Review article 297
Chronic immune thrombocytopenia in childhood
Giovanni C. Del Vecchioa, Attilio De Santisb, Lora Accetturaa,
Domenico De Mattiaa and Paola Giordanoa
Chronic thrombocytopenias are pathological conditions
defined as a persistent platelet count below the normal
range for more than 6–12 months, clinically characterized
by mucocutaneous bleeding. Recently, an International
Working Group of expert clinicians has redefined standard
terminology and definitions of primary and secondary
chronic immune thrombocytopenia (ITP). A document
issued on acute childhood idiopathic thrombocytopenic
purpura (AIEOP) provides parents and physicians with
guidelines for the management of chronic ITP and gives
prominence to the periodic re-evaluation of differential
diagnosis. The majority of chronic ITP children do not
require pharmacological treatments, especially if symptoms
are absent or minimal and the treatment decision depends
on several factors, in particular clinical conditions rather
than platelets count. The recommendations distinguish
three therapeutic strategies: emergency or symptomatic
treatment, maintenance therapy and treatment aiming at
definitive remission. Experimental/off-label treatment of
chronic ITP are reported in the literature, such as the use of
rituximab. Currently, other drugs (thrombopoiesis
Chronic thrombocytopenias include a heterogeneous
group of pathological conditions characterized by a plate-
let count persistently below the normal range for more
than 6–12 months after the first observation. Based on
their pathogenetic mechanisms, the main forms of
chronic thrombocytopenias in childhood are due to
decreased platelet production (congenital or acquired),
increased platelet destruction (immune and nonimmune)
and splenic sequestration [1].
Clinical manifestations of a low platelet count mainly
include haemorrhagic events in mucocutaneous tissues,
such as petechiae, ecchymosis, epistaxis, haematuria,
menorrhagia, gut bleeding and rarely intracranial hemor-
rhage.
The most commonly detected forms in pediatric patients
are chronic immune thrombocytopenias, with estimated
prevalence of 4.6/100.000 children [2]; these types of
thrombocytopenia are more frequent among patients
who receive the diagnosis after 10 years of age and have
platelet counts above 20  109/l [3].
Recently, a standard terminology and definitions of
immune thrombocytopenias (ITP) [4] has been outlined
by an International Working Group of recognized expert
clinicians. ITP can be subdivided in a primary form
and a secondary one, the latter broadly includes all forms
of immune-mediated thrombocytopenias except for
0957-5235 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
stimulating factors, mycophenolate, dapsone, danazol,
azathioprine, rFVIIa, cyclophosphamide, vinca alkaloids and
cyclosporine) are recommended in special cases or trials.
Blood Coagul Fibrinolysis 25:297–299 ß 2014 Wolters
Kluwer Health | Lippincott Williams & Wilkins.
Blood Coagulation and Fibrinolysis 2014, 25:297–299
Keywords: children, chronic thrombocytopenia, guidelines, management
a
Department of Biomedical Sciences and Human Oncology, Pediatric Unit ‘F.
Vecchio’, Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari and
b
Struttura Complessa di Pediatria, Ospedale ‘‘Umberto I’’, ASL BA, Altamura,
Bari, Italy
Correspondence to Giovanni C. Del Vecchio, Departement of Biomedical
Sciences and Human Oncology, Pediatric Unit ‘F. Vecchio’, Azienda Ospedialiero
Univesritaria Consorziale Policlinico di Bari, Piazza G. Cesare 11, 70124 Bari,
Italy
Tel: +39.080.5592276; fax: +39;080.5592290;
e-mail: giovanni.delvecchio@policlinico.ba.it
Received 8 January 2013 Revised 13 November 2013
Accepted 20 November 2013
primary ITP. Moreover, the platelet threshold used to
define ITP has been reduced from 150  109/l to
100  109/l and the temporal threshold for diagnosis of
‘chronic ITP’ has been increased to 12 months, instead of
6 months as previously established.
In the near future, it will be interesting to evaluate the
effects of these criteria on new clinical, therapeutic and
pathophysiological studies [5–7].
Although more than 50% of patients with chronic ITP
achieves spontaneous remission within 4 years from
diagnosis, the persistence of thrombocytopenia over time
impacts more and in a different way on sick children and
their family than acute ITP [8–10]. It is important to
consider the burden associated with repeated controls
and treatments, resulting in absence from school or work,
the achievement or otherwise of any benefits from the
various treatments suggested and their potential side-
effects. Moreover, the patients could suffer from an
excessively restrictive lifestyle. Finally, it is not uncom-
mon to observe migrations of patients from a doctor to
another searching for other resolving treatment. Further-
more, the physician could be led to consider differential
diagnosis, also previously evaluated, by continuously
analyzing the history and the evolution of his patient.
To meet those needs, it was decided to provide families
and physicians with a document on the management of
DOI:10.1097/MBC.0000000000000043
 298 Blood Coagulation and Fibrinolysis 2014, Vol 25 No 4
chronic ITP that could be accessible on the internet, a
resource widely used by families of children with chronic
diseases (http://www.aieop.org/area2/patologie_lineegui
da.htm), as well as be published in the medical literature
[11].
This document, in first instance, discusses the need to
reconsider differential diagnosis. Indeed, chronic ITP
patients may show a cyclic course or they could be
refractory or dependent on pharmacological treatment.
Moreover, in some other cases, the cause of ITP becomes
more evident over time. Therefore, it is appropriate to
periodically re-evaluate various etiological hypotheses
with respect to specifically the patient clinical condition
or at least every 6–12 months, even if they have been
previously evaluated.
It will be required to reconsider genetic thrombocytope-
nias and all the forms related to other diseases, for
example, autoimmune syndromes and infections, includ-
ing Helicobacter pylori infection [12]. Medical history and
clinical data suggestive of genetic thrombocytopenia in
chronic childhood immune thrombocytopenia is as fol-
lows:
(1) Family history of thrombocytopenia
(2) Family history of acute myeloid leukemia
(3) Treatment failure with steroids and/or intravenous
immunoglobins
(4) Diagnosis of thrombocytopenia at a neonatal age or in
the first months of life
(5) No data on normal platelet count before the diagnosis
of thrombocytopenia
(6) Occasional findings of moderate thrombocytopenia
(platelets >20  109/l)
(7) Persistence of moderate and long-term stable
thrombocytopenia
(8) Bleeding signs disproportionate with respect to the
platelet count
(9) Nonhematological manifestations: forearm or hand
malformation, short stature, skin lesions for example
eczema or hyperchromic spots), hypoacusia, cataract
and altered renal function.
In this context additional information may be obtained
from clinical history and evaluation of responses to
previous treatments.
With respect to genetic thrombocytopenia, it will be
helpful to carry out a critical review of clinical and
laboratory results to recognize when a low platelet count
does not mean ITP [13], as well as the use of specific
diagnostic algorithms [14] to distinguish clinical forms
that are gradually better defined [15,16].
In addition, it has been indicated that the re-examination
of peripheral blood smears and, similarly, bone marrow
aspiration should be performed or repeated, particularly
before splenectomy, if not done during within a period of
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
12 months. Evaluation of peripheral blood smears not
consistent with childhood immune thrombocytopenia is
as follows:
(1) Predominance of large or little or agranular platelets
(2) Alterated morphology of red blood cells: poikilocy-
tosis, schistocytes, macrocytes, polychromatophilia
(except for posthemorrhage), erythroblasts
(3) Leukocytosis or leukopenia with immature cells or
abnormal leukocyte inclusions (Dòhle-like bodies).
Furthermore, it is appropriate to refer to a center of
pediatric hematology for the differential diagnosis.
When considering therapy, the majority of chronic ITP
children do not require pharmacological treatments,
especially if symptomatology is absent or minimal,
because the circulating young platelets, of enlarged
volume, have better functionality. Indeed, most children
have less bleeding events than those with the acute form,
even if platelet count is very low (<20  109/l).
For this reason, it is necessary to reduce the number of
platelet count’s checks as much as possible and to ensure
the child has an almost normal lifestyle with respect to
both school/asylum attendance and to recreational activi-
ties/sports, despite some limitations associated with the
risk of trauma.
It is useful to provide parents/patients with practical gui-
dance, preferably written, about the most common clinical
occurrences and their management, with details of who to
contact in case of need (Family Practitioner and/or Care
Medical Center, Emergency Room Physician).
Even more than for acute ITP treatment decision should
be based on clinical conditions rather than on platelets
count and other factors must also be considered: clinical
history, clinical expression, entity of bleeding symptoms,
previous treatment response, comorbidities, age and life-
style, social and cultural condition and expectation of
the family.
Furthermore, treatment should be decided on the basis of
clinical effectiveness, presence of side-effects and the
guarantee of a good quality of life, by sharing with the
patients/parents the pros and cons of every option.
The recommendations contained in the document dis-
tinguish three therapeutic strategies:
(1) Emergency or symptomatic treatment should be
performed occasionally, as in acute ITP, assigning a
different value to the platelet count in relation to the
clinical history. Drugs and doses used are the same as
in acute form.
(2) Maintenance treatment consists of observation or
administration of drugs, including those to avoid or
delay the splenectomy, when the control of bleeding
symptoms is not satisfactory. Continuous steroids use

is not recommended because of its significant short
and long-term side-effects.
(3) Treatment aiming at definitive remission consists of a
splenectomy to be performed in children more than
5–6 years of age, in particular with a disease lasting at
least 4 years, being symptomatic or with low quality
of life, following failure or dependency or excess
toxicity of medical treatment. Patients, undergoing
splenectomy, must be protected with pneumococcal,
Hemophilus influenzae type b and meningococcal
vaccines and receive appropriate, instructions, pre-
ferably written, for management and possible pre-
vention of postsplenectomy infections.
Therapy should be chosen on individual basis, consider-
ing age, symptoms, response to previous treatments, need
of therapy aiming at definitive remission vs. maintenance
treatment. Resolving therapy, with associated possible
serious side-effects, should not be used in order to
address only the platelet count if a high bleeding risk
is not demonstrated and a spontaneous remission is
still achievable.
Experimental/off-label treatment of chronic ITP are
reported in the literature, such as rituximab, a monoclonal
antibody anti CD20 used in thrombocytopenia unrespon-
sive to conventional treatment and associated with
uncontrolled bleeding. Its response is quite variable
[17,18]; it could offer an option to avoid splenectomy,
even if a previous splenectomy is not a contraindication to
rituximab treatment.
Currently, the other drugs used (thrombopoiesis stimu-
lating factors, mycophenolate, dapsone, danazol,
azathioprine, rFVIIa, cyclophosphamide, vinca alkaloids
and cyclosporine) are only recommended in special cases
or in clinical trials.
It must be emphasized that thrombopoiesis-stimulating
agents are acquiring interest also in hereditary thrombo-
cytopenia which until now have been treated only with
platelet transfusions that can cause many problems, in
particular platelet refractoriness [19,20].
Acknowledgements
Conflicts of interest
The authors declare no conflict of interests.
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