Pediatr Blood Cancer 2006;47:734736

Critical Issues Concerning Splenectomy for Chronic Idiopathic Thrombocytopenic Purpura in Childhood
Milen Minkov,
Guidelines for management of chronic idiopathic thrombocytopenic purpura (ITP) in childhood are still based on expert opinions and therefore remain controversial. Splenectomy is an established option for chronic ITP in adults, but splenectomy in childhood is complex, due to higher probability for spontaneous recovery of ITP as compared to adults, psychological barrier of parents to accept a permanent organ loss, lack of reliable preoperative response prediction, and risk for overwhelming sepsis in young children.
MD, PhD*

Parents are confronted with fear of intracranial bleeding, burden of responsibility in daily life, frequent visits to doctors, and need for restrictions of physical activities. Decision is further complicated by emerging conservative options offering durable remissions. This article reviews existing recommendations for splenectomy in pediatric chronic ITP and delineates critical and unsolved issues. Pediatr Blood Cancer 2006;47:734736. 2006 Wiley-Liss, Inc.

Key words:

children; splenectomy; thrombocytopenia

INTRODUCTION Management of chronic idiopathic thrombocytopenic purpura (ITP) in childhood is still primarily based on expert opinion rather than on reliable clinical evidence. The most commonly used treatments include systemic steroids, intravenous immunoglobulin (IVIG), anti-D immune globulin (anti-D), or splenectomy. Among these therapies splenectomy was over decades considered the only one with proven long-lasting effect. While it is a cornerstone therapy and nds application relatively early in the disease course in adults, the decision for splenectomy in the pediatric setting is much more complex. The aim of this report is to delineate critical and unsolved issues considering splenectomy for pediatric ITP.

paediatric haematologist by individual consideration. While at a rst glance this recommendation seems more restrictive, it recognizes the complexity of this issue and is open for other indications (e.g., considerable lifestyle restrictions), which could be at least partially independent of clinically relevant bleeding. Current Evidence on Splenectomy for Pediatric ITP The outcome following splenectomy in children with primary chronic ITP seems good. The ASH guideline panel found a 72% complete remission rate after splenectomy in 16 case series (271 patients) published over a time period of 40 years. However, these had low level of evidence being case series without controls [2]. Similar results have been reported more recently [35]. A selection bias of the available data cannot be excluded, as they were derived from retrospective studies and the indication for splenectomy varied among the institutions. For example, the frequency of splenectomy for chronic ITP varied in published pediatric series between 10 and 40% [59]. In series with a more conservative management approach, splenectomy has been performed less frequently [10] or not at all [11]. Another weakness of the published data is that the effect of splenectomy on morbidity and mortality has not been shown directly. Furthermore, long-term follow-up studies are not available and failure rates could be underestimated. Briey, almost a decade after the ASH Guidelines have been published the quality of evidence for splenectomy in chronic ITP of childhood has not improved.

Existing Recommendations for Splenectomy in Pediatric ITP There are some published guidelines written on the basis of expert opinions and taking into account existing clinical practices and literature data [1,2]. The ASH panel [2] reached consensus that splenectomy is indicated for patients with disease persistence for 12 months with bleeding symptoms and a platelet count of <10,000 (ages 312 years) or 10,000 30,000 (ages 812), if the primary treatment (glucocorticoid, IVIG, and/or anti-D) was only transiently successful, and if there are no medical contraindications to the surgery. It has been explicitly stressed that the recommendation for splenectomy for pediatric ITP was based on expert opinion due to lack of evidence-based data. The respective Guideline of the British Society of Haematology [1] contains the even more restrictive statement: It (splenectomy) is occasionally justied for lifethreatening bleeding and for children with chronic unremitting and severe ITP whose disease has been present for more than 1224 months with demonstrable impairment of their quality of life. The decision should be made by a specialist
2006 Wiley-Liss, Inc. DOI 10.1002/pbc.20979

St. Anna Childrens Hospital, Vienna, Austria *Correspondence to: Milen Minkov, St. Anna Childrens Hospital, Kinderspitalgasse 6, A-1090 Vienna, Austria. E-mail: milen.minkov@stanna.at Received 20 June 2006; Accepted 20 June 2006

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Relevant Pediatric Issues Complexity of splenectomy decision making. The decision for splenectomy is a complex issue inuenced by a number of factors. Among them is the higher probability for spontaneous recovery of ITP as compared to adults, the psychological barrier of the parents to accept a permanent organ loss for their child, the lack of reliable preoperative response prediction, and the risk for overwhelming sepsis in young children. These are opposed to the fear of intracranial bleeding, the burden of responsibility for a child at risk for bleeding, the frequent visits to the doctor, and the need for restrictions of physical activities. The decision process is further complicated by emerging conservative options offering durable remissions. The need for splenectomy in chronic ITP. The demographics and clinical course of pediatric onset ITP are well characterized [12,13]. Chronic ITP accounts for about 2030% of all pediatric cases and remits spontaneously over the time in about one-third of them. In the ICIS Registry only 59% of the cases with sufcient follow-up had a platelet count of <20 109/L at 6 months [12]. Severe chronic ITP (persistent platelet count <30 109/L and clinically signicant hemorrhage), which could justify splenectomy, accounts for roughly 23% of all ITP cases. Alternatives to splenectomy in severe chronic ITP. The most widely accepted and used treatment options for chronic ITP in childhood are steroids, IVIG, and anti-D. To date there is no convincing evidence that early medical therapy can favorably change the natural history of chronic ITP in children. Good short-term platelet enhancement is seen with all three modalities, but this has to be weighted against the side effects associated with these drugs. The lack of a sustained platelet-enhancing effects in most of the cases leads in turn to frequent drug application and hence to more cumulative side effects. This is particularly true for steroids. The durable effects of a regimen using pulses of high-dose oral dexamethasone in adults could not be conrmed in subsequent pediatric series [14,15]. Moreover, given every 34 weeks these pulses are associated with high incidence of side effects (weight gain, acne, striae, fatigue, mood changes, etc.) responsible for low compliance in adolescents. For this reason the recommendation of some authors to complete at least six courses of steroids before considering another option needs a critical evaluation. The role of IVIG in the treatment of chronic ITP is limited by the high cost, mostly temporary increase of the platelet counts, long infusion duration, and relatively high frequency of adverse effects. In Rh-positive subjects, anti-D is a further option. It is preferred over IVIG because of its ease of administration, comparable efcacy, and lower cost. Anti-D could be given also as a subcutaneous bolus. The side effects are infrequent and mild. The main shortage is the need for regular infusions (46 weeks for most of the patients). An important consideration of the temporary platelet
Pediatr Blood Cancer DOI 10.1002/pbc

enhancement (achievable with the all three options) is the uncertainty about the bleeding risk at a particular time point and hence the need for restrictions of the life-style habits. Another therapy for chronic ITP is the monoclonal antibody anti-CD 20 (rituximab, Mabthera1). Wang et al. [16] observed complete response in 15/24 (63%) pediatric patients, which was ongoing in nine cases. The therapy was relatively well tolerated. Bennett et al. [17] observed a 31% response in 36 heavily pretreated patients under 18 years of age with acceptable toxicity. The favorable safety prole of rituximab and the possibility for durable complete responses, could justify its use instead of splenectomy in the therapeutic decision tree. This approach would be in line with the strategy to postpone or avoid splenectomy but has to be investigated in a prospective trial. There are some anecdotal reports showing efcacy of mycophenolate mofetil in adult patients with chronic refractory ITP. In view of the favorable safety prole of this drug, it also could be considered in pediatric patients before splenectomy. Prediction of splenectomy success. Most of the available data dealing with prediction of response to splenectomy based on parameters such as patients age, time since diagnosis, response to steroids, IVIG, or anti-D are derived from adult series and therefore not transferable to children. In pediatric series, preoperative parameters did not allow reliable prediction of response to splenectomy [4,18]. A good response to IVIG seems predictive of a response to splenectomy, but a non-response to IVIG did not preclude splenectomy success [19,20]. The place of splenectomy within the therapeutic decision tree. This is another quite controversial issue. The recommendations in the literature are based exclusively on expert opinions. There is general agreement that splenectomy should be deferred as long as possible and be preserved only for patients with severe chronic course who have failed conservative treatment. There is no agreement which conservative options and for how long they should be used before splenectomy. This point is especially important in the face of emerging conservative options offering longlasting platelet increments and potential cure. Guidelines for infection prophylaxis. The dreaded complication of splenectomy, overwhelming septicemia due to encapsulated organisms, is extremely rare. Preoperative immunization against pneumococcus, Hemophilus inuenza type b and meningococcus is recommended. Prophylactic penicillin is recommended by all existing guidelines, but the appropriate duration is controversial. Is it Possible to Improve our Knowledge through a Well-Designed Prospective Trial? There are several factors hampering a controlled prospective trial. Splenectomy appears to be a treatment option only for minority of the pediatric patients diagnosed with ITP.

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8. Wong MS, Chan GC, Ha SY, et al. Clinical characteristics of chronic idiopathic thrombocytopenia in chinese children. J Pediatr Hematol Oncol 2002;24:648652. 9. Jayabose S, Levendoglu-Tugal O, Ozkaynkak MF, et al. Long-term outcome of chronic idiopathic thrombocytopenic purpura in children. J Pediatr Hematol Oncol 2004;26:724726. 10. Bolton-Maggs PH, Moon I. Assessment of UK practice for management of acute childhood idiopathic thrombocytopenic purpura against published guidelines. Lancet 1997;350:620 623. 11. Dickerhoff R, von Ruecker A. The clinical course of immune thrombocytopenic purpura in children who did not receive intravenous immunoglobulins or sustained prednisone treatment. J Pediatr 2000;137:629632. hne T, Buchanan GR, Zimmerman S, et al. A prospective 12. 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. 13. Rosthoj S, Hedlund-Treutiger I, Rajantie J, et al. Duration and morbidity of newly diagnosed idiopathic thrombocytopenic purpura in children: A prospective Nordic study of an unselected cohort. J Pediatr 2003;143:302307. hne T, Freedman J, Semple JW, et al. Platelet and immune 14. Ku responses to oral cyclic dexamethasone therapy in childhood chronic immune thrombocytopenic purpura. J Pediatr 1997;130: 1724. 15. Borgna-Pignatti C, Rugolotto S, Nobili B, et al. A trial of high-dose dexamethasone therapy for chronic idiopathic thrombocytopenic purpura in childhood. J Pediatr 1997;130:1316. 16. Wang J, Wiley JM, Luddy R, et al. Chronic immune thrombocytopenic purpura in children: Assessment of rituximab treatment. J Pediatr 2005;146:217221. 17. Bennett CM, Rogers ZR, Kinnamon DD, et al. Prospective phase I/II study of rituximab in childhood and adolescent chronic immune thrombocytopenic purpura. Blood 2006;107:2639 2642. 18. Bussel JB, Kaufmann CP, Ware RE, et al. Do the acute platelet responses of patients with immune thrombocytopenic purpura (ITP) to iv anti-d and to iv gammaglobulin predict response to subsequent splenectomy? Am J Hematol 2001;67:2733. 19. Holt D, Brown J, Terrill K, et al. Response to intravenous immunoglobulin predicts splenectomy response in children with immune thrombocytopenic purpura. Pediatrics 2003;111: 8790. 20. Hemmila MR, Foley DS, Castle VP, et al. The response to splenectomy in pediatric patients with idiopathic thrombocytopenic purpura who fail high-dose intravenous immune globulin. J Pediatr Surg 2000;35:967971.

Therefore, sufcient patient numbers could be collected only in a setting of international cooperation. Second, intracranial hemorrhage is very rare and hence could not be used as a primary end-point of a study. Therefore, it could not be directly proved whether prevention of this life-threatening complication is possible. A simple, easy to apply but reproducible bleeding score is needed for prospective trials. Potential response parameters should include platelet count along with the frequency, severity, and duration of the bleeding episodes. A study design should take into account that life-style preferences of a patient or his parents could inuence the decision for or against splenectomy. This means that in certain cases (e.g., athletic children) a decision in favor of splenectomy might be met in the absence of clinical bleeding. The Intercontinental Childhood ITP Study Group offers a unique opportunity to address existing controversies. A prospective clinical trial could better dene the value of splenectomy in the management of chronic ITP in children. REFERENCES
1. British Committee for Standards in Haematology, General Haematology Tack Force. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haematol 2003;120:574596. 2. 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. 3. Mantadakis E, Buchanan GR. Elective splenectomy in children with idiopathic thrombocytopenic purpura. J Pediatr Hematol Oncol 2000;22:148153. 4. Wang T, Xu M, Ji L, et al. Splenectomy for chronic idiopathic thrombocytopenic purpura in children: A single center study in China. Acta Haematol 2006;115:3945. 5. Reid MM. Chronic idiopathic thrombocytopenic purpura: Incidence, treatment, and outcome. Arch Dis Child 1995;72:125128. 6. Watts RG. Idiopathic thrombocytopenic purpura: A 10-year natural history study at the childrens hospital of Alabama. Clin Pediatr (Phila) 2004;43:691702. 7. Lowe EJ, Buchanan GR. Idiopathic thrombocytopenic purpura diagnosed during the second decade of life. J Pediatr 2002; 141: 253258.

Pediatr Blood Cancer DOI 10.1002/pbc