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Plenary lecture 36

Diagnosis and management


of immune thrombocytopenia in
childhood
Thomas Kühne
UKBB Universitäts-Kinderspital, Oncology / Hematology, Basel, Switzerland

Keywords Schlüsselwörter Immune thrombocytopenia (ITP) is an


immune thrombocytopenia, pediatrics, plate- Immunthrombozytopenie, Pädiatrie, Throm- autoimmune-mediated acquired bleeding
lets, management bozyten, Therapie disorder occurring in children and adults
(1). Patients without a known etiology or
Summary Zusammenfassung trigger for thrombocytopenia (platelet count
< 100 × 109 / l) have primary ITP, whereas

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Evidence-based medicine is growing in im- Die Immunthrombozytopenie (ITP) hat einen
mune thrombocytopenia (ITP), but solid clini- eindrücklichen Wissenszuwachs erfahren, secondary ITP is triggered by diseases (e. g.
cal data are still lacking in many areas. A ma- aber klinische Daten fehlen noch in vielen infectious, lymphoproliferative and rheuma-
jority of children has self-limited ITP, but Bereichen. Bei vielen Kindern ist die ITP eine tological disorders) or immunodeficiencies
chronic symptomatic ITP exists also in pedi- selbstlimitierte Krankheit und muss nicht mit (2, 3). Additionally, many drugs are capable
atrics. Management includes a watch-and- Medikamenten behandelt werden, falls keine to cause thrombocytopenia.
wait strategy for children with newly diag- oder nur eine milde Blutung vorliegt. Für Kin-
nosed ITP and no or mild bleeding, and im- der mit stärkeren oder Schleimhautblutungen Primary ITP cannot be proven by labora-
munoglobulins and corticosteroids, if more stehen Immunglobuline und Steroide zur Ver- tory tests and thus is a diagnosis of exclu-
bleeding and mucous membrane involve- fügung. Behandlungsziele und Therapienot- sion. Differential diagnostic considerations
ment is present. Treatment endpoints differ in wendigkeit von Kindern mit ITP unterschei- are important during the whole course of
clinical research and in clinical practice. The den sich in klinischen Studien und im klini- thrombocytopenia.
requirement of platelet enhancing drugs schen Alltag. Sie sollten überprüft und in
needs to be better defined in guidelines. Sec- Richtlinien klarer festgelegt werden. Zweitli- Pediatric ITP occurs in all age groups. Be-
ond-line therapies for children are rarely nien-Therapien werden bei Kindern selten side some similarities in pathophysiology,
required and include thrombopoietin-recep- angewendet und beinhalten Thrombopoietin- presentation and management there exist
tor agonists, rituximab, dexamethasone and Rezeptor-Agonisten, Rituximab, Dexametha- specific clinical characteristics at different
immunosuppressants. Thrombopoietin-recep- son und Immunsuppressiva. Thrombopoietin- ages (4). These differences consist of clini-
tor agonists are successful in adult but also Rezeptor-Agonisten sind bei Erwachsenen cal features, such as
in pediatric ITP. The strategical position of wie auch bei Kindern erfolgreich. Die strate- • clinical presentation,
splenectomy differs from that in adults. Al- gische Stellung der Splenektomie bei Kindern • co-morbidities,
though effective in children it is less fre- unterscheidet sich von derjenigen bei er- • bleeding signs,
quently used because of its life-long cumu- wachsenen Patienten: Das lebenslängliche • natural history,
lative risk of infectious diseases and a higher Infektionsrisiko und höhere Remissions-Po- • sex and
potential of spontaneous remission in ITP, tenzial sprechen bei Kindern dafür, die Splen- • health-related quality of life (HR-QoL)
providing a strong argument to defer sple- ektomie zu verschieben. Die Seltenheit der (5–7).
nectomy. The rarity of ITP makes clinical re- ITP verursacht hohe Forschungskosten.
search expensive. During the last 20 years a large body of
knowledge has been accumulated with
consequences for patient management.
Korrespondenzadresse Diagnostik und Therapie der Immunthrombozyto- Some children – but also some adults –
Thomas Kühne, MD penie im Kindesalter don’t need any treatment (watch-and-wait
Division of Oncology / Hematology Hämostaseologie 2017; 37: 36–44 strategy), whereas standard therapy, in-
University Children’s Hospital https://doi.org/10.5482/HAMO-16-06-0017
cluding corticosteroids and intravenous
Spitalstrasse 33, 4031 Basel, Switzerland received: June 24, 2016
Phone: +41–61–704–1212 accepted in revised form: September 20, 2016 high-dose immunoglobulins (IVIG), is ad-
Fax: +41–61–704–1213 epub ahead of print: October 4, 2016 ministered to symptomatic patients.
E-Mail: thomas.kuehne@ukbb.ch There are new drugs which have been
studied intensely and that were – in con-
trast to the traditional ones – introduced

© Schattauer 2017 Hämostaseologie 1/2017


37 Kühne T. Immune thrombocytopenia in childhood

with evidence-based principles. Their stra- Severe ITP is defined by the presence of been discussed and resulted in a better
tegic position remains to be explored. This bleeding symptoms at presentation suffi- understanding of ITP. Nonetheless, the
review summarizes the diagnosis and man- cient to mandate treatment, or occurrence specific causes of loss of tolerance in this
agement of children with primary ITP. of new bleeding symptoms during the autoimmune disease are still poorly under-
course, requiring additional therapeutic in- stood, as well as how appropriate treat-
tervention with a different platelet-enhan- ments should be directed to restore physio-
Definitions cing agent or an increased dose (2). logical immunocompetence.
Refractory ITP refers to adult patients, The different forms of ITP with a broad
In 2007, an international working group who failed splenectomy and have severe spectrum – from self-limited, sponta-
(IWG) met at Vicenza, Italy, and harmon- ITP, or who are at risk of bleeding and neously remitted ITP to long-lasting, refrac-
ized the language of ITP (2). Definitions of require therapy. In children a consensus re- tory, severe ITP – suggest different patho-
the disease were achieved by a consensus garding refractory ITP could not yet be physiological mechanisms and a distortion
process and became a prerequisite to assess achieved, because of regulatory systems. Although it has been
and compare results of clinical research. • splenectomy is contraindicated in shown that autoantibodies, most frequently
young children and of the IgG type, play an important role in
ITP is diagnosed in a patient with or with- • a clear definition at which age a splenec- the development of thrombocytopenia,
out bleeding signs and in an otherwise tomy can be performed with a balanced there are also other immune mechanisms.

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healthy state with isolated thrombocyto- risk for overwhelming infectious dis-
penia without any other changes in com- eases is absent. In approximately one third of all patients
plete blood count and differentiation of autoantibodies cannot be detected (16).
blood cells.
Epidemiology T-cells play an important role both in auto-
Primary ITP is a diagnosis of exclusion antibody production by T-helper cells (Th),
with a long list of differential diagnostic ITP is a rare autoimmune disorder and but also as cytotoxic T-cells that contribute
considerations. The vagueness of the diag- occurs in its primary form in approx. 3–5 to the destruction of platelets. In patients
nosis creates many clinical and research per 100 000 children per year, depending with ITP a dysbalanced cytokine pattern
problems, e. g. on age and gender but also on seasonal and towards Th1-cells (interleukin-2 and inter-
• when and which laboratory tests need regional factors (10–13). Interestingly, in feron-gamma) can be typically seen. Addi-
to be done, infants – and less frequently in young tionally, it has been shown that CD8+
• when they should be repeated, children – ITP occurs more often in boys. T-cells are capable to lyse autologous pla-
• design of clinical trials and The reasons therefore are unknown (14, telets in vitro (17), which has been demon-
• inclusion / exclusion of study patients. 15). During school age and adolescence strated by other groups (18, 19). Immune
there is no gender difference, whereas dysregulation, resulting in T- and B-regula-
Although the term “idiopathic” is adequate female patients are more often seen in tory cell disturbances, plays also an impor-
for ITP, it has been realized that the im- adults. However, in patients > 65 years tant role (20, 21). There is evidence indicat-
mune system plays a major role in disease there is again a higher occurrence in men ing that some specific immune cells may
process, and therefore “idiopathic” was than in women (12, 13). ITP exhibits a first induce autoimmune diseases, such as
replaced by “immune”. Furthermore, “pur- peak between the age of 1 and 6 years (14). • Th17,
pura” was abandoned because there are Secondary ITP is rare in children and its • Th22 and
patients with ITP who do not bleed. The occurrence raises with age, although epi- • T-follicular helper cells (22, 23).
IWG proposed therefore to change ITP to demiologically not well investigated.
immune thrombocytopenia, and maintain There are also non-immune mechanisms
the abbreviation “ITP”. The different age peaks and gender dis- which may trigger ITP. Oxidative stress re-
There are three forms of ITP based on tribution at various ages suggest different sulting in over-production of reactive
the duration of thrombocytopenia: pathophysiological mechanisms. oxygen species and deficient antioxidant
1. newly diagnosed ITP (first 3 months): defense mechanisms may reflect such a
“Acute ITP” should not be used any- process (24).
more, because it doesn’t describe the Pathophysiology and Although ITP is an acquired autoim-
self-limited form of ITP precisely, and Pathogenesis mune disease, familial ITP has also been
because of its retrospective aspect. reported and suggests predisposing factors,
2. persistent ITP (3–12 months): It re- The knowledge of the pathophysiological secondary ITP or thrombocytopenia other
flects the appreciation of the high po- mechanisms of ITP has grown and is im- than ITP (25–28). An example represents
tential of improvement of ITP during portant because of its significance as a basis the autoimmune lymphoproliferative syn-
the first year after diagnosis (8, 9). for an adequate management and to find drome, which presents with autoimmune
3. chronic ITP (> 12 months) better therapies. Several mechanisms have cytopenia, mainly thrombocyte- and gra-

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Kühne T. Immune thrombocytopenia in childhood 38

nulocytopenia, chronic non-malignant tients without bleeding at time of diag- Infectious diseases
lymphoproliferation and secondary malig- nosis, bleeding type and severity of throm-
nancies (29). First described in the 1990s, it bocytopenia did not differ much (32). No- Infectious diseases of the upper respiratory
reflects an inherited abnormality of apop- netheless, bleeding during the course of and the gastrointestinal tract are frequently
tosis with mutated genes encoding proteins ITP can be very different in children and seen days or weeks before ITP in children.
that mediate apoptotic pathways, such as adults. The ICIS Registry I and Nordic Study have
Fas or caspase 10 (30, 31). demonstrated that 50 % of the children
Intracranial haemorrhage (ICH) exhibited an infectious disorder within
approximately 21 days from diagnosis of
Clinical presentation In a systematic review, ICH has been found ITP, and mainly in children aged 1–10
to be more common in adults, and other years (4, 43). These infections occur at the
Bleeding severe non-ICH bleeding is more common same peak age as ITP does.
Primary ITP in children often appears as in children occurring at all stages of ITP.
bleeding disorder with an abrupt onset of However, bleeding severity is not well de- It is still unclear whether infectious disor-
skin bleedings (e. g. petechiae or subcu- fined (38). ders are etiological significant for ITP. It
taneous hematomas) within hours that can The platelet count of children with ITP has been demonstrated that measles-
be accompanied by mucosal bleeding. Tra- at first presentation is less than 20 × 109 / l in mumps-rubella (MMR) vaccine and MMR

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ditionally, „dry bleeding“ stands for skin approximately 80 %. Nonetheless, major plus varicella vaccine may trigger ITP (44,
bleeding only, and „wet bleeding“ if mu- haemorrhage is rare – also in its broad defi- 45).
cous membranes are involved. The Pediat- nition, that has been used by the Inter-
ric and Adult Registry on chronic ITP continental Childhood ITP Study Group Frequency of clinical symptoms
(PARC-ITP) has demonstrated that there (ICIS) Registry II (39, 40), such as intra-
are children and adults without bleeding cranial or other overt internal or mucous The majority of children have self-limited
(9 and 31 %, respectively), and mucous membrane bleeding, which results in anae- ITP, and ICIS Registry II has shown that
membranes are less often involved (32). mia or requires local treatment to stop remission occurred in
haemorrhage. • 37 % of the thrombocytopenic children
Recently, it has been shown that occult ICIS Registry II was designed to investi- between 28 days and 6 months after in-
bleeding is more frequent than anticipated gate bleeding and platelet counts in itial diagnosis,
(33). children with ITP based on the hypothesis • 16 % between 6 and 12 months and
that major haemorrhage in pediatric ITP is • 24 % between 12 and 24 months (40).
An insidious onset of bleeding within days uncommon during 2 years after diagnosis.
and weeks is a typical manifestation of ITP At diagnosis 2.9 % of the children experi- In registries the percentage of children with
in adults. However, it also occurs in enced a severe haemorrhage with one non- chronic ITP is approximately 30 %. How-
children and is associated with chronic ITP. fatal ICH (0.15 % incidence) and subse- ever, patients with clinical symptoms are
It has also been shown that besides an quent development of new severe bleeding much more rare. A Nordic cohort of chil-
abrupt onset age younger than 10 years was very rare and did not depend on initial dren with chronic ITP has shown that
predicts resolution of ITP (34). treatment (39). • one half of the patients recovered
Bleeding phenotype in patients with Most information on ICH in children 5 years after diagnosis,
ITP depends on with ITP is derived from registries and • more than a half of them never required
• number of platelets, retrospective data. It appears that it is asso- hospitalization, and
• function of platelets, ciated with a platelet count of less than • serious bleeding episodes occurred in
• endogenous factors (e. g. inherited de- 20 × 109 / l in 90 % of the patients, and less < 10 %, always when a platelet count of
fects of the haemostatic system) and than 10 × 109 / l in 75 %. < 20 × 109 / l was present (9).
• exogenous factors (e. g. drugs or infec-
tions interfering with haemostasis). However, a clear correlation between blee- This high remission rate was also demon-
ding and platelet count has not been dem- strated in a Korean cohort (46).
Platelet function measurement in patients onstrated (41, 42).
with thrombocytopenia is a highly sophis-
ticated task, and several groups have dem- ICH does not only occur at the time when Diagnosis and differential
onstrated an association of impaired pla- ITP is diagnosed, but also later when severe diagnosis
telet function and bleeding severity thrombocytopenia exists. Head trauma
(35–37). Although pediatric and adult ITP and haematuria was found to be prominent Primary ITP is a diagnosis of exclusion. A
differs in many clinical aspects, there are features in an U. S. nationwide survey (42). threshold platelet count of less than
also similarities which have been shown by It can be estimated that ICH occurs in less 100 × 109 / l was established by the IWG
the PARC-ITP Registry. The number of pa- than 1 % of children with ITP. based on the observation that individuals

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39 Kühne T. Immune thrombocytopenia in childhood

with a platelet count of 100–150 × 109 / l • evaluation of infectious diseases in pres- dations in children with persistent and par-
have a low probability of developing severe ence of clinical suspicion or high local ticularly chronic ITP.
thrombocytopenia, and that platelet values prevalence, In this review article, recommendations
of 100–150 × 109 / l are frequently found in • antinuclear and anti-phospholipid anti- and suggestions are briefly summarized.
individuals of non-Western origin (2). bodies (including anti-cardiolipin anti- The aim of treating children with ITP is to
Although diagnosis of primary ITP is bodies), lupus anticoagulant and serum • prevent life-threatening bleeding,
simple, the differential diagnostic consider- immunoglobulins (IgG, IgM, IgA). • stabilize and reduce bleeding, if clini-
ations are complex. Any pathological find- cally needed, and
ing except bleeding questions the diagnosis Other considerations should focus on com- • increase HR-QoL.
of primary ITP. It is based on clinical and mon variable immunodeficiency, autoim-
laboratory information: mune lymphoproliferative syndrome and Other aims include transiently increasing
• ITP occurs in children with or even many other disorders. According to the the platelet count before surgery, defering
without haemorrhage, who are other- ASH guidelines there is insufficient evi- splenectomy and avoiding bleeding of pa-
wise healthy. dence to support a systematic approach to tients with comorbidities. Treatment end-
• Family history is usually negative regar- test for such conditions. points include
ding bleeding disorders. If positive, Bleeding has been classified with diag- • platelet count,
differential diagnostic considerations nostic and predictive significance but also • bleeding,

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should be undertaken, which is de- as treatment endpoint. The development of • HR-QoL,
scribed elsewhere (47–49). bleeding scores and their value as bedside • preventing drug treatment side effects,
• Physical examination does not reveal test is challenging. Bleeding is the result of • reducing the need for rescue and con-
any abnormalities except haemorrhagic many factors and is a dynamic process that comitant treatment,
diathesis consisting of petechiae and can change within minutes. It thus reflects • avoiding of splenectomy, and
subcutaneous hematomas, and some- a highly individual and complex character- • economical aspects.
times mucous membrane bleeding. istic of a given patient.
• Complete blood count is normal except The platelet count is an easily and rapidly
for the platelet count. Whether bleeding scores are useful tools in available bedside test. However, its value as
• Haemoglobin could be reduced in pres- clinical practice and reflect therapeutic an indicator of bleeding is limited, al-
ence of bleeding. requirements of patients with ITP has not though severe haemorrhage is frequently
• Blood smear is normal, and frequently been established and is still a matter of associated with a platelet count of less than
large platelets can be observed. discussion (51–54). Bleeding as a treat- 20 × 109 / l. It has to be demonstrated that
ment endpoint has the potential to change bleeding and HR-QoL may better describe
Additional tests may be necessary if pa- therapeutic requirements (55). patients with ITP and define their thera-
tient / family history, physical examination peutic requirements.
and / or laboratory results are not in agree- HR-QoL appears to be an attractive Pre-analytical and analytical difficulties
ment with the diagnosis of primary ITP. treatment endpoint, which may be cat- must always be considered, particularly,
According to the current guidelines of the egorized and expressed as a score. As in when the platelet count is low. The ques-
American Society of Hematology (ASH), other disciplines such as inherited bleed- tions “Who needs treatment?” and “What
bone marrow examination is not needed ing disorders or oncology, the develop- is the meaning of treatment requirement in
in the absence of additional findings, i. e. ment and validation of tools to measure current guidelines?” can only be answered
in children with the diagnosis of primary HR-QoL are complex and challenging by assessing all clinical and laboratory in-
ITP, even if corticosteroids will be admin- and still far away from clinical practice formation, and are highly individual. Many
istered (50). However, it is advisable to (56–58). Pediatric tools specific to ITP aspects of the management of children
perform it if there are any doubts in diag- were developed and practiced in clinical with ITP, e. g. treatment endpoint of severe
nosis. trials (59). life-threatening bleeding, are hard to study
in prospective randomized clinical trials
Follow-up diagnostics in persistent and because of the rarity of ITP.
chronic ITP is not standardized and needs Principles of treatment
an individual approach.
Treatment of children and adults with Treatment options
Basically, the testing is guided by clinical newly diagnosed, persistent and chronic
symptoms. The international guidelines ITP is based on national and international Life-threatening bleeding
recommend (60) practice guidelines. Some of them are For children with life-threatening bleeding,
• bone marrow investigations if ITP per- regularly revised (50, 61). In contrast to evidence-based clinical data are lacking.
sists without a prior therapeutic re- children with newly diagnosed ITP, the de- But there is a strong consensus to admin-
sponse, gree of evidence is low for recommen- ister immediately

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Kühne T. Immune thrombocytopenia in childhood 40

• platelet transfusions, no or mild bleeding. Former guidelines de- nosed ITP. This demonstrates the incom-
• intravenous high-dose immunoglobu- fined such mild bleeding as skin manifes- plete knowledge of first-line therapies (64).
lins (1g / kg) and tations only (e. g. bruising or petechiae), Second-line treatment (▶Tab. 2) is rarely
• intravenous methylprednisolone and stated that treatment decision could be needed in children with newly diagnosed ITP.
(30 mg / kg for 3 days). made regardless of the platelet count (50). It is indicated in symptomatic children that
In presence of more bleeding, particu- are not responding to first-line treatment.
In other situations platelet transfusions are larly of the mucous membranes, it is cur-
not indicated. rently recommended to administer first- Persistent ITP
Emergency splenectomy may be per- line treatment. It is a matter of discussion
formed; however, there are not sufficient whether such “wet” bleeding really repre- This category of ITP has been created to
data supporting this procedure. sents a higher risk for life-threatening point out the high potential of patients
There is limited experience for recombi- bleeding than „dry“ bleeding only. with ITP who will improve or recover with-
nant factor VIIa, also in combination with in 3–12 months after diagnosis. Treatment
fibrinogen (62, 63). So far, mucous membrane bleeding has not indications and options are the same as for
been graded for prognostic purposes and it children with newly diagnosed ITP.
Newly diagnosed ITP may be worthwhile to develop and vali- Splenectomy is not recommended for
date such a tool in pediatric patients in children with this form of ITP.

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Whether a child with newly diagnosed ITP order to have a better basis for treatment
will receive drug treatment or be observed decisions.
Chronic ITP
without depends more on clinical signs,
such as bleeding, than on platelet count. First-line treatment is shown in ▶ Tab. 1. Symptomatic children with chronic ITP
The revised 2011 ASH practice guidelines Recently, it has been shown that dexame- requiring treatment are a small group of
(50) and the International guidelines (60) thasone is more effective in inducing a patients. Short courses of first-line treat-
were the first ones that clearly recom- higher incidence of overall initial response ments, including watch-and-wait strategy,
mended watchful waiting for children with than prednisone in adults with newly-diag- are frequently helpful.

Tab. 1 First-line treatment options for children with newly diagnosed ITP with selected pros and cons (50, 60).

Intervention Administration Dose Interval Pros Cons Remarks


watch-and-wait – – – • same rate of • time-consuming based on practice
remission conversation guidelines (46, 56)
expected as for • experienced
drug treatment physician needed
• no drug related
side effects
IVIG i. v. 0.8–1.0 g / kg once daily, 1–2 × • platelet response • blood product consider
within • i. v. line needed premedication with
24–48 hours • infusion over paracetamol
• diagnostic several hours
significance • side effects
• price
Prednisone oral 1–2 mg / kg single morning • no need for side effects platelet response
dose or 2–3 daily hospitalization slower than after
doses for 14 days • availability IVIG (2–7 days)
and 1 week of • cheap
tapering • fast response
4 mg/kg 1–3 doses / day see above see above see above
for 4 days
Anti-D i. v. 75 µg / kg single dose • efficacy • side effects not used in Europe
• fast • patient: Rh D+, anymore
administration not splenectom-
• no need for ized, not
hospitalization anaemic,
DAT negative

i. v.: intravenous; DAT: direct antiglobulin test; IVIG: intravenous immunoglobulins

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41 Kühne T. Immune thrombocytopenia in childhood

Tab. 2 Second-line treatment options for children with selected pros and cons (50, 60, 65).

Intervention Administration Dose Dose interval Pros Cons Remarks


Dexamethasone oral 28 mg / m2 / day 3 doses / day × 4 for • availability • side effects not licensed for
6 months • cheap • low long-term ef- children, doses from
• high short-term ficacy reference (60)
efficacy
• deferral of
splenectomy
Eltrombopag oral • 25 mg once daily • efficacy • diet restrictions licensed for
(1–5 years) • safety profile • side effects children; currently
• 50 mg • deferral of • expensive as second-line ther-
(6–17 years) splenectomy • long-term safety: apy in chronic ITP,
• 25 mg in patients limited experi- doses from refer-
of East Asian ence ence (93)
descent
Romiplostim s. c. dose not yet estab- once weekly • efficacy • parenteral not licensed for
• safety profile

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lished, 1–10 µg / kg administration children; currently
in adults • deferral of • side effects as second-line ther-
splenectomy • expensive apy in adults with
• long-term safety: chronic ITP
limited experi-
ence
Rituximab i. v. 375 mg / m2, dose once weekly × 4 • efficacy • side effects not licensed for
not established (Cave: response • long-term children
may be delayed efficacy limited
to 8 weeks) in adults,
not known in
children
Azathioprine, i. v. / oral doses not different regimens • may be effective • experience individual
Cyclosporine A, established in individual limited approach,
Cyclophospha- patients • side effects, not licensed for
mide, Danazol, necessitating children
Dapsone, anti-infective
Mycophenolate measures
mofetil, Vinca
alkaloids
Splenectomy open or – – • efficacy in 80 %, • contraindicated • rarely performed
laparoscopic long-term in young children in children,
surgery response (approx. < 5 difficult to be
decreasing years) studied
• potential of cure • complications • prevention from
• standard (infections, infections
procedure thrombosis) (vaccinations,
• widely available • life without antibiotic pro-
spleen phylaxis)

s. c.: subcutaneous; i. v.: intravenous; ITP: immune thrombocytopenia

The aim of the treatment in chronic ITP is symptomatic ITP is that rare it is extremely same strategical significance as for adults
not to achieve a normal platelet count but hard to generate evidence-based data. (68). Thus, treatment refractoriness in
to avoid bleeding and to increase HR-QoL. pediatric patients has not been defined by
Splenectomy the IWG and still awaits consensus. In
Treatment refractoriness to first-line ther- adult patients it is defined by failure to
apy in children with chronic ITP is rarely Although splenectomy is an effective treat- splenectomy or a relapse thereafter and the
seen and if so, an individual approach is ment in children (66, 67) and has the po- presence of severe ITP or a risk of bleeding
needed (65). Because of the fact that chronic tential to cure the patient, it has not the that requires therapy (2).

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Kühne T. Immune thrombocytopenia in childhood 42

In children splenectomy is associated relation to comorbidity and concomi- pediatric patients necessitating international
with an increased risk for overwhelming tant drugs, research, the limited resources for investi-
infections by encapsulated bacteria, such as • stimulation of bone marrow reticulin gator-driven research and the difficulties to
• pneumococci, and collagen fibers, coordinate research represent challenges.
• hemophilus influenzae or • stimulation of malignant cells and There are internationally active groups, e. g.
• meningococci. • induction of malignancy, extramyeloid • IWG (2),
reactions, platelet activation, and hae- • ICIS (www.itpbasel.ch) and
The risk for infections in children after sple- matopoietic stem cell depletion. • working groups of societies, such as the
nectomy increases with decreasing age. European Haematology Association.
Whether the thrombotic risk is different in Long-term safety of TPO-RAs is an impor-
children than in adults is not clear. tant area of future pediatric clinical re- It is to be hoped that future activities will
search. Sustained response after stopping give answers to questions, such as
The care of splenectomized children is not TPO-RAs in adults has been observed and • etiology and pathophysiology of ITP,
trivial. Patients should be educated to the will be studied (81–83). Other second-line • prediction of the form of ITP (self-
lifelong risks and aspects of living without a therapies include limited or chronic),
spleen, e. g. • dexamethasone, • diagnostic algorithms for children with
• vaccinations, • rituximab and persistent and chronic ITP,

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• antibiotic prophylaxis, • immunosuppressants. • definitions of pediatric ITP, and
• planning travel aids, • clinical trials exploring efficacy and
• regular visits, Oral pulsed high-dose dexamethasone safety of newer drugs in children.
• carrying medical information etc. therapy has been attempted to modulate the
immune system with regular adminis-
Conflict of interest
In addition, surgical complications and the trations. Different dose regimens have been
risk of a relapse, poor or no response have used (60, 84, 85). Adverse effects of dexa- The author declares that he received re-
to be considered. The probably higher po- methasone can be substantial. search funds from Amgen and that he is a
tential of spontaneous improvement and Rituximab has been studied in adult pa- member of an advisory board of UCB
even cure in children is a further argument tients successfully with an acceptable safety CELLTECH.
to defer splenectomy. Mainly demonstrated profile (86) that could be reproduced in
in adults, there are several published ways children (87–89). However, there are no
to defer splenectomy (69–71). comparative studies and experience of this References
drug for children is still limited. 1. Kühne T. Immune thrombocytopenia (ITP). 1st
In summary, the poorly studied timing and Addition of dexamethasone to rituximab edition. Bremen: UNI-MED 2010.
indication of splenectomy, its risk of comp- has been shown to increase the effect (90). 2. Rodeghiero F, Stasi R, Gernsheimer T et al. Stan-
lications and the unforeseen potential of Combination therapies of rituximab, dexame- dardization of terminology, definitions and out-
come criteria in immune thrombocytopenic pur-
remission make splenectomy an effective thasone and cyclosporine, and TPO-RAs with pura (ITP) of adults and children. Report from an
but highly questionable procedure in rituximab in adult and also pediatric patients international working group. Blood 2009; 113:
children (72). with refractory ITP have been studied with 2386–2393.
some success and need to be studied in more 3. Price V. Auto-immune lymphoproliferative dis-
order and other secondary immune thrombocy-
Second-line therapy details (91, 92). However these regimens are topenias in childhood. Pediatric Blood Cancer
reserved for most severely affected patients 2013; 60: S12-S14.
Second-line therapy (▶Tab. 2) is rarely used and may be toxic, thus their benefit must be 4. Kühne T, Buchanan GR, Zimmerman S et al. A
in children. Thrombopoietin receptor agon- carefully weighed against their risks. prospective comparative study of 2540 infants and
children with newly diagnosed idiopathic throm-
ists (TPO-RAs) are successful drugs in Immunosuppressants have been less well bocytopenic purpura (ITP) from The Interconti-
adults and are also studied in children studied in children than in adults. Drugs nental Childhood ITP Study Group. J Pediatr
(73–75). Recently, Eltrombopag was with more favourable safety profiles, such 2003; 143: 605–608.
5. Arnold DM. Bleeding complications in immune
licensed for children and Romiplostim is as the TPO-RAs, appear to be more attract-
thrombocytopenia. Hematology Am Soc Hematol
still under investigation. These drugs appear ive and may play an important role in Educ Program 2015; 2015: 237–242.
to have similar response rates and favorable children with chronic ITP who do not re- 6. Zhou Z, Yang L, Chen Z et al. Health-related
safety profiles compared with adults (76, 77). spond to first-line therapies. quality of life measured by the Short Form 36 in
immune thrombocytopenic purpura: a cross-sec-
There is increasing knowledge of long- tional survey in China. Eur J Haematol 2007; 78:
term safety in adults (78–80) but not in 518–523.
children. Potential and theoretical risks in- Outlook 7. Sarpatwari A, Watson S, Erqou S et al. Health-re-
lated lifestyle in adults and children with primary
clude
• thromboembolic events that may be There are several challenges and questions immune thrombocytopenia (ITP). Br J Haematol
2010; 151: 189–191.
triggered by the TPO-RAs directly or in regarding pediatric ITP. The small number of

© Schattauer 2017 Hämostaseologie 1/2017


43 Kühne T. Immune thrombocytopenia in childhood

8. Imbach P, Kühne T, Müller D et al. Childhood ITP: 25. Rischewski JR, Imbach P, Paulussen M, Kühne T. 41. Lilleyman JS. Intracranial haemorrhage in idio-
12 months follow-up data from the prospective Idiopathic Thrombocytopenic Purpura (ITP): Is pathic thrombocytopenic purpura. Arch Dis Child
registry I of the Intercontinental Childhood ITP there a genetic predisposition? Pediatr Blood 1994; 71: 251–253.
Study Group (ICIS). Pediatr Blood Cancer 2006; Cancer 2006; 47: 678–680. 42. Psaila B, Petrovic A, Page LK et al. Intracranial
46: 351–356. 26. Buchanan GR. 50 years ago in the Journal of Pedi- hemorrhage (ICH) in children with immune
9. Rosthoj S, Rajantie J, Treutiger I et al. Duration atrics: familial idiopathic thrombocytopenic pur- thrombocytopenia (ITP): study of 40 cases. Blood
and morbidity of chronic immune thrombocyto- pura. J Pediatr 2013; 162: 704. 2009; 114: 4777–4783.
penic purpura in children: five-year follow-up of a 27. Drachman JG. Inherited thrombocytopenia: when 43. Rosthoj S, Hedlund-Treutiger I, Rajantie J et al.
Nordic cohort. Acta Paediatr 2012; 101: 761–766. a low platelet count does not mean ITP. Blood Duration and morbidity of newly diagnosed idio-
10. Sutor AH, Harms A, Kaufmehl K. Acute Immune 2004; 103: 390–398. pathic thrombocytopenic purpura in children: A
thrombocytopenia (ITP) in childhood: Retrospec- 28. Teachey DT, Lambert MP. Diagnosis and manage- prospective Nordic study of an unselected cohort. J
tive and prospective survey in Germany. Semin ment of autoimmune cytopenias in childhood. Pedatr 2003; 143: 302–307.
Thromb Hemost 2001; 27: 253–267. Pediatr Clin N Am 2013; 60: 1489–1511. 44. Cecinati V, Principi N, Brescia L et al. Vaccine ad-
11. Zeller B, Helgestad J, Hellebostad M et al. Immune 29. Teachey DT. New advances in the diagnosis and ministration and the development of immune
thrombocytopenic purpura in childhood in Nor- treatment of autoimmune lymphoproliferative thrombocytopenic purpura in children. Hum Vac-
way: a prospective, population-based registration. syndrome (ALPS). Curr Opin Pediatr 2012; 24: cin Immunother 2013; 9: 1158–1162.
Pediatr Hematol Oncol 2000; 17: 551–558. 1–8. 45. Klein NP, Lewis E, Fireman B et al. Safety of
12. Schoonen WM, Kucera G, Coalson J et al. Epi- 30. Oliveira JB, Bleesing JJ, Dianzani U et al. Revised measles-containing vaccines in 1-year-old
demiology of immune thrombocytopenic purpura diagnostic criteria and classification for the auto- children. Pediatrics 2015; 135: e321-e329.
in the General Practice Research Database. Br J immune lymphoprolifertive syndrome (ALPS): re- 46. Kim CY, Lee EH, Yoon HS. High Remission Rate
Haematol 2009; 145: 235–244. port from the 2009 NIH International Workshop. of Chronic Immune Thrombocytopenia in

Downloaded by: Queen Mary, University of London. Copyrighted material.


13. Moulis G, Palmaro A, Montastruc JL et al. Epi- Blood 2010; 116: e35–e40. Children: Result of 20-Year Follow-Up. Yonsei
demiology of incident immune thrombocytope- 31. Price V. Auto-immune lymphoproliferative dis- Med J 2016; 57: 127–131.
nia: a nationwide population-based study in order and other secondary immune thrombocy- 47. Kühne T, Imbach P. Management of children and
France. Blood 2014; 124: 3308–3315. topenias in childhood. Pediatr Blood Cancer 2013; adolescents with primary immune thrombocy-
14. Kühne T, Imbach P, Bolton-Maggs PHB et al. 60: S12S14. topenia: controversies and solutions. Vox Sang
Newly diagnosed idiopathic thrombocytopenic 32. Kühne T, Berchtold W, Michaels LA et al. Newly 2013; 104: 55–66.
purpura in childhood: an observational study. diagnosed immune thrombocytopenia in children 48. Teachey DT, Lambert MP. Diagnosis and manage-
Lancet 2001; 358: 2122–2125. and adults, a comparative prospective observa- ment of autoimmune cytopenias in childhood.
15. Yong M, Schoonen WM, Li L et al. Epidemiology tional registry of the Intercontinental Cooperative Pediatr Clin N Am 2013; 60: 1489–1511.
of paediatric immune thrombocytopenia in the Immune Thrombocytopenia Study Group. Hae- 49. Fiore M, Pillois X, Lorrain S et al. A diagnostic ap-
General Practice Research Database. Br J Haema- matologica 2011; 96: 1831–1837. proach that may help to discriminate inherited
tol 2010; 149: 855–864. 33. Flores A, Buchanan GR. Occult hemorrhage in thrombocytopenia from chronic immune throm-
16. Warner MN, Moore JC, Warkentin TE et al. A children with severe ITP. Am J Hematol 2016; 91: bocytopenia in adult patient. Platelets 2016; 27:
prospective study of protein-specific assays used to 287–290. 555–562.
investigate idiopathic thrombocytopenic purpura. 34. Revel-Vilk S, Yacobovich J, Frank S et al. Age and 50. Neunert C, Lim W, Crowther M et al. The Ameri-
Br J Haematol 1999; 104: 442–447. duration of bleeding symptoms at diagnosis best can Society of Hematology 2011 evidence-based
17. Olsson B, Andersson PO, Jernas M et al. T-cell- predict resolution of childhood immune throm- practice guideline for immune thrombocytopenia.
mediated cytotoxicity toward platelets in chronic bocytopenia at 3, 6, and 12 months. J Pediatr 2013; Blood 2011; 117: 4190–4207.
idiopathic thrombocytopenic purpura. Nat Med 163: 1335–1339. 51. Bolton-Maggs PH. Severe Bleeding in idiopathic
2003; 9: 1123–1124. 35. van Bladel ER, Laarhoven AG, van der Heijden LB thrombocytopenic purpura. J Pediatr Hematol
18. Zhang F, Chu X, Wang L et al. Cell-mediated lysis et al. Functional platelet defects in children with Oncol 2003; 25: S47-S51.
of autologous platelets in chronic idiopathic severe chronic ITP as tested with two novel assays 52. Buchanan GR, Adix L. Grading of hemorrhage in
thrombocytopenic purpura. Eur J Haematol 2006; applicable for low platelet counts. Blood 2014; 123: children with idiopathic thrombocytopenic pur-
76: 427–341. 1556–1563. pura. J Pediatr 2002; 141: 683–688.
19. Guo L, Kapur R, Aslam R et al. CD20+ B-cell de- 36. Frelinger AL, Grace RF, Gerrits AJ et al. Platelet 53. Edslev PW, Rosthøj S, Treutiger I et al. A clinical
pletion therapy suppresses murine CD8+ T-cell- function tests, independent of platelet count, are score predicting a brief and uneventful course of
mediated immune thrombocytopenia. Blood 2016; associated with bleeding severity in ITP. Blood newly diagnosed idiopathic trombocytopenic pur-
127: 735–738. 2015; 126: 873–879. pura in children. Br J Hematol 2007; 138: 513–516.
20. Nishimoto T1, Kuwana M. CD4+CD25+Foxp3+ 37. Middelburg RA, Carbaat-Ham JC et al. Platelet 54. Rodeghiero F, Michel M, Gernsheimer T et al.
regulatory T cells in the pathophysiology of im- function in adult ITP patients can be either in- Standardization of bleeding assessment in im-
mune thrombocytopenia. Semin Hematol 2013 creased or decreased, compared to healthy con- mune thrombocytopenia: report from the Inter-
Jan; 50: S43S49. trols, and is associated with bleeding risk. Hema- national Working Group. Blood 2013; 121:
21. Aslam R, Segel GB, Burack R et al. Splenic lymp- tology 2016; 21:549–551. 2596–2606.
hocyte subtypes in immune thrombocytopenia: 38. Neunert C, Noroozi N, Norman G et al. Severe 55. Khellaf M, Michel M, Schaeffer A et al. Assessment
increased presence of a subtype of B-regulatory bleeding events in adults and children with pri- of a therapeutic strategy for adults with severe
cells. Br J Haematol 2016; 173: 159–160. mary immune thrombocytopenia: a systematic re- autoimmune thrombocytopenic purpura based on
22. Jernas M, Nookaew I, Wadenvik H, Olsson B. view. J Thromb Haemost 2014; 13: 457–464. a bleeding score rather than platelet count. Hae-
MicroRNA regulate immunological pathways in 39. Neunert CE, Buchanan GR, Imbach P et al. Severe matologica 2005; 90: 829–832.
T-cells in immune thrombocytopenia (ITP). Blood hemorrhage in children with newly diagnosed im- 56. Klaassen RJ, Blanchette V, Burke TA et al. Quality
2013; 121: 2095–2098. mune thrombocytopenic purpura. Blood 2008; of life in childhood immune thrombocytopenia:
23. McKenzie CG, Guo L, Freedman J, Semple JW. 112: 4003–4008. international validation of the kids‘ ITP tools.
Cellular immune dysfunction in immune throm- 40. Neunert CE, Buchanan GR, Imbach P et al. Bleed- Pediatr Blood Cancer 2013; 60: 95–100.
bocytopenia (ITP). Br J Haematol 2013; 163: ing manifestations and management of children 57. Grainger JD, Young NL, Blanchette VS, Klaassen
10–23. with persistent and chronic immune thrombocy- RJ. Quality of life in immune thrombocytopenia
24. Zhang B, Lo C, Shen L et al. The role of vanin-1 topenia: data from the Intercontinental Cooper- following treatment. Arch Dis Child 2013; 98:
and oxidative stress–related pathways in distin- ative ITP Study Group (ICIS). Blood 2013; 121: 895–897.
guishing acute and chronic pediatric ITP. Blood 4457–4462. 58. Heitink-Pollé KMJ, Haverman L, Annink KV et al.
2011; 117: 4569–4579. Health-related quality of life in children with

Hämostaseologie 1/2017 © Schattauer 2017


Kühne T. Immune thrombocytopenia in childhood 44

newly diagnosed immune thrombocytopenia. 70. Wali YA, Al Lamki Z, Shah W et al. Pulsed high- servational study. Br J Haematol 2014; 165:
Haematologica 2014; 99: 1525–1531. dose dexamethasone therapy in children with 865–869.
59. Klaassen RJ, Mathias SD, Buchanan G et al. Pilot chronic idiopathic thrombocytopenic purpura. 82. Gonzalez-Lopez TJ, Pascual C, Alvarez-Roman
Study of the Effect of Romiplostim on Child Pediatr Hematol Oncol 2002; 19: 329–335. MT et al. Successful discontinuation of eltrombo-
Health-Related Quality of Life (HRQoL) and Par- 71. Khalafallah A, Rahman Z, Ogden K, Hannan T. pag after complete remission in patients with pri-
ental Burden in Immune Thrombocytopenia Successful treatment with thrombopoietin recep- mary immune thrombocytopenia. Am J Hematol
(ITP). Pediatr Blood Cancer 2012; 58: 395–398. tor agonist in avoiding splenectomy for patients 2015; 90: E40–E43.
60. Provan D, Stasi R, Newland AC et al. International with chronic refractory immune thrombocytope- 83. Schifferli A, Kühne T. Thrombopoietin Receptor
consensus report on the investigation and man- nia. Mediterr J Hematol Infect Dis 2012; 4: Agonists: A New Immune Modulatory Strategy in
agement of primary immune thrombocytopenia. e2012003. ITP? Sem Hematol 2016; 53: S31–S34.
Blood 2010; 115: 168–186. 72. Schifferli A, Kühne T. Chronic immune throm- 84. Kühne T, Freedman J, Semple JW et al. Platelet and
61. George JN, Woolf SH, Raskob GE et al. Idiopathic bocytopenia in children: who needs splenectomy? immune responses to oral cyclic dexamethasone
thrombocytopenic purpura: a practice guideline Semin Hematol 2013; 50: S58S62. therapy in childhood chronic immune throm-
developed by explicit methods for The American 73. Kühne T. Treatment of pediatric primary immune bocytopenic purpura. J Pediatr 1997; 130: 17–24.
Society of Hematology. Blood 1996; 88: 3–40. thrombocytopenia with thrombopoietin receptor 85. Borgna-Pignatti C, Rugolotto S, Nobili B et al. A
62. Salama A, Rieke M, Kiesewetter H, von Depka M. agonists. Sem Hematol 2015; 52: 25–30. trial of high-dose dexamethasone therapy for
Experiences with recombinant FVIIa in the 74. Tarantino MD, Bussel JB, Blanchette VS et al. chronic idiopathic thrombocytopenic purpura in
emergency treatment of patients with autoimmune Romiplostim in children with immune throm- childhood. J Pediatr 1997; 130: 13–16.
thrombocytopenia: a review of the literature. Ann bocytopenia: a phase 3, randomised, double-blind, 86. Khellaf M, Charles-Nelson A, Fain O et al. Safety
Hematol 2009; 88: 11–15. placebo-controlled study. Lancet 2016; 388: 45–54. and efficacy of rituximab in adult immune throm-
63. Larsen OH, Stentoft J, Radia D et al. Combination 75. Neunert C, Despotovic J, Haley K et al. Thrombo- bocytopenia: results from a prospective registry

Downloaded by: Queen Mary, University of London. Copyrighted material.


of recombinant factor VIIa and fibrinogen corrects poietin Receptor Agonist Use in Children: Data including 248 patients. Blood 2014; 124:
clot formation in primary immune thrombocy- From the Pediatric ITP Consortium of North 3228–3236.
topenia at very low platelet counts. Br J Haematol America ICON2 Study. Pediatr Blood Cancer 87. Liang Y, Zhang L, Gao J et al. Rituximab for
2013; 160: 228–236. 2016; 63: 1407–1413. children with immune thrombocytopenia: a sys-
64. Wie Y, Ji X, Wang Y et al. High-dose dexametha- 76. Bussel JB, de Miguel PG, Despotovic JM et a. El- tematic review. PLoS One 2012; 7: e36698.
sone vs prednisone for treatment of adult immune trombopag for the treatment of children with per- 88. Matsubara K, Takahashi Y, Hayakawa A et al.
thrombocytopenia: a prospective multicenter ran- sistent and chronic immune thrombocytopenia Long-term follow-up of children with refractory
domized trial. Blood 2016; 127: 296–302. (PETIT): a randomised, multicentre, placebo-con- immune thrombocytopenia treated with rituxi-
65. Cuker A, Neunert C. How I treat refractory im- trolled study. Lancet Hematol 2015; 2: e315e325. mab. Int J Hematol 2014; 99: 429–436.
mune thrombocytopenia. Blood 2016 [Epub ahead 77. Grainger JD, Locatelli F, Chotsampancharoen T et 89. Dai WJ, Zhang RR, Yang XC, Yuan YF. Efficacy of
of print] al. Eltrombopag for children with chronic immune standard dose rituximab for refractory idiopathic
66. Kühne T, Blanchette V, Buchanan GR et al. Sple- thrombocytopenia (PETIT2): a randomised, thrombocytopenic purpura in children. Eur Rev
nectomy in children with idiopathic thrombocyto- multicentre, placebo-controlled trial. Lancet 2015; Med Pharmacol Sci 2015; 19: 2379–2383.
penic purpura: A prospective study of 134 children 386: 1649–1658. 90. Bussel JB, Lee CS, Seery C et al. Rituximab and
from the Intercontinental Childhood ITP Study 78. Kuter DJ, Bussel JB, Newland A et al. Long-term three dexamethasone cycles provide responses
Group. Pediatr Blood Cancer 2007; 49: 829–834. treatment with romiplostim in patients with similar to splenectomy in women and those with
67. Aladjidi N, Santiago R, Pondarré C et al. Revisiting chronic immune thrombocytopenia: safety and ef- immune thrombocytopenia of less than two years
Splenectomy in Childhood Immune Thrombocy- ficacy. Br J Haematol 2013; 161: 411–423. duration. Haematologica 2014; 99: 1264–1271.
topenic Purpura in the Era of New Therapies: The 79. Saleh MN, Bussel JB, Cheng G et al. Safety and ef- 91. Choi PY, Roncolato F, Badoux X et al. A novel
French Experience. J Blood Disorders Transf 2012; ficacy of eltrombopag for treatment of chronic im- triple therapy for ITP using high-dose dexametha-
S3: 003. mune thrombocytopenia: results of the long-term, sone, low-dose rituximab, and cyclosporine (TT4).
68. Kojouri K, Vesely SK, Terrell DR, George JN. Sple- open-label EXTEND study. Blood 2013; 121: Blood 2015; 126: 500–503.
nectomy for adult patients with idiopathic throm- 537–545. 92. Zhou H, Xu M, Qin P et al. A multicenter random-
bocytopenic purpura: a systematic review to assess 80. Cines DB, Gernsheimer T, Wasser J et al. Inte- ized open-label study of rituximab plus rhTPO vs
long-term platelet count responses, prediction of grated analysis of long-term safety in patients with rituximab in corticosteroid-resistant or relapsed
response, and surgical complications. Blood 2004; chronic immune thrombocytopaenia (ITP) treated ITP. Blood 2015; 125: 1541–1547.
104: 2623–2634. with the thrombopoietin (TPO) receptor agonist 93. European Medicine Agency. Revolade.
69. Auger S, Duny Y, Rossi JF, Quittet P. Rituximab be- romiplostim. Int J Hematol 2015; 102: 259–270. http://www.ema.europa.eu/ema/index.jsp?
fore splenectomy in adults with primary idiopathic 81. Mahevas M, Fain O, Ebbo M et al. The temporary curl=pages/medicines/human/medicines/
thrombocytopenic purpura: a meta-analysis. Br J use of thrombopoietin-receptor agonists may in- 001110/human_med_001322.jsp&mid=
Haematol 2012; 158: 386–398. duce a prolonged remission in adult chronic im- WC0b01ac058001d124 (accessed October 1, 2016)
mune thrombocytopenia. Results of a French ob-

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