haemoglobin level above the basal in order
8
to prevent life-threatening anaemia in case of recurrence,
rather than decreasing the HbS fraction, as the latter has not
proven to decrease the risk of acute sequestration (Kinney
et al, 1990). In addition, transfusion may temper the inflammatory status in SCD and prolong the spleen’s immune
function. On the other hand, it may prolong the spleen’s
potential for sequestration by delaying autosplenectomy, and
lead to transfusion-related complications, such as iron overload, alloimmunization and bacterial and viral infections.
Splenectomy in SCA
Given that the natural history of the spleen in SCA leads to
autosplenectomy, no surgical procedure is required in the vast
majority of cases. The question of splenectomy arises when
strong evidence of sustained hypersplenism is present or lifethreatening episodes of acute splenic sequestration occur. The
underlying question regarding splenectomy is to what degree
the surgical removal of the spleen will further increase the
infectious risk, and therefore at what age the operation should
be performed. There is no clear answer to this question. In a
study of the post-splenectomy course of 53 children younger
than 4 years (of which 60% were <2 years) (Lesher et al, 2009)
a low risk of post-splenectomy sepsis was reported with 3
(57%) positive blood cultures and one documented pneumococcal sepsis, in 353 post-splenectomy admissions over a mean
post-operative follow-up period of 56 years. Similarly, febrile
events, bacteraemic episodes and mortality were not different
between a cohort of 130 splenectomized SCA children and a
control group matched for sex, age and duration of follow up
(Wright et al, 1999).
Another question raised by this comparative study, however,
was the significantly higher incidence of vaso-occlusive pain
and acute chest syndrome in the splenectomized group. This
increased prevalence was not explained by known determinants
of bone pain or chest syndrome, such as high haemoglobin or
low HbF, raising the hypothesis that splenic complications,
such as acute splenic sequestration, may be a predictive factor
of disease severity. A higher incidence of severe complications
in the pre- versus post-splenectomy period was also reported
(Kalpatthi et al, 2010) in 58 children splenectomized at a median age of 2 years. However, considering the young age of these
patients, a serious bias may well be the expected increasing
incidence of these complications with age.
Laparoscopic splenectomy has become the procedure of
choice for most children requiring splenectomy (Rescorla
et al, 2007).
Partial splenectomy has also been proposed as an alternative treatment in very young children, because of the possibility that leaving a splenic remnant might preserve immune
function. A retrospective web-based registry study comparing
partial and total splenectomy in 26 children found similar
laboratory and clinical haematological outcomes. No children
had recurrent splenic sequestration during a 52-week followup. One fatal event with overwhelming sepsis has nevertheª 2014 John Wiley & Sons Ltd, British Journal of Haematology
Review
less been reported following partial splenectomy (Svarch
et al, 1999).
Following splenectomy, leucocytosis and thrombocytosis
are common findings and generally return to expected basal
levels within a year. Whether this finding further contributes
to vascular complications remains to be determined.
Altogether, there is no consensual answer as to the safest
age at which splenectomy, if required, should be performed.
This needs to be considered at an individual level, balancing
relative risks and benefits by taking into account the indication, the medical environment, parental wishes and reliability, and the risks related to alternative treatment, such as
chronic transfusions. An algorithm is proposed in Fig 5.
Spleen dysfunction in HbSC disease
Splenic dysfunction in HbSC disease is poorly characterized.
It is generally believed that functional hyposplenism also
occurs in the SC genotype, albeit later and to a lesser extent
than in SCA. The majority of HbSC patients have normal
splenic function assessed by PIT counts before 5 years and
many maintain normal splenic function until the second decade of life (Pearson et al, 1985). In another study analysing
PIT counts in 201 SC subjects aged 6 months to 90 years, no
splenic dysfunction was found in children below 4 years of
age. Functional asplenia was demonstrated in 42% of patients
over 12 years of age (Lane et al, 1995).
The prevalence of splenomegaly by palpation or imaging
has been reported in up to 50–60% of adult patients with
HbSC disease. In a cohort of paediatric patients with HbSC,
palpable splenomegaly was found in 34 of 100 children over
2 years of age (mean age 110 54 years; range22–
238 years) (Zimmerman & Ware, 2000).
Acute splenic sequestration may also occur in HbSC
patients but its prevalence is much lower than in SCA and
generally later in life, possibly as late as the eighth decade
(Koduri & Nathan, 2006). In a study of 271 patients with
HbSC disease, 5% experienced acute splenic sequestration
with the initial event occurring at a mean age of 89 years
(range, 2–17 years). Of note, in two cases, this complication was life threatening, with a drop in the haemoglobin
value to <20 g/l. In almost half the 13 cases (46%),
splenomegaly was noted before the initial event. (Aquino
et al, 1997). Overall, among the 271 patients, 3% underwent splenectomy. Most treatment recommendations concerning spleen dysfunction in HbSC patients have been
extended from studies in SCA without an evidencebased rationale, and antibiotic prophylaxis and vaccination
recommendations are the same. As acute splenic sequestration occurs later in life, splenectomy can usually be under-
Fig 5. Suggested algorithm for the management of acute splenic sequestration.
ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
9
Review
taken without worrying about potential risks in young
children.
Conclusion
Spleen pathophysiology has been somewhat neglected in SCA,
probably because clinical manifestations are predominantly
paediatric and much effort has concentrated on treating the
consequences of spleen dysfunction rather than causes. However, because of its central function in red cell homeostasis, the
spleen is an important site of SCA pathophysiology. In addition, its role in vascular homeostasis is being progressively
unravelled. Early loss of spleen function may be both an indicator of disease severity and furthermore modulate phenotypic
expression. The spleen may thus gain renewed interest in the
future at the molecular, cellular and systemic level.
Acknowledgement
We wish to thank Dr Chantal Brouzes (Haematology Department, H^
opital Universitaire Necker Enfants Malades) for
providing Fig 1.
the paper. Pierre Buffet helped plan and wrote part of the
article, reviewed and edited the final version. David Rees
helped plan and wrote part of the article, reviewed and edited the final version.
Competing interests
Valentine Brousse has received funding from Novartis for
travel to meetings but does not act on behalf of any particular group or lobby. Pierre Buffet provided expertise and collaborates with Fast-track West Potomac that contributes to
the filing of intravenous artesunate for severe malaria in the
United States (Sigma-Tau Laboratories), is engaged in a collaboration with Guillin Laboratories, and has provided expertise to Sigma Tau and Sanofi Laboratories (antiparasitic
drugs). David Rees is a consultant for Eli Lilly for a trial of
prasugrelin in SCD, and also Principal Investigator (PI) for
this study in the UK. He is also PI for a study of Prevenar in
SCD, funded by Pfizer. He has received funding from Novartis for travel to meetings, and has an unrestricted educational
grant for £2500. He is an expert witness in 1–2 medico legal
cases per year but does not act on behalf of any particular
group or lobby.
Contributorship statement and guarantor
Valentine Brousse planned and wrote part of the article,
reviewed and edited the final version and is the guarantor of
References
Airede, A.I. (1992) Acute splenic sequestration in a
five-week-old infant with sickle cell disease.
Journal of Pediatrics, 120, 160.
Alkindi, S., Al-Maini, M. & Pathare, A. (2012)
Clinical and laboratory characteristics of patients
with sickle-cell and autoimmune/connective tissue diseases. Rheumatology International, 32,
373–378.
Al-Salem, A.H., Al-Aithan, S., Bhamidipati, P., AlJam’a, A. & Al Dabbous, I. (1998) Sonographic
assessment of spleen size in Saudi patients with
sickle cell disease. Annals of Saudi Medicine, 18,
217–220.
Ammann, A.J., Addiego, J., Wara, D.W., Lubin, B.,
Smith, W.B. & Mentzer, W.C. (1977) Polyvalent
pneumococcal-polysaccharide immunization of
patients with sickle-cell anemia and patients
with splenectomy. New England Journal of Medicine, 297, 897–900.
Aneni, E.C., Hamer, D.H. & Gill, C.J. (2013) Systematic review of current and emerging strategies for reducing morbidity from malaria in
sickle cell disease. Tropical Medicine & International Health, 18, 313–327.
Aquino, V.M., Norvell, J.M. & Buchanan, G.R.
(1997) Acute splenic complications in children
with sickle cell-hemoglobin C disease. Journal of
Pediatrics, 130, 961–965.
10
Baethge, B.A., Bordelon, T.R., Mills, G.M., Bowen,
L.M., Wolf, R.E. & Bairnsfather, L. (1990) Antinuclear antibodies in sickle cell disease. Acta
Haematologica, 84, 186–189.
Barrett-Connor, E. (1971) Bacterial infection and
sickle cell anemia. An analysis of 250 infections
in 166 patients and a review of the literature.
Medicine, 50, 97–112.
Barrios, N.J., Livaudais, F., McNeil, J., Humbert,
J.R. & Corrigan, J. (1993) Reversible splenic
hypofunction in hypertransfused children with
homozygous sickle cell disease. Journal of the
National Medical Association, 85, 677–680.
Baudelaire, C. (1869) Le Spleen de Paris. Michel
Levy, Paris.
Brousse, V., Elie, C., Benkerrou, M., Odievre,
M.H., Lesprit, E., Bernaudin, F., Grimaud, M.,
Guitton, C., Quinet, B., Dangiolo, S. & de Montalembert, M. (2012) Acute splenic sequestration
crisis: cohort of 190 paediatric patients. British
Journal of Haematology, 156, 643–648.
Brown, A.K., Sleeper, L.A., Miller, S.T., Pegelow,
C.H., Gill, F.M. & Waclawiw, M.A. (1994) Reference values and hematologic changes from
birth to 5 years in patients with sickle cell disease. Cooperative Study of Sickle Cell Disease.
Archives of Pediatrics and Adolescent Medicine,
148, 796–804.
Buffet, P.A., Milon, G., Brousse, V., Correas, J.M.,
Dousset, B., Couvelard, A., Kianmanesh, R., Far-
ges, O., Sauvanet, A., Paye, F., Ungeheuer,
M.N., Ottone, C., Khun, H., Fiette, L., Guigon,
G., Huerre, M., Mercereau-Puijalon, O. &
David, P.H. (2006) Ex vivo perfusion of human
spleens maintains clearing and processing functions. Blood, 107, 3745–3752.
Cameron, P.U., Jones, P., Gorniak, M., Dunster,
K., Paul, E., Lewin, S., Woolley, I. & Spelman,
D. (2011) Splenectomy associated changes in
IgM memory B cells in an adult spleen registry
cohort. PLoS One, 6, e23164.
Campbell, P.J., Olatunji, P.O., Ryan, K.E. &
Davies, S.C. (1997) Splenic regrowth in sickle
cell anaemia following hypertransfusion. British
Journal of Haematology, 96, 77–79.
Chen, L.T. & Weiss, L. (1972) Electron microscopy
of the red pulp of human spleen. The American
Journal of Anatomy, 134, 425–457.
Crary, S.E. & Buchanan, G.R. (2009) Vascular
complications after splenectomy for hematologic
disorders. Blood, 114, 2861–2868.
Deplaine, G., Safeukui, I., Jeddi, F., Lacoste, F.,
Brousse, V., Perrot, S., Biligui, S., Guillotte, M.,
Guitton, C., Dokmak, S., Aussilhou, B., Sauvanet, A., Cazals Hatem, D., Paye, F., Thellier, M.,
Mazier, D., Milon, G., Mohandas, N., Mercereau-Puijalon, O., David, P.H. & Buffet, P.A.
(2011) The sensing of poorly deformable red
blood cells by the human spleen can be
mimicked in vitro. Blood, 117, e88–e95.
ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
Review
Di Sabatino, A., Carsetti, R. & Corazza, G.R.
(2011) Post-splenectomy and hyposplenic states.
Lancet, 378, 86–97.
Diggs, L.W. (1935) Siderofibrosis of the spleen in
sickle cell anemia. JAMA, 104, 538–541.
Donald, D.E. & Aarhus, L.L. (1974) Active and
passive release of blood from canine spleen and
small intestine. American Journal of Physiology,
227, 1166–1172.
El Nemer, W., Gane, P., Colin, Y., Bony, V., Rahuel, C., Galacteros, F., Cartron, J.P. & Le Van
Kim, C. (1998) The Lutheran blood group
glycoproteins, the erythroid receptors for laminin, are adhesion molecules. Journal of Biological
Chemistry, 273, 16686–16693.
Emond, A.M., Collis, R., Darvill, D., Higgs, D.R.,
Maude, G.H. & Serjeant, G.R. (1985) Acute
splenic sequestration in homozygous sickle cell
disease: natural history and management. Journal of Pediatrics, 107, 201–206.
Ferster, A., Bujan, W., Corazza, F., Devalck, C.,
Fondu, P., Toppet, M., Verhas, M. & Sariban, E.
(1993) Bone marrow transplantation corrects
the splenic reticuloendothelial dysfunction in
sickle cell anemia. Blood, 81, 1102–1105.
Fontana, V., Jy, W., Ahn, E.R., Dudkiewicz, P.,
Horstman, L.L., Duncan, R. & Ahn, Y.S. (2008)
Increased procoagulant cell-derived microparticles (C-MP) in splenectomized patients with
ITP. Thrombosis Research, 122, 599–603.
Gaston, M.H., Verter, J.I., Woods, G., Pegelow, C.,
Kelleher, J., Presbury, G., Zarkowsky, H., Vichinsky, E., Iyer, R., Lobel, J.S., Diamond, S.,
Holbrook, C.T., Gill, F.M., Richey, K., Faletta,
J.M., & for the Prophylactic Penicillin Study
Group. (1986) Prophylaxis with oral penicillin
in children with sickle cell anemia. A randomized trial. New England Journal of Medicine, 314,
1593–1599.
Gladwin, M.T., Sachdev, V., Jison, M.L., Shizukuda, Y., Plehn, J.F., Minter, K., Brown, B., Coles,
W.A., Nichols, J.S., Ernst, I., Hunter, L.A.,
Blackwelder, W.C., Schechter, A.N., Rodgers,
G.P., Castro, O. & Ognibene, F.P. (2004) Pulmonary hypertension as a risk factor for death
in patients with sickle cell disease. New England
Journal of Medicine, 350, 886–895.
Gotthardt, M., Broker, S., Schlieck, A., Bauhofer,
A., Herbst, B., Behe, M., Corstens, F.H., Behr,
T.M. & Gorg, C. (2007) Scintigraphy with
99mTc-labeled heat-altered erythrocytes in diagnosing hyposplenia: prospective comparison to
99mTc-labeled colloids and colour-coded duplex
ultrasonography. Nuklearmedizin, 46, 135–140.
den Haan, J.M. & Kraal, G. (2012) Innate
immune functions of macrophage subpopulations in the spleen. Journal of Innate Immunity,
4, 437–445.
Harrod, V.L., Howard, T.A., Zimmerman, S.A.,
Dertinger, S.D. & Ware, R.E. (2007) Quantitative analysis of Howell-Jolly bodies in children
with sickle cell disease. Experimental Hematology,
35, 179–183.
Higgs, D.R., Aldridge, B.E., Lamb, J., Clegg, J.B.,
Weatherall, D.J., Hayes, R.J., Grandison, Y.,
Lowrie, Y., Mason, K.P., Serjeant, B.E. & Serjeant, G.R. (1982) The interaction of alpha-thalassemia and homozygous sickle-cell disease. New
England Journal of Medicine, 306, 1441–1446.
Hirst, C. & Owusu-Ofori, S. (2012) Prophylactic
antibiotics for preventing pneumococcal infection in children with sickle cell disease. Cochrane
Database Systematic Review, 9, CD003427.
Holroyde, C.P., Oski, F.A. & Gardner, F.H. (1969)
The “pocked” erythrocyte. Red-cell surface alterations in reticuloendothelial immaturity of the
neonate. New England Journal of Medicine, 281,
516–520.
Imbert, P., Rapp, C. & Buffet, P.A. (2009) Pathological rupture of the spleen in malaria: analysis
of 55 cases (1958–2008). Travel Medicine and
Infectious Disease, 7, 147–159.
Kalpatthi, R., Kane, I.D., Shatat, I.F., Rackoff, B.,
Disco, D. & Jackson, S.M. (2010) Clinical events
after surgical splenectomy in children with sickle
cell anemia. Pediatric Surgery International, 26,
495–500.
Kato, G.J., Hebbel, R.P., Steinberg, M.H. & Gladwin, M.T. (2009) Vasculopathy in sickle cell
disease: biology, pathophysiology, genetics,
translational medicine, and new research directions. American Journal of Hematology, 84, 618–
625.
Kinney, T.R., Ware, R.E., Schultz, W.H. & Filston,
H.C. (1990) Long-term management of splenic
sequestration in children with sickle cell disease.
Journal of Pediatrics, 117, 194–199.
Koduri, P.R. & Nathan, S. (2006) Acute splenic
sequestration crisis in adults with hemoglobin
S-C disease: a report of nine cases. Annals of
Hematology, 85, 239–243.
Komba, A.N., Makani, J., Sadarangani, M., AjalaAgbo, T., Berkley, J.A., Newton, C.R., Marsh, K.
& Williams, T.N. (2009) Malaria as a cause of
morbidity and mortality in children with homozygous sickle cell disease on the coast of Kenya.
Clinical Infectious Diseases, 49, 216–222.
Lane, P.A., O’Connell, J.L., Lear, J.L., Rogers, Z.R.,
Woods, G.M., Hassell, K.L., Wethers, D.L., Luckey, D.W. & Buchanan, G.R. (1995) Functional
asplenia in hemoglobin SC disease. Blood, 85,
2238–2244.
Lee, A., Thomas, P., Cupidore, L., Serjeant, B. &
Serjeant, G. (1995) Improved survival in homozygous sickle cell disease: lessons from a cohort
study. BMJ, 311, 1600–1602.
Lesher, A.P., Kalpatthi, R., Glenn, J.B., Jackson,
S.M. & Hebra, A. (2009) Outcome of splenectomy in children younger than 4 years with
sickle cell disease. Journal of Pediatric Surgery,
44, 1134–1138; discussion 1138.
Makani, J., Komba, A.N., Cox, S.E., Oruo, J.,
Mwamtemi, K., Kitundu, J., Magesa, P., Rwezaula, S., Meda, E., Mgaya, J., Pallangyo, K., Okiro, E., Muturi, D., Newton, C.R., Fegan, G.,
Marsh, K. & Williams, T.N. (2010) Malaria in
patients with sickle cell anemia: burden, risk
factors, and outcome at the outpatient clinic
and during hospitalization. Blood, 115,
215–220.
ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
McAuley, C.F., Webb, C., Makani, J., Macharia,
A., Uyoga, S., Opi, D.H., Ndila, C., Ngatia, A.,
Scott, J.A., Marsh, K. & Williams, T.N. (2010)
High mortality from Plasmodium falciparum
malaria in children living with sickle cell anemia
on the coast of Kenya. Blood, 116, 1663–1668.
McCarville, M.B., Luo, Z., Huang, X., Rees, R.C.,
Rogers, Z.R., Miller, S.T., Thompson, B., Kalpatthi, R. & Wang, W.C. (2011) Abdominal ultrasound with scintigraphic and clinical correlates
in infants with sickle cell anemia: baseline data
from the BABY HUG trial. AJR. American Journal of Roentgenology, 196, 1399–1404.
McCavit, T.L., Quinn, C.T., Techasaensiri, C. &
Rogers, Z.R. (2011) Increase in invasive Streptococcus pneumoniae infections in children with
sickle cell disease since pneumococcal conjugate
vaccine licensure. Journal of Pediatrics, 158, 505–
507.
Naik, R.P., Streiff, M.B., Haywood, Jr, C., Nelson,
J.A. & Lanzkron, S. (2013) Venous thromboembolism in adults with sickle cell disease: a serious
and
under-recognized
complication.
American Journal of Medicine, 126, 443–449.
Ohene-Frempong, K., Weiner, S.J., Sleeper, L.A.,
Miller, S.T., Embury, S., Moohr, J.W., Wethers,
D.L., Pegelow, C.H. & Gill, F.M. (1998) Cerebrovascular accidents in sickle cell disease: rates
and risk factors. Blood, 91, 288–294.
Owusu-Ofori, S. & Hirst, C. (2013) Splenectomy
versus conservative management for acute
sequestration crises in people with sickle cell
disease. Cochrane Database Systematic Review, 5,
CD003425.
Parent, F., Bachir, D., Inamo, J., Lionnet, F., Driss,
F., Loko, G., Habibi, A., Bennani, S., Savale, L.,
Adnot, S., Maitre, B., Yaici, A., Hajji, L.,
O’Callaghan, D.S., Clerson, P., Girot, R., Galacteros, F. & Simonneau, G. (2011) A hemodynamic study of pulmonary hypertension in sickle cell
disease. New England Journal of Medicine, 365,
44–53.
Payne, A.B., Link-Gelles, R., Azonobi, I., Hooper,
W.C., Beall, B.W., Jorgensen, J.H., Juni, B. &
Moore, M. (2013) Invasive pneumococcal disease among children with and without sickle cell
disease in the United States, 1998–2009. The
Pediatric Infectious Disease Journal, 32, 1308–
1312.
Pearson, H.A., Spencer, R.P. & Cornelius, E.A.
(1969) Functional asplenia in sickle-cell anemia.
New England Journal of Medicine, 281, 923–926.
Pearson, H.A., Cornelius, E.A., Schwartz, A.D.,
Zelson, J.H., Wolfson, S.L. & Spencer, R.P.
(1970) Transfusion-reversible functional asplenia
in young children with sickle-cell anemia. New
England Journal of Medicine, 283, 334–337.
Pearson, H.A., Gallagher, D., Chilcote, R., Sullivan,
E., Wilimas, J., Espeland, M. & Ritchey, A.K.
(1985) Developmental pattern of splenic dysfunction in sickle cell disorders. Pediatrics, 76,
392–397.
Piccin, A., Rizkalla, H., Smith, O., McMahon, C.,
Furlan, C., Murphy, C., Negri, G. & Mc Dermott, M. (2012) Composition and significance
11
Review
of splenic Gamna-Gandy bodies in sickle cell
anemia. Human Pathology, 43, 1028–1036.
van der Plas, E.M., van den Tweel, X.W., Geskus,
R.B., Heijboer, H., Biemond, B.J., Peters, M. &
Fijnvandraat, K. (2011) Mortality and causes of
death in children with sickle cell disease in the
Netherlands, before the introduction of neonatal
screening. British Journal of Haematology, 155,
106–110.
Powell, R.W., Levine, G.L., Yang, Y.M. & Mankad,
V.N. (1992) Acute splenic sequestration crisis in
sickle cell disease: early detection and treatment.
Journal of Pediatric Surgery, 27, 215–218; discussion 218-219.
Quinn, C.T., Rogers, Z.R., McCavit, T.L. & Buchanan, G.R. (2010) Improved survival of children
and adolescents with sickle cell disease. Blood,
115, 3447–3452.
Ram, S., Lewis, L.A. & Rice, P.A. (2010) Infections
of people with complement deficiencies and
patients who have undergone splenectomy. Clinical Microbiology Reviews, 23, 740–780.
Rescorla, F.J., West, K.W., Engum, S.A. & Grosfeld, J.L. (2007) Laparoscopic splenic procedures
in children: experience in 231 children. Annals
of Surgery, 246, 683–687; discussion 687–688.
Rice, T.W., Rubinson, L., Uyeki, T.M., Vaughn,
F.L., John, B.B., Miller, 3rd, R.R., Higgs, E.,
Randolph, A.G., Smoot, B.E. & Thompson, B.T.
(2012) Critical illness from 2009 pandemic
influenza A virus and bacterial coinfection in
the United States. Critical Care Medicine, 40,
1487–1498.
Rogers, Z.R., Wang, W.C., Luo, Z., Iyer, R.V., Shalaby-Rana, E., Dertinger, S.D., Shulkin, B.L.,
Miller, J.H., Files, B., Lane, P.A., Thompson,
B.W., Miller, S.T. & Ware, R.E. (2011) Biomarkers of splenic function in infants with sickle
cell anemia: baseline data from the BABY HUG
Trial. Blood, 117, 2614–2617.
Rosado, M.M., Gesualdo, F., Marcellini, V., Di
Sabatino, A., Corazza, G.R., Smacchia, M.P.,
Nobili, B., Baronci, C., Russo, L., Rossi, F., Vito,
R.D., Nicolosi, L., Inserra, A., Locatelli, F., Tozzi, A.E. & Carsetti, R. (2013) Preserved antibody levels and loss of memory B cells against
12
pneumococcus and tetanus after splenectomy:
tailoring better vaccination strategies. European
Journal of Immunology, 43, 2659–2670.
Sadarangani, M., Makani, J., Komba, A.N., AjalaAgbo, T., Newton, C.R., Marsh, K. & Williams,
T.N. (2009) An observational study of children
with sickle cell disease in Kilifi, Kenya. British
Journal of Haematology, 146, 675–682.
Safeukui, I., Correas, J.M., Brousse, V., Hirt, D.,
Deplaine, G., Mule, S., Lesurtel, M., Goasguen,
N., Sauvanet, A., Couvelard, A., Kerneis, S.,
Khun, H., Vigan-Womas, I., Ottone, C., Molina,
T.J., Treluyer, J.M., Mercereau-Puijalon, O., Milon, G., David, P.H. & Buffet, P.A. (2008)
Retention of Plasmodium falciparum ringinfected erythrocytes in the slow, open microcirculation of the human spleen. Blood, 112, 2520–
2528.
Serjeant, G.R. (2001) The spleen in sickle cell disease. In: The Complete Spleen: A Handbook of
Structure, Function, and Clinical Disorders (ed.
by A.J. Bowdler), pp. 251–257. Humana Press,
Totowa, NJ.
Stein, P.D., Beemath, A., Meyers, F.A., Skaf, E. &
Olson, R.E. (2006) Deep venous thrombosis and
pulmonary embolism in hospitalized patients
with sickle cell disease. American Journal of
Medicine, 119, 897, e7–11.
Svarch, E., Nordet, I. & Gonzalez, A. (1999)
Overwhelming septicaemia in a patient with
sickle cell/beta(0) thalassaemia and partial splenectomy. British Journal of Haematology, 104,
930.
Telfer, P., Coen, P., Chakravorty, S., Wilkey, O.,
Evans, J., Newell, H., Smalling, B., Amos, R.,
Stephens, A., Rogers, D. & Kirkham, F. (2007)
Clinical outcomes in children with sickle cell
disease living in England: a neonatal cohort in
East London. Haematologica, 92, 905–912.
Topley, J.M., Rogers, D.W., Stevens, M.C. & Serjeant, G.R. (1981) Acute splenic sequestration
and hypersplenism in the first five years in
homozygous sickle cell disease. Archives of
Disease in Childhood, 56, 765–769.
Wandersee, N.J., Punzalan, R.C., Rettig, M.P.,
Kennedy, M.D., Pajewski, N.M., Sabina, R.L.,
Paul Scott, J., Low, P.S. & Hillery, C.A. (2005)
Erythrocyte adhesion is modified by alterations
in cellular tonicity and volume. British Journal
of Haematology, 131, 366–377.
Wang, W.C., Wynn, L.W., Rogers, Z.R., Scott, J.P.,
Lane, P.A. & Ware, R.E. (2001) A two-year pilot
trial of hydroxyurea in very young children with
sickle-cell anemia. Journal of Pediatrics, 139,
790–796.
Wang, W.C., Ware, R.E., Miller, S.T., Iyer, R.V.,
Casella, J.F., Minniti, C.P., Rana, S., Thornburg,
C.D., Rogers, Z.R., Kalpatthi, R.V., Barredo,
J.C., Brown, R.C., Sarnaik, S.A., Howard, T.H.,
Wynn, L.W., Kutlar, A., Armstrong, F.D., Files,
B.A., Goldsmith, J.C., Waclawiw, M.A., Huang,
X. & Thompson, B.W. (2011) Hydroxycarbamide in very young children with sickle-cell
anaemia: a multicentre, randomised, controlled
trial (BABY HUG). Lancet, 377, 1663–1672.
Weller, S., Braun, M.C., Tan, B.K., Rosenwald, A.,
Cordier, C., Conley, M.E., Plebani, A., Kumararatne, D.S., Bonnet, D., Tournilhac, O.,
Tchernia, G., Steiniger, B., Staudt, L.M., Casanova, J.L., Reynaud, C.A. & Weill, J.C. (2004)
Human blood IgM “memory” B cells are circulating splenic marginal zone B cells harboring a
prediversified immunoglobulin repertoire. Blood,
104, 3647–3654.
WHO (2010) Guidelines for the treatment of
malaria, 2nd edn. World Health Organization,
Geneva.
William, B.M. & Corazza, G.R. (2007) Hyposplenism: a comprehensive review. Part I: basic
concepts and causes. Hematology, 12, 1–13.
Wright, J.G., Hambleton, I.R., Thomas, P.W.,
Duncan, N.D., Venugopal, S. & Serjeant, G.R.
(1999) Postsplenectomy course in homozygous
sickle cell disease. Journal of Pediatrics, 134,
304–309.
Zimmerman, S.A. & Ware, R.E. (2000) Palpable
splenomegaly in children with haemoglobin SC
disease: haematological and clinical manifestations. Clinical and Laboratory Haematology, 22,
145–150.
ª 2014 John Wiley & Sons Ltd, British Journal of Haematology