From bloodjournal.hematologylibrary.org at UNIVERSITY OF CALGARY on February 19, 2013.

For personal use

only.

2009 113: 2386-2393

Prepublished online November 12, 2008;
doi:10.1182/blood-2008-07-162503

Standardization of terminology, definitions and outcome criteria in

immune thrombocytopenic purpura of adults and children: report from
an international working group
Francesco Rodeghiero, Roberto Stasi, Terry Gernsheimer, Marc Michel, Drew Provan, Donald M.
Arnold, James B. Bussel, Douglas B. Cines, Beng H. Chong, Nichola Cooper, Bertrand Godeau,
Klaus Lechner, Maria Gabriella Mazzucconi, Robert McMillan, Miguel A. Sanz, Paul Imbach, Victor
Blanchette, Thomas Kühne, Marco Ruggeri and James N. George

Updated information and services can be found at:

http://bloodjournal.hematologylibrary.org/content/113/11/2386.full.html
Articles on similar topics can be found in the following Blood collections
Free Research Articles (1592 articles)
Perspectives (145 articles)
Thrombosis and Hemostasis (535 articles)

Information about reproducing this article in parts or in its entirety may be found online at:
http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#repub_requests

Information about ordering reprints may be found online at:

http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#reprints

Information about subscriptions and ASH membership may be found online at:
http://bloodjournal.hematologylibrary.org/site/subscriptions/index.xhtml

Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly

by the American Society of Hematology, 2021 L St, NW, Suite 900,
Washington DC 20036.
Copyright 2011 by The American Society of Hematology; all rights reserved.
 From bloodjournal.hematologylibrary.org at UNIVERSITY OF CALGARY on February 19, 2013. For personal use
only.
Perspective

Standardization of terminology, definitions and outcome criteria in immune

thrombocytopenic purpura of adults and children: report from an international
working group
Francesco Rodeghiero,1 Roberto Stasi,2 Terry Gernsheimer,3 Marc Michel,4 Drew Provan,5 Donald M. Arnold,6
James B. Bussel,7 Douglas B. Cines,8 Beng H. Chong,9 Nichola Cooper,10 Bertrand Godeau,4 Klaus Lechner,11
Maria Gabriella Mazzucconi,12 Robert McMillan,13 Miguel A. Sanz,14 Paul Imbach,15 Victor Blanchette,16 Thomas Kühne,15
Marco Ruggeri,1 and James N. George17
1Department of Hematology, San Bortolo Hospital, Vicenza, Italy; 2Department of Medical Sciences, Ospedale Regina Apostolorum, Albano Laziale, Italy; 3Puget
Sound Blood Center, University of Washington School of Medicine, Seattle; 4Université Paris 12, Faculté de Medecine, Assistance Publique-Hôpitaux de Paris
(AP-HP), Hopital Henri Mondor, Service de Medecine Interne, Créteil, France; 5Department of Haematology, Barts and The London School of Medicine and
Dentistry, London, United Kingdom; 6Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON; 7Weill Cornell
Medical College of Cornell University, New York, NY; 8Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine,
Philadelphia; 9Department of Hematology, St George Hospital, South Eastern Area Laboratory Service, and Department of Medicine, St George Clinical School,
University of New South Wales, Sydney, Australia; 10Molecular Immunology Unit, Institute of Child Health, London, United Kingdom; 11Department of Internal
Medicine I, Division of Haematology and Haemostaseology, Medical University of Vienna, Vienna, Austria; 12Department of Cellular Biotechnology and
Hematology, La Sapienza University, Rome, Italy; 13Scripps Research Institute, La Jolla, CA; 14Hematology Service, Hospital Universitario La Fe, Valencia,
Spain; 15Pediatric Oncology/Hematology, University Children’s Hospital Basel, Basel, Switzerland; 16Division of Hematology/Oncology, The Hospital for Sick
Children, Department of Pediatrics, University of Toronto, Toronto, ON; and 17Hematology-Oncology Section, College of Medicine, Department of Biostatistics
and Epidemiology, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City

Diagnosis and management of immune tion of new classes of therapeutic agents, These consensus criteria and definitions
thrombocytopenic purpura (ITP) remain such as thrombopoietin receptor ago- could be used by investigational clinical
largely dependent on clinical expertise nists, and innovative treatment modali- trials or cohort studies. Adoption of these
and observations more than on evidence ties, such as anti-CD 20 antibodies. To recommendations would serve to im-
derived from clinical trials of high scien- overcome the present heterogeneity, an prove communication among investiga-
tific quality. One major obstacle to the International Working Group of recog- tors, to enhance comparability among
implementation of such studies and in nized expert clinicians convened a 2-day clinical trials, to facilitate meta-analyses
producing reliable meta-analyses of exist- structured meeting (the Vicenza Consen- and development of therapeutic guide-
ing data is a lack of consensus on stan- sus Conference) to define standard termi- lines, and to provide a standardized frame-
dardized critical definitions, outcome cri- nology and definitions for primary ITP work for regulatory agencies. (Blood.
teria, and terminology. Moreover, the and its different phases and criteria for 2009;113:2386-2393)
demand for comparative clinical trials has the grading of severity, and clinically
dramatically increased since the introduc- meaningful outcomes and response.

Introduction
Immune thrombocytopenic purpura (ITP), also known as idio- have different mechanisms of action and heterogeneous patterns of
pathic thrombocytopenic purpura, is an immune-mediated acquired response. Furthermore, the importance of this harmonization has
disease of adults and children characterized by transient or become increasingly apparent by the necessity to develop and
persistent decrease of the platelet count and, depending upon the validate ITP-specific bleeding scales11-13 and quality of life14-16
degree of thrombocytopenia, increased risk of bleeding.1 questionnaires. To address these issues, an International Working
A recent review compared the definitions and clinical criteria Group (IWG) of recognized experts convened a 2-day structured
used in different studies.2 It showed widely discrepant criteria used face-to-face consensus conference in Vicenza, Italy (the Vicenza
to evaluate patient characteristics, determine responses, and report Consensus Conference) in October 2007. This article reports the
clinical outcomes. This heterogeneity makes comparison of the definitions and recommendations agreed upon by the members of
results of clinical trials or cohort description uneven and therefore this consensus conference.
unreliable and application of practical guidelines3-5 troublesome.
Many of these difficulties could be minimized by adopting a
common set of definitions. The need for standardization and Methodology of the conference
harmonization of response criteria has been recently highlighted by
clinical trials of novel targeted therapies, such as thrombopoietin The location of the conference, its funding, and the composition of
(TPO)–receptor agonists6-9 and anti–CD-20 antibodies,10 which the IWG were decided during the 5th official meeting of the

Submitted July 11, 2008; accepted October 28, 2008. Prepublished online as Blood © 2009 by The American Society of Hematology
First Edition paper, November 12, 2008; DOI 10.1182/blood-2008-07-162503.

2386 BLOOD, 12 MARCH 2009 䡠 VOLUME 113, NUMBER 11

 From bloodjournal.hematologylibrary.org at UNIVERSITY OF CALGARY on February 19, 2013. For personal use
BLOOD, 12 MARCH 2009 䡠 VOLUME 113, NUMBER 11 only. DEFINITIONS AND TERMINOLOGY IN ITP 2387

European Hematology Association (EHA) Scientific Working Table 1. Proposed definitions of disease
Group on Thrombocytopenias (EHASWGT; http://www.ehaweb. Primary ITP Primary ITP is an autoimmune disorder
org/eha/about_eha/eha_scientific_working_groups) held on June 7, characterized by isolated thrombocytopenia
2007, during the 12th EHA Congress in Vienna. It was decided that (peripheral blood platelet count ⬍100 ⫻ 109/L) in
the IWG members should include the 7 officers of the current the absence of other causes or disorders that may
be associated with thrombocytopenia. The
executive committee of the EHASWGT and be expanded by the
diagnosis of primary ITP remains one of
addition of 13 members selected for their recognized clinical
exclusion; no robust clinical or laboratory
expertise and wide geographic representation to provide an interna- parameters are currently available to establish its
tional scope. Preliminary agreement regarding the identification of diagnosis with accuracy. The main clinical
the main topics of the conference and the clarification of its problem of primary ITP is an increased risk of
objectives were previously agreed on through 2 rounds of Delphi- bleeding, although bleeding symptoms may not
like questionnaires circulated among the members. Specific aspects always be present.
pertinent to pediatrics that had been previously elaborated by the Secondary ITP All forms of immune-mediated thrombocytopenia
Intercontinental Childhood ITP Study (ICIS) Group (http:// except primary ITP*

pages.unibas.ch/itpbasel/) were also included for further examina- Phases of the disease Newly diagnosed ITP: within 3 months from
diagnosis
tion. Coordinated by the conference chairman, 5 working parties
Persistent ITP: between 3 to 12 months from
(WP) covered specific topics, guided the discussion interactively,
diagnosis. Includes patients not reaching
and prepared serial summaries of each topic. Consensus was spontaneous remission or not maintaining
reached by several meetings on specific topics by ad hoc subgroups complete response off therapy.
followed by plenary sessions. A second short conference was held Chronic ITP: lasting for more than 12 months
during the 49th Annual Meeting of the American Society of Severe ITP: Presence of bleeding symptoms at
Hematology in Atlanta (December 8, 2007) to approve the final presentation sufficient to mandate treatment, or
draft. Furthermore, 3 experts who did not attend the Vicenza occurrence of new bleeding symptoms requiring
Consensus Conference acted as external reviewers to ensure that additional therapeutic intervention with a different
platelet-enhancing agent or an increased dose
the proposal was intrinsically logical, consistent, clear, and reason-
ably applicable. The final version was finally circulated among all *The acronym ITP should be followed by the name of the associated disease (for
members for minor modifications and explicit approval. None of thrombocytopenia after exposure to drugs, the terms “drug-induced” should be used)
in parentheses: for example, “secondary ITP (lupus-associated),” “secondary ITP
the IWG members and external reviewers received honoraria.
(HIV-associated),” and “secondary ITP (drug-induced).” For manuscript titles, ab-
stracts, and so on, definitions such as lupus-associated ITP or HIV-associated ITP
can also be used.

Recommendations The term “secondary immune thrombocytopenia” or “secondary

Definition of primary and secondary immune ITP” has been proposed to broadly include all forms of immune-
thrombocytopenia (primary and secondary ITP) and platelet mediated thrombocytopenias except primary ITP. Secondary forms
count threshold include thrombocytopenias that are due to an underlying disease or to
drug exposure. Some rare secondary immune thrombocytopenias, such
The panel decided to avoid the term “idiopathic,” preferring as fetal and neonatal alloimmune thrombocytopenic purpura and
“immune,” to emphasize the immune-mediated mechanism of the posttransfusion purpura, would maintain their standard designation. For
disease and to choose “primary” (as opposed to idiopathic) to the other secondary forms of ITP, the name of the associated disease
indicate the absence of any obvious initiating and/or underlying should follow the designation in parentheses. For example: “secondary
cause. The term “purpura” was felt inappropriate, because bleeding ITP (systemic lupus erythematosus-associated or SLE-associated)” and
symptoms are absent or minimal in a large proportion of cases.17,18 “secondary ITP (human immunodeficiency virus or HIV-associated).”
The acronym ITP (now proposed to stand for immune thrombocy- For cases possibly initiated by or associated with Helicobacter pylori
topenia) was preserved because of its widespread and time- infection, considering the high prevalence of the infection in some
honored use and taking into account its utility for literature countries, a diagnosis of “secondary ITP (Helicobacter pylori–
searches. A platelet count less than 100 ⫻ 109/L was established as associated)” would require the demonstration of complete resolution of
the threshold for diagnosis. A uniform predefined cutoff, instead of ITP after proven eradication of the bacteria. In the case of thrombocyto-
local normal ranges or other thresholds based on frequency penia related to drug exposure (with the exclusion of myelosuppressive
distribution, is more convenient for practical use and comparisons chemotherapy), the term “drug-induced” was preferred. The name of the
across studies. This threshold was preferred to the more commonly incriminated drug should be indicated when known. For example:
used level of less than 150 ⫻ 109/L, based upon a prospective “Secondary ITP (quinine-induced).” Heparin-induced thrombocytope-
cohort of otherwise healthy subjects with a platelet count between nia will maintain its designation and acronym (HIT) because of its
100 and 150 ⫻ 109/L, showing that the 10-year probability of unique features.
developing more severe thrombocytopenia (persistent platelet The distinction between primary and secondary immune throm-
count below 100 ⫻ 109/L) is only 6.9% (95% confidence interval bocytopenia is clinically relevant because of their different natural
[CI], 4.0%-12.0%).19 Moreover, in some non-Western populations, histories and distinct treatments. For thrombocytopenias secondary
platelet count values between 100 and 150 ⫻ 109/L are frequently to an ongoing medical condition, treatment is often targeted toward
found in apparently healthy people.20-22 The new cutoff level will the underlying disorder.24,25 On the other hand, drug-induced ITP
also avoid inclusion of most women with pregnancy-related often remits quickly after the withdrawal of the inciting drug, and
thrombocytopenia, a well known physiologic phenomenon not most severe cases may require transfusion of platelets alone as
requiring specific follow-up in the absence of additional clinical initial treatment, as opposed to the application of immunomodula-
features23 (Table 1). tion often used in primary ITP.26 The coexistence of anti-nuclear
 From bloodjournal.hematologylibrary.org at UNIVERSITY OF CALGARY on February 19, 2013. For personal use
2388 RODEGHIERO et al only. BLOOD, 12 MARCH 2009 䡠 VOLUME 113, NUMBER 11

antibodies and/or anti-phospholipid antibodies (aPL) on their own, Table 2. Proposed criteria for assessing response to ITP treatments
in the absence of distinctive clinical manifestations suggestive of Quality of response*†
SLE27 and/or antiphospholipid syndrome,28 does not qualify these ● CR: platelet count ⱖ 100 ⫻ 109/L and absence of bleeding
cases as secondary ITP. The increased risk of thrombosis in aPL ● R: platelet count ⱖ 30 ⫻ 109/L and at least 2-fold increase the baseline count
antibody-positive cases reported in some studies is controversial,24 and absence of bleeding
● Time to response: time from starting treatment to time of achievement of CR or
and in our opinion, the available evidence does not warrant
R‡
consideration of the coexistence of thrombocytopenia with aPL
● NR: platelet count ⬍ 30 ⫻ 109/L or less than 2-fold increase of baseline
antibodies as a distinct clinical entity. We are aware that a different platelet count or bleeding
consensus was reached by the experts who updated previous ● Loss of CR or R: platelet count below 100 ⫻ 109/L or bleeding (from CR) or
Sapporo criteria for the classification of definite antiphospholipid below 30 ⫻ 109/L or less than 2-fold increase of baseline platelet count or
syndrome,28 which might contribute to confusion rather than harmoniza- bleeding (from R)
tion. However, in the updated criteria, the presence of aPL antibodies has Timing of assessment of response to ITP treatments
no impact on the clinical management of patients with ITP, bearing ● Variable, depends on the type of treatment (see Table 3)
relevance only for patient stratification in clinical trials. The impact of Duration of response§
these associated laboratory abnormalities should be further investigated ● Measured from the achievement of CR or R to loss of CR or R
● Measured as the proportion of the cumulative time spent in CR or R during the
in studies of the natural history of ITP. The IWG agreed that the
period under examination as well as the total time observed from which the
proposed definitions, therapeutic goals, and outcome assessment should
proportion is derived
be applied only to primary ITP. Corticosteroid-dependence
● The need for ongoing or repeated doses administration of corticosteroids for at
Definition of the different phases and severity of the disease least 2 months to maintain a platelet count at or above 30 ⫻ 109/L and/or to
avoid bleeding (patients with corticosteroid dependence are considered
Only those terms relevant for treatment and/or prognosis were nonresponders)
retained to describe the phases of ITP. The panel recommended that Supplemental outcomes (whenever possible)
the term “acute,” which has been used to describe a self-limited ● Bleeding symptoms measured by a validated scale (requires additional
form of the disease (eg, secondary to viral illness in children) be studies)
avoided because of both its vagueness and its post hoc or ● Health-related quality of life assessment measured by a validated instrument
retrospective definition. In the absence of reliable predictive (requires additional studies)
clinical or laboratory parameters of disease duration, the term For response criteria in refractory ITP, see Table 4.
“newly diagnosed ITP” was suggested for all cases at diagnosis. HRQoL indicates health-related quality-of-life assessment.
A new category, called “persistent ITP,” was introduced for patients *Platelet counts should be confirmed on at least 2 separate occasions (at least
7 days apart when used to define CR, R) or 1 day apart when used to define NR or
with ITP to define the period lasting between 3 and 12 months from
loss of response.
diagnosis. This category includes patients not achieving spontane- †Baseline platelet count refers to platelet count at the time of starting of the
ous remission or not maintaining their response after stopping investigated treatment; for postsplenectomy response evaluation, basal platelet
treatment between 3 and 12 months from diagnosis. The chances of count refers to the platelet count before patient was first treated (initial treatment).
‡Late responses not attributable to the investigated treatment should not be
spontaneous remissions are still significant during this period,29-31 defined as CR or R (see Table 3).
making deferral of more aggressive therapeutic approaches (such §The 2 definitions are not mutually exclusive: the first definition, collectively
as splenectomy) worthy of consideration. The term “chronic ITP” represented using Kaplan-Meyer analysis, is more suitable for short-course treat-
ments aimed at inducing prolonged remission of the disease, whereas the second
is to be reserved for patients with ITP lasting for more than one is more suitable to evaluate the overall benefit of continuous or intermittent
12 months (Table 1). repeated administration of agents requiring dose adjustments with anticipated
To date, disease severity (mild, moderate, severe) has been temporary losses of CR or R.
correlated with the degree of thrombocytopenia, which is taken as a
surrogate for risk of bleeding. However, the panel agreed that,
regardless of the phase of the disease, the term “severe” ITP should age of the patient, because the bleeding risk and the hemorrhagic
be used only in patients who have clinically relevant bleeding. This fatality rate increase with age36 and are the lowest in children of
is defined by the presence of bleeding symptoms at presentation post-toddler age. Most fatal bleeding has been reported to occur in
sufficient to mandate treatment, or by the occurrence of new adults with ITP who have platelet counts lower than 30 ⫻ 109/L.37
bleeding symptoms requiring additional therapeutic intervention Because of the real and potential toxicity of currently available
with a different platelet-enhancing agent or an increased dose. For treatments, a critical concept is to avoid unnecessary treatment of
example, using the proposed schema, a patient with chronic ITP, a asymptomatic patients with milder degrees of thrombocytopenia. Cur-
platelet count of 2 ⫻ 109/L, and just a few petechiae and ecchymo- rent guidelines3,4 suggest that treatment should be initiated in the
ses would not be classified as having “severe” disease. Unfortu- presence of bleeding symptoms. Treatment decisions based on platelet
nately, the few bleeding assessment tools specifically developed for count threshold remains controversial. Although most guidelines sug-
ITP11-13,32,33 have not been validated in large prospective studies gest that treatment should be considered with counts less than 30 ⫻ 109/
and so a more precise definition of “clinically relevant” bleeding L in adults, the ICIS group recommended that children without bleeding
cannot be given. This is an area of research that merits further may not require therapy regardless of their platelet count, with the
development. exception of “on-demand therapy.” This deserves further evaluation,
including better attempts at individualization.
Therapeutic goals Treatment of newly diagnosed adult patients or of patients
requiring treatment for the first time (initial treatment) is aimed at
The major goal for treatment of ITP is to provide a safe platelet rapidly obtaining a safe platelet count to prevent or stop hemor-
count (eg, one that prevents major bleeding) rather than correcting rhages and to ensure an acceptable quality of life with minimal
the platelet count to normal levels.3-5,34,35 Treatment of patients treatment-related toxicity. A minority of patients are expected to
with ITP should take into account the severity of the illness and the obtain spontaneous durable remission after initial treatment with
 From bloodjournal.hematologylibrary.org at UNIVERSITY OF CALGARY on February 19, 2013. For personal use
BLOOD, 12 MARCH 2009 䡠 VOLUME 113, NUMBER 11 only. DEFINITIONS AND TERMINOLOGY IN ITP 2389

Table 3. Individual agents for treatment of ITP and the time to the first and peak responses if using the reported dose range
Agent/treatment Reported dose range Time to initial response* Time to peak response*

Prednisone4,44 1-4 mg/kg po daily ⫻ 1-4 wk 4-14 d 7-28 d

Dexamethasone48,49 40 mg po or iv daily ⫻ 4 d for 4-6 courses every 14-28 d 2-14 d 4-28 d
IVIg41,46,50 0.4-1 g/kg per dose iv (1-5 doses) 1-3 d 2-7 d
Anti-D42,47 75 ␮g/kg per dose iv 1-3 d 3-7 d
Rituximab10,40,51 375 mg/m2 per dose iv (4 weekly doses) 7-56 d 14-180 d
Splenectomy43 Laparoscopic 1-56 d 7-56 d
Vincristine4 up to 2 mg/dose iv (4-6 weekly doses) 7-14 d 7-42 d
Vinblastine4,45 0.1 mg/kg per dose iv (6 weekly doses) 7-14 d 7-42 d
Danazol4,52 400-800 mg po daily 14-90 d 28-180 d
Azathioprine52 2 mg/kg po daily 30-90 d 30-180 d
AMG5316,7,9 3-10 ␮g/kg weekly sc 5-14 d 14-60 d
Eltrombopag8 50-75 mg po daily 7-28 d 14-90 d

In the times to the initial and peak responses, the first number of days is the first time that a response could be reasonably expected and the second number of days is the
time after which a response to this particular agent becomes less likely when administered at the dose and schedule listed in the table. Dosages, where not given on
kilogram/body weight basis, are intended for adults.
po indicates per os administration; iv, intravenous infusion; and sc, subcutaneous infusion.

standard commonly used corticosteroid-based regimens.38 How- sponders. Specific mention can be made of lessened dose or
ever, with the availability of new therapies, increasing the rate of frequency of this agent as indicative of at least some effect of the
long-lasting responses becomes a realistic aim of early interven- investigated agent, even if below the level of a response.
tion.39 The goal of treatment in persistent or chronic ITP is less well Time to platelet count response is an important facet of
defined and is often inspired by the desire to defer or avoid the risks management and should be reported in clinical studies. It varies
of more toxic treatments such as splenectomy or immunosuppres- depending on the mechanism of action of the specific agent (Table
sion. Thus “on-demand” treatment at the time of or in anticipation 3).4,6-10,40-52 The frequency of monitoring of platelet counts and the
of high-risk bleeding situations or surgical procedures is another timing of response assessment should be prespecified and will
approach that is often warranted. Minimal corticosteroid exposure depend on the expected kinetics of platelet increase after each
is a tenet of therapy for chronic ITP. As with initial treatment, the treatment. After splenectomy, the timing to assess the response in
rate of long-lasting responses may become an achievable goal terms of platelet count should be within 1 to 2 months after surgery
based on investigational studies.40 On the other hand, the goal of and removed from any treatment. Late responses not attributable to
splenectomy is long-term response (in terms of several years) to the investigated treatment (“spontaneous remission”), according to
avoid more toxic treatments, to establish or to increase health- Table 3, should not be defined as CR or R.
related quality of life, and to save costs. Duration of the response should be calculated from the time of
CR or R until loss of CR or R. Two different scenarios are envisioned:
Definition of response (1) short-course treatments aimed at curing the disease, or at least at
achieving prolonged remissions (eg, high-dose pulse dexamethasone,
The panel acknowledged that the definition of a treatment response
rituximab, splenectomy) and (2) treatments requiring continuous or
should ideally reflect clinically important endpoints including
repeated administrations (eg, TPO-receptor agonists, IVIg, anti-D, etc),
bleeding and quality of life, rather than rely exclusively on
for which it is anticipated that platelet count could fall temporarily below
surrogate end points (platelet count) with arbitrary thresholds.
or increase above the desired threshold.
Nevertheless, the platelet count is a useful measure of response that
For short-course treatments, the overall response duration in a
is objective, clinically relevant, and easily compared (Table 2).
patient cohort should be calculated using a time-dependent analy-
“Complete response” (CR) is defined as any platelet count of at
sis, such as the Kaplan-Meier product limit estimate, event rate per
least 100 ⫻ 109/L. “Response” (R) is defined as any platelet count
person-years, or similar approaches. For treatments requiring
between 30 and 100 ⫻ 109/L and at least doubling of the baseline
continuous prolonged or repeated administrations of the same
count. “No response” (NR) is defined as any platelet count lower
agent, one should calculate the cumulative time spent in CR or R.
than 30 ⫻ 109/L or less than doubling of the baseline count. The
This approach is also useful to evaluate the whole impact of a
definition of response requires concurrent resolution of bleeding
particular treatment plan, including different sequential treatments,
symptoms. The panel decided to avoid “partial” or “minimal”
allowing a more clinically meaningful estimation of response
response categories, often used in scientific articles, because of the
duration. When response duration includes time receiving treatment, this
wide heterogeneity in the criteria used in these definitions.2 CR and
should be specified, and CR or R with or without concomitant treatment
R could be with or without concomitant administration of the
should be calculated and reported separately.
investigated agent, and this should be specified. In a clinical trial,
Identical response criteria are proposed for splenectomy. Assess-
when, in addition to the treatment being investigated, any ongoing
ment of response should occur within 1 to 2 months and after
concomitant ITP-specific treatment is given, this latter, or the time
withholding concomitant treatment(s), if any, for a time sufficient
of its discontinuation, should be provided. Often, corticosteroids
to reasonably exclude a persistence of their effect (Table 3).
are administered together with other ITP-specific agents. In this
setting, as defined in Table 2, corticosteroid dependence is defined Refractory ITP: definition, therapeutic goals, and response
as the ongoing need for continuous corticosteroid administration or assessment
frequent courses of corticosteroids to maintain a platelet count at or
above 30 ⫻ 109/L and/or to avoid bleeding. Corticosteroid- or Refractory patients should fulfill 2 criteria. First, they should have
other treatment-dependent patients should be considered nonre- failed splenectomy or have relapsed thereafter. Second, they should
 From bloodjournal.hematologylibrary.org at UNIVERSITY OF CALGARY on February 19, 2013. For personal use
2390 RODEGHIERO et al only. BLOOD, 12 MARCH 2009 䡠 VOLUME 113, NUMBER 11

Table 4. Refractory ITP TPO-receptor agonists, anti–CD-20 antibodies; see Table 3) and
Definition (all should be met) should be assessed for any new drug.
● Failure to achieve at least R or loss of R after splenectomy* The main goal of therapy in refractory ITP is generally the
● Need of treatment(s) (including, but not limited to, low dose of corticosteroids) achievement of a platelet count sufficient to prevent clinically
to minimize the risk of clinically significant bleeding.† Need of on-demand or significant bleeding with the least toxicity.34,35 So, in this popula-
adjunctive therapy alone does not qualify the patient as refractory.
tion, treatments should be evaluated for the potential to induce an
● Primary ITP confirmed by excluding other supervened causes of
acute response and also a long-lasting response with minimum side
thrombocytopenia
Definition of on-demand therapy
effects/toxicity. As for any other phase of the disease, adjunctive or
● Any therapy used to temporarily increase the platelet count sufficiently to safely combination therapy or even platelet transfusion may be required
perform invasive procedures or in case of major bleeding or trauma‡ for severe mucosal/organ or life-threatening bleeding.
Definition of adjunctive therapy Strict application of the aforementioned definitions of re-
● Any non-ITP specific therapy that may decrease bleeding (eg, antifibrinolytic sponse (see Table 2) may not be appropriate when considering
agents, hormonal agents, DDAVP, recombinant factor VIIa, fibrin sealants). the risk-benefit ratio of therapy for a refractory patient. Accord-
Platelet transfusion is also included. ingly, clinically meaningful definitions were agreed on by the
Definition of response to therapy in refractory ITP panel (Table 4).
● Ability to maintain a platelet count sufficient to prevent clinically significant
bleeding†§
● Ability to decrease toxic therapy (eg, corticosteroids) does not qualify for Clinical trial–adapted criteria
response but should be reported
Definition of response to on-demand therapy
There have been several randomized clinical trials performed in adults
● Control of bleeding in the specific situation
with ITP,6-9,41,42,44-46,56-60 and their results can be compared only with
● Achievement of a platelet count sufficient to perform procedure or minimize great difficulty because of differences in the characteristics of the patient
bleeding from trauma populations included (newly diagnosed vs persistent or chronic/
refractory), study designs and end points, as well as the heterogeneous
DDAVP indicates deamino arginine vasopressin.
*May not be applicable in children or in patients with accessory spleen.
mechanisms of action and patterns of response to the various investiga-
†Bleeding symptoms measured by a validated scale whenever possible (re- tional treatments. Some of the problems of comparison are attributable
quires further studies). not only to these differences but also to the lack of description of key
‡Specific platelet thresholds cannot be provided, but in most instances, a platelet
features (eg, patient-related parameters). Even the more numerous
count of 50-70 ⫻ 109/L would fulfill this criterion.
§A strict definition of response in terms of predefined platelet count cannot be controlled studies in children47,61-75 present similar problems of interpre-
given and may not be appropriate when considering the risk/benefit ratio in refractory tation, particularly regarding the end points and definition of outcomes.
ITP, because the trade off between efficacy of a specific treatment and its short- and In summary, the results of clinical trials conducted to date with old or
long-term toxicity varies among patients.
new agents, including studies with anti-CD20 antibodies conducted
using uncontrolled designs,10 are not easily comparable for clinically
either exhibit severe ITP (see Table 1) or have a risk of bleeding
meaningful response rates and response duration and do not allow the
that in the opinion of the attending physician requires therapy.
drawing of definite conclusions in all instances. In turn, it is difficult to
On-demand treatment required only to safely perform an invasive
determine how they should be introduced into current clinical practice.
procedure or to prevent bleeding after major trauma is not a
To avoid these limitations in future trials, the panel recom-
sufficient criterion (Table 4). Refractory patients may have tempo-
mended minimal standardized criteria and definitions to be used in
rary responses to corticosteroids or intravenous immunoglobulin
interventional studies (specifically for phase II and III studies) in
(IVIg). The panel recognizes that many patients and an increasing
order that heterogeneity in study subjects and in result reporting
number of physicians prefer to delay or avoid splenectomy, such
can be minimized (Table 5).
that the surgical rate has fallen in more recent cohorts.53 Moreover,
splenectomy should not be performed in frail patients or in patients
with contraindication. Nevertheless, the available data consistently
demonstrate the curative potential of splenectomy in more than Conclusions
60% of cases, a result not yet achievable with any other available
treatment.43,54,55 Accordingly, it was felt that ITP in adults cannot The IWG was developed to harmonize current definitions and
truly be called refractory before splenectomy is attempted. terminology in primary ITP, recognizing that current nomenclature
A consensus as to when a child with chronic ITP should be is outdated, is limited by heterogeneity, and has not been critically
considered “refractory” has not been reached, considering that analyzed.2 The members of the IWG agreed that the unavoidable
splenectomy is often delayed in most children as long as possible in arbitrary nature of any proposal should be tempered by obtaining
view of the often benign natural history and delayed improvement the greatest possible consensus and by choosing only clinically
of these patients. Unsplenectomized patients (adults and children) sound definitions. Thus, the strength of this proposal lies in the
not responding to medical treatment(s) should be described as achievement of consensus from an international group of experts in
having “newly diagnosed, persistent or chronic (depending on the ITP after a series of face-to-face meetings and discussions.
duration of disease) ITP unresponsive to one or more agents” (with Consensus was reached through rational discussion in a structured
specification).These patients may have or not severe ITP (Table 4). plan including collection of opinions through questionnaires and a
On-demand therapy for refractory ITP is administered as 2-day conference. Unanimous agreement was obtained in all issues
needed before invasive procedures, for major bleeding, after within the present report (with the exception of the definition of
trauma, or in other instances in which a rapid, short-term increase refractory ITP in children). Definitions were designed to reflect
in platelet count to safe levels (defined by the procedure or clinical practice and to standardize clinical trial design. The
circumstance) with minimal toxicity is required. The definition of proposal is not intended to represent guidelines for diagnosis or
“rapid,” in terms of time needed to reach the safe platelet count, treatment, but it may be a valuable construct for new clinical
may differ by type of drug (eg, IVIg, high-dose corticosteroids, guideline development. A limitation is represented by the lack of
 From bloodjournal.hematologylibrary.org at UNIVERSITY OF CALGARY on February 19, 2013. For personal use
BLOOD, 12 MARCH 2009 䡠 VOLUME 113, NUMBER 11 only. DEFINITIONS AND TERMINOLOGY IN ITP 2391

Table 5. Trial-adapted criteria for eligibility and outcome (EHA) and the Intercontinental Childhood ITP Study (ICIS)
assessments in ITP Group. Critical revision of the manuscript by Paula Bolton-Maggs
Eligibility (all should be met) (United Kingdom), George Buchanan (United States), and David
● Previously treated or untreated patients fitting within one of the different phases
Kuter (United States) was highly appreciated. We thank Mrs
of the disease (in Table 1). Refractory patients defined as in Table 4.
● Entry platelet count: at least ⬍ 30 ⫻ 109/L. At least ⬍ 50 ⫻ 109/L in specific
Claudia Guzzoni and Dr Stefania Fortuna for their excellent
clinical settings or patients on steroids, or in the presence of bleeding organizing and secretarial assistance.
symptoms The conference was made possible thanks to the financial and
● Patients should be on a stable treatment or off any treatment for a time logistic support of Fondazione Progetto Ematologia (Vicenza),
sufficient to exclude a late effect (see Table 3) which received unrestricted grants from Amgen Europe and
Supplemental specifications
GlaxoSmithKline Europe to partially cover the costs of the project.
● Pediatric and adult patients analyzed separately
None of the IWG members and external reviewers received
● Response to previous treatment(s), if any, should be reported
End points
honoraria.
● Primary end points:
CR or R based on platelet count as in Table 2*
● Secondary end points:
Adverse events (safety), need for rescue interventions, Authorship
corticosteroids/concomitant treatment reduction, rate of splenectomies.
Could become primary end points according to the design of the clinical Contribution: F.R. coordinated the project, chaired the conference,
trial or patient characteristics.
and wrote the manuscript; D.P., R.S., T.G., M.M., and P.I. chaired
Bleeding scale, HRQoL assessment and, whenever possible,
the working parties during the conference and wrote the manu-
pharmacoeconomic analysis should be included
Timing of assessment of primary end points and duration of response
script; M.R. acted as scientific secretariat of the conference and
● Depends on the type of treatment wrote the manuscript; and D.M.A., V.B., J.B.B., D.B.C., B.H.C.,
● Patients enrolled while on a stable treatment with one or more agents must be N.C., B.G., T.K., K.L., M.G.M., R.M., M.A.S., and J.N.G. were
no longer receiving these treatments for a time sufficient to exclude any active members of the International Group and reviewed and gave
protracted effect† their approval to the final manuscript.
● Duration could be calculated as follows depending on study design:
Conflict-of-interest disclosure: F.R., R.S., M.M., and R.M.
The time from CR or R as defined in Table 2 to loss of response‡
have been members of scientific advisory boards for Amgen and
The cumulative time spent in CR or R or cumulative time spent without
meeting a predefined end point(s) GlaxoSmithKline. T.G. has received research support from
Adverse events Amgen and GlaxoSmithKline and has been a member of
● Bleeding episodes, rescue interventions, frequency of splenectomy, and advisory boards for Amgen, GlaxoSmithKline, and Baxter
treatment-related side effects occurring during or after the time of exposure to Pharmaceuticals. D.P. has received research support from Bax-
the experimental agent always reported. Duration of side effects monitoring ter, GlaxoSmithKline and Amgen, has consulted for Baxter,
time after the end of experimental treatment should be provided.
GlaxoSmithKline, Amgen, and Symphogen, is on the speakers
● For assessment of rebound thrombocytopenia or bleeding, the immediate
period after the suspension of the agent up to the attainment of a stable platelet
bureau for Baxter and Amgen, and he owns shares in GlaxoSmith-
count§ or institution of a new treatment should be considered. This treatment Kline (basic employee entry package). D.M.A. has received an
should be recorded. operating grant from Hoffman-LaRoche and has been a consul-
● A predefined exceedingly high platelet count induced by treatment could be tant for Amgen. J.B.B. has received research grants from
considered an adverse event, depending on the agent under investigation Amgen, Biogen-IDEC, Cangene, Genentech, GlaxoSmithKline,
HRQoL indicates health-related quality of life. Genzyme, Immunomedics, MGI Pharma, and Sysmex, has
*At variance with Table 4, these definitions should be also adopted for refractory received lecture fees from Baxter, has received consulting fees
cases, considering the experimental nature of clinical trials requiring objective
from Amgen, Symphogen, GlaxoSmithKline, and Baxter, has
measurements.
†Specify the duration that a subject should be off other treatments and/or the been a member of scientific advisory boards for Amgen,
time elapsed after any rescue medication at the time of response evaluation, see GlaxoSmithKline, Ligand, and Baxter, and has equity owner-
also Table 3. For patients enrolled while on a stable concomitant treatment, still
ship in Amgen and GSK. D.B.C. has been a member of scientific
requiring it at the time of response evaluation, only secondary end points can be
assessed advisory boards for Amgen, GlaxoSmithKline, and Symphogen.
‡For some agents requiring continuous treatment like TPO agonists an upper B.H.C. has received travel assistance to attend the meeting by
limit of acceptable platelet count should be predefined and thus cumulative time
spent within a therapeutic window is most suitable.
GlaxoSmith-Kline and has been a consultant to CSL and Amgen.
§Defined as a platelet count not requiring treatment or dosage modification for at N.C. has been a member of scientific advisory boards for
least 15 days. GlaxoSmithKline. B.G. received support from and is consultant for
Roche, Sanofi Pasteur (not for ITP), Amgen, and LFB (Laboratoire
validated tools to assess bleeding risk and QoL. A validated
Français de fractionnement et de biotechnologie). V.B. has been a
bleeding score and QoL assessment tool would be useful to help
member of scientific advisory boards for Baxter and Bayer. T.K. has
guide the need for treatment in ITP patients and further investiga-
received unrestricted grants from Hoffman-LaRoche and Amgen.
tions in this area are needed. IWG members are committed to the
continued re-evaluation of this proposal. J.N.G. has been a consultant for and also has received research support
from Amgen, Inc, related to their development of romiplostim for ITP.
The other authors declare no competing financial interests.
Acknowledgments Correspondence: Prof Francesco Rodeghiero, Department of
Cell Therapy and Hematology, Hematology Division, San Bortolo
This project was endorsed by the Scientific Working Group on Hospital, Via Rodolfi 37, I-36100 Vicenza, Italy; e-mail:
Thrombocytopenias of the European Hematology Association [email protected].
 From bloodjournal.hematologylibrary.org at UNIVERSITY OF CALGARY on February 19, 2013. For personal use
2392 RODEGHIERO et al only. BLOOD, 12 MARCH 2009 䡠 VOLUME 113, NUMBER 11

References
1. Cooper N, Bussel J. The pathogenesis of immune prospective study of a population-based cohort of 39. Stasi R, Evangelista ML, Stipa E, Buccisano F,
thrombocytopaenic purpura. Br J Haematol. 245 patients. Br J Hematol. 2003;122:966-974. Venditti A, Amadori S. Idiopathic thrombocytope-
2006;133:364-374. 19. Stasi R, Amadori S, Osborn J, Newland AC, nic purpura: current concepts in pathophysiology
2. Ruggeri M, Fortuna S, Rodeghiero F. Heteroge- Provan D. Long-term outcome of otherwise and management. Thromb Haemost. 2008;99:4-
neity of terminology and clinical definitions in healthy individuals with incidentally discovered 13.
adult idiopathic thrombocytopenic purpura: a criti- borderline thrombocytopenia. PLos Med. 2006;3: 40. Godeau B, Porcher R, Fain O, et al. Rituximab
cal appraisal from a systematic review of the lit- e24. efficacy and safety in adult splenectomy candi-
erature. Haematologica. 2008;93:98-103. 20. Adibi P, Faghih Imani E, Talaei M, Ghanei M. dates with chronic immune thrombocytopenic
Population-based platelet reference values for an purpura: results of a prospective multicenter
3. British Committee for Standard in Haematology
Iranian population. Int J Lab Hematol. 2007;29: phase 2 study. Blood. 2008;112:999-1004.
General Haematology Task Force (2003) Guide-
lines for the investigation and management of 195-199. 41. Godeau B, Chevret S, Varet B, et al. Intravenous
idiopathic thrombocytopenic purpura (ITP) in 21. Lugada ES, Mermin J, Kaharuza F, et al. Popula- immunoglobulin or high-dose methylpred-
adults, children and in pregnancy. Br J Haematol. tion-based hematologic and immunologic refer- nisolone, with or without oral prednisone, for
2003;120:574-596. ences values for a healthy Ugandan population. adults with untreated severe autoimmune throm-
Clin Diagn Lab Immunol. 2004;11:29-34. bocytopenic purpura: a randomised, multicentre
4. George JN, Woolf SH, Raskob GE, et al. Idio-
trial. Lancet. 2002;359:23-29.
pathic thrombocytopenic purpura: a practice 22. Bain BJ. Ethnic and sex differences in the total
guideline developed by explicit methods of Ameri- and differential white cell count and platelet 42. Newman GC, Novoa MV, Fodero EM, Lesser ML,
can Society of Hematology. Blood. 1996;88:3-40. count. J Clin Pathol. 1996;49:664-666. Woloski BM, Bussel JB. A dose of 75 ␮g/kg/d of
i.v. anti-D increases the platelet count more rap-
5. Cines DB, Bussel JB. How I treat thrombocytope- 23. Burrows RF, Kelton JG. Incidentally detected
idly and for a longer period of time than 50 ␮g/
nic purpura (ITP). Blood. 2005;106:2244-2251. thrombocytopenia in healthy mothers and their
kg/d in adults with immune thrombocytopenic pur-
infants. N Engl J Med. 1988;319:142-145.
6. Bussel JB, Kuter DJ, George JN, et al. AMG 531, pura. Br J Haematol. 2001;112:1076-1078.
a thrombopoiesis-stimulating protein, for chronic 24. Liebman HA, Stasi R. Secondary immune throm-
43. Kojouri K, Vesely SK, Terrell D, George J. Sple-
ITP. N Engl J Med. 2006;355:1672-1681. bocytopenic purpura. Curr Opin Hematol. 2007;
nectomy for adult patients with idiopathic throm-
14:557-573.
7. Newland A, Caulier MT, Kappers-Klunne M, et al. bocytopenic purpura: a systematic review to as-
An open-label, unit dose-finding study of AMG 25. Visco C, Ruggeri M, Evangelista ML, et al. Impact sess long-term platelet count responses,
531, a novel thrombopoiesis-stimulating pepti- of immune thrombocytopenia on the clinical prediction of response, and surgical complica-
body, in patients with immune thrombocytopenic course of chronic lymphocytic leukaemia. Blood. tions. Blood. 2004;104:2623-2634.
purpura. Br J Haematol. 2006;135:547-553. 2008;111:1110-1116.
44. Bellucci S, Charpak Y, Chastang C, Tobelem G.
26. Aster RH, Bougie DW. Drug-induced thrombocy- Low doses v conventional doses of corticoids in
8. Bussel JB, Cheng G, Saleh MN, et al. Eltrom-
topenia. N Engl J Med. 2007;357:580-587. immune thrombocytopenic purpura (ITP): results
bopag for the treatment of chronic idiopathic
thrombocytopenic purpura. N Engl J Med. 2007; 27. Hochberg M. Updating the American college of of a randomized clinical trial in 160 children, 223
357:2237-2247. Rheumatology revised criteria for classification of adults. Blood. 1988;71:1165-1169.
systemic lupus erythematosus. Arthritis Rheum. 45. Facon T, Caulier MT, Wattel E, Jouet JP, Bauters
9. Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of
1997;40:1725-1734. F, Fenaux P. A randomized trial comparing vin-
romiplostim in patients with chronic immune
thrombocytopenic purpura: a double-blind ran- 28. Miyakis S, Lockshin MD, Atsumi T, et al. Interna- blastine in slow infusion and by bolus i.v. injection
domised controlled trial. Lancet. 2008;371:395- tional consensus statement on an update of the in idiopathic thrombocytopenic purpura: a report
403. classification criteria for definite antiphospholipid on 42 patients. Br J Haematol. 1994;86:678-680.
syndrome (APS). J Thromb Haemost. 2006;4: 46. Godeau B, Caulier MT, Decuypere L, Rose C,
10. Arnold D, Dentali F, Crowther MA, et al. System- 295-306.
atic review: efficacy and safety of rituximab for Schaeffer A, Bierling P. Intravenous immuno-
29. Stasi R, Stipa E, Masi M, et al. Long-term obser- globulin for adults with autoimmune thrombocyto-
adults with idiopathic thrombocytopenic purpura.
vation of 208 adults with chronic idiopathic throm- penic purpura: results of a randomized trial com-
Ann Intern Med. 2007;146:25-33.
bocytopenic purpura. Am J Med. 1995;98:436- paring 0.5 and 1 g/kg b.w. Br J Haematol. 1999;
11. Khellaf M, Michel M, Schaeffer A, Bierling P, 442. 107:716-719.
Godeau B. Assessment of therapeutic strategy
30. Sailer T, Lechner K, Panzer S, Kyrle PA, Pabinger 47. Tarantino MD, Young G, Bertolone SJ, et al.
for adults with severe autoimmune thrombocyto-
I. The course of severe autoimmune thrombocy- Single dose of anti-D immune globulin at 75 mi-
penic purpura based on a bleeding score rather
topenia in patients not undergoing splenectomy. crog/kg is as effective as intravenous immune
than platelet count. Haematologica. 2005;90:829-
Haematologica. 2006;91:1041-1045. globulin at rapidly raising the platelet count in
832.
31. Imbach P, Kühne T, Müller D, et al. Childhood newly diagnosed immune thrombocytopenic pur-
12. Page KL, Psaila B, Provan D, et al. The immune ITP: 12 months follow-up data from the prospec- pura in children. J Pediatr. 2006;148:489-494.
thrombocytopenic purpura (ITP) bleeding score: tive registry I of the Intercontinental Childhood 48. Andersen JC. Response of resistant idiopathic
assessment of bleeding in patients with ITP. Br J ITP Study Group (ICIS). Pediatr Blood Cancer. thrombocytopenic purpura to pulsed high-dose
Haematol. 2007;138:245-248. 2006;46:351-356. dexamethasone therapy. N Engl J Med. 1994;
13. Buchanan GR, Adix L. Grading of hemorrhage in 32. Medeiros D, Buchanan GR. Major hemorrhage in 330:1560-1564.
children with idiopathic thrombocytopenic pur- children with idiopathic thrombocytopenic pur- 49. Mazzucconi MG, Fazi P, Bernasconi S, et. al.
pura. J Pediatr. 2002;141:683-688. pura: immediate response to therapy and long- Therapy with high-dose dexamethasone (HD-
14. Mathias SD, Bussel JB, George JN, McMillan R, term outcome. J Pediatr. 1998;133:334-339. DXM) in previously untreated patients affected by
Okano GJ, Nichol JL. A disease-specific measure 33. Bolton-Maggs PH, Moon I. Assessment of UK idiopathic thrombocytopenic purpura: a GIMEMA
of health-related quality of life for use in adults practice for management of acute childhood idio- experience. Blood. 2007;109:1401-1407.
with immune thrombocytopenic purpura: its de- pathic thrombocytopenic purpura against pub- 50. Bussel JB, Pham LC, Aledort L, Nachman R.
velopment and validation. Health Qual Life Out- lished guidelines. Lancet. 1997;350:620-623. Maintenance treatment of adults with chronic re-
comes. 2007;5:11. fractory immune thrombocytopenic purpura using
34. Arnold DM, Kelton JG. Current options for the
15. von Mackensen S, Nilsson C, Jankovic M, et al. treatment of idiopathic thrombocytopenic pur- repeated intravenous infusions of gammaglobu-
Development of a disease-specific quality of life pura. Semin Hematol. 2007;44:S12-S23. lin. Blood. 1988;72:121-127.
questionnaire for children & adolescents with idio- 35. Godeau B, Provan D, Bussel J. Immune thrombo- 51. Cooper N, Stasi R, Cunningham-Rundles S, et al.
pathic thrombocytopenic purpura (ITP-QoL). Pe- cytopenic purpura in adults. Curr Opin Hematol. The efficacy and safety of B-cell depletion with
diatr Blood Cancer. 2006;47(5 suppl):688-691. 2007;14:535-556. anti-CD20 monoclonal antibody in adults with
16. Klaassen RJ, Blanchette VS, Barnard D, et al. 36. Cortelazzo S, Finazzi G, Buelli M, Molteni A, chronic immune thrombocytopenic purpura. Br J
Validity, reliability, and responsiveness of a new Viero P, Barbui T. High risk of severe bleeding in Haematol. 2004;125:232-239.
measure of health-related quality of life in children aged patients with chronic idiopathic thrombocy- 52. Boruchov DM, Gururangan S, Driscoll MC,
with immune thrombocytopenic purpura: the Kids’ topenic purpura. Blood. 1991;77:31-33. Bussel JB. Multiagent induction and maintenance
ITP Tools. J Pediatr. 2007;150:510-515. therapy for patients with refractory immune
37. Cohen YC, Djulbegovic B, Shamai-Lubovitz O,
17. Frederiksen H, Schmidt K. The incidence of idio- Mozes B. The bleeding risk and natural history of thrombocytopenic purpura (ITP). Blood. 2007;
pathic thrombocytopenic Purpura in adults in- idiopathic thrombocytopenic purpura in patients 110:3526-3531.
creases with age. Blood. 1999;94:909-913. with persistent low platelet counts. Arch Intern 53. Rodeghiero F, Ruggeri M. Is splenectomy still the
18. Neylon AJ, Saunders PW, Howard MR, Proctor Med. 2000;160:1630-1638. gold standard for the treatment of chronic ITP?
SJ, Taylor PR; Northern Region Haematology 38. Stasi R, Provan D. Management of immune Am J Hematol. 2008;83:91.
Group. Clinically significant newly presenting au- thrombocytopenic purpura in adults. Mayo Clin 54. Vesely SK, Erdue JJ, Rizvi MA, Terrell D, George
toimmune thrombocytopenic purpura in adults: a Proc. 2004;79:504-522. JN. Management of adult patients with persistent
 From bloodjournal.hematologylibrary.org at UNIVERSITY OF CALGARY on February 19, 2013. For personal use
BLOOD, 12 MARCH 2009 䡠 VOLUME 113, NUMBER 11 only. DEFINITIONS AND TERMINOLOGY IN ITP 2393

idiopathic thrombocytopenic purpura following versus low-dose intravenous immunoglobulin in 69. Albayrak D, Içslek I, Kalaycí AG, Gürses N. Acute
splenectomy. Ann Intern Med. 2004;140:112-120. the treatment of childhood chronic idiopathic immune thrombocytopenic purpura: a compara-
55. Kühne T, Blanchette V, Buchanan GR, et al. Inter- thrombocytopenic purpura. Acta Haematol. 2006; tive study of very high oral doses of methylpred-
continental Childhood ITP Study Group. Splenec- 115:46-52. nisolone and intravenously administered immune
tomy in children with idiopathic thrombocytopenic 63. Erduran E, Aslan Y, Gedik Y, Orhan F. A random- globulin. J Pediatr. 1994;125:1004-1007.
purpura: a prospective study of 134 children from ized and comparative study of intravenous immu- 70. Blanchette V, Imbach P, Andrew M, et al. Ran-
the Intercontinental Childhood ITP Study Group. noglobulin and mega dose methylprednisolone domised trial of intravenous immunoglobulin G,
Pediatr Blood Cancer. 2007;49:829-834. treatments in children with acute idiopathic throm- intravenous anti-D, and oral prednisone in child-
56. Mazzucconi MG, Francesconi M, Fidani P, et al. bocytopenic purpura. Turk J Pediatr. 2003;45: hood acute immune thrombocytopenic purpura.
Treatment of idiopathic thrombocytopenic pur- 295-300. Lancet. 1994;344:703-707.
pura (ITP): results of a multicentric protocol. 64. Benesch M, Kerbl R, Lackner H, et al. Low-dose 71. Blanchette VS, Luke B, Andrew M, et al. A pro-
Haematologica. 1985;70:329-336. versus high-dose immunoglobulin for primary spective, randomized trial of high-dose intrave-
treatment of acute immune thrombocytopenic nous immune globulin G therapy, oral prednisone
57. Ferrari A, Pasqualetti D, Del Bianco P, Gandolfo
purpura in children: results of a prospective, ran- therapy, and no therapy in childhood acute im-
GM, Chistolini A, Mazzucconi MG. Prednisone
domized single-center trial. J Pediatr Hematol mune thrombocytopenic purpura. J Pediatr. 1993;
versus deflazacort in the treatment of autoim-
Oncol. 2003;25:797-800. 123:989-995.
mune thrombocytopenic purpura: evaluation of
clinical response and immunological modifica- 65. Hedlund-Treutiger I, Henter JI, Elinder G. Ran- 72. Ozsoylu S, Sayli TR, Oztürk G. Oral megadose
tions. Haematologica. 1991;76:342-345. domized study of IVIg and high-dose dexametha- methylprednisolone versus intravenous immuno-
sone therapy for children with chronic idiopathic globulin for acute childhood idiopathic thrombocy-
58. Tsutsumi Y, Kanamori H, Yamato H, et al. Ran-
thrombocytopenic purpura. J Pediatr Hematol topenic purpura. Pediatr Hematol Oncol. 1993;
domized study of Helicobacter pylori eradication
Oncol. 2003;25:139-144. 10:317-321.
therapy and proton pump inhibitor monotherapy
for idiopathic thrombocytopenic purpura. Ann He- 66. Ancona KG, Parker RI, Atlas MP, Prakash D. 73. Burdach SE, Evers KG, Geursen RG. Treatment
matol. 2005;84:807-811. Randomized trial of high-dose methylpred- of acute idiopathic thrombocytopenic purpura of
nisolone versus intravenous immunoglobulin for childhood with intravenous immunoglobulin G:
59. Suzuki T, Matsushima M, Masui A, et al. Effect of
the treatment of acute idiopathic thrombocytope- comparative efficacy of 7S and 5S preparations.
Helicobacter pylori eradication in patients with
nic purpura in children. J Pediatr Hematol Oncol. J Pediatr. 1986;109:770-775.
chronic idiopathic thrombocytopenic purpura-a
2002;24:540-544. 74. Imbach P, Gaedicke G, Joller P. Interim evalua-
randomized controlled trial. Am J Gastroenterol.
2005;100:1265-1270. 67. Fujisawa K, Iyori H, Ohkawa H, et al. Japanese tion of two cooperative studies assessing the ef-
Study Group on Childhood ITP. A prospective, fects of intravenous immunoglobulin (i.v. IgG) on
60. George JN, Raskob GE, Vesely SK, et al. Initial randomized trial of conventional, dose-acceler- childhood idiopathic thrombocytopenic purpura
management of immune thrombocytopenic pur- ated corticosteroids and intravenous immuno- (ITP): I. Randomized study comparing i.v. IgG
pura in adults: a randomized controlled trial com- globulin in children with newly diagnosed idio- with oral corticosteroids in previously untreated
paring intermittent anti-D with routine care. Am J pathic thrombocytopenic purpura. Int J Hematol. acute ITP. II. Prospective study of i.v. IgG in acute
Hematol. 2003;74:161-159. 2000;72:376-383. and chronic ITP unresponsive to previous treat-
61. Imbach P, Wagner HP, Berchtold W, et al. Intrave- 68. Rosthøj S, Nielsen SM, Pedersen FK. Random- ment. Blut. 1984;48:357-361.
nous immunoglobulin versus oral corticosteroids ized comparison of intravenous immunoglobulin 75. Buchanan GR, Holtkamp CA. Prednisone therapy
in acute immune thrombocytopenic purpura in and methylprednisolone pulse therapy in children for children with newly diagnosed idiopathic
childhood. Lancet. 1985;2:464-468. with newly diagnosed idiopathic thrombocytic thrombocytopenic purpura. A randomized clinical
62. El Alfy MS, Mokhtar GM, El-Laboudy MA, Khalifa purpura. The Danish ITP Study Group. Ugeskr trial. Am J Pediatr Hematol Oncol. 1984;6:355-
AS. Randomized trial of anti-D immunoglobulin Laeger. 1998;160:1640-1644. 361.