Primary immune thrombocytopenia (ITP) in children has an incidence of 5 in 100,000. It is seen most frequently in patients one to seven years of age, making it an important cause of morbidity in children and a significant burden of anxiety to parents, caregivers and older children. Rapid diagnosis, sensible care plans and education on the course of this disease will allay the fears of the child and family. This highlights the need for a homogenised approach to the management, which has been elusive. Efforts over the past decade have increased our knowledge in the pathophysiology and treatment of ITP in adults and children.1
Despite childhood ITP being a common disorder, historically there have been inconsistencies in the classification and treatment. There remains a wide variation in clinical practice concerning its diagnosis and management. Earlier guidelines made efforts to standardise the approach; however, these have been contradictory in some aspects, making management of these children challenging, particularly for the general paediatrician.2
Publications over the last few years have heralded major guidelines with the vision of overcoming these shortfalls. This is exemplified by a number of recent, pertinent papers. The International Working Group consensus panel of both adult and paediatric experts in ITP recently provided guidance on terminology, definitions, outcome criteria and treatment for this disorder.3 In 2011, the American Society for Hematology published an evidence-based practice guideline in view of recent advances in the treatment of ITP.4
This article will consider primary ITP in the paediatric population with a focus on recent updates in the nomenclature, classification and management. The aim is to update on the current management of ITP based around these guidelines and provide an insight into our experience as a large tertiary hospital that runs an expert regional ITP clinic and deals with tertiary referrals of complex cases.
Diagnosis
The diagnosis for children with suspected ITP is a presumptive one, made by excluding other causes. The history, physical examination, full blood count and examination of the blood film are key factors and often no further investigation is required. There is no ‘gold standard’ test but it is important to revisit the diagnosis if there is failure of spontaneous recovery or failure after treatment.
History
- In approximately 60% of children, there is a history of a preceding infection5
- An increased risk of ITP is associated with measles–mumps–rubella (MMR) vaccination but may be observed after any vaccination
- The possibility of abuse must be considered when dealing with a young child who presents with bruising and purpura for the first time in the absence of thrombocytopenia
- Children with infections such as meningococcal sepsis usually have other systemic features that help rapidly differentiate from ITP
- A history of bone pain, especially in the presence of additional cytopenia should raise concern about marrow infiltration.
In a young child this may be the first presentation for an inherited thrombocytopenia (Table 1).6
Physical examination
Bleeding manifestations should be the only clinical finding on physical examination. Splenomegaly is often described in the literature but this is uncommon in our practice. Height and weight should be plotted on appropriate growth charts and abnormal facies or skeletal anomalies noted and documented; these may provide a clue to an underlying unifying diagnosis of a congenital thrombocytopaenia. Lethargy is a feature that is becoming more readily recognised in association with ITP, and it is important to acknowledge and reassure carers.
Investigations
Peripheral blood count
Isolated thrombocytopenia is characteristic. Over 80% of children will present with a platelet count of <20 x 109/l; therefore a count greater than this should raise the suspicion of other causes.
Other useful tests include:
- Direct anti-globulin test (DAT)
- Immunoglobulins (IgGs)
- Reticulated platelet count (often high in ITP)
- Hepatitis and HIV screening in high-risk countries.
A positive DAT may suggest an underlying diagnosis of Evans syndrome. Baseline immunoglobulins should be considered in children with ITP and in those with persistent or chronic ITP as part of their reassessment. Low levels may indicate common variable immunodeficiency (CVID) or selective IgA deficiency.7 The reticulated platelet count can often help differentiate between aplastic anaemia and ITP. These tests should be performed prior to any treatment as the results may be affected.
Evaluation of blood film
Evaluation by an experienced haematologist is a vital step in making the diagnosis. Findings may reveal abnormalities that do not fit with ITP, such as red cell fragmentation suggesting thrombotic thrombocytopenic purpura (TTP) or haemolytic uremic syndrome (HUS), or leukocyte inclusion bodies as in MYH9-related disease. Excessive numbers of giant or small platelets may indicate an inherited thrombocytopenia. Pseudo-thrombocytopenia due to ethylenediamine-tetra acetic acid (EDTA)-dependent platelet agglutination should also be excluded.
Bone marrow examination (BMA)
BMA has an important role; however, routine BMA is not necessary for children with typical acute ITP. It should not be a part of routine work-up for diagnosing ITP in children and should be reserved for those having atypical clinical and laboratory features. It is indicated in those with:
- An atypical presentation (for example, abnormalities observed on peripheral blood smear suggestive of other haematological disorders)
- Additional cytopenia that cannot be readily explained
- Refractoriness or poor response to first line therapy
- Consideration for second line therapy (if not previously done)
- A change in the clinical/haematological pattern (bleeding or cytopenias).
In ITP, the bone marrow aspirate will show normal morphology, although there can be slightly increased numbers of megakaryocytes, with poor shedding of platelets.
Management
Certain factors including a classification that is simple and reproducible, a way to assess severity, and common therapeutic goals, are vital to ensure a consistent and standardised approach.
In 2009, Rodeghiero described the following classification for ITP8
- Newly diagnosed (
- Persistent (3–12 months)
- Chronic (>12 months).
Management should be based on bleeding severity and patient quality of life. Several ITP specific bleeding scores have been developed. Most children will only have mild or absent bleeding with no impairment of quality of life. Children with absent or mild bleeding do not usually require treatment. Severe bleeding can be regarded as that which is clinically relevant irrespective of platelet count leading to a fall in Hb by >2g/dl. Severe bleeding is unusual with platelet counts over 20 x 109/l but requires prompt treatment when it does occur. Therapeutic goals should include the avoidance of unnecessary treatment in milder ITP and minimisation of steroid exposure.
The health-related quality of life (HRQoL) should be considered to complete the holistic care of the child. An ITP disease specific QoL kit has been developed and validated for use in the UK. Currently this is only utilised in the clinical trial setting, but in the future may become a key component in management. It is an important aspect that can often be overlooked.9
The majority recover quickly with no bleeding. Evidence reflects a 50% resolution by six weeks and a platelet count >20 within a few days. Hence as a general guidance we regard a thrombocytopenia at three months from presentation as a point for review, to re-evaluate the presentation and to ensure all differentials have been excluded. At six months with no clear benefit from interventions, we recommend referral to a paediatric haematologist. The guidance is by no means definitive and early discussion with a paediatric haematologist is advisable to ensure best practice and allows the child to be known to their tertiary centre. Figure 2 shows a general treatment algorithm for ITP.
The patient should be referred to a paediatric haematologist when:
- There are atypical features on blood film
- There is excessive bleeding requiring treatment
- At three months, in the presence of persistent thrombocytopenia.
General measures must not be underestimated, including supportive, education, and local management of site-specific bleeding. Once these are in place specific modalities for acute, persistent and chronic ITP can be considered.
It can be useful to have an overall picture in mind. Only 3% of children with ITP will have clinically significant symptoms such as severe epistaxis or gastrointestinal bleeding. A platelet count of <10 x 109/l or more than two bleeding sites suggests increased risk for more severe bleeding. The incidence of ICH is approximately 0.1–0.5% and higher risk features include haematuria or other severe bleeding in the previous month.
Bleeding scores can aid grading of the ITP and management based on grading criteria has been described. This criterion guides the clinician as when to intervene. The majority of Grade 2 children can be managed with a watch-and-wait approach whereas Grade 3 indicates treatment or intervention (Table 2).10
It is imperative to consider psychosocial and lifestyle issues when deciding to treat or not to treat a child with ITP.
Supportive care
Supportive care is a core aspect, but is often overlooked. It encompasses education and support for children and families to aid understanding of the risks of serious life-threatening haemorrhage and about support available from dedicated groups. This enables families to move with you in the course of their ITP. School and extended family should not be forgotten.
Correction of anaemia maybe required. Careful use of supportive medication including anti-fibrinolytic agents such as tranexamic acid and the oral contraceptive pill are important treatment adjuncts.
Newly diagnosed ITP
The majority in this group will benefit from a watch-and-monitor approach. The advantage of active monitoring allows reassurance for parents, avoids unnecessary intervention preventing any side effects from treatment, and allows intervention at a timely manner. On the other hand watchful monitoring has the potential of inducing unnecessary anxiety.
Corticosteroids and intravenous immunoglobulin (IVIg) remain the first-line of treatment and all children with severe bleeding symptoms should be treated. Preference of one over the other is based primarily upon clinical experience and choice. Indeed, IVIg has a quicker time of action but bearing in mind the exposure to a blood product.
A combination of the main treatments can be utilised when there is severe or life threatening bleeding. In such situations, steroids (methylprednisolone)/IVIg and platelets can be utilised. Relevant multi-disciplinary teams may need to be consulted.
Prednisolone
Our preference involves the use of two regimens, both shown to be equally effective.11
- 4mg/kg for four days
- 1–2mg/kg for seven to ten days
Prolonged corticosteroid use in children can have serious implications on growth and development and hence prednisolone should only be used briefly to maintain haemostasis.
IVIg
The advantage of using IVIg is that it raises the platelet count more rapidly than using corticosteroids or no treatment. We currently utilise a short single dose of 0.8g/kg with a repeat treatment pending duration of response.12
Intravenous anti-D immunoglobulin
Although not licensed in the UK for the treatment of ITP, IV anti-D immunoglobulin can be given to rhesus D-positive children as a short infusion and can be valuable in raising the platelet count. It can, however, cause some problems including a mild extravascular haemolysis.13,14
Persistent ITP
Persistent ITP falls under a grey area and will often require the expertise of a tertiary centre. A classic example may be a teenage girl with heavy menstrual bleeding, attending her six-month appointment. It is probably best approached by overlapping modalities from acute and chronic management. The majority of persistent ITP children can be managed with the watch-and-monitor approach.
One approach used is IVIg or corticosteroids, but given four-to-six weekly. The alternative is rituximab or a thrombopoetin (TPO) mimetic, with the exception of splenectomy. These agents provide the mainstay of treatment and provide the necessary holding measure through a difficult persisting episode.
The key is to recognise that there is an overlap between the acute and chronic approaches and therefore an open mind to addressing the individual situation is vital.
Rituximab is a novel agent that can be useful in persistent ITP but varies in effectiveness. It is generally well tolerated in children, although they may have an increased incidence of serum sickness. Its long-term toxicity is not well documented, particularly in paediatrics. It is a costly treatment with rates of durable responses not exceeding 40%. Further studies on the use of rituximab in ITP are required because there are no randomised control trials in children and it remains unlicensed for ITP.15
Chronic ITP
This group of children should be referred to a tertiary centre to be reviewed by a paediatric haematologist. Although forming a small cohort per year; they can be the most challenging to manage and there is no consensus for best practice in this patient group.
The aim is to maintain haemostasis with first-line therapies (for example, IVIg, short-course IV) corticosteroids and to minimise the use of prolonged corticosteroids. Most will be asymptomatic; therefore can be managed through observation alone especially as spontaneous remission or ‘cure’ is seen in up to 10% of children per year. As most will remain free of severe bleeding, intervention is not always necessary.
Consideration of the impact of quality of life becomes important; it may be argued that if these children are not treated, they become subject to a restricted HRQoL and continue with the ongoing risk of severe- or life-threatening haemorrhage. They remain at risk of adverse effects of drugs used for break-through bleeds raising the following considerations when deciding on treatment:
- Frequent bleeding
- More than three treatments in six months
- Severe bleeding (single episode)
- Failure to respond to trial of steroids
- Co-morbidities
- Modify lifestyle or modify disease
- What level of HRQoL impairment
- Level of lifestyle restrictions
- Lethargy.
IVIg
The advantage of IVIg is that it raises the platelet count more quickly in more than 80% of children compared with corticosteroids or no therapy. The original two-to-five-day regimen has been superseded by a single dose of 0.8–1g/kg, with possible repeat treatment based on the short-term response.12
High-dose methylprednisolone (given as an oral seven-day course of 30mg/kg/day for three days followed by 20mg/kg/day for four days) has been used as an alternative to IVIg.
Rituximab
Rituximab has been used with success in children with chronic refractory ITP. Overall, the response rate is 31–68%. Rituximab may provide a long-term solution but, how long and how deep the remission will be, remains unclear.15
Splenectomy
The strategical position of splenectomy differs from that in adults. It is not a favoured approach and should be considered as a last resort. Studies involving children are sparse and long-term effects other than sepsis are not well documented. Conversely, there are relatively few late relapses of splenectomy in children.16
TPO mimetics
TPO mimetics are a non-curative option, which, through multiple placebo-controlled trials, have shown a greater response than other second-line treatments. The response is maintained while the drug is continued with rebound of thrombocytopenia after cessation. There is also evidence of improved quality of life. They are well tolerated with no adverse side effects to date. Studies have shown thrombosis and fibrotic changes in the marrow after commencing TPO mimetics, and how long to continue remains to be established. The potential of these agents is exciting ensuring the long-term safety of these agents is confirmed. These drugs are expensive and require funding through the necessary channels.
The preference for managing chronic ITP in our unit is to use a TPO mimetic agent. This is mainly based on the fact that there is a greater evidence base for these compared with rituximab.17,18 Our experience reflects good tolerability and a significant number of children have come off their medication as they enter spontaneous resolution. These agents are becoming more readily available either through clinical trial entry or primary care trust agreement.
Studies indicate that romiplostim has good efficacy and safety in children with persistent or chronic ITP. Side effects remain minor.18
The landmark PETIT 2 study showed that eltrombopag provided a sustained platelet response in 40% of patients with chronic ITP, thereby securing its place as a suitable therapeutic modality for children with chronic symptomatic ITP.19
References
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