ORIGINAL ARTICLE

Spontaneous improvement of chronic immune thrombocytopeniain children: experience of 56 patients at a single institute

Motohiro Kato • Katsuyoshi Koh • Akira Kikuchi •

Ryoji Hanada

Received: 18 July 2012 / Revised: 15 October 2012 / Accepted: 16 October 2012 / Published online: 27 October 2012

� The Japanese Society of Hematology 2012

Abstract Spontaneous improvement (SI) occurs more

frequently in children with chronic immune thrombocyto-

penia (cITP) than in adults. It is generally accepted that,

with the exception of splenectomy, conventional medical

approaches for cITP do not change the natural course of the

disease. Previous studies on pediatric cITP have reported

prognostic factors associated with SI; however, it is

important to know when such improvement occurs to

enable optimal treatment strategies for cITP. Here, we

report results of retrospective analysis of 56 consecutive

pediatric patients with cITP at our institution. The median

follow-up period after ITP diagnosis was 67 months

(11–185 months). Of the 44 patients without splenectomy,

17 achieved SI at a median age of 8.5 years

(2.3–16.5 years). The estimated incidence of SI was

24.6 ± 6.0 % at 36 months. In 16 of the 17 patients with

SI, the recovery was achieved within 18 months from

diagnosis, or at an age of less than 10 years, whereas

among the 24 who did not achieve spontaneous improve-

ment both at ‘‘an age of 10 years or more’’ and at

‘‘18 months or more from ITP diagnosis’’, only one

recovered spontaneously. A treatment decision tree,

including the indication for splenectomy, should be con-

sidered based on this watershed point.

Keywords Chronic idiopathic thrombocytopenic

purpura � Spontaneous improvement � Child � Splenectomy

Introduction

Approximately 20–30 % of children with immune

(formerly referred to as idiopathic) thrombocytopenic

purpura (ITP) continue to suffer from thrombocytopenia

for more than 6 months after diagnosis [1–4]. For

treatment of chronic ITP (cITP), various medical

approaches, such as intravenous immunoglobulin (IVIg),

steroids, other immunosuppressive agents, anticancer

agents, and splenectomy, have been used [1, 5–8]. It is

generally accepted that most of these treatments do not

change the natural course of ITP, except splenectomy

and stem cell transplantation [1]. Recently, thrombo-

poietin receptor agonists (TRAs) have been shown to

play important roles in cITP treatment [9–11], but they

are not curative agents.

Splenectomy is considered if persistent thrombocyto-

penia is resistant to other treatment strategies and affects

the quality of life or the patients are unable to tolerate

adverse medication effects. Although splenectomy is

effective and curative for cITP, it should be delayed by

other medications as long as possible because splenectomy,

especially at a younger age, increases the risk for serious

infections [12], while a certain fraction of children with

cITP recover spontaneously [13–15].

Previous studies on the outcome of pediatric cITP

showed that the incidence of spontaneous recovery was

44 % at 10 years [14], 30–52 % at 5 years [13, 14], and

15.8 % at 1 year [15]. Prognostic factors affecting cITP

recovery were age at diagnosis, sex, and platelet count at

diagnosis of cITP. However, it is important to not only

identify prognostic factors but also predict when sponta-

neous improvement occurs, to establish an optimal cITP

treatment strategy, including an indication for splenectomy.

Here, we present detailed information on spontaneous cITP

M. Kato (&) � K. Koh � A. Kikuchi � R. Hanada

Department of Hematology/Oncology, Saitama Children’s

Medical Center, 2100 Magome, Iwatsuki-ku, Saitama, Japan

e-mail: katom-tky@umin.ac.jp

123

Int J Hematol (2012) 96:729–732

DOI 10.1007/s12185-012-1211-x

improvement and report the results of a retrospective

analysis of the clinical courses of 56 children diagnosed

with cITP at our institution.

Patients and methods

In this study, the cITP criterion was defined as a platelet

count of \50,000/ll at 6 months or later after diagnosis.

Patients with other autoimmune abnormalities of the blood

cells (i.e., autoimmune neutropenia or autoimmune hemo-

lytic anemia) and those with other autoimmune disorders,

such as systemic lupus erythematosus, were excluded from

the study. In total, the medical records of 56 consecutive

children diagnosed with cITP at Saitama Children’s Med-

ical Center, Saitama, Japan, from 1983 to 2011 were ana-

lyzed in this study. In our institution, a standard treatment

strategy for acute ITP newly diagnosed is as follows: (1)

intravenous immunoglobulin (IVIg) for those with platelet

count less than 20,000/ll, or wet purpura, (2) steroid for

those who were refractory to IVIg, (3) observation only for

those with more than 30,000/ll without wet purpura. Fol-

low-up interval is 1 month until 1 year from diagnosis of

ITP, and 2–4 months after 1 year from diagnosis. Follow-

up is terminated when platelet count becomes [15,000/ll

for more than 6 months. A standard indication for sple-

nectomy was as follows: (a) 8 years or older, (b) throm-

bocytopenia lasting more than 12 months, although

splenectomy was performed for two patients without ful-

filling this criteria because of severe thrombocytopenia.

Spontaneous improvement was defined as platelet count

more than 50,000/ll which continued during follow-up

period. This criteria is based on complete response and

partial response in a previous study [16], which is enough

to be free from bleeding tendency, and avoid splenectomy.

To estimate the cumulative incidence of spontaneous

improvement, splenectomy, stem cell transplantation, and

death not associated with thrombocytopenia were treated as

competing risks. There was no patient who received stem cell

transplantation, and none died in our cohort during the fol-

low-up period. Statistical analysis was performed using R

statistical software version 2.10.1 (http://www.r-project.org/).

A two-sided p value of \0.05 was considered statistically

significant for analysis.

Results

Table 1 shows the patient characteristics. The median

follow-up period after ITP diagnosis was 67 months

(11–185 months). The median age at diagnosis was

7.3 years (range 1.6–16.2 years). Twelve patients under-

went splenectomy at a median age of 10.4 years (range

5.6–20.0 years), and 9 of the 12 (75.0 %) achieved

remission. Of 44 patients who did not undergo splenec-

tomy, 17 achieved spontaneous improvement at a median

period of 16 months (range 7–62 months). There are no

patients whose thrombocytopenia reoccurred after

achievement of the spontaneous improvement. The median

age at spontaneous improvement was 8.5 years (range

2.3–16.5 years) and the estimated incidence of spontaneous

Table 1 Patient characteristics and incidence of spontaneous

improvement

Characteristics n Incidence of spontaneous

improvement

p

At 3 years (%) At 6 years (%)

All 56 24.6 ± 6.0 35.1 ± 7.2

Age at diagnosis of ITP

\4 years 16 19.6 ± 10.6 46.0 ± 15.4 0.21

4–8 years 20 36.5 ± 11.5 43.4 ± 12.5

[8 years 20 15.7 ± 8.6 15.7 ± 8.6

Sex

Male 31 27.2 ± 8.4 31.0 ± 8.9 0.80

Female 25 21.6 ± 8.9 43.2 ± 13.0

Platelet count at diagnosis of ITP

\10,000/ll 11 18.2 ± 12.2 36.4 ± 15.7 0.90

10,000–30,000/ll 25 26.5 ± 9.7 37.0 ± 11.0

[30,000/ll 20 27.0 ± 10.9 27.0 ± 10.9

Platelet count at diagnosis of cITP 0.61

\30,000/ll 24 18.2 ± 8.5 36.7 ± 11.9

30,000–50,000/ll 32 29.3 ± 8.4 33.8 ± 9.1

The estimated incidences of spontaneous improvement are shown

with standard errors

Fig. 1 The cumulative incidence of spontaneous improvement. The

estimated incidence of spontaneous improvement was shown. Sple-

nectomy was treated as a censoring event

730 M. Kato et al.

123

improvement was 16.3 ± 5.0 % within 18 months from

diagnosis, 24.6 ± 6.0 % within 36 months, and 35.1 ± 7.2

within 72 months (Fig. 1). Age at diagnosis, sex, and

platelet count at diagnosis of ITP and cITP were not sta-

tistically correlated with the incidence of spontaneous

improvement (Table 1).

The period from diagnosis and age at end points, which

included spontaneous improvement, last follow-up without

platelet recovery, or splenectomy, are shown in Fig. 2.

Nine of the 17 patients achieved spontaneous improvement

within 18 months from diagnosis. Eight patients recovered

spontaneously after more than 18 months from ITP diag-

nosis, and 7 of them were younger than 10 years at

improvement (Fig. 2). The remaining patient achieved

spontaneous improvement at the age of 10 years and

8 months.

Conversely, there were 24 patients who did not achieve

improvement at an age of 10 years or more and at

18 months or more from ITP diagnosis in our cohort. Only

1 of the 24 patients achieved spontaneous improvement

within a median follow-up period of 56 months (range

2–151 months) after the watershed point.

Discussion

Various medications have been used for cITP treatment,

including IVIg, immunosuppressive agents, and anticancer

agents, to suppress the destruction of platelets by autoan-

tibodies. These treatment strategies are unable to terminate

the destruction of platelets or production of autoantibodies,

thus thrombocytopenia resumes in most patients when

these treatments are stopped. Recently, several randomized

control trials have reported the efficacy of TRAs [9–11],

noting that they have less adverse events; however, TRAs

are not curative agents. Recent studies have shown that

rituximab may be curative in cITP [17, 18], but the efficacy

has yet to be determined in children with cITP. On the

other hand, splenectomy can induce cITP remission by

improving platelet life span [7, 19]. Previous studies have

reported that the remission rate of splenectomy was more

than 70 % [20]. However, in addition to the invasive and

irreversible nature of splenectomy, it should be noted that

children with cITP have a higher probability of spontane-

ous improvement than adults. Consequently, there is a

consensus that splenectomy for pediatric cITP should be

delayed as long as possible, and medications for cITP

should be used to prevent severe bleeding by elevating

platelet counts and to wait for spontaneous improvement

[20, 21]. Thus, it is important to determine when clinicians

and patients should forgo waiting for spontaneous

improvement in favor of splenectomy.

Previous studies on the outcome of cITP in children

have described some prognostic factors and the incidence

of spontaneous improvement, but none have focused on the

timing of spontaneous improvement. Our results showed

that for patients with ITP under the age of 10 years without

improvement within 18 months from ITP diagnosis, it is

worthwhile to wait for spontaneous improvement until they

become 10 years old, even if they depend on some medi-

cations. On the other hand, for patients with persistent

thrombocytopenia at an 18-month follow-up and older than

10 years, spontaneous improvement is rare. Thus, an

appropriate treatment decision tree for children with cITP,

including the indication for splenectomy, should be con-

sidered. Splenectomy should be delayed until the water-

shed point, during which thrombocytopenia and therapeutic

medications do not affect the patient’s quality of life.

Traditionally, the definition of cITP has been thrombo-

cytopenia lasting for more than 6 months, but there have

been some reports showing a significant fraction of chil-

dren with ITP recovering in 6–12 months, and the Inter-

national Childhood ITP Study Group, American Society of

Hemaotlogy guideline, and the international consensus

statement suggested that cut-off point should be set at

12 months [3, 21]. However, our results showed that there

were some patients who achieved spontaneous improve-

ment in 12–18 months; hence, the definition of chronicity

of ITP should be re-evaluated.

This study had many limitations. For example, because

our study was retrospective, the criteria for treatment

decisions varied in each patient. Moreover, it should be

noted that our patients with cITP and without platelet

recovery might have included those with myelodysplastic

syndrome (MDS) or aplastic anemia. Although patients

Fig. 2 Information on the occurrence of spontaneous improvement.

The outcome of each patient is shown. Open circles indicate the time

of the last follow-up for patients without improvement. Filled circlesindicate the time of spontaneous improvement. Open trianglesindicate the time at which splenectomy was performed. Dotted linesare placed at watershed points: 18 months from ITP diagnosis and

10 years of age

Improvement of cITP in children 731

123

with anemia and leukopenia were excluded, repeating bone

marrow examinations is essential to exclude hematological

disorders such as MDS or aplastic anemia.

Our results revealed important information for cITP

treatment in children, because the definition and criteria for

cITP are still changing even now. Further prospective

studies are required to confirm our results, and investiga-

tions into molecular mechanisms will answer the unsolved

questions in pediatric thrombocytopenia.

Acknowledgments This study was supported by a grant from the

Kawano Masanori Memorial Foundation for the Promotion of Pedi-

atrics. We thank all the clinicians and staff members who treated

these patients. We also thank Ms. Yukiyo Fukuda, who helped with

data acquisition in this study. There is no conflict of interest to

disclose.

Conflict of interest None of the authors have a conflict of interest

to disclose.

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