Platelet proteins as autoantibody targets in idiopathic thrombocytopenic purpura

Idiopathic thrombocytopenic purpura (ITP), caused by autoantibodies directed against certain platelet antigens, is the most common entity of the immune thrombocytopenias. ITP is an acquired disorder and can affect both children and adults. However, the clinical syndromes of ITP are distinct between children and adults. Childhood (acute) ITP characteristically is acute in onset, occurs within 1-2 weeks of an infection, usually of viral origin, resolves spontaneously within 6 months. Adult (chronic) ITP has an insidious onset and rarely resolves spontaneously. Over the last decade considerable new information has accumulated as to the pathophysiological mechanisms of immune thrombocytopenias. In addition, most of the knowledge on this disorder has been obtained from studies of adult patients with chronic ITP. The present work gives an updated overview of the platelet autoantigens and the molecular immunological reactions in ITP.     

Platelet-associated immunoglobulin G in childhood idiopathic thrombocytopenic purpura

Childhood ITP is an acquired hemorrhagic disorder with a heterogeneous clinical course. We measured PAIgG levels in 20 children with ITP (7 acute, 13 chronic). Both groups had significantly greater PAIgG values than age-matched normal subjects and thrombocytopenic controls (P less than 0.001). In addition, PAIgG values in chronic ITP were significantly lower than those in acute ITP (P less than 0.003). Serial PAIgG values were obtained in some patients; most returned to normal in association with clinical recovery. The measurement of PAIgG is useful in the diagnosis and follow-up of childhood ITP. PAIgG values may assist in differentiating acute and chronic disease in children.     

Childhood ITP: 12 months follow-up data from the prospective registry I of the Intercontinental Childhood ITP Study Group (ICIS)

BACKGROUND: Acute and chronic idiopathic thrombocytopenic purpura (ITP) is traditionally based on the duration of thrombocytopenia at the cut-off point of 6 months after diagnosis. Registry I evaluated the diagnosis, definition, management, and follow-up of childhood ITP. This report focuses on children with thrombocytopenia persisting more than 6 months. PROCEDURE: Data were collected by questionnaires to the physicians caring for children with ITP, at diagnosis, 6, and 12 months later. Data were compared regarding initial features and follow-up with emphasis on children with persistent thrombocytopenia, and those with ITP who recovered their platelet counts between 7 and 12 months from diagnosis. RESULTS: At 12 months from diagnosis, 79 of 308 (25.6%) evaluable children recovered from ITP and 229 had ongoing ITP. Children with recovered ITP were younger than children with ongoing ITP (P = 0.043) and exhibited a lower frequency of bleeding symptoms during the first 6 months after diagnosis (P = 0.018). Frequency of hospitalization, bone marrow aspiration, and drug treatment differed regionally. CONCLUSIONS: The high rate of recovery from ITP between 7 to 12 months demonstrates, that the cut-off point of 6 months for the definition of chronic ITP does not adequately differentiate chronic from acute ITP. The majority of children with ITP have variable time to recovery with gradual improvement of platelet counts and disappearance of bleeding signs. ITP is a heterogeneous disorder with a diverse natural history and diverse pattern of treatment response.     

Chronic immune thrombocytopenic purpura in children: a survey of the canadian experience

BACKGROUND: Immune thrombocytopenic purpura (ITP) in children is a common pediatric bleeding disorder with heterogeneous manifestations and a natural history that is not fully understood. To better understand the natural history of chronic ITP and detect response trends and outcomes of therapy, we conducted a 10-year retrospective survey of children from age 1 to 18 years with a diagnosis of chronic ITP. RESULTS: Data on 198 patients from 8 Canadian Pediatric Hematology/Oncology centers were analyzed. The majority of patients were female (58%), and were previously diagnosed with acute (primary) ITP (85%). The age at diagnosis of chronic ITP ranged from 1.1 to 17.2 years with a mean of 8.2+/-4.4 years. Ninety percent of patients received some form of treatment. Untreated patients had a higher mean platelet count at diagnosis of chronic ITP (P=0.009) despite similarities in mean age at first presentation and mean duration of follow-up. Thirty-four (17%) patients underwent splenectomy. Splenectomized patients tended to be significantly older, had a lower mean platelet count at diagnosis of chronic ITP, and had a longer duration of follow-up. CONCLUSIONS: The results from this study are consistent with published reports.     

Platelet-Associated IgG in Children - Values and Evaluation of PAIgG in Various Thrombocytopenias -

Platelet-associated IgG (PAIgG) levels were measured in 60 children with ITP (46-chronic, 14-acute) using Fab-anti Fab radioimmunoassay method described by McMillan et al. In some patients platelet binding IgG in serum (PBIgG) was also determined at the same time. Patients with ITP had significantly greater PAIgG levels than 30 normal subjects and 13 non-immune thrombocytopenic controls. Elevated PAIgG values did not correlate with parameters of platelet size (mean platelet volume; MPV and percentage of large platelet; PLP) and so these data indicated that high levels of PAIgG in ITP were not due to nonspecific adhesion of serum IgG to megathrombocytes usually increased in this disorder, but due to specific immunological reaction. PBIgG IgG values were also elevated in patients with pretreated chronic ITP, but high levels remained even after successful splenectomy. Furthermore, serial determination of PAIgG values were obtained in some patients with chronic ITP who underwent splenectomy and with acute ITP who achieved spontaneous remission. PAIgG returned to normal levels when thrombocytopenia disappeared. PAIgG seems to be the most reproducible indicator which reflects transition of the clinical picture in this disorder.     

Idiopathic thrombocytopenic purpura of childhood

Idiopathic thrombocytopenic purpura (ITP) is a benign hemorrhagic disorder characterised by peripheral thrombocytopenia and increased megakaryocytes in the bone marrow. The exact pathogenesis of ITP is not well understood. The adherence of viral induced immune complexes to the platelet membrane is thought to trigger the phagocytosis of damaged platelets by macrophages in the reticuloendothelial system. The role of platelet associated IgG in the pathogenesis of ITP is under investigation. Although spontaneous recovery is observed in 80–90% of patients, a short course of steroid therapy is recommended to reduce the duration of thrombocytopenia. The steroids however, have no influence on the course or outcome of the disease, and their possible role in reducing the incidence of intracranial hemorrhage (ICH) is unknown. Emergency management of patients presenting with signs and symptoms suggestive of ICH is essential to prevent the fatal outcome. Approximately 10–20% of patients develop chronic ITP. Splenectomy, considered the treatment of choice in these patients, is not always curative. The post-splenectomy sepsis also imposes a great risk for these individuals. Recent experience with intravenous immunoglobulin (IV IgG) treatment indicates that the splenectomy could safely be deferred, or even avoided in chronic ITP. The use of IV IgG in acute ITP is being investigated.     

Intravenous immunoglobulin for idiopathic thrombocytopenic purpura (ITP) in childhood

IgG-SRK (identical with Sandoglobulin) is a polyvalent IgG concentrate obtained by modified alcohol cryoprecipitation, including mild acidification at pH 4. This product was given in high doses intravenously for the treatment of six children with acute ITP, four children with intermittent ITP, and three children with severe chronic idiopathic thrombocytopenic purpura (ITP). An impressive initial response was observed in all patients, the extent of which may be of prognostic significance in acute ITP. Maintenance therapy was required in two of six patients with acute ITP, in three out of four patients with intermittent ITP, and in all of the patients with severe chronic ITP. In the cases of severe chronic ITP, the disease could not be adequately controlled over long periods of time, but bleeding episodes subsided or became considerably less frequent. Although little is known of the effects of IgG-SRK, possible mechanisms were discussed. It is emphasized that a new model has been discovered to study the interrelations between structure and function of human immunoglobulin molecules.     

Interleukin-1beta exon 5 and interleukin-1 receptor antagonist in children with immune thrombocytopenic purpura

Immune thrombocytopenic purpura (ITP) is associated with cytokine response and dysregulation of the cytokine network. We investigated the polymorphisms of interleukin (IL)-1beta exon 5 and IL-1 receptor antagonist (IL-1 Ra) in 50 children with acute ITP, in 30 children with chronic ITP, and in 100 healthy children by polymerase chain reaction-based restriction analysis. No significant differences in either genotype distribution (P=0.52) or allelic frequencies (P=0.70) were found among children with acute ITP, chronic ITP, or controls for IL-1beta exon 5. However, significant differences in genotype distribution (P=0.02) and the allelic frequencies (P=0.007) were found among children with acute ITP, chronic ITP, and controls for IL-1 Ra. We found that the IL-1 Ra but not IL-1beta gene polymorphism was associated with childhood ITP. This finding suggests that the IL-1 Ra gene polymorphism is implicated in the pathophysiology of childhood ITP.     

Soluble P-selectin,interleukin 6, and thrombopoietin levels in children with acute and chronic idiopathic thrombocytopenic purpura and their relationship with mega-dose methylprednisolone therapy: a pilot study

We observed less severe symptoms in patients with chronic idiopathic thrombocytopenic purpura (ITP) than in patients with acute ITP with similar platelet counts. Thrombopoietin (TPO), soluble P-selectin, soluble P-selectin per platelet, and interleukin 6 (IL-6) were evaluated in children with ITP before treatment in 16 acute and 22 chronic cases and after treatment in 10 acute and chronic cases who received mega-dose methylprednisolone. The levels of IL-6, soluble P-selectin, soluble P-selectin per platelet, and platelet count were similar in acute and chronic ITP (P > 0.05) but TPO in acute ITP was higher than that of the patients with chronic ITP (P < 0.05). The posttreatment IL-6 and TPO declined (P < 0.05), but soluble P-selectin and platelet count increased (P < 0.05). Posttreatment soluble P-selectin per platelet levels were higher than the normal values (P < 0.05). These results suggest that IL-6, soluble P-selectin, and soluble P-selectin per platelet are not responsible for the milder symptoms in chronic than in acute ITP. Mega-dose methylprednisolone seems to keep the soluble P-selectin levels elevated.     

Development of disease-specific health-related quality-of-life instruments for children with immune thrombocytopenic purpura and their parents

PURPOSE: Immune thrombopenic purpura (ITP) is an important childhood hematologic disorder that is often frightening to patients and their parents because of its acute onset and bleeding symptoms. There is no consensus on the management of ITP in children. Pediatric hematologists have differing management philosophies, yet most, explicitly or implicitly, incorporate into their management approach the potential impact on the child's and family's quality of life. There is no validated ITP-specific health-related quality-of-life instrument for use with children with ITP, nor is there one to evaluate the burden experienced by their parents. ITP is usually a self-limited disorder. With current controversy over management approaches, an evaluation of the disease burden experienced by the child and the family may assist with the assessment of alternative treatment approaches. METHODS: Using standard clinimetric methodology, 88 children with acute or chronic ITP, along with their parents, participated in the development of the instruments. RESULTS: The 26-item ITP-Child Quality-of-Life Questionnaire includes five domains: treatment side effect-related, intervention-related, disease-related, activity-related, and family-related. This instrument can be used as a self-completed instrument for most children older than 7 years or as a proxy-completed instrument by parents of children younger than 7 years. The 26-item ITP-Parental Burden Quality-of-Life Questionnaire includes six domains: concerns related to diagnosis/investigation, treatment/disease monitoring, monitoring of child's activities, interference with daily life, disease outcome, and emotional impacts. CONCLUSIONS: The first steps of the development of these formally developed instruments are complete. The instruments are available for study to validate and test their responsiveness through use in clinical research studies. Such instruments are increasingly recognized as important for comprehensive measurement of patient outcomes in this and other areas of pediatric hematology/oncology practice.     

Analysis of health-related quality of life in children with immune thrombocytopenia and their parents using the kids' ITP tools

The diagnosis, treatment, and prognosis of immune trombocytopenic purpura (ITP) have been extensively studied, but data on its effect on health-related quality of life in children remain sparse. To shed more light on this issue, we administered the Kids' ITP Tools (KIT) questionnaire to 17 children with ITP attending a tertiary pediatric medical center and their parents (n=34). The mean KIT score was significantly lower in the parents' group than in the children's group (P=0.000). The main domains of concern for the parents were disease side effects and their child's future; the children were mostly concerned about the need to restrict physical activities. The presence of acute versus chronic disease had no impact on the KIT score in either group. These findings stress the need to develop different interventional programs for children with ITP and their parents to provide appropriate support to each.     

特发性血小板减少性紫癜患儿糖皮质激素受体研究

目的探讨糖皮质激素受体(GR)在特发性血小板减少性紫癜(ITP)儿童外周血淋巴细胞的表达与临床意义。方法采用流式细胞术分别测定17例急性ITP、23例慢性ITP和20例正常儿童细胞内受体(iGR)与膜受体(mGR)水平。结果ITP组mGP和iGR水平均高于正常儿童组(P<0.01),急性ITP组和慢性ITP组间mGR差异无显著性(P>0.05),急性ITP组iGR水平高于慢性组(P<0.05)。结论mGR、iGR均可能在ITP的发病机制中起重要作用,iGR的表达可能更重要;iGR低者更易发展成慢性患者,iGR水平可作为预测ITP预后的一项参考指标。     

Management of idiopathic thrombocytopenic purpura

Idiopathic thrombocytopenic purpura is not an uncommon bleeding disorder with a prevalence of 40–80 per million children per year. Over the last six decades, the subject of ITP has attracted the attention of pediatricians and hematologists. It is one of the subjects which has many controversies because of its unpredictable course heralded by remission relapses, and chronicity with mortality in less than 1% of cases. In the present review only the controversies in the management of acute and chronic ITP have been reviewed as it interests most pediatricians. Management of intracranial hemorrhage (ICH), severe gastrointestinal hemorrhage and menorrhagia continues to still remain a challenge in spite of newer therapies.     

The role of Helicobacter pylori infection in children with acute immune thrombocytopenic purpura

The outcome of immune thrombocytopenic purpura (ITP) is classified as acute or chronic depending on whether platelet count returns to normal. The prevalence of Helicobacter pylori infection increases with age and is independent of gender. We investigated the prevalence of H. pylori infection in Chinese children from Northern Taiwan and analyzed the association between H. pylori infection and acute ITP. Our prospective cohort studies found no statistically significant relation between H. pylori infection and acute ITP. There is therefore no indication to screen children with presumed acute ITP for H. pylori infection.     

ITP患儿外周血T细胞T-bet/GATA-3基因的检测及意义

目的研究急慢性ITP患儿Th1、Th2类细胞因子和转录因子T-bet和GATA-3的相关性,探讨其在ITP发病机制。方法选择30例ITP患儿,运用T细胞分离富聚柱得纯化的T细胞,分别用ELISA法和RT-PCR技术检测ITP患儿血清中的IFN-γ、IL-4水平和外周血T细胞转录因子T-bet和GATA-3的表达状态,设30例健康儿童为对照组。结果慢性ITP患儿血清中IL-4水平较正常人降低,IFN-γ的水平升高,GATA-3 mRNA表达水平下降,T-be tmRNA表达水平升高;而急性ITP患儿外周血中IL-4水平较正常人升高,血清中IFN-γ水平及T-bet/GATA-3比值无显著性差异。结论慢性ITP患儿外周血Th1/Th2比例失衡,T-bet/GATA-3的表达失调,可能引起慢性ITP的免疫紊乱:而急性ITP患儿的发病机制可能与T-bet/GATA-3的表达无关。     

Platelet-associated immunoglobulin G in childhood idiopathic thrombocytopenic purpura

Platelet-associated IgG was studied in children with acute and chronic ITP and in patients with thrombocytopenic SLE, using the microtiter solid-phase radioimmunoassay. Of the children with acute ITP, 85% had elevated PAIgG levels. The degree of elevation of PAIgG at onset of disease did not correlate with the development of chronicity. Of the children with acute ITP, clinically and hematologically indistinguishable from the rest, 15% had normal PAIgG values. All of 22 children with chronic ITP had elevated PAIgG values. Although there was good correlation between the platelet count and the PAIgG value in children with chronic ITP, the association was not as striking in those with acute ITP; thus, factors in addition to the level of PAIgG may contribute to the thrombocytopenia in the latter group. Patients with SLE and thrombocytopenia had higher values of PAIgG than would be predicted from the platelet count; the PAIgG value is probably not the only factor determining the degree of immune thrombocytopenia.     

Chronic idiopathic thrombocytopenic purpura (ITP:) development of acute non-lymphocytic leukemia subsequent to treatment with cyclophosphamide

Chronic idiopathic thrombocytopenic purpura (ITP) is most often treated successfully with steroids and/or splenectomy. In those who fail to respond with the foregoing treatment, immunosuppressive drugs are sometimes added to the regimen. Cyclophosphamide has been reported heretofore to be effective with a minimum of side effects and complications. However, the use of alkylating agents and the induction of a second malignancy is now well recognized. This report describes three cases of refractory ITP treated with cyclophosphamide who subsequently developed an acute non-lymphocytic leukemia. Cyclophosphamide should be used with discretion in the treatment of chronic idiopathic thrombocytopenic purpura which is a non-neoplastic disorder.     

Anti-D immunoglobulin in the treatment of idiopathic thrombocytopenic purpura

Anti-D was evaluated in 8 RhD positive patients (6 males, 2 females) aged 2–21 years (mean 10 years) with idiopathic Thrombocytopenic Purpura (ITP). Five patients with chronic ITP and 3 patients with acute ITP were administered Anti-D in the dosage of 50 ug/kg intramuscularly (IM) for 3 consecutive days. One patient of chronic ITP received two courses of Anti-D. Patients were followed up for 7 to 16 months (mean 9 months). All three cases of acute ITP had a complete response and are in remission between 3 to 12 months of follow up. Two of five cases of chronic ITP had a partial response. Rise in platelet count was observed within 72–124 hours, and duration of response varied between 10 to 15 days. None of these patients had any significant side effects of anti-D immunoglobulin therapy. Intramuscular administration of anti-D is safe, effective and low cost alternative to IVlgG in the treatment of acute ITP.     

儿童慢性特发性血小板减少性紫癜免疫紊乱与治疗

目的探讨儿童慢性特发性血小板减少性紫癜(1TP)自身免疫的病理机制,以及α-2b干扰素的治疗效果。方法慢性ITP组18例,健康儿童17例,均采用流式细胞术检测外周T淋巴细胞亚群,以及免疫荧光抗体双标记法检测单个核细胞内Th1/Th2细胞因子的表达情况;18例慢性ITP病人均给予α-2b干扰素治疗,总疗程3个月。结果儿童慢性ITP患者存在T淋巴细跑表型及功能异常,其外周血CD4+减少,CD8+升高,CD4+/CD8+明显降低;且Th1/Th2功能失衡,是一种Th2优势疾病。本组18例应用α-2b干扰素治疗,其中显效6例,良效4例,进步3例,无效5例。结论儿童ITP是一种自身免疫性疾病,T淋巴细胞表型和功能异常在慢性ITP的发病中起重要作用。α-2b干扰素治疗可使患儿Th1细胞因子产生增加,而Th2细胞因子产生减少,因而抑制B淋巴细胞产生抗血小板抗体;α-2b干扰素价格低廉,毒付作用轻,应用方便,为儿童慢性ITP开辟了另一条治疗途径。     

急慢性ITP患儿细胞免疫功能变化及临床意义

目的 　观察ITP患儿细胞免疫功能的变化及临床意义。方法　 采用流式细胞仪单克隆抗体免疫荧光法动态检测 3 5例急慢性ITP患儿的T淋巴细胞亚群、NK细胞。结果 　急慢性组均有CD4+、CD4+ CD8+显著降低 ,CD8+显著升高 ,P <0 0 1;慢性组CD3+、CD4+ CD8+显著低于急性组 ,P <0 0 5 ,NK细胞在慢性组中显著降低P <0 0 1。激素不降低急性组CD4+,丙球升高慢性组的CD4+、NK细胞两者分别能降低急慢性组的CD8+。 结论 　急慢性组均有T细胞亚群比例失调 ,慢性型更为明显 ,CD4+ CD8+、NK细胞对判断病程、预后有一定意义 ,激素不增加感染机会。