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.

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.

[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.

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.

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.

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.

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.

[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.

Can drugs cause autoimmune thrombocytopenic purpura?

A wide range of medications can cause life-threatening immune thrombocytopenia (ITP), hemolytic anemia, or neutropenia in sensitive individuals. The antibodies associated with these conditions usually require soluble drug to be present in order to react with the cell membrane glycoproteins for which they are specific. However, some patients make drug-independent antibodies (autoantibodies) as well. Occasionally, only autoantibodies are produced following exposure to a drug. Although drugs and other small molecules can become conjugated to proteins in vivo, which may induce an immune response, only fragmentary information is available to explain how exogenous substances sometimes perturb the immune system in such a way that antibodies capable of causing immune cytopenia are produced. Platelets are affected by drug-induced antibodies more often than any other blood element. For many drug-induced thrombocytopenias, the targeted membrane glycoproteins are readily accessible for laboratory investigation and methods for detecting the responsible antibodies are well developed. Techniques for studying cellular aspects of the immune response induced by drugs through in vitro manipulation of T and B lymphocytes are also advancing rapidly. Studies of drug-induced ITP may provide clues to the general mechanisms whereby drugs and other xenobiotics induce immune diseases. Clinicians should consider the possibility of an exogenous trigger in patients who present with apparent autoimmune thrombocytopenia.

Approach to the investigation and management of immune thrombocytopenic purpura in children.

Childhood immune thrombocytopenic purpura (ITP) is typically a benign, self-limiting disorder occurring in young (<10 years of age) previously healthy children. More than 80% of such children enter a complete sustained remission within a few weeks to a few months of initial presentation, irrespective of any therapy given. The major concern is the small but finite (0.1 to 0.9%) risk of intracranial hemorrhage, which occurs in children with very low platelet counts (<20 x 10(9)/L), and is the justification for treatment to increase the circulating platelet count. Effective treatment strategies are single-dose intravenous immunoglobulin G (IVIgG; approximately 1 g/kg) and medium to high-dose corticosteroids, administered orally or parenterally. The necessity for initial bone marrow aspiration and hospitalization continues to be debated. In children with chronic ITP, defined by persistence of thrombocytopenia for > or =6 months, splenectomy should be considered for the relatively small subgroup with symptomatic, severe thrombocytopenia who have either failed an adequate trial (> or = 12 months) of primary therapy (IVIgG, intravenous anti-D, corticosteroids) or are intolerant of such therapy. Laparoscopic splenectomy is preferred over open splenectomy. Children who fail to respond to splenectomy ( < or = 20% of cases) should be evaluated for the presence of accessory spleens; their management is often difficult and must be individualized. In severe refractory cases, second-line therapies (such as azathioprine or vinca alkaloids) need to be considered. Secondary ITP in children is relatively rare and is sometimes associated with other autoimmune cytopenias (Evan's syndrome, ITP with autoimmune neutropenia). These cases often respond poorly to conventional medical therapies and response rates to splenectomy are considerably lower than in children with primary chronic ITP.

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.

The serological investigation of patients with autoimmune thrombocytopenia.

Techniques for measuring the plasma factor responsible for idiopathic thrombocytopenic purpura (ITP) have been sought for some 40 years, but unlike red cell serological techniques, platelet antibody testing has proved difficult and, at times, generated controversial results. The difficulty in measuring platelet antibodies probably reflects the intrinsic nature of the platelet membrane--to act as a sponge and nonspecifically bind plasma proteins. There have now been three different general types of techniques used to measure platelet autoantibodies: phase I assays measuring a platelet-dependent endpoint after incubating test serum and control platelets. These assays lack sufficient sensitivity and specificity to be useful. Except for special instances (the diagnosis of heparin-induced thrombocytopenia), they are no longer used. Phase II assays measure IgG on the surface of platelet or within the platelets following lysis. The immunoglobulin detected is termed platelet associated IgG. PAIgG assays are falling out of favour because they lack the sensitivity and specificity to be useful diagnostic tools. Most recently, the ability to isolate individual platelet glycoproteins and measure the binding of IgG to these glycoproteins has dramatically increased our understanding of ITP. These Phase III assays may prove useful diagnostic tools for the investigation and classification of immune thrombocytopenic disorders.

Vascular dementia in patients with immune thrombocytopenic purpura.

INTRODUCTION: Platelets have been implicated in memory disorders but this has not been investigated in patients with immune or idiopathic thrombocytopenia (ITP). ITP is an autoimmune disorder in which autoantibodies bring about platelet destruction. We previously reported a group of ITP patients who manifested TIA-like syndrome and gradual memory loss leading to dementia: platelet microparticles (PMP), a marker of platelet activation, were often elevated, suggesting that procoagulant PMP released from stimulated platelets contributed to thrombosis in small vessels. We have expanded on those studies to better define the clinical, laboratory, and radiologic characteristics of this syndrome. MATERIALS AND METHODS: Twenty ITP patients with this syndrome were studied in comparison to twenty-three ITP patients without it (patient controls). Clinical and laboratory features were compared and radiologic images were analyzed. Factors influencing the rate of progression to advanced dementia were also investigated. RESULTS AND CONCLUSION: Recurring dizzy or weak spells, TIA-like syndrome, recent memory loss, and cognitive impairment were common initial complaints. In some, these symptoms progressed rapidly to dementia but was indolent in others. Progression was faster in those with splenectomy and higher platelet counts. MRI showed enhanced signal in subcortical, periventricular areas, consistent with ischemic small vessel disease. Compared to patient controls, bleeding was less frequent and platelet activation (increased PMP, CD62p) was more frequent in the study group. Thrombotic complications may occur in ITP, manifested as TIA-like syndrome or memory loss due to ischemic small vessel disease, progressing to vascular dementia. Memory disturbances associated with platelet disorders warrants further investigation.

Interferon-alpha therapy for refractory idiopathic thrombocytopenic purpura in children.

Interferon (IFN)-alpha therapy was presented as a possible treatment for refractory immune thrombocytopenic purpura (ITP). We used 3 x 10(6) U recombinant IFN alpha, subcutaneously three times a week, every other day, for a total of 12 doses, in five children with refractory ITP. Three patients showed no response and were classified with Type III. One patient gave a partial response, and the other one had been in remission for 71 weeks as of this writing. This is the longest remission period reported for IFN therapy. The patients were classified Types IIb and I, respectively. The therapy was well tolerated. We conclude that further studies are to needed evaluate IFN-alpha therapy in childhood ITP.

[Analysis of the correlations between immunological changes and syndrome groups in patients with immunological thrombocytopenic purpura (ITP)].

To study the relationship between the immunological changes and syndrome (Zheng,) groups by TCM of ITP, the T-lymphocyte subsets, B-lymphocyte, NK cell, platelet-associated IgG (PAIgG, PAIgA, PAIgM) and antiplatelet-autoantibodies (GPIIb, GPIIIa, GP I b) of 66 patients with ITP were assisted using APAAP and ELISA method separately. It was found that the T-lymphocyte subsets, PAIg and syndrome groups of ITP were closely related. From the group of blood-heat (Xuerewangxing) to the group of deficiency of both Qi and blood, the group of asthenia of both Spleen and Kidney, the group of deficiency of Liver-yin and Kidney-yin, and the group of deficiency Yin and Yang Ts lymphocyte successfully increased (from 29. 0 +/- 8.0% to 47.2 +/- 10.0%), Th/Ts ratio declined (from 1.35 +/- 0.60% to 0.69 +/- 10%), PAIg increased gradually except for PAIgM,PAIgG of the group of deficiency Yin and Yang. Only the Th of the group of asthenia of both Spleen and Kidney among 5 syndrome groups was decreased significantly and contrary to the group of deficiency of Liver-Yin and Kidney-Yin. These results indicated that every syndrome group has specific characteristics, and immunological changes of ITP could have prognostic value.

[Research of the relation between the type of asthenia of the spleen and kidney and platelet associated antibodies and T-lymphocyte subsets in idiopathic thrombocytopenic purpura].

Idiopathic thrombocytopenic purpura (ITP) is a kind of disease associated with immunity. At present a great quantity of study on ITP has been made on humoral and cellular immunity. But there are few reports about the relationship between the types based on the differential diagnosis of TCM and immune rationale of ITP. In order to deeply explore the relationship between the types based on differential diagnosis of TCM and immune rationale of ITP., the authors measured PAIg and T lymphocyte subsets of 34 ITP patients of asthenia of both Spleen and Kidney. The value of PAIgG increased in both types of Spleen failing to control blood (SFCB) and deficiency of Spleen-yin and Kidney -yin (DSYKY), and the value of PAIgG of the type of DSYKY was significantly higher than that of SFCB (P less than 0.01). OKT3, OKT4/OKT8 of the type of SFCB remarkably decreased (P less than 0.05), OKT4, OKT4/OKT8 of DSYKY also remarkably decreased (P less than 0.001), while OKT8 significantly increased (P less than 0.001). The above results suggested that the type of DSYKY has more serious immune dysfunction than the type of SFCB, and the types of SFCB and DSYKY has close relationship with PAIg T lymphocyte subsets.

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.