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Management of Immune Thrombocytopenic Purpura in Children

Bredlau, Amy Lee Tekan tombol Escape untuk menutup; Semple, John W 13.4 (Aug 2011): 213-23. Aktifkan sorotan temuan untuk peramban bicara ; Segel, George B . Paediatric Drugs

Abstrak (ringkasan)
[[missing key: loadingAnimation]] The treatment of immune thrombocytopenic purpura (ITP) in children is controversial, requiring individualized assessment of the patient and consideration of treatment options. If the platelet count is >10 000/L and the patient is asymptomatic, a 'watch and wait' strategy is appropriate since most children with ITP will recover completely without pharmacotherapy. If therapy is indicated because of bleeding or a platelet count <10 000/L, then treatment with glucocorticoids, intravenous immunoglobulin (IVIg), or anti-D are possible initial choices. Glucocorticoid treatment is the least expensive and is our usual first choice of therapy. Its use assumes that the blood counts and blood film have been evaluated to ensure the absence of evidence of alternative diagnoses, such as thrombotic thrombocytopenic purpura or incipient acute leukemia. IVIg is expensive and often causes severe headache, nausea and vomiting, and requires hospitalization at our institution. Anti-D therapy is also expensive and can only be used in patients who are Rhesus D positive. These therapies, even if only transiently effective, can be repeated if necessary. Children usually recover from newly diagnosed ITP, with or without multiple courses of medical therapy. If the disease becomes 'persistent' with severe thrombocytopenia and/or bleeding, and is no longer responsive to the three first-line therapies, the next approach includes the use of thrombopoietin receptor agonists or rituximab. When the disease persists for more than 1 year, it is considered chronic, and, if symptomatic, it may become necessary to consider third-line therapies, including splenectomy, alternative immunosuppressive agents, or combination or investigative chemoimmunotherapy. This review considers the indications, mechanism of action, and effectiveness of the traditional and novel treatment options for patients with ITP. [PUBLICATION ABSTRACT]

Teks Lengkap
[[missing key: loadingAnimation]] Immune thrombocytopenic purpura (ITP), previously referred to as idiopathic thrombocytopenic purpura, is an autoimmune disease, characterized clinically by a platelet count <100 000/L without any another explanation. ITP is a disease of adults (>18 years) and children (18 years), although the two diseases are different in duration and prognosis. This paper will focus on the pathogenesis and treatment of ITP in children. ITP affects approximately 3/100 000 children each year worldwide.[1] Most will experience a brief course of thrombocytopenia, with or without bleeding, and will recover completely within 12 months. The International Working Group Consensus reclassified ITP into three groups. ITP cases within the first 3 months from presentation are classified as 'newly diagnosed' and those lasting from 3 to 12 months are classified as 'persistent'.[2] These classifications account for about 80% of patients with childhood ITP.[2]

Approximately 20% of affected children develop chronic ITP,[3] defined as a platelet count of <100 000/L lasting for 12 months or more. The platelet count generally improves over time, even in children with chronic ITP;[4] however, the decision to treat the child between onset and resolution of ITP can be challenging. In this review we will catalog the available treatments for acute and chronic ITP, and relate their mechanism of action to the pathophysiology of the disease. When the published literature does not provide clear therapeutic strategies for ITP, we will share the experience of therapies administered at our institution. 1. Pathogenesis The pathogenesis of ITP was first described by Harrington in 1951. He infused plasma from a patient with ITP into himself and later other adult volunteers, and monitored platelet response. He found that within 24 hours of plasma infusion, platelet counts plummeted to those seen in ITP patients.[5] Subsequent studies showed that the offending component in the plasma of ITP patients was an immunoglobulin (Ig) G antibody[6] with specificity for epitopes such as GPIb/IX and GPIIb/IIIa on the platelet surface.[7] The antibody activity in ITP may not be directed solely against platelets and may activate the Fc-receptor bearing mononuclear cells of the spleen (and other tissues of the mononuclear phagocyte system), resulting in increased platelet phagocytosis and destruction.[8] Antiplatelet antibodies may also fix complement leading to increased platelet lysis and phagocytosis.[8-10] Adults may have chronic or relapsing disease, and, in contrast, most children have a self-limited course wherein about 80% recover within 1 year.[11] The concept of 'antigenic mimicry' in response to a viral infection may account for the marked but relatively brief duration of childhood immune-mediated thrombocytopenia. Similarity of epitopes on the viral surface to the epitopes, IIb/IIIa, Ib, or others, on the platelet produce a B-lymphocyte response with IgG antibody production that binds to platelets by a cross-reaction, resulting in platelet removal and an acute fall in the patient's platelet count. Resolution of the viral infection is facilitated by the antiviral antibody response. In time, the virus is eliminated and the primary stimulus for antibody production is removed. The half-life of IgG is approximately 3 weeks and the titer of antibody gradually decreases, followed by recovery of the platelet count, accounting for the clinical course of ITP in most children.[12] The persistence of platelet destruction in approximately 20% of children and the majority of adults is likely related to alterations of T-lymphocyte regulation. T-lymphocyte defects have been documented in patients with ITP[13] and a much clearer picture of the T-cell role in the pathogenesis of the disorder has emerged.[14] Probably the major underlying defect in the autoimmune pathogenesis of ITP lies in decreased activity of T-regulatory cells (Tregs), as indicated by decreased suppression of CD4 +CD25- cells by CD4+CD25+ Tregs,[15] as well as by

decreased blood levels of Th2 cells and Tc2 cells.[16] These alterations are thought to reduce selftolerance and facilitate autoimmune platelet destruction (figure 1). Fig. 1 Diagram outlining the major lymphocyte abnormalities in patients with chronic immune thrombocytopenic purpura, which is related to T-cell dysfunction. (1) Defective T-regulatory cells (Tregs) are deficient, defective and/or non-functional, which leads to a break in immune tolerance. This abnormality allows for (2) platelet auto-antigens to be presented by macrophages to autoreactive CD4+ T-helper cells, which subsequently mediate a series of abnormal cellular processes such as (3) autoreactive effector cell responses, e.g. antiplatelet and/or megakaryocytespecific autoantibodies and CD8+ cytotoxic T lymphocyte (CTL) responses which produce thrombocytopenia (adapted from Semple et al.,[14] with permission). APC = antigen presenting cell. [Figure omitted.] On the other hand, in patients with ITP devoid of platelet autoantibodies, thrombocytopenia can be mediated by CD8+ T cells.[17] In these patients with thrombocytopenia there are blood cytotoxic T lymphocytes (CTL) that bind to and cause significant lysis of platelets in vitro, whereas those patients in remission had little antiplatelet CTL reactivity. This observation was confirmed in a large clinical study.[18] It may be that CTL in patients with chronic ITP are not cleared by normal apoptotic mechanisms and persist to destroy platelets.[19] An animal model of ITP suggests that CTL may enter the marrow and injure megakaryocytes, perhaps leading to a platelet production defect.[20] The production of platelets is also impaired in ITP patients. The megakaryocytes in ITP are abnormal, showing distended demarcation membranes, vacuolated cytoplasm, swollen mitochondria, condensed nuclear chromatin, and disrupted cytoplasmic peripheral zones, occasionally with activated monocytes in the vicinity.[19] In vivo, there is suppression of megakaryocytes in the presence of anti GPIb/IX with or without anti-GPIIb/IIIa antibodies.[19] The activity of antiplatelet antibodies and CTLs[19] leads to megakaryocyte damage, apoptosis, and decreased thrombopoiesis.[8] 2. Treatment Options 2.1 Newly Diagnosed Immune Thrombocytopenic Purpura (ITP) If the platelet count is >10 000/L with minimal signs of bleeding (e.g. slight blood tinge in mucous, brief epistaxis, or mild bleeding on brushing of teeth without identifiable source of bleeding), if there is a reliable caregiver, and the child has not experienced head trauma or taken an antiplatelet agent such as aspirin (acetylsalicylic acid), it is appropriate to monitor the child without pharmacotherapy.[11] Alternatively, if there is significant bleeding (e.g. mucosal, gastrointestinal, urinary, menstrual, or nervous system bleeding) treatment is indicated. In our

view, it is prudent to treat an asymptomatic patient if platelet count is below 10 000/L because the frequency of moderate (e.g. epistaxis or menorrhagia that is troublesome but not requiring hospitalization) to severe (e.g. poorly-controlled epistaxis, melena, or menorrhagia requiring hospitalization) bleeding increases below this threshold;[21] however, some clinicians prefer to observe patients with few symptoms and platelet counts below 10 000/L. Agents available for treatment of newly diagnosed ITP include glucocorticoids, intravenous immunoglobulin (IVIg), and anti-Rhesus (anti-D) immunoglobulin (table I).[16] Table I. Established and novel treatment options for newly diagnosed, persistent, and chronic immune thrombocytopenic purpura (ITP)[superscript] a[/superscript] [Table omitted.] These treatments inhibit platelet binding to the Fc receptors of macrophages and block the removal of antibody-coated platelets. Glucocorticoids may also stabilize the integrity of the blood vessel endothelium. 2.1.1 Glucocorticoids Glucocorticoids are the most cost-effective treatment of acute ITP.[12] The hemoglobin, total and differential white cell count are characteristically normal in patients with ITP. If hemoglobin is low or the white cell or differential counts are abnormal, the patient should be evaluated for an alternative diagnosis, particularly to avoid treating lymphoblastic leukemia with glucocorticoids alone. The usual dosage of prednisone is 2-4 mg/kg/day in two divided doses, administered for no more than 2 weeks, at which time the platelet count is usually >100 000/L. The dose is then rapidly tapered to the minimum required to maintain a platelet level (usually >30 000/L) that renders the patient asymptomatic. It is our institutional practice to change administration of prednisone to once per day and then every other day if the platelet count remains >30 000/L. An alternative prednisone dosing schedule is 4 mg/kg/day for 4 days.[35] This approach reduces the adverse side effects of long-term glucocorticoid treatment. High-dose oral dexamethasone at 20 mg/m2/day for 4 days may be used in lieu of prednisone.[28] The platelet count may respond less rapidly to glucocorticoid therapy than to IVIg or anti-D. Approximately 30% of patients respond in 24 hours and 70% respond in 48 hours with glucocorticoids.[33] Nearly all treated patients responded with an increase in platelet count to over 50 000/L after 1 week of treatment. The presumptive mechanisms of glucocorticoid action involve decreased antibody attachment to macrophage Fc receptors,[36] decreased phagocytosis of platelets by macrophages,[11] stabilization of the vascular endothelium,[37] and inhibition of B-lymphocyte antibody production (longer-term effect).[38]

The side effects of glucocorticoid therapy include gastrointestinal symptoms (a histamine H 2 blocker can be prescribed with prolonged glucocorticoid therapy), impaired glucose tolerance, Cushingoid changes, hypertension, loss of bone density, impaired immunity and impaired growth with long-term treatment, but these are a function of the dose and duration of glucocorticoid use. They are usually not an issue during a few weeks of treatment. 2.1.2 Intravenous Immunoglobulin It is our recommendation that IVIg be used to treat acute ITP when there are contraindications to the use of glucocorticoids, such as glucose intolerance, hypertension, or intestinal ulceration, or at the preference of the therapist. Its use rapidly increases the platelet count in approximately 75% of patients in 24 hours.[30] It should be administered slowly at a single dose of 0.8-1.0 g/kg. The specific mechanism of action remains unknown, but it presumably blocks phagocytosis and destruction of antibody-coated cells. IVIg contains anti-A, anti-B and potentially anti-D that may coat red cells with the corresponding antigens, blocking Fc receptors on macrophages via mass action in a fashion similar to anti-D (WinRho

) [see section 2.1.3]. It may also reduce the affinity

of macrophage low affinity Fc receptor types (FcRIIA and FcRIIIA) in binding the Fc portion of the antibody molecule[11] and/or enhance inhibitory receptors (FcRIIB).[39] Antigen-presenting dendritic cells modulate the upregulation of the inhibitory receptors.[39] In our institution, the use of IVIg requires hospitalization, making it a more intrusive and expensive procedure than the use of glucocorticoids. Adverse events such as headache, fever, nausea and vomiting, allergic reactions, aseptic meningitis, and severe hemolysis and renal failure have been reported in children, and thrombosis has been reported in adults.[40] Headache, in particular, is a troublesome complication in a thrombocytopenic patient because of concern about potential intracranial hemorrhage. Such patients require computerized tomographic imaging of the head to evaluate this possibility. Headache and other side effects can be reduced by pretreatment with acetaminophen (paracetamol) and diphenhydramine, and by prolonging the duration of the infusion to 6-8 hours or longer. 2.1.3 Anti-D Anti-D (WinRho) is an alternative to the use of IVIg and may be chosen for the treatment of ITP if the patient is Rhesus D positive or has had a severe reaction to IVIg. It is administered intravenously at either 50 or 75 g/kg during a 20-minute infusion. Response is somewhat more rapid at the higher dose, with 70% of patients treated with 75 g/kg (vs 50% of patients treated with 50 g/kg) experiencing an increase in platelet count above 20 000/L within 24 ho urs.[30] The mechanism of action of this agent is related to the very high ratio of red cells to platelets. When the red cells are coated with immunoglobulin (anti-D), they saturate the Fc receptor sites of

macrophages, particularly in the spleen and liver, preventing binding of the IgG-coated platelets. In most circumstances, the coated platelets remain functional in the circulation. The complications are similar to those seen with the use of IVIg, but headache is a less prominent problem. A fall in hemoglobin concentration of 1-2 g/dL is an expected consequence of treatment.[41] Fever, chills, nausea, and vomiting may occur and may be decreased by premedication, as with IVIg. Severe hemolysis with renal failure may follow treatment with anti-D, and observation for at least 8 hours following infusion is now required.[41] Similar to the use of IVIg, in our institution this hospitalization increases the cost of therapy in contrast to glucocorticoids. 2.2 Persistent or Chronic ITP The Associazione Italiana di Ematologia e Oncologia Pediatrica (AEIOP) indicates the use of either methylprednisolone (15-30 mg/kg/day intravenously for 3 days), IVIg, or anti-D for first-line therapy for emergent chronic childhood ITP treatment.[42] Second- and third-line therapy for persistent and chronic ITP includes agents such as rituximab, thrombopoietin receptor agonists, splenectomy, and, less commonly, azathioprine, cyclosporin (cyclosporine; ciclosporin), cyclophosphamide, danazol, dapsone, mycophenolate mofetil, and vinca alkaloids;[42] however, danazol and dapsone have not been approved for use in children. 2.2.1 Rituximab Rituximab is an anti-CD20 antibody that depletes B cells for as long as 12-18 months.[43] It induces a long-term therapeutic response (increase in platelet count over 150 000/L) in a subset of patients with chronic ITP, although only half of treated adult patients have an increase in platelet count to that level, and about one-third of patients have a sustained response off therapy.[8] The modest long-term response to rituximab may be related to the fact that CD20 is present on mature antibody-producing B-lymphocytes, but is not an epitope present on B-cell precursors. Responding patients who are retreated after relapse have a 75% response rate. Overall, the response rate is lower than that produced by splenectomy, which is approximately 70%.[29] Rituximab can exacerbate systemic lupus erythematosus or reactivate the disease in carriers of hepatitis B.[8] Rituximab should be avoided in patients with immune dysfunction, since severe, potentially fatal, viral infections can occur. There is no need for concomitant administration of IVIg in patients without underlying immunocompromise.[44] Approximately 30% of children with chronic ITP responded to four doses of weekly rituximab with platelet counts >50 000/L. Multiple studies show that approximately one -third of children with chronic ITP have a continuous response off therapy, usually after receiving 4 weekly doses of 375 mg/m
2

intravenously.[31] Rituximab works best for children when they have not been

splenectomized.[45] Adverse events include infusion reactions, serum sickness, acute or delayed neutropenia, and reactivation of chronic infections (e.g. hepatitis B).[27,44,46] Rituximab has a sustained effect in children with chronic ITP as long as 1 year after therapy has been discontinued, although there are some children who will relapse after several months of normal platelet counts.[47] 2.3 Newer Therapies for Chronic ITP 2.3.1 Rozrolimupab Rozrolimupab (Sym001) is a target-specific recombinant polyclonal antibody against RhD. It competitively inhibits phagocytosis of platelets in the mononuclear phagocyte system. Its utility is currently being tested in Europe in adults with chronic ITP.[48] 2.3.2 Fostamatinib Fostamatinib (R788) is an orally available prodrug of the Syk tyrosine kinase inhibitor. It inhibits the Syk kinase-mediated IgG Fc receptor and consequently diminishes B-cell, macrophage, and mast-cell activity.[49] It has been used in a therapeutic trial in adults at a dose of 75-175 mg twice daily. Initial data suggest a 50% dose-dependent response rate, although it is not yet approved for this use.[26] 2.3.3 Thrombopoietin Receptor Agonists Early data published by Dameshek and Miller[50] in 1946 suggested that platelet production by megakaryocytes was diminished in both acute and chronic ITP when compared with normal marrow or marrow from patients with hypersplenism. Data also indicate that the plasma from patients with ITP suppresses megakaryocyte proliferation in vitro.[51] These observations suggest that stimulation of platelet production may be a viable treatment option for patients with chronic ITP. Two non-antigenic thrombopoietin receptor agonists, romiplostim (Nplate

, Amgen) and

eltrombopag (Promacta, GlaxoSmithKline), increase thrombopoiesis and platelet counts in patients with chronic ITP. These new agents are being tested in children but have proven both safe and effective in a number of adult trials.[24,25,52-54] Recombinant thrombopoietin was also studied. It was ineffective because of the development of antithrombopoietin antibodies, neutralizing its effect.[8] 2.3.4 Romiplostim Romiplostim is a fusion product of an Fc fragment and a thrombopoietin mimetic peptide, termed a 'peptibody'. It binds to the thrombopoietin receptor (figure 2) and activates the Janus kinase

(JAK), signal transducers and activators of transcription (STAT) and mitogen-activated protein (MAP) kinase enzymatic pathways, which result in increased platelet production.[56] It has no sequence homology with thrombopoietin and has not elicited an immunologic reaction and antibody production.[54] It is administered parenterally at a dose of 1-10 g/kg once weekly and has produced a platelet count above 50 000/L in approximately 80% of treated patients.[57] Marrow fibrosis developed in a small percentage of treated patients. Other unsubstantiated concerns include thrombosis, stimulation of tumor growth, antibody generation, and platelet activation. Improved platelet counts are generally not sustained off romiplostim. The long-term risks of its use have not yet been established. Fig. 2 Description of romiplostim activation of the Janus kinase (JAK), signal transducers and activators of transcription (STAT), and mitogen-activated protein kinase (MAPK) pathways of signal transduction to increase platelet production. Romiplostim activates the thrombopoietin receptor (adapted from Gernsheimer,[55] with permission). AK1 = adenylate kinase 1; ERK = extracellular signal-related kinase; GRB2 = growth factor receptor-bound protein 2; P = phosphate; SHC = Src homology 2 (SH2) domain-containing adapter protein; SoS = son of sevenless. [Figure omitted.] 2.3.5 Eltrombopag Eltrombopag is a small molecule in comparison with romiplostim (59 kDa, compared with a molecular weight of 442 Da). Eltrombopag is orally bioavailable and is effective with a once-daily dose of 25-75 mg/day.[25] It does not bind directly to the thrombopoietin receptor, but rather traverses the receptor to bind in the transmembrane region[25] (figure 3). Its signal transduction differs from that of romiplostim because there is much less activation of the STAT family of signal transducers and no activation of the AK1 pathway.[58] However, the impaired platelet production characteristic of chronic ITP is improved with its use, and clinical studies indicate that platelet counts >50 000/L can be produced in chronic ITP patients for more than 1 year if the drug is continued.[59] Moreover, the eltrombopag stimulatory effect is additive to the effect of thrombopoietin in vitro.[60] A number of phase III clinical trials, including the RAndomized placebo-controlled Idiopathic thrombocytopenic purpura (ITP) Study with Eltrombopag (RAISE) study[52] and the Kuter et al.[54] study, have substantiated the effectiveness of eltrombopag in treating chronic ITP. The concerns about adverse reactions with this agent are similar to those for romiplostim noted in section 2.3.4, and the long-term adverse effects have not been established. Fig. 3 Description of eltrombopag activation of the Janus kinase (JAK), signal transducers and activators of transcription (STAT), and mitogen-activated protein kinase (MAPK) activation of signal transduction to increase platelet production. Eltrombopag activates the same receptor as romiplostim, at the transmembrane region of the receptor; however, its signal transduction differs from that of romiplostim (see section 2.3.4) [adapted from Gernsheimer,[55] with permission].

ERK = extracellular signal-related kinase; GRB2 = growth factor receptor-bound protein 2; P = phosphate; SHC = Src homology 2 (SH2) domain-containing adapter protein; SoS = son of sevenless. [Figure omitted.] 2.3.6 AKR-501 AKR-501 (E5501) is a new thrombopoietin receptor agonist that has not yet been approved for clinical use. It is a small molecule that appears more potent than eltrombopag, and it stimulates growth of thrombopoietin-dependent megakaryocyte cell lines.[61] It causes a dose-dependent increase in platelet count in healthy humans.[22,62] 2.4 Other Therapies for Chronic ITP 2.4.1 Splenectomy If the spleen is the major site of platelet destruction in ITP, an improvement in platelet count is often sustained after splenectomy. However, if other organs of the mononuclear phagocytic system, such as the liver and marrow, are major sites of platelet removal, the effectiveness of splenectomy may be compromised. Two-thirds of adult patients having a splenectomy for chronic ITP have resolution of their thrombocytopenia,[19] although this response can be time-limited, and patients may have a recurrence within the following 4-9 years.[27] Data for children are similar, with a response rate as high as 86% after splenectomy,[29] of whom 70% have durable responses. However, splenectomized children have heightened susceptibility to infection with encapsulated bacteria and an increased risk of fatal sepsis.[27] The younger the child, the more substantial is the risk of this complication, particularly for those children under 6 years of age. The use of pneumococcal, meningococcal, and hemophilus influenza vaccines several weeks prior to splenectomy plus chronic administration of prophylactic antibiotics, usually penicillin, reduce but do not eliminate this complication. 2.4.2 Vincristine Vincristine is a vinca alkaloid that has been used to block phagocytosis of platelets by mononuclear phagocytes.[11] It may be used both as a single agent[34] or as part of combination therapy.[63,64] When used as a single agent, 12 of 21 patients responded with platelet counts over 50 000/L for 2-24 months. No lasting responses were seen.[34] In combination with IVIg and glucocorticoids, 75% of patients respond to therapy with an increase in platelet counts of at least 30 000/L.[63] Vincristine has also been given in weekly doses in combination with weekly methylprednisolone and twice-daily cyclosporin. In this study, vincristine and methylprednisolone were given to children with chronic ITP as induction agents, followed by continuation of cyclosporin

for 3-6 months. Seven of the ten children treated had continued complete responses, attaining remission for a median of 13 months, and one had a partial response for 3 months.[64] 2.4.3 Mycophenolate Mofetil Mycophenolate mofetil is a prodrug of mycophenolic acid, an inhibitor of inosine monophosphate dehydrogenase, an important enzyme in purine synthesis, especially in proliferating T and B lymphocytes,[32] and thus its inhibition suppresses B-lymphocyte function and antibody production as well as T-lymphocyte-mediated cytotoxic activities. It is likely this effect is the mechanism for the decrease in immune platelet destruction. Nine children with chronic ITP secondary to autoimmune lymphoproliferative syndrome were treated with mycophenolate mofetil 600 mg/m
2

orally twice daily for up to 240 weeks. Of these patients, all had increased platelet

counts of at least 20 000/L, which were sustained responses, altho ugh mycophenolate mofetildependent. Side effects included headache and stomach pain.[32] Another study, conducted in China in 20 patients, one of whom was a child with refractory ITP, showed nine sustained responses with mycophenolate mofetil at 1.5-2 g/day for 1-4 months.[65] The only other reported study, except case reports, examined responses to mycophenolate mofetil 750 mg/day in 18 patients with chronic ITP, one of whom was a child, and showed a mycophenolate mofetildependent sustained response in seven patients, including the child.[66] 2.5 Other Considerations In adults, studies have shown that chronic ITP associated with Helicobacter pylori infection of the stomach can be improved after treatment with antimicrobials. H. pylori appears to have epitopes with similarity to those on platelets that, by 'molecular mimicry', results in platelet destruction.[8] Treatment of H. pylori in children produces varying results. In Italy, a prospective trial of H. pylori eradication for children infected with H. pylori who had ITP for at least 12 months showed an improvement in platelet counts when compared with matched patients without H. pylori infection.[67] However, in Thailand, a randomized controlled study did not show any difference in resolution of chronic ITP in children treated for H. pylori infection.[68] 2.6 Combination Therapies Many combination therapies have been reported in adult patients with chronic ITP, although the published data on these combinations in pediatric patients are few. However, many combinations include a glucocorticoid and a second therapy (such as IVIg, anti-D, or rituximab).[8,69] Other combination therapies attempted in adults include weekly vincristine and methylprednisolone combined with oral daily cyclosporin. This therapy achieved a complete, sustained response in seven of ten adolescent patients.[64] Another combination tested included methylprednisolone, IVIg, and either anti-D or vincristine for acute control followed by azathioprine and danazol orally

as maintenance therapy. These combination therapies were effective at inducing increased platelet counts in 71% of patients, and long-term, therapy-dependent responses to maintenance therapy were seen in two-thirds of treated patients.[63] 3. Conclusions Figure 4 shows the therapy options for children who present with ITP. If the platelet count is >10 000/L and the patient has minimal bleeding, a 'watch and wait' strategy is appropriate.[11] If therapy is indicated because of bleeding or a platelet count <10 000/L, then glucocorticoids, IVIg, or anti-D (if patient is RhD positive) are possible choices. These therapies may be repeated safely if the patient relapses. If the disease becomes 'persistent' with severe thrombocytopenia and/or bleeding, and is no longer responsive to the first-line therapies, the second-line of medications, including thrombopoietin receptor agonists or rituximab, may be considered. When the disease becomes chronic and remains symptomatic, it may become necessary to consider third-line therapies (splenectomy, alternative immunosuppression, or investigative chemotherapy). Fig. 4 Algorithm for the management of ITP. When a patient is seen with newly diagnosed immune thrombocytopenic purpura (ITP), treatment is only necessary if they have severe hemorrhage or a platelet count <10 000/L. Otherwise, watchful waiting with weekly blood counts is adequate management. If the patient has hemorrhage in excess of scattered petechiae and/or minor bruising, or has a platelet count <10 000/L, treatment with glucocorticoids is suggested, as outlined in the text, after evaluation of the blood counts and blood film to minimize the possibility of an alternate diagnosis, such as thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, or incipient acute leukemia. Alternatively, intravenous immunoglobulin (IVIg) or anti-D may be used as initial therapy. This is our preferred sequence of management because it is affordable and effective, but some institutions prefer IVIg or anti-D for initial therapy. These treatments can be repeated for bleeding or a platelet count <10 000/L. If the patient develops persistent or chronic ITP and is no longer responsive to these therapies, then the thrombopoietin receptor agonists, such as romiplostim or eltrombopag, may be used. If these newer treatments are ineffective, rituximab may be used. We prefer that the thrombopoietin receptor agonists be used first because of the toxicities of rituximab. If the child is more than 6 years of age and the preceding therapies fail, splenectomy can be considered after immunization against encapsulated organisms (pneumococcus, meningococcus, and Hemophilus influenza). Splenectomy in younger patients may be carried out but there is a greater risk of post-splenectomy sepsis. If splenectomy does not produce a sustained platelet response, a repeat trial of glucocorticoids, IVIg, and anti-D, or the alternative therapies, may be attempted. 1 Severe hemorrhage - epistaxis, mucosal bleeding, gastrointestinal bleeding, genitourinary or nervous system bleeding. 2 The choice among glucocorticoids, IVIg, and anti-D (for Rh+ patients) for first-line therapy is controversial. The algorithm reflects the authors' preference. RhD = rhesus D. [Figure omitted.]

These recommendations are largely consistent with the recently published recommendations by the American Society of Hematology,[70] except for our preference to use thrombopoietin receptor agonists before rituximab in persistent disease because of the toxicity of rituximab. Acknowledgments A.L. Bredlau and G.B. Segel conceived and wrote the manuscript. J.W. Semple was instrumental in describing the pathophysiology of ITP and in designing the relevant figure. No authors received funding for this review. No conflicts of interest were present for any of the authors. We thank Marshall A. Lichtman, MD, for his helpful review. References 1. Terrell DR, Beebe LA, Vesely SK, et al. The incidence of immune thrombocytopenic purpura in children and adults: a critical review of published reports. Am J Hematol 2010 Mar; 85 (3): 17480. 2. Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood 2009 Mar 12; 113 (11): 2386-93. 3. Zeller B, Rajantie J, Hedlund-Treutiger I, et al. Childhood idiopathic thrombocytopenic purpura in the Nordic countries: epidemiology and predictors of chronic disease. Acta Paediatr 2005 Feb; 94 (2): 178-84. 4. Imbach P, Kuhne T, Muller D, et al. Childhood ITP: 12 months follow-up data from the prospective registry I of the Intercontinental Childhood ITP Study Group (ICIS). Pediatr Blood Cancer 2006 Mar; 46 (3): 351-6. 5. Sprague CC, Harrington WJ, Lange RD, et al. Platelet transfusions and the pathogenesis of idiopathic thrombocytopenic purpura. J Am Med Assoc 1952 Nov 22; 150 (12): 1193-8. 6. Shulman NR, Marder VJ, Weinrach RS. Similarities between known antiplatelet antibodies and the factor responsible for thrombocytopenia in idiopathic purpura: physiologic, serologic and isotopic studies. Ann N Y Acad Sci 1965 Jun 30; 124 (2): 499-542. 7. Luiken GA, McMillan R, Lightsey AL, et al. Platelet-associated IgG in immune thrombocytopenic purpura. Blood 1977 Aug; 50 (2): 317-25. 8. Psaila B, Bussel JB. Refractory immune thrombocytopenic purpura: current strategies for investigation and management. Br J Haematol 2008 Oct; 143 (1): 16-26.

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67. Russo G, Miraglia V, Branciforte F, et al. Effect of eradication of Helicobacter pylori in children with chronic immune thrombocytopenia: a prospective, controlled, multicenter study. Pediatr Blood Cancer 2011 Feb; 56(2): 273-8. 68. Treepongkaruna S, Sirachainan N, Kanjanapongkul S, et al. Absence of platelet recovery following Helicobacter pylori eradication in childhood chronic idiopathic thrombocytopenic purpura: a multi-center randomized controlled trial. Pediatr Blood Cancer 2009 Jul; 53 (1): 72-7. 69. Zaja F, Baccarani M, Mazza P, et al. Dexamethasone plus rituximab yields higher sustained response rates than dexamethasone monotherapy in adults with primary immune thrombocytopenia. Blood 2010 Apr 8; 115 (14): 2755-62. 70. Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidencebased practice guideline for immune thrombocytopenia. Blood 2011 Mar; 117 (16): 4190-207. AuthorAffiliation 1. Amy Lee Bredlau, Department of Pediatrics, Division of Hematology/Oncology, University of Rochester, Rochester, NY, USA 2. John W Semple, Keenan Research Centre, Li Ka Shing Knowledge Institute of St Michael's Hospital, Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada 3. George B Segel, Departments of Pediatrics and Medicine, Division of Hematology/Oncology, University of Rochester, Rochester, NY, USA Correspondence: Dr Amy Lee Bredlau, MD, University of Rochester, Box 777, 601 Elmwood Avenue, Rochester, NY 14642, USA. E-mail: amy-lee_bredlau@urmc.rochester.edu Jumlah kata: 6579 Copyright Wolters Kluwer Health Adis International Aug 2011

Pengindeksan (detail)
Kutip MeSH Animals, Child, Drug Costs, Glucocorticoids -- economics, Humans, Immunoglobulins, Intravenous -- adverse effects, Immunoglobulins, Intravenous -- immunology, Isoantibodies -- economics, Isoantibodies -- immunology, Isoantibodies -- therapeutic use, Platelet Count, Purpura, Thrombocytopenic, Idiopathic -- immunology, Splenectomy -- methods, Glucocorticoids -therapeutic use (utama), Immunoglobulins, Intravenous -- therapeutic use (utama), Purpura, Thrombocytopenic, Idiopathic -- therapy (utama) Substansi

Glucocorticoids; Immunoglobulins, Intravenous; Isoantibodies; RHO(D) antibody Pengidentifikasi/kata kunci Children; Glucocorticoids; Immune-globulin; Immune-thrombocytopenic-purpura; Immunosuppressants; Rituximab; Thrombopoietin-receptor-agonists. Judul Management of Immune Thrombocytopenic Purpura in Children Pengarang Bredlau, Amy Lee; Semple, John W; Segel, George B Judul publikasi Paediatric Drugs Volume 13 Edisi 4 Halaman 213-23 Jumlah halaman 11 Tahun publikasi 2011 Tanggal publikasi Aug 2011 Tahun 2011 Penerbit Wolters Kluwer Health Adis International Tempat publikasi Auckland Negara publikasi United Kingdom Subjek publikasi Medical Sciences--Pediatrics, Pharmacy And Pharmacology ISSN 11745878 Jenis sumber Scholarly Journals Bahasa publikasi English Jenis dokumen Leading Article, Journal Article DOI http://dx.doi.org/10.2165/11591640-000000000-00000 Nomor aksesi 21692546 ID dokumen ProQuest 872833637 URL Dokumen http://search.proquest.com/docview/872833637?accountid=50673 Hak cipta Copyright Wolters Kluwer Health Adis International Aug 2011 Terakhir diperbarui

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