REVIEW Controversies in the Diagnosis and Management of Childhood Acute Immune Thrombocytopenic Purpura

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1 Pediatr Blood Cancer 2009;53: REVIEW Controversies in the Diagnosis and Management of Childhood Acute Immune Thrombocytopenic Purpura George B. Segel, MD 1 * and Stephen A. Feig, MD 2 Acute immune thrombocytopenic purpura (ITP) occurs most commonly in young children who present with severe isolated thrombocytopenia and purpura. A marrow examination is not required unless glucocorticoids are used, lest treatment mask incipient acute lymphoblastic leukemia, but controversy exists here. The recommendations for evaluation and management remain controversial, since prospective controlled trials have not been done. There is some consensus based on experience and empiric data. Almost all children with acute ITP will recover completely without therapy. Although the various treatments may increase the platelet count, they do not influence the outcome of the illness, may increase cost, and cause significant side effects. Therefore, careful observation may be the best management option for the patient with ITP, in the absence of severe bleeding. The data available relevant to these issues are discussed. Pediatr Blood Cancer 2009;53: ß 2009 Wiley-Liss, Inc. Key words: immune cytopenias; immune thrombocytopenia; thrombocytopenia INTRODUCTION Acute immune thrombocytopenia (ITP) is a diagnosis of exclusion since there is no definitive diagnostic test. The patient presents with a low platelet count, usually with petechiae and ecchymoses. The hemoglobin concentration, the white cell count, and the white cell differential count are normal. The patient is afebrile and otherwise well, and there is no family history of a bleeding disorder. Acute ITP may follow a viral infection or have no antecedent illness. Infrequently, the onset of thrombocytopenia may be associated with an immunologic (immunodeficiency or systemic lupus erythematosis) or neoplastic B-cell disorder (e.g., Hodgkin lymphoma). It is also important to consider drugs that are associated with immune thrombocytopenia (e.g., heparin, quinidine). In spite of the many publications on this subject, there are a number of issues that are controversial [1 7]. This study will address (1) the pathogenesis of acute ITP, (2) the value of a marrow examination to support the diagnosis, (3) the morbidity and risk of serious bleeding, (4) which patients should be treated, and (5) the conventional and investigative therapies. WHAT IS THE PATHOGENESIS OF ACUTE CHILDHOOD ITP? Immune Mechanisms There are conclusive data indicating that the thrombocytopenia in ITP is generated by an IgG autoantibody [8,9]. The initial observations of Harrington et al. [10] established that plasma of a patient with ITP could induce thrombocytopenia in healthy volunteer subjects, and subsequent studies showed that the effecting agent inducing thrombocytopenia in patents with ITP is in the gamma globulin fraction and presumably an antibody [11]. Antibodies with specificity to GPIIb/IIIa and GPIb/IX have been identified in plasma from patients with ITP; they result in platelet destruction, and GPIb/IX also can damage megakaryocytes and impair thrombopoiesis [12]. IgM, IgA, C3, and C4 also have been found on platelets in ITP, but their role in the pathogenesis is not clear [13,14]. The generation of an autoantibody likely involves an antigen-presenting dendritic cell, an autoreactive B-lymphocyte, and a Th-1 (T-helper) cell and its cytokines such as TNFa and INFg (Fig. 1). Alternatively, there is evidence that a defect in the function ß 2009 Wiley-Liss, Inc. DOI /pbc Published online 22 January 2009 in Wiley InterScience ( of T-regulatory cells may lead to the inability to suppress B-cell production of autoantibodies in ITP [15,16]. Immune thrombocytopenia in children is most commonly associated with a preceding viral illness, and the mechanism of molecular mimicry (Fig. 2) along with an inflammatory state may play a central role in its genesis. IgG antibodies generated to antigens on the surface of varicella-zoster [17], HIV1 [18,19], and EBV [20] can cross-react with antigens such as glycoprotein IIb IIIa on the platelet surface. Antibodies to Helicobactor pylori also have been implicated in the genesis of chronic ITP in adults [21,22], but their role in the pathogenesis of childhood ITP is unclear [23]. Other possible mechanisms for viral-induced ITP [14] include adsorption of viral epitopes on the platelet surface resulting in antiviral antibodies and complement destruction of platelets, immune complex adherence to platelets with consequent platelet destruction, alteration of platelet epitopes making them antigenic, as well as non-immune direct platelet or megakaryocyte damage. The initial antibody response to a viral infection normally plays a role in clearing the virus, thus removing the primary antigenic stimulus. IgG antibodies, however, have a half-life of approximately 3 weeks, and hence, if there is cross-reactivity with platelets, the thrombocytopenia may persist after the viral illness has subsided. Eventually, the titer of antibody wanes, and the platelet count recovers. Resolution within 6 months occurs in about 80% of childhood cases [24 26] (Fig. 3). Drug Induced Antibodies to platelets may also be associated with drugs such as quinine or heparin [27]. Drugs such as quinine or quinidine may 1 Department of Pediatrics, Golisano Children s Hospital at the University of Rochester School of Medicine, Rochester, New York; 2 Gwynne Hazen Cherry Memorial Laboratories, Mattel Children s Hospital at UCLA, David Geffen School of Medicine at UCLA, Los Angeles, California *Correspondence to: George B. Segel, Department of Pediatrics, University of Rochester School of Medicine, Box 777, 601 Elmwood Ave., Rochester, NY george_segel@urmc.rochester.edu Received 7 August 2008; Accepted 4 December 2008

2 Controversies in ITP 319 Fig. 1. The generation of auto-antibodies. APC, antigen-presenting cell; GM-CSF, granulocyte-macrophage colony stimulating factor; IFN, interferon; IL, interleukin; M-CSF, macrophage colony stimulating factor; MHC, major histocompatibility complex; R, receptor; TGF, transforming growth factor; Th, T-helper cell; TNF, tumor necrosis factor. From Kalpatthi and Bussel [13]. Reproduced with the permission of the publisher. Fig. 3. The time course of acute ITP, in relation to preceding viral infection. Note the persistence of the immunoglobulin antibody for weeks after the end of the infection. This accounts for the prolonged course of thrombocytopenia after the resolution of the viral infection. Reproduced from a figure presented at the Sixth Annual Review of ITP with the permission of J. Semple, University of Toronto. [Color figure can be viewed in the online issue, which is available at induce antibody formation by changing the configuration of a surface epitope of the platelet. The altered antigen is recognized by the immune system as foreign. Alternatively, in heparin-induced thrombocytopenia, heparin, which is relatively non-antigenic, binds to platelet factor 4, and antibodies are produced to this complex. Platelets are both activated, precipitating thrombosis, and destroyed, causing thrombocytopenia. Chronic ITP A small proportion (fewer than 20%) of children who present with what appears to be acute ITP will remain thrombocytopenic beyond 8 12 months and are considered chronic. Children with chronic ITP should be assessed for the presence of an associated illness, such as an underlying autoimmune disease including systemic lupus erythematosis, anti-phospholipid syndrome, common variable immunodeficiency, HIV/AIDS, Crohn s disease, or a B-cell lymphoma. Genetic conditions, especially those which result in immune dysregulation, may predispose to the development of chronic ITP, but attempts to demonstrate a direct link of hereditary ITP to specific HLA genotypes have not been convincing [28,29]. A number of mechanisms have been proposed to explain platelet destruction in chronic ITP. These include antibody-induced platelet destruction by macrophages, antibody-induced complement lysis, antibody-mediated megakaryocyte suppression, and T lymphocytemediated platelet lysis [30]. Other Causes of Thrombocytopenia in Children Fig. 2. Molecular mimicry. Note the resemblance of antigens between the VZV (Varicella Zoster virus) and the platelet. The antibody is unable to differentiate between the inciting antigen on the virus and the similar antigen on the platelet. Modified from a figure presented at the Sixth Annual Review of ITP 2004, and reproduced with the permission of J. Semple, University of Toronto. [Color figure can be viewed in the online issue, which is available at wiley.com.] There are a variety of diagnostic considerations when a child presents to the physician with petechiae and ecchymoses. The diagnosis of acute ITP requires that features such as fever, rash, anemia, or uremia are absent to diminish the likelihood of other disorders such as meningococcemia, thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome. Chronic ITP may be confused with type 2b Von Willebrand (VW) disease in which there is a hyperactive VW factor that consumes platelets and increases clot formation. In contrast to most patients presenting with acute ITP, these individuals present with mild-to-moderate thrombocytopenia. There are other rare genetic causes of chronic thrombocytopenia, such as Wiskott Aldrich Syndrome (WAS). Eczema and frequent infections, as well as the

3 320 Segel and Feig presence of small platelets on the blood smear, suggest this diagnosis. In addition to thrombocytopenia, platelet function is abnormal [31]. A mutation in the same gene causes X-linked thrombocytopenia (XLT). XLT may be more difficult to identify, since it is not accompanied by the immunologic and cutaneous manifestations of WAS [32]. Like WAS, XLT is characterized by the presence of small defective platelets. Genetic defects in the nonmuscle myosin heavy chain (MYH9 disorders) may produce giant platelet syndromes with thrombocytopenia and normal platelet function such as the May Heggelin anomaly [33 35] The giant platelet syndromes are not associated typically with bleeding manifestations. Rarely, marrow failure syndromes (e.g., Fanconi anemia) can mimic chronic ITP at onset, although the involvement of other hematopoietic cell lines soon distinguishes these entities. WHAT IS THE ROLE OF THE MARROW EXAMINATION? A number of studies [6,36 40] suggest that examination of the marrow is usually unnecessary for the diagnosis of ITP, although none of these reports were based on prospective trials. Marrow examination is recommended for those patients who have atypical laboratory or clinical findings such as anemia, neutropenia, or splenomegaly. Data from the Pediatric Oncology Group (POG) indicate that patients presenting with isolated thrombocytopenia are unlikely to have acute leukemia. This was concluded from observations in more than 2,000 patients with acute leukemia [41]. In a natural history study of ITP, 296 of 409 patients underwent marrow examination, and this procedure did not result in a change in diagnosis [42]. The admonition in these recommendations is that the blood counts are normal except for the platelet count, that the patient does not have splenomegaly, and that there are no abnormal cells (i.e., leukemic blasts) on the peripheral blood smear. What is not considered is who is evaluating the blood smear. The majority of patients with ITP are initially seen by primary care physicians who are not necessarily in proximity to a medical center with experts in pediatric hematology/oncology who can reliably identify leukemic cells on a blood smear. The requirement for a marrow is primarily important if glucocorticoids are chosen as the initial treatment, which remains a common practice. Prednisone or prednisolone are lympholytic and highly effective in the treatment of acute lymphoblastic leukemia (ALL). Some ALL patients achieved a short-lived remission when either ACTH or glucocorticoids were used [43]. The inadvertent prescription of monotherapy with glucocorticoids to a patient with acute leukemia may compromise their long-term outcome and is not consistent with the current standard of care for these patients. Therefore, the necessity of a marrow examination depends on who is evaluating the patient. Marrow examination is recommended in the BSH guidelines if glucocorticoids are prescribed [40]. The published data suggest that in a pediatric center with pediatric hematologist/oncologists providing the evaluation, there is little chance of an initial error in diagnosis, for example, misdiagnosing ITP in a patient with acute leukemia. However, there are no data regarding patients evaluated without this expertise. An ASPHO survey of 218 pediatric hematologists using a typical ITP patient showed no consensus regarding the need for a marrow examination when glucocorticoids were used (Table I) [44]. We would suggest caution with regard to the general recommendations minimizing the need for a marrow examination. A marrow examination is not necessary if glucocorticoids are not used as initial treatment. In our centers, a marrow examination is performed if glucocorticoids are used initially, even with trained hematologist/oncologists as the responsible physicians. In a patient who has been treated successfully with immunotherapy in the past and then requires retreatment, a marrow examination may be unnecessary, even if glucocorticoids are prescribed. WHAT IS THE RISK OF SEVERE BLEEDING AS A COMPLICATION OF ITP? Patients with ITP may bleed from any site particularly when the platelet count is below 10,000/ml. The most common types of bleeding include epistaxis, oral bleeding, uterine bleeding (menorrhagia), and hematuria [42]. Approximately 10 of 425 children had severe bleeding when the platelet count was fewer than 10,000/ml, but only 1 of the 425 had severe bleeding when the count was between 10,000 and 19,000/ml [45]. Recent data from the Childhood ITP Study Group indicated that the incidence of severe bleeding in the first 28 days after diagnosis was 0.6% in 505 patients with platelet counts of 20,000/ml or fewer, but without severe bleeding at diagnosis (97% of the patients) [46]. Life-threatening bleeding, including intracranial hemorrhage (ICH), appears associated with wet purpura (as manifested by mucosal bleeding), the concomitant use of anti-platelet agents such as aspirin or dipyridamole, or head trauma [47,48]. These observations suggest that the complications of treatment may exceed the complications of the disease at platelet levels above 10,000/ml in children with ITP. The most dreaded complication of ITP is ICH. There were 56 patients with ITP and ICH reported between 1975 and 1996, representing an occurrence of 2 3 reported cases per year. Fifty-five of these children had platelet counts below 20,000/ml and most (73% of the 56) were below 10,000/ml [47]. In another report there were 75 reported patients with ICH from 1954 to 1998 or about 2 per year [48]. Thirty-five of these patients were on treatment at the time of the ICH, and the median time from the diagnosis was 1 month. The TABLE I. ASPHO Practice Survey of Pediatric Hematologists Treatment a Always Usually Sometimes Rarely Glucocorticoids, IVIG, or anti-d Patient hospitalized Marrow aspiration With the use of glucocorticoids Without the use of glucocorticoids a Treatment of a 5-year-old child with a platelet count of 7000/ml and a brief nosebleed; table constructed using data published by Vesely et al. [44]. Data represent the percent of respondents.

4 Controversies in ITP 321 estimated incidence of an ICH in ITP is 0.1 1% of ITP patients, with the lower estimation more likely. The effect of therapy on the mortality in ITP is quite small [49]. The mortality was unchanged before and after the institution of IVIG therapy in In the prospective study of 2,540 children by the Intercontinental Childhood ITP Study Group, there were 3 patients who developed an ICH, an incidence of 0.17% [50], and in a 10-year study in a single institution 1 patient of 409 (0.24%) in the series had this complication [42]. Although one cannot predict the severity of bleeding from the platelet count alone [51], patients with overt petechiae, ecchymosis, and mucosal bleeding should be considered at higher risk of severe bleeding even if their platelet counts are above 20,000/ml. However, there are insufficient data to suggest that therapy diminishes the occurrence of intracranial bleeding [52,53]. WHO SHOULD BE TREATED? There are no data to suggest that the treatment of children with acute ITP alters the course of the illness. More than 80% of children with ITP will revert to normal platelet counts within 1 year of presentation, and most of those will do so within 2 4 months [51,54]. Therefore, treatment should be reserved for those patients who are at risk of serious bleeding such as those whose daily lives are impacted by severe frequent epistaxis, excessive menstruation, urinary or gastrointestinal bleeding, or similar problems. Mucosal bleeding in the mouth, oral cavity, urinary, and gastrointestinal tracts portends more severe bleeding and has been used as an indication for treatment. There are other situations in which common sense might warrant treatment because of the heightened risk of serious bleeding. These include the need for surgery, the use of inhibitors of platelet function such as aspirin or dipyridamole, and the presence of antecedent head trauma. The family s distance from the medical center, the reliability of the caregivers, and the age of the child also may influence the decision to treat. A toddler who has just begun to walk is more prone to falls and head trauma, particularly if the supervision is not optimal. The absolute platelet count is not the only factor that affects the risk of bleeding. Patients with ITP have large platelets reflecting their young age, and the larger platelet volume is correlated with heightened function that mitigates the risk of severe bleeding. The patient bleeding times reported in ITP may be in the normal range even though the platelet count is low [55]. When platelet function is impaired as in uremia, VW disease, exposure to aspirin or marrow failure, the platelet count may be higher, but the tendency to bleed greater. The published ASH and BSH guidelines [38 40] for treatment are of little help in Pediatrics, since the substantiating evidence is sparse. Attempts to define the practice of pediatric hematologists in treating childhood ITP have shown marked variability (Table I) [44]. The investigators invariably conclude that controlled prospective trials are needed. Since the risk of bleeding is generally low and the number of patients required for such a prospective trial is large, the cost and time required make execution of such a study difficult. Furthermore, the inclusion of a randomization to observation only might lead therapeutic advocates to withhold patients from the study. Tarantino and Buchanan [56] summarized the evidencebased support for and against drug treatment of uncomplicated ITP, and these data are summarized in Table II with the corresponding references. TABLE II. Evidence-Based Support for and Against Drug Treatment of the Minimally Symptomatic Child With ITP References In favor of observation with drug treatment Treatment increases the platelet count more rapidly [71 73] than no treatment Severe hemorrhage more likely with platelet counts [48] below /L Drug treatment is cost effective if it prevents bleeding [74] In favor of observation without drug treatment Severe hemorrhage is rare, 0.1 1% [39] Drug treatment may not prevent severe hemorrhage [52] Drug treatment unnecessarily increases the cost [70] of management Drug treatment may be harmful [>40] Reproduced with permission from Tarantino and Buchanan [56]. WHAT SHOULD BE USED FOR TREATMENT? Acute ITP Although observation may be the best option for most patients with ITP, there are several primary therapies available for patients with significant bleeding. These include glucocorticoids, intravenous anti-d (WinRho), and IVIg. The advantages and disadvantages of each of these treatments are listed in Table III. None of these therapies is benign and some are quite costly (Table IV). The use of immunotherapy with anti-d or IVIg avoids the need for a marrow since immunotherapy, in contrast to glucocorticoids, has no masking effect on the diagnosis of ALL. However, both anti-d and IVIg share the problem of drug reactions including fever, chills, urticaria, and particularly headache (Table III). In a patient with a platelet count below 10,000/ml and a severe headache, a CT scan is required to rule out an intracerebral hemorrhage. Less common complications from immunotherapy include severe acute hemolytic anemia with possible renal failure with both anti-d [57] and IVIg. For those patients with platelet counts greater than 10,000/ml and little bleeding, the best treatment is careful observation. In the uncommon patient who has persistent epistaxis, menstrual, or gastrointestinal bleeding, aminocaproic acid may be a useful adjunct to treatment, and can be given orally or intravenously. When the bleeding is life threatening, platelet transfusions should be given. Although the platelet count may not increase substantially, bleeding often can be controlled. Chronic ITP The treatment of refractory and more chronic forms of ITP is a difficult problem, and the decision to treat usually is related to the severity of symptoms, the impairment of daily activities, and the compromise in the quality of life [58]. A variety of modalities are available, including rituximab and other agents [59,60], splenectomy [61], and combination chemotherapy [62]. Approximately one-third of patients will have a 2-year sustained response to rituximab, an anti-cd20 antibody that markedly depletes B-lymphocytes [63,64]. Some patients who are infected with H. pylori respond to antibiotic treatment of this condition [21], but the usefulness of treatment has not been substantiated in children [23].

5 322 Segel and Feig TABLE III. Comparison of the Interventional Treatments for ITP Prednisone/prednisolone IVIg Anti-D Advantages Oral No marrow required No marrow required Inexpensive Response faster than glucocorticoids Response faster than glucocorticoids Does not require a treatment center Side effects depend on duration of treatment Disadvantages May require a marrow examination Must be given IV Must be given IV Slower response than immunotherapy May require hospital admission or a treatment center Requires a treatment center Very expensive Very expensive Requires pre-medication to reduce side effects Requires pre-medication to reduce side Requires the longest post-infusion monitoring effects Requires the patient to be Rhþ Results in a 1 2 g/dl fall in Hb Adverse events Cushinoid changes Headache Fever Weight gain Fever Chills Hypertension Nausea and vomiting Nausea and vomiting Impaired glucose tolerance Allergic reactions Severe hemolysis and renal failure Gastric irritation and possible bleeding Behavior problems: irritability, hyperactivity, insomnia Aseptic meningitis Thrombosis (adults) Severe hemolysis and renal failure TABLE IV. Comparison of Price for ITP Therapy Product Unit price (15 kg child) Price Price (40 kg child) IVIg (Gammagard) (2 g/kg) $112/gm $3,360 $8,960 WinRho (75 mcg/kg) $1/mcg $1,125 $3,000 Prednisone (2 mg/kg) $0.06/10 mg $1.80 $4.80/day These data were obtained from the pharmacy at the Mattel Children s Hospital at UCLA in October Actual cost varies with the contracts to various payers. Splenectomy is not commonly recommended in affected children because of the risk of post-splenectomy infection with encapsulated organisms such as pneumococcus. A survey of American Society of Pediatric Hematology Oncology members revealed that only onethird would recommend splenectomy in a 5-year-old child who was refractory to treatment after 1 year [65]. Trials of second-generation thrombopoietic growth factors, such as the thrombopoietin peptide mimetic, AMG531 (Nplate or Romiplastin) and the non-peptide, eltrombopag, have shown promise in increasing the platelet count in chronic ITP [66 68]. All of these treatments should be reserved for patients with chronic, symptomatic disease. Some patients will have a concomitant autoimmune disease (e.g., SLE) or some variant of congenital or acquired immunodeficiency and require treatment of the underlying problem. CONCLUSIONS ITP is still subject to many of the same debates that have been ongoing for many years. Perhaps it is the nature of the disease that produces this conundrum. Almost every patient will do well, regardless of whether treatment is administered or what that treatment is [69,70]. Since adverse events are uncommon, the value of treatment is uncertain; furthermore, since a definitive, evidencebased study requires substantial funding, the cooperation of multiple institutions and a large number of patients, these controversies may never be fully resolved. The clinical trial comparing observation versus treatment with a primary outcome of central nervous system hemorrhage is not possible because of the limited number of patients with this complication. Our impression is that most pediatric hematologists have decided empirically to observe patients who have minimal bruising, petechiae, and platelet counts greater than 10,000/ml; a recent publication shows that severe bleeding is not often observed at diagnosis or in the first 4 weeks of the illness [46]. The decision to treat often is based on the presence of mucosal hemorrhage, volume of blood loss, concomitant trauma, or the need for surgery. REFERENCES 1. Kuhne T. Idiopathic thrombocytopenic purpura in childhood: Controversies and solutions. Pediatr Blood Cancer 2006;47: Nugent DJ. Controversies in the treatment of pediatric immune thrombocytopenias. Blood Rev 2002;16: Nugent DJ. Immune thrombocytopenic purpura of childhood. American Society of Hematology Education Program Book. Hematology 2006;

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