Thrombopoietin receptor agonist switch in children with persistent and chronic severe immune thrombocytopenia: A retrospective analysis in a large tertiary center.

We retrospectively analyzed sequential therapy with romiplostim and eltrombopag in 23 children with immune thrombocytopenia: switching from romiplostim to eltrombopag (10 patients) or vice versa (13 patients). The median age of patients at enrollment in the study was 5.6 years (2-15 years). Switching from romiplostim to eltrombopag was effective in eight (80%) patients, whereas switching from eltrombopag to romiplostim was effective in eight (62%) patients. The response rate was similar in patients failing the first thrombopoietin receptor agonist and those who had previous response. To date, all responders continue to maintain platelets over 50 × 109 /L at 13-39 months after switching.

[Analysis of Differentially Expressed Genes and the Interaction Network between Acute and Chronic Idiopathic Thrombocytopenic Purpura in Children].

Objective To analyze the differentially expressed genes and key proteins in T cells between acute and chronic idiopathic thrombocytopenic purpura (ITP) in children and provide the basis for the prevention and therapies of this disease. Methods Microarray gene chip data from T cells of children with acute or chronic ITP were downloaded from the GEO Database. The gene expression profiles,gene function,and protein interaction network were analyzed by R,QOE,Networkanalyst,GCBI,and GenClip. Results The gene expression profiles between these two groups were significantly different. Among the 54 675 genes analyzed,there were 457 (0.84%) differentially expressed genes between these two groups. In the protein interaction networks among top 20 differentially expressed genes,the core was JUN(down-regulated) and ITCH(up-regulated),which were both related to the tumor necrosis factor signaling pathway;differentially expressed genes were mainly related to the activation and tolerance of T cell. Conclusions The gene expression profiles differ between acute and chronic ITP patients,suggesting that the gene transcription profile plays a regulatory role in the different stages of ITP. JUN and ITCH may play a role in predict the progression of ITP and may exert their biological functions by regulating the tumor necrosis factor signaling pathway.

A comparative prospective observational study of children and adults with immune thrombocytopenia: 2-year follow-up.

Comparative clinical studies of children and adults with immune thrombocytopenia (ITP) are poorly covered in the literature. However, the accepted classification of ITP-childhood ITP and adult ITP-results in considerable differences in treatment protocols and practice guidelines. The analysis of the Pediatric and Adult Registry on Chronic ITP (PARC-ITP) of patients at first presentation demonstrated fewer differences in clinical and laboratory findings at initial diagnosis between children and adults than expected. The present report of 2-year follow-up data supports the hypothesis that there are common aspects of childhood and adult ITP. Data of 3360 children and 420 adults were collected during the time of 2004 until 2015 at initial diagnosis. Follow-up information was available for 51% and 33% of children and 66% and 49% of adults at 12- and 24-months, respectively. Similarities were found in unexpected areas of ITP, such as the rate of late remission at 12 and 24 months, reported bleeding sites, platelet count in bleeders, and the frequency of treated patients with persistent or chronic ITP. Differences were confirmed for the overall rate of remission and treatment modalities. Unexpected differences were found in the percentage of nonbleeders, with more adults in the nonbleeder group. More studies are needed to investigate different age groups with the aim to optimize their management.

[Classification therapy in 405 children with immune thrombocytopenia].

OBJECTIVE: To explore the efficiency and safety of immune thrombocytopenia（ITP）in children through classification treatment. METHODS: 405 newly diagnosed ITP patients were enrolled in this study from January 1st 2013 to August 31st 2014. The cases were divided into observation group and therapy group according to the initial platelet count of less than 20×109/L or the cases of active bleeding. There were 104 male cases and 76 female cases in observation group with the media platelet count of 46 （20-89）×109/L. They were followed up with a median of 20 months. The therapy group，including 131 males and 94 females with a median platelet count of 11（1-19）×109/L, were followed up by 22 months. RESULTS: The total curative rate at acute period was 80.44%（181/225）in therapy group with the first line treatment. In observation group, 148 cases（82.22%）reached complete response（CR）or response（R） criteria. 44 patients came into persistent period with an effective rate of 34.09%（15/44）in therapy group. The overall effectiveness over one year was 87.11%（196/255）. In observation group, 32 cases came into persistent period and 13 cases（40.63%）got the CR or R line. After one year of observation, 161 cases （89.44%）reached the CR or R standard. In therapy group, 5 out of 29 patients（17.24%）in chronic period got CR or R. While in observation group, 6 out of 19 cases（31.58%）reached the CR or R standard. The elder children over 10 years had risk factors in response in two groups. There was no severe bleeding or adverse effect or dead cases in this study. CONCLUSION: It is reasonable to take platelet count <20×109/L and（or）active bleeding as the dividing line for classification therapy indications. Nearly half of the cases could avoid over therapy and decreased the risk of drugs side effect to improve life quality.

Determining a definite diagnosis of primary immune thrombocytopenia by medical record review.

The objective of this study is to establish a method to identify patients with primary immune thrombocytopenia (ITP) utilizing administrative data from diverse data sources that would be appropriate for epidemiologic studies of ITP, regardless of patients' age and source of health care. Medical records of the Oklahoma University Medical Center, 1995-2004, were reviewed to document the accuracy of the administrative code ICD-9-CM 287.3 for identifying children and adults with ITP, using novel, explicit levels of evidence to identify patients with a definite diagnosis. The proportion of patients diagnosed by hematologists compared to non-hematologists and the proportion of patients diagnosed as outpatients compared to inpatients were determined. For children, age <16 years, 323 outpatient medical records were reviewed; 225 adult outpatient medical records were reviewed. The positive predictive value for the administrative code for identifying patients with a definite diagnosis of ITP by a hematologist was 0.72 in children and 0.69 in adults. In 98% of children and 92% of adults seen as outpatients, the definite diagnosis of ITP was established by a hematologist. One hundred eighteen child and 141 adult inpatient medical records were reviewed. In 95% of children and 83% of adults, the definite diagnosis of ITP by a hematologist was established as an outpatient. This study confirmed the previously reported positive predictive value for the administrative code for identifying patients with ITP. Additionally, it was determined that analysis of hematologists' outpatient administrative codes identified most children and adults with ITP. Am. J. Hematol. 2012. © 2012 Wiley Periodicals, Inc.

Selective validation of the WHO Bleeding Scale in patients with chronic immune thrombocytopenia.

OBJECTIVE: To evaluate the World Health Organization's (WHO) Bleeding Scale in two studies of eltrombopag in adults with chronic immune thrombocytopenia (ITP). RESEARCH DESIGN AND METHODS: Validated scales assessing bleeding in adults with ITP are lacking. Data from two long-term, phase 3 clinical trials (RAISE: NCT00370331; EXTEND: NCT00351468) that assessed eltrombopag in adults with chronic ITP were analyzed to evaluate the performance of the WHO Bleeding Scale. RESULTS: In RAISE, effect size (0.71), standardized response (0.75), and responsiveness statistics (0.57) were moderate for bleeding and bruising assessments. In EXTEND, effect size (0.62) and responsiveness statistics (0.59) were moderate; the standardized response statistic was 0.487. Intraclass correlation for test-retest reliability was 0.75 in RAISE and 0.71 in EXTEND. A positive correlation was observed between the WHO Bleeding Scale and the ITP Bleeding Scale. Bleeding scores and quality-of-life measures were inversely correlated (p < 0.05 for all). Minimal important differences for the WHO Bleeding Scale were 0.33-0.40 at baseline and last on-treatment assessment in both studies. LIMITATIONS: The majority of bleeding in these studies was mild to moderate, so this analysis cannot provide strong evidence of the validity of the WHO Bleeding Scale in patients with more severe bleeding. Potential limitations to the WHO Bleeding Scale itself include dependence on clinician interpretation of patient recall, inability to distinguish among bleeding events occurring at different anatomical sites, and an inherent assumption of linear increases in severity of bleeding across the response categories. CONCLUSIONS: These findings suggest potential usefulness of the WHO Bleeding Scale in adult patients with chronic ITP for standardizing grading of bleeding across research studies and in clinical practice.

Applicability of 2009 international consensus terminology and criteria for immune thrombocytopenia to a clinical pediatric population.

BACKGROUND: Since pediatric immune thrombocytopenia (ITP) is relatively infrequent, comparisons among clinical studies are critical but have previously been limited by differences in terminology. In 2009, an international working group (IWG) developed consensus criteria to enhance comparability in future studies in adults and children. METHODS: We performed a retrospective medical record review of all pediatric ITP patients seen at a single children's hospital with a first visit between 2003 and 2010 and applied both historical (criteria(Hist) ) and IWG (criteria(IWG) ) ITP criteria to available clinical data. RESULTS: Among the 505 patients seen for ITP over 7 years, 98% could be classified as "acute" or "chronic" ITP using the criteria(Hist) , while only 90.7% could be classified as "newly diagnosed," "persistent," or "chronic" ITP using the criteria(IWG) (P < 0.01). Only 33.7% met criteria(IWG) for severe ITP, whereas 77.4% met criteria(Hist) for severe ITP. A striking difference was that overall response to therapies was lower if the criteria(IWG) were used rather than the criteria(Hist) , particularly for IVIG (55.4% vs. 70%, P = 0.02) and rituximab (35.3% vs. 83.3% P = 0.05). Only 2 subjects (0.4%) met the criteria(IWG) for refractory ITP. CONCLUSIONS: Most ITP patients could easily be classified using the 2009 criteria(IWG) . Limitations to applying the criteria(IWG) included absence of treatment response durations, incomplete definition of pediatric "refractory ITP," and exclusion of secondary ITP. Nevertheless, the criteria(IWG) were more clinically relevant given the reliance on definitions based on bleeding and their ability to be applied prospectively. The utility of using the criteria(IWG) within prospective trials remains to be determined.

Púrpura trombocitopênica idiopática na infância: estudo de base populacional no Catar / Idiopathic thrombocytopenic purpura in childhood: a population-based study in Qatar

OBJETIVO: Definir o padrão da púrpura trombocitopênica idiopática (PTI) (aguda/crônica), e descrever seus sintomas e características clínicas em crianças com menos de 14 anos de idade em uma sociedade árabe recentemente desenvolvida. MÉTODOS: Este estudo descritivo retrospectivo foi realizado no Departamento de Pediatria do Hospital Geral de Hamad, Hamad Medical Corporation, Catar. Foram incluídas neste estudo 50 crianças com idade inferior a 14 anos e diagnóstico de PTI durante o período de 2000 a 2005. RESULTADOS: Das crianças estudadas (50), 62 por cento foram diagnosticadas com PTI aguda e 38 por cento com PTI crônica. A PTI aguda foi mais prevalente em meninos (64,5 por cento) em comparação com meninas (35,5 por cento), enquanto que a PTI crônica apresentou uma distribuição quase igual em meninos (57,9 por cento) e meninas (42,1 por cento). História de infecção viral foi comum em casos de PTI tanto aguda (71 por cento) quanto crônica (63,2 por cento); 68 por cento das crianças com PTI apresentaram contagem de plaquetas abaixo de 20x10(9)/L ao diagnóstico. A maioria das crianças estudadas (74 por cento) foi tratada com imunoglobulina intravenosa. CONCLUSÕES: O estudo revelou uma alta incidência de PTI entre as crianças no Catar. As descobertas do estudo são semelhantes às de outros relatos internacionais.

OBJECTIVE: To find the pattern of idiopathic thrombocytopenic purpura (ITP) (acute/chronic) and to describe presenting features and clinical characteristics of the disease in children below 14 years of age in a newly developed Arabian society. METHODS: This retrospective, descriptive study was carried out at the Pediatric Department of the Hamad General Hospital, Hamad Medical Corporation, Qatar. A total of 50 children below 14 years of age who were diagnosed with ITP during the period 2000-2005 were included. RESULTS: Among the studied children (50), 62 percent were diagnosed with acute ITP and 38 percent with chronic ITP. Acute ITP was more prevalent in boys (64.5 percent) when compared with girls (35.5 percent), whereas for chronic ITP, nearly an equal distribution was found in boys (57.9 percent) and girls (42.1 percent). Preceding viral infection was common in both acute (71 percent) and chronic (63.2 percent) ITP cases; 68 percent of the children with ITP showed a platelet count below 20x10(9)/L at the time of presentation. Most of the studied children were treated with intravenous immunoglobulin (74 percent). CONCLUSIONS: The study revealed a high incidence of ITP among children in Qatar. The study findings are in line with other international reports.

Idiopathic thrombocytopenic purpura in childhood: a population-based study in Qatar.

OBJECTIVE: To find the pattern of idiopathic thrombocytopenic purpura (ITP) (acute/chronic) and to describe presenting features and clinical characteristics of the disease in children below 14 years of age in a newly developed Arabian society. METHODS: This retrospective, descriptive study was carried out at the Pediatric Department of the Hamad General Hospital, Hamad Medical Corporation, Qatar. A total of 50 children below 14 years of age who were diagnosed with ITP during the period 2000-2005 were included. RESULTS: Among the studied children (50), 62% were diagnosed with acute ITP and 38% with chronic ITP. Acute ITP was more prevalent in boys (64.5%) when compared with girls (35.5%), whereas for chronic ITP, nearly an equal distribution was found in boys (57.9%) and girls (42.1%). Preceding viral infection was common in both acute (71%) and chronic (63.2%) ITP cases; 68% of the children with ITP showed a platelet count below 20x10(9)/L at the time of presentation. Most of the studied children were treated with intravenous immunoglobulin (74%). CONCLUSIONS: The study revealed a high incidence of ITP among children in Qatar. The study findings are in line with other international reports.

Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group.

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.

[Recent progress of study on mechanism of immune thrombocytopenic purpura and its clinical treatment - review].

Immune thrombocytopenia purpura (ITP) is a disorder mediated by antiplatelet antibodies and characterized by accelerated destruction of platelets and impaired platelet production. The mainstay therapies for ITP have included corticosteroids, the immune globulin intravenous immunoglobulin and IV anti-D (monoclonal antibodies against the D antigen of the Rh system), vinblastine or a monoclonal anti-CD20 antibody that transiently depletes CD20(+) B cells, danazol, cyclophosphamide and even splenectomy to refractory one. Most of ITP patients responded to those treatment, while more than 30% of whom may relapse sooner or later. The recombinant forms of human TPO were discontinued from human use in clinic because recipients of these agents developed significant thrombocytopenia secondary to production of neutralizing antibodies that cross-reacted with endogenous TPO. All above mentioned treatments have side effects and severe infection may arise post splenectomy. The more powerful treatment with less side effects are needed. There are two TPO receptor agonist, AMG531 and Eltrompobag, have approved in Europe for the treatment of ITP. Both of them can improve the differentiation of megakaryocyte and platelets production. Combination treatment including pancytoprotector shows good effect in the treatment of refractory and relapsed ITP in China. Altogether, individual treatment of ITP is the contemporary trend in both clinical and preclinical practice. In this review the pathogenesis of ITP and its clinical therapies were reviewed, the individual regiments for treating ITP patients were discussed.

Prediction of clinical outcome in patients with idiopathic thrombocytopenic purpura by evaluating bone marrow clot CD20+ B lymphocytes and morphological changes of megakaryocytes.

The pathology of B-lymphocytes in the bone marrow of patients with idiopathic thrombocytopenic purpura (ITP) has not been well described, even though B-lymphocytes may be involved in the etiology of ITP. We retrospectively reviewed the medical records of 73 ITP patients between January 1997 and June 2005 with platelet counts of < 50 x 10(9)/L. Bone marrow clots were available for pathological review in 56 patients who were classified into 3 groups based on the results of the bone marrow clot examination : Group A (21 patients) had increased CD20+ lymphocytes (> or =1% of nucleated cells) and megakaryocytes with morphologic changes ; Group B (21 patients) had morphologic changes but no increase in CD20+ lymphocytes ; and Group C (14 patients) had neither morphologic changes nor increased CD20+ lymphocytes. Multivariate analysis showed that, compared to Group A, Group B had a significant prognostic factor (p = 0.04 ; odds ratio, 6.65 ; 95% confidence interval, 1.09 to 40.54) for achieving complete response, while Group C had a significant prognostic factor for any treatment response (p = 0.04 ; odds ratio, 14.26 ; 95% confidence interval, 1.08 to 188.02). Thus, ITP patients can be classified with different clinical outcomes based on immunohistopathological examination of bone marrow clots.

Heterogeneity of terminology and clinical definitions in adult idiopathic thrombocytopenic purpura: a critical appraisal from a systematic review of the literature.

Clinical definitions and terminology vary greatly in clinical studies on idiopathic thrombocytopenic purpura (ITP). An objective assessment of this heterogeneity may be of interest, providing a basis for standardizing ITP terminology. A systematic review of the recent literature on ITP in adults was carried out. The following items were extracted from the articles for comparison: platelet count cut-off values to decide treatment and type of response; timing for evaluating the response to treatment; evaluation of bleeding symptoms; criteria to define initial, chronic and refractory forms. A total of 79 papers, among those published or referenced from 2000 to 2006, were considered eligible. No consensus among the different authors was found on several issues, including:platelet count for definition of ITP; grading of severity; definition of chronic ITP; platelet threshold to start treatment; platelet count to define response to treatment and timing for evaluating the response to therapy. There was only major consensus for the length of disease duration required to diagnose chronic ITP, the criteria for splenectomy and the definition of refractory ITP. Confusing terminology and an unacceptable heterogeneity of clinical definitions used for management decisions and to describe outcomes were evident in recent ITP literature. This makes it very difficult to compare different studies and to share data and clinical experiences. A standardization of terminology and definitions used in ITP is urgently needed.

Congenital macrothrombocytopenias.

Congenital macrothrombocytopenias comprise a heterogeneous group of rare disorders, characterized by abnormal giant platelets, thrombocytopenia and bleeding tendency with variable severity. Many of these disorders share common clinical and laboratory features, making accurate diagnosis difficult and patients are often misdiagnosed with and treated for idiopathic thrombocytopenic purpura. Recent progress in the elucidation of underlying defects and further developments of specific diagnostic techniques for several congenital macrothrombocytopenias have renewed our approach to the classification and the diagnosis of the disease. This review summarizes the current knowledge on the clinical and laboratory features of common congenital macrothrombocytopenias and discusses how that knowledge aids in making a proper diagnosis.

Inherited thrombocytopenia: when a low platelet count does not mean ITP.

Congenital thrombocytopenias, once considered rare and obscure conditions, are today recognized with increasing frequency, especially due to the measurement of platelet number as part of routine blood testing. The clinical spectrum of congenital thrombocytopenia ranges from severe bleeding diatheses, recognized within the first few weeks of life, to mild conditions that may remain undetected even in adulthood. For the latter group of diseases, distinguishing between inherited (primary) and acquired (secondary) thrombocytopenia, especially immune thrombocytopenia purpura (ITP), is essential to avoid unnecessary and potentially harmful treatments. In this review, the congenital thrombocytopenia syndromes are discussed with specific attention focused on diagnostic criteria, clinical presentations, genetic etiology, and current medical management. The mutated genes responsible for each syndrome are reviewed as well as the potential implications for using gene therapy or gene repair in the future.

Bleeding signs in children with idiopathic thrombocytopenic purpura.

Too little emphasis has been placed upon bleeding signs in children with idiopathic thrombocytopenic purpura (ITP). The frequency, location, and severity of clinical bleeding should dominate management considerations and the actual platelet count should be de-emphasized. With the notable exception of intracranial bleeding, virtually all prior literature reports describing case series or randomized trials of ITP have not addressed or even mentioned bleeding signs in study subjects. Future clinical investigations in childhood ITP should include a careful description of bleeding manifestations in the study populations and should assess outcome in terms of bleeding signs, quality of life, toxicity of therapy, cost, and, incidentally, the platelet count.

Presence of platelet antibodies in idiopathic thrombocytopenic purpura may discriminate acute from chronic disease.

UNLABELLED: This study estimated the prevalence of serum antibodies against thrombocyte glycoproteins, at disease onset (54 patients) and later on during the course of the disease (71 patients), in sera from children with idiopathic thrombocytopenic purpura (ITP). Only a minority had serum antibodies at disease onset, with a significantly higher frequency in those who developed the acute form of the disease than in those who developed the chronic form. Serum antibodies may persist after spontaneous cure of acute disease. There was no switch from immunoglobulin M (IgM) to IgG antibodies over time. CONCLUSION: The pathogenesis of the acute and chronic forms of ITP may be different.

MYH9-related disease: May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but represent a variable expression of a single illness.

May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are autosomal dominant macrothrombocytopenias distinguished by different combinations of clinical and laboratory signs, such as sensorineural hearing loss, cataract, nephritis, and polymorphonuclear Döhle-like bodies. Mutations in the MYH9 gene encoding for the nonmuscle myosin heavy chain IIA (NMMHC-IIA) have been identified in all these syndromes. To understand the role of the MYH9 mutations, we report the molecular defects in 12 new cases, which together with our previous works represent a cohort of 19 families. Since no genotype-phenotype correlation was established, we performed an accurate clinical and biochemical re-evaluation of patients. In addition to macrothrombocytopenia, an abnormal distribution of NMMHC-IIA within leukocytes was observed in all individuals, including those without Döhle-like bodies. Selective, high-tone hearing deficiency and cataract was diagnosed in 83% and 23%, respectively, of patients initially referred as having May-Hegglin anomaly or Sebastian syndrome. Kidney abnormalities, such as hematuria and proteinuria, affected not only patients referred as Fechtner syndrome and Epstein syndrome but also those referred as May-Hegglin anomaly and Sebastian syndrome. These findings allowed us to conclude that May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but rather a single disorder with a continuous clinical spectrum varying from mild macrothrombocytopenia with leukocyte inclusions to a severe form complicated by hearing loss, cataracts, and renal failure. For this new nosologic entity, we propose the term "MHY9-related disease," which better interprets the recent knowledge in this field and identifies all patients at risk of developing renal, hearing, or visual defects.