Diagnosis and management of immune thrombocytopenic purpura (ITP) remain largely dependent on clinical expertise and observations more than on evidence derived from clinical trials of high scientific quality. One major obstacle to the implementation of such studies and in producing reliable meta-analyses of existing data is a lack of consensus on standardized critical definitions, outcome criteria, and terminology. Moreover, the demand for comparative clinical trials has dramatically increased since the introduction of new classes of therapeutic agents, such as thrombopoietin receptor agonists, and innovative treatment modalities, such as anti-CD 20 antibodies. To overcome the present heterogeneity, an International Working Group of recognized expert clinicians convened a 2-day structured meeting (the Vicenza Consensus Conference) to define standard terminology and definitions for primary ITP and its different phases and criteria for the grading of severity, and clinically meaningful outcomes and response. These consensus criteria and definitions could be used by investigational clinical trials or cohort studies. Adoption of these recommendations would serve to improve communication among investigators, to enhance comparability among clinical trials, to facilitate meta-analyses and development of therapeutic guidelines, and to provide a standardized framework for regulatory agencies.

Introduction

Immune thrombocytopenic purpura (ITP), also known as idiopathic thrombocytopenic purpura, is an immune-mediated acquired disease of adults and children characterized by transient or persistent decrease of the platelet count and, depending upon the degree of thrombocytopenia, increased risk of bleeding.1 

A recent review compared the definitions and clinical criteria used in different studies.2  It showed widely discrepant criteria used to evaluate patient characteristics, determine responses, and report clinical outcomes. This heterogeneity makes comparison of the results of clinical trials or cohort description uneven and therefore unreliable and application of practical guidelines3,45  troublesome. Many of these difficulties could be minimized by adopting a common set of definitions. The need for standardization and harmonization of response criteria has been recently highlighted by clinical trials of novel targeted therapies, such as thrombopoietin (TPO)–receptor agonists6,7,89  and anti–CD-20 antibodies,10  which have different mechanisms of action and heterogeneous patterns of response. Furthermore, the importance of this harmonization has become increasingly apparent by the necessity to develop and validate ITP-specific bleeding scales11,1213  and quality of life14,1516  questionnaires. To address these issues, an International Working Group (IWG) of recognized experts convened a 2-day structured face-to-face consensus conference in Vicenza, Italy (the Vicenza Consensus Conference) in October 2007. This article reports the definitions and recommendations agreed upon by the members of this consensus conference.

Methodology of the conference

The location of the conference, its funding, and the composition of the IWG were decided during the 5th official meeting of the European Hematology Association (EHA) Scientific Working Group on Thrombocytopenias (EHASWGT; http://www.ehaweb.org/eha/about_eha/eha_scientific_working_groups) held on June 7, 2007, during the 12th EHA Congress in Vienna. It was decided that the IWG members should include the 7 officers of the current executive committee of the EHASWGT and be expanded by the addition of 13 members selected for their recognized clinical expertise and wide geographic representation to provide an international scope. Preliminary agreement regarding the identification of the main topics of the conference and the clarification of its objectives were previously agreed on through 2 rounds of Delphi-like questionnaires circulated among the members. Specific aspects pertinent to pediatrics that had been previously elaborated by the Intercontinental Childhood ITP Study (ICIS) Group (http://pages.unibas.ch/itpbasel/) were also included for further examination. Coordinated by the conference chairman, 5 working parties (WP) covered specific topics, guided the discussion interactively, and prepared serial summaries of each topic. Consensus was reached by several meetings on specific topics by ad hoc subgroups followed by plenary sessions. A second short conference was held during the 49th Annual Meeting of the American Society of Hematology in Atlanta (December 8, 2007) to approve the final draft. Furthermore, 3 experts who did not attend the Vicenza Consensus Conference acted as external reviewers to ensure that the proposal was intrinsically logical, consistent, clear, and reasonably applicable. The final version was finally circulated among all members for minor modifications and explicit approval. None of the IWG members and external reviewers received honoraria.

Recommendations

Definition of primary and secondary immune thrombocytopenia (primary and secondary ITP) and platelet count threshold

The panel decided to avoid the term “idiopathic,” preferring “immune,” to emphasize the immune-mediated mechanism of the disease and to choose “primary” (as opposed to idiopathic) to indicate the absence of any obvious initiating and/or underlying cause. The term “purpura” was felt inappropriate, because bleeding symptoms are absent or minimal in a large proportion of cases.17,18  The acronym ITP (now proposed to stand for immune thrombocytopenia) was preserved because of its widespread and time-honored use and taking into account its utility for literature searches. A platelet count less than 100 × 109/L was established as the threshold for diagnosis. A uniform predefined cutoff, instead of local normal ranges or other thresholds based on frequency distribution, is more convenient for practical use and comparisons across studies. This threshold was preferred to the more commonly used level of less than 150 × 109/L, based upon a prospective cohort of otherwise healthy subjects with a platelet count between 100 and 150 × 109/L, showing that the 10-year probability of developing more severe thrombocytopenia (persistent platelet count below 100 × 109/L) is only 6.9% (95% confidence interval [CI], 4.0%-12.0%).19  Moreover, in some non-Western populations, platelet count values between 100 and 150 × 109/L are frequently found in apparently healthy people.20,2122  The new cutoff level will also avoid inclusion of most women with pregnancy-related thrombocytopenia, a well known physiologic phenomenon not requiring specific follow-up in the absence of additional clinical features23  (Table 1).

Table 1

Proposed definitions of disease

Primary ITP Primary ITP is an autoimmune disorder characterized by isolated thrombocytopenia (peripheral blood platelet count <100 × 109/L) in the absence of other causes or disorders that may be associated with thrombocytopenia. The diagnosis of primary ITP remains one of exclusion; no robust clinical or laboratory parameters are currently available to establish its diagnosis with accuracy. The main clinical problem of primary ITP is an increased risk of bleeding, although bleeding symptoms may not always be present. 
Secondary ITP All forms of immune-mediated thrombocytopenia except primary ITP* 
Phases of the disease Newly diagnosed ITP: within 3 months from diagnosis 
 Persistent ITP: between 3 to 12 months from diagnosis. Includes patients not reaching spontaneous remission or not maintaining complete response off therapy. 
 Chronic ITP: lasting for more than 12 months 
 Severe ITP: Presence of bleeding symptoms at presentation sufficient to mandate treatment, or occurrence of new bleeding symptoms requiring additional therapeutic intervention with a different platelet-enhancing agent or an increased dose 
Primary ITP Primary ITP is an autoimmune disorder characterized by isolated thrombocytopenia (peripheral blood platelet count <100 × 109/L) in the absence of other causes or disorders that may be associated with thrombocytopenia. The diagnosis of primary ITP remains one of exclusion; no robust clinical or laboratory parameters are currently available to establish its diagnosis with accuracy. The main clinical problem of primary ITP is an increased risk of bleeding, although bleeding symptoms may not always be present. 
Secondary ITP All forms of immune-mediated thrombocytopenia except primary ITP* 
Phases of the disease Newly diagnosed ITP: within 3 months from diagnosis 
 Persistent ITP: between 3 to 12 months from diagnosis. Includes patients not reaching spontaneous remission or not maintaining complete response off therapy. 
 Chronic ITP: lasting for more than 12 months 
 Severe ITP: Presence of bleeding symptoms at presentation sufficient to mandate treatment, or occurrence of new bleeding symptoms requiring additional therapeutic intervention with a different platelet-enhancing agent or an increased dose 
*

The acronym ITP should be followed by the name of the associated disease (for thrombocytopenia after exposure to drugs, the terms “drug-induced” should be used) in parentheses: for example, “secondary ITP (lupus-associated),” “secondary ITP (HIV-associated),” and “secondary ITP (drug-induced).” For manuscript titles, abstracts, and so on, definitions such as lupus-associated ITP or HIV-associated ITP can also be used.

The term “secondary immune thrombocytopenia” or “secondary ITP” has been proposed to broadly include all forms of immune-mediated thrombocytopenias except primary ITP. Secondary forms include thrombocytopenias that are due to an underlying disease or to drug exposure. Some rare secondary immune thrombocytopenias, such as fetal and neonatal alloimmune thrombocytopenic purpura and posttransfusion purpura, would maintain their standard designation. For the other secondary forms of ITP, the name of the associated disease should follow the designation in parentheses. For example: “secondary ITP (systemic lupus erythematosus-associated or SLE-associated)” and “secondary ITP (human immunodeficiency virus or HIV-associated).” For cases possibly initiated by or associated with Helicobacter pylori infection, considering the high prevalence of the infection in some countries, a diagnosis of “secondary ITP (Helicobacter pylori–associated)” would require the demonstration of complete resolution of ITP after proven eradication of the bacteria. In the case of thrombocytopenia related to drug exposure (with the exclusion of myelosuppressive chemotherapy), the term “drug-induced” was preferred. The name of the incriminated drug should be indicated when known. For example: “Secondary ITP (quinine-induced).” Heparin-induced thrombocytopenia will maintain its designation and acronym (HIT) because of its unique features.

The distinction between primary and secondary immune thrombocytopenia is clinically relevant because of their different natural histories and distinct treatments. For thrombocytopenias secondary to an ongoing medical condition, treatment is often targeted toward the underlying disorder.24,25  On the other hand, drug-induced ITP often remits quickly after the withdrawal of the inciting drug, and most severe cases may require transfusion of platelets alone as initial treatment, as opposed to the application of immunomodulation often used in primary ITP.26  The coexistence of anti-nuclear antibodies and/or anti-phospholipid antibodies (aPL) on their own, in the absence of distinctive clinical manifestations suggestive of SLE27  and/or antiphospholipid syndrome,28  does not qualify these cases as secondary ITP. The increased risk of thrombosis in aPL antibody-positive cases reported in some studies is controversial,24  and in our opinion, the available evidence does not warrant consideration of the coexistence of thrombocytopenia with aPL antibodies as a distinct clinical entity. We are aware that a different consensus was reached by the experts who updated previous Sapporo criteria for the classification of definite antiphospholipid syndrome,28  which might contribute to confusion rather than harmonization. However, in the updated criteria, the presence of aPL antibodies has no impact on the clinical management of patients with ITP, bearing relevance only for patient stratification in clinical trials. The impact of these associated laboratory abnormalities should be further investigated in studies of the natural history of ITP. The IWG agreed that the proposed definitions, therapeutic goals, and outcome assessment should be applied only to primary ITP.

Definition of the different phases and severity of the disease

Only those terms relevant for treatment and/or prognosis were retained to describe the phases of ITP. The panel recommended that the term “acute,” which has been used to describe a self-limited form of the disease (eg, secondary to viral illness in children) be avoided because of both its vagueness and its post hoc or retrospective definition. In the absence of reliable predictive clinical or laboratory parameters of disease duration, the term “newly diagnosed ITP” was suggested for all cases at diagnosis. A new category, called “persistent ITP,” was introduced for patients with ITP to define the period lasting between 3 and 12 months from diagnosis. This category includes patients not achieving spontaneous remission or not maintaining their response after stopping treatment between 3 and 12 months from diagnosis. The chances of spontaneous remissions are still significant during this period,29,3031  making deferral of more aggressive therapeutic approaches (such as splenectomy) worthy of consideration. The term “chronic ITP” is to be reserved for patients with ITP lasting for more than 12 months (Table 1).

To date, disease severity (mild, moderate, severe) has been 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 be used only in patients who have clinically relevant bleeding. This is defined by the presence of bleeding symptoms at presentation sufficient to mandate treatment, or by the occurrence of new bleeding symptoms requiring additional therapeutic intervention with a different platelet-enhancing agent or an increased dose. For example, using the proposed schema, a patient with chronic ITP, a platelet count of 2 × 109/L, and just a few petechiae and ecchymoses would not be classified as having “severe” disease. Unfortunately, the few bleeding assessment tools specifically developed for ITP11,1213,32,33  have not been validated in large prospective studies and so a more precise definition of “clinically relevant” bleeding cannot be given. This is an area of research that merits further development.

Therapeutic goals

The major goal for treatment of ITP is to provide a safe platelet count (eg, one that prevents major bleeding) rather than correcting the platelet count to normal levels.3,45,34,35  Treatment of patients with ITP should take into account the severity of the illness and the age of the patient, because the bleeding risk and the hemorrhagic fatality rate increase with age36  and are the lowest in children of post-toddler age. Most fatal bleeding has been reported to occur in adults with ITP who have platelet counts lower than 30 × 109/L.37 

Because of the real and potential toxicity of currently available treatments, a critical concept is to avoid unnecessary treatment of asymptomatic patients with milder degrees of thrombocytopenia. Current guidelines3,4  suggest that treatment should be initiated in the presence of bleeding symptoms. Treatment decisions based on platelet count threshold remains controversial. Although most guidelines suggest that treatment should be considered with counts less than 30 × 109/L in adults, the ICIS group recommended that children without bleeding may not require therapy regardless of their platelet count, with the exception of “on-demand therapy.” This deserves further evaluation, including better attempts at individualization.

Treatment of newly diagnosed adult patients or of patients requiring treatment for the first time (initial treatment) is aimed at rapidly obtaining a safe platelet count to prevent or stop hemorrhages and to ensure an acceptable quality of life with minimal treatment-related toxicity. A minority of patients are expected to obtain spontaneous durable remission after initial treatment with standard commonly used corticosteroid-based regimens.38  However, with the availability of new therapies, increasing the rate of long-lasting responses becomes a realistic aim of early intervention.39  The goal of treatment in persistent or chronic ITP is less well defined and is often inspired by the desire to defer or avoid the risks of more toxic treatments such as splenectomy or immunosuppression. Thus “on-demand” treatment at the time of or in anticipation of high-risk bleeding situations or surgical procedures is another approach that is often warranted. Minimal corticosteroid exposure is a tenet of therapy for chronic ITP. As with initial treatment, the rate of long-lasting responses may become an achievable goal based on investigational studies.40  On the other hand, the goal of splenectomy is long-term response (in terms of several years) to avoid more toxic treatments, to establish or to increase health-related quality of life, and to save costs.

Definition of response

The panel acknowledged that the definition of a treatment response should ideally reflect clinically important endpoints including bleeding and quality of life, rather than rely exclusively on surrogate end points (platelet count) with arbitrary thresholds. Nevertheless, the platelet count is a useful measure of response that is objective, clinically relevant, and easily compared (Table 2).

Table 2

Proposed criteria for assessing response to ITP treatments

Quality of response*†
  • CR: platelet count ≥ 100 × 109/L and absence of bleeding

  • R: platelet count ≥ 30 × 109/L and at least 2-fold increase the baseline count and absence of bleeding

  • Time to response: time from starting treatment to time of achievement of CR or R‡

  • NR: platelet count < 30 × 109/L or less than 2-fold increase of baseline platelet count or bleeding

  • Loss of CR or R: platelet count below 100 × 109/L or bleeding (from CR) or below 30 × 109/L or less than 2-fold increase of baseline platelet count or bleeding (from R)

 
Timing of assessment of response to ITP treatments
  • Variable, depends on the type of treatment (see Table 3)

 
Duration of response§
  • 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 period under examination as well as the total time observed from which the proportion is derived

 
Corticosteroid-dependence
  • The need for ongoing or repeated doses administration of corticosteroids for at 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 nonresponders)

 
Supplemental outcomes (whenever possible)
  • Bleeding symptoms measured by a validated scale (requires additional studies)

  • Health-related quality of life assessment measured by a validated instrument (requires additional studies)

 
Quality of response*†
  • CR: platelet count ≥ 100 × 109/L and absence of bleeding

  • R: platelet count ≥ 30 × 109/L and at least 2-fold increase the baseline count and absence of bleeding

  • Time to response: time from starting treatment to time of achievement of CR or R‡

  • NR: platelet count < 30 × 109/L or less than 2-fold increase of baseline platelet count or bleeding

  • Loss of CR or R: platelet count below 100 × 109/L or bleeding (from CR) or below 30 × 109/L or less than 2-fold increase of baseline platelet count or bleeding (from R)

 
Timing of assessment of response to ITP treatments
  • Variable, depends on the type of treatment (see Table 3)

 
Duration of response§
  • 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 period under examination as well as the total time observed from which the proportion is derived

 
Corticosteroid-dependence
  • The need for ongoing or repeated doses administration of corticosteroids for at 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 nonresponders)

 
Supplemental outcomes (whenever possible)
  • Bleeding symptoms measured by a validated scale (requires additional studies)

  • Health-related quality of life assessment measured by a validated instrument (requires additional studies)

 

For response criteria in refractory ITP, see Table 4.

HRQoL indicates health-related quality-of-life assessment.

*

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 loss of response.

Baseline platelet count refers to platelet count at the time of starting of the investigated treatment; for postsplenectomy response evaluation, basal platelet count refers to the platelet count before patient was first treated (initial treatment).

Late responses not attributable to the investigated treatment should not be defined as CR or R (see Table 3).

§

The 2 definitions are not mutually exclusive: the first definition, collectively represented using Kaplan-Meyer analysis, is more suitable for short-course treatments aimed at inducing prolonged remission of the disease, whereas the second one is more suitable to evaluate the overall benefit of continuous or intermittent repeated administration of agents requiring dose adjustments with anticipated temporary losses of CR or R.

“Complete response” (CR) is defined as any platelet count of at least 100 × 109/L. “Response” (R) is defined as any platelet count between 30 and 100 × 109/L and at least doubling of the baseline count. “No response” (NR) is defined as any platelet count lower than 30 × 109/L or less than doubling of the baseline count. The definition of response requires concurrent resolution of bleeding symptoms. The panel decided to avoid “partial” or “minimal” response categories, often used in scientific articles, because of the wide heterogeneity in the criteria used in these definitions.2  CR and R could be with or without concomitant administration of the investigated agent, and this should be specified. In a clinical trial, when, in addition to the treatment being investigated, any ongoing concomitant ITP-specific treatment is given, this latter, or the time of its discontinuation, should be provided. Often, corticosteroids are administered together with other ITP-specific agents. In this setting, as defined in Table 2, corticosteroid dependence is defined as the ongoing need for continuous corticosteroid administration or frequent courses of corticosteroids to maintain a platelet count at or above 30 × 109/L and/or to avoid bleeding. Corticosteroid- or other treatment-dependent patients should be considered nonresponders. Specific mention can be made of lessened dose or frequency of this agent as indicative of at least some effect of the investigated agent, even if below the level of a response.

Time to platelet count response is an important facet of management and should be reported in clinical studies. It varies depending on the mechanism of action of the specific agent (Table 3).4,6,7,8,910,40,41,42,43,44,45,46,47,48,49,50,5152  The frequency of monitoring of platelet counts and the timing of response assessment should be prespecified and will depend on the expected kinetics of platelet increase after each treatment. After splenectomy, the timing to assess the response in terms of platelet count should be within 1 to 2 months after surgery and removed from any treatment. Late responses not attributable to the investigated treatment (“spontaneous remission”), according to Table 3, should not be defined as CR or R.

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 μg/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 μg/kg weekly sc 5-14 d 14-60 d 
Eltrombopag8  50-75 mg po daily 7-28 d 14-90 d 
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 μg/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 μg/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.

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: (1) short-course treatments aimed at curing the disease, or at least at achieving prolonged remissions (eg, high-dose pulse dexamethasone, rituximab, splenectomy) and (2) treatments requiring continuous or repeated administrations (eg, TPO-receptor agonists, IVIg, anti-D, etc), for which it is anticipated that platelet count could fall temporarily below or increase above the desired threshold.

For short-course treatments, the overall response duration in a patient cohort should be calculated using a time-dependent analysis, such as the Kaplan-Meier product limit estimate, event rate per person-years, or similar approaches. For treatments requiring continuous prolonged or repeated administrations of the same agent, one should calculate the cumulative time spent in CR or R. This approach is also useful to evaluate the whole impact of a particular treatment plan, including different sequential treatments, allowing a more clinically meaningful estimation of response duration. When response duration includes time receiving treatment, this should be specified, and CR or R with or without concomitant treatment should be calculated and reported separately.

Identical response criteria are proposed for splenectomy. Assessment of response should occur within 1 to 2 months and after withholding concomitant treatment(s), if any, for a time sufficient to reasonably exclude a persistence of their effect (Table 3).

Refractory ITP: definition, therapeutic goals, and response assessment

Refractory patients should fulfill 2 criteria. First, they should have failed splenectomy or have relapsed thereafter. Second, they should either exhibit severe ITP (see Table 1) or have a risk of bleeding that in the opinion of the attending physician requires therapy. On-demand treatment required only to safely perform an invasive procedure or to prevent bleeding after major trauma is not a sufficient criterion (Table 4). Refractory patients may have temporary responses to corticosteroids or intravenous immunoglobulin (IVIg). The panel recognizes that many patients and an increasing number of physicians prefer to delay or avoid splenectomy, such 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 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 truly be called refractory before splenectomy is attempted. A consensus as to when a child with chronic ITP should be considered “refractory” has not been reached, considering that splenectomy is often delayed in most children as long as possible in view of the often benign natural history and delayed improvement of these patients. Unsplenectomized patients (adults and children) not responding to medical treatment(s) should be described as having “newly diagnosed, persistent or chronic (depending on the duration of disease) ITP unresponsive to one or more agents” (with specification).These patients may have or not severe ITP (Table 4).

Table 4

Refractory ITP

Definition (all should be met)
  • Failure to achieve at least R or loss of R after splenectomy*

  • Need of treatment(s) (including, but not limited to, low dose of corticosteroids) to minimize the risk of clinically significant bleeding. Need of on-demand or adjunctive therapy alone does not qualify the patient as refractory.

  • Primary ITP confirmed by excluding other supervened causes of thrombocytopenia

 
Definition of on-demand therapy
  • Any therapy used to temporarily increase the platelet count sufficiently to safely perform invasive procedures or in case of major bleeding or trauma‡

 
Definition of adjunctive therapy
  • Any non-ITP specific therapy that may decrease bleeding (eg, antifibrinolytic agents, hormonal agents, DDAVP, recombinant factor VIIa, fibrin sealants). Platelet transfusion is also included.

 
Definition of response to therapy in refractory ITP
  • Ability to maintain a platelet count sufficient to prevent clinically significant bleeding†§

  • Ability to decrease toxic therapy (eg, corticosteroids) does not qualify for response but should be reported

 
Definition of response to on-demand therapy
  • Control of bleeding in the specific situation

  • Achievement of a platelet count sufficient to perform procedure or minimize bleeding from trauma

 
Definition (all should be met)
  • Failure to achieve at least R or loss of R after splenectomy*

  • Need of treatment(s) (including, but not limited to, low dose of corticosteroids) to minimize the risk of clinically significant bleeding. Need of on-demand or adjunctive therapy alone does not qualify the patient as refractory.

  • Primary ITP confirmed by excluding other supervened causes of thrombocytopenia

 
Definition of on-demand therapy
  • Any therapy used to temporarily increase the platelet count sufficiently to safely perform invasive procedures or in case of major bleeding or trauma‡

 
Definition of adjunctive therapy
  • Any non-ITP specific therapy that may decrease bleeding (eg, antifibrinolytic agents, hormonal agents, DDAVP, recombinant factor VIIa, fibrin sealants). Platelet transfusion is also included.

 
Definition of response to therapy in refractory ITP
  • Ability to maintain a platelet count sufficient to prevent clinically significant bleeding†§

  • Ability to decrease toxic therapy (eg, corticosteroids) does not qualify for response but should be reported

 
Definition of response to on-demand therapy
  • Control of bleeding in the specific situation

  • Achievement of a platelet count sufficient to perform procedure or minimize bleeding from trauma

 

DDAVP indicates deamino arginine vasopressin.

*

May not be applicable in children or in patients with accessory spleen.

Bleeding symptoms measured by a validated scale whenever possible (requires further studies).

Specific platelet thresholds cannot be provided, but in most instances, a platelet count of 50-70 × 109/L would fulfill this criterion.

§

A strict definition of response in terms of predefined platelet count cannot be given and may not be appropriate when considering the risk/benefit ratio in refractory ITP, because the trade off between efficacy of a specific treatment and its short- and long-term toxicity varies among patients.

On-demand therapy for refractory ITP is administered as needed before invasive procedures, for major bleeding, after trauma, or in other instances in which a rapid, short-term increase in platelet count to safe levels (defined by the procedure or circumstance) with minimal toxicity is required. The definition of “rapid,” in terms of time needed to reach the safe platelet count, may differ by type of drug (eg, IVIg, high-dose corticosteroids, TPO-receptor agonists, anti–CD-20 antibodies; see Table 3) and should be assessed for any new drug.

The main goal of therapy in refractory ITP is generally the achievement of a platelet count sufficient to prevent clinically significant bleeding with the least toxicity.34,35  So, in this population, treatments should be evaluated for the potential to induce an acute response and also a long-lasting response with minimum side effects/toxicity. As for any other phase of the disease, adjunctive or combination therapy or even platelet transfusion may be required for severe mucosal/organ or life-threatening bleeding.

Strict application of the aforementioned definitions of response (see Table 2) may not be appropriate when considering the risk-benefit ratio of therapy for a refractory patient. Accordingly, clinically meaningful definitions were agreed on by the panel (Table 4).

Clinical trial–adapted criteria

There have been several randomized clinical trials performed in adults with ITP,6,7,89,41,42,44,4546,56,57,58,5960  and their results can be compared only with great difficulty because of differences in the characteristics of the patient populations included (newly diagnosed vs persistent or chronic/refractory), study designs and end points, as well as the heterogeneous mechanisms of action and patterns of response to the various investigational treatments. Some of the problems of comparison are attributable not only to these differences but also to the lack of description of key features (eg, patient-related parameters). Even the more numerous controlled studies in children47,61,62,63,64,65,66,67,68,69,70,71,72,73,7475  present similar problems of interpretation, particularly regarding the end points and definition of outcomes. In summary, the results of clinical trials conducted to date with old or new agents, including studies with anti-CD20 antibodies conducted using uncontrolled designs,10  are not easily comparable for clinically meaningful response rates and response duration and do not allow the drawing of definite conclusions in all instances. In turn, it is difficult to determine how they should be introduced into current clinical practice.

To avoid these limitations in future trials, the panel recommended minimal standardized criteria and definitions to be used in interventional studies (specifically for phase II and III studies) in order that heterogeneity in study subjects and in result reporting can be minimized (Table 5).

Table 5

Trial-adapted criteria for eligibility and outcome assessments in ITP

Eligibility (all should be met)
  • Previously treated or untreated patients fitting within one of the different phases 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 clinical settings or patients on steroids, or in the presence of bleeding symptoms

  • Patients should be on a stable treatment or off any treatment for a time sufficient to exclude a late effect (see Table 3)

 
Supplemental specifications
  • Pediatric and adult patients analyzed separately

  • Response to previous treatment(s), if any, should be reported

 
End points
  • Primary end points:

    • CR or R based on platelet count as in Table 2 *

  • Secondary end points:

    • Adverse events (safety), need for rescue interventions, corticosteroids/concomitant treatment reduction, rate of splenectomies.

    • Could become primary end points according to the design of the clinical trial or patient characteristics.

    • Bleeding scale, HRQoL assessment and, whenever possible, pharmacoeconomic analysis should be included

 
Timing of assessment of primary end points and duration of response
  • Depends on the type of treatment

  • Patients enrolled while on a stable treatment with one or more agents must be no longer receiving these treatments for a time sufficient to exclude any protracted effect†

  • Duration could be calculated as follows depending on study design:

    • The time from CR or R as defined in Table 2 to loss of response‡

    • The cumulative time spent in CR or R or cumulative time spent without meeting a predefined end point(s)

 
Adverse events
  • Bleeding episodes, rescue interventions, frequency of splenectomy, and treatment-related side effects occurring during or after the time of exposure to the experimental agent always reported. Duration of side effects monitoring time after the end of experimental treatment should be provided.

  • For assessment of rebound thrombocytopenia or bleeding, the immediate period after the suspension of the agent up to the attainment of a stable platelet count§ or institution of a new treatment should be considered. This treatment should be recorded.

  • A predefined exceedingly high platelet count induced by treatment could be considered an adverse event, depending on the agent under investigation

 
Eligibility (all should be met)
  • Previously treated or untreated patients fitting within one of the different phases 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 clinical settings or patients on steroids, or in the presence of bleeding symptoms

  • Patients should be on a stable treatment or off any treatment for a time sufficient to exclude a late effect (see Table 3)

 
Supplemental specifications
  • Pediatric and adult patients analyzed separately

  • Response to previous treatment(s), if any, should be reported

 
End points
  • Primary end points:

    • CR or R based on platelet count as in Table 2 *

  • Secondary end points:

    • Adverse events (safety), need for rescue interventions, corticosteroids/concomitant treatment reduction, rate of splenectomies.

    • Could become primary end points according to the design of the clinical trial or patient characteristics.

    • Bleeding scale, HRQoL assessment and, whenever possible, pharmacoeconomic analysis should be included

 
Timing of assessment of primary end points and duration of response
  • Depends on the type of treatment

  • Patients enrolled while on a stable treatment with one or more agents must be no longer receiving these treatments for a time sufficient to exclude any protracted effect†

  • Duration could be calculated as follows depending on study design:

    • The time from CR or R as defined in Table 2 to loss of response‡

    • The cumulative time spent in CR or R or cumulative time spent without meeting a predefined end point(s)

 
Adverse events
  • Bleeding episodes, rescue interventions, frequency of splenectomy, and treatment-related side effects occurring during or after the time of exposure to the experimental agent always reported. Duration of side effects monitoring time after the end of experimental treatment should be provided.

  • For assessment of rebound thrombocytopenia or bleeding, the immediate period after the suspension of the agent up to the attainment of a stable platelet count§ or institution of a new treatment should be considered. This treatment should be recorded.

  • A predefined exceedingly high platelet count induced by treatment could be considered an adverse event, depending on the agent under investigation

 

HRQoL indicates health-related quality of life.

*

At variance with Table 4, these definitions should be also adopted for refractory cases, considering the experimental nature of clinical trials requiring objective measurements.

Specify the duration that a subject should be off other treatments and/or the time elapsed after any rescue medication at the time of response evaluation, see also Table 3. For patients enrolled while on a stable concomitant treatment, still requiring it at the time of response evaluation, only secondary end points can be assessed

For some agents requiring continuous treatment like TPO agonists an upper limit of acceptable platelet count should be predefined and thus cumulative time spent within a therapeutic window is most suitable.

§

Defined as a platelet count not requiring treatment or dosage modification for at least 15 days.

Conclusions

The IWG was developed to harmonize current definitions and terminology in primary ITP, recognizing that current nomenclature is outdated, is limited by heterogeneity, and has not been critically analyzed.2  The members of the IWG agreed that the unavoidable arbitrary nature of any proposal should be tempered by obtaining the greatest possible consensus and by choosing only clinically sound definitions. Thus, the strength of this proposal lies in the achievement of consensus from an international group of experts in ITP after a series of face-to-face meetings and discussions. Consensus was reached through rational discussion in a structured plan including collection of opinions through questionnaires and a 2-day conference. Unanimous agreement was obtained in all issues within the present report (with the exception of the definition of refractory ITP in children). Definitions were designed to reflect clinical practice and to standardize clinical trial design. The proposal is not intended to represent guidelines for diagnosis or treatment, but it may be a valuable construct for new clinical guideline development. A limitation is represented by the lack of validated tools to assess bleeding risk and QoL. A validated bleeding score and QoL assessment tool would be useful to help guide the need for treatment in ITP patients and further investigations in this area are needed. IWG members are committed to the continued re-evaluation of this proposal.

Acknowledgments

This project was endorsed by the Scientific Working Group on Thrombocytopenias of the European Hematology Association (EHA) and the Intercontinental Childhood ITP Study (ICIS) Group. Critical revision of the manuscript by Paula Bolton-Maggs (United Kingdom), George Buchanan (United States), and David Kuter (United States) was highly appreciated. We thank Mrs Claudia Guzzoni and Dr Stefania Fortuna for their excellent organizing and secretarial assistance.

The conference was made possible thanks to the financial and logistic support of Fondazione Progetto Ematologia (Vicenza), which received unrestricted grants from Amgen Europe and GlaxoSmithKline Europe to partially cover the costs of the project. None of the IWG members and external reviewers received honoraria.

Authorship

Contribution: F.R. coordinated the project, chaired the conference, and wrote the manuscript; D.P., R.S., T.G., M.M., and P.I. chaired the working parties during the conference and wrote the manuscript; M.R. acted as scientific secretariat of the conference and wrote the manuscript; and D.M.A., V.B., J.B.B., D.B.C., B.H.C., N.C., B.G., T.K., K.L., M.G.M., R.M., M.A.S., and J.N.G. were active members of the International Group and reviewed and gave their approval to the final manuscript.

Conflict-of-interest disclosure: F.R., R.S., M.M., and R.M. have been members of scientific advisory boards for Amgen and GlaxoSmithKline. T.G. has received research support from Amgen and GlaxoSmithKline and has been a member of advisory boards for Amgen, GlaxoSmithKline, and Baxter Pharmaceuticals. D.P. has received research support from Baxter, GlaxoSmithKline and Amgen, has consulted for Baxter, GlaxoSmithKline, Amgen, and Symphogen, is on the speakers bureau for Baxter and Amgen, and he owns shares in GlaxoSmithKline (basic employee entry package). D.M.A. has received an operating grant from Hoffman-LaRoche and has been a consultant for Amgen. J.B.B. has received research grants from Amgen, Biogen-IDEC, Cangene, Genentech, GlaxoSmithKline, Genzyme, Immunomedics, MGI Pharma, and Sysmex, has received lecture fees from Baxter, has received consulting fees from Amgen, Symphogen, GlaxoSmithKline, and Baxter, has been a member of scientific advisory boards for Amgen, GlaxoSmithKline, Ligand, and Baxter, and has equity ownership in Amgen and GSK. D.B.C. has been a member of scientific advisory boards for Amgen, GlaxoSmithKline, and Symphogen. B.H.C. has received travel assistance to attend the meeting by GlaxoSmith-Kline and has been a consultant to CSL and Amgen. N.C. has been a member of scientific advisory boards for GlaxoSmithKline. B.G. received support from and is consultant for Roche, Sanofi Pasteur (not for ITP), Amgen, and LFB (Laboratoire Français de fractionnement et de biotechnologie). V.B. has been a member of scientific advisory boards for Baxter and Bayer. T.K. has received unrestricted grants from Hoffman-LaRoche and Amgen. 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.

Correspondence: Prof Francesco Rodeghiero, Department of Cell Therapy and Hematology, Hematology Division, San Bortolo Hospital, Via Rodolfi 37, I-36100 Vicenza, Italy; e-mail: rodeghiero@hemato.ven.it.

References

References
1
Cooper
N
Bussel
J
The pathogenesis of immune thrombocytopaenic purpura.
Br J Haematol
2006
133
364
374
2
Ruggeri
M
Fortuna
S
Rodeghiero
F
Heterogeneity of terminology and clinical definitions in adult idiopathic thrombocytopenic purpura: a critical appraisal from a systematic review of the literature.
Haematologica
2008
93
98
103
3
British Committee for Standard in Haematology General Haematology Task Force
Guidelines for the investigation and management of idiopathic thrombocytopenic purpura (ITP) in adults, children and in pregnancy.
Br J Haematol
2003
120
574
596
2003
4
George
JN
Woolf
SH
Raskob
GE
et al. 
Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods of American Society of Hematology.
Blood
1996
88
3
40
5
Cines
DB
Bussel
JB
How I treat thrombocytopenic purpura (ITP).
Blood
2005
106
2244
2251
6
Bussel
JB
Kuter
DJ
George
JN
et al. 
AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP.
N Engl J Med
2006
355
1672
1681
7
Newland
A
Caulier
MT
Kappers-Klunne
M
et al. 
An open-label, unit dose-finding study of AMG 531, a novel thrombopoiesis-stimulating peptibody, in patients with immune thrombocytopenic purpura.
Br J Haematol
2006
135
547
553
8
Bussel
JB
Cheng
G
Saleh
MN
et al. 
Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura.
N Engl J Med
2007
357
2237
2247
9
Kuter
DJ
Bussel
JB
Lyons
RM
et al. 
Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial.
Lancet
2008
371
395
403
10
Arnold
D
Dentali
F
Crowther
MA
et al. 
Systematic review: efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura.
Ann Intern Med
2007
146
25
33
11
Khellaf
M
Michel
M
Schaeffer
A
Bierling
P
Godeau
B
Assessment of therapeutic strategy for adults with severe autoimmune thrombocytopenic purpura based on a bleeding score rather than platelet count.
Haematologica
2005
90
829
832
12
Page
KL
Psaila
B
Provan
D
et al. 
The immune thrombocytopenic purpura (ITP) bleeding score: assessment of bleeding in patients with ITP.
Br J Haematol
2007
138
245
248
13
Buchanan
GR
Adix
L
Grading of hemorrhage in children with idiopathic thrombocytopenic purpura.
J Pediatr
2002
141
683
688
14
Mathias
SD
Bussel
JB
George
JN
McMillan
R
Okano
GJ
Nichol
JL
A disease-specific measure of health-related quality of life for use in adults with immune thrombocytopenic purpura: its development and validation.
Health Qual Life Outcomes
2007
5
11
15
von Mackensen
S
Nilsson
C
Jankovic
M
et al. 
Development of a disease-specific quality of life questionnaire for children & adolescents with idiopathic thrombocytopenic purpura (ITP-QoL).
Pediatr Blood Cancer
2006
47
5
suppl
688
691
16
Klaassen
RJ
Blanchette
VS
Barnard
D
et al. 
Validity, reliability, and responsiveness of a new measure of health-related quality of life in children with immune thrombocytopenic purpura: the Kids' ITP Tools.
J Pediatr
2007
150
510
515
17
Frederiksen
H
Schmidt
K
The incidence of idiopathic thrombocytopenic Purpura in adults increases with age.
Blood
1999
94
909
913
18
Northern Region Haematology Group
Neylon
AJ
Saunders
PW
Howard
MR
Proctor
SJ
Taylor
PR
Clinically significant newly presenting autoimmune thrombocytopenic purpura in adults: a prospective study of a population-based cohort of 245 patients.
Br J Hematol
2003
122
966
974
19
Stasi
R
Amadori
S
Osborn
J
Newland
AC
Provan
D
Long-term outcome of otherwise healthy individuals with incidentally discovered borderline thrombocytopenia.
PLos Med
2006
3
e24
20
Adibi
P
Faghih Imani
E
Talaei
M
Ghanei
M
Population-based platelet reference values for an Iranian population.
Int J Lab Hematol
2007
29
195
199
21
Lugada
ES
Mermin
J
Kaharuza
F
et al. 
Population-based hematologic and immunologic references values for a healthy Ugandan population.
Clin Diagn Lab Immunol
2004
11
29
34
22
Bain
BJ
Ethnic and sex differences in the total and differential white cell count and platelet count.
J Clin Pathol
1996
49
664
666
23
Burrows
RF
Kelton
JG
Incidentally detected thrombocytopenia in healthy mothers and their infants.
N Engl J Med
1988
319
142
145
24
Liebman
HA
Stasi
R
Secondary immune thrombocytopenic purpura.
Curr Opin Hematol
2007
14
557
573
25
Visco
C
Ruggeri
M
Evangelista
ML
et al. 
Impact of immune thrombocytopenia on the clinical course of chronic lymphocytic leukaemia.
Blood
2008
111
1110
1116
26
Aster
RH
Bougie
DW
Drug-induced thrombocytopenia.
N Engl J Med
2007
357
580
587
27
Hochberg
M
Updating the American college of Rheumatology revised criteria for classification of systemic lupus erythematosus.
Arthritis Rheum
1997
40
1725
1734
28
Miyakis
S
Lockshin
MD
Atsumi
T
et al. 
International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).
J Thromb Haemost
2006
4
295
306
29
Stasi
R
Stipa
E
Masi
M
et al. 
Long-term observation of 208 adults with chronic idiopathic thrombocytopenic purpura.
Am J Med
1995
98
436
442
30
Sailer
T
Lechner
K
Panzer
S
Kyrle
PA
Pabinger
I
The course of severe autoimmune thrombocytopenia in patients not undergoing splenectomy.
Haematologica
2006
91
1041
1045
31
Imbach
P
Kühne
T
Müller
D
et al. 
Childhood ITP: 12 months follow-up data from the prospective registry I of the Intercontinental Childhood ITP Study Group (ICIS).
Pediatr Blood Cancer
2006
46
351
356
32
Medeiros
D
Buchanan
GR
Major hemorrhage in children with idiopathic thrombocytopenic purpura: immediate response to therapy and long-term outcome.
J Pediatr
1998
133
334
339
33
Bolton-Maggs
PH
Moon
I
Assessment of UK practice for management of acute childhood idiopathic thrombocytopenic purpura against published guidelines.
Lancet
1997
350
620
623
34
Arnold
DM
Kelton
JG
Current options for the treatment of idiopathic thrombocytopenic purpura.
Semin Hematol
2007
44
S12
S23
35
Godeau
B
Provan
D
Bussel
J
Immune thrombocytopenic purpura in adults.
Curr Opin Hematol
2007
14
535
556
36
Cortelazzo
S
Finazzi
G
Buelli
M
Molteni
A
Viero
P
Barbui
T
High risk of severe bleeding in aged patients with chronic idiopathic thrombocytopenic purpura.
Blood
1991
77
31
33
37
Cohen
YC
Djulbegovic
B
Shamai-Lubovitz
O
Mozes
B
The bleeding risk and natural history of idiopathic thrombocytopenic purpura in patients with persistent low platelet counts.
Arch Intern Med
2000
160
1630
1638
38
Stasi
R
Provan
D
Management of immune thrombocytopenic purpura in adults.
Mayo Clin Proc
2004
79
504
522
39
Stasi
R
Evangelista
ML
Stipa
E
Buccisano
F
Venditti
A
Amadori
S
Idiopathic thrombocytopenic purpura: current concepts in pathophysiology and management.
Thromb Haemost
2008
99
4
13
40
Godeau
B
Porcher
R
Fain
O
et al. 
Rituximab efficacy and safety in adult splenectomy candidates with chronic immune thrombocytopenic purpura: results of a prospective multicenter phase 2 study.
Blood
2008
112
999
1004
41
Godeau
B
Chevret
S
Varet
B
et al. 
Intravenous immunoglobulin or high-dose methylprednisolone, with or without oral prednisone, for adults with untreated severe autoimmune thrombocytopenic purpura: a randomised, multicentre trial.
Lancet
2002
359
23
29
42
Newman
GC
Novoa
MV
Fodero
EM
Lesser
ML
Woloski
BM
Bussel
JB
A dose of 75 μg/kg/d of i. v. anti-D increases the platelet count more rapidly and for a longer period of time than 50 μg/kg/d in adults with immune thrombocytopenic purpura.
Br J Haematol
2001
112
1076
1078
43
Kojouri
K
Vesely
SK
Terrell
D
George
J
Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet count responses, prediction of response, and surgical complications.
Blood
2004
104
2623
2634
44
Bellucci
S
Charpak
Y
Chastang
C
Tobelem
G
Low doses v conventional doses of corticoids in immune thrombocytopenic purpura (ITP): results of a randomized clinical trial in 160 children, 223 adults.
Blood
1988
71
1165
1169
45
Facon
T
Caulier
MT
Wattel
E
Jouet
JP
Bauters
F
Fenaux
P
A randomized trial comparing vinblastine in slow infusion and by bolus i.v. injection in idiopathic thrombocytopenic purpura: a report on 42 patients.
Br J Haematol
1994
86
678
680
46
Godeau
B
Caulier
MT
Decuypere
L
Rose
C
Schaeffer
A
Bierling
P
Intravenous immunoglobulin for adults with autoimmune thrombocytopenic purpura: results of a randomized trial comparing 0.5 and 1 g/kgb.w.
Br J Haematol
1999
107
716
719
47
Tarantino
MD
Young
G
Bertolone
SJ
et al. 
Single dose of anti-D immune globulin at 75 microg/kg is as effective as intravenous immune globulin at rapidly raising the platelet count in newly diagnosed immune thrombocytopenic purpura in children.
J Pediatr
2006
148
489
494
48
Andersen
JC
Response of resistant idiopathic thrombocytopenic purpura to pulsed high-dose dexamethasone therapy.
N Engl J Med
1994
330
1560
1564
49
Mazzucconi
MG
Fazi
P
Bernasconi
S
et al. 
Therapy with high-dose dexamethasone (HD-DXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura: a GIMEMA experience.
Blood
2007
109
1401
1407
50
Bussel
JB
Pham
LC
Aledort
L
Nachman
R
Maintenance treatment of adults with chronic refractory immune thrombocytopenic purpura using repeated intravenous infusions of gammaglobulin.
Blood
1988
72
121
127
51
Cooper
N
Stasi
R
Cunningham-Rundles
S
et al. 
The efficacy and safety of B-cell depletion with anti-CD20 monoclonal antibody in adults with chronic immune thrombocytopenic purpura.
Br J Haematol
2004
125
232
239
52
Boruchov
DM
Gururangan
S
Driscoll
MC
Bussel
JB
Multiagent induction and maintenance therapy for patients with refractory immune thrombocytopenic purpura (ITP).
Blood
2007
110
3526
3531
53
Rodeghiero
F
Ruggeri
M
Is splenectomy still the gold standard for the treatment of chronic ITP?
Am J Hematol
2008
83
91
54
Vesely
SK
Erdue
JJ
Rizvi
MA
Terrell
D
George
JN
Management of adult patients with persistent idiopathic thrombocytopenic purpura following splenectomy.
Ann Intern Med
2004
140
112
120
55
Intercontinental Childhood ITP Study Group
Kühne
T
Blanchette
V
Buchanan
GR
et al. 
Splenectomy in children with idiopathic thrombocytopenic purpura: a prospective study of 134 children from the Intercontinental Childhood ITP Study Group.
Pediatr Blood Cancer
2007
49
829
834
56
Mazzucconi
MG
Francesconi
M
Fidani
P
et al. 
Treatment of idiopathic thrombocytopenic purpura (ITP): results of a multicentric protocol.
Haematologica
1985
70
329
336
57
Ferrari
A
Pasqualetti
D
Del Bianco
P
Gandolfo
GM
Chistolini
A
Mazzucconi
MG
Prednisone versus deflazacort in the treatment of autoimmune thrombocytopenic purpura: evaluation of clinical response and immunological modifications.
Haematologica
1991
76
342
345
58
Tsutsumi
Y
Kanamori
H
Yamato
H
et al. 
Randomized study of Helicobacter pylori eradication therapy and proton pump inhibitor monotherapy for idiopathic thrombocytopenic purpura.
Ann Hematol
2005
84
807
811
59
Suzuki
T
Matsushima
M
Masui
A
et al. 
Effect of Helicobacter pylori eradication in patients with chronic idiopathic thrombocytopenic purpura-a randomized controlled trial.
Am J Gastroenterol
2005
100
1265
1270
60
George
JN
Raskob
GE
Vesely
SK
et al. 
Initial management of immune thrombocytopenic purpura in adults: a randomized controlled trial comparing intermittent anti-D with routine care.
Am J Hematol
2003
74
161
159
61
Imbach
P
Wagner
HP
Berchtold
W
et al. 
Intravenous immunoglobulin versus oral corticosteroids in acute immune thrombocytopenic purpura in childhood.
Lancet
1985
2
464
468
62
El Alfy
MS
Mokhtar
GM
El-Laboudy
MA
Khalifa
AS
Randomized trial of anti-D immunoglobulin versus low-dose intravenous immunoglobulin in the treatment of childhood chronic idiopathic thrombocytopenic purpura.
Acta Haematol
2006
115
46
52
63
Erduran
E
Aslan
Y
Gedik
Y
Orhan
F
A randomized and comparative study of intravenous immunoglobulin and mega dose methylprednisolone treatments in children with acute idiopathic thrombocytopenic purpura.
Turk J Pediatr
2003
45
295
300
64
Benesch
M
Kerbl
R
Lackner
H
et al. 
Low-dose versus high-dose immunoglobulin for primary treatment of acute immune thrombocytopenic purpura in children: results of a prospective, randomized single-center trial.
J Pediatr Hematol Oncol
2003
25
797
800
65
Hedlund-Treutiger
I
Henter
JI
Elinder
G
Randomized study of IVIg and high-dose dexamethasone therapy for children with chronic idiopathic thrombocytopenic purpura.
J Pediatr Hematol Oncol
2003
25
139
144
66
Ancona
KG
Parker
RI
Atlas
MP
Prakash
D
Randomized trial of high-dose methylprednisolone versus intravenous immunoglobulin for the treatment of acute idiopathic thrombocytopenic purpura in children.
J Pediatr Hematol Oncol
2002
24
540
544
67
Fujisawa
K
Iyori
H
Ohkawa
H
et al. 
Japanese Study Group on Childhood ITP. A prospective, randomized trial of conventional, dose-accelerated corticosteroids and intravenous immunoglobulin in children with newly diagnosed idiopathic thrombocytopenic purpura.
Int J Hematol
2000
72
376
383
68
The Danish ITP Study Group
Rosthøj
S
Nielsen
SM
Pedersen
FK
Randomized comparison of intravenous immunoglobulin and methylprednisolone pulse therapy in children with newly diagnosed idiopathic thrombocytic purpura.
Ugeskr Laeger
1998
160
1640
1644
69
Albayrak
D
Içslek
I
Kalaycí
AG
Gürses
N
Acute immune thrombocytopenic purpura: a comparative study of very high oral doses of methylprednisolone and intravenously administered immune globulin.
J Pediatr
1994
125
1004
1007
70
Blanchette
V
Imbach
P
Andrew
M
et al. 
Randomised trial of intravenous immunoglobulin G, intravenous anti-D, and oral prednisone in childhood acute immune thrombocytopenic purpura.
Lancet
1994
344
703
707
71
Blanchette
VS
Luke
B
Andrew
M
et al. 
A prospective, randomized trial of high-dose intravenous immune globulin G therapy, oral prednisone therapy, and no therapy in childhood acute immune thrombocytopenic purpura.
J Pediatr
1993
123
989
995
72
Ozsoylu
S
Sayli
TR
Oztürk
G
Oral megadose methylprednisolone versus intravenous immunoglobulin for acute childhood idiopathic thrombocytopenic purpura.
Pediatr Hematol Oncol
1993
10
317
321
73
Burdach
SE
Evers
KG
Geursen
RG
Treatment of acute idiopathic thrombocytopenic purpura of childhood with intravenous immunoglobulin G: comparative efficacy of 7S and 5S preparations.
J Pediatr
1986
109
770
775
74
Imbach
P
Gaedicke
G
Joller
P
Interim evaluation of two cooperative studies assessing the effects of intravenous immunoglobulin (i.v. IgG) on childhood idiopathic thrombocytopenic purpura (ITP): I. Randomized study comparing i.v. IgG with oral corticosteroids in previously untreated acute ITP. II. Prospective study of i.v. IgG in acute and chronic ITP unresponsive to previous treatment.
Blut
1984
48
357
361
75
Buchanan
GR
Holtkamp
CA
Prednisone therapy for children with newly diagnosed idiopathic thrombocytopenic purpura. A randomized clinical trial.
Am J Pediatr Hematol Oncol
1984
6
355
361