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Management of Immune Thrombocytopenic Purpura in Children

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DOI: 10.2165/11591640-000000000-00000 · Source: PubMed

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 Pediatr Drugs 2011; 13 (4): 213-223
LEADING ARTICLE 1174-5878/11/0004-0213/$49.95/0

ª 2011 Adis Data Information BV. All rights reserved.

Management of Immune Thrombocytopenic

Purpura in Children
Potential Role of Novel Agents
Amy Lee Bredlau,1 John W. Semple2 and George B. Segel3
1 Department of Pediatrics, Division of Hematology/Oncology, University of Rochester, Rochester, NY, USA

This material is
2 Keenan Research Centre, Li Ka Shing Knowledge Institute of St Michael’s Hospital, Department of Pharmacology and Toxicology,
University of Toronto, Toronto, ON, Canada
3 Departments of Pediatrics and Medicine, Division of Hematology/Oncology, University of Rochester, Rochester, NY, USA

Abstract
the copyright of the
The treatment of immune thrombocytopenic purpura (ITP) in children is controversial, requiring in-
dividualized assessment of the patient and consideration of treatment options. If the platelet count is
>10 000/mL and the patient is asymptomatic, a ‘watch and wait’ strategy is appropriate since most children

original publisher.
with ITP will recover completely without pharmacotherapy. If therapy is indicated because of bleeding or a
platelet count <10 000/mL, then treatment with glucocorticoids, intravenous immunoglobulin (IVIg), or anti-
D are possible initial choices. Glucocorticoid treatment is the least expensive and is our usual first choice of
therapy. Its use assumes that the blood counts and blood film have been evaluated to ensure the absence of

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evidence of alternative diagnoses, such as thrombotic thrombocytopenic purpura or incipient acute leu-
kemia. IVIg is expensive and often causes severe headache, nausea and vomiting, and requires hospital-
ization at our institution. Anti-D therapy is also expensive and can only be used in patients who are Rhesus
D positive. These therapies, even if only transiently effective, can be repeated if necessary. Children usually

and distribution
recover from newly diagnosed ITP, with or without multiple courses of medical therapy.
If the disease becomes ‘persistent’ with severe thrombocytopenia and/or bleeding, and is no longer
responsive to the three first-line therapies, the next approach includes the use of thrombopoietin receptor
agonists or rituximab. When the disease persists for more than 1 year, it is considered chronic, and, if
symptomatic, it may become necessary to consider third-line therapies, including splenectomy, alternative

is prohibited.
immunosuppressive agents, or combination or investigative chemoimmunotherapy. This review considers
the indications, mechanism of action, and effectiveness of the traditional and novel treatment options for
patients with ITP.

Immune thrombocytopenic purpura (ITP), previously re-
ferred to as idiopathic thrombocytopenic purpura, is an auto-
immune disease, characterized clinically by a platelet count
<100 000/mL without any another explanation. ITP is a disease
of adults (>18 years) and children (£18 years), although the two
diseases are different in duration and prognosis. This paper will
focus on the pathogenesis and treatment of ITP in children.
ITP affects approximately 3/100 000 children each year world-
wide.[1] Most will experience a brief course of thrombocyto-
penia, with or without bleeding, and will recover completely
within 12 months. The International Working Group Con-
sensus reclassified ITP into three groups. ITP cases within the
first 3 months from presentation are classified as ‘newly diag-
nosed’ and those lasting from 3 to 12 months are classified
as ‘persistent’.[2] These classifications account for about 80%
of patients with childhood ITP.[2] Approximately 20% of affected
children develop chronic ITP,[3] defined as a platelet count of
<100 000/mL lasting for 12 months or more. The platelet count
generally improves over time, even in children with chronic
ITP;[4] however, the decision to treat the child between onset
and resolution of ITP can be challenging. In this review we will
catalog the available treatments for acute and chronic ITP, and
relate their mechanism of action to the pathophysiology of the
disease. When the published literature does not provide clear
214
therapeutic strategies for ITP, we will share the experience of
therapies administered at our institution.
1. Pathogenesis
The pathogenesis of ITP was first described by Harrington in
1951. He infused plasma from a patient with ITP into him-
self and later other adult volunteers, and monitored platelet
response. He found that within 24 hours of plasma infusion,
platelet counts plummeted to those seen in ITP patients.[5]
This material is
Subsequent studies showed that the offending component in the
plasma of ITP patients was an immunoglobulin (Ig) G anti-
body[6] with specificity for epitopes such as GPIb/IX and GPIIb/
IIIa on the platelet surface.[7] The antibody activity in ITP
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may not be directed solely against platelets and may activate
the Fcg-receptor bearing mononuclear cells of the spleen (and
other tissues of the mononuclear phagocyte system), resulting
in increased platelet phagocytosis and destruction.[8] Anti-
original publisher.
platelet antibodies may also fix complement leading to in-
creased platelet lysis and phagocytosis.[8-10]
Adults may have chronic or relapsing disease, and, in con-
trast, most children have a self-limited course wherein about
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80% recover within 1 year.[11] The concept of ‘antigenic mimi-
cry’ in response to a viral infection may account for the marked
but relatively brief duration of childhood immune-mediated
thrombocytopenia. Similarity of epitopes on the viral surface
to the epitopes, IIb/IIIa, Ib, or others, on the platelet produce a
and distribution
B-lymphocyte response with IgG antibody production that
binds to platelets by a cross-reaction, resulting in platelet re-
moval and an acute fall in the patient’s platelet count. Resolu-
tion of the viral infection is facilitated by the antiviral antibody
is prohibited.
response. In time, the virus is eliminated and the primary stim-
ulus for antibody production is removed. The half-life of IgG is
approximately 3 weeks and the titer of antibody gradually de-
creases, followed by recovery of the platelet count, accounting
for the clinical course of ITP in most children.[12]
The persistence of platelet destruction in approximately 20%
of children and the majority of adults is likely related to alter-
ations of T-lymphocyte regulation. T-lymphocyte defects have
been documented in patients with ITP[13] and a much clearer
picture of the T-cell role in the pathogenesis of the disorder
has emerged.[14] Probably the major underlying defect in the
autoimmune pathogenesis of ITP lies in decreased activity of
T-regulatory cells (Tregs), as indicated by decreased suppres-
sion of CD4+CD25- cells by CD4+CD25+ Tregs,[15] as well as by
decreased blood levels of Th2 cells and Tc2 cells.[16] These al-
terations are thought to reduce self-tolerance and facilitate
autoimmune platelet destruction (figure 1).
ª 2011 Adis Data Information BV. All rights reserved.
Bredlau et al.
Platelet and
megakaryocyte
destruction
Autoantibodies
3.
CTL Plasma
Cell
Platelet
CD8
B
APC Processing
(macrophage) presentation 2.
Help
CD4
Treg
1.
Fig. 1. Diagram outlining the major lymphocyte abnormalities in patients
with chronic immune thrombocytopenic purpura, which is related to T-cell
dysfunction. (1) Defective T-regulatory cells (Tregs) are deficient, defective
and/or non-functional, which leads to a break in immune tolerance. This ab-
normality allows for (2) platelet auto-antigens to be presented by macro-
phages to autoreactive CD4+ T-helper cells, which subsequently mediate a
series of abnormal cellular processes such as (3) autoreactive effector cell
responses, e.g. antiplatelet and/or megakaryocyte-specific autoantibodies
and CD8+ cytotoxic T lymphocyte (CTL) responses which produce throm-
bocytopenia (adapted from Semple et al.,[14] with permission). APC = antigen
presenting cell.
On the other hand, in patients with ITP devoid of platelet
autoantibodies, thrombocytopenia can be mediated by CD8+
T cells.[17] In these patients with thrombocytopenia there are
blood cytotoxic T lymphocytes (CTL) that bind to and cause
significant lysis of platelets in vitro, whereas those patients in
remission had little antiplatelet CTL reactivity. This obser-
vation was confirmed in a large clinical study.[18] It may be that
CTL in patients with chronic ITP are not cleared by normal
apoptotic mechanisms and persist to destroy platelets.[19] An
animal model of ITP suggests that CTL may enter the marrow
and injure megakaryocytes, perhaps leading to a platelet pro-
duction defect.[20]
The production of platelets is also impaired in ITP patients.
The megakaryocytes in ITP are abnormal, showing distended
demarcation membranes, vacuolated cytoplasm, swollen mito-
chondria, condensed nuclear chromatin, and disrupted cyto-
plasmic peripheral zones, occasionally with activated monocytes
Pediatr Drugs 2011; 13 (4)
Novel Treatments for ITP
in the vicinity.[19] In vivo, there is suppression of megakaryo-
cytes in the presence of anti GPIb/IX with or without anti-
GPIIb/IIIa antibodies.[19] The activity of antiplatelet antibodies
and CTLs[19] leads to megakaryocyte damage, apoptosis, and
decreased thrombopoiesis.[8]
2. Treatment Options
2.1 Newly Diagnosed Immune Thrombocytopenic
Purpura (ITP)
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If the platelet count is >10 000/mL with minimal signs of
bleeding (e.g. slight blood tinge in mucous, brief epistaxis, or
mild bleeding on brushing of teeth without identifiable source
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of bleeding), if there is a reliable caregiver, and the child has not
experienced head trauma or taken an antiplatelet agent such as
aspirin (acetylsalicylic acid), it is appropriate to monitor the
child without pharmacotherapy.[11] Alternatively, if there is
significant bleeding (e.g. mucosal, gastrointestinal, urinary,
original publisher.
menstrual, or nervous system bleeding) treatment is indicated.
In our view, it is prudent to treat an asymptomatic patient if
platelet count is below 10 000/mL because the frequency of
moderate (e.g. epistaxis or menorrhagia that is troublesome but
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not requiring hospitalization) to severe (e.g. poorly-controlled
epistaxis, melena, or menorrhagia requiring hospitalization)
bleeding increases below this threshold;[21] however, some
clinicians prefer to observe patients with few symptoms and
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platelet counts below 10 000/mL.
Agents available for treatment of newly diagnosed ITP in-
clude glucocorticoids, intravenous immunoglobulin (IVIg),
and anti-Rhesus (anti-D) immunoglobulin (table I).[16]
is prohibited.
These treatments inhibit platelet binding to the Fc receptors
of macrophages and block the removal of antibody-coated
platelets. Glucocorticoids may also stabilize the integrity of the
blood vessel endothelium.
2.1.1 Glucocorticoids
Glucocorticoids are the most cost-effective treatment of
acute ITP.[12] The hemoglobin, total and differential white cell
count are characteristically normal in patients with ITP. If
hemoglobin is low or the white cell or differential counts are
abnormal, the patient should be evaluated for an alternative
diagnosis, particularly to avoid treating lymphoblastic leuke-
mia with glucocorticoids alone.
The usual dosage of prednisone is 2–4 mg/kg/day in two
divided doses, administered for no more than 2 weeks, at which
time the platelet count is usually >100 000/mL. The dose is then
rapidly tapered to the minimum required to maintain a platelet
ª 2011 Adis Data Information BV. All rights reserved.
215
level (usually >30 000/mL) that renders the patient asympto-
matic. It is our institutional practice to change administration
of prednisone to once per day and then every other day if the
platelet count remains >30 000/mL. An alternative prednisone
dosing schedule is 4 mg/kg/day for 4 days.[35] This approach
reduces the adverse side effects of long-term glucocorticoid
treatment. High-dose oral dexamethasone at 20 mg/m2/day for
4 days may be used in lieu of prednisone.[28] The platelet count
may respond less rapidly to glucocorticoid therapy than to IVIg
or anti-D. Approximately 30% of patients respond in 24 hours
and 70% respond in 48 hours with glucocorticoids.[33] Nearly all
treated patients responded with an increase in platelet count to
over 50 000/mL after 1 week of treatment. The presumptive
mechanisms of glucocorticoid action involve decreased anti-
body attachment to macrophage Fc receptors,[36] decreased
phagocytosis of platelets by macrophages,[11] stabilization of
the vascular endothelium,[37] and inhibition of B-lymphocyte
antibody production (longer-term effect).[38]
The side effects of glucocorticoid therapy include gastro-
intestinal symptoms (a histamine H2 blocker can be prescribed
with prolonged glucocorticoid therapy), impaired glucose tol-
erance, Cushingoid changes, hypertension, loss of bone density,
impaired immunity and impaired growth with long-term treat-
ment, but these are a function of the dose and duration of
glucocorticoid use. They are usually not an issue during a few
weeks of treatment.
2.1.2 Intravenous Immunoglobulin
It is our recommendation that IVIg be used to treat acute
ITP when there are contraindications to the use of glucocorti-
coids, such as glucose intolerance, hypertension, or intestinal
ulceration, or at the preference of the therapist. Its use rapidly
increases the platelet count in approximately 75% of patients in
24 hours.[30] It should be administered slowly at a single dose of
0.8–1.0 g/kg. The specific mechanism of action remains un-
known, but it presumably blocks phagocytosis and destruction
of antibody-coated cells. IVIg contains anti-A, anti-B and po-
tentially anti-D that may coat red cells with the corresponding
antigens, blocking Fc receptors on macrophages via mass ac-
tion in a fashion similar to anti-D (WinRho) [see section 2.1.3].
It may also reduce the affinity of macrophage low affinity Fc
receptor types (FcgRIIA and FcgRIIIA) in binding the Fc
portion of the antibody molecule[11] and/or enhance inhibitory
receptors (FcgRIIB).[39] Antigen-presenting dendritic cells
modulate the upregulation of the inhibitory receptors.[39]
In our institution, the use of IVIg requires hospitalization,
making it a more intrusive and expensive procedure than the
use of glucocorticoids. Adverse events such as headache, fever,
Pediatr Drugs 2011; 13 (4)
 Table I. Established and novel treatment options for newly diagnosed, persistent, and chronic immune thrombocytopenic purpura (ITP)a

216
Study (y) Recommended Approximate rate of response Approximate Toxicities Duration of sustained response
treatment strategy time to response
Bussel et al.[22] AKR-501 65–90% response 2 wk Fatigue, headache, epistaxis, thrombosis Therapy dependent, but
(2010)b 2.5–40 mg PO daily long-term responses
Beck et al.[23] Romiplostim 1 pediatric case report 2 wk Headache, rare marrow fibrosis >2 mo
(2010) 1–10 mg/kg/wk SC
Bussel et al.[24,25] Eltrombopag 70% response 1–2 wk Nausea and vomiting, increased liver function Therapy dependent, but long-
(2009)b 25–75 mg PO daily enzymes, rare thromboembolus term responses
Podolanczuk Fostamatinib 50% response NS Diarrhea, vomiting, increased liver function enzymes 50% with sustained responses
et al.[26] (2009)b 75–175 mg PO bid on therapy

ª 2011 Adis Data Information BV. All rights reserved.

Tarantino and IVIg Effective in more than 1–2 d Headache (which can be severe), fever, One-third of patients become
Bolton-Maggs[27] 0.8–1 g/kg once 80% of patients vomiting, hemolysis, rare renal failure symptomatic after 2–6 wk
(2007)
Mazzucconi Dexamethasone Up to 80% achieve a platelet 3d Sleeplessness, behavioral changes, hypertension, Responses may be short-term
et al.[28] (2007) 20 mg/m2/d PO daily response anxiety, gastric distress, cataract, diabetes mellitus unless cycles are repeated
for 1–4 days
Kuhne et al.[29] Splenectomy 70% long-term response 24 h Postsplenectomy sepsis 80% of responders maintain
(2007) platelet response for 4 y
Tarantino Anti-D 50–70% achieve a platelet ‡50% respond Headache, fever, chills (less common than with Similar to IVIg although longer
et al.[30] (2006) 50–75 mg/kg IV response depending on dose within 24 h IVIg), hemolysis, rare renal failure responses described with
repeated dosing
Buchanan and Watch and wait Two thirds of children improve Days to ~6 mo Questionable risk of severe hemorrhage, Spontaneous remissions are
Adix[11] (2006) spontaneously within 6 mo activity restriction, anxiety generally durable
Bennett et al.[31] Rituximab 30–80% response rates Within a few wk Serum sickness, infusion reaction, maculopapular 65% achieved a CR lasting
(2006) 375 mg/m2/wk IV reported (CR/PR/MR) rash, arthralgia, low-grade fever, malaise, pruritus, 4–30 mo; however, this is
for 4 wk urticaria. Usually mild and easily resolved variable in the literature
Rao et al.[32] Mycophenolate mofetil 25–100% response rates Within 2 wk Commonly headache, diarrhea, hypertension, Therapy-dependent, but CR
(2005) 600 mg/m2 PO bid reported (CR/PR/MR) nausea, abdominal pain. Severe – leukopenia, 1–240 mo

is prohibited.
anemia, thrombocytopenia
Calderwood Prednisone Up to 75% of patients will 2–7 d Sleeplessness, behavioral changes, hypertension, Variable – may require
This material is

and distribution
et al.[33] (1994) 1–2 mg/kg/d PO for up respond, depending on dose anxiety, gastric distress, cataract, diabetes, and continued treatment
to 2 wk weight gain. Caution in presence of active infection
original publisher.

(especially varicella) or GI bleeding

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Ahn et al.[34] Vincristine 60% response as single Within 2 wk Reversible peripheral neuropathy, jaw pain, CR 2–24 mo
(1974) 1 mg IV every 7–10 d therapy constipation, impotence, SIADH (rare) with
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larger doses
a See section 2 for mechanism of action of these agents.
b Adult data only.
bid = twice daily; CR = complete response; GI = gastrointestinal; IV = intravenously; IVIg = intravenous immunoglobulin; MR = maintained response; NS = not stated; PO = orally; PR = partial
response; SC = subcutaneously; SIADH = syndrome of inappropriate antidiuretic hormone hypersecretion.

Pediatr Drugs 2011; 13 (4)

Bredlau et al.
Novel Treatments for ITP
nausea and vomiting, allergic reactions, aseptic meningitis, and
severe hemolysis and renal failure have been reported in chil-
dren, and thrombosis has been reported in adults.[40] Headache,
in particular, is a troublesome complication in a thrombocy-
topenic patient because of concern about potential intracranial
hemorrhage. Such patients require computerized tomographic
imaging of the head to evaluate this possibility. Headache and
other side effects can be reduced by pretreatment with aceta-
minophen (paracetamol) and diphenhydramine, and by pro-
longing the duration of the infusion to 6–8 hours or longer.
2.1.3 Anti-D This material is
Anti-D (WinRho) is an alternative to the use of IVIg and
may be chosen for the treatment of ITP if the patient is Rhesus
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D positive or has had a severe reaction to IVIg. It is ad-
ministered intravenously at either 50 or 75 mg/kg during a
20-minute infusion. Response is somewhat more rapid at the
higher dose, with 70% of patients treated with 75 mg/kg (vs 50%
original publisher.
of patients treated with 50 mg/kg) experiencing an increase in
platelet count above 20 000/mL within 24 hours.[30] The mech-
anism of action of this agent is related to the very high ratio of
red cells to platelets. When the red cells are coated with im-
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munoglobulin (anti-D), they saturate the Fc receptor sites of
macrophages, particularly in the spleen and liver, preventing
binding of the IgG-coated platelets. In most circumstances, the
coated platelets remain functional in the circulation.
and distribution
The complications are similar to those seen with the use of
IVIg, but headache is a less prominent problem. A fall in hemo-
globin concentration of 1–2 g/dL is an expected consequence
of treatment.[41] Fever, chills, nausea, and vomiting may occur
is prohibited.
and may be decreased by premedication, as with IVIg. Severe
hemolysis with renal failure may follow treatment with anti-D,
and observation for at least 8 hours following infusion is now
required.[41] Similar to the use of IVIg, in our institution this
hospitalization increases the cost of therapy in contrast to
glucocorticoids.
2.2 Persistent or Chronic ITP
The Associazione Italiana di Ematologia e Oncologia Pe-
diatrica (AEIOP) indicates the use of either methylprednisolone
(15–30 mg/kg/day intravenously for 3 days), IVIg, or anti-D
for first-line therapy for emergent chronic childhood ITP
treatment.[42] Second- and third-line therapy for persistent and
chronic ITP includes agents such as rituximab, thrombopoietin
receptor agonists, splenectomy, and, less commonly, azathio-
prine, cyclosporin (cyclosporine; ciclosporin), cyclophos-
phamide, danazol, dapsone, mycophenolate mofetil, and vinca
ª 2011 Adis Data Information BV. All rights reserved.
217
alkaloids;[42] however, danazol and dapsone have not been
approved for use in children.
2.2.1 Rituximab
Rituximab is an anti-CD20 antibody that depletes B cells for
as long as 12–18 months.[43] It induces a long-term therapeutic
response (increase in platelet count over 150 000/mL) in a subset
of patients with chronic ITP, although only half of treated adult
patients have an increase in platelet count to that level, and
about one-third of patients have a sustained response off
therapy.[8] The modest long-term response to rituximab may be
related to the fact that CD20 is present on mature antibody-
producing B-lymphocytes, but is not an epitope present on
B-cell precursors. Responding patients who are retreated after
relapse have a 75% response rate. Overall, the response rate is
lower than that produced by splenectomy, which is approx-
imately 70%.[29] Rituximab can exacerbate systemic lupus
erythematosus or reactivate the disease in carriers of hepatitis
B.[8] Rituximab should be avoided in patients with immune
dysfunction, since severe, potentially fatal, viral infections can
occur. There is no need for concomitant administration of IVIg
in patients without underlying immunocompromise.[44]
Approximately 30% of children with chronic ITP responded
to four doses of weekly rituximab with platelet counts
>50 000/mL. Multiple studies show that approximately one-
third of children with chronic ITP have a continuous response
off therapy, usually after receiving 4 weekly doses of 375 mg/m2
intravenously.[31] Rituximab works best for children when they
have not been splenectomized.[45] Adverse events include in-
fusion reactions, serum sickness, acute or delayed neutropenia,
and reactivation of chronic infections (e.g. hepatitis B).[27,44,46]
Rituximab has a sustained effect in children with chronic ITP as
long as 1 year after therapy has been discontinued, although
there are some children who will relapse after several months of
normal platelet counts.[47]
2.3 Newer Therapies for Chronic ITP
2.3.1 Rozrolimupab
Rozrolimupab (Sym001) is a target-specific recombinant
polyclonal antibody against RhD. It competitively inhibits
phagocytosis of platelets in the mononuclear phagocyte system.
Its utility is currently being tested in Europe in adults with
chronic ITP.[48]
2.3.2 Fostamatinib
Fostamatinib (R788) is an orally available prodrug of the
Syk tyrosine kinase inhibitor. It inhibits the Syk kinase-mediated
Pediatr Drugs 2011; 13 (4)
218 Bredlau et al.

IgG Fcg receptor and consequently diminishes B-cell, macro-
phage, and mast-cell activity.[49] It has been used in a ther-
apeutic trial in adults at a dose of 75–175 mg twice daily. Initial
data suggest a 50% dose-dependent response rate, although it is
not yet approved for this use.[26]
2.3.3 Thrombopoietin Receptor Agonists
Early data published by Dameshek and Miller[50] in 1946
suggested that platelet production by megakaryocytes was di-
minished in both acute and chronic ITP when compared with
kinase (JAK), signal transducers and activators of transcription
(STAT) and mitogen-activated protein (MAP) kinase enzymatic
pathways, which result in increased platelet production.[56]
It has no sequence homology with thrombopoietin and has not
elicited an immunologic reaction and antibody production.[54] It
is administered parenterally at a dose of 1–10 mg/kg once weekly
and has produced a platelet count above 50 000/mL in approx-
imately 80% of treated patients.[57] Marrow fibrosis developed in a
small percentage of treated patients. Other unsubstantiated con-
cerns include thrombosis, stimulation of tumor growth, antibody

This material is
normal marrow or marrow from patients with hypersplenism.
Data also indicate that the plasma from patients with ITP
suppresses megakaryocyte proliferation in vitro.[51] These ob-
generation, and platelet activation. Improved platelet counts are
generally not sustained off romiplostim. The long-term risks of its
use have not yet been established.
servations suggest that stimulation of platelet production may

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be a viable treatment option for patients with chronic ITP. Two
non-antigenic thrombopoietin receptor agonists, romiplostim
(Nplate, Amgen) and eltrombopag (Promacta, Glaxo-
2.3.5 Eltrombopag
Eltrombopag is a small molecule in comparison with romi-
plostim (59 kDa, compared with a molecular weight of 442 Da).
SmithKline), increase thrombopoiesis and platelet counts in Eltrombopag is orally bioavailable and is effective with a once-

original publisher.
patients with chronic ITP. These new agents are being tested in
children but have proven both safe and effective in a number of
adult trials.[24,25,52-54] Recombinant thrombopoietin was also
studied. It was ineffective because of the development of anti-
daily dose of 25–75 mg/day.[25] It does not bind directly to the
thrombopoietin receptor, but rather traverses the receptor
to bind in the transmembrane region[25] (figure 3). Its signal
transduction differs from that of romiplostim because there is

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thrombopoietin antibodies, neutralizing its effect.[8]
2.3.4 Romiplostim
Romiplostim is a fusion product of an Fc fragment and a
thrombopoietin mimetic peptide, termed a ‘peptibody’. It binds to
much less activation of the STAT family of signal transducers
and no activation of the AK1 pathway.[58] However, the im-
paired platelet production characteristic of chronic ITP is im-
proved with its use, and clinical studies indicate that platelet
counts >50 000/mL can be produced in chronic ITP patients for

and distribution
the thrombopoietin receptor (figure 2) and activates the Janus more than 1 year if the drug is continued.[59] Moreover, the

Thrombopoietin

is prohibited.
receptor

Romiplostim Thrombopoietin

SHC GRB2
RAS/RAF
P P SoS
STAT3 P
P JAK2
STAT5
Cytoplasm
AK1 ERK1/2
P38 MAPK

Signal transduction

Increased platelet production

Fig. 2. Description of romiplostim activation of the Janus kinase (JAK), signal transducers and activators of transcription (STAT), and mitogen-activated protein
kinase (MAPK) pathways of signal transduction to increase platelet production. Romiplostim activates the thrombopoietin receptor (adapted from Gern-
sheimer,[55] with permission). AK1 = adenylate kinase 1; ERK = extracellular signal-related kinase; GRB2 = growth factor receptor-bound protein 2; P = phos-
phate; SHC = Src homology 2 (SH2) domain-containing adapter protein; SoS = son of sevenless.

ª 2011 Adis Data Information BV. All rights reserved. Pediatr Drugs 2011; 13 (4)
Novel Treatments for ITP
Eltrombopag
Cytoplasm
This material is
Increased platelet production
the copyright of the
Fig. 3. Description of eltrombopag activation of the Janus kinase (JAK), signal transducers and activators of transcription (STAT), and mitogen-activated
protein kinase (MAPK) activation of signal transduction to increase platelet production. Eltrombopag activates the same receptor as romiplostim, at the
transmembrane region of the receptor; however, its signal transduction differs from that of romiplostim (see section 2.3.4) [adapted from Gernsheimer,[55] with
permission]. ERK = extracellular signal-related kinase; GRB2 = growth factor receptor-bound protein 2; P = phosphate; SHC = Src homology 2 (SH2) domain-
original publisher.
containing adapter protein; SoS = son of sevenless.
eltrombopag stimulatory effect is additive to the effect of
thrombopoietin in vitro.[60] A number of phase III clinical trials,
including the RAndomized placebo-controlled Idiopathic
Unauthorised copying
thrombocytopenic purpura (ITP) Study with Eltrombopag
(RAISE) study[52] and the Kuter et al.[54] study, have sub-
stantiated the effectiveness of eltrombopag in treating chronic
ITP. The concerns about adverse reactions with this agent are
and distribution
similar to those for romiplostim noted in section 2.3.4, and the
long-term adverse effects have not been established.
is prohibited.
2.3.6 AKR-501
AKR-501 (E5501) is a new thrombopoietin receptor agonist
that has not yet been approved for clinical use. It is a small
molecule that appears more potent than eltrombopag, and it
stimulates growth of thrombopoietin-dependent megakaryocyte
cell lines.[61] It causes a dose-dependent increase in platelet count in
healthy humans.[22,62]
2.4 Other Therapies for Chronic ITP
2.4.1 Splenectomy
If the spleen is the major site of platelet destruction in ITP,
an improvement in platelet count is often sustained after sple-
nectomy. However, if other organs of the mononuclear phago-
cytic system, such as the liver and marrow, are major sites of
platelet removal, the effectiveness of splenectomy may be com-
promised. Two-thirds of adult patients having a splenectomy
for chronic ITP have resolution of their thrombocytopenia,[19]
ª 2011 Adis Data Information BV. All rights reserved.
219
Thrombopoietin
receptor
Thrombopoietin
SHC GRB2
RAS/RAF
P P SoS
STAT3 P
P JAK2
STAT5
ERK1/2
P38 MAPK
Signal transduction
although this response can be time-limited, and patients may
have a recurrence within the following 4–9 years.[27] Data for
children are similar, with a response rate as high as 86% after
splenectomy,[29] of whom 70% have durable responses. How-
ever, splenectomized children have heightened susceptibility to
infection with encapsulated bacteria and an increased risk of
fatal sepsis.[27] The younger the child, the more substantial is the
risk of this complication, particularly for those children under
6 years of age. The use of pneumococcal, meningococcal, and
hemophilus influenza vaccines several weeks prior to splenectomy
plus chronic administration of prophylactic antibiotics, usually
penicillin, reduce but do not eliminate this complication.
2.4.2 Vincristine
Vincristine is a vinca alkaloid that has been used to block
phagocytosis of platelets by mononuclear phagocytes.[11] It
may be used both as a single agent[34] or as part of combination
therapy.[63,64] When used as a single agent, 12 of 21 patients
responded with platelet counts over 50 000/mL for 2–24 months.
No lasting responses were seen.[34] In combination with IVIg
and glucocorticoids, 75% of patients respond to therapy with
an increase in platelet counts of at least 30 000/mL.[63] Vincris-
tine has also been given in weekly doses in combination with
weekly methylprednisolone and twice-daily cyclosporin. In this
study, vincristine and methylprednisolone were given to chil-
dren with chronic ITP as induction agents, followed by con-
tinuation of cyclosporin for 3–6 months. Seven of the ten
children treated had continued complete responses, attaining
Pediatr Drugs 2011; 13 (4)
220 Bredlau et al.

remission for a median of 13 months, and one had a partial
response for 3 months.[64]
2.4.3 Mycophenolate Mofetil
Mycophenolate mofetil is a prodrug of mycophenolic acid,
an inhibitor of inosine monophosphate dehydrogenase, an
important enzyme in purine synthesis, especially in proliferat-
ing T and B lymphocytes,[32] and thus its inhibition suppresses
B-lymphocyte function and antibody production as well as
T-lymphocyte-mediated cytotoxic activities. It is likely this effect
20 000/mL, which were sustained responses, although mycophe-
nolate mofetil-dependent. Side effects included headache and
stomach pain.[32] Another study, conducted in China in 20 pa-
tients, one of whom was a child with refractory ITP, showed nine
sustained responses with mycophenolate mofetil at 1.5–2 g/day for
1–4 months.[65] The only other reported study, except case reports,
examined responses to mycophenolate mofetil 750 mg/day in
18 patients with chronic ITP, one of whom was a child, and
showed a mycophenolate mofetil-dependent sustained res-
ponse in seven patients, including the child.[66]

This material is
is the mechanism for the decrease in immune platelet destruc-
tion. Nine children with chronic ITP secondary to autoimmune
lymphoproliferative syndrome were treated with mycopheno-
2.5 Other Considerations

late mofetil 600 mg/m2 orally twice daily for up to 240 weeks. In adults, studies have shown that chronic ITP associated

the copyright of the

Of these patients, all had increased platelet counts of at least with Helicobacter pylori infection of the stomach can be improved

Patient with ITP

Evidence of severe hemorrhage1 No evidence of severe hemorrhage1

original publisher. or platelet count <10 000/µL

Glucocorticoids2
Test for RhD
and platelets >10 000/µL

Watch and wait

Evidence of severe hemorrhage1

Unauthorised copying If RhD + and

inadequate response
or platelet count <10 000/µL
If RhD − and
inadequate response

Anti-D IVIg

and distribution
If inadequate response
If persistent or chronic ITP

Thrombopoietin receptor agonists

If inadequate response

is prohibited. Rituximab

If inadequate response

Splenectomy

If inadequate response

Alternate therapies

Fig. 4. Algorithm for the management of ITP. When a patient is seen with newly diagnosed immune thrombocytopenic purpura (ITP), treatment is only
necessary if they have severe hemorrhage or a platelet count <10 000/mL. Otherwise, watchful waiting with weekly blood counts is adequate management. If the
patient has hemorrhage in excess of scattered petechiae and/or minor bruising, or has a platelet count <10 000/mL, treatment with glucocorticoids is suggested,
as outlined in the text, after evaluation of the blood counts and blood film to minimize the possibility of an alternate diagnosis, such as thrombotic thrombo-
cytopenic purpura, hemolytic uremic syndrome, or incipient acute leukemia. Alternatively, intravenous immunoglobulin (IVIg) or anti-D may be used as initial
therapy. This is our preferred sequence of management because it is affordable and effective, but some institutions prefer IVIg or anti-D for initial therapy. These
treatments can be repeated for bleeding or a platelet count <10 000/mL. If the patient develops persistent or chronic ITP and is no longer responsive to these
therapies, then the thrombopoietin receptor agonists, such as romiplostim or eltrombopag, may be used. If these newer treatments are ineffective, rituximab
may be used. We prefer that the thrombopoietin receptor agonists be used first because of the toxicities of rituximab. If the child is more than 6 years of age and
the preceding therapies fail, splenectomy can be considered after immunization against encapsulated organisms (pneumococcus, meningococcus, and
Hemophilus influenza). Splenectomy in younger patients may be carried out but there is a greater risk of post-splenectomy sepsis. If splenectomy does not
produce a sustained platelet response, a repeat trial of glucocorticoids, IVIg, and anti-D, or the alternative therapies, may be attempted. 1 Severe hemorrhage –
epistaxis, mucosal bleeding, gastrointestinal bleeding, genitourinary or nervous system bleeding. 2 The choice among glucocorticoids, IVIg, and anti-D
(for Rh+ patients) for first-line therapy is controversial. The algorithm reflects the authors’ preference. RhD = rhesus D.

ª 2011 Adis Data Information BV. All rights reserved. Pediatr Drugs 2011; 13 (4)
Novel Treatments for ITP
after treatment with antimicrobials. H. pylori appears to have
epitopes with similarity to those on platelets that, by ‘molecular
mimicry’, results in platelet destruction.[8] Treatment of H. pylori
in children produces varying results. In Italy, a prospective trial of
H. pylori eradication for children infected with H. pylori who had
ITP for at least 12 months showed an improvement in platelet
counts when compared with matched patients without H. pylori
infection.[67] However, in Thailand, a randomized controlled
study did not show any difference in resolution of chronic ITP
in children treated for H. pylori infection.[68]
This material is
2.6 Combination Therapies
Many combination therapies have been reported in adult
the copyright of the
patients with chronic ITP, although the published data on these
combinations in pediatric patients are few. However, many
combinations include a glucocorticoid and a second therapy
(such as IVIg, anti-D, or rituximab).[8,69] Other combination
therapies attempted in adults include weekly vincristine and
original publisher.
methylprednisolone combined with oral daily cyclosporin. This
therapy achieved a complete, sustained response in seven of ten
adolescent patients.[64] Another combination tested included
methylprednisolone, IVIg, and either anti-D or vincristine for
Unauthorised copying
acute control followed by azathioprine and danazol orally as
maintenance therapy. These combination therapies were ef-
fective at inducing increased platelet counts in 71% of patients,
and long-term, therapy-dependent responses to maintenance
and distribution
therapy were seen in two-thirds of treated patients.[63]
3. Conclusions
is prohibited.
Figure 4 shows the therapy options for children who present
with ITP. If the platelet count is >10 000/mL and the patient has
minimal bleeding, a ‘watch and wait’ strategy is appropriate.[11]
If therapy is indicated because of bleeding or a platelet count
<10 000/mL, then glucocorticoids, IVIg, or anti-D (if patient is
RhD positive) are possible choices. These therapies may be
repeated safely if the patient relapses. If the disease becomes
‘persistent’ with severe thrombocytopenia and/or bleeding, and
is no longer responsive to the first-line therapies, the second-line
of medications, including thrombopoietin receptor agonists or
rituximab, may be considered. When the disease becomes chron-
ic and remains symptomatic, it may become necessary to consider
third-line therapies (splenectomy, alternative immunosuppres-
sion, or investigative chemotherapy).
These recommendations are largely consistent with the re-
cently published recommendations by the American Society of
Hematology,[70] except for our preference to use thrombo-
ª 2011 Adis Data Information BV. All rights reserved.
221
poietin receptor agonists before rituximab in persistent disease
because of the toxicity of rituximab.
Acknowledgments
A.L. Bredlau and G.B. Segel conceived and wrote the manuscript.
J.W. Semple was instrumental in describing the pathophysiology of ITP
and in designing the relevant figure. No authors received funding for this
review. No conflicts of interest were present for any of the authors. We
thank Marshall A. Lichtman, MD, for his helpful review.
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Correspondence: Dr Amy Lee Bredlau, MD, University of Rochester, Box 777,
601 Elmwood Avenue, Rochester, NY 14642, USA.
E-mail: amy-lee_bredlau@urmc.rochester.edu
Pediatr Drugs 2011; 13 (4)