Introduction

Immune thrombocytopenia (ITP) is an acquired autoimmune condition which is characterised by abnormally low levels of platelets in the blood, typically manifesting as a widespread petechial rash. It is a relatively rare condition which is more common in younger populations, occurring in approximately 4 in every 100,000 children per year. The prognosis of this condition in children is very good, with 80% achieving full remission with conservative management.

Epidemiology

  • Incidence: 1.00 cases per 100,000 person-years
  • Peak incidence: 6-15 years
  • Sex ratio: 1:1
Condition Relative
incidence
Henoch-Schonlein purpura10.00
Bacterial meningitis8.00
Immune thrombocytopenia (ITP) in children1
Acute lymphoblastic leukaemia1.00
<1 1-5 6+ 16+ 30+ 40+ 50+ 60+ 70+ 80+

Pathophysiology

  • The exact aetiology of ITP is still unknown, however most cases arise after a preceding viral illness
    • Antibodies directed against viral antigens during a viral illness may cross-react with normal platelet antigens (molecular mimicry)
  • It is thought that genetic immune dysregulation via T-cell anomalies may be responsible
  • The pathophysiological process is multi-factorial and complex, but is thought to be initiated by the following autoimmune processes:
    • Increased destruction of platelets in the spleen (by anti-platelet auto antibodies directed against platelet membrane antigens)
    • Inhibition of platelet production via suppression of megakaryocyte precursors, also by auto-antibodies
    • T-cell mediated destruction of platelets and megakaryocyte precursors in the bone marrow (possibly due to T-cell mediated cytotoxicity, and/or dysregulated mechanisms of regulatory T-cells and B-cells)
  • The auto-antibody production is thought to be caused by dysregulated CD4+ helper T-cells reacting to platelet surface glycoproteins (e.g. glycoprotein IIb/IIIa complex)

Clinical features

The most typical presentation of ITP is an otherwise well child with a petechial rash alone. Usually there is a history of a recent viral illness, in approximately 60% of children. This tends to be a viral upper respiratory tract infection, however can also be gastrointestinal in nature.

Cutaneous rash
  • ITP most frequently manifests as the sudden appearance of a petechial rash (small, purpuric lesions up to 2mm diameter), however larger purpura or bruising can also be present
  • This cutaneous rash is present in approximately 86% of children with diagnosed ITP
  • In greater than 50% of children with ITP, a cutaneous rash is the only clinical symptom

Mucocutaneous bleeding
  • Bleeding from mucosal surfaces occurs in approximately 40% of children with ITP
  • The location of the bleeding can vary:
    • Epistaxis (20%)
    • Oral bleeding, for example buccal and gingival surfaces (20%)
    • Very infrequently, bleeding can occur from the gastrointestinal, menstrual or urinary tract (<5%)

Severe haemorrhage
  • A very rare clinical symptom of ITP is severe haemorrhage (<3%)
  • Intracranial haemorrhage (<1%) may present with signs and symptoms such as:
    • Headache
    • Persistent vomiting
    • Altered mental state e.g. confusion, drowsiness
    • Seizures

Investigations

According to BMJ best practice, ITP is a diagnosis of exclusion and therefore majority of investigations are directed towards ruling out other differential diagnoses.

Full blood count
  • Platelets
    • An isolated thrombocytopenia with a platelet count of <100x109/L is usually the only blood abnormality
    • According to UptoDate, most presenting cases have a count of <30x109/L because those with a higher count tend to be asymptomatic and therefore do not get investigated
  • White blood cells
    • Should be within normal limits
    • If abnormal, should spark suspicion of another condition (see below)
  • Haemoglobin
    • Usually within normal limits
    • Anaemia is very occasionally seen, usually in children who have had significant haemorrhage

Peripheral blood smear
  • Platelets will appear reduced in number
  • Red and white blood cells will be of normal count and morphology
  • In patients with severe haemorrhage, microcytic hypochromic red blood cells may be seen (reflecting an iron deficiency anaemia)

Bone marrow biopsy
  • BMJ recommend performing this test only if there is an atypical blood film
  • The bone marrow biopsy should appear normal in ITP, otherwise one must consider other differentials

Investigation findings prompting further evaluation
  • As stated prior, in ITP, there should be an isolated thrombocytopenia
  • UptoDate suggest that the following findings should steer away from an ITP diagnosis:
    • Premature white cells e.g. blasts (consider possible lymphoma or leukaemia)
    • Predominant giant platelets, or very small platelets (consider inherited thrombocytopaenia syndromes)
    • Reticulocytosis (consider haemolytic anaemia)
    • Schistocytosis (consider microangiopathic haemolytic anaemia)

Differential diagnosis

Henoch Schonlein purpura
  • In an otherwise well child with a cutaneous rash, this is a very likely differential, given the characteristic similarities between both conditions
  • Similarities
    • Both can have petechiae
    • Both more common in children than adults
    • Both tend to have a viral prodrome
  • Differences
    • HSP tends to be characterised by palpable purpura
    • Arthritis/arthralgia present
    • Rash tends to be present in lower limbs and buttock area

Haematological malignancy
  • For example, leukaemia and lymphoma
  • Both ITP and leukaemia have a similar incidence in the UK, with rates of 4 cases per 100,000, therefore this is a more common differential than one night predict
  • It is an important one to exclude and therefore it is imperative to check for red flags in a child with symptoms of bleeding
  • Similarities
    • Both can present with symptoms of bleeding e.g. petechiae, bruising, mucosal bleeding
  • Differences
    • In malignancy, patients may have concurrent signs of concern including enlarged lymph nodes, splenomegaly, bone pain, joint pain and/or unexpected weight loss
    • Bloods may show abnormalities such as neutropenia, atypical or immature cells, marked anaemia and/or leukocytosis

Meningococcal disease
  • In an otherwise well child, this is an unlikely differential diagnosis
  • However, if a child is concurrently unwell, this should be a differential diagnosis high on the list given its high incidence in children (31 per 100,000 in children aged 0-4, and 5 per 100,000 in children aged 5-9)
  • Similarities
    • Both can present with petechial rash
    • More common in children
  • Differences
    • Children will be unwell (e.g. irritability, lethargy)
    • Usually will have abnormal vital signs (e.g. tachycardia, tachypnoea, widened pulse pressure, febrile)
    • Bloods may show raised white cell count and CRP

Congenital thrombocytopenic syndromes
  • Similarities
  • Differences
    • Positive family history of congenital thrombocytopenic syndromes
    • Predominantly large (giant) or small platelets on blood film
    • May see Döhle body-like inclusions on blood smear

Disseminated intravascular coagulation (DIC)
  • Similarities
    • Present with mucocutaneous bleeding
    • Petechiae usually present
  • Differences
    • Usually patients are very unwell
    • Can present with sepsis (e.g. hypotension, tachypnoea, fever)
    • Bloods may show elevated prothrombin time (PT), activated partial thromboplastin time (APTT) and D-dimer

Management

The management of ITP is different in children compared to adults. This topic focuses only on the treatment of children.

Initial platelet count
  • The initial platelet count is not a sole determinator of what form of management is initially required
  • Normally, the platelet count together with the clinical picture (particularly the symptoms of bleeding) are used as a guide for the management approach
  • According to the BMJ best practice guidelines, a platelet count of <20-30,000/microL is a threshold for active treatment, as this is the count where the risk of active bleeding increases
  • An initial platelet count of <10,000/microL is considered severe and in these situations it is more likely that active management will be undertaken regardless of the symptom profile

Conservative management
  • ITP in children will resolve spontaneously within 3 weeks in 30-70% of children, according to BMJ
  • In children who are asymptomatic (e.g. ITP noted incidentally on blood tests), or with minor bleeding symptoms (e.g. cutaneous manifestations), observation without active management is appropriate

Active management
  • This is restricted to children with major bleeding symptoms (e.g. ongoing epistaxis, mucosal bleeding) or a severely low platelet count
  • In general, if treatment is required, a platelet target of ≥20,000 to 30,000/microL is used (the platelet count threshold above which the risk of serious bleeding is reduced)
  • Corticosteroids
    • According to BMJ best practice, this is the usual first-line treatment
    • Prednisolone 1-2mg/kg/day orally, with tapering as soon as symptoms begin to clear
  • IVIg and anti-D immunoglobulin
    • Reserved for if corticosteroids are contraindicated or ineffective
  • In those who are resistant to the above treatment, or in those with chronic ITP, medications such as mycophenolate, rituximab and thrombopoietin receptor agonists can be considered (with specialist input)

Severe life-threatening bleeding
  • In those with severe haemorrhage, aggressive treatment is required
  • According to BMJ best practice, the first line management is with IVIg, corticosteroids, plus platelet transfusions
    • IVIg 1g/kg intravenously as a single dose
    • Prednisolone 1-2mg/kg/day orally
    • Alternatively, UptoDate suggest methylprednisolone 30 mg/kg per day (up to 1 g) intravenously for 3-4 days
  • Platelet transfusions
    • UptoDate recommend platelet transfusions of a bolus dose of 10-30 mL/kg, then followed by a continuous infusion
    • The role of these platelet transfusions is to ensure that the child maintains a haemostatic platelet count and to guide further treatment
    • Therefore, platelet transfusions are not curative in nature, as the platelets will continue to be destroyed at a more rapid rate due to the auto-immune processes in ITP
  • If severe haemorrhage results in hypovolaemia, fluid resuscitation is also indicated, however this is extremely rare

Monitoring
  • All patients with ITP, regardless of whether a conservative or active management approach is taken, should have their platelet count monitored regularly
  • Typically, UptoDate recommend monitoring platelet count weekly in the initial stages, with the interval between tests increasing as the clinical picture of the patient stabilises
  • Normally, monitoring will continue until the platelet count is within normal limits (>150,000/microL) and is stable without any active management

Complications

Severe bleeding
  • The risk of severe bleeding as a result of ITP in children is approximately 3%, therefore is relatively rare
  • Severe bleeding is defined by UptoDate as epistaxis which lasts >5-15 minutes in duration, gastrointestinal bleeding, other severe mucosal bleeding requiring hospital admission and/or blood transfusions
  • Those at higher risk of severe bleeding include:
    • Those with platelet count <10,000/microL
    • Traumatic event, e.g. head injury, falls
    • Concurrent use of blood thinning medications e.g. aspirin, NSAIDs, warfarin, heparin (rare in children)

Intracranial haemorrhage
  • This is the most severe and life threatening complication of ITP
  • The risk is extremely low, less than 0.5%
  • The risk factors for developing intracranial haemorrhage are the same as the risk for severe bleeding (as above)
  • Children with ITP and symptoms of possible ICH (e.g. headache, vomiting, seizures, confusion) should have neuroimaging completed in a timely manner, particularly if the platelet count is <10,000 to 20,000/microL (according to UptoDate)

Chronic ITP
  • Chronic ITP can be considered a complication of ITP, as the majority of cases resolve spontaneously
  • Chronic ITP is defined as ITP which persists for >12 months since presentation

Prognosis

  • The prognosis of ITP in children is very good, with over 70% of children recovering spontaneously within 3 weeks
  • The best prognosis is for children less than 10 years old, who tend to be more likely to recover completely compared to older patients
  • Only 2.5-5% of patients will be refractory to all treatments available
  • Even after many years of having chronic ITP, spontaneous remission still occurs in over 50% of children
  • The mortality is very low, with deaths usually being a result of catastrophic severe bleeding with complications