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http://search.proquest.com/docview/872833637/13FD8EF28F33C5C3989/9?accountid=50673

Management of Immune Thrombocytopenic Purpura in Children

Bredlau, Amy Lee

Tekan tombol Escape untuk menutup;Semple, John W ;Segel, George B .Paediatric Drugs

13.4 (Aug 2011): 213-23.

Aktifkan sorotan temuan untuk peramban bicara

Abstrak (ringkasan)

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The treatment of immune thrombocytopenic purpura (ITP) in children is controversial, requiringindividualized 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 appropriatesince most children with ITP will recover completely without pharmacotherapy. If therapy isindicated because of bleeding or a platelet count

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Approximately 20% of affected children develop chronic ITP,[3] defined as a platelet count of

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decreased blood levels of Th2 cells and Tc2 cells.[16] These alterations are thought to reduce self-

tolerance 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 megakaryocyte-

specific 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

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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]

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The side effects of glucocorticoid therapy include gastrointestinal symptoms (a histamine H2

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 anddestruction 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 hours.[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

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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

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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

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(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].

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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

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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, although mycophenolate mofetil-dependent. 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 mofetil-

dependent 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

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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

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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.

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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: 6579Copyright 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

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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 InternationalTempat publikasi

Auckland

Negara publikasi

United Kingdom

Subjek publikasi

Medical Sciences--Pediatrics,Pharmacy And Pharmacology

ISSN

11745878

Jenis sumber

Scholarly Journals

Bahasa publikasi

EnglishJenis 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 2011Terakhir diperbarui

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2013-02-21

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