Immune Thrombocytopenia Nomenclature, Consensus

Reports, and Guidelines: What Are the Consequences

for Daily Practice and Clinical Research?
Marc Michel

New insights into the pathophysiology and the natural history of immune thrombocytopenia
(ITP) and new therapeutical approaches have emerged in the last 10 years that have made
necessary the update of previous guidelines. An important step towards the harmonization on
both the definition of the disease and the phases of the disease, the objectives of treatment, and
the criteria of response to be used in clinical trials has been first made possible throughout the
International Working group on ITP. This important step has been followed by an international
consensus report and the updated American Society of Hematology (ASH) guidelines focused
on the investigation and management of ITP taking into account the data from the most recent
clinical trials in the field. In this article, the consequences and translation that these guidelines
may have or not on daily practice and on future clinical trials are discussed and the few
controversies are pointed out. Whereas these guidelines are helpul for the investigation of ITP
and for the harmonization of clinical trials, some area of uncertainties do remain for the best
management of ITP and especially the choice of the best second-line strategy in persistent ITP
is still far from being consensual.
Semin Hematol 50:S50–S54. C 2013 Published by Elsevier Inc.
Open access under CC BY-NC-ND license.

agonists4,5—supported by several prospective ⫾

T he American Society of Hematology (ASH)

published a comprehensive guideline on
immune thrombocytopenia (ITP) in 1996
mainly based on expert opinion, which has long
been the standard reference for both the diagnosis
and treatment of the disease.1 Following this, in
2003, the British Committee for Standards in Hae-
matology published a guideline that provided a
practical and rational approach to the investigation
and management of patients with ITP in various
clinical situations, also based on a systematic review
of the literature.2 However, in the last 10 years, the
emergence of new therapies—first rituximab3,4 and
subsequently the thrombopoietin-receptor (Tpo-R)
Department of Internal Medicine, National Referral Center for Adult
Immune Cytopenias, Henri-Mondor University Hospital, Créteil,
France.
Publication of this article was supported by the International Co-
operative ITP Study Group (ICIS).
Conflicts of interest: none.
Address correspondence to Marc Michel, MD, Department of Internal
Medicine, National Referral Center for Adult Immune Cytopenias,
Henri-Mondor University Hospital, Assistance Publique
Hopitaux de Paris, Université Paris-Est Créteil, 51 Av. du Mal de
Lattre de Tassigny, 94010 Créteil cedex, France. E-mail:
marc.michel@hmn.aphp.fr
0037-1963
& 2013 Published by Elsevier Inc. Open access under CC BY-NC-ND license.
http://dx.doi.org/10.1053/j.seminhematol.2013.03.008
randomized studies3–5 have significantly changed
the ITP panorama. A significant effort has thus been
made in the last few years not only to harmonize the
terminology (definitions, phases of the disease, dis-
ease outcome) of ITP but also to update the recom-
mendations and guidelines for both investigation and
treatment of ITP taking these new insights into
consideration. These efforts have translated into
three distinct international publications reported in
Blood,6–8 two of which came from international
collaborative groups involved in ITP and were
mainly based on expert opinion (most of the experts
were involved in both manuscripts) and delphi-like
panels,7,8 the third being an update of the 1996 ASH
guidelines.9 A number of European countries such as
France, Germany, Spain, Norway, and Sweden have
also established national recommandations or guide-
lines adapted from these three publications (recently
summarized by Ghanima et al).10
Since there might sometimes be a gap between
guidelines and the daily clinical practice, the pur-
pose of this article is to briefly analyze the impact
that these publications may have already had on
clinical practice and research, and to point out the
questions and important issues that these guidelines
did not address especially in term of management.

S50 Seminars in Hematology, Vol 50, No 1, Suppl 1, January 2013, pp S50–S54

ITP nomenclature, consensus reports and guidelines
TERMINOLOGY
According to the new definitions for terminology,7
the acronym ITP remains but should not stand any-
more for ‘‘idiopathic thrombocytopenic purpura’’
but rather for ‘‘immune thrombocytopenia’’ since a
significant proportion of patients with ITP do not
have purpura. Moreover, to avoid any misdiagnosis
and to take into account the variability of the normal
range of the platelet count in different populations, a
platelet cut-off of less than 100  109/L is now
required for considering the diagnosis of ITP. Look-
ing at the last 200 publications reported on PubMed
(http://www.ncbi.nlm.nih.gov/pubmed) on Septem-
ber 10, 2012, using only the acronym ‘‘itp’’ as a
keyword (and after the exclusion of basic science
and animal models reports); it appears that 80% of
them are in keeping with the new standards of
terminology and that the terms immune, idiopathic,
or seldom autoimmune thrombocytopenic purpura
are still used in only approximately 20% of the
reports. Furthermore, 90% of these publications use
a platelet number of 100  109/L as the threshold for
considering ITP diagnosis and quote at least one of
the three references6–8 mentioned in the introduc-
tion. The degree of compliance with this terminology
seemed much less obvious in ongoing or planned
clinical trials focused on ITP as they appear on the
www.clinicaltrials.gov website but this point was
more difficult to determine as several trials appearing
on the website could have been designed prior to the
publication of guidelines and consensus reports.
PHASES OF THE DISEASE
One of the major new concepts provided by the
International Working Group (IWG) focused on ITP
was to split the disease into three different phases
based on what is known of the natural history of ITP
especially in adults.7 While ITP has formerly been
defined as ‘‘chronic’’ if it lasted for more than
6 months and ‘‘acute’’ if it was a self-limited and
transient disease, the IWG members agreed on three
distinct phases of the disease, namely (1) the initial
« acute ITP »
6 months
Newly-diagnosed
ITP
(initial phase)
3 months
Disease onset
Figure 1. New definitions for the phases of the disease.6
S51
phase, ‘‘newly diagnosed ITP,’’ from the time of
diagnosis up to 3 months; (2) ‘‘persistent,’’ between
3 and 12 months from diagnosis; and (3) ‘‘chronic
phase,’’ now defined as a disease duration of more
than 12 months, a period of time beyond which the
occurrence of a spontaneous remission becomes less
likely although still possible.11 This distinction of
three different phases is actually very important in
term of potential consequences in that it suggests
that different therapeutic options should be consid-
ered for every phase and at least theoretically
implied that both the time of splenectomy, the
recognized ‘‘gold standard’’ of treatment for adult
chronic severe ITP as well as the use of Tpo-R
agonists licensed in Europe only for chronic ITP
should be postponed (Figure 1).
Has this terminology now entered into clinical
pratice? Again, looking at the recently designed trials
listed on the www.clinicaltrials.gov website, it
appears that a number of studies do not include
specifically the phase in the eligibility criteria taking
into account these new definitions while few others
do (eg, Prednisone or Dexamethasone in Treating
Patients With Newly Diagnosed, Previously Untreated
Primary Immune Thrombocytopenic Purpura, Clini-
calTrials.gov Identifier: NCT00657410; The Efficacy
of Dexamethasone Versus Dexamethasone Combined
With Rituximab in Patients With Newly Diagnosed
Idiopathic Thrombocytopenic Purpura (ITP) NCT00-
909077).12 The terms ‘‘refractory,’’ ‘‘untreated ITP,’’
or yet ‘‘steroid-resistant ITP’’ are still predominantly
used in most of the studies. However, it is likely that
this new terminology will be increasingly used in
future in clinical trials in order to facilitate the
comparison of data from different studies and to
improve our knowledge about the natural history of
the disease.
DEFINITION OF RESPONSE TO TREATMENT:
WHERE DO WE STAND IN RECENTLY
DESIGNED CLINICAL TRIALS?
The report from the IWG proposed standardization
of the criteria for response to therapy that should be
chronic ITP BEFORE
Chronic phase
Persistent phase
12 months
NOW
S52
used in clinical trials. Hence, a complete response
(CR) has been defined as an increase in platelet count
to 4 100  109/L, and a clinically relevant response
as a platelet increase to 4 30  109/L with at least a
twofold increase of the baseline (ie, pretreatment)
count and the absence of bleeding. Obviously, the
expected time of response as well as the duration of
the response could be highly variable depending on
the mechanism of the drug or procedure. The ASH
2011 guidelines also recommend use of the same
criteria.9 These definitions, which were not addressed
in past guidelines, are also an important step towards
standardization for future clinical trials and have
already been used in recently designed and/or ongoing
trials (see, eg, the study design of the NCT01356511
and NCT01525836 trials on www.clinicaltrials.gov).
Conversely, in ongoing trials designed to assess the
efficacy of Tpo-R agonists in childhood ITP, a durable
response has been defined as an increase of the
platelet count Z 50  109/L over at least 6 of the
8 last weeks of the treatment period (studies
NCT01444417 and NCT01520909). This criterion is
the same as the one previously used in the romiplostim
pivotal studies in adult ITP,13 but some researchers
would consider this to be an unnecessarily high cut-off
since a count of 30109/L is usually regarded as ‘‘safe.’’
INITIAL WORKUP TO RULE OUT SECONDARY
ITP
The criteria for diagnosis of ITP in both children
and adults in both the international consensus report
and the new ASH guidelines8,9 are similar and both
agreed on the unproven or uncertain benefit of
various tests, including measurement of antiplatelet
antibodies or the bleeding time. The only important
difference beetween these two guidelines was the
place of the bone marrow examination, which was
considered as required in selected patients (especially
in patients aged 60 years and above) in the consensus
report whereas in the ASH guideline, it was consid-
ered as ‘‘not necessary irrespective of age in patients
presenting with typical ITP’’ (grade 2C recommenda-
tion). There are insufficient data in the literature to
estimate compliance in daily practice with these
recommendations. The relevance of performing or
not at time of ITP onset some tests such as the direct
antiglobulin test, the antinuclear antibodies or anti-
phospholipid antibodies remain a matter of debate.
GUIDELINES AND RECOMMENDATIONS FOR
TREATMENT
Newly Diagnosed ITP
There is general agreement that adults with a
count ofo30  109/L with bleeding at diagnosis
M. Michel
require treatment. The platelet count alone is not
the only consideration.8 The efforts made by the
IWG on ITP for proposing and validating a consen-
sual bleeding assessment tool14 tailored for ITP are
an important step toward the standardization of the
management. The first line of treatment for newly
diagnosed ITP is generally agreed and based on the
use of corticosteroids ⫾ intravenous immunoglobu-
lin (IVIg) since anti-D is not licensed and available for
ITP in most if not all European countries. The
treatment strategy in adults with newly diagnosed
ITP has not changed significantly in the last 10 years
and overall, by using corticosteroids ⫾ IVIg, approx-
imately 85%–90% of the patients have at least a
transient initial response. The ‘‘only’’ controversial
question in adult ITP not answered by the recent
guidelines is whether dexamethasone may be better
than a course of prednisone/prednisolone in terms
of the magnitude and the duration of response.15,16
To address this question, the statement reported in
the 2011 ASH guidelines, ‘‘longer courses of cortico-
steroids are preferred over shorter courses of corti-
costeroids or IVIg as first-line treatment,’’ is
ambiguous and not very helpful. As suggested in
the international consensus report,8 only a prospec-
tive randomized controlled trial comparing the effi-
cacy of a single course of dexamethasone at 40 mg/d
for 4 days with a ‘‘standard’’ corticosteroids regimen
(prednisone at 1 mg/kg per day over 2–4 weeks)
could answer this question. However, indirect evi-
dence suggests that dexamethasone is unlikely to
modify the natural course of ITP,4 and some of the
data suggesting the opposite were biased by the use
of repeated (every 4 weeks) courses of dexametha-
sone.15 In newly diagnosed childhood ITP, the
debate has long been focused on whether or not
the ‘‘wait and watch’’ strategy (ie, observation)
should be preferred to the ‘‘intervention’’ one. The
2011 ASH guidelines, based on review of the data
from the literature,9,12 now clearly recommend that
children with no bleeding or mild bleeding should
Table 1. First-Line Treatment Options
Clinical Therapy Option
Situation
Newly  Dexamethasone
diagnosed
 or
ITP
 Prednisone (?)
 Methylprednisolone
 IVIg
 Intravenous anti-D (Rho)
immunoglobulin
Abbreviations: ITP, immune thrombocytopenia; IVIg, intra-
venous immunoglobulin.
ITP nomenclature, consensus reports and guidelines S53

guidelines (see Table 2). Indeed, whereas Tpo-R

Table 2. Strength of Recommendations for
Second- and Third-Line Treatments in Adults
With Chronic ITP
Treatments Strength of
Recommendation
Consensus ASH
Report Guidelines
Second-line treatments
TPO receptor agonists A 2C
Rituximab B 2C
Splenectomy C 1B
Third-line treatments
TPO receptor agonists A 1B
be managed by observation alone regardless of
platelet count (grade 2B), which is a major change
from the 1996 guideline (Table 1).
Persistent and Chronic ITP
The best second-line treatment in both adults and
children is still a matter of debate and this point has
not been addressed either by the international con-
sensus report or by the ASH guidelines, mainly
because there is no clear answer from review of
the literature, and there is no drug specifically
licensed in Europe for persistent ITP. Most experts
and national guidelines9,17 now agree that splenec-
tomy, the long-recognized gold standard second-line
therapy18 should be delayed as much as possible and
considered only in patients with chronic and severe
(ie, serious bleeding) ITP, and they also agree that
the long-term use of corticosteroids should be
avoided.8 However, there were significant discrep-
ancies in the strength of recommendation between
the international consensus report and the ASH
agonists were stongly recommended by the IWG,
the strength for recommending splenectomy was
higher in the ASH guidelines as summarized by the
following statement ‘‘we recommend splenectomy.-
for patients who have failed corticosteroid therapy’’
(grade 1B) (ie, either unresponsive or who have a
relapse after a transient initial response). These
differences reflect the fact that the best corticosteroid-
sparing strategy for the management of a patient with
severe persistent ITP, in adults as in children, is far from
being established. In keeping with these uncertainties,
some studies have clearly shown the high degree of
heterogeneity in the choice of second-line treatment
among various European countries,19 this choice being
mainly based on personal experience, on the availabil-
ity of the drugs, and on the patient profile,9 as well as
pharmacoeconomic criteria, noting that for expensive
drugs, the rate and mode of reimbursement may be
highly variable. In the future, a particular effort should
be made in order to find and test the efficacy
and safety of new second-line therapeutic options for
persistent ITP.
Figure 2 summarizes the different treatment
options that may be used in different phases of
disease in adults with ITP who require treatment.
The use of Tpo-R agonists for few months could be
an attractive way for managing persistent ITP in
adults as a bridge toward splenectomy, but currently
their high cost limits promotion of their wider use.
CONCLUSION
Great efforts have been made in the last 5 years to
harmonize the terminology and definitions for ITP
and to provide some recommendations about who
should be treated and how, taking into account the
place of new therapies that have emerged in the past
10 years. The translation of these new definitions
into recent clinical studies and beyond is increasing

- corticosteroids (less is better)

-Steroids*
-IVIg* - dapsone, danazol, vinka-alkaloids (?)
-(Anti-D) - Rituximab (?) -TPO-R agonists*
- TPO-R agonists (?) Consider -Rituximab
Splenectomy
-Immunosuppressors
(azathioprine)
O * Hp eradication
N T0 3 months 12 months
if applicable
S
E
T

Note : * labelled for ITP

Figure 2. Therapeutic options for first-, second-, and third-line treatment in adult ITP (Europe).
S54
reflecting a rather good compliance with the guide-
lines. However, despite these efforts, there are still
some unmet clinical needs that none of the recent
reports have addressed due to a lack of data. It is
thus still difficult to provide strong recommenda-
tions to the clinicians for the management of persis-
tent ITP. In the future, based on better knowledge of
the pathophysiology of the disease, it will be neces-
sary to promote collaborative prospective clinical
trials to assess the efficacy and safety of new second-
line treatments currently being developed in other
autoimmune disease (such as drugs targeting B cells,
costimulatory molecules, or interleukin-17). More-
over, some recommendations could be provided for
the management of secondary ITPs, which may
require a more specific approach. Lastly, the panels
of experts should integrate colleagues from other
parts of the world, in addition to those from Europe
and North America, who may have different per-
spectives on the disease.
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