Childhood Immune Thrombocytopenic Purpura: Diagnosis and Management

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Immune thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by a low circulating platelet count caused by destruction of antibody-sensitized platelets in the reticuloendothelial system. ITP can be classified as childhood versus adult, acute versus chronic, and primary versus secondary. Persistence of thrombocytopenia defines the chronic form of the disorder. Secondary causes of ITP include collagen vascular disorders, immune deficiencies, and some chronic infections. This review focuses on the diagnosis and management of children who have acute and chronic ITP. Emphasis is placed on areas of controversy and new therapies.

Section snippets

Pathophysiology

The pathophysiology of ITP increasingly is understood better (reviewed by Cines and Blanchette [1]). Not surprisingly, it is complex with involvement of many players in the human immune orchestra, including antibodies, cytokines, antigen-presenting cells, costimulatory molecules, and T and B lymphocytes (including T-helper, T-cytotoxic, and T-regulatory lymphocytes). Current knowledge is summarized later.

A key element in the pathophysiology of ITP is loss of self tolerance leading to the

Differential diagnosis

Primary ITP is a diagnosis of exclusion. The question, “When does a low platelet count not mean ITP?” is important, especially for atypical cases. When an unexpected low platelet count in a child is obtained, artifact or laboratory error should be considered first and excluded. Pseudothrombocytopenia is an example of spurious thrombocytopenia that is caused by platelet aggregation and clumping in the presence of ethylenediamine tetraacetic acid (EDTA) anticoagulant [9]. Examination of

Clinical and laboratory features

Thrombocytopenia for less than 6 months defines the entity acute ITP. Typically, children who have acute ITP are young, of previous good health, and present with sudden onset of bruising or a petechial rash. In a series of 2031 children who had newly diagnosed ITP, reported by Kühne and colleagues [12] in 2001 for the Intercontinental Childhood ITP Study Group (ICIS), the mean age at presentation was 5.7 years. Approximately 70% of the cohort were children ages 1 to 10 years with 10% of the

Observation

The case for observation of children who have acute ITP rests with the knowledge that acute ITP is, for the majority of affected children, a benign self-limiting disorder, usually with mild clinical symptoms and has a low risk for serious bleeding (approximately 3% with ICH being rare) and the fact that there are no prospective studies that clearly indicate a decrease in the incidence of ICH associated with treatment [32]. Several children who had ITP-associated ICH were receiving

To perform a bone marrow aspirate or not

There is consensus that bone marrow aspiration is not necessary for children who have newly diagnosed typical acute ITP if management involves observation or plasma based therapies, such as IVIG or anti-D. The contentious issue is whether or not a bone marrow aspirate should be performed in children who have typical acute ITP before starting corticosteroids to avoid missing, and therefore treating inappropriately, an underlying leukemia. The results of a retrospective study of bone marrow

To hospitalize or not

The majority of children who have newly diagnosed acute ITP and platelet counts less than 20 × 109/L are hospitalized. The figure was 83% in the first United Kingdom National Survey [14] and 78% of 1995 children who had newly diagnosed ITP reported by Kühne and colleagues [12] on behalf of the ICIS. This high hospitalization rate is driven by the decision to treat and the perceived need for a bone marrow aspirate before starting corticosteroid therapy. If a conservative management approach is

Chronic immune thrombocytopenic purpura

Conventionally, chronic ITP is defined as thrombocytopenia (platelet count less than 150 × 109/L) persisting for longer than 6 months from the onset of illness. Using this definition, approximately 20% to 25% of children manifest chronic ITP at 6 months after the initial diagnosis of ITP. Many children who have platelet counts in the range of 30 to 150 × 109/L, however, require no platelet-enhancing therapy and some enter a spontaneous complete remission in the 6 to 24 months after initial

Presplenectomy management

Medical management is preferred over splenectomy for children who have chronic ITP for less than 12 months. Treatment options include oral corticosteroids (including pulse oral dexamethasone), IVIG, and IV anti-D (reviewed by Blanchette and Price [56]). Avoidance of medications known to affect platelet function adversely, especially aspirin, should be stressed and high-risk competitive or contact activities should be avoided during periods of severe thrombocytopenia. The goal should be to

Protection against overwhelming postsplenectomy infection

Before elective splenectomy, children who have ITP should be immunized with the hemophilus influenza type b and pneumococcal vaccines; depending on their age and immunization history, meningococcal vaccine also is recommended [66]. Because the protection provided after immunization is incomplete (not all pneumococcal serotypes are included in the currently available vaccines), daily prophylaxis with penicillin, or an equivalent antibiotic if the child is allergic to penicillin, is recommended

Emergency treatment

On rare occasions, children who have acute ITP and severe thrombocytopenia may manifest symptoms or signs suggestive of organ- or life-threatening hemorrhage (eg, ICH). Management of such cases is challenging and should involve measures that have the potential to increase the circulating platelet count rapidly. An approach commonly used involves the immediate IV administration of methylprednisolone (30 mg/kg, maximum dose 1 g) over 20 to 30 minutes plus a larger than usual (two- to threefold)

Combined cytopenias

The combination of ITP and clinically significant autoimmune hemolytic anemia (Evans's syndrome) or autoimmune neutropenia occurs in a minority of cases [69], [70], [71], [72], [73]. Affected children often are older than those who present with typical acute ITP. The clinical course is variable and often prolonged with significant morbidity and mortality reported in retrospective series (Table 3). Response to single-agent therapy or splenectomy often is poor [74]; combination immunosuppressive

New therapies

First-line therapies in children include corticosteroids, high-dose IVIG, and, for children who are rhesus positive, IV anti-D. Splenectomy is the traditional second-line treatment of those children who have well-established, symptomatic chronic ITP who have failed or are intolerant of first-line therapies. An array of third-line therapies is available for children in whom splenectomy is refused or contraindicated. Agents include azathioprine, cyclophosphamide, danazol, vinca alkaloids,

Future directions

Although much has been learned about the pathogenesis and treatment of ITP over the past 3 decades, many questions remain unanswered. Optimal management of children who have newly diagnosed acute ITP and platelet counts less than 20 × 109/L remains the subject of debate and there is an urgent need for a well-designed large trial to address the issues of to treat or not, to perform a bone marrow aspirate or not, and whether or not to hospitalize such children. Experience from the United Kingdom

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