The spleen and sickle cell disease: the sick(led) spleen

Valentine Brousse,1,2,3 Pierre Buffet3,4,5 and David Rees6

1Department of Paediatrics, Reference Centre for Sickle Cell Disease, Hopital Universitaire Necker-Enfants Malades, APHP, 2Univer-

sit�e Paris Descartes, 3Laboratory of Excellence GR-Ex, 4Centre d’Immunologie et des Maladies Infectieuses de Paris, CIMI-PARIS, U

1135 INSERM/UPMC Universit�e Paris VI, 5Service de Parasitologie, AP-HP, Hopital Piti�e-Salpetri�ere, 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. Hyposple-

nism increases the susceptibility of SCA children to infection

with encapsulated bacteria, which is notably reduced by peni-

cillin prophylaxis and immunization. Whether hyposplenism

indirectly increases the risk of vaso-occlusion or other circu-

latory 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 microanat-

omy (Chen & Weiss, 1972), the spleen continues to remain

a mysterious organ, often considered as an unnecessary

reservoir. Progressive evidence is pointing, however, to the

role of the spleen as a major contributor to immune, vascu-

lar and blood homeostasis. Hyposplenism, therefore, is

increasingly recognized as a pathological condition with

potentially major consequences, such as vascular complica-

tions and immune dysfunction, in addition to the long iden-

tified susceptibility to encapsulated bacteria. In sickling

disorders, the spleen is prone to early injury and hyposple-

nism 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 blood-

borne antigens. It is a major filter of the blood, which initi-

ates and links innate and adaptive immune responses against

pathogens. The spleen is histologically divided in three func-

tional interconnected compartments: the white pulp, essen-

tially 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 trabecu-

lar arteries that branch throughout the parenchyma to a ter-

minating 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 paren-

chyma and discharge its blood content into the cords of the

red pulp. In this latter case, blood cells and blood-borne bac-

teria are in close and prolonged contact with specialized

macrophages and resident spleen cells. This interaction trig-

gers phagocytosis of pathogens or red blood cells (RBC)

Correspondence: Valentine Brousse, Department of Paediatrics,

Reference Centre for Sickle Cell Disease, Hopital Universitaire

Necker-Enfants Malades, APHP, 149 rue de Sevres, 75015 Paris,

France.

E-mail: valentine.brousse@nck.aphp.fr

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ª 2014 John Wiley & Sons Ltd, British Journal of Haematology doi:10.1111/bjh.12950

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 sys-

tem after squeezing through narrow (1–3-lm wide), inter-

endothelial slits in the wall of venous sinuses. At this ulti-

mate 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 circula-

tion. 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 veloc-

ity 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 special-

ized 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 acces-

sory 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 plasmo-

cytes, producing high affinity antibodies and participate

mainly in T cell-dependent immune responses upon re-infec-

tion 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 poly-

saccharide IgMs, which are essential to the phagocytosis of

otherwise poorly opsonised encapsulated bacteria, such as

Streptococcus pneumoniae, Nesseiria meningitidis and Haemo-

philus 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 erythro-

phagocytosis, scavenging blood-borne debris and recycling

iron (den Haan & Kraal, 2012).

The main clinical consequences of defective spleen func-

tion derive from the alteration of both the filtering and

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 evalua-

tion.

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 immuno-

logical 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 micros-

copy.

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2 ª 2014 John Wiley & Sons Ltd, British Journal of Haematology

sidered diagnostic of asplenia in SCA patients (Rogers et al,

2011). Similarly, PIT or pocked RBC observed with interfer-

ence 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 <1�2% in SCA patients with normal splenic

function vs. ≥4�5% in asplenic patients (Rogers et al, 2011).

Measurement of circulating IgM memory B cells after

splenectomy has also been evaluated as a biomarker of hy-

posplenism. 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 signifi-

cantly reduced. The decrease in IgM memory B cells follow-

ing 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 morphologi-

cal 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 with99mTc-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

to their rigidity, allows quantitative determination of the

spleen uptake and anatomy (Gotthardt et al, 2007).

Altogether, these investigational tools have limited applica-

tion in sickling disorders as hyposplenism is expected and

does not need to be demonstrated nor followed up. Measur-

ing spleen function may occasionally be useful when splenec-

tomy 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 anti-

biotic prophylaxis.

Spleen dysfunction in sickle cell anaemia (SCA):SS and S beta° genotypes

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 hyposple-

nism results from splenic atrophy (Di Sabatino et al, 2011),

SCA may combine, notably in infancy, functional hyposple-

nism and splenomegaly. At birth, the spleen in SCA is mor-

phologically 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 pre-

cise sequence of pathogenic events leading to splenic altera-

tions 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 deoxygen-

ation 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 phos-

phatidyl serine promoting direct clearance through phagocy-

tosis (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 iden-

Fig 2. Pitted cells on blood smear (black arrows) by differential con-

trast interference (Normarski optics), original magnification 91000.

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ª 2014 John Wiley & Sons Ltd, British Journal of Haematology 3

tified by Pearson et al (1969).The pathophysiology of func-

tional hyposplenism is hypothetical but two non-mutually

exclusive mechanisms have been proposed resulting from the

congestion of the red pulp: one is the haemodynamic diver-

sion 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 macro-

phages 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

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 seques-

tration 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 lead-

ing to an increased risk of infection and reduced pitting rates

(hyposplenism).

Clinical manifestations of splenic injury in SCA

In children with SCA, the spleen can either be clinically pal-

pable or not, functional or not, with no correlation between

size and function.

Splenomegaly

Moderate splenomegaly (1–2 cm below the left costal mar-

gin) with no haematological consequence is classically

described early in life before atrophy occurs. It is hypothe-

sized 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 7�5–18 months, was 105 ml vs. 18 ml in 18 height-

matched 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 (6�6%) patients had auto-

splenectomy 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 vol-

ume increased with age until about 40 years and then gradu-

ally 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, spleno-

megaly was present in 41 (33%) subjects at a median age of

6�3 years (Sadarangani et al, 2009).

Fig 4. Haematin-eosin-saffron stained spleen sample following sple-

nectomy 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.

Fig 3. Haematin-eosin-saffron stained spleen sample following sple-

nectomy in a 3-year-old child with sickle cell anaemia, showing con-

gestion and fibrosis of the red pulp. Original magnification 9100.

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4 ª 2014 John Wiley & Sons Ltd, British Journal of Haematology

Hypersplenism

Hypersplenism classically refers to splenomegaly and any

combination of anaemia, leucopenia and/or thrombocytope-

nia, with compensatory bone marrow hyperplasia for a sus-

tained period, and improvement after splenectomy. In SCA

patients, diagnosis is difficult because splenomegaly is fre-

quent, 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 seques-

tration. Excessive destruction of red cells in SCA children

with prolonged hypersplenism may lead to subsequent

growth impairment and bone marrow hyperplasia. Transfu-

sion 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 epi-

sodes may lead to hypovolaemic shock and death from car-

diovascular 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 lead-

ing to acute splenic sequestration is unknown. A precipitat-

ing event, such as fever or infection may trigger or amplify

red cell sickling in the splenic red pulp. Upon random accu-

mulation 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 exten-

sion 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 med-

ian age at first episode was 1�4 years (0�1–7) in a retrospec-

tive study of 190 cases (Brousse et al, 2012), with 75% of

first cases occurring before 2 years. Acute splenic sequestra-

tion 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

infection, vaso occlusive crisis. Whether these events are trig-

gering 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, 0�60; 95%confidence interval, 0�41–0�88; P = 0�025).

Since the implementation of neonatal SCA screening pro-

grammes 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 Decem-

ber 1981 (Lee et al, 1995). In countries where SCA is diag-

nosed at birth and comprehensive care is available, mortality

from acute splenic sequestration has now become very infre-

quent (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 phagocyto-

sis, 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 pro-

duce natural antibidodies against poorly-opsonized encapsu-

lated bacteria, such as Streptococcus pneumoniae, Nesseiria

meningitidis and Hib. This feature, which may be viewed as

physiological splenic immaturity, explains the early suscepti-

bility 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, con-

sequently, 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 dra-

matically increases the risk of life-threatening infections with

encapsulated bacteria. Before pneumococcal immunization

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ª 2014 John Wiley & Sons Ltd, British Journal of Haematology 5

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 unencap-

sulated, 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 associ-

ated 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 endo-

thelium. In SCA, which combines asplenia, chronic haemoly-

sis and sickling, the risk of vascular complications is,

therefore, expected to be greatly increased. Additional endo-

thelial dysfunction caused by the haemolysis-related nitric

oxide depletion (Kato et al, 2009) and the basal hypercoagu-

lable state further contribute to the pathogenesis of vascular

complications.

The specific contribution of hyposplenism to arterio-

thrombotic complication in SCA is difficult to assess: cere-

brovascular stroke is a major multifactorial complication in

SCA with an overall prevalence rate of 4�01% (Ohene-Frem-

pong 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 ret-

rospective 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 non-

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 investiga-

tional 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 pathol-

ogy and development of autoimmunity. Antinuclear antibody

positivity has been shown to be more common in SCD (Bae-

thge et al, 1990). Clinical manifestations of immune disor-

ders 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. Transfu-

sion 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; Bar-

rios et al, 1993; Campbell et al, 1997). Along the same lines,

HSCT in three SCA children aged 10–14 years, was associ-

ated with restoration of splenic filtering function as evi-

denced 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 random-

ized controlled trial of hydroxycarbamide versus placebo in

179 SCA infants (mean age at enrolment 13�6 months), hy-

droxycarbamide did not prevent the decline in splenic func-

tion as assessed by qualitative spleen scan uptake: 19 of 70

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6 ª 2014 John Wiley & Sons Ltd, British Journal of Haematology

patients presented decreased spleen function at exit in the

hydroxycarbamide group vs. 28 of 74 patients in the placebo

group, P = 0�21. Interestingly, episodes of splenic sequestra-

tion 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 consid-

ered as potential beneficial effects, notably in terms of infec-

tious protection. Hyposplenism, however, is not considered

an indication for such interventions.

Principles of management

Hyposplenism and infectious risk

The reduction of infectious risk, particularly to encapsulated

bacteria, is pivotal and based on antibiotic prophylaxis, vac-

cination 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 infec-

tion in SCA infants with an 84% reduction in pneumococcal

septicaemia (Gaston et al, 1986). Discontinuation of antibi-

otic prophylaxis is controversial and no evidence-based rec-

ommendation 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).

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.

SCA and Malaria

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 com-

plete, 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 (Ane-

ni et al, 2013). Antimalarial chemoprophylaxis is also indi-

cated 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 2, 3 and 4 months Routine vaccination for all children in many countries

13-valent pneumococcal

conjugated vaccine

2, 4 and 13 months Routine vaccination for all children in many countries

Meningitis C conjugated vaccine 3 and 13 months Routine vaccination for all children in many countries

23-valent polysaccharide

pneumococcal vaccine

2 years, repeated every 3–5 years, life-long

Meningococcal ACWY

conjugated vaccine

5 months

Influenza 1 year, repeated annually New vaccine produced each year

Hepatitis B 12, 13 and 18 months with booster

depending on antibody levels

If likely to travel to countries with endemic Hepatitis B, and

in regularly transfused cases

Hepatitis A 12, 13 and 18 months If significant liver disease, travel, or regular transfusions

Review

ª 2014 John Wiley & Sons Ltd, British Journal of Haematology 7

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 analy-

sed 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 sup-

portive transfusion programme can be initiated or splenec-

tomy 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 transfu-

sion 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 impor-

tance 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. Indi-

cations 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 conserva-

tive 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 fol-

lowing the first episode or the first recurrence of acute sple-

nic sequestration. The rationale is to allow permanent

elevation of the haemoglobin level above the basal in order

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 inflam-

matory 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 over-

load, 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 life-

threatening 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

(5�7%) positive blood cultures and one documented pneumo-

coccal sepsis, in 353 post-splenectomy admissions over a mean

post-operative follow-up period of 5�6 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 med-

ian 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 alterna-

tive treatment in very young children, because of the possi-

bility 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 follow-

up. One fatal event with overwhelming sepsis has neverthe-

Review

8 ª 2014 John Wiley & Sons Ltd, British Journal of Haematology

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 indica-

tion, the medical environment, parental wishes and reliabil-

ity, 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 dec-

ade 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 11�0 � 5�4 years; range2�2–23�8 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 8�9 years

(range, 2–17 years). Of note, in two cases, this complica-

tion 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% under-

went splenectomy. Most treatment recommendations con-

cerning spleen dysfunction in HbSC patients have been

extended from studies in SCA without an evidence-

based rationale, and antibiotic prophylaxis and vaccination

recommendations are the same. As acute splenic sequestra-

tion occurs later in life, splenectomy can usually be under-

Fig 5. Suggested algorithm for the manage-

ment of acute splenic sequestration.

Review

ª 2014 John Wiley & Sons Ltd, British Journal of Haematology 9

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. How-

ever, because of its central function in red cell homeostasis, the

spleen is an important site of SCA pathophysiology. In addi-

tion, its role in vascular homeostasis is being progressively

unravelled. Early loss of spleen function may be both an indi-

cator 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 Depart-

ment, Hopital Universitaire Necker Enfants Malades) for

providing Fig 1.

Contributorship statement and guarantor

Valentine Brousse planned and wrote part of the article,

reviewed and edited the final version and is the guarantor of

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 edi-

ted the final version.

Competing interests

Valentine Brousse has received funding from Novartis for

travel to meetings but does not act on behalf of any particu-

lar group or lobby. Pierre Buffet provided expertise and col-

laborates 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 col-

laboration with Guillin Laboratories, and has provided exper-

tise 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 Novar-

tis 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.

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