Splenectomy in children with idiopathic thrombocytopenic purpura: A prospective study of 134 children from the Intercontinental Childhood ITP Study Group

BACKGROUND: Splenectomy is an effective procedure for children and adults with severe or refractory idiopathic thrombocytopenic purpura (ITP). Data regarding pediatric patients are limited. PROCEDURE: Sixty-eight Intercontinental Childhood ITP Study Group (ICIS) investigators from 57 institutions in 25 countries participated in a splenectomy registry. Data from 153 patients were submitted, of whom 134 had a splenectomy and were analyzed. RESULTS: The median age at splenectomy was 11.8 (2.7-20.7) years. The median postsplenectomy follow-up was 2.0 (0.1-4.5) years. Pre-splenectomy vaccination was not administered in 21 children (15.7%). Open and laparoscopic splenectomy procedures were performed in 67 and 65 evaluable children, respectively. Surgical technique was not reported in two children. Overall immediate platelet response to splenectomy was achieved in 113 patients (86.3%). Eighty percent of responders maintained their status of response during the following 4 years. Older age, longer duration of ITP, and male gender correlated with a complete response. Post-splenectomy sepsis was reported in seven patients without lethal outcome, although sepsis might be differently defined at participating institutions. CONCLUSIONS: Splenectomy is effective in children with ITP. Management varies greatly in different institutions. These Registry data may serve as a basis for future clinical trials to assess the indication and timing of splenectomy.     

New developments in idiopathic thrombocytopenic purpura (ITP): cooperative, prospective studies by the Intercontinental Childhood ITP Study Group

Based on 6 years of experience with worldwide cooperation of investigators in the field of hematology, the International Childhood ITP Study Group (ICIS) has provided a long-term concept for prospective studies and new, evidence-based definitions of idiopathic thrombocytopenic purpura (ITP). Structured interactions between the cooperating investigators, the ICIS board, the writing committees, an expert panel, and the central operative office are summarized in the Rules of the ICIS. Preliminary experience shows high acceptance of the activities of the ICIS by participants from many countries. There is good cooperation, resulting in analyses and publication of results. New areas of focus for ICIS include the formation of an expert panel, regular meetings, and publication of results from current studies. Long-term financial resources must be found. ICIS is looking back on 6 constructive years of international cooperation resulting in new or confirmatory evidence regarding the demographics, diagnosis, natural history, and management of childhood ITP. New structures and cooperation must be identified to continue this productive endeavor.     

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.     

HLA frequencies and haplotypes in children with idiopathic thrombocytopenic purpura (ITP)

26 patients with an acute reversible ITP and 6 with chronic ITP were tissue typed, together with their healthy first-degree relatives. The HLA frequencies of the different groups were compared with those of a normal control population. The only significant difference between the groups was an increase in the frequency of Aw32 in acute ITP patients. HLA-Aw32 was present in 26.9% of patients, but in only 0.8% of the controls (corrected P=0.000027). The possible importance of associations between antigens of the HLA-A locus with certain diseases are discussed. Family analyses and haplotype determinations proved to be unproductive because no familial clustering of ITP was found.     

Duration and morbidity of newly diagnosed idiopathic thrombocytopenic purpura in children: A prospective Nordic study of an unselected cohort

OBJECTIVE: To determine the duration of the risk period with platelet counts <20 x 10(9)/L and the frequency of bleeding episodes in unselected children with idiopathic thrombocytopenic purpura (ITP). STUDY DESIGN: We established a registry for patients with newly diagnosed ITP in the five Nordic countries, enrolling children aged 0 to 14 years with platelet counts <30 x 10(9)/L. Treatment centers prospectively reported presenting features, management details, and disease-related events during the first six months after diagnosis. RESULTS: At presentation (n=501), more than half of the children had a platelet count <10 x 10(9)/L, but only 15 (3.0%) had a hemorrhage requiring blood transfusion. During follow-up of 409 patients, thrombocytopenia resolved uneventfully in 277. A risk period was present in 376 cases. Among 283 with self-limiting ITP, 26 were at risk >1 month and 25 had 30 events. Among 93 patients with chronic ITP, 73 were at risk >1 month and 44 had 111 events. Events occurred with an average frequency of 0.39 per month at risk. Life-threatening hemorrhages did not occur in the first six months after diagnosis. CONCLUSION: Most children with ITP are at risk for serious bleeding for less than one month. Continuing severe thrombocytopenia is associated with little morbidity, bleeding episodes being infrequent and very rarely serious.     

Initial management of children with newly diagnosed idiopathic thrombocytopenic purpura in the Nordic countries

AIM: To describe the management practices of newly diagnosed childhood idiopathic thrombocytopenic purpura (ITP) in the Nordic countries. METHODS: A prospective registration was done from 1998 to 2000, including all children with newly diagnosed ITP aged 0-14 years and at least one platelet count < 30 x 10(9)/L. RESULTS: 506 children from 98 departments were registered. A diagnostic bone marrow aspiration was obtained within 14 days in 33%. Platelet and/or red blood cell transfusion was given in 11%. 287 children (57%) received platelet-enhancing therapy with intravenous immune globulin (IVIG) or corticosteroids within 14 days of diagnosis, IVIG being the first line choice in over 90% of the cases. There were noticeable national differences in the management. The decision to start drug treatment within two days of diagnosis was influenced mainly by the platelet count. Neither early treatment nor response to treatment changed the risk of chronic disease. CONCLUSION: This study has shown a great variation in the management practices of children with newly diagnosed ITP. Prospective studies are required to produce evidence-based recommendations for this patient group.     

Prednisone therapy for children with newly diagnosed idiopathic thrombocytopenic purpura. A randomized clinical trial

The efficacy of corticosteroids in childhood acute idiopathic thrombocytopenic purpura (ITP) is controversial and has infrequently been evaluated in a controlled randomized fashion. We administered prednisone (2 mg/kg/day for 14 days with subsequent tapering and discontinuation by day 21) or placebo to 27 children, aged 10 years or less, with newly diagnosed ITP. Platelet count, bleeding time (a test of the integrity of the platelet-microvasculature interaction), and clinical bleeding score (based on a 0-4 scale) were determined before (day 0) and six times following initiation of drug therapy (days 1-2, 3-5, 7, 14, 21, and 28). There were no statistically significant (p less than 0.05) differences between the two treatment groups in any of the three study parameters except on day 7 of therapy when children receiving prednisone had higher platelet counts and lower bleeding scores and bleeding times than those taking placebo. Bleeding time correlated inversely with the platelet count in both treatment groups. Prednisone did not appear to influence bleeding time independent of its effect on platelet count. This treatment regimen of prednisone did not clearly improve hemostasis in childhood acute ITP except transiently at the end of 1 week of treatment.     

Predictors of remission in children with newly diagnosed immune thrombocytopenia: Data from the Intercontinental Cooperative ITP Study Group Registry II participants

1 Background

Immune thrombocytopenia (ITP) during childhood spontaneously remits in up to 80% of children. Predictors of remission are not well understood.

2 Procedure

We analyzed data from Intercontinental Cooperative ITP Study Group (ICIS) Registry II, a large prospective cohort of children with ITP, to investigate factors that might predict remission.

3 Results

In ICIS Registry II, 705 patients had data collected through 12 months following diagnosis, with 383 patients having data available at 24 months as well. Younger age and pharmacologic treatment at diagnosis were significantly associated with disease resolution at 12 and 24 months (P < 0.0001 for both) as was bleeding at diagnosis (P < 0.0001 and P = 0.0213, respectively). Gender and platelet count at diagnosis were not significantly correlated with remission. In the multivariable analysis, remission at 12 months was associated with younger age, higher bleeding grade at diagnosis, and treatment with a combination of intravenous immunoglobulin (IVIG) and corticosteroids at diagnosis. Only younger age and treatment with IVIG and steroids in combination at diagnosis were associated with remission at 24 months. Patients <1 year of age had the highest odds of achieving remission at both 12 months (OR 4.7, 95% CI: 2.0–10.6) and 24 months (OR 7.0, 95% CI: 2.3–20.8).

4 Conclusions

Younger age, bleeding severity at diagnosis, and initial treatment with a combination of corticosteroids and IVIG are associated with remission at 12 months in the ICIS Registry II. Patients <1 year of age have the highest likelihood of remission. The relationship of bleeding and treatment at diagnosis requires further study to clarify whether these are independent predictors of remission.     

Guidelines for therapy of idiopathic thrombocytopenic purpura (ITP) in childhood

The term "idiopathic thrombocytopenic purpura (ITP)" comprises a rather heterogeneous group of diseases with different etiology and pathogenesis. 80% of the cases are acute forms following viral infections. Within the first 6 months the spontaneous remission rate is higher than 80%. The remaining patients develop an intermittent or chronic form of the disease. Lethal complications, commonly cerebral hemorrhage, are rare (less than 2%). Following a review of the established and the recent experimental therapeutic approaches, the authors try to give comprehensive therapeutical guide-lines for the management of the various clinical forms of the disease. If there is only a minor bleeding diathesis, it is recommended to withhold therapy for 2 to 3 weeks, irrespective of the platelet count. If no spontaneous remission occurs, we suggest therapy with corticosteroids. In case of failure of this therapy, infusions of high-dose immunoglobulins are advisable. Short-lasting successes may even be prolonged with further infusions (once a week or at longer intervals)--thus postponing splenectomy. In addition, a combination of high-dose immunoglobulins and corticosteroids may be effective. Following pneumococcal vaccination and penicillin prophylaxis, splenectomy should be performed not earlier than one year after diagnosis of ITP and only in children older than 5 years. If splenectomy does not lead to recovery of the platelet count, immunoglobulin infusions--possibly combined with corticosteroids--may be repeated. Finally, if all the above proposed therapeutic actions have failed, immunosuppressive drugs (azathioprime or vincristine) may be necessary.(ABSTRACT TRUNCATED AT 250 WORDS)     

A cost-utility analysis of treatment for acute childhood idiopathic thrombocytopenic purpura (ITP)

BACKGROUND: The primary objective in the treatment of acute pediatric idiopathic thrombocytopenic purpura (ITP) is to rapidly increase the platelet count. METHODS: We built a decision analytic model to evaluate the cost-utility of four commonly used treatment strategies: intravenous immunoglobulin G (IVIG) 0.8 g/kg, anti-D 75 mcg/kg, methylprednisolone (30 mg/kg for 3 days), and prednisone (4 mg/kg/day for 4 days). In our baseline model, all children were hospitalized upon presentation, and discharged once the platelet count reached > or =20,000. We performed a literature search to estimate time to platelet count > or =20,000 for each strategy, as well as the probability of side effects. We obtained cost data and quality of life measures from institutional and published data sources. RESULTS: Total cost of one-time treatment for a 20 kg child was US dollars 786 with prednisone, US dollars 1,346 with methylprednisolone, US dollars 2,035 with anti-D, and US dollars 2,492 with IVIG. The strategies of IVIG and methylprednisolone were less effective and more expensive than anti-D and prednisone, respectively. Although anti-D caused the most rapid rise in platelet counts, the incremental cost-utility ratio (costs incurred by using anti-D instead of prednisone divided by health benefit of using anti-D instead of prednisone) was US dollars 7,616 per day of severe thrombocytopenia avoided, primarily due to the much higher medication cost of anti-D. Utilizing an outpatient model, the cost difference between anti-D and prednisone was even more striking. CONCLUSIONS: The clinical benefit of anti-D is offset by a substantial cost increase. Although often overlooked in favor of newer agents, a brief course of high-dose prednisone is an inexpensive and effective treatment for acute ITP.     

Role of the T cell receptor in idiopathic thrombocytopenic purpura (ITP)

During the past few decades a number of studies has described T cell defects and attempted to elucidate their role in the pathogenesis of idiopathic thrombocytopenic purpura (ITP). Some studies implicate T cells as potential initiators of autoantibody production in ITP. However, only a few of these have studied the role that the T cell receptor may play in the pathogenesis of ITP. In a variety of autoimmune syndromes interest has focused on the α- and β-chains of the T cell receptor. Deviations from the normal T cell receptor gene usage have been reported in rheumatoid arthritis, systemic lupus erythaematosus and multiple sclerosis. Usually, these studies have shown a restricted heterogeneity of T cell receptor variable gene usage. The studies on the T cell receptor in ITP have included a limited number of patients, which makes it difficult to evaluate the significance of the role that the T cell receptor may play in the pathogenesis of ITP. Further studies are warranted.     

儿童特发性血小板减少性紫癜小巨核细胞的研究

目的 探讨巨核细胞生长发育、小巨核细胞的出现在儿童特发性血小板减少性紫癜(idiopathic thrombocytopenia purpura,ITP)中的意义。方法 对46例儿童ITP进行常规骨髓形态学、骨髓涂片CD41免疫酶标染色检测,并采用ELISA方法检测血小板相关抗体的含量。并分为急性ITP(acute ITP,AITP)组和慢性ITP(chronic：ITP,CITP)组进行统计学分析。结果 46例中36例为AITP,1O例为CITP;45例骨髓巨核细胞计数增高或正常,1例降低者为CITP。小巨核细胞检出率为98％,(45／46),I型淋巴样小巨核细胞检出率为35％(16／46)。CITPI型淋巴样小巨核细胞的检出率及计数高于AITP,其他三型小巨核细胞计数低于AITP,产板巨核细胞比例以及各型小巨核细胞数量与血小板相关抗体的含量无相关性。结论 儿童ITP骨髓巨核细胞系存在不同程度病态造血,其原因可能并非完全由于免疫因素,部分病例可能以骨髓巨核细胞自身异常为主。I型淋巴样小巨核细朐的出现以及数量的高低可存一定程度上提示ITP病程的长短和预后。     

Analysis of transmembrane signalling and T cell defects associated with idiopathic thrombocytopenic purpura (ITP)

Adult chronic idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease characterized by production of autoreactive antibodies to platelet antigens. It is now becoming clear that autoantibody production, in general, is regulated by T helper (Th) cells. Several recent studies have examined potential defects in T cell function in this disease and have demonstrated that patients with ITP possess abnormal lymphocyte activation and Th₁/Th₂-mediated cytokine production. Although the underlying cause(s) of aberrant T cell function in this disease are not known, studies from other models of autoimmune disease indicate that defects in T cell transmembrane signalling can be causally linked to abnormal T cell activation and cytokine production. This review will present some of the major T cell signalling pathways and discuss how altered T cell signalling may be linked to autoimmunity with an emphasis on ITP. Recent preliminary findings of a potential defect in the signal transduction apparatus in lymphocytes from three patients with ITP will also be presented.     

Investigation and management of newly diagnosed childhood idiopathic thrombocytopenic purpura: problems and proposed solutions

The purpose of this paper is to describe current problems in investigation and management of newly diagnosed childhood idiopathic thrombocytopenic purpura (ITP). An Intercontinental Childhood ITP Study Group was established in 1997 with the aim to promote international clinical research based on a research environment and network of physicians. Initial and still ongoing projects include registries to collect data on the natural history of ITP, demographics of patients with ITP, and its management. Registry I was successful, with data on almost 3,000 patients from 38 countries. Registry II investigates the occurrence and severity of bleeding at the time of diagnosis and within 2 years of follow-up. Current problems are listed and discussed. An international network of physicians similar to that of malignant diseases for the conduct of clinical research and regular scientific meetings is the basis for solutions of the identified problems.     

Short-course oral prednisone therapy in children presenting with acute immune thrombocytopenic purpura (ITP)

Immune thrombocytopenic purpura (ITP) is a disorder for which management remains controversial. The ongoing goal is to define the minimal therapy required for children with acute ITP. A pilot study of short-course oral prednisone (4 mg⁻¹ kg⁻¹ d⁻¹ for 4 d with no tapering) was undertaken in 25 consecutive children with acute ITP and platelet counts under 20 × 10⁹ 1⁻¹. Of the 25 children, 22 responded to the prednisone therapy by achieving a platelet count higher than 20 × 10⁹ 1⁻¹ within 1 week of commencing treatment. This regimen was found to be safe, inexpensive and effective in increasing the platelet count of children to a haemostatically safe level.     

A randomized and comparative study of intravenous immunoglobulin and mega dose methylprednisolone treatments in children with acute idiopathic thrombocytopenic purpura

The most common cause of mortality in childhood acute idiopathic thrombocytopenic purpura (ITP) is intracranial hemorrhage (ICH), which occurs in about 0.1% of children with platelet counts below 20,000/microl. Forty-two children (1-13 years) with ITP and platelet counts < or = 20,000/microl were randomly divided into two groups. Twenty patients received mega-dose methylprednisolone (MDMP) in a dosage of 30 mg/kg/d for three days and 20 mg/kg/d for four days. Twenty-two patients received intravenous immunoglobulin (IVIG) in a dosage of 1 g/kg/d two days. Platelet counts of the patients were determined at diagnosis, at 2, 4, 7, 14, 30, 60, 90, 120, 150, and 180 days and at three-month intervals after the 6th month. The mean platelet counts of both groups gradually increased and peaked on the 7th day (p > 0.05). There were no significant differences between the mean platelet counts of patients, in the two groups on treatment days 0, 2, 4, 7, and 14. The mean time for achievement of platelet counts above 20,000/microg in the MDMP group and the IVIG group was 4.1 and 2.9 days (p < 0.05) and above 50,000/microl was 5.0 and 5.2 days (p > 0.05), respectively. The percentages of patients with platelet counts above 20,000/microl at the 2nd day of the treatment were 50% in the MDMP group, and 86% in the IVIG group (p < 0.05). No significant differences were observed in the mean platelet counts of the two groups treatment days 30, 60, 90, 120 and 180 (p > 0.05). Chronic ITP developed in five patients (25%) in the MDMP group, and in four patients (18%) in the IVIG group (p > 0.05). Intravenous immunoglobulin (IVIG) (1 g/kg/d for 2 days) and MDMP treatments (30 mg/kg/d for 3 days, 20 mg/kg/d for 4 days, perorally) are equally effective in the treatment of acute ITP. Because of its nonbiologic source, lower cost, fewer side effects and oral use, we prefer oral preparations of MDMP in the treatment of childhood ITP.