Immune thrombocytopenia

What is immune thrombocytopenia?

Synonym: immune thrombocytopenic purpura

Immune thrombocytopenia (ITP) describes an autoimmune disorder in which the number of circulating platelets is reduced. This is due to their increased destruction, and sometimes also due to reduced production. ITP was previously known as idiopathic thrombocytopenic purpura but this is outdated, now that it is known to have an autoimmune cause.

Causes of immune thrombocytopenia (aetiology)^{1 2}

In ITP, otherwise normal platelets are destroyed, most often in response to an unknown stimulus. This may occur in isolation (primary ITP) or in association with other disorders (secondary).

Causes of secondary ITP include:

• Other autoimmune disorders (including antiphospholipid antibody syndrome and systemic lupus erythematosus).

• Viral infections (including cytomegalovirus, varicella-zoster, hepatitis C and HIV).

• Infection with Helicobacter pylori.

• Medication.

• Lymphoproliferative disorders.

Antibodies bind to platelet antigens, resulting in a persistent thrombocytopenia. As well as antibody-mediated platelet destruction, there also appears to be an element of antibody-mediated inhibition of platelet production. It is a condition which can occur both in adults and in children and can be acute or chronic in nature.

A few studies reported clusters of ITP incidence within families, but it is unknown whether a family history of autoimmune disorder can be a risk factor for developing ITP.³

ITP in children most commonly occurs following a viral infection, or occasionally following immunisation.⁴ It is usually a self-limiting disorder which follows a benign course and recovers spontaneously after 6-8 weeks.

Unlike ITP in children, adult ITP does not normally follow an infection and usually has an insidious onset.⁵ It is more likely to follow a chronic course in affected adults than in children.

Definitions and classification⁶

An international working party in 2009 attempted to standardise definitions and classifications for ITP. Their recommendation was that primary ITP should be defined as a platelet count of <100 x 10⁹/L in the absence of other causes or disorders associated with thrombocytopenia. The working group also defined persistent ITP as lasting 3-12 months, and chronic ITP as having lasted more than 12 months.

How common is immune thrombocytopenia? (Epidemiology)^{4 7}

About 40% of all diagnosed ITP is in children aged under 10 years. In children the incidence is commonest between the ages of 2 and 4 and is equal in males and females. Between adolescence and the age of 60, females are more likely to be affected than males. The highest prevalence is in the over-60s when males and females are equally affected.⁸

The incidence of childhood ITP is of the order of 2.2-5.3 per 100,000 children per year. Up to 20% may go on to develop the chronic form.

Overall 18-year prevalence was found to be 50 per 100,000 adults in the UK in a 2011 study.⁹

Symptoms and signs of immune thrombocytopenia⁴

The clinical picture ranges from no symptoms whatsoever to life-threatening intracranial haemorrhage. Some children with ITP will have no symptoms at all. The most common presentation is petechiae or bruising. Up to a quarter present with nosebleeds. Haematuria and gastrointestinal bleeds are less common. Older girls may have menorrhagia. Intracranial bleeds occur very rarely.

Differential diagnosis⁴

In infants, hereditary thrombocytopenia must be considered, as must ITP in the mother.

In older children the differential diagnosis includes:

• Aplastic anaemia.

• Leukaemia.

• Fanconi's anaemia.

• Von Willebrand's disease.

• Meningococcal septicaemia.

• Non-accidental injury.

• Pseudothrombocytopenia (false platelet count caused by platelet clumping).

• Thrombotic thrombocytopenia purpura.

• Disseminated intravascular coagulation (DIC).

In adults the differential diagnosis includes:

• Aplastic anaemia.

• Effects of drugs or toxins on bone marrow - eg, alcohol.

• Leukaemia.

• Von Willebrand's disease.

• Marrow infiltration by secondary tumour.

• DIC.

• Systemic lupus erythematosus.

• Thrombotic thrombocytopenic purpura.

Diagnosing immune thrombocytopenia (investigations)^{1 10}

• FBC.

• Peripheral blood smear

• Bone marrow examination - only required if there are atypical features or the diagnosis is in doubt.

• Guidelines from the American Society of Hematology suggest there is no evidence for the routine testing for antibodies such as antinuclear antibodies (ANAs) or immunoglobulin levels in children with typical features of ITP. However, the international consensus recommends that these are tested in both adults and children and then retested in children with chronic ITP.

• Helicobacter pylori testing (stool or breath testing, not serology) should be considered in patients with ITP if they are in an area of high prevalence or have symptoms; evidence does not support routine testing.

• HIV and HCV testing should occur in adults with thrombocytopenia, regardless of their perceived personal risk; thrombocytopenia associated with HIV or HCV can be indistinguishable from ITP for several years after infection.

• A direct anti-globulin test (DAT) is advised if anaemia is also present with a high reticulocyte count; a positive DAT is found in around 20% of people with ITP. If the DAT is positive it should be followed by tests for haptoglobin, lactate dehydrogenase and bilirubin to assess for haemolysis.

• Further investigations may be prompted by findings from the history, family history and examination. These will help to determine causes of secondary ITP, or exclude differential diagnoses.

• Splenomegaly suggests an alternative cause should be sought. ¹⁰

• Constitutional symptoms such as weight loss, organomegaly or lymphadenopathy may suggest an underlying cause. ¹⁰

Management of Immune Thrombocytopenia¹

Treatment is considered on the basis of clinical symptoms and not on the basis of platelet count alone, as children with severe thrombocytopenia are often asymptomatic and do not have a serious risk of a bleed. The majority of children with ITP do not need therapy and have a spontaneous resolution of the disease.¹¹

No study has shown that any one treatment decreases mortality or alters the risk of ITP becoming chronic. Treatment is based on the individual, taking into account factors such as platelet count, age, clinical picture, duration, lifestyle issues, cost, and concerns of all involved.⁴

Children

• The majority of children with acute or chronic ITP will require only advice, support and observational monitoring. Management is based on symptoms rather than platelet count.

• Further testing of the FBC is not required unless a change in the child's condition takes place to suggest that remission has occurred, or that deterioration has taken place. Children with no symptoms or skin petechiae or bleeding only may be managed by observation alone regardless of their platelet count.

• Trauma prevention advice - avoid contact sports.

• Advice to avoid aspirin and non-steroidal anti-inflammatory drugs (NSAIDs).

• Education about symptoms to look out for and report urgently.

Adults⁵

Adults with ITP, like children, will only require active management if their symptoms are severe enough to warrant it. Treatment is initiated in a specialist setting. Any decision to treat should bear the following in mind:

• The extent of bleeding.

• Comorbidities predisposing to bleeding - eg, need for major surgery.

• Complications of specific therapies.

• Activity and lifestyle.

• Tolerance of side-effects.

• Potential interventions that may cause bleeding.

• Accessibility of care.

• Expectations and worry or anxiety about disease burden.

• Need for non-ITP medications that may create a bleeding risk.

General measures

• Stopping medication which has an effect on platelet function (eg, NSAIDs).

• Control of blood pressure.

• Inhibition of menses.

• Avoidance of trauma.

Pharmacological

Any of the following may be used in a specialist setting if it is thought that the clinical condition requires that the platelet count should be raised:

First-line treatment

• Prednisolone.

• Intravenous immunoglobulin.

• Intravenous anti-D immunoglobulin (in rhesus-positive children).

Second-line treatment for those resistant to first-line treatment and with significant bleeding

Robust evidence:

• Rituximab.

• Thrombopoietin receptor agonists (TPO-RAs) such as eltrombopag, avatrombopag, romiplostim. In 2022, the National Institute for Care and Health Excellence (NICE) recommended avatrombopag as an option for treating primary chronic immune thrombocytopenia (ITP) refractory to other treatments (for example, corticosteroids, immunoglobulins) in adults. It has been shown to be more effective than placebo at increasing the number of platelets to reduce the risk of bleeding.¹²

• Fostamatinib. In 2022, NICE recommended fostamatinib as an option for treating refractory chronic immune thrombocytopenia (ITP) in adults if they have previously had a thrombopoietin receptor agonist (TPO-RA), or a TPO-RA is unsuitable. Evidence shows that fostamatinib is effective compared with placebo. An indirect comparison shows that fostamatinib works better than rituximab at increasing the number of platelets in the blood.¹³

Less robust evidence:

• Azathioprine.

• Cyclophosphamide.

• Cyclosporin A.

• Danazol.

• Dapsone.

• Mycophenolate mofetil.

• TPA-RA switch.

• Vinca alkaloids.

Other treatments

• Tranexamic acid is used for menorrhagia, but is contra-indicated if there is haematuria.

• Emergency platelet transfusions are sometimes used.

Surgical

Splenectomy is rarely indicated in childhood ITP and is only used in the event of life-threatening bleeding, or in children with severe, chronic, unremitting ITP present for 12-24 months with severe symptoms.

In adults it is sometimes offered as a second or third-line treatment option. 80% respond to splenectomy, and remission is maintained in 66% for at least five years with no additional treatment. Complications include infection/septicaemia, bleeding, thrombosis and relapse.

Prognosis of Immune Thrombocytopenia¹

• 75-80% of children have completely recovered within six months and will go on to have no further problems.

• A small number will develop a chronic thrombocytopenia, but most of these will require no treatment.

• Adolescents (over the age of 10 years) may be more likely to develop persistent or chronic ITP.

• Less than 1% of children develop intracranial haemorrhage.

• The natural history of ITP in adults is very variable, depending on the severity of the symptoms and the response to any therapy. Spontaneous remission occurs less frequently than in children. Prognosis is generally benign even in refractory cases.