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Immune thrombocytopenia in children and adults: What's the same, what's different?

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Harald Schulze at University of Wuerzburg
Harald Schulze
Gerhard Gaedicke at Medizinische Universität Innsbruck
Gerhard Gaedicke
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Editorials and Perspectives
haematologica | 2011; 96(12) 1739
Immune thrombocytopenia in children and adults: what's the same, what's different?
Harald Schulze1and Gerhard Gaedicke2
1Charité - Universitätsmedizin Berlin, Charité CC14, HLA Tissue Typing Laboratory; 2Charité Medical School, Reformed Medical
Curriculum, Berlin, Germany
E-mail: harald.schulze@charite.de doi:10.3324/haematol.2011.055830
(Related Original Article on pages 1831 and 1883)
Patients are diagnosed with immune thrombocytope-
nia (ITP) when they suffer from isolated thrombocy-
topenia due to an unknown etiology.1Bleedings are
found in approximately 2 out of 3 patients, typically
petechiae, mucosal bleedings, menorrhagia and
hematoma after minor trauma. While the abbreviation
ITP has formerly been used for idiopathic thrombocy-
topenic purpura, it is now restricted to those patients
with pathologies with an immunological cause. However,
autoantibodies are only diagnosed in 50-60% of patients.
ITP is, therefore, an "exclusion diagnosis," assuming that
antibodies (circulating or platelet-bound) are not always
detectable with standard diagnostic means, including
Monoclonal Antibody Immobilization of Platelet
Antigens (MAIPA). ITP is believed to be triggered by
autoantibodies generated in response to bacterial or viral
infections, vaccinations or drugs by a hapten mechanism.
Some authors state that a diagnosis of ITP can also be
applied as secondary to other (auto)immune diseases,
including systemic lupus erythematodes, antiphospho-
lipid syndrome, Evans syndrome, or AIDS.1,2 Most anti-
bodies are directed against the platelet surface receptors
GPIIb/IIIa or GPIb/V/IX, although other receptors have
also been targeted.3Several mechanisms for increased
platelet turnover have been suggested: i) there is clear evi-
dence that anti-platelet antibodies cause the decorated
platelets to be recognized by the reticulo-endothelial sys-
tem and degraded mainly in the spleen; ii) for some anti-
platelet antibodies the activation of the complement sys-
tem has been shown to contribute to accelerated decrease
in platelets by detection of the degradation components
C1q or C4d in platelet-antibody complexes;4iii) in addi-
tion, in vitro stimulated T cells of some patients with ITP
were able to trigger cytotoxic lysis of platelets by either
CD3+CD8+T cells or CD56+natural killer cells,5eventual-
ly in those patients in whom no circulating or platelet-
bound antibodies can be detected. Taken together, these
data provide evidence that both T- and B-cell dependent
processes are involved in the pathogenesis of ITP. This
has recently been shown in an elegant mouse model of
ITP.6
In contrast, the influence of anti-platelet antibodies on
thrombopoiesis by inhibiting megakaryocyte maturation
in the bone marrow or platelet release across the endothe-
lial barrier is still poorly characterized. It has long been
known that antibodies present in the serum of ITP
patients can bind to megakaryocytes7that share most of
their surface receptors with platelets. Immunoglobulins
present in the plasma of some patients inhibited or atten-
uated the differentiation of megakaryocytes from cord
blood-derived CD34+hematopoietic stem cells.8,9 In addi-
tion, megakaryocyte maturation and proplatelet forma-
tion is reduced in the presence of plasma of some ITP
patients, implying that low platelet counts can also be due
to an impaired production rate. However, the platelets
that are released in ITP are much larger than in patients in
whom thrombopoiesis is hampered due to a production
defect, either congenital or in response to chemotherapy.
Thus, the fraction of large, reticulated platelets or the
"immature platelet fraction" has the power to distinguish
ITP from production defects.10 While normal or increased
numbers of megakaryocytes are typically found within
the bone marrow of patients, these cells are often smaller
and show atypical features. So far, the role and degree of
apoptosis in megakaryocytes has remained a matter of
debate.8,11
Treatment of ITP involves corticosteroids, intraveneous
immunoglobulins, anti-D, and rituximab (anti-CD20) that
are used differentially during the acute and persist -
ent/chronic phase of the disease (Table 1). Splenectomy is
predominantly considered for refractory adult patients in
the chronic phase.1Recently, the 2nd generation throm-
bomimics eltrombopag and romiplostim have received
approval from both the US and the European agencies for
treatment of this group of patients. First studies demon-
strate that megakaryopoiesis and thrombopoiesis can fur-
ther be stimulated in most of these patients and many
long-term studies in adults with chronic form have been
reported for each drug. However, it is worth mentioning
that side effects, including bleeding, thrombotic events
and myelofibrosis, have been recognized in a subset of
patients in response to long-term application of either
eltrombopag or romiplostim, respectively.12In the light of
these data, the first published studies with throm-
bomimetics in children with chronic ITP should be con-
sidered with caution in order to avoid underestimating
the risk of early reticulin deposition in the bone mar-
row.13,14
A substantial fraction of patients with ITP undergo
spontaneous remission within three to six months after
the initial diagnosis. These patients have formerly been
referred to as "acute" while those with persistent low
counts are referred to as "chronic". Recently, a new strat-
ification has been suggested:15 the term "acute" has now
been attributed to those patients in whom remission
occurs within three months after initial diagnosis and
"persistent" when platelet counts normalize between
three and 12 months. By definition, patients become
"chronic" one year after diagnosis. Surprisingly, while
about 80% of children undergo spontaneous remission,
this rate is only 20% in adults. This finding implies two
major findings in ITP. First, there are substantial differ-
ences in the occurrence of ITP in children and adults.
Second, it is still not clear which factors might be predic-
Editorials and Perspectives
1740 haematologica | 2011; 96(12)
Table 1. Key features of ITP in children and adults.
ITP In children In adults
Clinical Extensive purpura
Hemorrhagica (petechiae and hematoma), epistaxis, hematuria, bloody stools, metro- menorrhagia,
conjunctival purpura, retinal bleeding, ICH (<0.5%)
Prevalence Prevalence of males Prevalence of females
Bleeding tendency: 90% Bleeding tendency: 70%
Diagnostic tools Increased platelet size, reticulated platelets (Platelet-associated immunoglobulins, IPF)
Platelet-associated immunoglobulins (PAIgs), MAIPA
Spontaneous remission approx. 80% within one year Approx. 20-30% within one year
First-line treatment “Wait and see” (if platelets are >20¥109/L) Corticosteroids
IvIG (if platelets are <20¥109/L and mucosal IvIG
bleeding symptoms ) anit-D
Other treatment options Corticosteroids, anti D, Platelet concentrates and high dose Rituximab
corticosteroids in critical situations
Splenectomy in refractory chronic ITP Should be avoided in children because of lifelong risk Remission induction rate: approx. 65%
of OPSI syndrome
Remission induction rate: 70-80%
Thrombomimetics First studies published Approved for chronic ITP
tive for patients with ITP to undergo spontaneous remis-
sion compared to those who develop a chronic course. In
this issue of Haematologica, both questions have been
addressed.
Kühne and co-workers analyze the difference between
adult and pediatric ITP.16They present a large study
derived from prospective data collected by the
Intercontinental Cooperative ITP Study Group (ICIS).
The registry comprises data on 2,124 ITP patients at time
of initial diagnosis among which 340 were adults.
Kühne's work confirms that more male patients are found
in the pediatric group while females were the majority in
the adult group. However, despite this, there was far less
difference in clinical and laboratory findings between the
groups than expected. This includes the likelihood of
overall bleeding when platelets were below 20¥109/L, the
initial platelet count and the percentage of patients who
remained untreated. Obvious differences were found to
be co-morbidities and the initial treatment: while IvIG
was given in children, adults were more likely to have
been treated with corticosteroids.
Polymorphisms in the Fcγreceptor IIA and IIIA have
been identified that are over-represented in children with
both acute or chronic ITP suggesting that carriers of this
genetic constellation are more prone to develop ITP.17 The
second study presented in this issue provides exciting evi-
dence that the Q63R polymorphism in the cannabinoid
receptor CNR2 might be involved in the progression
toward chronic ITP. Rossi et al. found that ITP patients
homo- or heterozygous for the R allele of CNR2 have a
markedly increased chance of becoming chronic.18 The
cannabinoid receptors are known to modulate the adap-
tive immune response, including the balance between TH1
and TH2 cells. Chronic ITP is known to have a balance
towards the TH1 cell subset.19 T cells from CNR2 63R
homozygous individuals show a 2-fold reduction in inhi-
bition of T-cell proliferation compared to Q-homozygous
individuals. This polymorphism is more often found in
patients with auto-immune diseases.20Therefore, it is fea-
sible that the patients carrying at least one 63R allele
might be prone to a chronic course of ITP. Further
prospective studies will be required to address the prog-
nostic value of this polymorphism.
Harald Schulze has studied biochemistry in Hannover and
wrote his thesis on congenital and acquired thrombocytopenia. He
received his postdoctoral training at the Dana-Farber Cancer
Institute at Harvard Medical School, Boston. Since 2005, he has
been heading an independent research group on megakaryocyte
and platelet function and biology at the Charité Hospital. Gerhard
Gaedicke became interested in hematology during his medical
studies at the University of Hamburg. Later he joined Professor
Kleihauer´s group at the University of Ulm and was trained in
pediatric hematology and oncology, including blood stem cell trans-
plantation. Soon after Germany’s reunification he became Full
Professor of Pediatrics and Chairman of the Dept. of Pediatrics at
the Charité University Medical Center, Berlin. His main interest
besides hematolgy is the reform of the medical curriculum.
Financial and other disclosures provided by the author using
the ICMJE (www.icmje.org) Uniform Format for Disclosure of
Competing Interests are available with the full text of this paper
at www.haematologica.org.
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Editorials and Perspectives
haematologica | 2011; 96(12) 1741
... In order to rule out serious conditions such as hematopoiesis insufficiency, bone marrow infiltration, other autoimmune disorders, viral infections, etc., patients with isolated primary ITP undergo several kinds of examinations. Primary ITP is diagnosed if there are no deviations from the norm and only isolated thrombocytopenia (platelets <100×10 9 /l) is seen (3,4). ...
... In older times, bone marrow tests were frequently carried out in thrombocytopenia patients in order to rule out bone marrow pathology. Studies have revealed that significant bone marrow pathologies are not often found in asymptomatic patients (4). Because of this, the most recent guidelines from the American Society of Hematology and the International Consensus do not advise regular bone marrow tests if there are no symptoms or signs of an underlying illness (1,5,6). ...
... Because of this, the most recent guidelines from the American Society of Hematology and the International Consensus do not advise regular bone marrow tests if there are no symptoms or signs of an underlying illness (1,5,6). Avatrombopag and fostamatinib, two recently produced extremely effective medications, increase the possibilities for treating this disease (1)(2)(3)(4)(5)9). ...
Treatment of immune thrombocytopenia in adults in Kyrgyzstan: a two-center retrospective observational study
Article
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Introduction and Aim: Immune thrombocytopenia (ITP) is an acquired thrombocytopenia characterized by a platelet count of 100x109/l and caused by immune-mediated destruction of platelets. This study aimed to assess the efficacy and tolerability of the first and subsequent lines of therapy for adult patients with ITP. Materials and Methods: This retrospective study included 172 patients with ITP and a mean age of 44.2±5.71 years at the time of diagnosis and/or who were treated for ITP at participating centers such as south and republican centers in Kyrgyzstan during the study period from 2015–2022. Analyzing patient medical records yielded detailed data on treatment strategies and results. Results: There was a significant difference in the mean number of platelets between clinical centers (26.2 versus 14.5×109 cells/l, p<0.05), and the mean number of platelets at admission to the hospital was 17.1±1.84×109 cells/l. 113 (65.7%) had primary ITP, and the remaining 59 (34.3%) had secondary ITP. 35.6% of patients with secondary causes were infected (including those with Helicobacter pylori but not others). Conclusion: Patients with adult ITP can be effectively treated with conservative methods in 45.4–77.6% of cases. These treatments include prednisone, dexamethasone, and their combination with intravenous immunoglobulin, rituximab, and azathioprine.
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... ITP can occur in both children and adults and is more common in women than in men. 1 It can present with severe mucocutaneous, in rare occasions even life-threatening bleeding symptoms. 2 Classically, ITP is primarily caused by the production of autoantibodies against platelet cell surface molecules, such as the glycoprotein (GP) IIb/IIIa complex 3,4 . ...
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... Before the 2000s, limited medical treatment choices were available for idiopathic or induced thrombocytopenia. For instance, although corticosteroids and intravenous immunoglobulin have been the first-line treatment for ITP, an autoimmune disease characterised by isolated thrombocytopenia, about 20 % of children and 80 % of adults show a chronic course [7], suggesting the need for second-line therapy. ...
Knowledge map of thrombopoietin receptor agonists: A bibliometric analysis
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  • Jan 2024
Background Thrombopoietin receptor agonists (TPO-RAs) have been widely used to treat thrombocytopenia, however, a scientometric profile of TPO-RAs research is lacking. Methods: This study uses VOSviewer, CiteSpace, and R software to provide an overview of current research, highlight study hotspots, and predict future research directions of TPO-RAs. Results: One thousand seven hundred and nineteen relevant studies from 1993 to 2022 with 43962 citations were identified from the Web of Science Core Collection. Over three decades, the USA has been leading TPO-RAs publications. Industries and academic institutions have been actively involved in TPO-RAs research, with funding provided by pharmaceutical companies and public funding bodies. The most productive and cited journals are British Journal of Hematology and Blood, respectively. When author keywords were categorised into three clusters, i.e., cluster 1 (immune thrombocytopenic purpura (ITP)), cluster 2 (avatrombopag, lusutrombopag, and thrombocytopenia), and cluster 3 (TPO-RAs for ITP and off-label drug use), ITP was found to be the current research hotspot, while oral TPO-RAs and licensed or unlicensed drug indications of thrombocytopenic diseases require further investigation. Conclusion: This study has generated the knowledge map of TPO-RAs, which provides a dynamic roadmap for future research in this field.
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... При современных методах терапии ИТП неизле чима, но возможно достижение ремиссии различной длительности [10]. ...
Management of patients with immune thrombocytopenia in the Moscow region
Article
Full-text available
  • Nov 2022
Background. Idiopathic thrombocytopenic purpura (ITp) is an autoimmune disease characterized by antibody-mediated platelets destruction and impairment of their production, which manifests itself as: isolated thrombocytopenia, risk of spontaneous hemorrhage and bleeding of varying severity. ITp is a hematological, orphan disease with an incidence of 1–4 cases per 100,000 population. In modern literature, primary and secondary immune thrombocytopenias are distinguished. primary immune thrombocytopenia is a diagnosis of exclusion. To verify it, a certain diagnostic search is required.Aim. To evaluate clinical characteristics and treatment efficacy in patients with a confirmed primary immune thrombocytopenia in the Moscow region.Materials and methods. This article presents the results of an analysis of more than 2,400 outpatient records of patients diagnosed with thrombocytopenia (for the period from 2010 to 2022). Of these, about 400 confirmed clinical cases of various ITp forms were included in the ITp registry of the Moscow Region. All patients live in the Moscow region, receive treatment and are observed at the Center for Orphan diseases of the M.f. vladimirskiy Moscow Regional Research Clinical Institute.Results. There are 415 patients with a verified diagnosis of ITp in the register of the Moscow Region Center for Orphan diseases of the M.f. vladimirskiy Moscow Regional Research Clinical Institute (71 % (n = 294) are female). In 69.8 % (n = 290) of patients at the time of disease manifestation, hemorrhagic syndrome was recorded. As a first-line therapy, 92.8 % (n = 385) of patients received corticosteroids (prednisolone, methylprednisolone, dexamethasone), in the second-line therapy, 82 % (n = 340) of patients were recommended therapy with thrombopoietin receptor agonists (romiplostim, eltrombopag). The options for third-line therapy in patients with ITp are rituximab monotherapy, splenectomy, and intravenous immunoglobulin. Splenectomy was performed in 3.37 % (n = 14) of patients.Conclusion. when evaluating this register, the highest efficiency of thrombopoietin receptor agonists (romiplostim, eltrombopag) is observed – 84.1 % of the objective response.
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... A multimodal incidence with 1 peak seen in childhood whereby the second and third peaks observed in young adults and the elderly. 34 Our study confirms the higher incidence of ITP in females in younger adults as reported by previous population-based literature but not in the elderly (>65 years). The prevalence of ITP in men and women in the elderly is almost even in previous studies. ...
Clinical Epidemiology, Treatment Outcome and Mortality Rate of Newly Diagnosed Immune Thrombocytopenia in Adult Multicentre Study in Malaysia
Article
Full-text available
  • Jun 2022
Background Immune thrombocytopenia (ITP) is well characterized in Western, European and other Asia-Pacific countries. Nevertheless, the clinical epidemiology, treatment pattern and disease outcome of ITP in Malaysia are still limited and not well known. Objective This study aimed to describe the clinical epidemiology, treatment outcome and mortality of ITP patients in haematology tertiary multicentre in Malaysia. Methods Clinical and laboratory data of newly diagnosed adults with ITP by a platelet count <100 × 10⁹/L from January 2010 to December 2020 were identified and analyzed. Results Out of 500 incident ITP, 71.8% were females with a striking age preponderance of both genders among those aged 18–29 years. The median age was 36 years. The median platelet count was 17.5 × 10⁹/L, 23.0% had a secondary ITP, 34.6% had a Charlson’s score ≥1, 53.0% had bleeding symptoms including 2.2% intracranial bleedings (ICB). Helicobacter pylori screening was performed in <5% of cases. Persistency and chronicity rates were 13.6% and 41.8%, respectively. Most (80.6%) were treated at diagnosis onset and 31.2% needed second-line treatment. Throughout the course of ITP, 11.0% of patients died; 3.0% and 8.0% with bleeding and non-bleeding related ITP. Conclusion This study confirms the epidemiology of ITP is comparable with worldwide studies. Our incidence is high in the female, Malay ethnicity, primary ITP and events of cutaneous bleeding at ITP onset with 18–29 years predominance age group for both genders. The frequency of persistent and chronic ITP is inconsistent with published literature. Corticosteroids and immunotherapies are the most prescribed first-line and second-line pharmacological treatments. Thrombopoietin receptor agonist medications (TPO-RAs) usage is restricted and splenectomy is uncommon. Our mortality rate is similar but ITP related bleeding death is fourth-fold lower than previous studies. Mortality risks of our ITP patients include age ≥60 years, male, severe bleeding at presentation, CCI≥1 and secondary ITP.
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... 9 There are also distinguishable features of the disease in adults and children that prompt their separate study. 10 Adult ITP is predominantly diagnosed and treated in the secondary care setting (through inpatient or outpatient services) in the United Kingdom (UK). Two previous studies, using primary care data with information drawn from inpatient and outpatient discharge summaries or communications, independently estimated the incidence rate (IR) of ITP in the UK at around 3.9 per 100 000 person-years for 2000 to 2005. ...
Incidence of adult primary immune thrombocytopenia in England—An update
Article
Full-text available
Background Adult primary immune thrombocytopenia (ITP) is a rare bleeding disorder of unknown cause. Recent estimates of its incidence and trend over time were acquired for England. Method The primary ITP population (using ICD 10 code D693 and excluding secondary ITP cases; positive predictive value: 82.6%) was sourced from NHS Digital inpatient and outpatient. Incidence rate (IR) for England and by age groups, sex, and regions were calculated and trends were assessed using average annual percent change (AAPC). Results A total of 25 805 patients (mean age 59 years; females 57.8%) diagnosed between 2003 and 2014 was identified. IRs increased from 4.2/100 000 to 6.4/100 000 over this period (AAPC:4.3%). For all sex‐specific age groups, the IRs significantly increased over time, except 18–29 years males. The greatest increase was among females aged 30–39 (AAPC:8.7%). In contrast, among ≥70 years, ITP was more common in males (highest IR among ≥80 years males: 23.9/100 000). England's average annual IR was 6.1/100 000 for 2010–14. An estimated 2.5/100 000 (based on UKITP Registry data) was estimated to require 1st line treatment whereas 2.4/100 000 would have 1st and 2nd line treatments within 6 months from diagnosis. IRs for London and East Midlands were the highest (6.5/100 000). Conclusions This study found a rising incidence of primary ITP, with sharp increases among young women and elderly men. These findings put in context the impact of ITP on patients' lives and the healthcare services in England, especially with 17%–50% who may develop chronic ITP and require long‐term care.
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... Primary ITP is still diagnosed by exclusion and it is a must to be differentiated from non-autoimmune causes of thrombocytopenia along with secondary etiologies of ITP [4]. In the infectious cases, it is possible that the viral antigens were recognized as being the same as the platelet antigen, a process called molecular mimicry that leads to cross-reactive anti-platelet autoantibodies [5]. Chemokine 1 2 is produced by various cells including bone marrow cells and is incorporated in the proliferation and differentiation megakaryocytes(MKs) along with platelet production Nearly 80% of patients suffering primary ITP, and 20% can be identified as secondary variety [6]. ...
Chemokine 12 plasma level in pediatric patients with Immune Thrombocytopenic purpura and its relation to Disease Activity
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The goal of this study was to investigate a possible association of chemokine 12 plasma level and its association to ITP , This was a prospective, observational, case-control study which was conducted on 60 patients with ITP with age ranging from 1 -18 years old together with 90 healthy controls. The plasma level of chemokine 12 in pediatric ITP patients and healthy controls were determined using enzyme linked immunosorbent assay (ELISA) The detection limit for this assay was 1.5 pg per ml. Patients were subjected also to lab investigation in the form of CBC and BM aspirate and There was a high plasma level of chemokine 12 in cases than controls (p value
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... nedenler ile morbidite ve mortalitesi artmaktadır (16). Literatürde kronik İTP'li erişkinlerin psikolojik durumunu değerlendiren sınırlı sayıda çalışma olduğu gibi çocuklarla yapılan çalışma sayısı da yetersizdir (17,18). Yapılan çalışmalar yaşam kalitesini ölçmeye yöneliktir (3,19,20). ...
Psychopathological Evaluation In Children with Chronic Idiopathic Trombocytopenic Purpura (Kronik İdiyopatik Trombositopenik Purpuralı Çocuklarda Psikopatolojik Değerlendirme)
Article
Full-text available
  • Apr 2022
Abstract Introduction: Idiopathic thrombocytopenic purpura (ITP) is a disease with a risk of becoming chronic in which physical and mental difficulties are experienced during diagnosis, treatment and follow-up. In this study, we aimed to determine the psychological status, importance and significance of psychopathology in children with chronic ITP using psychiatric scales. Materials and Methods: It was planned to conduct a cross-sectional study by collecting the records of our patients with chronic ITP aged 3-18 years, who are being followed in the 3rd level health center, for evaluation. The study included 35 chronic ITP and 40 age- and sex-matched healthy volunteers. The psychological states of the patients, healthy control group and their parents were evaluated with the help of proven data collection tools under the guidance of a specialist psychiatrist. Results: In the chronic ITP group, a difference was found between the Rosenberg self-esteem scale mean scores, mother’s Beck hopelessness scale median scores, mother’s perceived stress scale mean scores, strengths difficulties parent form total difficulty score median, strengths parental form social behavior median values, median values of the adolescent form total strengths difficulty score (p<0.001; for each), and between the two groups in the assessment of strengths and difficulties adolescent form social behaviors (p=0.003). There was no statistically significant difference between the distribution of other variables between the patient and control groups (p>0.050). Conclusion: Attention deficit, hyperactivity, behavioral problems, emotional problems, peer problems, social behavior and ego problems are common in chronic ITP in childhood. This challenging situation also affects parents. It should be known that chronic ITP, like other chronic diseases, causes chronic and intractable mental problems, and this psychiatric process should be managed together with the medical treatment of the disease.
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Article
  • Apr 2022
Introduction: Primary immune thrombocytopenia (ITP) is an autoimmune hemorrhagic disorder characterized by a low platelet count and increased risk of bleeding. We previously reported that low-dose chidamide, a histone deacetylase (HDAC) inhibitor, restores immune tolerance in patients with ITP. This study aimed to evaluate the association of a single-nucleotide polymorphism (SNP) rs2530223 in the HDAC3 gene with susceptibility to ITP and its clinical features. Methods: Patients with ITP and age-matched healthy participants were recruited for this case-control study. Genotyping of the HDAC3 rs2530223 polymorphism was performed using MassARRAY platform. Results: Individuals with T allele of HDAC3 rs2530223 exhibited a 1.472-fold increased risk of ITP susceptibility (OR 1.472; 95% CI 1.100-1.969; p = .009), while ones with the TT genotype under the codominant and recessive models, and the TC/TT genotypes under the dominant model all revealed increased risk of ITP susceptibility (dominant odds ratio[OR] 1.965; 95% CI: 1.046-3.656; p = .036; codominant OR 2.264; 95% CI 1.175-4.360; p = .015; and recessive OR 1.512; 95% CI 1.028-2.224; p = .036, respectively). Regarding platelet counts in ITP patients, we observed that the TC/TT genotypes exhibited a 3.932-fold increased risk for platelet (PLT) <30 × 109 /L (OR 3.932; 95% CI 1.426-10.842; p = .008). Conclusion: This study indicates that HDAC3 rs2530223 may be an important genetic factor related to ITP susceptibility and platelet count in ITP patients, providing new perspectives on disease progression, new therapeutic targets, and severity prediction.
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Newly diagnosed immune thrombocytopenia in children and adults: a comparative prospective observational registry of the Intercontinental Cooperative Immune Thrombocytopenia Study Group
Article
Full-text available
  • Jul 2011
Acknowledgments: we thank all patients who continue to partici-pate in the PARC-ITP Registry and the staff of the participating institutions. We are indebted to Verena Stahel, Caroline Asal Martin and Monika Imbach for data administration and secretar-ial work. We thank all investiga-tors of the PARC-ITP Registry who support ICIS and generously pro-vided us with their patient data.
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Newly diagnosed immune thrombocytopenia in children and adults: A comparative prospective observational registry of the Intercontinental Cooperative Immune Thrombocytopenia Study Group
Article
Full-text available
  • Aug 2011
  • HAEMATOL-HEMATOL J
Primary immune thrombocytopenia is a bleeding diathesis with an unknown etiology in predisposed individuals with immune disturbances. Although it is claimed that children and adults differ in clinical and laboratory aspects, few data exist to corroborate this observation. Our objective was to assess comparative data from children and adults with newly diagnosed immune thrombocytopenia. Clinical and laboratory data of 1,784 children and 340 adults were extracted from the Pediatric and Adult Registry on Chronic Immune Thrombocytopenia. The registry represents a prospective cohort of children and adults with newly diagnosed immune thrombocytopenia. Participating investigators registered their patients immediately after the diagnosis using a web based data transfer. Children aged under 16 years were compared with adults aged 16 years and over with descriptive statistical analyses. The presenting mean platelet count of children and adults was 18.1 and 25.4 × 10(9)/L. Signs of bleeding were reported in 24% of children and in 23% of adults, and intracranial hemorrhage in 10 of 1,784 children and in 6 of 340 adults. Co-morbidity was observed in 3.9% of children and in 30% of adults. Bone marrow aspiration and laboratory tests (antinuclear antibodies, human immunodeficiency and hepatitis C virus) were performed more frequently in adults. Children and adults were followed with a 'watch and wait' strategy in 20% and in 29%, respectively. Immunoglobulins were used more frequently in children and corticosteroids in adults. Comparative data of children and adults with newly diagnosed immune thrombocytopenia revealed similarities in presenting platelet counts and in bleeding, whereas differences occurred in co-morbidity, diagnostic procedures and therapy.
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CNR2 functional variant (Q63R) influences childhood immune thrombocytopenic purpura
Article
Full-text available
  • Aug 2011
  • HAEMATOL-HEMATOL J
Immune thrombocytopenic purpura is an acquired autoimmune disorder that is the most common cause of thrombocytopenia in children. The endocannabinoid system is involved in immune regulation. We evaluated a common missense variant (CAA/CGG; Q63R) of the gene encoding the cannabinoid receptor type 2 (GeneID 1269) in 190 children with immune thrombocytopenic purpura and 600 healthy controls. The allelic frequencies and genotype distribution of the polymorphism in the patients were significant compared to control samples (P=0.006 and P=0.0001, respectively). Interestingly, when acute and chronic immune thrombocytopenic purpura patients were analyzed separately with respect to controls, a significant overrepresentation of the RR genotype and of the R allele was observed only for the chronic form (P=0.00021 and P=0.011, respectively). The relative odds ratio suggested the risk of developing chronic form was more than double in immune thrombocytopenic purpura children homozygous for the variant (odds ratio=2.349, 95% CI: 1.544-3.573; P<0.001).
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Romiplostim in children with chronic refractory ITP: Randomized placebo controlled study
Article
Full-text available
  • Feb 2011
  • ANN HEMATOL
Romiplostim stimulates thrombopoietin receptor to increase platelet production of megakaryocytes in idiopathic thrombocytopenic purpura (ITP). This study aimed to evaluate the safety and efficacy of romiplostim in children with chronic ITP. Eighteen patients with chronic ITP, either none responsive or failed to maintain response on two or more therapeutic modalities, were enrolled. Patients were randomized (2:1) to receive romiplostim or placebo for 12 weeks, initiated at 1 μg/kg/week, escalated to 5 μg/kg/week, and then tapered. Median patients' age was 8.5 years, and the median baseline platelet count (PC) was 10.5 × 10(9)/L. The median weekly dose of romiplostim was 2 μg/kg. Fifty percent of patients in both romiplostim and placebo arms had at least one adverse event (AE); none was serious. Ten patients on romiplostim (83.3%) maintained the efficacy endpoint (PC > 50,000). Romiplostim was well-tolerated and efficient in treating the children with chronic refractory ITP with no unexpected AEs.
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A murine model of severe immune thrombocytopenia is induced by antibody- and CD8+ T cell-mediated responses that are differentially sensitive to therapy
Article
Full-text available
  • Dec 2009
  • BLOOD
Immune thrombocytopenia (ITP) is a bleeding disorder characterized by antibody-opsonized platelets being prematurely destroyed in the spleen, although some patients with ITP may have a cell-mediated form of thrombocytopenia. Although several animal models of ITP have been developed, few mimic primary chronic ITP nor have any shown cell-mediated platelet destruction. To create this type of model, splenocytes from CD61 knockout mice immunized against CD61(+) platelets were transferred into severe combined immunodeficient (SCID) (CD61(+)) mouse recipients, and their platelet counts and phenotypes were observed. As few as 5 x 10(4) splenocytes induced a significant thrombocytopenia and bleeding mortality (80%) in recipients within 3 weeks after transfer. Depletion of lymphocyte subsets before transfer showed that the splenocyte's ability to induce thrombocytopenia and bleeding completely depended on CD4(+) T helper cells and that both CD19(+) B cell (antibody)- and CD8(+) T cell (cell)-mediated effector mechanisms were responsible. Treatment of the SCID mouse recipients with intravenous gamma-globulins raised platelet counts and completely prevented bleeding mortality induced by antibody-mediated effector mechanisms but did not affect cell-mediated disease. This novel model not only shows both antibody- and cell-mediated ITP and bleeding but also suggests that these 2 effector mechanisms have a differential response to therapy.
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Fluorescence of Megakaryocytes in Idiopathic Thrombocytopenic Purpura (ITP) Stained with Fluorescent Antiglobulin Serum
Article
  • Jun 1962
  • BLOOD
1. A technic is described for the direct and indirect visualization of affinity between fluorescein labeled antiglobulin serum and megakaryocytes. 2. Fluorescent megakaryocytes have been found with this technic in the marrow of some patients with chronic ITP, but not in acute ITP. It was possiple to confer fluorescence on normal megakaryocytes by incubating them with sera from patients with chronic ITP, and from a woman who had a child with neonatal thrombocytopenia. 3. Similar reactions were noted in three patients with systemic lupus erythematosus. 4. These findings indicate adherence of a humoral substance (antibody?) for megakaryocytes, which may have etiologic significance in chronic ITP.
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Immature Platelet Count: A Simple Parameter for Distinguishing Thrombocytopenia in Pediatric Acute Lymphocytic Leukemia From Immune Thrombocytopenia
Article
  • Oct 2011
  • PEDIATR BLOOD CANCER
Platelet counts below normal values define thrombocytopenia. However, platelet counts alone do not reveal the underlying pathomechanism. New blood cell counters provide additional information on platelet size and volume, and enable the distinction of sub-populations. In this preliminary study, we evaluate whether one of these markers can be used for diagnosis of isolated thrombocytopenia in children. We provide normal values for mean platelet volume (MPV), platelet distribution width (PDW), plateletcrit (PCT), platelet large cell ratio (P-LCR), platelet mean-frequent volume (P-MFV), relative immature platelet fraction (IPF%), and absolute IPF (IPF#) for 100 healthy children and analyzed 87 children with thrombocytopenia. In children with platelet production defects, IPF% was low, while in acute immune thrombocytopenia (ITP), IPF% was markedly increased (median 25.2%, P < 0.01), representing accelerated platelet turnover. Interestingly, children diagnosed with acute lymphocytic leukemia (ALL) also had elevated IPF% (median 10%, P < 0.01), suggesting that thrombopoiesis is stimulated despite virtual absence of bone marrow progenitors. Low IPF# was only found in patients with acute ITP. IPF% is a marker for thrombocytopenia due to defective platelet production while IPF#, representing the immature platelet count, might become a practical parameter to distinguish acute ITP from thrombocytopenia in children with newly diagnosed ALL (P < 0.01).
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A randomized, double-blind study of romiplostim to determine its safety and efficacy in children with immune thrombocytopenia
Article
  • Apr 2011
  • BLOOD
Romiplostim, a thrombopoietin-mimetic peptibody, increases and maintains platelet counts in adults with immune thrombocytopenia (ITP). In this first study of a thrombopoietic agent in children, patients with ITP of ≥ 6 months' duration were stratified by age 1:2:2 (12 months-< 3 years; 3-< 12 years; 12-< 18 years). Children received subcutaneous injections of romiplostim (n = 17) or placebo (n = 5) weekly for 12 weeks, with dose adjustments to maintain platelet counts between 50 × 109/L and 250 × 109/L. A platelet count ≥ 50 × 109/L for 2 consecutive weeks was achieved by 15/17 (88%) patients in the romiplostim group and no patients in the placebo group (P = .0008). Platelet counts ≥ 50 × 109/L were maintained for a median of 7 (range, 0-11) weeks in romiplostim patients and 0 (0-0) weeks in placebo patients (P = .0019). The median weekly dose of romiplostim at 12 weeks was 5 μg/kg. Fourteen responders received romiplostim for 4 additional weeks for assessment of pharmacokinetics. No patients discontinued the study. There were no treatment-related, serious adverse events. The most commonly reported adverse events in children, as in adults, were headache and epistaxis. In this short-term study, romiplostim increased platelet counts in 88% of children with ITP and was well-tolerated and apparently safe. The trial was registered with http://www.clinicaltrials.gov as NCT00515203.
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Complement Activation on Platelets Correlates with a Decrease in Circulating Immature Platelets in Patients with Immune Thrombocytopenic Purpura
Article
The role of the complement system in immune thrombocytopenic purpura (ITP) is not well defined. We examined plasma from 79 patients with ITP, 50 healthy volunteers, and 25 patients with non-immune mediated thrombocytopenia, to investigate their complement activation/fixation capacity (CAC) on immobilized heterologous platelets. Enhanced CAC was found in 46 plasma samples (59%) from patients with ITP, but no samples from patients with non-immune mediated thrombocytopenia. Plasma from healthy volunteers was used for comparison. In patients with ITP, an enhanced plasma CAC was associated with a decreased circulating absolute immature platelet fraction (A-IPF) (<15 x 10(9)/l) (P = 0.027) and thrombocytopenia (platelet count < 100 x 10(9)/l) (P = 0.024). The positive predictive value of an enhanced CAC for a low A-IPF was 93%, with a specificity of 77%. The specificity and positive predictive values increased to 100% when plasma CAC was defined strictly by enhanced C1q and/or C4d deposition on test platelets. Although no statistically significant correlation emerged between CAC and response to different pharmacological therapies, an enhanced response to splenectomy was noted (P < 0.063). Thus, complement fixation may contribute to the thrombocytopenia of ITP by enhancing clearance of opsonized platelets from the circulation, and/or directly damaging platelets and megakaryocytes.
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