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Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by persistent thrombocytopenia (peripheral blood platelet count < 150×10⁹/l) due to autoantibody binding to platelet antigen(s) causing their premature destruction by the reticuloendothelial system, and in particular the spleen (Woods et al, 1984a,b).

Although the basic underlying pathophysiology of ITP has been known for 50 years (Harrington et al, 1951), the literature shows that the investigation and management of patients with thrombocytopenia vary widely, and is not evidence-based, due to a lack of clinical trials and quality research. Despite major advances in our understanding of the molecular basis of many blood disorders, the diagnosis of ITP remains one of exclusion; there are currently no robust clinical or laboratory parameters that are able to establish the diagnosis of ITP with accuracy. This guideline aims to assess available diagnostic tests and therapies, and attempts to provide a rational approach to the diagnosis and treatment in adults, children and in pregnancy. Although natural history data are becoming available (Cohen et al, 2000; Djulbegovic & Cohen, 2001; Portielje et al, 2001), there are few randomized trials in ITP and many of the recommendations, like those of the American Society of Hematology (ASH) Panel (George et al, 1996), are based on expert opinion.

AIMS OF THE GUIDELINE

The purpose of this guideline is to provide a rational approach to the laboratory investigation and management of patients with ITP, including pregnant and non-pregnant adults and children, and patients with refractory disease. The Guideline development group includes individuals from relevant professional groups, and we have sought the views of patients, through The ITP Support Association. Target users of the Guideline include clinical haematologists involved in the care of adults and children with ITP, obstetricians and anaesthetists involved in the care of ITP in pregnancy, paediatricians and physicians.

METHODS

MedLine was searched via PubMed using the following criteria: 'thrombocytopenia', 'platelet count', autoimmune thrombocytopenic purpura￠, 'ITP', 'thrombocytopenia + randomized', 'thrombocytopenia + randomised', 'thrombocytopenic + randomized', 'thrombocytopenic + randomised'’, 'thrombocytopenia + trial', 'thrombocytopenic + trial', 'thrombocytopenic + therapy', 'thrombocytopenia + therapy'. The search excluded 'thrombotic', 'neonatal alloimmune' and 'drug-induced thrombocytopenia'. For paediatric reports the previous search terms were combined with 'child' and 'children'.

DESCRIPTION AND EPIDEMIOLOGY

Immune-mediated thrombocytopenias comprise, among others: drug-induced thrombocytopenia, neonatal alloimmune thrombocytopenia, post-transfusion purpura, ITP, acute ITP and secondary ITP. This guideline aims to deal with ITP in children, adults and pregnancy. Previous guidelines for the management of thrombocytopenia in pregnancy have been published (Greaves & Letsky, 1997).

Adult chronic ITP has an incidence of 58–66 new cases per million population per year (5.8–6.6 per 100 000) in the US (McMillan, 1997) with a similar incidence in the UK. This form of ITP affects mainly women of childbearing age (Female:Male, 3:1) (Waters, 1992). Childhood ITP has an incidence of between 4.0 and 5.3 per 100 000 (Lilleyman, 1999; Zeller et al, 2000).
Acute abrupt onset ITP is seen mainly in childhood, and often follows a viral illness or immunization. The majority of children require no treatment and in 80–85% of cases the disorder resolves within 6 months. Some 15–20% of children develop a chronic form of ITP, which, in some cases, resembles the more typical adult disease. Chronic ITP in childhood has an estimated incidence of 0.46 per 100 000 children per year (Reid, 1995) and prevalence of 4.6 per 100 000 children at any one time (Hedman et al, 1997).

Secondary immune thrombocytopenias occur in patients with other underlying autoimmune disorders (e.g. systemic lupus erythematosus), or malignant disease (e.g. chronic lymphocytic leukaemia).

ADULT ITP

Clinical features

ITP in adults is quite distinct from the typically acute disorder seen in childhood. In adults, ITP typically has an insidious onset, with no preceding viral or other illness. Symptoms and signs are highly variable and range from the fairly common asymptomatic patient with mild bruising, mucosal bleeding (e.g. oral or gastrointestinal tract) through to frank haemorrhage from any site, the most serious of which is intracranial. Overall, bleeding symptoms are uncommon unless the ITP is severe (platelet count <30 · 109 ? l) (George & Raskob, 1998). ITP in adults is a disease predominantly of women of childbearing age. The natural history is poorly defined but studies are being conducted, looking at the long-term outcome in terms of morbidity and mortality in patients with ITP (Portielje et al, 2001).

Diagnostic approach for adults

Clinical history

The patient’s history is used to:

♦ Determine the type of bleeding and to distinguish ‘platelet-type’ mucocutaneous bleeding from ‘coagulation-type’haematomas

♦ Assess the severity, extent and duration of bleeding. A history of bleeding with previous surgery, dentistry and trauma may be useful in determining the duration of chronic thrombocytopenia in the absence of blood counts

♦ Determine the presence of other medical disorders which may be responsible for thrombocytopenia by:
i) immune mechanisms, e.g. is there a recent history of transfusion raising the possibility of post-transfusion purpura?
ii) non-immune mechanisms, e.g. is there a history of excess alcohol consumption or a family history of thrombocytopenia suggesting an inherited nonimmune thrombocytopenia?
iii) Evolving aplastic anaemia, particularly relevant in children
iv) Marrow in?ltration with acute leukaemia
v) Type IIB von Willebrand’s disease

♦ Determine the presence of medical conditions which may be associated with autoimmune thrombocytopenia, e.g. drugs, human immunode?ciency virus (HIV) infection, other autoimmune disorders, malignancy (e.g. lymphoproliferative disorders)

♦ Conditions which may increase the risk of bleeding, e.g. local abnormalities in the gastrointestinal, genitourinary or central nervous systems

Physical examination

The physical examination is used to:

♦ Assess the type, severity and extent of bleeding

♦ Exclude conditions that might cause non-immune thrombocytopenia, e.g. severe infection, acute thrombocytopenia with neurological signs which may indicate a diagnosis of thrombotic thrombocytopenic purpura (TTP), skeletal and other abnormalities associated with congenital thrombocytopenias, lymphadenopathy, which may suggest the presence of a lymphoproliferative disease, and splenomegaly. It should be noted that splenomegaly has been reported to occur in less than 3% of adult patients with ITP (Doan et al, 1960) and its presence should prompt a search for an alternative diagnosis

♦ Determine the presence of medical conditions that may be associated with autoimmune thrombocytopenia, e.g. HIV infection, other autoimmune disorders, malignancy

Laboratory investigations

The finding of thrombocytopenia on a routine blood count may be the first indication of autoimmune thrombocytopenia. Thrombocytopenia should be confirmed by examination of the blood film to exclude pseudothrombocytopenia due to EDTA-dependent platelet agglutination as the cause of the spuriously low platelet count; this condition occurs in about 0.1% of adults, and is easily confirmed by the finding of a normal platelet count using a sample taken into citrate rather than EDTA anticoagulant (Pegels et al, 1982).

The blood film should also be examined to exclude nonimmune thrombocytopenias such as those associated with acute or chronic leukaemia, myelodysplasia, megaloblastic anaemia, microangiopathic anaemia, inherited thrombocytopenias and pseudothrombocytopenia. An autoimmune profile ? screen should be carried out to exclude other underlying autoimmune diseases.

If the history, physical examination, blood count and blood film examination are consistent with the diagnosis of ITP with no atypical findings, it can be argued that additional investigations such as bone marrow examination and assays for platelet antibodies are unnecessary. If atypical findings are present, particularly those suggesting alternative haematological diagnoses, additional investigations including bone marrow examination should be carried out (Evidence level IV).