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Keywords:

  • thrombocytopenia;
  • investigation;
  • management;
  • adults;
  • paediatrics;
  • pregnancy

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

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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

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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

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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).

Clinical features

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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

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Clinical history

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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 infiltration 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 immunodeficiency 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

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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

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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 pseudo-thrombocytopenia 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 non-immune 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).

Bone Marrow Examination in adults

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This is a contentious issue, and one where there was no agreed consensus reached by the ASH panel, apart from suggesting this investigation for patients older than 60 years or where splenectomy was being considered (George et al, 1996). In a study of adults with suspected ITP, 61 of 66 patients had bone marrow findings consistent with ITP; four had mild hypocellularity and one had neutrophil hypersegmentation and giant metamyelocytes, but all five had a subsequent clinical course consistent with chronic ITP (Westerman & Grigg, 1999). More recently, a retrospective Chinese study evaluated 83 patients (aged between 16 and 60 years) with suspected ITP, all of whom underwent bone marrow examination. Apart from 11 cases in which marrow iron was reduced or absent, the marrows were otherwise normal. Their recommendations were that bone marrow sampling should be reserved for patients who are older than 60 years, or have atypical features, or have a poor response to first line (e.g. prednisolone) treatment or in whom splenectomy is being considered (Mak et al, 2000).

Specialized laboratory assays in the diagnosis of itp

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Assays for anti-platelet antibodies

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The direct platelet immunofluorescence test (PIFT) is used to investigate referred samples for the presence of platelet-associated immunoglobulin (PAIg); indirect testing of the patient's plasma against donor platelets is of little value in the investigation of suspected ITP because the sensitivity and specificity is even lower than for direct testing (see below).

Increased levels of platelet-associated IgG (PAIgG) can be detected in most patients with ITP, but the results are not sufficiently sensitive or specific (patients with non-immune thrombocytopenias, e.g. septicaemia, frequently have positive results) to justify the routine use of these assays in patients with suspected ITP (Mueller-Eckhardt et al, 1980; von dem Borne et al, 1986; Kelton et al, 1989).

Assays for antibodies to specific platelet membrane glycoproteins (GP) IIb/IIIa and Ib/IX are less sensitive (50–65%) but more specific (90%) in ITP (Berchtold & Wenger, 1993; Brighton et al, 1996; Warner et al, 1999). Although they may be useful in distinguishing between immune and non-immune thrombocytopenia in complex cases, their routine use in the diagnosis of ITP is not considered to be justified.

Investigation of platelet autoantibodies may be of value in adults with

  • • 
    Combination of bone marrow failure associated with immune-mediated thrombocytopenia
  • • 
    ITP patients refractory to first and second line treatment
  • • 
    Drug-dependent immune thrombocytopenia (DDITP)
  • • 
    Miscellaneous disorders (rare), e.g. monoclonal gammopathies and acquired autoantibody-mediated thrombasthenia

Bone marrow failure and immune-mediated thrombocytopenia.  Antibody-mediated platelet destruction may aggravate thrombocytopenia in some patients with thrombocytopenia in whom there is inadequate thrombopoiesis, e.g. patents with disorders such as chronic lymphocytic leukaemia (CLL) or bone marrow transplant recipients. Reactive megakaryocytopoiesis is often a feature of ITP, and there may be doubt as to whether there is platelet autoimmunity in addition to bone marrow infiltration or failure; a PAIg test with determination of antibody specificity may be of use.

ITP patients refractory to first and second line treatment.  For ITP patients for whom third line treatment is considered, measuring the autoantibody titre in addition to the platelet count and clinical signs of bleeding can be used to monitor the effect of treatment. A PAIg test and determination of antibody specificity is recommended.

Drug-dependent immune thrombocytopenia (DDITP).  Many drugs are associated with thrombocytopenia. For some drugs there is firm evidence that the thrombocytopenia is antibody-mediated. Serological investigations to determine whether the drug is the causative factor in the thrombocytopenia are important in clinical management. Testing for DDITP is of value for the following drugs: heparin, quin(id)ine, and teicoplanin (Terol et al, 1993; Veldman et al, 1996).

Thrombopoietin (TPO) assays

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Measurement of the TPO level may be informative in complex cases of thrombocytopenia, and is particularly useful in distinguishing between reduced production of platelets (high TPO level) and increased destruction of platelets (normal level) (Porcelijn et al, 1998). However, this assay is not available in routine practice, and is not recommended as part of the routine investigation of ITP.

Reticulated platelets

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Measurement of platelet RNA by flow cytometry using thiazole orange staining can be used to assess platelet maturity. Reticulated platelets are significantly increased in children with ITP, reflecting increased platelet production, compared with normal children and other causes of thrombocytopenia, e.g. acute leukaemia, aplastic anaemia (Saxon et al, 1998). The precise role for the reticulated platelet assay has not been established and its use is not currently recommended.

Helicobacter pylori infection

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A number of studies have reported the presence of H. pylori in patients with autoimmune disease, particularly ITP. In some series antibiotic therapy aimed at eradication of H. pylori has ameliorated ITP in patients resistant to other therapies (Gasbarrini et al, 1998; Emilia et al, 2001; Kohda et al, 2002) although other studies have generated conflicting data (Jarque et al, 2001). Despite this, in patients refractory to therapy it is worthwhile performing serological assays and breath tests aimed at detecting the microorganism (Evidence level III).

Recommendation for adults:

The diagnosis of ITP is based principally on the exclusion of other causes of thrombocytopenia using the history, physical examination, blood count, peripheral blood film, autoimmune profile and other investigations. Further investigations are not indicated in the routine work-up of patients with suspected ITP if the history, examination, blood count and film are typical of the diagnosis of ITP and do not include unusual features that are uncommon in ITP, or suggestive of other causes (Evidence IIb–IV; Grade B, C).

A bone marrow examination is unnecessary in adults unless there are atypical features, or the patient is over the age of 60 years, or the patient relapses following complete remission, on or off therapy, or splenectomy is being considered (Evidence Level III).

PAIg is elevated in both immune and non-immune thrombocytopenia and therefore has no role in the diagnosis of uncomplicated ITP (Evidence level III).

It is worth determining the presence of H. pylori in patients refractory to therapy since some patients have shown improvement in platelet counts following eradication therapy (Evidence level III, Grade B recommendation).

Management of adult itp

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General note: to date there have been few randomized controlled trials conducted in ITP. Treatment should be tailored to the individual patient.

Natural history of adult ITP and the requirement for medical or surgical treatment

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The requirement for treatment varies from patient to patient, and is dictated by factors such as clinical status (asymptomatic, bruising, bleeding or planned intervention likely to induce bleeding in a patient with ITP who is thrombocytopenic). Haemorrhagic death is a major concern in thrombocytopenic patients, but recent data from 17 case series have been reviewed and show that the rate of fatal haemorrhage is between 0.0162 and 0.0389 cases per patient-year at risk (the time at risk was defined as the time when the platelet count is < 30 × 109/l) (Cohen et al, 2000). A recent review by Portielje et al (2001) found that more patients died of infection than of bleeding. In this same review the authors studied the natural history of 152 adult patients with ITP that were consistently managed and followed up over a 10 year period, and showed that 93% of patients ultimately achieving a platelet count of > 30 × 109/l did so within 2 years. Some 85% achieved platelet counts above 30 × 109/l off treatment and had a long-term mortality identical to that of the general population; 9% of patients with severe ITP (platelets < 30 × 109/l) had refractory ITP with an associated mortality risk of 4.2 (bleeding and infection contributing equally). Six per cent of patients had platelets > 30 × 109/l while on maintenance therapy; the mortality in this group was only slightly above that of the general population. The study concludes that most adults with ITP have a good outcome with few in-patient admissions and no excess mortality. These findings would tend to favour a policy of using therapy only when absolutely required, thereby minimizing the risks of infection through immunosuppression, and reserving treatment for those who actually require it, for example patients with severe symptomatic ITP.

First line therapy

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Standard first line therapy

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In general, patients with platelet counts exceeding 30 × 109/l require no treatment unless they are undergoing any procedure likely to induce blood loss including surgery, dental extraction or delivery (Yang & Zhong, 2000) (Grade C recommendation).

Recommendation for “safe” platelet counts in adults

Dentistry ≥ 10 × 109/l

Extractions ≥ 30 × 109/l

Regional dental block ≥ 30 × 109/l

Minor surgery ≥ 50 × 109/l

Major surgery ≥ 80 × 109/l

Obstetrics see Thrombocytopenia in pregnancy

Evidence Level IV

First line therapy comprises oral corticosteroids and intravenous immunoglobulin (IVIg). Splenectomy is often cited as first line therapy but this mode of treatment is seldom used as first line, and rather should be considered as second line therapy.

Prednisolone.  Prednisolone (or prednisone) is the initial therapy for most patients with ITP who require treatment (McMillan, 1981; Bussel, 1990; Warkentin & Kelton, 1990). Some two-thirds of patients will respond to prednisolone at 1 mg/kg body weight per day for 2–4 weeks, tapering off over several weeks (Ben-Yehuda et al, 1994; George et al, 1994; Stasi et al, 1995). Reported response rates vary widely (from 3% to 50%) (George et al, 1996). A single randomized trial showed no difference in response to low dose 0.25 mg/kg/d vs 1 mg/kg/d in 160 children and 223 adults (Bellucci et al, 1988). Relapse of thrombocytopenia is common when the dose is reduced. Around one-third of patients can expect a long-term response (Berchtold & McMillan, 1989; George et al, 1996; Manoharan, 1991; Blanchette et al, 1998). Corticosteroids should be rapidly tapered and stopped in patients who fail to respond to oral prednisolone after 4 weeks (Pizzuto & Ambriz, 1984; Ben-Yehuda et al, 1994). Long-term remission is seen in only 10–20% of patients following cessation of prednisolone therapy (Ben-Yehuda et al, 1994; Stasi et al, 1995). Patients who fail to respond to treatment with corticosteroids or require unacceptably high doses of corticosteroid in order to maintain a safe platelet count should be considered for splenectomy (Ben-Yehuda et al, 1994; George et al, 1994).

IVIg.  Pooled normal human immunoglobulin is effective in elevating the platelet count in 75% of patients, of which 50% will achieve normal platelet counts. However, responses are transient and 3–4 weeks following IVIg treatment platelet counts drift back to pre-treatment levels (Dwyer, 1992; George et al, 1996), and there is little evidence of a lasting effect. A prospective randomized trial involving 30 adult patients with chronic ITP (comparing IVIg, prednisolone or combination of the two) with a minimum follow-up of 2 years showed quite clearly that the response rates, duration of response and requirement for splenectomy were the same in all arms (Jacobs et al, 1994) (Evidence level Ib, Grade B). A single randomized study showed no difference in efficacy between the two dosing schedules 0.4 g/kg/d for 5 d and 1 g/kg/d as a single infusion (Godeau et al, 1993). The mechanism of action of IVIg in ITP remains largely unknown but is believed to involve the blockade of Fc receptors on macrophages and other effectors of antibody-dependent cytotoxicity (Geha & Rosen, 1996), the presence of anti-idiotype antibodies in IVIg which block autoantibody binding to circulating platelets and immune suppression (Godeau et al, 1993; Chong, 1995). While IVIg is a pooled blood product, it has an excellent safety record although renal impairment or failure has been reported with some preparations (Schiavotto et al, 1993; Cayco et al, 1997).

Recommendations for first line therapy in adults:

There are no randomized studies comparing no treatment vs. therapy with corticosteroids or IVIg. There is no indication for therapy in adults in whom there are no symptoms or signs, or in whom the platelet count is greater than 30 × 109/l (Grade C recommendation). IVIg is useful in 75% of patients in whom the platelet count has to be raised either due to symptoms or signs, or where there is predictable bleeding (e.g. surgery, pregnancy/labour or operative dentistry).

Second line therapy

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Splenectomy

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Splenectomy has been used for many years, before steroid therapy was introduced in 1950 (Chong, 1995; George et al, 1996), as a means of prolonging the survival of antibody-coated platelets. The procedure is not strictly ‘curative’ since opsonization still takes place but the effector of platelet destruction is removed. Two-thirds of patients with ITP who undergo splenectomy will achieve a normal platelet count, which is often sustained with no additional therapy. Patients who do not have a complete response can still expect some improvement in counts (e.g. partial response) or transient increases in platelet count (George et al, 1996).

Intraoperative platelet support.  There is a suggestion, with little evidence, that if random donor platelets are deemed necessary to cover the surgery, these should be given once the splenic artery has been clamped. Physiologically this would appear logical but has never been subjected to rigorous study (Level IV evidence).

Post-operative complications of splenectomy. Early studies reported complication rates of around 22% and two series from New Zealand and France showed no mortality and morbidity of only 7% in 48 and 72 patients respectively (Shaw, 1966; Naouri et al, 1993). In the study by Portielje et al (2001), two deaths occurred (out of 78 patients undergoing splenectomy) and 26% had early post-operative complications (pulmonary embolism, intra-abdominal bleeding, abdominal abscess, abdominal wall haematoma, gram negative sepsis, and others). Some 5% of patients suffered late complications. Overall, the complication rate was higher in patients greater than 65 years of age.

Platelet count pre-splenectomy. Stasi et al (1995) recommended a platelet count of 30 × 109/l; this may require treatment with oral corticosteroids or IVIg pre-operatively if the platelets are below 30 × 109/l. Others have used oral dexamethasone (40 mg/d for 4 d) to prepare 13 patients for splenectomy, 11 of whom had sufficient rise in the platelet count for surgery (Gillis & Eldor, 1998).

Predicting response to splenectomy.  Various indicators of the likely response to splenectomy have been reviewed including response to oral steroids, which has a low predictive value, response to high dose IVIg which, in two small series, correlated well with response to splenectomy (Chirletti et al, 1992; Law et al, 1997), and indium-labelled autologous platelet scanning which appears to be the most sensitive predictor of response to splenectomy, to date (Najean et al, 1997). Recent work using indium-labelled autologous platelets in 528 patients, has shown that when platelet destruction was splenic, then 96% of patients between the age of 5–30 years and 91% of those above the age of 30 years could expect to obtain a remission. However, where the platelet destruction was hepatic or diffuse (mixed splenic and hepatic) 92% of patients failed to normalize their platelet counts or had incomplete responses to splenectomy (Najean et al, 1997; Evidence level III). The indium-labelled autologous platelet scan appears to offer objective evidence of likely response to splenectomy and is recommended, where available, prior to splenectomy. (Evidence level III.)

Accessory splenic tissue.  The presence of an accessory spleen (or spleens) should be considered in patients who fail to respond to splenectomy or relapse following an initial response (George et al, 1994). Imaging techniques have shown the presence of accessory splenic tissue in up to 12% of such patients (Facon et al, 1992).

Prevention of infection post-splenectomy.  Patients should be given prophylactic polyvalent pneumococcal vaccine (Pneumovax II), Haemophilus influenzae b (Hib) and meningococcal C conjugate vaccinations at least 2 weeks prior to splenectomy (Centers for Disease Control (CDC), 1993; British Committee for Standards in Haematology (BCSH), 1996). Revaccination with pneumococcal vaccine should be offered every 5 years but is not currently recommended for Hib. The recommendation for booster doses of meningococcal C conjugate virus may be introduced in the future. Annual influenza vaccine is recommended in asplenic patients. The patients' vaccination status should be recorded in the case notes. Following splenectomy patients should be offered phenoxymethylpenicillin 250–500 mg twice daily, or equivalent, or erythromycin (500 mg bd) possibly for life, in order to reduce the incidence of post-splenectomy pneumococcal infection (McMullin & Johnston, 1993; Reid, 1994) (Grade C recommendation). The efficacy of such a regimen remains unproven (Makris et al, 1994). Some authorities would suggest antibiotic prophylaxis for 3 years post-splenectomy. Patients should have a supply of broad-spectrum antibiotics at home for use if fever develops. In addition there are cards available that should be carried by patients, to alert physicians that the patient is asplenic. Some patients may wish to purchase alert bracelets or pendants.

Adult patients failing first and second line therapies – chronic refractory itp

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This defines patients who fail to respond to first line treatment or require unacceptably high doses of corticosteroids to maintain a safe platelet count. The actual percentage of patients defined as having refractory ITP varies from 11% (Portielje et al, 2001) to 35% (George et al, 1994). A large number of drugs have been used as second line therapy for ITP with variable success. The therapy used will depend on the age of the patient, the severity of the presentation, the level of the platelet count, whether the disease is primary refractory or relapsed, and the length of time prior to relapse.

When considering second line therapy the original first line therapies (corticosteroids, IVIg or splenectomy) should be reconsidered and implemented if possible (George et al, 1996), although the doses may have to be altered compared with those used in first line therapy. Additional supportive therapy may need to be considered to allow their chronic use. For example, there is a small but significant risk of osteoporosis and avascular necrosis in patients on long-term corticosteroids and they should be assessed for this and treated accordingly with bisphosphonates or hormonal replacement if indicated.

The actual necessity for treatment should always be considered, weighing up the risks and side effects of treatment, against the risks of no treatment. In some patients symptomatic therapy such as fibrinolytic inhibitors may be used, particularly if there is only mucous membrane bleeding, and in severe bleeding, such as gastrointestinal haemorrhage, then platelets may be transfused. Although these are rapidly cleared from the circulation and have a severely shortened half-life they are often effective in stopping bleeding (Carr et al, 1986).

Conventional second-line treatment approaches

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For the patient in whom further conventional treatment with standard dose corticosteroids is inappropriate there are a wide variety of therapeutic options (Collins & Newland, 1992). These include: (i) high dose steroids, (ii) high dose IVIg, (iii) intravenous anti-D, (iv) vinca alkaloids, (v) danazol, (vi) immunosuppressive agents including azathioprine and cyclophosphamide, (vii) combination chemotherapy, and (viii) dapsone. The wide variety of treatments available for second line therapy reflects their relative lack of efficacy, and treatment should be tailored to suit the individual.

High dose corticosteroids.  As an alternative to prednisolone, Andersen (1994) reported favourable responses in refractory patients using an oral high dose dexamethasone regimen, comprising 40 mg of dexamethasone daily for 4 d, repeated every 28 d for six cycles. Ten patients were treated in this small study with favourable responses in all patients (all had platelet counts exceeding 100 × 109/l), sustained for at least 6 months. At this dose, side effects are common and subsequent studies conducted by other groups have not met with such success (Caulier et al, 1995; Arruda & Annichino-Bizzacchi, 1996; Demiroglu & Dundar, 1997; Kuhne et al, 1997).

Methylprednisolone.  Parenteral steroids such as methylprednisolone have been used as second and third line treatments for patients with refractory ITP. One study reported the results of nine adult patients with platelets < 50 × 109/l, all of whom were treated initially with oral corticosteroids (prednisolone/prednisone at 1 mg/kg/d). Methylprednisolone was given at 30 mg/kg/d for 3 d, 20 mg/kg/d for 4 d then 5, 2 and 1 mg/kg/d each for 1 week. The platelet count became normal within 3–5 d in all patients, although in seven of nine the response lasted only a few weeks before dropping to pre-treatment levels (Akoglu et al, 1991). von dem Borne et al, 1988) compared the effect of methylprednisolone with IVIg in 22 adult patients with a control series (17 patients treated with standard oral corticosteroids). The methylprednisolone was found to be as effective as IVIg in terms of the frequency of response, with no reported side effects. The major difference noted between the modalities was that the response to oral steroids was slower than that to intravenous methylprednisolone (von dem Borne et al, 1988). Again, the response to intravenous steroids was transient in all patients and maintenance with oral steroids was required to achieve an adequate platelet count.

High dose IVIg.  High dose intravenous immunoglobulin at a dose of 1 g/kg per day for two consecutive days, often in combination with corticosteroids, will raise the platelet count rapidly in a proportion of patients (Bussel & Hilgartner, 1984; Imbach et al, 1985). Side effects, particularly headaches, may occur, but if successful can be given on an intermittent basis or substituted with intravenous anti-D (Blanchette et al, 1993). Godeau et al (1993) reported good responses, including sustained complete response (CR), in some patients with refractory ITP treated with IVIg (1–2 g/kg) repeated every 2–3 weeks. In general, however, the platelet response to IVIg is transient with rare durable remissions (Schiavotto et al, 1995). IVIg is usually reserved for patients with symptomatic ITP in whom a rapid increase in platelet count is required, prior to operative procedures likely to cause blood loss, or in pregnancy.

Intravenous anti-D.  Intravenous anti-D has been shown to elevate the platelet count in 79–90% of adults (Scaradavou et al, 1997). The mechanism of action is believed to be mediated through the destruction of Rh (D) positive red cells which are preferentially removed by the reticuloendothelial system, particularly the spleen, thus sparing autoantibody-coated platelets through Fc receptor blockade (Bussel et al, 1991a).

In a single arm, open-label study of anti-D in 261 non-splenectomized and 11 splenectomized patients, 72% of patients showed an increase in platelet count of greater than 20 × 109/l, and in 46% of patients the platelet count rose by more than 50 × 109/l. The improvement lasted for more than 3 weeks in 50% of patients who responded (Scaradavou et al, 1997). Anti-D treatment is suitable for Rh (D) positive patients who are not splenectomized, and is not recommended for refractory patients following splenectomy.

Vinca alkaloids.  This group of drugs may cause a transient increase in the platelet count lasting between 1 and 3 weeks in two-thirds of patients treated. Around 50% of splenectomized patients will respond, but sustained responses are observed in less than 10% of patients (Berchtold & McMillan, 1989; Manoharan, 1991; George et al, 1996; Blanchette et al, 1998). Available drugs include vincristine 1 mg (occasionally 2 mg) intravenously (IV), or vinblastine 5–10 mg IV weekly for 4–6 weeks.

Danazol.  Danazol, an attenuated androgen, appears to be especially effective in patients with overlap syndromes between ITP and lupus and can often be used as a corticosteroid-sparing agent in responsive patients who require longer term unacceptably high doses. Ahn et al (1989) reported the outcome of 22 patients, of which 15 had undergone splenectomy, treated with danazol at a dose of 200 mg 2–4 times daily for more than 2 months.

Around 60% showed elevation of the platelet count above 50 × 109/l that was sustained for more than 2 months. Older females and those who have undergone splenectomy appeared to have the best response (Ahn et al, 1989). Danazol, when given for longer than a year, induced remissions lasting for years even after its discontinuation, but early relapses were frequent when it was administered for less than 6 months (Ahn et al, 1989). The mechanism of action of danazol is unknown but it is postulated to downregulate the number of Fc receptors on splenic macrophages (Schneider et al, 1997).

Immunosuppressive agents.  Immunosuppression may be required in patients who fail to respond to alternative therapies. Treatment with azathioprine (2 mg/kg, usually up to a maximum of 150 mg/d) or cyclophosphamide as single agents may be considered and up to 25% of patients may have a sustained response.

Bouroncle & Doan (1969) used azathioprine in 17 patients and reported excellent responses in 23.5% and good responses in 41% after treatment for an average of 10 months (a good response was one in which the normal platelet count was sustained only with continued use of azathioprine). Another review of the use of azathioprine (Quiquandon et al, 1990) reported 53 patients with chronic ITP who were treated with azathioprine at 150 mg per day for a median of 18 months; 40 of the 53 patients had previously undergone splenectomy. Platelet responses were documented in 64% of patients and were complete in 45% of these.

Azathioprine is slow-acting, and should be continued for up to 6 months before being deemed a failure. When a platelet response occurs the dose should be reduced, while maintaining a safe platelet count (Blanchette et al, 1998).

Cyclosporin A has been shown to increase the platelet count when given either alone or with prednisolone but its side effects make it unlikely to be of widespread practical use. It may, however, sustain the patient over a difficult period. Emilia et al. (1996) reported eight patients treated over a 13–62 month period with cyclosporin A (three patients had autoimmune haemolytic anaemia (AIHA), four ITP and one Evans' syndrome). Responses were seen in all patients (six CR and two partial responses). Side effects were moderate but transient. In most cases cyclosporin A had to be continued in order to maintain an adequate platelet count (Emilia et al, 1996). In a recent study (Kappers-Klunne & van't Veer, 2001), 20 patients with ITP all of whom were refractory to corticosteroids and half of whom had undergone splenectomy, were treated with cyclosporin A for at least 4 weeks. The dose was reduced by 50 mg/d every 2 weeks in those showing responses. Five patients remained in complete remission for at least 2 years after discontinuing cyclosporin A, and a further six patients showed partial responses. Cyclosporin A was discontinued in six patients due to side effects.

Dapsone.  In a series of 66 adults with chronic ITP and platelet counts < 50 × 109/l treated with dapsone at 75–100 mg orally, responses were observed in 33 of 66 patients (50%), with a median duration of treatment required to achieve a response of 21 d. Sustained responses were observed in 19 patients (Godeau et al, 1997). Dapsone's mechanism of action is unknown but may be due to reticuloendothelial blockade through increased red cell destruction (Godeau et al, 1997; Radaelli et al, 1999).

Half of all patients with chronic ITP treated with dapsone will show some response within 3 weeks, but it appears to be less effective in severe cases of ITP. The response rate to dapsone is low in patients who have undergone splenectomy (Hernandez et al, 1995).

Recommendation for second line therapy in adults:

Methylprednisolone is a useful second line treatment especially where there is a need to elevate the platelet count quickly, in combination with IV cyclophosphamide and/or IVIg. Evidence level IIa. Because of the relatively frequent incidence of accessory splenic tissue, this should be sought in those failing to respond to splenectomy. Agents such as high dose IVIg, vinca alkaloids, anti-D, danazol, azathioprine and cyclosporine are worth considering in non-urgent or ‘semi-urgent’ cases where there is a need to elevate the platelet count.

Patients failing first and second line therapies

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Fortunately, most adult patients with chronic refractory ITP are able to tolerate marked thrombocytopenia relatively well (Blanchette et al, 1998), and are able to have a normal or near normal quality of life. For those who fail to respond to standard first and second line therapy and who require treatment the options are limited and include: (i) interferon-α (IFN-α), (ii) anti-CD20, (iii) Campath 1H, (iv) mycophenolate mofetil, (v) protein A columns, and (vi) other treatments.

IFN-α.  There are several case series that report on the use of IFN-α in refractory ITP, and have shown that 25% of patients can achieve a platelet count of over 100 × 109/l for between 1 week and 7 months after the IFN-α treatment (George et al, 1996). The mechanism of action is unknown but may be due to modulation of effector B lymphocytes involved in the autoimmune process. Because available data suggest that IFN-α appears most effective in less severe ITP (Proctor et al, 1989), and previous reports of exacerbation of ITP while receiving IFN-α, with a fatal outcome in one patient (Matthey et al, 1990), IFN-α does not have a current role in the management of ITP.

Anti-CD20 antibody.  Rituximab (chimaeric anti-CD20 monoclonal antibody) has been evaluated in a single study (Stasi et al, 2001) in which 25 patients with ITP resistant to 2–5 therapeutic options were treated with 375 mg/m2 rituximab weekly for 4 weeks. Five patients showed a complete response and a partial response was seen in a further five. In seven patients the responses were sustained for over 6 months. There was a suggestion that younger patients showed better response rates.

Campath-1H. Lim et al (1993) treated six patients with refractory ITP (three patients had underlying CLL/non-Hodgkin's lymphoma and one had Hodgkin's disease). A response was seen in four of five evaluable patients, and in three of these the response lasted more than 4–9 months. In most cases it took between 4 and 6 weeks for a response to occur. Side effects were significant and included rigors and fever during the infusion, and marked lymphopenia (< 0.1 × 109/l) in all patients treated. Worsening of thrombocytopenia was noted in two patients during therapy. A more recent study of the use of Campath-1H in patients with a variety of cytopenias has shown that it was well tolerated with encouraging responses (Willis et al, 2001).

Mycophenolate mofetil.  This antiproliferative immunosuppressant, licensed for the prophylaxis of acute renal, cardiac or liver transplant rejection, has been shown to be of value in some patients with autoimmune cytopenias including refractory ITP (Evidence Level IV). However, the numbers of patients treated to date are small and larger studies are required (Zimmer-Molsberger et al, 1997; Allison & Eugui, 2000; Howard et al, 2002).

Protein A immunoadsorption column.Snyder et al (1992) reported on the use of protein A columns in 72 patients with refractory ITP, 49 of whom had undergone splenectomy. All 72 patients were given six immunoadsorption treatments for 2–3 weeks. Twenty nine of the 72 (40%) were continued on low dose steroid (prednisone <30 mg/d). Some 25% of patients had good responses (platelets exceeding 100 × 109/l, while 21% had fair responses (platelets between 50 and 100 × 109/l). Over half the patients (54%) had poor responses (Snyder et al, 1992). The mechanism of action of the protein A columns may involve reducing platelet activation (Cahill et al, 1998). The use of protein A columns requires good venous access, is cumbersome and relatively expensive (Karpatkin, 1997).

For patients who fail to respond to these therapies there are limited data on the use of ascorbic acid (Brox et al, 1988), chlorodeoxyadenosine, colchicine (Strother et al, 1984; Jim, 1986), liposomal doxorubicin, and peripheral blood stem cell transplantation (Lim et al, 1997; Skoda et al, 1997).

Plasmapheresis.  This treatment has been used in order to remove antiplatelet antibodies and immune complexes. There are several reports, the largest of which documented the treatment of 14 patients, some of whom had acute ITP (Marder et al, 1981). Five of nine with acute ITP responded to plasmapheresis. Bussel et al (1988) have reported success using a combination of plasmapheresis and IVIg for patients with chronic refractory ITP. The general consensus is that plasmapheresis is not a useful therapeutic manoeuvre in the treatment of chronic ITP.

Liposomal doxorubicin.  This has been used in the context of small non-randomized studies only, with variable success (Cosgriff et al, 1998).

Recommendation for therapy in adults failing first and second line therapies:

Campath-1H and rituximab are agents that may be of value for patients in whom there is no response to other therapies and in whom there is a definite requirement to elevate the platelet count (e.g. active bleeding). Mycophenolate mofetil appears to be effective in some patients with severe refractory ITP but larger studies are required to confirm its efficacy and safety. In terms of the risk: benefit ratio, treatments with interferon-α, protein A columns, plasmapheresis and liposomal doxorubicin are not recommended.

Emergency treatment in adult patients

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Urgent treatment is required for adults with severe thrombocytopenia (e.g. platelets < 30 × 109/l) and who have active bleeding from the gastrointestinal (GI) or genitourinary tracts, into the central nervous system or other sites. In this situation, treatment is aimed at elevating the platelet count to a “safe” level quickly (i.e. in less than 24 h). Clearly, many of the treatments discussed earlier take much longer to achieve this effect, and therapies that work almost immediately include platelet transfusion, intravenous methylprednisolone and IVIg.

Combination chemotherapy.  This mode of therapy may be useful for patients who have failed other therapies but in whom the need to elevate the platelet count is less urgent, e.g. patients who are not actively bleeding. There is a risk of second malignancies, including acute leukaemia, in patients treated with these medications and the use of cytotoxic agents, especially in younger patients, should be carefully considered. In those patients with severe, symptomatic chronic ITP refractory to multiple previous treatments the use of cyclophosphamide, vincristine and prednisolone combined in regimens such as those used in the lymphomas have been shown to be effective. Figueroa et al (1993) reported their results in 10 patients with refractory ITP. Two patients had underlying malignant disease (Hodgkin's disease and CLL). All 10 had been treated previously with steroids and had undergone splenectomy. The platelet count was less than 5 × 109/l in all patients. A complete response was seen in six patients (durable in four); a partial response was observed in two (one durable) and two died of intracerebral haemorrhage.

Recommendations for emergency treatment in adults:

For rapid elevation of the platelet count in extreme emergencies transfusion of random donor platelets is appropriate. When a higher platelet count is required but there is less urgency, IVIg and/or IV methylprednisolone and/or IV cyclophosphamide may be useful. Evidence Level IV.

Investigation and management of itp in children

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ITP in children is uncommon. It is usually a benign disorder that requires no active management other than careful explanation and counselling. This is because serious bleeding is rare, and about 80% of children with ITP will recover spontaneously within 6–8 weeks. Children and their parents may benefit from the contacts and literature available from ITP support groups such as The ITP Support Association (http://www.itpsupport.org.uk).

Diagnosis

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The diagnosis of childhood ITP is by exclusion. It can occur at any time of childhood, but in the neonatal period must be distinguished from maternal ITP or alloimmune thrombocytopenia. In children older than 10 years a chronic course may be more common. In acute ITP, the history is short with the appearance of purpura and bruising over a 24–48 h period. The platelet count is usually less than 10–20 × 109/l. Children with higher platelet counts rarely show any symptoms. The presenting platelet count may be unrecordable in the face of few symptoms and signs. The illness may follow an acute viral infection or immunisation. ITP associated with varicella needs special caution as occasional cases have more complex coagulation disorders with antibodies directed against proteins S and/or C (Ganesan & Kirkham, 1997). ITP may be provoked by the measles, mumps and rubella (MMR) vaccine, with an estimated risk of 1 in 24 000 doses (Farrington et al, 1995), usually occurring within 6 weeks of vaccination. There is no evidence of a vaccine-associated recurrence in children who developed ITP independently of and before MMR vaccination (Miller et al, 2001). The Committee on the Safety of Medicines (CSM) recommend that children who develop ITP within 6 weeks of the first dose of MMR should have their serological status for the three viruses evaluated before the second dose is due. If serology suggests that a child is not fully immune to measles, mumps and rubella, then a second dose of MMR is recommended. The Public Health laboratory Service is offering a free serological testing service for children developing ITP within 6 weeks of the first dose of MMR. Those not protected against rubella by MMR are at risk of developing ITP from infection with rubella itself when the risk is 1 in 3000 (data from the Department of Health Education Authority, http://www.immunisation.org.uk). The MMR vaccine package inserts are being upgraded to reflect the CSM's advice.

Differential diagnosis

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The history of bruising and purpura is sometimes more chronic, with symptoms developing more slowly over weeks or months. In these children caution should be exercised and particular attention paid to the possibility of a congenital disorder. These are most often missed because they are uncommon and are therefore not considered.

Congenital disorders that may resemble ITP

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(a)In a young child (within a few weeks or months of birth)

Wiskott Aldrich syndrome

Bernard Soulier syndrome

Other occasional families with isolated congenital or hereditary thrombocytopenias of unspecified type

(b) In older children

Evolving Fanconi anaemia

von Willebrand's disease type IIB (Donner et al, 1987)

Serious marrow disorders

  Acute leukaemia (NB especially Down syndrome)

  Aplastic anaemia

Special diagnostic considerations in older children

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Children over the age of about 10 years may be more likely to have a chronic course (Walker & Walker, 1984; Reid, 1995). Other autoimmune diseases associated with thrombocytopenia should be considered, particularly systemic lupus erythematosus (SLE) and antiphospholipid syndrome. Older children should have additional investigations performed (see below). Thrombocytopenia has not commonly been reported as the initial presentation of HIV infection in children, but can occur during the course of the disease.

Special diagnostic considerations in the Accident & Emergency (A & E) Department

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The possibility of non-accidental injury (NAI) and meningococcal disease must be considered by A & E staff when dealing with a young child presenting with bruising and purpura for the first time. Children with infection usually have other features and non-accidental injury does not present with generalized purpura.

Investigations

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Full blood count and careful film examination by an experienced morphologist.  If a low platelet count does not fit the clinical picture the count should be repeated to exclude a spurious result.

Coagulation screening.  Only necessary if there is a possibility of meningococcal infection, features to suggest an inherited bleeding disorder in addition, or a suspicion of NAI.

Antiplatelet antibodies.  Measurement of antiplatelet antibodies does not assist in the diagnosis (Taub et al, 1995; George et al, 1998).

H. pylori infection.  This is discussed above. There is no information about this infection as a precipitating cause of ITP in children, although H. pylori infection does occur in childhood. There is therefore no indication to screen children with ITP unless there are other clinical indicators to suggest infection (Sherman & Macarthur, 2001).

Bone marrow aspiration.  Bone marrow examination excludes some causes of thrombocytopenia but can only confirm that the picture is consistent with peripheral destruction. Although it is argued that if a child has a sinister underlying disorder there will be other clues in the blood picture or the clinical examination (Halperin & Doyle, 1988; Calpin et al, 1998) this is not always reliable (Reid, 1992).

Recommendation for investigation of suspected childhood ITP:

In a child with typical clinical and laboratory features who needs no treatment, a bone marrow examination is not required (Grade B recommendation). If therapy is considered, it must be recognised that occasionally the diagnosis of ITP will be incorrect. Bone marrow examination will usually reveal this. Marrow examination is necessary in the presence of atypical clinical features or if there is no response to treatment. It is also recommended that the bone marrow be examined before steroid therapy is given (Evidence Level IV). Marrow aspiration should ideally be accompanied by a trephine biopsy because this gives a better estimate of megakaryopoiesis (Beardsley & Nathan, 1998). Marrow examination is painful and is more acceptable when performed under general anaesthesia (Evidence levels: IIb, III).

Management of ITP in childhood: general measures

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It is essential that children are classified clinically and not by platelet count, because children with severe thrombocytopenia (less than 10 × 109/l) have usually “mild” clinical symptoms. Pronounced skin purpura and bruising, however, extensive, do not indicate a serious bleeding risk on their own. To date there has been a universal tendency to treat the count alone rather than the child's symptoms. Two UK national surveys of children with ITP have demonstrated that only 4% of children with ITP have serious symptoms such as severe epistaxis or GI bleeding (Bolton-Maggs & Moon, 1997; Bolton-Maggs & Moon, 2001). Similar data are available from Germany (Sutor et al, 2001) and Norway (Zeller et al, 2000). Several studies have confirmed that the incidence of intracranial haemorrhage (ICH) is much less than the 1–3% widely quoted, and is closer to 0.1–0.5% (Lilleyman, 1994). In the two UK national surveys there were two ICH in 703 cases (0.3%), with complete recovery in both cases, similar to the incidence derived from a retrospective national survey (Lilleyman, 1994, 1997). Similarly, a recent Japanese study found an incidence of 4 in 772 (0.52%) children, with no deaths (Iyori et al, 2000). It is impossible to predict which children will develop an ICH, and it may be that there are other predisposing factors that contribute to this for example an underlying vascular anomaly.

ICH has occurred in children who have been treated and in one study this was the case in a third of children reviewed (Lee & Kim, 1998). It is worth noting that in the first randomized study of IVIg the only child to have ICH did so early, was on IVIg and died 6 d after presentation (Imbach et al, 1985). As discussed earlier, the need for treatment in children with acute ITP should not be driven by the platelet count alone, but mainly by symptoms. Children who continue to be severely thrombocytopenic with significant bleeding symptoms are very rare indeed, and should be referred to a specialist centre for management (Lilleyman, 1999).

Clinical classifications

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Two clinical scoring systems have been used, the first in the two UK national surveys for analysis of 703 newly diagnosed children (Bolton-Maggs & Moon, 1997, 2001), and the second was reported from a single centre in Texas where it has been analysed on 109 occasions in 54 patients, both at diagnosis and in established ITP (Buchanan & Adix, 2001). Both of these confirm that the majority of children do not have serious bleeding problems despite very low platelet counts. The severity of bleeding at any given time, especially at presentation does not predict the risk of subsequent episodes of serious bleeding. Children should not be treated on the basis of cutaneous signs alone, however, dramatic and widespread the purpura.

Recommendation:

Clinical severity, in addition to platelet count, should be used to define the severity of acute ITP in children. Treatment should be considered on the basis of other clinical symptoms in addition to cutaneous signs, and not the platelet count alone (Level IIb evidence, Grade B recommendation).

Treatment: Expectant ‘Watch and Wait’ policy

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More than 80% of children with acute ITP do not have significant bleeding symptoms and can be managed without specific therapy directed at raising the platelet count (Buchanan et al, 1997; Baronci et al, 1998; Dickerhoff & von Ruecker, 2000; Bolton-Maggs et al, 2001; Bolton-Maggs & Moon, 1997, 2001; Sutor et al, 2001) (Evidence levels III and IV). It is essential that the parents, and child where able, have an explanation that this is usually a self-limiting benign disorder (Dickerhoff & von Ruecker, 2000). Most children can be managed well at home, and do not require hospital admission, which should be reserved for children with clinically important bleeding (severe epistaxis, i.e. lasting more than 30 min with heavy bleeding, GI bleeding, etc.). Parents should be advised to watch for other signs of bleeding and be given a contact name and 24 h telephone number; similar advice as that given to families with a child with severe haemophilia is often the most appropriate, with, as far as possible, avoidance of formal contact sports or activities with high risk of trauma or head injury. Other activities can be continued as normal, and the child should be encouraged to continue schooling on the basis that ITP is a disorder that may last some weeks or months (Evidence levels: III and IV, Grade B and C recommendation).

Most children with mild or moderate symptoms only (the majority) can be safely managed as outpatients with weekly or less frequent visits (level III evidence) (Dickerhoff & von Ruecker, 2000; Bolton-Maggs et al, 2001). A repeat platelet count is not necessary while a child still has purpura as this symptom is an indication that the count is likely to be less than 20 × 109/l; however, a repeat count should be performed within the first 7–10 d to check that there is no evidence of a serious marrow disorder emerging, particularly aplasia. Otherwise the count can be performed when clinically indicated by a change of symptoms, or if the family feel more at ease knowing the result. However, too close a focus on numbers is not helpful. When the thrombocytopenia persists but the child remains well, the intervals between visits can be stretched out in order to minimise interference with schooling. With increasing duration of a very low platelet count and limitation of some sporting activities, lifestyle issues become relatively more important and should be sympathetically discussed. These issues may influence decisions about treatment. ‘Most parents and patients can live quite comfortably with petechiae and low platelets awaiting spontaneous remission providing their physician can’ (Dickerhoff, 1994).

Recommendation:

Children with acute ITP and mild clinical disease may be managed expectantly with supportive advice and a 24 h contact point, irrespective of platelet count (Grade B recommendation). The full blood count should be repeated within 10 d of diagnosis to ensure there is no evidence of evolution to a serious marrow disorder; thereafter the count need not be monitored until resolution of clinical symptoms suggests the onset of remission or there are other clinical indicators suggesting the need.

Specific treatment to raise the platelet count

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Several therapies raise the count faster than no treatment (Ib evidence). However, all have significant side effects and none alters the underlying pathology nor increases the chance of complete remission. These strategies are appropriate for children with severe bleeding symptoms.

Corticosteroids

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Prednisolone.  Conventional doses of 1–2 mg/kg/d for a maximum of 14 d may be effective in raising the count but perhaps is little faster than no therapy (Buchanan & Holtkamp, 1984) (Level 1b evidence). Prednisolone should be discontinued after a maximum of 2–3 weeks irrespective of platelet count because of the serious side effects associated with prolonged treatment. There is evidence that smaller doses (0.25 mg/kg/d for 21 d) may produce a rise in count (Bellucci et al, 1988). A high dose regimen (prednisolone 4 mg/kg/d) has been compared in two randomized controlled trials and been shown to be more effective (Level Ib evidence). Fifty three children were randomized between IVIg, high dose (4 mg/kg/d) oral prednisolone with tapering and cessation by 21 d and no therapy in one study (Blanchette et al, 1993). The median time to reach a count of > 50 × 109/l was 4 d in the prednisolone group compared with 16 d in the ‘no treatment group, and 2 d in those given IVIg. The same regimen was used in a later study of 146 children which included a treatment arm with anti-D (Blanchette et al, 1994). In the latter study 28/39 (72%) of children in the high dose steroid arm achieved a count > 50 × 109/l within 72 h.

The disadvantage of this steroid regimen is the duration at high dose. A short course may be sufficient. A pilot study of 25 children given 4 mg/kg for 4 d (Carcao et al, 1998) demonstrated that 22 children achieved a count of > 20 × 109/l within a week with minimal side effects (Level III evidence). If a child requires treatment for symptoms, an early effect on count is reassuring. It is essential that steroids are not continued for longer than 2 to 3 weeks or titrated against the platelet count as this may lead to inappropriate doses and duration, with very significant long-term side effects.

Other steroid regimens

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High dose methyl prednisolone (HDMP). This has been used as an alternative to IVIg because it is cheaper and effective. A small study of 22 children given an oral 7 d course (30 mg/kg/d for 3 d followed by 20 mg/kg/d for 4 d) demonstrated that all patients achieved platelet counts > 50 × 109/l by d 7. Courses were repeated monthly if the count was less than 20 × 109/l on d 30, for up to six courses (Ozer et al, 2000). Other small studies have demonstrated HDMP to be as effective as IVIg in raising the platelet count (Ozsoylu et al, 1989, 1993). Two studies demonstrated the efficiency of a combined approach using HDMP with IVIg but these were small uncontrolled studies (Barrios et al, 1993; Gereige & Barrios, 2000).

Pulsed high dose dexamethasone.  This treatment appears to be less effective in children than in adults in producing long-term remission, but may be useful as a temporary measure. There is no evidence that this treatment, or any of the treatments that can produce an increase in the platelet count, increases the chance of complete remission. Three small studies of 11 (Kuhne et al, 1997), 17 (Borgna-Pignatti et al, 1997) and seven children (Chen et al, 1997) demonstrated some benefit in some children – 78% children achieved a platelet count > 100 × 109/l within 72 h in 41 cycles of treatment given to 11 children with chronic ITP (Kuhne et al, 1997). However, side effects were unacceptable in 3/11 children. This treatment cannot be recommended as first line therapy in symptomatic children.

Recommendation:

If a child has mucous membrane bleeding and more extensive cutaneous symptoms, high dose prednisolone 4 mg/kg/d is effective (Grade A recommendation, Level Ib evidence). It can be given as a very short course (maximum 4 d). There are no direct comparisons of low dose (1–2 mg/kg/d) with high dose therapy. If lower doses of 1–2 mg/kg/d are used the treatment should be given for no longer than 14 days, irrespective of response.

Intravenous immunoglobulin

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Intravenous immunoglobulin is effective in raising the platelet count in more than 80% of children, and does so more rapidly than steroids or no therapy (Blanchette et al, 1994) (Level 1b evidence). It is expensive and invasive, and should be reserved for emergency treatment of patients who do not remit or respond to steroids and who have active bleeding. It is an appropriate treatment to enable essential surgery or dental extractions. It should not be used to raise the platelet count in children with cutaneous symptoms alone. IVIg is a pooled blood product, the risks of which must be explained to patients. It has significant side effects, noted in 75% of children treated in a recent trial (Blanchette et al, 1993). Severe headache can be troublesome (Kattamis et al, 1997). In addition, IVIg has transmitted hepatitis C, a life-threatening infection (Duhem et al, 1994). Its use in children with trivial symptoms is not justified.

Dose regimen.  The traditional dose is 0.4 g/kg daily for 5 d. This has now been superseded by short course high dose treatment either with a single dose of 0.8 g/kg or 1 g/kg given on 1 or 2 d (Blanchette et al, 1994; Tarantino et al, 1999). These larger doses may be associated with a higher risk of side effects. Another small, randomized multicentre study demonstrated lower doses of 250, 400 or 500 mg/kg/d for 2 d to be effective (count increasing by more than 30 × 109/l) in 16/17 (94%) children aged 5–12 years (Warrier et al, 1997). The product chosen should be one with at least two viral inactivation steps included in the manufacturing process.

Recommendation:

IVIg can raise the platelet count rapidly, but should be reserved for emergency treatment of serious bleeding symptoms or in children undergoing procedures likely to induce blood loss. It is effective given as a single dose of 0.8 g/kg (Evidence level Ib, Grade A recommendation). Lower doses are also effective, and fewer side effects are seen, in younger children.

Other therapies

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Anti-D immunoglobulin.  This is less expensive than IVIg and can be given to Rh (D) positive individuals as a short infusion, and is therefore amenable to outpatient therapy. It is effective in children (Scaradavou et al, 1997), but the mechanism of action is not fully understood. Like IVIg, anti-D has the disadvantage of being a pooled blood product, but produces a rise in platelet count as rapidly as IVIg when given at sufficient dosage (45–50 µg/kg) (Tarantino et al, 1999). Some degree of haemolysis is quite commonly seen, which can occasionally be severe and is associated with renal failure (Gaines, 2000). Lower dose treatment is less effective at raising the platelet count than IVIg (Blanchette et al, 1994).

Other treatments

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As with adult ITP, a variety of other drugs have been tried in patients with persistent thrombocytopenia and bleeding. There is insufficient information concerning their use in children to make specific recommendations concerning what should be used or in which order. Cytotoxic drugs should be used with extreme caution in children, with appropriate consideration given to infertility and carcinogenesis.

Use of blood products – platelet transfusions

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Life-threatening haemorrhage is the only indication for platelet transfusion in ITP, a destructive platelet disorder where transfusions of normal doses are unlikely to be effective. National surveys have demonstrated that platelet transfusions are sometimes given for simple thrombocytopenia. This is never justified. In a life-threatening situation (such as the rare ICH) larger than normal doses are required with monitoring of the increment as a guide, and other modalities such as high dose IV steroids and IVIg should be given at the same time to maximise the chances of raising the count and stopping the haemorrhage.

Recommendation:

Platelet transfusions should only be given for ICH or other life-threatening bleeding, and then in much larger doses than for marrow failure. At the same time, immunomodulatory treatment should be given with high dose intravenous steroids or IVIg (Grade C recommendation).

Chronic ITP in childhood

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Most children with ITP will remit within 6 months. The management of children with continuing thrombocytopenia is essentially the same as for acute ITP. Many children settle with an adequate platelet count (i.e. more than 20 × 109/l) and have no symptoms unless injured. In children under 10 years of age at diagnosis spontaneous remission is likely to occur eventually; expectant management can continue. Children more than 10 years of age at diagnosis, and in particular adolescent females, are more likely to sustain a chronic course and management considerations are much as for adults. Most children need no specific therapy to raise the count unless injured or requiring surgery or dental extraction. Particular problems may arise for girls at the onset of menstruation. Children and parents should not forget the vulnerability to excessive bleeding following serious accidents and it is advisable for the family to carry a card or letter with details of the disorder in case of emergency. A medical bracelet or pendant may be helpful.

Children with counts persistently below 10 × 109/l are likely to have some symptoms, e.g. easy bruising or odd petechiae. Such children have been described as having chronic severe ITP (CSITP), are very rare (estimated annual incidence of perhaps 1 in 2 500 000; Lilleyman, 1999) and are the most difficult to manage (Lilleyman, 2000). There is a strong case for these children to be referred to paediatric haematologists with a special interest. Occasionally, girls carry ITP into adulthood, but it tends to attenuate over time (anecdotal reports). There are no data on boys with persistent ITP beyond their teens.

The risk of serious bleeding is a function of the duration of time with a low count and has been estimated at 0.5% at 12 months in those with a count less than 20 × 109/l (Lilleyman, 1999). There is insufficient evidence in the literature to determine the best course of management for these patients (George et al, 1996; Lilleyman, 2000). Treatment must be tailored to the child and situation, based on three criteria: the therapy should be effective, it should not carry more risk than the untreated condition, and it should make the child feel better (George et al, 1996; Lilleyman, 2000).

A significant group of children with ITP have counts of 10–30 × 109/l, and although they have no serious bleeding, are nevertheless troubled by purpura. Children, particularly once at secondary school, become very conscious of their appearance and need sympathetic support. Lifestyle issues and restrictions on sporting activities become more important and should be taken into account in considering therapy. Intermittent treatment with IVIg can be given to cover activity holidays after appropriate discussion of the risks. However, it should be noted that this might cause additional problems with insurance cover when a child has been in hospital within 6 months of going on holiday. There is no evidence that air travel predisposes to bleeding in patients with ITP; there is no indication to treat the count prior to holidays other than to cover activities. Parents should always declare the illness to their insurance company before travelling in case treatment is required while on holiday.

Bleeding complications must be managed according to severity and circumstances; there is no straightforward strategy for these young people. Splenectomy is often considered, but it is ineffective in around 25% of cases, and with longer follow-up it is clear that the relapse rate is high, although often the platelet count runs at a more acceptable level with fewer symptoms.

Recommendations:

1. Children with chronic ITP usually do not need active therapy but should be followed up regularly and reminded to report to hospital after injuries. They should have a designated contact person and number.

2. Children with chronic severe ITP should be referred to a paediatric haematologist for management and long term follow-up.

Splenectomy

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Splenectomy is rarely indicated in children with ITP. Long-term follow-up demonstrates that spontaneous remissions continue to occur at least up to 15 years from diagnosis (Reid, 1995), so the persistence of a low count beyond 6 or 12 months is therefore not on its own an indication for surgery. Given that the risk of dying from ITP in childhood is extremely low (less than 1 in 500), that the mortality associated with splenectomy is 1.4 (Najean et al, 1997) to 2.7% (Eraklis & Filler, 1972) and that the risk of overwhelming sepsis probably persists for life, splenectomy is only justified in exceptional circumstances (Eden & Lilleyman, 1992). Severe lifestyle restrictions, crippling menorrhagia or life threatening haemorrhage may give good reason for the procedure, but only 70–75% will respond (George et al, 1996), and full precautions against sepsis should be undertaken (BCSH, 1996).

Recommendation:

Splenectomy is rarely indicated in childhood ITP. It is occasionally justified for life-threatening bleeding and for children with chronic unremitting and severe ITP whose disease has been present for more than 12–24 months with demonstrable impairment of their quality of life, but these children are rare, and should be referred to a specialist paediatric haematologist for individual consideration (Grade C recommendation).

Thrombocytopenia in pregnancy

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Incidence of ITP in pregnancy

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The advent of routine platelet counting using automated blood cell counters highlighted the fact that mild to moderate thrombocytopenia is common in healthy women with an apparently normal pregnancy. Excluding those cases with spurious counts due to EDTA-induced in vitro platelet aggregation, the large majority of these women have ‘gestational thrombocytopenia’ (GT), a benign self-limiting phenomenon with no significant bleeding-risk to mother or infant. However, it may be difficult or impossible to distinguish GT from idiopathic (autoimmune) thrombocytopenia (ITP) in which the transmission of platelet antibodies across the placenta has the potential to cause fetal or neonatal thrombocytopenia and haemorrhage. Maternal thrombocytopenia may also be an indicator of significant complications of pregnancy such as pre-eclampsia or disseminated intravascular coagulation (DIC) in addition to a range of less common acquired or congenital disorders (Table I). Thus, the assessment of individual cases of thrombocytopenia in pregnancy focuses on excluding important secondary causes and weighing the risks of bleeding in mother and infant against the hazards of diagnostic and therapeutic interventions.

Table I.  The major causes of maternal thrombocytopenia in pregnancy.
  • *

    Haemolysis, elevated liver enzymes and low platelets.

Spurious – EDTA-induced platelet aggregation
Gestational thrombocytopenia
Pre-eclampsia and HELLP* syndrome
Autoimmune thrombocytopenia
– idiopathic
– drug-related
– SLE
– antiphospholipid syndrome
– HIV-related
Disseminated intravascular coagulation
Haemolytic uraemic syndrome/thrombotic thrombocytopenic purpura
Folate deficiency
Congenital platelet disorders
Coincidental marrow disease
Hypersplenism

Normal platelet count in pregnancy

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Most pregnant women have platelet counts within the non-pregnant reference range. However, large prospective studies (level III evidence) have confirmed that platelet counts tend to fall during pregnancy and levels of 120–150 × 109/l are not uncommon in the third trimester (Sill et al, 1985; Burrows & Kelton, 1988). A single-institutional study (Burrows & Kelton, 1988) of 1357 women with normal pregnancy, delivering at term, showed a mean platelet count of 225 × 10/l with 95% confidence intervals of 109–341 × 109/l.

Presentation and diagnosis

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Gestational thrombocytopenia (incidental thrombocytopenia of pregnancy)

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The best evidence for the natural history of this phenomenon comes from a sequence of prospective studies reported by the McMaster group in Ontario (Burrows & Kelton, 1988, 1990, 1993) (Level III evidence). At term, thrombocytopenia was present in 5.4–8.3% of healthy mothers. Platelet counts were only mildly reduced in most patients (mean 135 × 109/l) and were between 100 and 150 × 109/l in 95% of cases. It is exceptional for the platelet count to fall below 80 × 109/l but rare cases, subsequently confirmed as GT, had counts as low as 50 × 109/l.

The incidence of thrombocytopenia in cord blood samples taken from the infants of women with GT and women with normal platelet counts was identical at 4%.

Hence, GT is characterized by:

  • • 
    Mild thrombocytopenia (rarely < 80 × 109/l)
  • • 
    Occurrence in healthy women with otherwise normal blood counts
  • • 
    Most commonly occurs in the third trimester of pregnancy
  • • 
    Normal platelet counts before and after pregnancy
  • • 
    No association with maternal haemorrhage
  • • 
    No association with fetal or neonatal thrombocytopenia

GT is difficult to distinguish from ITP when thrombocytopenia is identified for the first time during pregnancy and no previous counts have been documented.

Idiopathic (autoimmune) thrombocytopenia (ITP)

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Chronic ITP is most common in women of reproductive age and is therefore encountered in pregnancy. The estimated prevalence is 1–5 cases per 10,000 pregnancies (Kessler et al, 1982), i.e. around 100 times less common than GT. Patients occasionally present for the first time with severe thrombocytopenia in pregnancy and women with previously diagnosed ITP may experience an exacerbation in pregnancy, the nadir platelet count usually occurring in the third trimester (Burrows & Kelton, 1992). However, the most common presentation is the finding of asymptomatic thrombocytopenia on routine laboratory testing, when the distinction from GT may be difficult.

As in the non-pregnant patient, the diagnosis of ITP is largely one of exclusion as there is no confirmatory laboratory test (Burrows & Kelton, 1992). Documentation of a low platelet count outside pregnancy is invaluable. It is important to exclude pre-eclamptic syndromes, DIC or autoimmune disorders such as SLE and the antiphospholipid syndrome, which carry significant prognostic and therapeutic implications (Table II). Patients should be carefully examined for hepatosplenomegaly and lymphadenopathy or features of pre-eclampsia (hypertension, proteinuria, intrauterine growth restriction).

Table II.  Recommended laboratory investigations of thrombocytopenia in pregnancy (Grade C recommendation)
  1. PT, prothrombin time; APTT, activated partial thromboplastin time; DRVVT, dilute Russell's viper venom time.

Blood film (to exclude spurious thrombocytopenia, red cell fragments, other haematological disorders)
Coagulation screen (PT, APTT, fibrinogen, d-dimer)
Liver function tests
Anticardiolipin antibodies/lupus anticoagulant
SLE serology

If there are no additional clinical features and the blood count and film are otherwise normal, bone marrow examination is not recommended (Letsky & Greaves, 1996).

As with non-pregnant adults and paediatric ITP, platelet-associated IgG is of no diagnostic value. Despite recent innovative methodologies, measurement of serum platelet autoantibodies are not clearly diagnostic of ITP in individual patients and do not predict the likelihood of neonatal thrombocytopenia (Burrows & Kelton, 1992; Letsky & Greaves, 1996; Sainio et al, 1998; Boehlen et al, 1999).

Recommendation for investigation of suspected ITP in pregnancy:

As in non-pregnant patients, the diagnosis of ITP is one of exclusion. Benign gestational thrombocytopenia is 100 times more common but, as there are no definitive diagnostic tests, it may be impossible to distinguish these conditions until a non-pregnant platelet count is available. All women with platelet counts < 100 × 109/l should be screened for clinical or laboratory evidence of pre-eclampsia, coagulopathy or autoimmune disease. Bone marrow examination is unnecessary unless there is suspicion of leukaemia or lymphoma. The routine measurement of PAIg or platelet antibodies is not recommended (Evidence Levels III/IV, Grade C recommendations).

Options for treatment

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Optimum management of ITP in pregnancy requires close collaboration between the obstetrician, haematologist and paediatrician. There are no high quality prospective studies or randomized clinical trials to inform management of the mother, delivery or the neonate. Recommendations are based on clinical experience and expert consensus (Grade C recommendation).

Management of the pregnant woman with ITP

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The decision to treat the pregnant woman with ITP is based on assessment of the risk of significant haemorrhage. The count usually falls as pregnancy progresses, the greatest rate of decline and nadir occurring in the third trimester (Burrows & Kelton, 1992). Therefore, careful planning is required to ensure a ‘safe’ platelet count at the time of delivery. Frequency of monitoring depends on the individual case, taking into account the absolute platelet count, rate of change and proximity of delivery.

Targets for treatment

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Asymptomatic patients with platelet counts > 20 × 109/l do not require treatment until delivery is imminent but should be carefully monitored, both clinically and haematologically (Letsky & Greaves, 1996). Platelet counts of > 50 × 109/l are regarded as safe for normal vaginal delivery (Letsky & Greaves, 1996) and some experts extend this to levels of 30–50 × 109/l (Lichtin, 1996). A platelet count of > 50 × 109/l is also safe for Caesarian section but would preclude the use of epidural anaesthesia for which the platelet count should be > 80 × 109/l. Because of the theoretical risk of haematoma formation and neurological damage, spinal or epidural anaesthesia is not recommended if the platelet count is < 80> 50 × 109/l (Letsky & Greaves, 1996). There is no evidence that the template bleeding time predicts the risk of haemorrhage in this situation.

Treatment options

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The major treatment options for maternal ITP are corticosteroids or IVIg. Vinca alkaloids, androgens and most immunosuppressive drugs should not be used in pregnancy although azathioprine has been used safely in transplant patients.

If the duration of treatment is likely to be short, i.e. starting in the third trimester, corticosteroids are a cost-effective option. An initial dose of 1 mg/kg (based on pre-pregnancy weight) is recommended (Burrows & Kelton, 1992; Letsky & Greaves, 1996), subsequently tapered to the minimum haemostatically effective dose. Patients must be carefully monitored for significant side effects such as hypertension, hyperglycaemia, osteoporosis, excessive weight gain and psychosis. As 90% of the administered dose of prednisolone is metabolised in the placenta (Smith & Torday, 1982), serious fetal side effects such as adrenal suppression are unlikely. The only systematic study showed no beneficial effect of low dose maternal steroids on the fetal platelet count (Christiaens et al, 1990).

If steroid therapy is likely to be prolonged, significant side effects occur or an unacceptably high maintenance dose is required (perhaps > 7.5 mg prednisolone daily) IVIg therapy should be considered. There are no published comparative trials of steroids and IVIg in pregnancy. The conventional dose of IVIg is 0.4 g/kg/d for 5 d although 1 g/kg for 2 d has been used successfully and may be more convenient (Burrows & Kelton, 1992). The response rate (80%) and duration of response (2–3 weeks) is similar to non-pregnant patients. After an initial response, repeat single infusions can be used to prevent haemorrhagic symptoms and ensure an adequate platelet count for delivery. The ability of maternal IVIg therapy to improve fetal platelet counts remains controversial (Nicolini et al, 1990). IVIg carries the same potential risks and side effects as in the non-pregnant patient and the financial cost is much higher than corticosteroids.

Therapeutic options for those women with severely symptomatic ITP refractory to oral steroids or IVIg include high dose intravenous methyl prednisolone (1000 mg), perhaps combined with IVIg, or azathioprine (Letsky & Greaves, 1996). From available data, the latter appears to cause no significant problems to either mother or fetus (Erkman & Blythe, 1972; Price et al, 1976; Alstead et al, 1990). Splenectomy in pregnancy is now rarely performed. If essential, it is best carried out in the second trimester and may be successfully performed by the laparoscopic route, although this may be technically difficult beyond 20 weeks gestation.

Recommendation: (All Grade C)

  • • 
    Asymptomatic women with platelet counts > 20 × 109/l do not need treatment until delivery is imminent
  • • 
    Platelet counts > 50 × 109/l are safe for normal vaginal delivery in patients with otherwise normal coagulation
  • • 
    Platelet counts > 80 × 109/l are safe for caesarean section, spinal or epidural anaesthesia in patients with otherwise normal coagulation
  • • 
    In women who need treatment, both oral corticosteroids and IVIg appear to have a similar response rate to the use of these agents in the non-pregnant patient Although many clinicians now favour the use of IVIg in pregnancy there are no good comparative studies and the decision must take into account maternal clinical factors and preference in addition to the expense, availability and (remote) risks of microbial transmission by IVIg.
  • • 
    There are no convincing data on the effect (beneficial or otherwise) of corticosteroids or IVIg on the fetal/neonatal platelet count.
  • • 
    Severe refractory ITP may respond to high dose IV methyl prednisolone ± IVIg or azathioprine. If essential, splenectomy may be performed (ideally in the second trimester) and the laparoscopic route may have clinical advantages similar to those seen in non-pregnant patients.

Management of delivery and the newborn infant

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Historically, management of the delivery in mothers with ITP was dominated by concerns over the risk of severe neonatal thrombocytopenia and haemorrhage. In 1976, caesarean section was recommended for all patients based on a reported perinatal mortality of 12–21%, largely due to birth trauma and ICH (Murray & Harris, 1976). These data were clearly selective and excessively pessimistic; more recent reviews suggesting a neonatal mortality of around 0.6% (Burrows & Kelton, 1992). Large prospective studies published in the 1990s show an incidence of severe neonatal thrombocytopenia (< 50 × 109/l) of 8.9–14.7% with ICH occurring in 0–1.5% of infants (Bussel et al, 1991b; Burrows & Kelton, 1993). There is no evidence that caesarean section is safer for the thrombocytopenic neonate than uncomplicated vaginal delivery (which is unequivocally safer for the mother). In any event, most haemorrhagic events in neonates occurred 24–48 h after delivery at the nadir of the platelet count.

Attempts have been made to predict which neonates will have severe thrombocytopenia to inform management decisions. It is reported (evidence level III) that the fetal or neonatal platelet count cannot be reliably predicted from the maternal platelet count, maternal platelet antibody levels (by a variety of techniques) or a history of maternal splenectomy for ITP (Samuels et al, 1990; Burrows & Kelton, 1992; Letsky & Greaves, 1996; Sainio et al, 1998; Boehlen et al, 1999). Fetal blood sampling by cordocentesis has been explored (Scioscia et al, 1988) but this procedure carries a mortality of 1–2%, which is at least as high as the risk of ICH. Scalp blood sampling in early labour to measure the fetal platelet count has also been advocated (Scott et al, 1980). This procedure is technically difficult, commonly produces artefactually low results because of clotting due to exposure to vernix or amniotic fluid and can cause significant haemorrhage. For these reasons, both cordocentesis and fetal scalp blood sampling have now been largely abandoned in the management of ITP in pregnancy.

In view of the difficulty in predicting those few neonates with severe thrombocytopenia and the very low risk of serious haemorrhage, it is now generally agreed (Level III evidence, Grade B recommendation) that the mode of delivery in ITP should be determined by purely obstetric indications (Bussel et al, 1991c; Burrows & Kelton, 1992; Letsky & Greaves, 1996).

Following delivery, a cord blood platelet count should be determined in all cases (Level III evidence, Grade C recommendation). Those infants with subnormal counts should be closely observed clinically and haematologically as the platelet count tends to fall further to a nadir between d 2 and 5 after birth (Burrows & Kelton, 1992). Treatment of the neonate is rarely required. In those with clinical haemorrhage or platelet counts < 20 × 109/l treatment with IVIg 1 g/kg produces a rapid response. Life-threatening haemorrhage should be treated by platelet transfusion combined with IVIg (Burrows & Kelton, 1992).

Severe thrombocytopenia and clinical haemorrhage in neonates are sufficiently unusual in association with maternal ITP that where they occur, neonatal alloimmune thrombocytopenia should be excluded by laboratory testing. This is important not only for the appropriate management of the neonate, but also in relation to the antenatal management of subsequent pregnancies.

Obstetric anaesthetics

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Anaesthetic management options

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The obstetric anaesthetist is often called upon to make a decision regarding the advisability of regional analgesia and anaesthesia in these cases. Several textbooks and articles offer guidance on this subject, and the general trend in recent years has been to lower the ‘cut-off point’ from a platelet count of 80–100 × 109/l (Beilin et al, 1997). In fact, there is no evidence to support this sort of “all-or-nothing” approach, and every case must therefore be considered on its own merits, with the risk of the procedure (epidural/spinal haematoma) balanced against the benefits (pain relief, better blood pressure control, avoidance of general anaesthesia).

When monitoring platelet levels, the trend as well as the absolute value is important, and the mother with a rapidly falling count should be regarded with more suspicion than the one with a low, but stable, platelet level (Greaves & Letsky, 1997). At the same time, the cause of the thrombocytopenia must be taken into account since different pathologies have different effects upon the haemostatic mechanism for a given platelet count. In general, patients with a platelet count of > 80 × 109/l in the absence of pre-eclampsia are unlikely to have significantly altered platelet function. Tests of platelet function, such as bleeding time, are operator-dependent and therefore of limited predictive value. Thromboelastography is a promising development in this field, but its place in clinical practice has yet to be determined, and will require further clinical trials (Gorton & Lyons, 1999). Routine coagulation studies are usually indicated in thrombocytopenia in case any other defect should be present. The mother should always be questioned about excessive bruising or bleeding since the presence of these may signify impaired platelet function in borderline cases.

The use of powerful non-steroidal anti-inflammatory drugs for post-partum or post-operative analgesia should be avoided in women with platelet counts less than 100 × 109/l because of their anti-platelet activity which may increase the risk of haemorrhage (Level IV Evidence, Grade C Recommendation).

Venous thromboembolism (VTE) is the commonest cause of maternal mortality in the UK and all women with ITP should be considered for thromboprophylaxis if they are undergoing surgical delivery, are immobilized by other medical complications, have a congenital or acquired thrombophilia (especially the antiphospholipid syndrome) or recent venous thrombosis. In each case an individual risk assessment must be made about the desirability and safety of anticoagulant therapy taking into account factors such as age, obesity and personal and family history. Although there are no published data to guide clinical practice, treatment or prophylaxis with standard doses of unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) should be used in women with platelet counts > 50 × 109/l (Level IV Evidence, Grade C Recommendation) in whom the risk of haemorrhage is very low. In women regarded at especially high risk of VTE (e.g. antiphospholipid syndrome, antithrombin deficiency) the balance of risks would probably favour thromboprophylaxis at platelet counts down to 50 × 109/l, especially if LMWH with its more favourable ‘therapeutic window’ is used. All at-risk patients should use appropriate graduated compression hosiery and be considered for intermittent mechanical pneumocompression of the calves during surgery (Level IV Evidence, Grade C Recommendation).

Recommendation:

  • • 
    The mode of delivery in women with ITP should be decided by primarily obstetric indications. There is no evidence to support the routine use of caesarean section (Grade B)
  • • 
    Platelet counts > 50 × 109/l are safe for normal vaginal delivery if coagulation is otherwise normal
  • • 
    Platelet counts > 80 × 109/l are safe for spinal/epidural anaesthesia or caesarean section if coagulation is otherwise normal
  • • 
    Women undergoing operative delivery should be considered for thromboprophylaxis according to their individual clinical risk factors. Standard prophylactic doses of UFH or LMW heparin should be used if the maternal platelet count is > 100 × 109/l (Grade C)
  • • 
    Non-steroidal anti-inflammatory drugs should be avoided for post-partum or post-operative analgesia in women with platelet counts < 100 × 109/l (Grade C)
  • • 
    The risk of clinically dangerous thrombocytopenia in the neonate is very low but cannot be predicted by clinical or laboratory parameters in the mother. Attempts to measure the fetal platelet count by cordocentesis or fetal scalp blood sampling are not recommended as they carry more risks than potential clinical benefits (Grade B)
  • • 
    Because of the risk of haemorrhagic complications in the neonate the application of scalp electrodes for monitoring in labour and fetal blood sampling should be avoided. The use of vacuum extraction (ventouse) is contraindicated and complicated instrumental delivery (e.g. rotational forceps) should be avoided if possible (Grade C)
  • • 
    Cord platelet counts should be measured in all neonates of mothers with ITP and those with subnormal levels monitored clinically and with daily counts until after the nadir which usually occurs on d 2–5 after delivery (Grade C)
  • • 
    Treatment of the thrombocytopenic neonate should be reserved for those with clinical evidence of haemorrhage or a platelet count < 20 × 109/l when there is usually a prompt response to IVIg (1 g/kg). Life-threatening haemorrhage should be treated with immediate platelet transfusion and IVIg (Grade C).

Management of menorrhagia

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For patients with ITP in whom heavy menstrual bleeding occurs, symptom control may be achieved using tranexamic acid and/or oral contraceptives. The Mirena coil is a progestogen-loaded intrauterine contraceptive that induces endometrial atrophy, and is effective in controlling menorrhagia.

Patient support

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The ITP Support Association was formed in 1995 to offer support to those with adult, childhood and maternal ITP. Assisted by its medical advisors the Association publishes a quarterly newsletter and a wealth of reader friendly booklets and factsheets on ITP and its associated concerns, including guidelines for schools, protocol for dentists of affected patients, splenectomy patient's guide and holiday guidelines. ITP HealthCare cards are supplied for a small fee, giving personal details on a wallet-size laminated card in case of emergency.

Annual national conventions featuring ITP specialists from the UK and USA allow patients to overcome their feelings of isolation by meeting fellow sufferers. The Association has funded research and part funded the National Register of Patients and the first ITP Specialist Nurse. By sending an A5 SAE with 2x 1st class stamps to The ITP Support Association, Synehurste, Kimbolton Road, Bolnhurst, Bedfordshire, MK44 2EW, UK, ITP sufferers/families can receive a free information pack. There is no membership fee, the ITP Support Association is run by volunteers and relies mainly on voluntary donations to fund its operation. Further information can be found on http://www.itpsupport.org.ukand Where to Get Help patient leaflets can be ordered free of charge by e-mailing shirley@itpsupport.org.uk.

Acknowledgments

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The section on paediatric ITP is based on an article by Dr Bolton-Maggs (2002), written for Current Paediatrics and is reproduced with permission by Elsevier Science Ltd.

Disclaimer

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Although the advice and information contained in these guidelines is believed to be true and accurate at the time of going to press, neither the authors nor the publishers can accept any legal responsibility for any errors or omissions that may have been made.

British Committee for Standards in Haematology General Haematology Task Force 

Working party

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Dr Drew Provan, Bart's & The London, Queen Mary's School of Medicine and Dentistry, London, UK

Professor Adrian Newland, Bart's & The London, Queen Mary's School of Medicine and Dentistry, London UK

Dr Derek Norfolk, Department of Haematology, General Infirmary at Leeds, Leeds, UK

Dr Paula Bolton-Maggs, Department of Haematology, Alder Hey Children's Hospital, Liverpool, UK

Professor John Lilleyman, Bart's & The London, Queen Mary's School of Medicine and Dentistry, London, UK

Professor Ian Greer, Department of Obstetrics, University of Glasgow, Glasgow Royal Infirmary, Glasgow, UK

Dr Anne May, Department of Anaesthetics, Leicester Royal Infirmary, Leicester, UK

Dr Mike Murphy, National Blood Service, Department of Haematology, Oxford Radcliffe Hospitals, and University of Oxford, UK

Dr Willem Ouwehand, Department of Transfusion Medicine, Cambridge and NBS Cambridge

Mrs Shirley Watson, ITP Support Association, Bedford, UK

Table 3. Classification of Evidence Levels
  • *

    Refers to a situation in which implementation of an intervention is outwith the control of the investigators, but an opportunity exists to evaluate its effect.

IaEvidence obtained from meta-analysis of randomized controlled trials
IbEvidence obtained from at least one randomized controlled trial
IIaEvidence obtained from at least one well-designed controlled study without randomization
IIbEvidence obtained from at least one other type of well-designed quasi-experimental study*
IIIEvidence obtained from well-designed non-experimental descriptive studies, such as comparative studies, correlated studies and case studies
IVEvidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities
Table 4. Classification of Grades of Recommendations
ARequires at least one randomized controlled trial as part of a body of literature of overall good quality and consistency addressing specific recommendationEvidence levels Ia, Ib
BRequires the availability of well-conducted clinical studies but no randomized clinical trials on the topic of recommendationEvidence levels IIa, IIb, III
CRequires evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities. Indicates an absence of directly applicable clinical studies of good qualityEvidence level IV

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