YBLRE-00467; No of Pages 14

Blood Reviews xxx (2017) xxx–xxx

Contents lists available at ScienceDirect

Blood Reviews

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

REVIEW

The role of splenectomy in autoimmune hematological disorders:

Outdated or still worth considering?
Judith Sys a, Drew Provan b, Alexander Schauwvlieghe c, Steven Vanderschueren d,1, Daan Dierickx e,⁎,1
a
KU Leuven – University of Leuven, Department of General Internal Medicine, University Hospitals Leuven, B-3000, Leuven, Belgium
b
Department of Hematology, Barts and The London School of Medicine and Dentistry, Whitechapel, London, UK
c
Department of Hematology, University Hospital Ghent, B-9000, Ghent, Belgium
d
KU Leuven – University of Leuven, Department of Microbiology and Immunology, Laboratory for Clinical Infectious and Inflammatory Disorders, University Hospitals Leuven, Department of Gen-
eral Internal Medicine, B-3000, Leuven, Belgium
e
KU Leuven – University of Leuven, Department of Oncology, Laboratory for Experimental Hematology, University Hospitals Leuven, Department of Hematology, B-3000, Leuven, Belgium

a r t i c l e i n f o a b s t r a c t

Available online xxxx We discuss the role of splenectomy in the autoimmune hematological disorders immune thrombocytopenia
Keywords: (ITP), autoimmune hemolytic anemia (AIHA) and thrombotic thrombocytopenic purpura (TTP). Management
Immune thrombocytopenia of these disorders has dramatically changed the past decade as increasing knowledge of the
Autoimmune hemolytic anemia immunopathogenesis has led to the introduction of new therapies. Until 10 years ago, splenectomy was the
Thrombotic thrombocytopenic purpura
established second-line treatment for ITP, considered when corticosteroids failed to induce a sustained response.
Splenectomy
Second-line treatment
Concurrently, novel treatments, including anti-CD20 antibodies (rituximab) and thrombopoietin receptor ago-
nists are increasingly used. This has led to uncertainty as to when splenectomy is advisable as the next step.
The lack of comparative studies of second-line treatment options further fuels this uncertainty. Splenectomy con-
tinues to provide the highest cure rate, but it is an invasive, irreversible treatment option with a downside of post-
operative complications and a largely unpredictable outcome. Careful selection of patients, widespread adoption of a
laparoscopic approach, perioperative thromboprophylaxis, and better approaches to prevent and mitigate sepsis
have however reduced morbidity and mortality. As in ITP, splenectomy is considered the standard second-line treat-
ment in warm AIHA as well, although its position is nowadays less robust as rituximab tends to reach approximately
the same success rate in second-line treatment. The role of splenectomy in TTP has never been clarified. Although
rituximab is forwarded as best second-line therapy in recent guidelines, there are some case series suggesting
that splenectomy is a safe and effective option in refractory or relapsing disease as well.
© 2017 Published by Elsevier Ltd.

1. Introduction increasingly viewed as the last resort. This is evidenced by a decrease

Immune thrombocytopenia (ITP), autoimmune hemolytic anemia
(AIHA) and thrombotic thrombocytopenic purpura (TTP) are well-
defined, predominantly immune-mediated conditions with significant
morbidity and mortality. Although first-line treatment induces a re-
sponse in a substantial proportion of patients, refractory disease and re-
lapse are frequently encountered. Splenectomy is a possible second-line
treatment in each of these diseases, but its role has changed dramatical-
ly the past years, with the introduction of new promising therapies. Be-
side new therapeutic options, also the fear of important postoperative
complications and the unpredictable response to splenectomy, have re-
sulted in physicians tending to avoid or defer splenectomy, which is
in the rate of splenectomy for ITP of 50–60% in older cohorts to 15–
25% in more recent studies [1,2]. Nevertheless, the evolution of new
therapies was accompanied by an evolution in the approach to splenec-
tomy as well, with the adoption of laparoscopy instead of open surgery
and new measures to reduce the thrombotic and infectious risk. We
highlight new insights regarding the pathogenesis of ITP, TTP and
AIHA, we explain novel treatment options and we investigate the pres-
ent position of splenectomy in each of the three disorders while focus-
ing on the durability of response. Finally, we discuss the current risks
and preventable measures that should be undertaken.
2. Immune thrombocytopenia

⁎ Corresponding author. 2.1. Definition, classification and epidemiology

E-mail addresses: judith.sys@student.kuleuven.be (J. Sys), a.b.provan@qmul.ac.uk
(D. Provan), alexander.schauwvlieghe@ugent.be (A. Schauwvlieghe),
steven.vanderschueren@uzleuven.be (S. Vanderschueren), daan.dierickx@uzleuven.be
Immune thrombocytopenia is an acquired autoimmune disorder
(D. Dierickx). characterized by a peripheral blood platelet count b100 × 109/l, without
1
Shared senior authorship. abnormalities in the erythroid and myeloid/lymphoid lineages [3]. ITP

http://dx.doi.org/10.1016/j.blre.2017.01.001
0268-960X/© 2017 Published by Elsevier Ltd.

Please cite this article as: Sys J, et al, The role of splenectomy in autoimmune hematological disorders: Outdated or still worth considering?, Blood
Rev (2017), http://dx.doi.org/10.1016/j.blre.2017.01.001
2 J. Sys et al. / Blood Reviews xxx (2017) xxx–xxx

may be found in the absence of any obvious initiating or underlying
cause and is then called primary ITP. If associated with other disorders,
including autoimmune conditions (e.g. antiphospholipid antibody syn-
drome), infections (e.g. hepatitis C virus, HIV, H. pylori) and certain
drugs, it is defined as secondary ITP. ITP can also be classified based on
disease duration by the following definitions: newly diagnosed (from di-
agnosis until 3 months), persistent (3–12 months duration), and chronic
(N12 months duration) [4]. The incidence of ITP in adults is estimated at
approximately 2.2–3.9 per 105 persons per year [5,6].
2.2. Immunopathogenesis of ITP
ITP is a complex immune process in which cellular and humoral im-
munity are involved in the destruction of platelets as well as impaired
platelet production. Several theories have emerged in the last decade
to explain this autoimmune process. The main mechanisms are summa-
rized in Fig. 1.
2.2.1. Role of B-cells
1. IgG autoantibodies against GP IIb/IIIa and Ib/IX
2. Elevated expression of BAFF and APRIL
3. Impaired regulatory B-cells
In 1951, Harrington and Hollingsworth demonstrated that the pas-
sive transfer of plasma from ITP patients induced a transient thrombo-
cytopenia in healthy recipients [7]. Further studies demonstrated the
presence of platelet-reactive antibodies (Abs), mainly of the IgG1 sub-
class. The most commonly identified antigenic targets of these IgG auto-
antibodies are platelet glycoproteins (GP) IIb/IIIa and Ib/IX, with a
number of ITP patients having antibodies directed to multiple platelet
antigens [8].
There is no straightforward explanation as to why patients develop
autoantibodies to several structurally unrelated platelet surface pro-
teins. It has been theorized that proteosomal degradation of antibody-
coated platelets in antigen presenting cells (APCs) may generate novel
immunogenic epitopes from normal platelet proteins, leading to epi-
tope spread. Alternative explanations, including somatic mutation of
autoantibodies and crossreactivity to unrecognized sharing of structural
motifs, have not been excluded [9].
Antibodies are only detectable in 40 to 50% of patients. This may be
explained because brisk clearance of some types of antibody-platelet
complexes may reduce circulating antibody titers to below the thresh-
old of detection. Also tightly bound antiplatelet Abs may be difficult to
dissociate for study. Secondly, there may be some undetected antigens,
such as minor or cryptic antigens on platelets or antigens that reside pri-
marily on megakaryocytes. Finally, there may simply be a subset of pa-
tients in which there are other mechanisms of platelet loss [10].

Fig. 1. Schematic representation of the pathophysiology of ITP. Platelets opsonized by autoantibodies are destroyed by macrophages in the spleen and peptide fragments expressed with
MHC class II stimulate helper T-cells, that in turn activate autoreactive B-cells. Impaired regulatory T-cells (Tregs) fail to suppress this vicious cycle. Regulatory B-cells (Bregs), which induce
the recruitment or differentiation of regulatory T-cells, are also impaired. Autoantibodies furthermore suppress megakaryocytopoiesis. Platelet autoantibodies may fix complement,
enhancing opsonization or facilitating direct platelet lysis. They can also cause platelet destruction via induction reactive oxygen species (ROS). Autoreactive cytotoxic T-cells may play
a role in the destruction of platelets and megakaryocytes. Finally, decreased levels of TPO (thromopoietin) impair an effective megakaryocytosis.
This figure is modified with permission from a figure originally published in International Journal of Hematology. Kashiwagi H, Tomiyama Y. Pathophysiology and management of primary
immune thrombocytopenia. Int J Hematol. 2013;98(1):24–33. The original publication is available at www.springerlink.com.

Please cite this article as: Sys J, et al, The role of splenectomy in autoimmune hematological disorders: Outdated or still worth considering?, Blood
Rev (2017), http://dx.doi.org/10.1016/j.blre.2017.01.001
 J. Sys et al. / Blood Reviews xxx (2017) xxx–xxx
Several features of the platelet-reactive autoantibodies indicate that
they arise as part of an antigen-driven clonal expansion. The destruction
of B-cell equilibrium in ITP could be partially mediated by the elevated
expression of B-cell activating factor (BAFF) and a proliferation inducing
ligand (APRIL), which has been shown to support the survival and dif-
ferentiation of B-cells [11,12].
In addition to the regulatory role undertaken by regulatory T-cells
(Tregs) in immune tolerance, there is recent evidence for a new subset
of peripheral immune regulatory cells, known as regulatory B-cells
(Bregs), associated with chronic ITP. Bregs promote peripheral toler-
ance by the production of IL-10, thereby inducing the recruitment
and/or differentiation of Tregs, and reducing the function of CD4+ T-
cells. It was recently suggested that non-splenectomized patients with
chronic ITP exhibit functionally impaired Bregs, concomitant with
lowered IL-10 levels in all B-cells [13]
2.2.2. Role of T-cells
1. Auto-reactive T-cells against cryptic GPIIB/IIIa epitopes
2. Increase of oligoclonal T-cells
3. Cytotoxic T-cells
4. Imbalanced Th1/Th2 ratio
5. Increase of Th17 cells and Th22 cells
6. Reduced regulatory T-cells
7. Altered gene expression of CD3+ T-lymphocytes
Recent evidence also links T-cells to the pathogenic process in ITP.
Platelet-reactive T-cells have been found in the blood of patients with
ITP, with the major target antigen being GPIIb/IIIa [14]. In these patients,
T-cells stimulate the synthesis of antibody after exposure to fragments
of GPIIb/IIIa, but not after exposure to native proteins [15]. Other studies
have shown an expansion of oligoclonal T-cells and the presence of cy-
totoxic T-cells with a direct lytic effect on autologous platelets and/or
megakaryocytes [16].
The emergence of anti-platelet autoantibodies and anti-platelet cy-
totoxic T-cells is a consequence of the loss of immunological tolerance
for self-antigens. As in the majority of autoimmune diseases, this is
caused by an imbalance in pro-inflammatory and anti-inflammatory
mechanisms [17]. For example, chronic ITP patients exhibit an imbal-
anced Th1/Th2 ratio (ratio between type 1 T helper and type 2 T helper
cells) favoring autoreactive B-cell development [18]. Furthermore, IL-17
produced by pro-inflammatory CD4+ T helper 17 cells is increased in
patients with ITP [19]. Likewise, Th22 cells - another newly identified
potent proinflammatory T-cell subset - were significantly elevated in
active ITP patients [20] and glucocorticoid therapy could downregulate
expression of Th22 as well as plasma IL-22 [21].
On the other hand, it has been shown that CD4+ CD25+ immunoreg-
ulatory T-cells (Tregs), which suppress cell-mediated and antibody-
mediated immune responses and protect a host against autoimmunity,
have an impaired suppressive activity when compared to healthy sub-
jects [22]. Also, CD3+ lymphocytes from patients with active ITP present
an altered expression of genes associated with apoptosis and are signif-
icantly more resistant to dexamethasone-induced suppression com-
pared to normal lymphocytes [16,23].
2.2.3. Mechanisms of accelerated platelet clearance
1. Destruction by macrophages in spleen via Fc receptors
2. Complement-mediated platelet lysis
3. Induction of reactive oxygen species
4. Clearance by CD8+ T-cell mediated cytotoxicity
Platelets opsonized by IgG antibodies are destroyed mainly by mac-
rophages in spleen via low-affinity Fc receptors. Functionally, there are
two different classes of Fc receptors: the activation and the inhibitory
receptors, which transmit their signals via immunoreceptor tyrosine-
Please cite this article as: Sys J, et al, The role of splenectomy in autoimmune hematological disorders: Outdated or still worth considering?, Blood
Rev (2017), http://dx.doi.org/10.1016/j.blre.2017.01.001
3
based activation motifs (ITAM) or inhibitory motifs (ITIM), respectively.
FcγRIIA and FcγRIIIA have ITAM domains and activate phagocytosis.
FcγRIIB contains an ITIM domain and inhibit phagocytosis and pro-
inflammatory cytokine release [24]. Evidence has accumulated to indi-
cate that FcγRIIA and FcγRIIIA are primarily responsible for removal of
opsonized platelets [25]. Shifting of the monocyte FcγR balance toward
the inhibitory FcγRIIB has been demonstrated in ITP patients who
responded to H. pylori eradication [26] or high-dose dexamethasone
treatment [27].
In addition to Fc-mediated phagocytosis, platelet autoantibodies
may fix complement, enhancing opsonization or facilitating direct
platelet lysis [10,28,29]. Moreover, Nardi et al. [30] showed that anti-
GPIIIa antibodies found in an HIV-associated ITP patient caused platelet
destruction via induction of reactive oxygen species (ROS) and that
these mechanisms may also contribute to primary ITP. Some patients
with ITP lack detectable anti-platelet antibodies, and platelet clearance
in these cases may result from CD8+ T-cell mediated cytotoxicity [16,
31].
2.2.4. Impaired platelet production
1. Antibodies against megakaryocytes
2. Lowered serum thrombopoietin (TPO) concentration
Because megakaryocytes express also GPIIb/IIIa and GPIb/IX on their
surfaces, these cells may also be affected by autoantibodies, leading to
impaired megakaryocytopoiesis and/or platelet production and release
from the bone marrow. Two in vitro studies using megakaryocyte cul-
ture systems from cord blood derived CD34+ cells showed that autoan-
tibodies against anti-GPIb/IX and GPIIb/IIIa in ITP patients reduce
megakaryocyte production and maturation [32,33].
Electron microscopy studies of bone marrow megakaryocytes from
patients with ITP have shown extensive cellular abnormalities (e.g. mi-
tochondrial swelling, distension of demarcation membranes and con-
densation of nuclear chromatin) in a significant percentage of all
stages of the ITP megakaryocyte. This para-apoptotic phenomenon sug-
gests that autoantibodies may initiate the cascade of programmed cell
death [34].
Thrombopoietin (TPO) is the major physiologic regulator of platelet
production. Serum TPO levels in patients with ITP were within the nor-
mal range or only slightly elevated in ITP patients compared with other
thrombocytopenic disorders such as aplastic anemia with TPO levels up
to 10 times higher [35,36]. Taken together with the moderately im-
paired platelet production in ITP, the finding of relatively low levels of
TPO paved the way for treatment with TPO receptor agonists.
2.3. Treatment
Treatment is generally confined to patients who are bleeding or are
perceived to be at significant risk of bleeding. Although a platelet count
of b30 × 109/l is often used as a surrogate marker, lower (10–20 × 109/l)
or higher (50 × 109/l) thresholds are pursued depending on the bleed-
ing risk of the patient, which needs to be weighed against the probable
benefits and the risk of treatment [37].
2.3.1. First-line treatment
2.3.1.1. Corticosteroids. Corticosteroids are the main first line therapy.
The mechanism by which steroids act is believed to be through their im-
munosuppressant effect on T-cells. Oral prednisone is usually given at
0.5 to 2 mg/kg/day in tapering doses until the platelet count increases
(which requires on average 1 to 6 weeks). An alternative is high dose
dexamethasone (HDD), 40 mg daily for 4 days per month for several cy-
cles. Approximately two-thirds of patients achieve a complete or partial
response with corticosteroids at these standard doses [3]. However,
4 J. Sys et al. / Blood Reviews xxx (2017) xxx–xxx
only 5% to 30% of patients have sustained remission, depending on age
and type of ITP (primary versus secondary), and further depending on
the criteria used to define a response, and the duration of follow-up
[38].
2.3.1.2. Intravenous immunoglobulin. Intravenous immunoglobulin
(IVIg) is recommended for patients who are unresponsive to corticoste-
roids and is often used in pregnancy. It is thought to act by blocking Fc
receptors in the reticulo-endothelial system [39]. Intravenous immuno-
globulin rapidly increases platelet counts in 65% to 80% of patients but
the effect is transient, lasting no longer than 3 to 4 weeks, and the
drug requires frequent administration [3].
2.3.2. Second-line treatment
Second-line treatment is defined as treatment of patients who are
unresponsive to, have intolerable adverse effects of, or relapse after
first-line therapy. As there have been no comparative trials of treatment
options in this setting, second-line treatment is challenging. Available
treatment modalities have quite different mechanisms of action. In
this review we will discuss the three main therapies used in second-
line treatment: splenectomy, rituximab and TPO receptor agonists,
with a focus on splenectomy. The choice among these three options
for second-line treatment of adults with ITP has been addressed in
two recent guidelines, the International Consensus Report (2010) [40]
and the American Society of Hematology Practice guideline (2011)
[41]. Table 1 compares the grade of recommendation of both guidelines
to the three main therapies used in second-line treatment. In Table 2 we
summarize their efficacy, advantages, side effects and contra-
indications.
2.3.2.1. Splenectomy. Splenectomy was the first effective treatment in ITP
and still has the highest curative potential now. By removing the spleen,
the clearance of autoantibody-coated platelets by Fcγ receptors
expressed on macrophages is impaired. Besides, splenectomy works
by impairing the interactions between T-cells and B-cells that are in-
volved in the synthesis of antibodies.
In the Consensus guideline, splenectomy was given a recommenda-
tion grade of C, the lowest level of recommendation and evidence. The
statement with this recommendation was to ‘wait at least 6 months
from diagnosis before performing splenectomy due to the chance of
spontaneous remission’. The ASH guideline gave a strong recommenda-
tion (Grade 1) for splenectomy as the treatment for patients who have
failed initial corticosteroid therapy supported by an intermediate level
of evidence (level B).
This discussion focuses mainly on primary ITP, as splenectomy has a
lesser role in secondary ITP.
2.3.2.1.1. Durability of complete responses. It is estimated that two-
thirds of patients achieve durable complete responses with splenecto-
my. A large systematic review of Kojouri et al. [42] that included case
Table 1
Second-line treatments for ITP: Recommendations of the International Consensus Report
(ICR) and the American Society of Hematology Practice Guideline [40,41].
Treatments Strength of recommendation
Consensus reporta ASH guidelinesb
Splenectomy C 1B
Rituximab B 2C
TPO receptor agonists A 2C
a In many institutions splenectomy is recommended if the patient still
For the ICR, the level of evidence and recommendations were linked together: A:
strong recommendation based on evidence from RCT's; B: intermediate recommendation
based on evidence from well-designed studies; C: weak recommendation based on expert
opinion and clinical experience.
2b
For the ASH Practice Guideline, the levels of evidence and recommendations were
assessed according to the GRADE system and were not linked: 1: strong recommendation;
2: weak recommendation; A: RCT or exceptionally strong observational studies; B: RCT
with important limitations or strong observational studies; C: RCT with serious flaws or
weaker observational study.
Please cite this article as: Sys J, et al, The role of splenectomy in autoimmune hematological disorders: Outdated or still worth considering?, Blood
Rev (2017), http://dx.doi.org/10.1016/j.blre.2017.01.001
series over 58 years and across 29 countries, found that 1731 (66%) of
2623 patients had a complete response (defined as a platelet count of
N100 × 109/l) and 1853 (88%) of 2116 had a complete or partial re-
sponse (defined as a platelet count of N 50 × 109/l) following splenecto-
my. Similar results were found in a smaller study of Vianelli et al., that
followed 402 splenectomized patients until 5 years after surgery, with
a complete response in 66% of patients and a complete or partial re-
sponse in 86% of patients [43].
The rate of relapse in Vianelli et al. was estimated 23% with a median
time to relapse of 8 months, whereas in Kojouri et al. relapses occurred
in a median 15% of patients, with a median follow-up of 33 months
(range 3–153 months). The relapse rate appeared to increase with dura-
tion of follow-up, but the correlation did not reach statistical signifi-
cance. Two case series with follow-up durations of N7 years (longer
than most case series that were reviewed) reported however a continu-
ing occurrence of relapses with long-term follow-up [44,45]. Therefore,
it is possible that publication of more case series with longer follow-up
will demonstrate a decreasing frequency of complete remissions over
time. We consider however that these results have been created by
adding several retrospective series and smaller cohorts, which brings
about a risk of publication bias.
2.3.2.1.2. Pre-operative factors to predict outcome. A lot of factors have
been studied to better predict the response of patients undergoing sple-
nectomy. The large review of Kojouri et al. reviewed all articles pub-
lished before 2004 in which data were presented to support the
conclusion that a variable did or did not predict a response to splenecto-
my [42]. Predictors that were studied include patient age, previous re-
sponse to corticosteroid and IVIg therapies, preoperative and
postoperative platelet count. In the review of Kojouri et al., none of
these factors was consistently found to be a statistically significant inde-
pendent predictor of a good response to splenectomy. Later studies
[46–49] also reported conflicting results.
An interesting method to demonstrate the site of platelet destruc-
tion is by radionuclide labeling. Indium-labeled autologous platelet
scanning (ILAPS) is a nuclear imaging modality in which autologous
platelets are reinfused into the patient after ex vivo labeling with
111
In. Subsequent scintigraphy demonstrates the site(s) of platelet se-
questration and clearance. It has been proposed that patients with pre-
dominantly splenic sequestration determined by ILAPS may be more
likely to respond to splenectomy than those exhibiting hepatic, mixed,
or diffuse patterns [50]. Kojouri et al. mentioned 6 studies showing a
correlation of predominant splenic sequestration with response, 8
other studies not reporting a correlation and one study that was not in-
terpretable. In a pooled analysis of six 111In sequestration studies from
1986 to 2010, of which 5 studies were not included in the review of
Kojouri et al., Cuker and Cines [51] found that patients with a predomi-
nantly splenic pattern of platelet sequestration demonstrated a higher
response rate (91.4%) following splenectomy than those with a hepatic,
diffuse, or mixed pattern (40.9%). All of these studies included patients
with different clinical characteristics, used different techniques and dif-
ferent definitions of response. It is clear that additional prospective
studies utilizing well-defined patient populations, definitions of re-
sponse and standardized methods for ILAPS are needed to confirm the
value of this procedure. The ASH guideline does not recommend the
routine use of ILAPS for predicting response to splenectomy in centers
without extensive experience with this modality (Grade 2C).
2.3.2.1.3. Timing of splenectomy. Chronic ITP in adults has a variable
and unpredictable course, with very wide inter-patient heterogeneity.
has severe steroid-dependent thrombocytopenia after a trial with ste-
roid or high-dose immunoglobulins after 6 weeks to 6 months from di-
agnosis [52], because remission is regarded as unlikely thereafter.
However, there is increasing evidence that remissions can occur up to
1 or 2 years after onset, suggesting that surgery may be deferred for
prolonged periods. For instance, Sailer et al. [53] found that in 114 pa-
tients with platelet counts b 20 × 109/l at diagnosis who were treated
 J. Sys et al. / Blood Reviews xxx (2017) xxx–xxx 5

Table 2
Comparison of the three main second-line treatment options for ITP in terms of efficacy, advantages, adverse effects and contra-indications.

Therapy Efficacy Advantages Adverse effects Contra-indications

Splenectomy - Short term response 80%
- Long term response 60–70% at
5–10 years
- Response hard to predict
Rituximab - Short term response 50–60%
- Long term response 20% at
3–5 years
TPO RAs - Platelet activation in 79–95%
- Sustained response in 70–90%
in long-treatment studies
- Maintenance treatment, but
recent evidence that it may
modify clinical course of ITP
Romiplostim
Eltrombopag
- Over 60 years of experience - 0.2% mortality and 10% post-- - Patients with comorbid
- Most effective treatment for ITP operative complications conditions that increase
(bleeding, infections, thrombo- the risk of complications
sis) - Relative: elderly patients
- Increased risk of infection with over 60–70 years
rare occurrence of OPSI - Patients with immunode-
- Increased risk for arterial or ve- ficiency and secondary ITP
nous thrombosis
- Increased risk for pulmonary
hypertension
- Non-surgical treatment - Infusion-related side effects - Active hepatitis B virus
- Extensive experience since first reported use (chills, fever, dyspnea) - Known clinical allergy in-
for ITP in 1999 - Neutropenia cluding past serum sick-
- Increased risk of infection and ness
viral reactivation - Pregnancy and lactation
- Hypogammaglobulinemia
- Serum sickness
- Increased risk of PML
- Non-surgical treatment - Bone marrow reticulin fibrosis - Pregnancy and lactation
- Daily oral agent (eltrombopag) or weekly (1.4%) - Relative: past history of
subcutaneous injection (romiplostim) with - Arterial and venous thrombosis venous or arterial
the potential for self-administration - Progression to AML if MDS thrombosis
- Rebound thrombocytopenia
- Upper respiratory infection
- Nasofaryngitis
- Fatigue
- Headache
- Elevated liver enzymes - Child-Pugh ≥ 5
- Nausea, vomiting
- Cataract

Abbreviations: OPSI (overwhelming post-splenectomy infection), PML (progressive multifocal leukoencephalopathy), AML (acute myeloid leukemia), MDS (myelodysplasia).

with first-line therapies (corticosteroids and/or IVIg), complete or par-
tial remission was most likely to occur within the first 6 months (28 pa-
tients and 15 patients respectively), but another 17 complete and 8
partial responses occurred between 6 months and 3 years. Thus, ap-
proximately 60% of patients eventually achieved remission, supporting
the argument for delaying definitive decisions as splenectomy.
2.3.2.2. Rituximab. Rituximab is a chimeric anti-CD20+ monoclonal anti-
body that targets B-cells responsible for antiplatelet antibody produc-
tion by Fc-mediated cell lysis. It also has an influence on the different
T-cell subsets (including elevation of Tregs and restoration of the Th1/
Th2 balance) and it may lead to macrophage Fc-receptor blockade
[54]. In the largest systematic review of published reports of rituximab
use in ITP, Arnold et al. [55] reported an overall response (platelet
count N50 × 109/l) in 62.5% of patients and a complete response (plate-
let count N 150 × 109/l) in 44% after four once-weekly intravenous infu-
sions of 375 mg/m2. The median duration of response was 10.5 months
(range 3–20). The complete response rate falls to approximately 20% by
2–5 years [56,57].
A recent multicenter, randomized, double masked, placebo-
controlled trial enrolled 112 corticosteroid unresponsive adult patients
with primary ITP. They were randomly assigned (1:1) to four weekly in-
fusions of 375 mg/m2 rituximab or placebo. Treatment failure was seen
in 32 (58%) of the 55 patients in the rituximab group and 37 (69%) of 54
patients in the placebo group. There was no reduction in long-term
treatment failure with rituximab, but results suggested apparently lon-
ger duration of response [58].
The ASH guideline gave a weak recommendation for rituximab
(Grade 2) supported by a weak level of evidence (level C), based on
the relatively poor durable response rate and the relatively high fre-
quency of adverse effects. The Consensus guideline gave a recommen-
dation grade of B for treatment with rituximab.
2.3.2.3. TPO receptor agonists. Because recent evidence suggests that sub-
optimal platelet production is an underlying cause of ITP, increasing
platelet production has become a potential treatment option. The TPO
receptor agonists now used are the TPO peptide mimetic romiplostim
(Nplate®) and the nonpeptide mimetic eltrombopag (Revolade® or
Promacta®).
Recent phase II and III trials confirmed the efficacy and safety of
these agents in splenectomized and non-splenectomized patients. In
patients with previously treated chronic ITP and platelets b 30 × 109/l,
a response (defined as a platelet count N 50 × 109/l at least once during
the study) was observed in 79 to 95% of patients during a follow-up pe-
riod of 6 months to 5 years [59–63]. In the 5-year study of Kuter et al.
[63], platelet response which happened in 95% of patients, was main-
tained over 92% of their time on study.
The expectation is that these responses are maintained while the
drugs are taken, but will drop to baseline levels when the drug is
stopped. However, published reports show that 25–30% of patients
may expect a sustained response tot the TRAs even after the drugs
have been stopped. The mechanism for this sustained response is not
clear. It is suggested that TRAs may have an effect on regulatory T-
cells [64].
The Consensus guideline gave a recommendation Grade of A for
treatment with TPO RAs for patients, either before or after splenectomy,
based on randomized clinical trials [61,62,65] evaluating romiplostim
and eltrombopag compared to placebo in patients with or without pre-
vious splenectomy. The ASH guideline distinguished between patients
who have not had a splenectomy and patients who relapse after a sple-
nectomy or in whom a splenectomy is contraindicated. The ASH guide-
line gave a weak recommendation (Grade 2) supported by a weak level
of evidence (level C) for patients who have not had a splenectomy. The
basis for the weak recommendation was infrequent sustained remis-
sions when treatment with TPO receptor agonists is discontinued and
the lack of long-term follow-up for adverse events. For patients who re-
lapse after a splenectomy or in whom a splenectomy is contraindicated,

Please cite this article as: Sys J, et al, The role of splenectomy in autoimmune hematological disorders: Outdated or still worth considering?, Blood
Rev (2017), http://dx.doi.org/10.1016/j.blre.2017.01.001
6 J. Sys et al. / Blood Reviews xxx (2017) xxx–xxx
TPO receptor agonists were given a strong recommendation (Grade
1) supported by an intermediate level of evidence (level B).
2.3.3. Suggested treatment algorithm for ITP
Fig. 2 presents a flowchart in which overall factors that direct physi-
cians toward a certain treatment option are presented.
3. Autoimmune hemolytic anemia
3.1. Definition and classification
Autoimmune hemolytic anemia (AIHA) is a group of diseases de-
fined by autoantibody mediated red blood cell (RBC) destruction with
inadequate compensation. It has an estimated incidence of 1–3 per
105 persons per year [66,67]
Classification divides AIHA into warm (wAIHA) or cold-reactive
(cAIHA) subtypes based on the optimal RBC-autoantibody reactivity
temperatures. Warm AIHA can be further classified into primary (idio-
pathic) and secondary in nature. The classification of all types of AIHA
and their prevalence is summarized in Table 3. We will confine our dis-
cussion to idiopathic wAIHA, being the only subtype in which splenec-
tomy is a possible treatment.
3.2. Immunopathogenesis of warm AIHA
The pathogenesis of AIHA is a complex process in which many fac-
tors play an essential role. Barros et al. [68] report 7 mechanisms,
Fig. 2. Evidence based treatment algorithm for ITP. *The size of the arrows reflect the current strength of evidence. Based on recent FDA and EMEA decisions, TPO RAs are considered second
line treatment in both adult and pediatric populations.
Please cite this article as: Sys J, et al, The role of splenectomy in autoimmune hematological disorders: Outdated or still worth considering?, Blood
Rev (2017), http://dx.doi.org/10.1016/j.blre.2017.01.001
which are listed and briefly explained underneath. They are derived
from both experimental animal models as well as from human studies.
1. Autoantibodies
2. Complement mediated clearance
3. Loss of self-tolerance
4. Functional abnormalities of B- and T-cells
5. Polyclonal lymphocyte activation
6. Th1/Th2 imbalance
7. Immunoregulatory T-cells
AIHA is mediated by immunoglobulins (most frequently IgG) direct-
ed against self-RBC antigens, with Rhesus (Rh) polypeptides as the
commonest target [69,70]. The mechanisms that have been proposed
to explain the cause of autoantigens are cross-reactivity or molecular
mimicry between environmental antigens and autoantigens [71–73].
Control of complement activation may be critical in erythrocytes to
resist spontaneous complement attack. This is done by membrane-
anchored proteins including complement receptor (CR1 or CD35),
decay-accelerating factor (DAF or CD55) and also CD59. Recent studies
in mice indicate that mouse RBCs deficient in CR1 or DAF are cleared
spontaneously by the alternative pathway of complement [74]. Like-
wise, a deficiency of CD59 expression has been reported in patients
with autoimmune cytopenias, including warm AIHA [75,76].
Another proposed mechanism is the loss of tolerance of
autoantigens. Normally, antigen-presenting cells (APCs) capture self-
antigens from other cells and present them to autoreactive T-cells to in-
duce T-cell tolerance by either deletion or anergy [77]. There are several
 J. Sys et al. / Blood Reviews xxx (2017) xxx–xxx
Table 3
Classification of autoimmune hemolytic anemia.
Subtype of AIHA (% of all AIHA cases)
I Warm reactive AIHA: optimal reactivity of autoantibodies at 37 °C (75%)
A. Primary or idiopathic (37.5%)
B. Secondary (37.5%)
i. Associated with various lymphoproliferative disorders (e.g. non-Hodgkin
lymphoma, chronic lymphatic leukemia)
ii. Associated with rheumatic disorders (e.g. systemic lupus erythematosus)
iii. Associated with non-lymphoid malignancies (e.g. ovarian cancer)
iv. Associated with chronic inflammatory disorders (e.g. ulcerative colitis)
v. Drug induced autoimmune hemolytic anemia
II Cold reactive AIHA: optimal reactivity of autoantibodies at b37 °C (17–25%)
A. Cold agglutinin mediated AIHA (CAS) (15%)
i. Primary cold agglutinin disease (CAD)
ii. Secondary cold agglutinin syndrome (CAS)
a. Post-infectious (e.g. mycoplasma or infectious mononucleosis)
b. Associated with aggressive lymphoma
B. Paroxysmal cold hemoglobinuria (Donath-Landsteiner syndrome)
(2–10%)
III Mixed type AIHA: presence of both warm and cold type antibodies (b5%)
A. Primary of idiopathic
B. Secondary: often associated with rheumatic disorders
IV Drug induced AIHA: associated with an estimated 150 drugs (1/106)
A. Drug dependent AIHA
i. Hapten or drug absorption
ii. Immune (ternary) complex
B. Drug independent AIHA
hypotheses to explain the lack of effective presentation of autoantigens.
One hypothesis is that the APCs remain relatively immature and there-
fore tolerate rather than activate self-reactive cells [77]. A second expla-
nation is that many self-epitopes may be inefficiently processed and
presented by APCs. This would result in minimal cross-presentation
and as a result, the self-reactive naïve T-cells would remain a part of
the peripheral T-cell repertoire by escaping thymic deletion [78].
In several murine models of AIHA, functional abnormalities of B- and
T-cells have been investigated, particularly their lymphocyte activation,
cytokine production and their role in the onset of their autoimmunity.
Polyclonal activation of B-cells by activation of superantigens or mi-
togens, that are associated with a failure to control lymphoproliferation,
has been suggested as a possible mechanism by which viruses trigger
autoimmune disease [79,80].
As in ITP, there is also an imbalance in Th1/Th2 cells. T-cells from
murine models of AIHA produce high levels of the Th1 cytokine
interferon-γ (IFN-γ) but little or no of the Th2 cytokines IL-4, IL-5 or
IL-10 [81]. Interleukin-12, a cytokine produced primarily by APCs, pro-
motes the development of Th1 cells and suppresses Th2-cell expansion,
promoting B-cell maturation and pathologic antibody generation. In
support of the hypothesis that Th2 cytokines protect against autoim-
mune disease and Th1 cytokines promote autoimmune disease, it has
been shown that high IL-10 responses in AIHA patients were associated
with less severe anemia [82] and that IL-4 treatment ameliorates the
anemia in AIHA mice models [83].
As in ITP, AIHA is also associated with abnormalities in the number
or function of regulatory T-cells (Tregs), which play an important role
Please cite this article as: Sys J, et al, The role of splenectomy in autoimmune hematological disorders: Outdated or still worth considering?, Blood
Rev (2017), http://dx.doi.org/10.1016/j.blre.2017.01.001
7
in the generation and maintenance of peripheral tolerance. It has been
shown that older CD25 knockout mice develop autoimmune disease, in-
cluding AIHA [84]. Furthermore, the peripheral blood of patients with
AIHA has been found to contain Tregs capable of inhibiting the Th1 ef-
fector responses in vitro by secretion of IL-10 [82].
3.3. Treatment
Treatment of AIHA is still not evidence-based, but essentially
experience-based. There are no randomized studies and only a few pro-
spective phase 2 trials. Otherwise, only retrospective studies, small se-
ries of patients or single cases have been reported (evidence level V).
There is no formal consensus on the definition of complete (CR) or par-
tial (PR) hematologic remission and refractoriness. Therefore, all state-
ments on treatment recommendations in the literature have to be
regarded with caution [85].
3.3.1. First line treatment
Glucocorticoids are the mainstay of treatment of newly diagnosed
wAIHA. For most cases prednisone at a dose of 1 mg/kg/day is the first
line treatment of choice. After three weeks of treatment with predni-
sone, about 80–90% of all patients have a clear clinical response (i.e. he-
moglobin N 10.0 g/dl). Patients who have no clinical response at that
time are unlikely to improve from continuation of steroids, and should
thus be switched to alternative treatments [86].
Nevertheless, only about 20% of patients will remain in remission
after withdrawal of steroids and are possibly cured. Subsequently,
most responders require maintenance steroids to maintain an accept-
able hemoglobin value (N 9–10 g/dl). Approximately 40% to 50% of pa-
tients need 15 mg/day or less prednisone (which is generally regarded
as the highest tolerable dose for long-term treatment), but 15 to 20%
need higher maintenance prednisone doses [86–88].
3.3.2. Second-line treatment
Patients who are refractory to initial steroids or who need N15 mg
prednisone per day or who relapse after initial response are absolute
candidates for a second-line therapy. Splenectomy and rituximab are
the only second-line treatments with a proven short-term efficacy [85].
3.3.2.1. Splenectomy. Because the spleen is a major organ for antibody
synthesis and destruction of immunoprotein-coated erythrocytes, sple-
nectomy has classically been proposed as the logical second-line ap-
proach. In their guidelines, Lechner et al. [85] recommend
splenectomy to all patients without contraindications as the best
second-line therapy because of a high short-term efficacy and a good
evidence of a long-term response.
3.3.2.1.1. Durability of response. After splenectomy short-term com-
plete response or partial response can be expected in two-thirds of pa-
tients [89] with a range of 38% to 82% [86,88,90–94]. Although no high-
quality data on long-term success are available, there is good evidence
that a substantial number of patients will remain in remission without
need of medical intervention for years. The best data on follow-up
were provided by Coon [94]. In 52 patients who had undergone splenec-
tomy they found that 63% of patients had a hematocrit level N30% with-
out steroids after a mean follow-up of 33 months, and 21% had a
hematocrit level N30% with a prednisone requirement of 15 mg/d or
less after a mean follow-up of 73 months. In a study of Allgood and
Chaplin [88], 44% of patients were in complete remission after N1 year
after splenectomy. It is also the experience of many hematologists that
patients with recurrence after splenectomy require lower doses of ste-
roids to maintain acceptable hemoglobin levels [92].
3.3.2.1.2. Prediction of response. As in ITP, it would be desirable to
identify patient characteristics that could predict the response to sple-
nectomy. Studies about this are not to the same extent available in liter-
ature as they were for ITP and are mostly of older age. Chertkow and
Dacie [91] suggested that people under the age of forty, those with a
8 J. Sys et al. / Blood Reviews xxx (2017) xxx–xxx
small spleen, low platelet counts and severe anemia, tended to have
poorer results from splenectomy than people over the age of forty or
those with large spleen, normal platelet counts and mild to moderate
degrees of anemia. Allgood et al. [88] found no correlation between
the effectiveness of splenectomy and the patient's age, race, sex, initial
hemoglobin level, reticulocyte count, white blood cell count or platelet
count. Yet it appeared that patients with a prior good response to corti-
costeroid therapy had a good response to splenectomy. The number of
patients in each group was nonetheless too small to make this correla-
tion statistically significant.
Most of research, however, went to the role of radioisotopic 51Cr-
RBC sequestration studies. Beside the use of spleen to liver ratios in sev-
eral studies, Jandl et al. [95] suggested to rely on an index of sequestra-
tion calculated by a complex formula. McCurdy and Roth [96]
introduced still another formula, which they termed the spleen localiza-
tion index (SLI). In all these studies, irrespective of the index used, the
finding of significant splenic sequestration seemed to predict a favor-
able response to splenectomy, but the lack of evidence for significant
splenic sequestration did not preclude a good response to splenectomy.
As to give an example, Allgood et al. [88] showed in their study that 11
of 13 patients with a spleen to liver ratio of N2.3 benefited of splenecto-
my, but also 4 of 7 patients with a spleen to liver ratio of b2.3 responded
to splenectomy.
Since no factor consistently or significantly predicted response on
splenectomy, the decision remains a difficult one and is better made
on the basis of individual considerations, taking into account operative
risk, probability of thrombosis, availability of rituximab, and patient
preferences.
3.3.2.2. Rituximab. Rituximab is used for relapsed or refractory AIHA as a
second-line alternative instead of splenectomy, or after its failure. Sev-
eral retrospective studies and case series regarding its use in AIHA
have shown variable response rates ranging from 40 to 100% with a me-
dian of 60% and disease-free survival of 50% in 2 years [97–103]. Wheth-
er some patients can be considered cured after rituximab
administration is not clear, given the lack of long-term follow-up in
most published series [104]. Although it is unknown if refractoriness
to its administration will develop, retreatment with rituximab has
been reported to be effective for relapsing cases, and extended rituxi-
mab therapy has also been used [98]. As to reduce the side effects of ri-
tuximab (listed in Table 2), recently, a prospective phase-II study was
performed using low-dose rituximab in AIHA. In this study, overall re-
sponse rate and relapse-free survival at 12 months were both 100% in
the warm type, with an estimated relapse-free survival of 81% at
2 years. These results suggests that lower doses of rituximab may be suf-
ficient to produce long-term responses in most patients, with a lower
incidence of side effects [105]. Guidelines recommend rituximab as
the best option for patients who are not eligible for or who refuse sple-
nectomy [85].
Birgens et al. [106] published the first randomized trial of 64 patients
who received prednisolone and rituximab combined (N = 32) or pred-
nisolone monotherapy (N = 32) as first-line treatment for warm AIHA.
After 36 months, about 70% of the patients were still in remission in the
rituximab-prednisolone group, whereas only about 45% were still in
complete or partial remission in the prednisolone group. These data
suggest that rituximab combined with prednisolone for the first-line
treatment of warm AIHA can increase both the rate and the duration
of response.
4. Thrombotic thrombocytopenic purpura
4.1. Definition and classification
Thrombotic thrombocytopenic purpura (TTP) is classically described
as a pentad of severe thrombocytopenia, hemolytic anemia with
schistocytosis, fever and neurologic and renal abnormalities. It is caused
Please cite this article as: Sys J, et al, The role of splenectomy in autoimmune hematological disorders: Outdated or still worth considering?, Blood
Rev (2017), http://dx.doi.org/10.1016/j.blre.2017.01.001
by a severe deficiency of the protease ADAMTS13. This deficiency is ei-
ther the result of an autoantibody which binds to ADAMTS13 and im-
pairs its function (so called ‘acquired TTP’, approximately 95% of
cases), or a congenital deficiency in ADAMTS13 due to mutations pres-
ent in the ADAMTS13 gene (also called Upshaw-Shulman syndrome). In
the majority of patients with acquired TTP, there is no associated clini-
cally overt immune dysregulation and the condition is termed ‘primary’
or ‘idiopathic’. In the smaller proportion of patients in which an overt
cause of immune dysregulation is identifiable (e.g. systemic lupus ery-
thematosus, HIV infection), the term ‘secondary’ acquired TTP is used
[107].
4.2. Pathophysiology
The pathophysiology of TTP can be largely explained by a deficiency
of the von Willebrand Factor (VWF)-cleaving protease ADAMTS13,
which is a metalloproteinase produced by the liver in response to in-
creased vascular shear stress. Under normal conditions, ultra-large
(UL), hyperreactive VWF multimers are secreted from endothelial
cells. Due to shear stress in flowing blood, they unfold and are processed
by ADAMTS13 into normally sized, quiescent multimers. This process
prevents spontaneous interaction between UL-VWF and the glycopro-
tein (GP) Ib/IX/V receptor on circulating platelets. In the absence of
ADAMTS13 activity, UL-VWF multimers can accumulate, leading to
formation of disseminated thrombi that are rich in platelets and VWF
(Fig. 3). These microthrombi can block arterioles and capillaries
resulting in organ failure and death when left untreated. Thrombocyto-
penia observed in TTP is explained by consumption of platelets in this
thrombotic process, and microangiopathic hemolytic anemia is as-
sumed to be caused by mechanical rupture of red blood cells in the
obstructed microvasculature [108,109].
4.3. Treatment
4.3.1. First line treatment
4.3.1.1. Plasma exchange therapy (PEX). PEX has reduced mortality from
N90% without treatment to about 10–20% [110–112]. However, about
35–50% of patients surviving an acute bout of TTP will relapse after ini-
tial response to PEX [113,114], and some are plasma-refractory or re-
main PEX-dependent for long periods [115–117]. About 10% of
patients with TTP have multiple relapses and develop a chronic relaps-
ing form of TTP [117].
4.3.1.2. Corticosteroids. In conjunction to PEX, steroids should be used in
the initial treatment of TTP to achieve relatively rapid immunosuppres-
sion [107]. There is no firm evidence to guide the choice and dose of ste-
roid; however, there is some prospective evidence that higher doses of
methylprednisolone (10 mg/kg/day) are associated with an improved
patient outcome [118].
4.3.1.3. Caplacizumab. Caplacizumab, an anti-von Willebrand factor hu-
manized immunoglobulin, inhibits the interaction between ultralarge
von Willebrand factor multimers and platelets. In a recent phase 2 con-
trolled study, caplacizumab or placebo were given during plasma ex-
change and for 30 days afterwards. Caplacizumab induced a faster
resolution of the acute TTP episode than did placebo [119]. If this is con-
firmed in further studies, Caplacizumab has the potential to become a
new treatment of TTP in addition to PEX and immunosuppressive
therapy.
4.3.2. Second-line treatment
4.3.2.1. Rituximab. In patients refractory to daily PEX and in relapsed
acute idiopathic TTP where rituximab was administred together with
reinitiation of PEX, remission rates of N85% were reached in some
 J. Sys et al. / Blood Reviews xxx (2017) xxx–xxx 9

Fig. 3. ADAMTS13 and its role in the pathophysiology of TTP. (A) UL-VWF (blue) is secreted from endothelial cells, after which it unfolds shear forces in the flowing blood thereby exposing
the ADAMTS13 cleavage site. ADAMTS13 (scissors) proteolysis trims the UL-VWF multimers into smaller multimers that do not spontaneously react with platelets (red). (B) When
ADAMTS13 is absent or inactive, UL-VWF is not cleaved and accumulates. Spontaneous interaction of UL-VWF with platelets results in the formation of microthrombi that block
capillaries and arterioles.
Figure adopted from Vanhoorelbeke K, De Meyer SF. Animal models form thrombotic thrombocytopenic purpura. J Thromb Haemost. 2013;11 Suppl 1:2–10. Used with permission from
John Wiley and Sons.

studies [120,121]. Typically, 375 mg/m2 has been used weekly for
4 weeks. Although in most reported cases no relapses were observed,
length of follow-up was limited. Chemnitz et al. [122] published long-
term follow-up data for 12 patients, all achieving an initial remission
after application of rituximab. However, after a mean follow-up of
49.6 months, 3 patients relapsed. The investigators conclude that ex-
tended follow-up remains necessary.
Furthermore, a prospective multicenter trial has shown benefit in
using rituximab as a first-line therapy [123]. In this study examining
the use of rituximab in newly diagnosed or relapsed patients with TTP,
rituximab has been shown to decrease the number of PEX required to
achieve remission, to decrease the hospital duration and to reduce the
risk of relapse by over 80% when compared to historical controls.
British guidelines recommend rituximab in acute idiopathic TTP
with neurological/cardiac pathology, which are associated with a high
mortality, in conjunction with PEX and steroids (Grade 1B) and in pa-
tients with refractory or relapsing immune-mediated TTP (Grade 1B)
[124].
4.3.2.2. Splenectomy. In TTP, splenectomy has been controversial since
employed. The first splenectomy for the treatment of TTP was in 1927.
In 1957, steroids and splenectomy were first combined in the treatment
of TTP with response rates of about 50% [125–127]. Introduction of plas-
ma therapy in the 1970s significantly improved prognosis with remis-
sion rates of over 70–80% [112,114]. Since then, splenectomy was
predominantly performed in patients primarily refractory or with pro-
gressive disease despite plasma exchange. In these unfavorable situa-
tions, splenectomy was associated with a high fatality rate of up to
40% [116,125,128].
The mechanism by which splenectomy induces remissions in TTP is
unclear. It is speculated that removal of the spleen may alter either
ADAMTS13-antibody complex clearance and/or decrease antibody pro-
duction. In plasmapheresis-refractory TTP, splenectomy produces re-
missions within days. This suggests that in this situation, splenectomy
does not work by decreasing antibody production, but rather by de-
creasing clearance of the antibody-antigen complexes [129].
4.3.2.2.1. Durability of response. Dubois et al. [130] reviewed a total of
74 reported cases who underwent splenectomy for refractory disease
with a mean follow-up of 39 months and 87 cases who underwent
splenectomy for relapsing TTP with a mean follow-up of 53 months.
The authors conclude that the relapse rate following splenectomy was
lower for patients with refractory disease than for patients with relaps-
ing TTP (8% vs 17%). The reviewed studies have several limitations. First,
available data are from retrospectively performed small case series lack-
ing control groups. Secondly, follow-up duration in most studies was
b3 years, which likely results in an underestimation of the true relapse
rate. Thirdly, other therapies used in these studies also varied, with
some patients undergoing splenectomy alone and others taking immu-
nosuppressant medication before splenectomy [130,131].
The evidence by these retrospective trials is not as convincing as
some prospective studies performed with rituximab. Blombery and
Scully state that rituximab should be considered the mainstay of treat-
ment for relapsing disease, as there is little good evidence regarding
the efficacy and safety of splenectomy [107]. British guidelines state
that splenectomy may rarely be considered in the non-acute period of
immune-mediated TTP but has limited proven benefit (Grade 2C) [124].
4.3.2.2.2. Prediction of response. In the search for parameters that can
be used to tailor patient treatment, it is important to know whether an-
tibodies against ADAMTS13 are useful as a surrogate predictor for dis-
ease outcome. Some small studies indicate that response to plasma
exchange may occur independent of the level of ADAMTS13 or inhibito-
ry activity [110,132]. This still remains to be established in larger
studies.
5. Point of focus: splenectomy: risks and preventive measures
5.1. Perioperative complications and mortality
In the past, removal of the spleen had been performed by open sur-
gery with the surgical approach made through a midline abdominal in-
cision. The surgical wound has been responsible for much of the
morbidity leading to wound infection or herniation, difficulty in mobili-
zation after surgery, increased risk of thromboembolic events and ob-
struction due to adhesions. Modern surgical approaches to
splenectomy for ITP have sought to minimize these complications and
maximize response to treatment by utilizing minimally invasive (lapa-
roscopic) techniques [133].

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Rev (2017), http://dx.doi.org/10.1016/j.blre.2017.01.001
10 J. Sys et al. / Blood Reviews xxx (2017) xxx–xxx
In the review of Kojouri et al. [42], the complication rate in the im-
mediate postoperative period was 9.6% for laparoscopic splenectomy
and 12.9% for open splenectomy, while associated mortality rates
were very low, 48 deaths on 4955 laparatomies were reported (1%),
and 3 deaths on 1301 laparoscopies (0.2%). Severe hemorrhage was re-
sponsible for 22.9% of deaths; other causes included infection, thrombo-
embolic and cardiovascular events. These relatively high rates of
complications and death, despite advances in anesthesia and surgical
care, may be due to the increasing recognition of ITP among older per-
sons [134,135], the greater risk of surgical complications in older pa-
tients [136], and the willingness of surgeons to perform surgery in
older patients.
5.2. Infectious risk
1. Epidemiology of infections after splenectomy
2. Characteristics of ‘OPSI’
3. Vaccinations
4. Preventive antibiotic therapy
5. Patient education
Splenectomized patients are exposed to an increased risk of severe
infections, particularly with encapsulated bacteria. This is due to the re-
moval of a large pool of B-lymphocytes, especially in the marginal zone,
as well as to a global insufficiency in the phagocytosis of certain patho-
gens [137]. The meta-analysis of Kojouri et al. estimated the prevalence
of infectious events to be 3.2% [42]. Pneumococcal infections are the
most common infections, but splenectomy also exposes to other bacte-
rial pathogens (Haemophilus influenzae type b, Neisseria meningitidis,
Escherichia coli, Capnocytophaga canimorsus), but also to fungal infec-
tions and intra-erythrocytic pathogens (Babesia, Plasmodium
falciparum, Ehrlichia). A cohort study in Denmark on 3812 splenecto-
mies performed for various indications between 1966 and 2005 showed
a significant increase in the risk of infection within 90 days after sple-
nectomy (10.2% vs 0.6% in the general population) [138]. After one
year, the risk was much lower especially in the subgroup
splenectomized for ITP (relative risk 1.2), probably because of the effec-
tiveness of preventive measures (antibiotics, vaccination, patient infor-
mation). Nevertheless, this study does not allow to assess the late
infection risk. The long-term risk of infection in ITP patients still has to
be evaluated.
The one major and feared complication associated with splenectomy
is the spectrum of overwhelming post-splenectomy infection (OPSI).
The term OPSI defines fulminating sepsis, meningitis or pneumonia,
mainly caused by encapsulated bacteria, such as pneumococci, menin-
gococci and Haemophilus influenzae type b (Hib) [139–141]. OPSI has
a high mortality risk of approximately 40% to as much as 70%
[141–143]. The risk is estimated at 0.89% per person per year [143].
Patients are usually given prophylactic polyvalent pneumococcal,
meningococcal C conjugate and Hib vaccines at least 4 weeks before
(preferably) or 2 weeks after splenectomy and are revaccinated accord-
ing to the country-specific recommendations [40]. These vaccines may
not be effective in patients who have received rituximab in the
6 months prior to splenectomy.
Antigenic diversity of S. pneumoniae is significant (N 90 known an-
tigens) and is responsible for the difficulties in obtaining effective cover-
age. Two types of vaccines are available, the unconjugated T-cell
independent polysaccharide vaccine covering 23 serotypes
(Pneumo23®), and the conjugated vaccine covering 13 serotypes
(Prévenar13®). The latter was originally developed to protect young
children whose immature immune system and in particular the absence
of marginal zone in the spleen makes the polysaccharide vaccine ineffi-
cient before the age of 2 years. Response to polysaccharide vaccine is
also reduced in splenectomized patients with more than a quarter of
poor antibody response in a cohort of splenectomized patients [144].
Please cite this article as: Sys J, et al, The role of splenectomy in autoimmune hematological disorders: Outdated or still worth considering?, Blood
Rev (2017), http://dx.doi.org/10.1016/j.blre.2017.01.001
The Advisory Committee on Immunization Practices (ACIP) proposes a
dose of the conjugated vaccine first, followed by a dose of the polysac-
charide vaccine at least 8 weeks later [145]. Vaccination against H.
influenzae type b with a conjugated vaccine is also recommended.
The vaccine mainly protects against the risk of meningitis caused by
H. influenzae type b. Furthermore, the conjugated tetravalent
ACDYW135 vaccine against N. meningitidis is recommended before
splenectomy and has to be repeated when traveling in endemic areas.
Finally, vaccination against influenza is recommended in winter. A ret-
rospective case-control study showed a reduction in mortality and the
risk of OPSI in splenectomized patients vaccinated against influenza,
prompting strongly to follow these recommendations [146]. We note
that, in patients treated with rituximab in the previous 6 months, vacci-
nation may not be effective. Vaccination for these patients should be
readdressed once B-cell recovery has occurred [40].
The risk of severe sepsis throughout life, led some authors to propose
a course of antibiotics of indefinite duration. Patient adherence to such
recommendations however, has not been studied which led some phy-
sicians to limit the duration of this antibiotic to a period of 2 years for
adults and 5 years for children. These recommendations are not based
on controlled trials. In fact, continuation of antibiotics should be
discussed in consideration of persistent risk factors for infection, severe
immunosuppression or history of invasive pneumococcal infection
[147]. Some authors propose to develop a better predictive approach
based on genetic profiling of patients with different susceptibility to in-
fectious pathogens, host-pathogens interactions as well as to identify
the impact of factors such as age on immunological competence [148].
The best prophylaxis to infection, however, is patient education. Pa-
tients should be advised to go to the emergency department if fever
higher than 38 °C occurs. Each splenectomized patient should have a
card, reminding the medical corps of his statute and the measures that
should be taken in case of fever. If patients have fever greater than or
equal to 38.5 °C, an antibiotic active against pneumococcal fever should
be immediately started. A practical policy for splenectomized patients is
to have a home supply of broad spectrum antibiotics for use in case of a
febrile illness [40,147].
5.3. Thrombotic risk
1. Venous thrombosis in the splenic and portal venous system
2. Venous thrombosis at distance of the spleen
3. Pulmonary arterial hypertension
The risk of thrombosis after splenectomy is not well evaluated. The
real incidence is not known, the pathophysiology is still debated and it
is impossible to propose preventive measures based on solid evidence
[147]. One of the explanations for the increase of thrombotic risk after
splenectomy is the loss of the role as filter (carried out by the red
pulp), suggested by studies that showed an increase in the amount of
circulating microparticles of platelet and red cell origin, with pro-
thrombotic properties [149,150].
Immediately after surgery, there is a risk of thrombosis in the splenic
and portal venous (SPV) system. The number of portal vein thrombosis
varies from 5 to 37% [151–154].
Occurrence of deep vein thrombosis (DVT) outside the SPV system
or pulmonary embolism (PE) seems to be very low (0.63% and 0.73% re-
spectively) in the first 90 days after splenectomy according to data from
the Danish National Patient registry. Nevertheless, the overall adjusted
odds ratio for venous thromboembolism in splenectomized patients
was 32.6 versus the general population and 3.2 versus appendectomy
patients in the first 90 days after surgery, falling to 7.1 and 2.8 respec-
tively at 91–365 days, and 3.4 and 3.2 respectively, at N1 year [155].
These data suggest a pro-thrombogenic effect of splenectomy.
 J. Sys et al. / Blood Reviews xxx (2017) xxx–xxx
Prescribing prophylactic anticoagulation in patients splenectomized in
thrombogenic situation should be discussed on a case by case basis.
Splenectomy is also a newly identified risk factor for the develop-
ment of post-embolic pulmonary arterial hypertension (PAH). In a
study conducted by Jaïs et al. [156] involving N250 patients with post-
embolic pulmonary hypertension, the prevalence of splenectomy was
8.6% while this prevalence was significantly lower in patients with
other chronic lung diseases. Post-embolic PAH occurred on average
16 ± 9 years after splenectomy and almost exclusively in patients
with a hemolytic anemia or who had been splenectomized in the after-
math of trauma, while none of the patients in this study had ITP. The risk
of post-embolic pulmonary hypertension in ITP remains to be deter-
mined and certainly does not warrant a systematic cardiac ultrasound
monitoring as proposed in other diseases at risk of PAH.
6. Conclusion
The autoimmune disorders ITP, AIHA and TTP are three rare but in-
teresting conditions with a complex pathogenesis and a difficult man-
agement. In recent years, major advances in understanding the
immunopathogenesis has led to the introduction of new therapies, stag-
gering the role of splenectomy as standard second-line treatment. Ri-
tuximab and TPO receptor agonists could be valid alternatives to
splenectomy but, unfortunately, the international guidelines fail to
offer a consistent approach. Whereas the European guidelines consider
splenectomy at the same level of rituximab and TPO RAs, the ASH guide-
line definitely recommends reserving TPO RAs and rituximab to pa-
tients failing or with a contra-indication to splenectomy.
In warm AIHA, guidelines still propose splenectomy as best second-
line therapy. However, in some studies with low-dose rituximab in
combination with steroids, success rates similar to splenectomy were
attained in steroid-refractory patients. In TTP, rituximab conquered
the throne of standard second-line therapy. Splenectomy seems to
play a minor role in the treatment of TTP, although in small studies
the efficacy and safety of splenectomy is demonstrated. The great vari-
ability of opinion and interpretation of current data, shows that treat-
ment should be personalized and adapted to the patient's condition
and opinion. Unfortunately, of all factors proposed as predictors of re-
sponse to splenectomy in ITP and AIHA, none was found to be statistical-
ly significant. Therefore, selection of patients remains to be based on
their surgical risk, their possible contra-indications and the personal
preferences of patient and physician.
While the complication rate of splenectomy is still relatively high,
the mortality rate has considerably decreased with the introduction of
a laparoscopic approach. However, the occurrence of infections, espe-
cially OPSI, remains a big fear of many physicians. Several preventive
measures, about which no consensus is reached, can be undertaken,
but the risk of infection persists a whole lifetime and education of pa-
tients about this is indispensable.
It is reasonable to expect that, the more the pathogenesis is clarified,
the more specific targets for therapy will arise. It needs to be seen in the
future if new therapies will surpass splenectomy or if on the other hand,
possible complications of splenectomy will become better prevented,
making this old treatment option more popular. In the meanwhile, sple-
nectomy certainly stays worth considering.
It is notable that evidence in our review came mainly from small ret-
rospective studies. Consequently, future research must be focused on
carefully designed randomized trials and multicentre prospective co-
hort studies. Furthermore, there is a need of standardization of termi-
nology such as partial and complete response, refractoriness and
relapse, so that study results can be better compared.
Practice points
1. Immune thrombocytopenia
Please cite this article as: Sys J, et al, The role of splenectomy in autoimmune hematological disorders: Outdated or still worth considering?, Blood
Rev (2017), http://dx.doi.org/10.1016/j.blre.2017.01.001
11
• Treatment of ITP is confined to patients who are bleeding or are at
significant risk of bleeding.
• First-line therapy for ITP consists of corticosteroids.
• Second-line therapies for ITP are splenectomy, rituximab and TPO
receptor agonists (comparison: Table 2).
• International guidelines fail to offer a consistent approach about
second-line therapy. Treatment should be personalized (proposed
treatment algorithm: Fig. 2).
• There are no clinical relevant variables that predict the success of
splenectomy.
• The best timing for splenectomy is debatable.
2. Autoimmune hemolytic anemia
• Treatment is essentially experience-based.
• Corticosteroids are the mainstay of first-line treatment.
• Splenectomy or rituximab are the second-line treatment options.
• There are no clinical factors significantly predicting response on
splenectomy.
• Rituximab combined with corticosteroids can increase both the rate
and the duration of response. Further research is warranted.
3. Thrombotic thrombocytopenic purpura
• Pathophysiology is largely explained by a deficiency of ADAMTS13.
• First-line treatment is plasma exchange therapy combined with
corticosteroids.
• The preferred second-line treatment is rituximab.
• Splenectomy seems to play a minor role in the treatment of TTP, al-
though in small studies the efficacy is demonstrated.
• Caplacizumab, an anti-von Willebrand factor humanized immuno-
globulin, induces a faster resolution of the acute TTP episode. It
has the potential to become a new treatment of TTP in addition to
PEX en steroids.
4. Splenectomy
• Splenectomy is irreversible and has 3 major categories of important
complications: postoperative, infectious and thrombotic.
• Mortality rate has decreased with the laparoscopic approach.
• The infectious risk can be reduced but not erased by preventive
measures (e.g. vaccinations) and the occurrence of OPSI remains a
big fear. The best prophylaxis is patient education.
• Splenectomy causes an increased risk of thrombosis in the splenic
and portal venous (SPV) system and at distance of the spleen.
Research agenda
• Evidence in our review came mainly from small retrospective studies.
Future research must be focused on carefully designed randomized
trials and multicentre prospective cohort studies.
• There is a need of standardization of terminology such as partial and
complete response, refractoriness and relapse.
• Better comprehension of pathogenesis will reveal more specific tar-
gets for therapy in the future.
Conflict of interest
None of the authors declare any conflicts of interest.
Acknowledgement
The authors wish to thank Dr. Emilie Beke and Esther Sys for their
help with the figures.
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