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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 ITP was previously known as idiopathic thrombocytopenic purpura but this is outdated, now that it is known to have an autoimmune cause.
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.
- 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.
Definitions and classification
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.
IMMUNE THROMBOCYTOPENIA IN CHILDREN
ITP in children most commonly occurs following a viral infection, or occasionally following immunisation. It is usually a self-limiting disorder which follows a benign course and recovers spontaneously after 6-8 weeks.
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.
The mean age at onset has been found to be around 5.7 years.
Symptoms and signs
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.
In infants, hereditary thrombocytopenia must be considered, as must ITP in the mother.
In older children the differential diagnosis includes:
- Aplastic anaemia.
- 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).
- Peripheral blood smear
- Bone marrow examination - only required if atypical features or diagnosis are 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.
- 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.
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.
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.
- 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.
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:
- Intravenous immunoglobulin.
- Intravenous anti-D immunoglobulin (in rhesus-positive children).
Second-line treatment for those resistant to first-line treatment and with significant bleeding
- High-dose dexamethasone.
- Tranexamic acid is used for menorrhagia, but is contra-indicated if there is haematuria.
- Emergency platelet transfusions are sometimes used.
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.
- 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% develop intracranial haemorrhage.
IMMUNE THROMBOCYTOPENIA IN ADULTS
Unlike ITP in children, adult ITP does not normally follow an infection and usually has an insidious onset. It is more likely to follow a chronic course in affected adults than in children.
The incidence of ITP in adults is estimated at approximately 3.3 per 100,000 persons per year. Overall 18-year prevalence was found to be 50 per 100,000 adults in the UK in a 2011 study. ITP affects both sexes equally, except between the ages of 30-60, when it is more common in women.
Signs and symptoms
As in children, adults with ITP may demonstrate a range of symptoms from none at all through to severe haemorrhage.
FBC and peripheral blood smear are the essential first-line tests. All those with ITP should be screened for HIV and hepatitis C, as treating the underlying cause may alter the disease course.
The American Society of Hematology found no evidence for routine autoantibody or immunoglobulin tests unless there are other abnormalities than a low platelet count. American guidelines also state that there is no necessity for a bone marrow examination, regardless of age, if features are typical of ITP.
The International Consensus Report guidelines, however, recommend routine testing of immunoglobulin levels in all patients as well as consideration of bone marrow examination in those over the age of 60.
- Aplastic anaemia.
- Effects of drugs or toxins on bone marrow - eg, alcohol.
- Von Willebrand's disease.
- Marrow infiltration by secondary tumour.
- Systemic lupus erythematosus.
- Thrombotic thrombocytopenic purpura.
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.
First-line treatments include observation or steroids. Intravenous immunoglobulin (IVIG) can be used with corticosteroids when a more rapid increase in platelet count is required. Second-line therapies include splenectomy, a thrombopoietin receptor agonist (TPO-RA): eltrombopag or romiplostim; or rituximab.
Dr Krishna Vakharia, 21st October 2022
Fostamatinib for treating refractory chronic immune thrombocytopenia
The National Institute for Care and Health Excellence (NICE) has 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.
Dr Krishna Vakharia, 15th December 2022
Avatrombopag for treating primary chronic immune thrombocytopenia
NICE has 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.
- Stopping medication which has an effect on platelet function (eg, NSAIDs).
- Control of blood pressure.
- Inhibition of menses.
- Avoidance of trauma.
First-line management options
- Oral corticosteroids - eg, prednisolone for three weeks then tapered off. Generally first-line treatment, and alternatives used where contra-indicated.
- Intravenous immunoglobulin.
- Intravenous anti-D (in rhesus-positive non-splenectomised people).
Second-line management options
Recent guidelines state that evidence is not sufficient to guide the sequence of management where first-line treatment has failed.
- Splenectomy. 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.
- Thrombopoietin receptor agonists - romiplostim and eltrombopag. These stimulate platelet production and may be considered for those who are at risk of bleeding and have failed to respond to other treatments. When stopped, platelet levels may drop even lower than before treatment, so careful monitoring is required. Both are approved by the NICE in refractory cases under specific conditions.[12, 13]
- Rituximab. This can also be used off-licence as a second-line option in certain refractory cases, but long-term safety data are lacking.
- Other treatments used include azathioprine, ciclosporin, cyclophosphamide, danazol, dapsone, mycophenolate, and vinca alkaloids. Emergency platelet transfusion is sometimes required.
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.
Further reading and references
Neunert C, Terrell D, Arnold D et al; The American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Advances Volume 3, Issue 23. December 10 2019: 3829–3866.
Cines DB, Cuker A, Semple JW; Pathogenesis of immune thrombocytopenia. Presse Med. 2014 Apr43(4 Pt 2):e49-59. doi: 10.1016/j.lpm.2014.01.010. Epub 2014 Mar 12.
Grimaldi-Bensouda L, Nordon C, Michel M, et al; Immune thrombocytopenia in adults: a prospective cohort study of clinical features and predictors of outcome. Haematologica. 2016 Sep101(9):1039-45. doi: 10.3324/haematol.2016.146373. Epub 2016 May 26.
Rodeghiero F, Stasi R, Gernsheimer T, et al; Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood. 2009 Mar 12113(11):2386-93. doi: 10.1182/blood-2008-07-162503. Epub 2008 Nov 12.
Warrier R, Chauhan A; Management of immune thrombocytopenic purpura: an update. Ochsner J. 2012 Fall12(3):221-7.
Terrell DR, Beebe LA, Vesely SK, et al; The incidence of immune thrombocytopenic purpura in children and adults: A critical review of published reports. A Am J Hematol. 2010 Mar85(3):174-80.
Singh G, Bansal D, Wright NAM; Immune Thrombocytopenia in Children: Consensus and Controversies. Indian J Pediatr. 2020 Feb87(2):150-157. doi: 10.1007/s12098-019-03155-4. Epub 2020 Jan 11.
International consensus report on the investigation and management of primary immune thrombocytopenia; Blood Journal, January 2010
Bennett D, Hodgson ME, Shukla A, et al; Prevalence of diagnosed adult immune thrombocytopenia in the United Kingdom. Adv Ther. 2011 Dec28(12):1096-104. doi: 10.1007/s12325-011-0084-3. Epub 2011 Dec 1.
Fostamatinib for treating refractory chronic immune thrombocytopenia; NICE Technology appraisal guidance, October 2022
Avatrombopag for treating primary chronic immune thrombocytopenia; NICE Technology appraisal guidance, December 2022
Romiplostim for the treatment of chronic immune or idiopathic thrombocytopenic purpura; NICE Technology Appraisal Guidance, April 2011 - last updated October 2018
Eltrombopag for treating chronic immune (idiopathic) thrombocytopenic purpura; NICE Technology Appraisal Guidance, July 2013 - last updated October 2018
Immune (idiopathic) thrombocytopenic purpura: rituximab; NICE advice, October 2014