Pediatr Blood Cancer 2006;47:650652

Idiopathic Thrombocytopenic Purpura in Childhood: Controversies and Solutions

hne, MD* Thomas Ku
Idiopathic thrombocytopenic purpura (ITP) is a bleeding disorder in patients who are otherwise healthy and present with thrombocytopenia with normal red cells and leukocytes. ITP is a diagnosis of exclusion and is in origin heterogeneous. The unknown etiology and the lack of clinical data from controlled prospective studies are reasons for controversies in diagnosis and management. Study endpoints traditionally include the velocity of platelet increase after drug intervention or observation, although a rapid elevation of the platelet count is of questionable clinical value. Evaluation of other endpoints is needed. Pediatr Blood Cancer 2006;47:650652.
2006 Wiley-Liss, Inc.

Key words:

ITP; registry; thrombocytopenia

INTRODUCTION Idiopathic thrombocytopenic purpura (ITP) affects children and adults and is characterized by a shortened platelet survival due to premature platelet destruction by the monocytic phagocytic system. The etiology is unknown and it has been demonstrated that many different mechanisms may cause ITP. This heterogeneous background of ITP accompanied by a substantial lack of clinical data cause controversies in managing patients with ITP [1,2]. The aim of this review is to discuss some of the main difculties encountered in patients with ITP. HETEROGENEITY OF ITP Idiopathic thrombocytopenic purpura, which is synonymous with Werlhofs disease, suggests a disease with a single cause, and appears to be assessable by standardized diagnostic procedures and managed according to straight forward algorithms. Unfortunately this is not the case. During the time since its description by Werlhof, it has been realized that purpura is a symptom of complex background and that many other diseases may mimic ITP (Table I) [3,4]. Thus, clinical research results in the literature with patients with purpura must be studied and compared carefully. Patients who present with bleeding and who are otherwise healthy, with thrombocytopenia but otherwise a normal complete blood count and smear, may be diagnosed with ITP; however, this description is characteristic for many other diseases (Table I), questioning the homogeneity of study populations in clinical trials. ITP is associated with wide interindividual and intraindividual variations. The etiology, pathophysiology, and pathogenesis of ITP are as complex as the potentially involved parts of the immune system and hemostasis. STUDY ENDPOINTS The management of ITP is based on the knowledge gained from retrospective studies and case series and on expert opinion. Prospective clinical trials have been performed, but
2006 Wiley-Liss, Inc. DOI 10.1002/pbc.20973

are generally characterized by a short follow-up and were not performed to study the natural history of ITP. These prospective studies assessed the platelet count and its course over a certain time period after drug interventions and/or observation as study endpoints. The velocity of the platelet count increase was considered successful, when a shortening of thrombocytopenia was achieved. This endpoint is associated with several problems including pre-analytical and analytical difculties of platelet count measurement, different methods of platelet measurements used in multi-centric trials, the signicance of the platelet count in predicting bleeding in ITP patients, and the unanswered question whether a rapid platelet increase is of clinical benet. Alternative endpoints, which may be evaluated, include clinical aspects, such as bleeding symptoms, health-related quality of life issues, adverse effects of drugs, and economical considerations. The investigation of bleeding signs has resulted in establishing bleeding scores for children [5,6] and adults [7], which are currently evaluated in children of Registry II [8] but also in adults [9]. CLASSIFICATION OF ITP The unknown etiology of ITP and the various mechanisms as potential causes of thrombocytopenia make a classication difcult. Traditionally ITP has been divided into an acute form with a duration of thrombocytopenia of less than 6 months, whereas chronic ITP lasts longer than 6 months. This differentiation is of practical value, because it suggests two main clinical courses of ITP with specic clinical characteristics. Acute ITP is a self-limited disorder occurring typically in children and is associated with a low risk of

Department of Oncology/Hematology, University Childrens Hospital Basel, Basel, Switzerland hne, Department of Oncology/ *Correspondence to: Thomas Ku mergasse 8, Hematology, University Childrens Hospital Basel, Ro CH-4005 Basel, Switzerland. E-mail: Thomas.Kuehne@ukbb.ch Received 20 June 2006; Accepted 20 June 2006

ITP Controversies and Solutions

TABLE I. Differential Diagnosis of Thrombocytopenia Acquired peripheral destruction Idiopathic thrombocytopenic purpura Neonatal alloimmune thrombocytopenia Post-transfusion purpura Disseminated intravascular coagulation Thrombotic thrombocytopenic purpura Heparin-induced thrombocytopenia Splenic sequestration Kassabach-Merrit syndrome Cardiovascular diseases Infectious diseases Systemic lupus erythematosus Antiphospholipid autoantibody syndrome Pregnancy Acquired deciency of production Drug-induced thrombocytopenia Infectious diseases Alcohol Myelodysplastic syndrome Hematological neoplasms Bone marrow inltration by neoplastic process Aplastic anemia Inherited thrombocytopenia Thrombasthenia Glanzmann MYH-9 related (May-Hegglin anomaly, Fechtner, Epstein, and Sebastian syndrome) Mediterranean thrombocytopenia Bernard-Soulier syndrome Gray Platelet syndrome Paris-Trousseau thrombocytopenia/Jacobsen syndrome Velocardiofacial syndrome, DiGeorge syndrome Wiskott-Aldrich syndrome X-linked thrombocytopenia Congenital amegakaryocytemia Thrombocytopenia with absent or dysplastic radii syndrome Fanconi anemia GATA1 mutation Autoimmune lymphoproliferative disease

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time of diagnosis is not known and difcult to foresee at that time, and results in vague information to the patient. Probably more meaningful for clinical practice may be a differentiation into a symptomatic, oligo-symptomatic, and asymptomatic ITP. Nevertheless, an optimal diagnosis and classication necessitates the knowledge of the pathophysiological background of each patient with ITP. BLEEDING RISK The individual bleeding risk at the time of diagnosis and later in the course of ITP is difcult or impossible to estimate. The risk of fatal bleeding, such as intracranial hemorrhage is rare in childhood with an incidence of less than 0.5% of the patients [12,13]. It seems to increase with age, particularly in elderly patients [14]. The phenotype of hemorrhage depends on the grade of thrombocytopenia, but possibly also on other factors, such as platelet function, endogenous factors, such as concomitant disorders affecting the hemostasis, arteriovenous malformations, polymorphisms in genes involved in hemostasis and immune response, and exogenous factors, such as drugs and infectious diseases. SOLUTIONS AND FUTURE DIRECTIONS In their comprehensive literature review, George et al. [1] revealed a substantial lack of evidence in diagnosing and managing patients with ITP. This situation motivated a group of pediatric hematologists to establish the Intercontinental Childhood ITP Study Group (ICIS), with the aim to create a network of physicians involved in the management of patients with ITP and to provide a tool for basic science and clinical research [15]. ICIS started with registries (Table II) to study the natural history of ITP (Registry I, closed) [13,16], the bleeding signs at diagnosis and during a follow-up time of 2 years (Registry II, closed) [8], and the management of children in whom a splenectomy was performed with assessment of the long-term follow-up (Splenectomy Registry, open since 1998) [17]. In 2004 the Pediatric and Adult Registry on Chronic ITP (PARC ITP) was opened. This registry brings pediatric and adult hematology together and studies patients with chronic ITP. Every patient with ITP (acute or chronic) is eligible, registration is performed via Internet (www.parc-itp.net). The study has a core database with the potential to add subsequent side studies as modules. Currently, there is a side

severe bleeding [10]. Chronic ITP is an autoimmune disorder which occurs more often in adults and, if symptomatic, may cause considerable clinical problems. However, chronic ITP also occurs in children and acute ITP occurs in adults. It has been demonstrated from data of Registry I, that approximately 25% of children with thrombocytopenia after 6 months may have a platelet count remission (platelets >150 109/L) after 12 months [11], questioning the clinical value of these two forms of ITP in pediatrics. Furthermore, whether a patient with ITP has the acute or chronic form at the

TABLE II. Projects of the Intercontinental Childhood ITP Study Group (ICIS) Duration of project 19972000 20022004 Since 1998 Since 2004 Patients (N) 2,786 1,186 157 494 Investigators (N) 228 96 70 56 Institutions (N) 153 69 57 51 Countries (N) 41 42 26 22

Name of the project Registry I Registry II Splenectomy Registry PARC ITP Pediatric and Adult Registry on Chron. ITP

References [11,13,16] [8] [17]

Pediatr Blood Cancer DOI 10.1002/pbc

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hne Ku
7. Godeau B, Cheveret S, Varet B, et al. Intravenous immunoglobulin or high-dose methylprednisolone, with or without oral prednisone, for adults with untreated severe autoimmune thrombocytopenic purpura: A randomised, multicentre trial. Lancet 2002;359: 2329. hne T, Bolton-Maggs P, et al. Frequency, 8. Buchanan GR, Ku location, and timing of severe hemorrhage in children with newlydiagnosed idiopathic thrombocytopenic purpura: A study of the Intercontinental Childhood ITP Study Group. Blood 2003;102: 298a. 9. Khellaf M, Michel M, Schaeffer A, et al. Assessment of a therapeutic strategy for adults with severe autoimmune thrombocytopenic purpura based on a bleeding score rather than platelet count. Haematologica 2005;90:829832. 10. Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med 2002;346:9951008. hne T, Mu ller D, et al. Childhood ITP: 12 months 11. Imbach P, Ku follow-up data from the prospective registry I of the Intercontinental Childhood ITP Study Group (ICIS). Pediatr Blood Cancer 2006;46:351356. 12. Lilleyman JS. Intracranial hemorrhage in idiopathic thrombocytopenic purpura. Arch Dis Child 1994;71:251253. hne T, Imbach P, Bolton-Maggs PHB, et al. Newly diagnosed 13. Ku idiopathic thrombocytopenic purpura in childhood: An observational study. Lancet 2001;358:21222125. 14. Cohen YC, Djulbegovic B, Shamai-Lubovitz O, et al. The bleeding risk and natural history of idiopathic thrombocytopenic purpura in patients with persistent low platelet counts. Arch Intern Med 2000 160:16301638. 15. www.unibas.ch/itpbasel. hne T, Buchanan GR, Zimmerman S, et al. A prospective 16. Ku comparative study of 2540 infants and children with newly diagnosed idiopathic thrombocytopenic purpura (ITP) from The Intercontinental Childhood ITP Study Group. J Pediatr 2003;143: 605608. hne T, Blanchette V, Smith O, et al. Splenectomy in childhood 17. Ku idiopathic thrombocytopenic purpura: Results of the Splenectomy Registry. Blood 2003;102;78b.

study open assessing the role of polymorphisms in immune response genes. CONCLUSIONS Idiopathic thrombocytopenic purpura is heterogeneous in pathophysiology and better insights into the various mechanisms leading to thrombocytopenia are needed in order to adequately diagnose and manage patients with ITP. Clinical endpoints in addition to the platelet count need to be evaluated in prospective clinical trials. ICIS may provide a functioning network and represents a solution to coordinate research and to overcome administrative barriers. REFERENCES
1. George JN, Woolf SH, Raskob GE, et al. Idiopathic thrombocytopenic purpura: A practice guideline developed by explicit methods for The American Society of Hematology. Blood 1996; 88:340. 2. British Committee for Standards in Haematology General Haematology Task Force. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haematol 2003;120:574596. hne T, Signer E. Historical aspects and present 3. Imbach P, Ku knowledge of idiopathic thrombocytopenic purpura. Br J Haematol 2002;119:894900. 4. Provan D, Newland A. Fifty years of idiopathic thrombocytopenic purpura (ITP): Management of refractory ITP in adults. Br J Haematol 2002;118:933944. 5. Bolton-Maggs PHB, Moon I. Assessment of UK practice for management of acute childhood idiopathic thrombocytopenic purpura against published guidelines. Lancet 1997;350:620623. 6. Buchanan GR, Adix L. Grading of hemorrhage in children with idiopathic thrombocytopenic purpura. J Pediatr 2002;141:683 688.

Pediatr Blood Cancer DOI 10.1002/pbc