GUIDELINES FOR THE INVESTIGATION AND MANAGEMENT OF IDIOPATHIC
THROMBOCYTOPENIC PURPURA IN ADULTS, CHILDREN AND IN PREGNANCY
Idiopathic thrombocytopenic purpura (ITP) is an autoim- thrombocytopenic purpura, ITP, thrombocytopenia +
mune disorder characterized by persistent thrombocyto- randomized, thrombocytopenia + randomised, thrombo- penia (peripheral blood platelet count < 150 109 l) due to cytopenic + randomized, thrombocytopenic + random- autoantibody binding to platelet antigen(s) causing their ised, thrombocytopenia + trial, thrombocytopenic + premature destruction by the reticuloendothelial system, trial, thrombocytopenic + therapy, thrombocytopenia + and in particular the spleen (Woods et al, 1984a,b). therapy. The search excluded thrombotic, neonatal Although the basic underlying pathophysiology of ITP alloimmune and drug-induced thrombocytopenia. For has been known for 50 years (Harrington et al, 1951), the paediatric reports the previous search terms were combined literature shows that the investigation and management of with child and children. patients with thrombocytopenia vary widely, and is not evidence-based, due to a lack of clinical trials and quality DESCRIPTION AND EPIDEMIOLOGY research. Despite major advances in our understanding of the molecular basis of many blood disorders, the diagnosis Immune-mediated thrombocytopenias comprise, among of ITP remains one of exclusion; there are currently no others: drug-induced thrombocytopenia, neonatal allo- robust clinical or laboratory parameters that are able to immune thrombocytopenia, post-transfusion purpura, ITP, establish the diagnosis of ITP with accuracy. This guideline acute ITP and secondary ITP. This guideline aims to deal aims to assess available diagnostic tests and therapies, and with ITP in children, adults and pregnancy. Previous attempts to provide a rational approach to the diagnosis and guidelines for the management of thrombocytopenia in treatment in adults, children and in pregnancy. Although pregnancy have been published (Greaves & Letsky, 1997). natural history data are becoming available (Cohen et al, Adult chronic ITP has an incidence of 5866 new cases 2000; Djulbegovic & Cohen, 2001; Portielje et al, 2001), per million population per year (5.86.6 per 100 000) in there are few randomized trials in ITP and many of the the US (McMillan, 1997) with a similar incidence in the UK. recommendations, like those of the American Society of This form of ITP affects mainly women of childbearing age Hematology (ASH) Panel (George et al, 1996), are based on (Female:Male, 3:1) (Waters, 1992). Childhood ITP has an expert opinion. 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 AIMS OF THE GUIDELINE often follows a viral illness or immunization. The majority of The purpose of this guideline is to provide a rational children require no treatment and in 8085% of cases the approach to the laboratory investigation and management disorder resolves within 6 months. Some 1520% of chil- of patients with ITP, including pregnant and non-pregnant dren develop a chronic form of ITP, which, in some cases, adults and children, and patients with refractory disease. resembles the more typical adult disease. Chronic ITP in The Guideline development group includes individuals from childhood has an estimated incidence of 0.46 per 100 000 relevant professional groups, and we have sought the views children per year (Reid, 1995) and prevalence of 4.6 per of patients, through The ITP Support Association. Target 100 000 children at any one time (Hedman et al, 1997). users of the Guideline include clinical haematologists Secondary immune thrombocytopenias occur in patients involved in the care of adults and children with ITP, with other underlying autoimmune disorders (e.g. systemic obstetricians and anaesthetists involved in the care of ITP in lupus erythematosus), or malignant disease (e.g. chronic pregnancy, paediatricians and physicians. lymphocytic leukaemia).
METHODS ADULT ITP
MedLine was searched via PubMed using the following cri- Clinical features teria: thrombocytopenia, platelet count, autoimmune 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. Correspondence: The Secretary, BCSH, British Society for Haema- Symptoms and signs are highly variable and range from the tology, 2 Carlton House Terrace, London SW1Y 5AF, UK. E-mail: fairly common asymptomatic patient with mild bruising, jenny.duguid@new-tr.wales.nhs.uk mucosal bleeding (e.g. oral or gastrointestinal tract)
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Guideline 575 through to frank haemorrhage from any site, the most Laboratory investigations serious of which is intracranial. Overall, bleeding symptoms The finding of thrombocytopenia on a routine blood are uncommon unless the ITP is severe (platelet count count may be the first indication of autoimmune < 30 109 l) (George & Raskob, 1998). ITP in adults is a thrombocytopenia. Thrombocytopenia should be confirmed disease predominantly of women of childbearing age. The by examination of the blood film to exclude pseudo- natural history is poorly defined but studies are being thrombocytopenia due to EDTA-dependent platelet agglu- conducted, looking at the long-term outcome in terms of tination as the cause of the spuriously low platelet count; morbidity and mortality in patients with ITP (Portielje et al, this condition occurs in about 0.1% of adults, and is easily 2001). confirmed by the finding of a normal platelet count using a sample taken into citrate rather than EDTA anticoagulant Diagnostic approach for adults (Pegels et al, 1982). Clinical history The blood film should also be examined to exclude non- The patients history is used to: immune thrombocytopenias such as those associated with Determine the type of bleeding and to distinguish plate- acute or chronic leukaemia, myelodysplasia, megaloblastic let-type mucocutaneous bleeding from coagulation-type anaemia, microangiopathic anaemia, inherited thrombo- haematomas cytopenias and pseudothrombocytopenia. An autoimmune Assess the severity, extent and duration of bleeding. A profile screen should be carried out to exclude other history of bleeding with previous surgery, dentistry and underlying autoimmune diseases. trauma may be useful in determining the duration of If the history, physical examination, blood count and chronic thrombocytopenia in the absence of blood counts blood film examination are consistent with the diagnosis of Determine the presence of other medical disorders which ITP with no atypical findings, it can be argued that may be responsible for thrombocytopenia by: additional investigations such as bone marrow examination i) immune mechanisms, e.g. is there a recent history of and assays for platelet antibodies are unnecessary. If transfusion raising the possibility of post-transfusion atypical findings are present, particularly those suggesting purpura? alternative haematological diagnoses, additional investiga- ii) non-immune mechanisms, e.g. is there a history of tions including bone marrow examination should be carried excess alcohol consumption or a family history of out (Evidence level IV). thrombocytopenia suggesting an inherited non- immune thrombocytopenia? Bone Marrow Examination in adults iii) Evolving aplastic anaemia, particularly relevant in This is a contentious issue, and one where there was no children agreed consensus reached by the ASH panel, apart from iv) Marrow infiltration with acute leukaemia suggesting this investigation for patients older than v) Type IIB von Willebrands disease 60 years or where splenectomy was being considered Determine the presence of medical conditions which may (George et al, 1996). In a study of adults with suspected be associated with autoimmune thrombocytopenia, e.g. ITP, 61 of 66 patients had bone marrow findings consistent drugs, human immunodeficiency virus (HIV) infection, with ITP; four had mild hypocellularity and one had other autoimmune disorders, malignancy (e.g. lympho- neutrophil hypersegmentation and giant metamyelocytes, proliferative disorders) but all five had a subsequent clinical course consistent with Conditions which may increase the risk of bleeding, e.g. chronic ITP (Westerman & Grigg, 1999). More recently, a local abnormalities in the gastrointestinal, genitourinary retrospective Chinese study evaluated 83 patients (aged or central nervous systems between 16 and 60 years) with suspected ITP, all of whom underwent bone marrow examination. Apart from 11 cases Physical examination in which marrow iron was reduced or absent, the mar- The physical examination is used to: rows were otherwise normal. Their recommendations were Assess the type, severity and extent of bleeding that bone marrow sampling should be reserved for patients Exclude conditions that might cause non-immune who are older than 60 years, or have atypical features, or thrombocytopenia, e.g. severe infection, acute thrombo- have a poor response to first line (e.g. prednisolone) cytopenia with neurological signs which may indicate a treatment or in whom splenectomy is being considered diagnosis of thrombotic thrombocytopenic purpura (TTP), (Mak et al, 2000). skeletal and other abnormalities associated with congen- ital thrombocytopenias, lymphadenopathy, which may SPECIALIZED LABORATORY ASSAYS suggest the presence of a lymphoproliferative disease, and IN THE DIAGNOSIS OF ITP splenomegaly. It should be noted that splenomegaly has been reported to occur in less than 3% of adult patients Assays for anti-platelet antibodies with ITP (Doan et al, 1960) and its presence should The direct platelet immunofluorescence test (PIFT) is used to prompt a search for an alternative diagnosis investigate referred samples for the presence of platelet- Determine the presence of medical conditions that may be associated immunoglobulin (PAIg); indirect testing of the associated with autoimmune thrombocytopenia, e.g. HIV patients plasma against donor platelets is of little value in infection, other autoimmune disorders, malignancy the investigation of suspected ITP because the sensitivity
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576 Guideline and specificity is even lower than for direct testing (see this assay is not available in routine practice, and is below). not recommended as part of the routine investigation of Increased levels of platelet-associated IgG (PAIgG) can be ITP. detected in most patients with ITP, but the results are not sufficiently sensitive or specific (patients with non-immune Reticulated platelets thrombocytopenias, e.g. septicaemia, frequently have pos- Measurement of platelet RNA by flow cytometry using itive results) to justify the routine use of these assays in thiazole orange staining can be used to assess platelet patients with suspected ITP (Mueller-Eckhardt et al, 1980; maturity. Reticulated platelets are significantly increased in von dem Borne et al, 1986; Kelton et al, 1989). children with ITP, reflecting increased platelet production, Assays for antibodies to specific platelet membrane compared with normal children and other causes of glycoproteins (GP) IIb IIIa and Ib IX are less sensitive thrombocytopenia, e.g. acute leukaemia, aplastic anaemia (5065%) but more specific (90%) in ITP (Berchtold & (Saxon et al, 1998). The precise role for the reticulated Wenger, 1993; Brighton et al, 1996; Warner et al, 1999). platelet assay has not been established and its use is not Although they may be useful in distinguishing between currently recommended. immune and non-immune thrombocytopenia in complex cases, their routine use in the diagnosis of ITP is not Helicobacter pylori infection considered to be justified. A number of studies have reported the presence of H. pylori Investigation of platelet autoantibodies may be of value in patients with autoimmune disease, particularly ITP. In in adults with some series antibiotic therapy aimed at eradication of Combination of bone marrow failure associated with H. pylori has ameliorated ITP in patients resistant to other immune-mediated thrombocytopenia therapies (Gasbarrini et al, 1998; Emilia et al, 2001; Kohda ITP patients refractory to first and second line treatment et al, 2002) although other studies have generated conflict- Drug-dependent immune thrombocytopenia (DDITP) ing data (Jarque et al, 2001). Despite this, in patients Miscellaneous disorders (rare), e.g. monoclonal gammo- refractory to therapy it is worthwhile performing serological pathies and acquired autoantibody-mediated thrombas- assays and breath tests aimed at detecting the microorgan- thenia ism (Evidence level III). Bone marrow failure and immune-mediated thrombocytope- nia. Antibody-mediated platelet destruction may aggravate thrombocytopenia in some patients with thrombocyto- Recommendation for adults: penia in whom there is inadequate thrombopoiesis, e.g. The diagnosis of ITP is based principally on the exclusion patents with disorders such as chronic lymphocytic leuk- of other causes of thrombocytopenia using the history, aemia (CLL) or bone marrow transplant recipients. React- physical examination, blood count, peripheral blood film, ive megakaryocytopoiesis is often a feature of ITP, and autoimmune profile and other investigations. Further there may be doubt as to whether there is platelet investigations are not indicated in the routine work-up of autoimmunity in addition to bone marrow infiltration or patients with suspected ITP if the history, examination, failure; a PAIg test with determination of antibody speci- blood count and film are typical of the diagnosis of ITP ficity may be of use. and do not include unusual features that are uncommon ITP patients refractory to first and second line treatment. For in ITP, or suggestive of other causes (Evidence IIbIV; ITP patients for whom third line treatment is considered, Grade B, C). measuring the autoantibody titre in addition to the platelet A bone marrow examination is unnecessary in adults count and clinical signs of bleeding can be used to monitor unless there are atypical features, or the patient is over the effect of treatment. A PAIg test and determination of the age of 60 years, or the patient relapses following antibody specificity is recommended. complete remission, on or off therapy, or splenectomy is Drug-dependent immune thrombocytopenia (DDITP). Many being considered (Evidence Level III). drugs are associated with thrombocytopenia. For some PAIg is elevated in both immune and non-immune drugs there is firm evidence that the thrombocytopenia is thrombocytopenia and therefore has no role in the antibody-mediated. Serological investigations to determine diagnosis of uncomplicated ITP (Evidence level III). whether the drug is the causative factor in the thrombo- It is worth determining the presence of H. pylori in cytopenia are important in clinical management. Testing for patients refractory to therapy since some patients have DDITP is of value for the following drugs: heparin, shown improvement in platelet counts following eradi- quin(id)ine, and teicoplanin (Terol et al, 1993; Veldman cation therapy (Evidence level III, Grade B recommen- et al, 1996). dation).
Thrombopoietin (TPO) assays
Measurement of the TPO level may be informative in MANAGEMENT OF ADULT ITP complex cases of thrombocytopenia, and is particularly useful in distinguishing between reduced production of General note: to date there have been few randomized platelets (high TPO level) and increased destruction of controlled trials conducted in ITP. Treatment should be platelets (normal level) (Porcelijn et al, 1998). However, tailored to the individual patient.
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Guideline 577 Natural history of adult ITP and the requirement Some two-thirds of patients will respond to prednisolone at for medical or surgical treatment 1 mg kg body weight per day for 24 weeks, tapering off The requirement for treatment varies from patient to patient, over several weeks (Ben-Yehuda et al, 1994; George et al, and is dictated by factors such as clinical status (asympto- 1994; Stasi et al, 1995). Reported response rates vary widely matic, bruising, bleeding or planned intervention likely to (from 3% to 50%) (George et al, 1996). A single randomized induce bleeding in a patient with ITP who is thrombocytop- trial showed no difference in response to low dose enic). Haemorrhagic death is a major concern in thrombo- 0.25 mg kg d vs 1 mg kg d in 160 children and 223 cytopenic patients, but recent data from 17 case series have adults (Bellucci et al, 1988). Relapse of thrombocytopenia is been reviewed and show that the rate of fatal haemorrhage is common when the dose is reduced. Around one-third of between 0.0162 and 0.0389 cases per patient-year at risk patients can expect a long-term response (Berchtold & (the time at risk was defined as the time when the platelet McMillan, 1989; George et al, 1996; Manoharan, 1991; count is < 30 109 l) (Cohen et al, 2000). A recent review Blanchette et al, 1998). Corticosteroids should be rapidly by Portielje et al (2001) found that more patients died of tapered and stopped in patients who fail to respond to oral infection than of bleeding. In this same review the authors prednisolone after 4 weeks (Pizzuto & Ambriz, 1984; Ben- studied the natural history of 152 adult patients with ITP Yehuda et al, 1994). Long-term remission is seen in only that were consistently managed and followed up over a 1020% of patients following cessation of prednisolone 10 year period, and showed that 93% of patients ultimately therapy (Ben-Yehuda et al, 1994; Stasi et al, 1995). Patients achieving a platelet count of > 30 109 l did so within who fail to respond to treatment with corticosteroids or 2 years. Some 85% achieved platelet counts above require unacceptably high doses of corticosteroid in order to 30 109 l off treatment and had a long-term mortality maintain a safe platelet count should be considered for identical to that of the general population; 9% of patients with splenectomy (Ben-Yehuda et al, 1994; George et al, 1994). severe ITP (platelets < 30 109 l) had refractory ITP with IVIg. Pooled normal human immunoglobulin is effective an associated mortality risk of 4.2 (bleeding and infection in elevating the platelet count in 75% of patients, of which contributing equally). Six per cent of patients had platelets 50% will achieve normal platelet counts. However, res- > 30 109 l while on maintenance therapy; the mortality in ponses are transient and 34 weeks following IVIg treat- this group was only slightly above that of the general ment platelet counts drift back to pre-treatment levels population. The study concludes that most adults with ITP (Dwyer, 1992; George et al, 1996), and there is little have a good outcome with few in-patient admissions and no evidence of a lasting effect. A prospective randomized trial excess mortality. These findings would tend to favour a policy involving 30 adult patients with chronic ITP (comparing of using therapy only when absolutely required, thereby IVIg, prednisolone or combination of the two) with a minimizing the risks of infection through immunosuppres- minimum follow-up of 2 years showed quite clearly that the sion, and reserving treatment for those who actually require response rates, duration of response and requirement for it, for example patients with severe symptomatic ITP. splenectomy were the same in all arms (Jacobs et al, 1994) (Evidence level Ib, Grade B). A single randomized study First line therapy showed no difference in efficacy between the two dosing Standard rst line therapy schedules 0.4 g kg d for 5 d and 1 g kg d as a single In general, patients with platelet counts exceeding infusion (Godeau et al, 1993). The mechanism of action of 30 109 l require no treatment unless they are undergo- IVIg in ITP remains largely unknown but is believed to ing any procedure likely to induce blood loss including involve the blockade of Fc receptors on macrophages and surgery, dental extraction or delivery (Yang & Zhong, 2000) other effectors of antibody-dependent cytotoxicity (Geha & (Grade C recommendation). Rosen, 1996), the presence of anti-idiotype antibodies in IVIg which block autoantibody binding to circulating Recommendation for safe platelet counts in adults platelets and immune suppression (Godeau et al, 1993; Dentistry 10 109 l Chong, 1995). While IVIg is a pooled blood product, it Extractions 30 109 l has an excellent safety record although renal impairment Regional dental block 30 109 l or failure has been reported with some preparations Minor surgery 50 109 l (Schiavotto et al, 1993; Cayco et al, 1997). Major surgery 80 109 l Obstetrics see Thrombocytopenia in pregnancy Recommendations for first line therapy in adults: Evidence Level IV There are no randomized studies comparing no treat- ment vs. therapy with corticosteroids or IVIg. There is no First line therapy comprises oral corticosteroids and indication for therapy in adults in whom there are no intravenous immunoglobulin (IVIg). Splenectomy is often symptoms or signs, or in whom the platelet count is cited as first line therapy but this mode of treatment is greater than 30 109 l (Grade C recommendation). seldom used as first line, and rather should be considered as IVIg is useful in 75% of patients in whom the platelet second line therapy. count has to be raised either due to symptoms or signs, Prednisolone. Prednisolone (or prednisone) is the initial or where there is predictable bleeding (e.g. surgery, therapy for most patients with ITP who require treatment pregnancy labour or operative dentistry). (McMillan, 1981; Bussel, 1990; Warkentin & Kelton, 1990).
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578 Guideline Second line therapy objective evidence of likely response to splenectomy and Splenectomy is recommended, where available, prior to splenectomy. Splenectomy has been used for many years, before steroid (Evidence level III.) therapy was introduced in 1950 (Chong, 1995; George Accessory splenic tissue. The presence of an accessory et al, 1996), as a means of prolonging the survival of spleen (or spleens) should be considered in patients who fail antibody-coated platelets. The procedure is not strictly to respond to splenectomy or relapse following an initial curative since opsonization still takes place but the response (George et al, 1994). Imaging techniques have effector of platelet destruction is removed. Two-thirds of shown the presence of accessory splenic tissue in up to 12% patients with ITP who undergo splenectomy will achieve a of such patients (Facon et al, 1992). normal platelet count, which is often sustained with no Prevention of infection post-splenectomy. Patients should be additional therapy. Patients who do not have a complete given prophylactic polyvalent pneumococcal vaccine (Pneu- response can still expect some improvement in counts (e.g. movax II), Haemophilus influenzae b (Hib) and meningo- partial response) or transient increases in platelet count coccal C conjugate vaccinations at least 2 weeks prior to (George et al, 1996). splenectomy (Centers for Disease Control (CDC), 1993; Intraoperative platelet support. There is a suggestion, with British Committee for Standards in Haematology (BCSH), little evidence, that if random donor platelets are deemed 1996). Revaccination with pneumococcal vaccine should necessary to cover the surgery, these should be given once be offered every 5 years but is not currently recommended the splenic artery has been clamped. Physiologically this for Hib. The recommendation for booster doses of meningo- would appear logical but has never been subjected to coccal C conjugate virus may be introduced in the future. rigorous study (Level IV evidence). Annual influenza vaccine is recommended in asplenic Post-operative complications of splenectomy. Early studies patients. The patients vaccination status should be recor- reported complication rates of around 22% and two series ded in the case notes. Following splenectomy patients from New Zealand and France showed no mortality and should be offered phenoxymethylpenicillin 250500 mg morbidity of only 7% in 48 and 72 patients respectively twice daily, or equivalent, or erythromycin (500 mg bd) (Shaw, 1966; Naouri et al, 1993). In the study by possibly for life, in order to reduce the incidence of post- Portielje et al (2001), two deaths occurred (out of 78 splenectomy pneumococcal infection (McMullin & Johnston, patients undergoing splenectomy) and 26% had early 1993; Reid, 1994) (Grade C recommendation). The efficacy post-operative complications (pulmonary embolism, intra- of such a regimen remains unproven (Makris et al, 1994). abdominal bleeding, abdominal abscess, abdominal wall Some authorities would suggest antibiotic prophylaxis for haematoma, gram negative sepsis, and others). Some 5% 3 years post-splenectomy. Patients should have a supply of of patients suffered late complications. Overall, the com- broad-spectrum antibiotics at home for use if fever develops. plication rate was higher in patients greater than 65 years In addition there are cards available that should be carried of age. by patients, to alert physicians that the patient is asplenic. Platelet count pre-splenectomy. Stasi et al (1995) recom- Some patients may wish to purchase alert bracelets or mended a platelet count of 30 109 l; this may require pendants. treatment with oral corticosteroids or IVIg pre-operatively if the platelets are below 30 109 l. Others have used ADULT PATIENTS FAILING FIRST AND SECOND oral dexamethasone (40 mg d for 4 d) to prepare LINE THERAPIES CHRONIC REFRACTORY ITP 13 patients for splenectomy, 11 of whom had sufficient rise in the platelet count for surgery (Gillis & Eldor, This defines patients who fail to respond to first line 1998). treatment or require unacceptably high doses of cortico- Predicting response to splenectomy. Various indicators of steroids to maintain a safe platelet count. The actual the likely response to splenectomy have been reviewed percentage of patients defined as having refractory ITP including response to oral steroids, which has a low varies from 11% (Portielje et al, 2001) to 35% (George et al, predictive value, response to high dose IVIg which, in two 1994). A large number of drugs have been used as second small series, correlated well with response to splenectomy line therapy for ITP with variable success. The therapy used (Chirletti et al, 1992; Law et al, 1997), and indium-labelled will depend on the age of the patient, the severity of the autologous platelet scanning which appears to be the most presentation, the level of the platelet count, whether the sensitive predictor of response to splenectomy, to date disease is primary refractory or relapsed, and the length of (Najean et al, 1997). Recent work using indium-labelled time prior to relapse. autologous platelets in 528 patients, has shown that when When considering second line therapy the original first platelet destruction was splenic, then 96% of patients line therapies (corticosteroids, IVIg or splenectomy) should between the age of 530 years and 91% of those above be reconsidered and implemented if possible (George et al, the age of 30 years could expect to obtain a remission. 1996), although the doses may have to be altered compared However, where the platelet destruction was hepatic or with those used in first line therapy. Additional supportive diffuse (mixed splenic and hepatic) 92% of patients failed to therapy may need to be considered to allow their chronic normalize their platelet counts or had incomplete responses use. For example, there is a small but significant risk of to splenectomy (Najean et al, 1997; Evidence level III). The osteoporosis and avascular necrosis in patients on long-term indium-labelled autologous platelet scan appears to offer corticosteroids and they should be assessed for this and
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Guideline 579 treated accordingly with bisphosphonates or hormonal steroids was required to achieve an adequate platelet replacement if indicated. count. The actual necessity for treatment should always be High dose IVIg. High dose intravenous immunoglobulin considered, weighing up the risks and side effects of at a dose of 1 g kg per day for two consecutive days, often treatment, against the risks of no treatment. In some in combination with corticosteroids, will raise the platelet patients symptomatic therapy such as fibrinolytic inhibitors count rapidly in a proportion of patients (Bussel & may be used, particularly if there is only mucous membrane Hilgartner, 1984; Imbach et al, 1985). Side effects, bleeding, and in severe bleeding, such as gastrointestinal particularly headaches, may occur, but if successful can haemorrhage, then platelets may be transfused. Although be given on an intermittent basis or substituted with these are rapidly cleared from the circulation and have a intravenous anti-D (Blanchette et al, 1993). Godeau et al severely shortened half-life they are often effective in (1993) reported good responses, including sustained com- stopping bleeding (Carr et al, 1986). plete response (CR), in some patients with refractory ITP treated with IVIg (12 g kg) repeated every 23 weeks. In Conventional second-line treatment approaches general, however, the platelet response to IVIg is transient For the patient in whom further conventional treatment with rare durable remissions (Schiavotto et al, 1995). IVIg with standard dose corticosteroids is inappropriate there is usually reserved for patients with symptomatic ITP in are a wide variety of therapeutic options (Collins & whom a rapid increase in platelet count is required, prior Newland, 1992). These include: (i) high dose steroids, (ii) to operative procedures likely to cause blood loss, or in high dose IVIg, (iii) intravenous anti-D, (iv) vinca alkaloids, pregnancy. (v) danazol, (vi) immunosuppressive agents including Intravenous anti-D. Intravenous anti-D has been shown to azathioprine and cyclophosphamide, (vii) combination elevate the platelet count in 7990% of adults (Scaradavou chemotherapy, and (viii) dapsone. The wide variety of et al, 1997). The mechanism of action is believed to be treatments available for second line therapy reflects their mediated through the destruction of Rh (D) positive red cells relative lack of efficacy, and treatment should be tailored to which are preferentially removed by the reticuloendothelial suit the individual. system, particularly the spleen, thus sparing autoantibody- High dose corticosteroids. As an alternative to predniso- coated platelets through Fc receptor blockade (Bussel et al, lone, Andersen (1994) reported favourable responses in 1991a). refractory patients using an oral high dose dexamethasone In a single arm, open-label study of anti-D in 261 non- regimen, comprising 40 mg of dexamethasone daily for 4 d, splenectomized and 11 splenectomized patients, 72% of repeated every 28 d for six cycles. Ten patients were treated patients showed an increase in platelet count of greater than in this small study with favourable responses in all patients 20 109 l, and in 46% of patients the platelet count rose by (all had platelet counts exceeding 100 109 l), sustained more than 50 109 l. The improvement lasted for more for at least 6 months. At this dose, side effects are common than 3 weeks in 50% of patients who responded (Scara- and subsequent studies conducted by other groups have not davou et al, 1997). Anti-D treatment is suitable for Rh (D) met with such success (Caulier et al, 1995; Arruda & positive patients who are not splenectomized, and is not Annichino-Bizzacchi, 1996; Demiroglu & Dundar, 1997; recommended for refractory patients following splenectomy. Kuhne et al, 1997). Vinca alkaloids. This group of drugs may cause a Methylprednisolone. Parenteral steroids such as methyl- transient increase in the platelet count lasting between 1 prednisolone have been used as second and third line and 3 weeks in two-thirds of patients treated. Around 50% treatments for patients with refractory ITP. One study of splenectomized patients will respond, but sustained reported the results of nine adult patients with platelets responses are observed in less than 10% of patients < 50 109 l, all of whom were treated initially with oral (Berchtold & McMillan, 1989; Manoharan, 1991; George corticosteroids (prednisolone prednisone at 1 mg kg d). et al, 1996; Blanchette et al, 1998). Available drugs include Methylprednisolone was given at 30 mg kg d for 3 d, vincristine 1 mg (occasionally 2 mg) intravenously (IV), or 20 mg kg d for 4 d then 5, 2 and 1 mg kg d each for vinblastine 510 mg IV weekly for 46 weeks. 1 week. The platelet count became normal within 35 d Danazol. Danazol, an attenuated androgen, appears to be in all patients, although in seven of nine the response especially effective in patients with overlap syndromes lasted only a few weeks before dropping to pre-treatment between ITP and lupus and can often be used as a levels (Akoglu et al, 1991). von dem Borne et al, 1988) corticosteroid-sparing agent in responsive patients who compared the effect of methylprednisolone with IVIg in require longer term unacceptably high doses. Ahn et al 22 adult patients with a control series (17 patients (1989) reported the outcome of 22 patients, of which 15 treated with standard oral corticosteroids). The methyl- had undergone splenectomy, treated with danazol at a dose prednisolone was found to be as effective as IVIg in terms of 200 mg 24 times daily for more than 2 months. of the frequency of response, with no reported side effects. Around 60% showed elevation of the platelet count The major difference noted between the modalities was above 50 109 l that was sustained for more than that the response to oral steroids was slower than that to 2 months. Older females and those who have undergone intravenous methylprednisolone (von dem Borne et al, splenectomy appeared to have the best response (Ahn et al, 1988). Again, the response to intravenous steroids was 1989). Danazol, when given for longer than a year, induced transient in all patients and maintenance with oral remissions lasting for years even after its discontinuation,
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580 Guideline but early relapses were frequent when it was administered dapsone is low in patients who have undergone splenectomy for less than 6 months (Ahn et al, 1989). The mechanism of (Hernandez et al, 1995). action of danazol is unknown but it is postulated to downregulate the number of Fc receptors on splenic Recommendation for second line therapy in adults: macrophages (Schneider et al, 1997). Methylprednisolone is a useful second line treatment Immunosuppressive agents. Immunosuppression may be especially where there is a need to elevate the platelet required in patients who fail to respond to alternative count quickly, in combination with IV cyclophospha- therapies. Treatment with azathioprine (2 mg kg, usually mide and or IVIg. Evidence level IIa. Because of the up to a maximum of 150 mg d) or cyclophosphamide as relatively frequent incidence of accessory splenic tissue, single agents may be considered and up to 25% of patients this should be sought in those failing to respond to may have a sustained response. splenectomy. Agents such as high dose IVIg, vinca Bouroncle & Doan (1969) used azathioprine in 17 patients alkaloids, anti-D, danazol, azathioprine and cyclosporine and reported excellent responses in 23.5% and good respon- are worth considering in non-urgent or semi-urgent ses in 41% after treatment for an average of 10 months (a cases where there is a need to elevate the platelet count. 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, Patients failing first and second line therapies 1990) reported 53 patients with chronic ITP who were Fortunately, most adult patients with chronic refractory ITP treated with azathioprine at 150 mg per day for a median of are able to tolerate marked thrombocytopenia relatively well 18 months; 40 of the 53 patients had previously under- (Blanchette et al, 1998), and are able to have a normal or gone splenectomy. Platelet responses were documented in near normal quality of life. For those who fail to respond to 64% of patients and were complete in 45% of these. standard first and second line therapy and who require Azathioprine is slow-acting, and should be continued for treatment the options are limited and include: (i) interferon-a up to 6 months before being deemed a failure. When a (IFN-a), (ii) anti-CD20, (iii) Campath 1H, (iv) mycophenolate platelet response occurs the dose should be reduced, while mofetil, (v) protein A columns, and (vi) other treatments. maintaining a safe platelet count (Blanchette et al, 1998). IFN-a. There are several case series that report on the Cyclosporin A has been shown to increase the platelet use of IFN-a in refractory ITP, and have shown that 25% of count when given either alone or with prednisolone but its patients can achieve a platelet count of over 100 109 l side effects make it unlikely to be of widespread practical for between 1 week and 7 months after the IFN-a treatment use. It may, however, sustain the patient over a difficult (George et al, 1996). The mechanism of action is unknown period. Emilia et al. (1996) reported eight patients treated but may be due to modulation of effector B lymphocytes over a 1362 month period with cyclosporin A (three involved in the autoimmune process. Because available data patients had autoimmune haemolytic anaemia (AIHA), four suggest that IFN-a appears most effective in less severe ITP ITP and one Evans syndrome). Responses were seen in all (Proctor et al, 1989), and previous reports of exacerbation of patients (six CR and two partial responses). Side effects were ITP while receiving IFN-a, with a fatal outcome in one moderate but transient. In most cases cyclosporin A had to patient (Matthey et al, 1990), IFN-a does not have a current be continued in order to maintain an adequate platelet role in the management of ITP. count (Emilia et al, 1996). In a recent study (Kappers- Anti-CD20 antibody. Rituximab (chimaeric anti-CD20 Klunne & vant Veer, 2001), 20 patients with ITP all of monoclonal antibody) has been evaluated in a single study whom were refractory to corticosteroids and half of whom (Stasi et al, 2001) in which 25 patients with ITP resistant to had undergone splenectomy, were treated with cyclosporin 25 therapeutic options were treated with 375 mg m2 A for at least 4 weeks. The dose was reduced by 50 mg d rituximab weekly for 4 weeks. Five patients showed a every 2 weeks in those showing responses. Five patients complete response and a partial response was seen in a remained in complete remission for at least 2 years after further five. In seven patients the responses were sustained discontinuing cyclosporin A, and a further six patients for over 6 months. There was a suggestion that younger showed partial responses. Cyclosporin A was discontinued patients showed better response rates. in six patients due to side effects. Campath-1H. Lim et al (1993) treated six patients with Dapsone. In a series of 66 adults with chronic ITP and refractory ITP (three patients had underlying CLL non- platelet counts < 50 109 l treated with dapsone at Hodgkins lymphoma and one had Hodgkins disease). A 75100 mg orally, responses were observed in 33 of 66 response was seen in four of five evaluable patients, and in patients (50%), with a median duration of treatment three of these the response lasted more than 49 months. In required to achieve a response of 21 d. Sustained responses most cases it took between 4 and 6 weeks for a response to were observed in 19 patients (Godeau et al, 1997). occur. Side effects were significant and included rigors and Dapsones mechanism of action is unknown but may be fever during the infusion, and marked lymphopenia due to reticuloendothelial blockade through increased red (< 0.1 109 l) in all patients treated. Worsening of cell destruction (Godeau et al, 1997; Radaelli et al, 1999). thrombocytopenia was noted in two patients during therapy. Half of all patients with chronic ITP treated with dapsone A more recent study of the use of Campath-1H in patients will show some response within 3 weeks, but it appears to be with a variety of cytopenias has shown that it was well less effective in severe cases of ITP. The response rate to tolerated with encouraging responses (Willis et al, 2001).
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Guideline 581 Mycophenolate mofetil. This antiproliferative immunosup- have active bleeding from the gastrointestinal (GI) or pressant, licensed for the prophylaxis of acute renal, cardiac genitourinary tracts, into the central nervous system or or liver transplant rejection, has been shown to be of value other sites. In this situation, treatment is aimed at elevating in some patients with autoimmune cytopenias including the platelet count to a safe level quickly (i.e. in less than refractory ITP (Evidence Level IV). However, the numbers of 24 h). Clearly, many of the treatments discussed earlier patients treated to date are small and larger studies are take much longer to achieve this effect, and therapies that required (Zimmer-Molsberger et al, 1997; Allison & Eugui, work almost immediately include platelet transfusion, 2000; Howard et al, 2002). intravenous methylprednisolone and IVIg. Protein A immunoadsorption column. Snyder et al (1992) Combination chemotherapy. This mode of therapy may be reported on the use of protein A columns in 72 patients with useful for patients who have failed other therapies but in refractory ITP, 49 of whom had undergone splenectomy. All whom the need to elevate the platelet count is less urgent, 72 patients were given six immunoadsorption treatments e.g. patients who are not actively bleeding. There is a risk of for 23 weeks. Twenty nine of the 72 (40%) were continued second malignancies, including acute leukaemia, in patients on low dose steroid (prednisone <30 mg d). Some 25% of treated with these medications and the use of cytotoxic patients had good responses (platelets exceeding agents, especially in younger patients, should be carefully 100 109 l, while 21% had fair responses (platelets considered. In those patients with severe, symptomatic between 50 and 100 109 l). Over half the patients chronic ITP refractory to multiple previous treatments the (54%) had poor responses (Snyder et al, 1992). The use of cyclophosphamide, vincristine and prednisolone mechanism of action of the protein A columns may involve combined in regimens such as those used in the lymphomas reducing platelet activation (Cahill et al, 1998). The use of have been shown to be effective. Figueroa et al (1993) protein A columns requires good venous access, is cumber- reported their results in 10 patients with refractory ITP. some and relatively expensive (Karpatkin, 1997). Two patients had underlying malignant disease (Hodgkins For patients who fail to respond to these therapies disease and CLL). All 10 had been treated previously with there are limited data on the use of ascorbic acid (Brox steroids and had undergone splenectomy. The platelet count et al, 1988), chlorodeoxyadenosine, colchicine (Strother et al, was less than 5 109 l in all patients. A complete response 1984; Jim, 1986), liposomal doxorubicin, and peripheral was seen in six patients (durable in four); a partial response blood stem cell transplantation (Lim et al, 1997; Skoda et al, was observed in two (one durable) and two died of 1997). intracerebral haemorrhage. Plasmapheresis. This treatment has been used in order to remove antiplatelet antibodies and immune complexes. Recommendations for emergency treatment in adults: There are several reports, the largest of which documented For rapid elevation of the platelet count in extreme the treatment of 14 patients, some of whom had acute ITP emergencies transfusion of random donor platelets is (Marder et al, 1981). Five of nine with acute ITP responded appropriate. When a higher platelet count is required but to plasmapheresis. Bussel et al (1988) have reported success there is less urgency, IVIg and or IV methylprednisolone using a combination of plasmapheresis and IVIg for patients and or IV cyclophosphamide may be useful. Evidence with chronic refractory ITP. The general consensus is that Level IV. plasmapheresis is not a useful therapeutic manoeuvre in the treatment of chronic ITP. INVESTIGATION AND MANAGEMENT Liposomal doxorubicin. This has been used in the context OF ITP IN CHILDREN of small non-randomized studies only, with variable success (Cosgriff et al, 1998). 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 bleed- Recommendation for therapy in adults failing first and ing is rare, and about 80% of children with ITP will recover second line therapies: spontaneously within 68 weeks. Children and their par- Campath-1H and rituximab are agents that may be of ents may benefit from the contacts and literature available value for patients in whom there is no response to other from ITP support groups such as The ITP Support Associ- therapies and in whom there is a definite requirement to ation (http://www.itpsupport.org.uk). elevate the platelet count (e.g. active bleeding). Myco- phenolate mofetil appears to be effective in some patients Diagnosis with severe refractory ITP but larger studies are required The diagnosis of childhood ITP is by exclusion. It can occur to confirm its efficacy and safety. In terms of the risk: at any time of childhood, but in the neonatal period must be benefit ratio, treatments with interferon-a, protein A distinguished from maternal ITP or alloimmune thrombo- columns, plasmapheresis and liposomal doxorubicin are cytopenia. In children older than 10 years a chronic course not recommended. may be more common. In acute ITP, the history is short with the appearance of purpura and bruising over a Emergency treatment in adult patients 2448 h period. The platelet count is usually less than Urgent treatment is required for adults with severe 1020 109 l. Children with higher platelet counts rarely thrombocytopenia (e.g. platelets < 30 109 l) and who show any symptoms. The presenting platelet count may be
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582 Guideline unrecordable in the face of few symptoms and signs. The Special diagnostic considerations in the illness may follow an acute viral infection or immunisation. Accident & Emergency (A & E) Department ITP associated with varicella needs special caution as The possibility of non-accidental injury (NAI) and menin- occasional cases have more complex coagulation disorders gococcal disease must be considered by A & E staff when with antibodies directed against proteins S and or C dealing with a young child presenting with bruising and (Ganesan & Kirkham, 1997). ITP may be provoked by the purpura for the first time. Children with infection usually measles, mumps and rubella (MMR) vaccine, with an have other features and non-accidental injury does not estimated risk of 1 in 24 000 doses (Farrington et al, 1995), present with generalized purpura. usually occurring within 6 weeks of vaccination. There is no evidence of a vaccine-associated recurrence in children Investigations who developed ITP independently of and before MMR Full blood count and careful film examination by an vaccination (Miller et al, 2001). The Committee on the experienced morphologist. If a low platelet count does not fit Safety of Medicines (CSM) recommend that children who the clinical picture the count should be repeated to exclude develop ITP within 6 weeks of the first dose of MMR should a spurious result. have their serological status for the three viruses evaluated Coagulation screening. Only necessary if there is a possi- before the second dose is due. If serology suggests that a bility of meningococcal infection, features to suggest an child is not fully immune to measles, mumps and rubella, inherited bleeding disorder in addition, or a suspicion of then a second dose of MMR is recommended. The Public NAI. Health laboratory Service is offering a free serological Antiplatelet antibodies. Measurement of antiplatelet anti- testing service for children developing ITP within 6 weeks bodies does not assist in the diagnosis (Taub et al, 1995; of the first dose of MMR. Those not protected against George et al, 1998). rubella by MMR are at risk of developing ITP from infection H. pylori infection. This is discussed above. There is no with rubella itself when the risk is 1 in 3000 (data from the information about this infection as a precipitating cause of Department of Health Education Authority, http:// ITP in children, although H. pylori infection does occur in www.immunisation.org.uk). The MMR vaccine package childhood. There is therefore no indication to screen inserts are being upgraded to reflect the CSMs advice. children with ITP unless there are other clinical indicators to suggest infection (Sherman & Macarthur, 2001). Differential diagnosis Bone marrow aspiration. Bone marrow examination The history of bruising and purpura is sometimes more excludes some causes of thrombocytopenia but can only con- chronic, with symptoms developing more slowly over weeks firm that the picture is consistent with peripheral destruction. or months. In these children caution should be exercised Although it is argued that if a child has a sinister underlying and particular attention paid to the possibility of a congen- disorder there will be other clues in the blood picture or ital disorder. These are most often missed because they are the clinical examination (Halperin & Doyle, 1988; Calpin uncommon and are therefore not considered. et al, 1998) this is not always reliable (Reid, 1992).
Congenital disorders that may resemble ITP
Recommendation for investigation of suspected child- (a) In a young child (within a few weeks or months of birth) hood ITP: Wiskott Aldrich syndrome In a child with typical clinical and laboratory features Bernard Soulier syndrome who needs no treatment, a bone marrow examination is Other occasional families with isolated congenital or not required (Grade B recommendation). If therapy is hereditary thrombocytopenias of unspecified type considered, it must be recognised that occasionally the (b) In older children diagnosis of ITP will be incorrect. Bone marrow exam- Evolving Fanconi anaemia ination will usually reveal this. Marrow examination is von Willebrands disease type IIB (Donner et al, 1987) necessary in the presence of atypical clinical features or if Serious marrow disorders there is no response to treatment. It is also recommended Acute leukaemia (NB especially Down syndrome) that the bone marrow be examined before steroid Aplastic anaemia therapy is given (Evidence Level IV). Marrow aspiration should ideally be accompanied by a trephine biopsy Special diagnostic considerations in older children because this gives a better estimate of megakaryopoiesis Children over the age of about 10 years may be more (Beardsley & Nathan, 1998). Marrow examination is likely to have a chronic course (Walker & Walker, 1984; painful and is more acceptable when performed under Reid, 1995). Other autoimmune diseases associated with general anaesthesia (Evidence levels: IIb, III). thrombocytopenia should be considered, particularly sys- temic lupus erythematosus (SLE) and antiphospholipid syndrome. Older children should have additional investi- Management of ITP in childhood: general measures gations performed (see below). Thrombocytopenia has not It is essential that children are classified clinically and not commonly been reported as the initial presentation of HIV by platelet count, because children with severe thrombo- infection in children, but can occur during the course of cytopenia (less than 10 109 l) have usually mild the disease. clinical symptoms. Pronounced skin purpura and bruising,
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Guideline 583 however, extensive, do not indicate a serious bleeding risk Treatment: Expectant Watch and Wait policy on their own. To date there has been a universal More than 80% of children with acute ITP do not have tendency to treat the count alone rather than the childs significant bleeding symptoms and can be managed without symptoms. Two UK national surveys of children with ITP specific therapy directed at raising the platelet count have demonstrated that only 4% of children with ITP (Buchanan et al, 1997; Baronci et al, 1998; Dickerhoff & have serious symptoms such as severe epistaxis or GI von Ruecker, 2000; Bolton-Maggs et al, 2001; Bolton-Maggs bleeding (Bolton-Maggs & Moon, 1997; Bolton-Maggs & & Moon, 1997, 2001; Sutor et al, 2001) (Evidence levels III Moon, 2001). Similar data are available from Germany and IV). It is essential that the parents, and child where able, (Sutor et al, 2001) and Norway (Zeller et al, 2000). have an explanation that this is usually a self-limiting benign Several studies have confirmed that the incidence of disorder (Dickerhoff & von Ruecker, 2000). Most children intracranial haemorrhage (ICH) is much less than the 1 can be managed well at home, and do not require hospital 3% widely quoted, and is closer to 0.10.5% (Lilleyman, admission, which should be reserved for children with 1994). In the two UK national surveys there were two clinically important bleeding (severe epistaxis, i.e. lasting ICH in 703 cases (0.3%), with complete recovery in both more than 30 min with heavy bleeding, GI bleeding, etc.). cases, similar to the incidence derived from a retrospective Parents should be advised to watch for other signs of bleeding national survey (Lilleyman, 1994, 1997). Similarly, a and be given a contact name and 24 h telephone number; recent Japanese study found an incidence of 4 in 772 similar advice as that given to families with a child with (0.52%) children, with no deaths (Iyori et al, 2000). It is severe haemophilia is often the most appropriate, with, as far impossible to predict which children will develop an ICH, as possible, avoidance of formal contact sports or activities and it may be that there are other predisposing factors with high risk of trauma or head injury. Other activities can that contribute to this for example an underlying vascular be continued as normal, and the child should be encouraged anomaly. to continue schooling on the basis that ITP is a disorder that ICH has occurred in children who have been treated and may last some weeks or months (Evidence levels: III and IV, in one study this was the case in a third of children reviewed Grade B and C recommendation). (Lee & Kim, 1998). It is worth noting that in the first Most children with mild or moderate symptoms only (the randomized study of IVIg the only child to have ICH did so majority) can be safely managed as outpatients with weekly early, was on IVIg and died 6 d after presentation (Imbach or less frequent visits (level III evidence) (Dickerhoff & von et al, 1985). As discussed earlier, the need for treatment in Ruecker, 2000; Bolton-Maggs et al, 2001). A repeat platelet children with acute ITP should not be driven by the platelet count is not necessary while a child still has purpura as this count alone, but mainly by symptoms. Children who symptom is an indication that the count is likely to be less continue to be severely thrombocytopenic with significant than 20 109 l; however, a repeat count should be per- bleeding symptoms are very rare indeed, and should be formed within the first 710 d to check that there is no referred to a specialist centre for management (Lilleyman, evidence of a serious marrow disorder emerging, particularly 1999). aplasia. Otherwise the count can be performed when clinic- ally indicated by a change of symptoms, or if the family feel Clinical classifications more at ease knowing the result. However, too close a focus Two clinical scoring systems have been used, the first in on numbers is not helpful. When the thrombocytopenia the two UK national surveys for analysis of 703 newly persists but the child remains well, the intervals between visits diagnosed children (Bolton-Maggs & Moon, 1997, 2001), can be stretched out in order to minimise interference with and the second was reported from a single centre in Texas schooling. With increasing duration of a very low platelet where it has been analysed on 109 occasions in 54 count and limitation of some sporting activities, lifestyle patients, both at diagnosis and in established ITP (Bucha- issues become relatively more important and should be nan & Adix, 2001). Both of these confirm that the sympathetically discussed. These issues may influence deci- majority of children do not have serious bleeding problems sions about treatment. Most parents and patients can live quite despite very low platelet counts. The severity of bleeding at comfortably with petechiae and low platelets awaiting spontaneous any given time, especially at presentation does not predict remission providing their physician can (Dickerhoff, 1994). the risk of subsequent episodes of serious bleeding. Children should not be treated on the basis of cutaneous Recommendation: signs alone, however, dramatic and widespread the Children with acute ITP and mild clinical disease may be purpura. managed expectantly with supportive advice and a 24 h contact point, irrespective of platelet count (Grade B Recommendation: recommendation). The full blood count should be repea- Clinical severity, in addition to platelet count, should be ted within 10 d of diagnosis to ensure there is no used to define the severity of acute ITP in children. evidence of evolution to a serious marrow disorder; Treatment should be considered on the basis of other thereafter the count need not be monitored until clinical symptoms in addition to cutaneous signs, and resolution of clinical symptoms suggests the onset of not the platelet count alone (Level IIb evidence, Grade B remission or there are other clinical indicators suggesting recommendation). the need.
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584 Guideline Specific treatment to raise the platelet count Pulsed high dose dexamethasone. This treatment appears Several therapies raise the count faster than no treatment to be less effective in children than in adults in producing (Ib evidence). However, all have significant side effects and long-term remission, but may be useful as a temporary none alters the underlying pathology nor increases the measure. There is no evidence that this treatment, or any chance of complete remission. These strategies are appro- of the treatments that can produce an increase in the priate for children with severe bleeding symptoms. platelet count, increases the chance of complete remission. Three small studies of 11 (Kuhne et al, 1997), 17 (Borgna- Corticosteroids Pignatti et al, 1997) and seven children (Chen et al, 1997) Prednisolone. Conventional doses of 12 mg kg d for a demonstrated some benefit in some children 78% maximum of 14 d may be effective in raising the count but children achieved a platelet count > 100 109 l within perhaps is little faster than no therapy (Buchanan & 72 h in 41 cycles of treatment given to 11 children with Holtkamp, 1984) (Level 1b evidence). Prednisolone should chronic ITP (Kuhne et al, 1997). However, side effects be discontinued after a maximum of 23 weeks irrespective were unacceptable in 3 11 children. This treatment of platelet count because of the serious side effects cannot be recommended as first line therapy in sympto- associated with prolonged treatment. There is evidence matic children. 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 Recommendation: (prednisolone 4 mg kg d) has been compared in two If a child has mucous membrane bleeding and more randomized controlled trials and been shown to be more extensive cutaneous symptoms, high dose prednisolone effective (Level Ib evidence). Fifty three children were 4 mg kg d is effective (Grade A recommendation, Level randomized between IVIg, high dose (4 mg kg d) oral Ib evidence). It can be given as a very short course prednisolone with tapering and cessation by 21 d and no (maximum 4 d). There are no direct comparisons of low therapy in one study (Blanchette et al, 1993). The median dose (12 mg kg d) with high dose therapy. If lower time to reach a count of > 50 109 l was 4 d in the doses of 12 mg kg d are used the treatment should be prednisolone group compared with 16 d in the no given for no longer than 14 days, irrespective of treatment group, and 2 d in those given IVIg. The same response. regimen was used in a later study of 146 children which included a treatment arm with anti-D (Blanchette et al, Intravenous immunoglobulin 1994). In the latter study 28 39 (72%) of children in the Intravenous immunoglobulin is effective in raising the high dose steroid arm achieved a count > 50 109 l platelet count in more than 80% of children, and does so within 72 h. more rapidly than steroids or no therapy (Blanchette et al, The disadvantage of this steroid regimen is the duration 1994) (Level 1b evidence). It is expensive and invasive, at high dose. A short course may be sufficient. A pilot study and should be reserved for emergency treatment of patients of 25 children given 4 mg kg for 4 d (Carcao et al, 1998) who do not remit or respond to steroids and who have demonstrated that 22 children achieved a count of active bleeding. It is an appropriate treatment to enable > 20 109 l within a week with minimal side effects (Level essential surgery or dental extractions. It should not be III evidence). If a child requires treatment for symptoms, an used to raise the platelet count in children with cutaneous early effect on count is reassuring. It is essential that symptoms alone. IVIg is a pooled blood product, the risks steroids are not continued for longer than 2 to 3 weeks or of which must be explained to patients. It has significant titrated against the platelet count as this may lead to side effects, noted in 75% of children treated in a recent inappropriate doses and duration, with very significant trial (Blanchette et al, 1993). Severe headache can be long-term side effects. troublesome (Kattamis et al, 1997). In addition, IVIg has transmitted hepatitis C, a life-threatening infection (Duhem Other steroid regimens et al, 1994). Its use in children with trivial symptoms is High dose methyl prednisolone (HDMP). This has been not justified. used as an alternative to IVIg because it is cheaper and Dose regimen. The traditional dose is 0.4 g kg daily for effective. A small study of 22 children given an oral 7 d 5 d. This has now been superseded by short course high course (30 mg kg d for 3 d followed by 20 mg kg d for dose treatment either with a single dose of 0.8 g kg or 4 d) demonstrated that all patients achieved platelet 1 g kg given on 1 or 2 d (Blanchette et al, 1994; counts > 50 109 l by d 7. Courses were repeated Tarantino et al, 1999). These larger doses may be monthly if the count was less than 20 109 l on d 30, associated with a higher risk of side effects. Another for up to six courses (Ozer et al, 2000). Other small studies small, randomized multicentre study demonstrated lower have demonstrated HDMP to be as effective as IVIg in doses of 250, 400 or 500 mg kg d for 2 d to be raising the platelet count (Ozsoylu et al, 1989, 1993). effective (count increasing by more than 30 109 l) in Two studies demonstrated the efficiency of a combined 16 17 (94%) children aged 512 years (Warrier et al, approach using HDMP with IVIg but these were small 1997). The product chosen should be one with at least uncontrolled studies (Barrios et al, 1993; Gereige & two viral inactivation steps included in the manufacturing Barrios, 2000). process.
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Guideline 585 with an adequate platelet count (i.e. more than 20 109 l) Recommendation: and have no symptoms unless injured. In children under IVIg can raise the platelet count rapidly, but should be 10 years of age at diagnosis spontaneous remission is likely reserved for emergency treatment of serious bleeding to occur eventually; expectant management can continue. symptoms or in children undergoing procedures likely to Children more than 10 years of age at diagnosis, and in induce blood loss. It is effective given as a single dose of particular adolescent females, are more likely to sustain a 0.8 g kg (Evidence level Ib, Grade A recommendation). chronic course and management considerations are much Lower doses are also effective, and fewer side effects are as for adults. Most children need no specific therapy to raise seen, in younger children. the count unless injured or requiring surgery or dental extraction. Particular problems may arise for girls at the Other therapies onset of menstruation. Children and parents should not Anti-D immunoglobulin. This is less expensive than IVIg forget the vulnerability to excessive bleeding following and can be given to Rh (D) positive individuals as a short serious accidents and it is advisable for the family to carry infusion, and is therefore amenable to outpatient therapy. It a card or letter with details of the disorder in case of is effective in children (Scaradavou et al, 1997), but the emergency. A medical bracelet or pendant may be helpful. mechanism of action is not fully understood. Like IVIg, Children with counts persistently below 10 109 l are anti-D has the disadvantage of being a pooled blood product, likely to have some symptoms, e.g. easy bruising or odd but produces a rise in platelet count as rapidly as IVIg when petechiae. Such children have been described as having given at sufficient dosage (4550 lg kg) (Tarantino et al, chronic severe ITP (CSITP), are very rare (estimated annual 1999). Some degree of haemolysis is quite commonly seen, incidence of perhaps 1 in 2 500 000; Lilleyman, 1999) and which can occasionally be severe and is associated with are the most difficult to manage (Lilleyman, 2000). There is renal failure (Gaines, 2000). Lower dose treatment is less a strong case for these children to be referred to paediatric effective at raising the platelet count than IVIg (Blanchette haematologists with a special interest. Occasionally, girls et al, 1994). carry ITP into adulthood, but it tends to attenuate over time (anecdotal reports). There are no data on boys with Other treatments persistent ITP beyond their teens. As with adult ITP, a variety of other drugs have been tried in The risk of serious bleeding is a function of the duration of patients with persistent thrombocytopenia and bleeding. time with a low count and has been estimated at 0.5% at There is insufficient information concerning their use in 12 months in those with a count less than 20 109 l children to make specific recommendations concerning what (Lilleyman, 1999). There is insufficient evidence in the should be used or in which order. Cytotoxic drugs should literature to determine the best course of management for be used with extreme caution in children, with appropri- these patients (George et al, 1996; Lilleyman, 2000). ate consideration given to infertility and carcinogenesis. Treatment must be tailored to the child and situation, based on three criteria: the therapy should be effective, it Use of blood products platelet transfusions should not carry more risk than the untreated condition, Life-threatening haemorrhage is the only indication for and it should make the child feel better (George et al, 1996; platelet transfusion in ITP, a destructive platelet disorder Lilleyman, 2000). where transfusions of normal doses are unlikely to be A significant group of children with ITP have counts of effective. National surveys have demonstrated that platelet 1030 109 l, and although they have no serious bleeding, transfusions are sometimes given for simple thrombocy- are nevertheless troubled by purpura. Children, particularly topenia. This is never justified. In a life-threatening situation once at secondary school, become very conscious of their (such as the rare ICH) larger than normal doses are required appearance and need sympathetic support. Lifestyle issues with monitoring of the increment as a guide, and other and restrictions on sporting activities become more import- modalities such as high dose IV steroids and IVIg should be ant and should be taken into account in considering therapy. given at the same time to maximise the chances of raising Intermittent treatment with IVIg can be given to cover the count and stopping the haemorrhage. activity holidays after appropriate discussion of the risks. However, it should be noted that this might cause additional Recommendation: problems with insurance cover when a child has been in Platelet transfusions should only be given for ICH or hospital within 6 months of going on holiday. There is no other life-threatening bleeding, and then in much larger evidence that air travel predisposes to bleeding in patients doses than for marrow failure. At the same time, with ITP; there is no indication to treat the count prior to immunomodulatory treatment should be given with holidays other than to cover activities. Parents should high dose intravenous steroids or IVIg (Grade C recom- always declare the illness to their insurance company before mendation). travelling in case treatment is required while on holiday. Bleeding complications must be managed according to Chronic ITP in childhood severity and circumstances; there is no straightforward Most children with ITP will remit within 6 months. The strategy for these young people. Splenectomy is often management of children with continuing thrombocytopenia considered, but it is ineffective in around 25% of cases, is essentially the same as for acute ITP. Many children settle and with longer follow-up it is clear that the relapse rate is
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586 Guideline high, although often the platelet count runs at a more Table I. The major causes of maternal thrombocytopenia in preg- acceptable level with fewer symptoms. nancy.
1. Children with chronic ITP usually do not need Gestational thrombocytopenia active therapy but should be followed up regularly Pre-eclampsia and HELLP* syndrome and reminded to report to hospital after injuries. Autoimmune thrombocytopenia idiopathic They should have a designated contact person and drug-related number. SLE 2. Children with chronic severe ITP should be referred antiphospholipid syndrome to a paediatric haematologist for management and HIV-related long term follow-up. Disseminated intravascular coagulation Haemolytic uraemic syndrome thrombotic thrombocytopenic Splenectomy purpura Folate deficiency Splenectomy is rarely indicated in children with ITP. Long- Congenital platelet disorders term follow-up demonstrates that spontaneous remissions Coincidental marrow disease continue to occur at least up to 15 years from diagnosis Hypersplenism (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 *Haemolysis, elevated liver enzymes and low platelets. 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 over- indicator of significant complications of pregnancy such whelming sepsis probably persists for life, splenectomy is as pre-eclampsia or disseminated intravascular coagula- only justified in exceptional circumstances (Eden & Lilley- tion (DIC) in addition to a range of less common acquired man, 1992). Severe lifestyle restrictions, crippling menor- or congenital disorders (Table I). Thus, the assessment rhagia or life threatening haemorrhage may give good of individual cases of thrombocytopenia in pregnancy reason for the procedure, but only 7075% will respond focuses on excluding important secondary causes and (George et al, 1996), and full precautions against sepsis weighing the risks of bleeding in mother and infant should be undertaken (BCSH, 1996). against the hazards of diagnostic and therapeutic inter- ventions. Recommendation: Normal platelet count in pregnancy Splenectomy is rarely indicated in childhood ITP. It is Most pregnant women have platelet counts within the non- occasionally justified for life-threatening bleeding and for pregnant reference range. However, large prospective stud- children with chronic unremitting and severe ITP whose ies (level III evidence) have confirmed that platelet counts disease has been present for more than 1224 months tend to fall during pregnancy and levels of 120 with demonstrable impairment of their quality of life, but 150 109 l are not uncommon in the third trimester (Sill these children are rare, and should be referred to a et al, 1985; Burrows & Kelton, 1988). A single-institutional specialist paediatric haematologist for individual consid- study (Burrows & Kelton, 1988) of 1357 women with eration (Grade C recommendation). normal pregnancy, delivering at term, showed a mean platelet count of 225 10 l with 95% confidence intervals of 109341 109 l. THROMBOCYTOPENIA IN PREGNANCY Incidence of ITP in pregnancy PRESENTATION AND DIAGNOSIS The advent of routine platelet counting using automated blood cell counters highlighted the fact that mild to Gestational thrombocytopenia (incidental thrombocytopenia moderate thrombocytopenia is common in healthy women of pregnancy) with an apparently normal pregnancy. Excluding those The best evidence for the natural history of this phenom- cases with spurious counts due to EDTA-induced in vitro enon comes from a sequence of prospective studies reported platelet aggregation, the large majority of these women by the McMaster group in Ontario (Burrows & Kelton, have gestational thrombocytopenia (GT), a benign self- 1988, 1990, 1993) (Level III evidence). At term, thrombo- limiting phenomenon with no significant bleeding-risk to cytopenia was present in 5.48.3% of healthy mothers. mother or infant. However, it may be difficult or Platelet counts were only mildly reduced in most patients impossible to distinguish GT from idiopathic (autoim- (mean 135 109 l) and were between 100 and mune) thrombocytopenia (ITP) in which the transmission 150 109 l in 95% of cases. It is exceptional for the of platelet antibodies across the placenta has the potential platelet count to fall below 80 109 l but rare cases, to cause fetal or neonatal thrombocytopenia and haemor- subsequently confirmed as GT, had counts as low as rhage. Maternal thrombocytopenia may also be an 50 109 l.
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Guideline 587 The incidence of thrombocytopenia in cord blood samples innovative methodologies, measurement of serum platelet taken from the infants of women with GT and women with autoantibodies are not clearly diagnostic of ITP in individual normal platelet counts was identical at 4%. patients and do not predict the likelihood of neonatal Hence, GT is characterized by: thrombocytopenia (Burrows & Kelton, 1992; Letsky & Mild thrombocytopenia (rarely < 80 109 l) Greaves, 1996; Sainio et al, 1998; Boehlen et al, 1999). Occurrence in healthy women with otherwise normal blood counts Recommendation for investigation of suspected ITP in Most commonly occurs in the third trimester of preg- pregnancy: nancy As in non-pregnant patients, the diagnosis of ITP is one Normal platelet counts before and after pregnancy of exclusion. Benign gestational thrombocytopenia is No association with maternal haemorrhage 100 times more common but, as there are no definitive No association with fetal or neonatal thrombocytopenia diagnostic tests, it may be impossible to distinguish these GT is difficult to distinguish from ITP when thrombocy- conditions until a non-pregnant platelet count is avail- topenia is identified for the first time during pregnancy and able. All women with platelet counts < 100 109 l no previous counts have been documented. should be screened for clinical or laboratory evidence of pre-eclampsia, coagulopathy or autoimmune disease. Idiopathic (autoimmune) thrombocytopenia (ITP) Bone marrow examination is unnecessary unless there is Chronic ITP is most common in women of reproductive age suspicion of leukaemia or lymphoma. The routine and is therefore encountered in pregnancy. The estimated measurement of PAIg or platelet antibodies is not prevalence is 15 cases per 10,000 pregnancies (Kessler recommended (Evidence Levels III IV, Grade C recom- et al, 1982), i.e. around 100 times less common than GT. mendations). Patients occasionally present for the first time with severe thrombocytopenia in pregnancy and women with previ- OPTIONS FOR TREATMENT ously diagnosed ITP may experience an exacerbation in pregnancy, the nadir platelet count usually occurring in the Optimum management of ITP in pregnancy requires close third trimester (Burrows & Kelton, 1992). However, the collaboration between the obstetrician, haematologist and most common presentation is the finding of asymptomatic paediatrician. There are no high quality prospective studies thrombocytopenia on routine laboratory testing, when the or randomized clinical trials to inform management of the distinction from GT may be difficult. mother, delivery or the neonate. Recommendations are As in the non-pregnant patient, the diagnosis of ITP is based on clinical experience and expert consensus (Grade C largely one of exclusion as there is no confirmatory recommendation). laboratory test (Burrows & Kelton, 1992). Documentation of a low platelet count outside pregnancy is invaluable. It is Management of the pregnant woman with ITP important to exclude pre-eclamptic syndromes, DIC or The decision to treat the pregnant woman with ITP is based autoimmune disorders such as SLE and the antipho- on assessment of the risk of significant haemorrhage. The spholipid syndrome, which carry significant prognostic count usually falls as pregnancy progresses, the greatest and therapeutic implications (Table II). Patients should be rate of decline and nadir occurring in the third trimester carefully examined for hepatosplenomegaly and lympha- (Burrows & Kelton, 1992). Therefore, careful planning is denopathy or features of pre-eclampsia (hypertension, required to ensure a safe platelet count at the time of proteinuria, intrauterine growth restriction). delivery. Frequency of monitoring depends on the individual If there are no additional clinical features and the blood case, taking into account the absolute platelet count, rate of count and film are otherwise normal, bone marrow change and proximity of delivery. examination is not recommended (Letsky & Greaves, 1996). As with non-pregnant adults and paediatric ITP, platelet- Targets for treatment associated IgG is of no diagnostic value. Despite recent Asymptomatic patients with platelet counts > 20 109 l do not require treatment until delivery is imminent but should be carefully monitored, both clinically and haema- Table II. Recommended laboratory investigations of thrombocy- tologically (Letsky & Greaves, 1996). Platelet counts of topenia in pregnancy (Grade C recommendation) > 50 109 l are regarded as safe for normal vaginal delivery (Letsky & Greaves, 1996) and some experts extend Blood film (to exclude spurious thrombocytopenia, red cell this to levels of 3050 109 l (Lichtin, 1996). A platelet fragments, other haematological disorders) count of > 50 109 l is also safe for Caesarian section but Coagulation screen (PT, APTT, fibrinogen, D-dimer) would preclude the use of epidural anaesthesia for which Liver function tests the platelet count should be > 80 109 l. Because of the Anticardiolipin antibodies lupus anticoagulant theoretical risk of haematoma formation and neurological SLE serology damage, spinal or epidural anaesthesia is not recommended if the platelet count is < 80> 50 109 l (Letsky & Greaves, PT, prothrombin time; APTT, activated partial thromboplastin 1996). There is no evidence that the template bleeding time time; DRVVT, dilute Russells viper venom time. predicts the risk of haemorrhage in this situation.
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588 Guideline Treatment options In women who need treatment, both oral corticoster- The major treatment options for maternal ITP are oids and IVIg appear to have a similar response rate to corticosteroids or IVIg. Vinca alkaloids, androgens and the use of these agents in the non-pregnant patient most immunosuppressive drugs should not be used in Although many clinicians now favour the use of IVIg pregnancy although azathioprine has been used safely in in pregnancy there are no good comparative studies transplant patients. and the decision must take into account maternal If the duration of treatment is likely to be short, i.e. clinical factors and preference in addition to the starting in the third trimester, corticosteroids are a cost- expense, availability and (remote) risks of microbial effective option. An initial dose of 1 mg kg (based on pre- transmission by IVIg. pregnancy weight) is recommended (Burrows & Kelton, There are no convincing data on the effect (beneficial 1992; Letsky & Greaves, 1996), subsequently tapered to the or otherwise) of corticosteroids or IVIg on the minimum haemostatically effective dose. Patients must be fetal neonatal platelet count. carefully monitored for significant side effects such as Severe refractory ITP may respond to high dose IV hypertension, hyperglycaemia, osteoporosis, excessive methyl prednisolone IVIg or azathioprine. If essen- weight gain and psychosis. As 90% of the administered tial, splenectomy may be performed (ideally in the dose of prednisolone is metabolised in the placenta (Smith & second trimester) and the laparoscopic route may have Torday, 1982), serious fetal side effects such as adrenal clinical advantages similar to those seen in non- suppression are unlikely. The only systematic study showed pregnant patients. 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 Management of delivery and the newborn infant effects occur or an unacceptably high maintenance dose is Historically, management of the delivery in mothers with required (perhaps > 7.5 mg prednisolone daily) IVIg ther- ITP was dominated by concerns over the risk of severe apy should be considered. There are no published compar- neonatal thrombocytopenia and haemorrhage. In 1976, ative trials of steroids and IVIg in pregnancy. The caesarean section was recommended for all patients based conventional dose of IVIg is 0.4 g kg d for 5 d although on a reported perinatal mortality of 1221%, largely due to 1 g kg for 2 d has been used successfully and may be more birth trauma and ICH (Murray & Harris, 1976). These data convenient (Burrows & Kelton, 1992). The response rate were clearly selective and excessively pessimistic; more (80%) and duration of response (23 weeks) is similar to recent reviews suggesting a neonatal mortality of around non-pregnant patients. After an initial response, repeat 0.6% (Burrows & Kelton, 1992). Large prospective studies single infusions can be used to prevent haemorrhagic published in the 1990s show an incidence of severe symptoms and ensure an adequate platelet count for neonatal thrombocytopenia (< 50 109 l) of 8.914.7% delivery. The ability of maternal IVIg therapy to improve with ICH occurring in 01.5% of infants (Bussel et al, fetal platelet counts remains controversial (Nicolini et al, 1991b; Burrows & Kelton, 1993). There is no evidence that 1990). IVIg carries the same potential risks and side effects caesarean section is safer for the thrombocytopenic neonate as in the non-pregnant patient and the financial cost is than uncomplicated vaginal delivery (which is unequivo- much higher than corticosteroids. cally safer for the mother). In any event, most haemor- Therapeutic options for those women with severely symp- rhagic events in neonates occurred 2448 h after delivery tomatic ITP refractory to oral steroids or IVIg include high at the nadir of the platelet count. dose intravenous methyl prednisolone (1000 mg), perhaps Attempts have been made to predict which neonates will combined with IVIg, or azathioprine (Letsky & Greaves, have severe thrombocytopenia to inform management 1996). From available data, the latter appears to cause no decisions. It is reported (evidence level III) that the fetal or significant problems to either mother or fetus (Erkman & neonatal platelet count cannot be reliably predicted from Blythe, 1972; Price et al, 1976; Alstead et al, 1990). Splen- the maternal platelet count, maternal platelet antibody ectomy in pregnancy is now rarely performed. If essential, it levels (by a variety of techniques) or a history of maternal is best carried out in the second trimester and may be splenectomy for ITP (Samuels et al, 1990; Burrows & successfully performed by the laparoscopic route, although Kelton, 1992; Letsky & Greaves, 1996; Sainio et al, 1998; this may be technically difficult beyond 20 weeks gestation. Boehlen et al, 1999). Fetal blood sampling by cordocentesis has been explored (Scioscia et al, 1988) but this procedure carries a mortality of 12%, which is at least as high as the Recommendation: (All Grade C) risk of ICH. Scalp blood sampling in early labour to Asymptomatic women with platelet counts > 20 measure the fetal platelet count has also been advocated 109 l do not need treatment until delivery is imminent (Scott et al, 1980). This procedure is technically difficult, Platelet counts > 50 109 l are safe for normal commonly produces artefactually low results because vaginal delivery in patients with otherwise normal of clotting due to exposure to vernix or amniotic fluid coagulation and can cause significant haemorrhage. For these reasons, Platelet counts > 80 109 l are safe for caesarean both cordocentesis and fetal scalp blood sampling have now section, spinal or epidural anaesthesia in patients with been largely abandoned in the management of ITP in otherwise normal coagulation pregnancy.
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Guideline 589 In view of the difficulty in predicting those few neonates defect should be present. The mother should always be with severe thrombocytopenia and the very low risk of questioned about excessive bruising or bleeding since the serious haemorrhage, it is now generally agreed (Level III presence of these may signify impaired platelet function in evidence, Grade B recommendation) that the mode of borderline cases. delivery in ITP should be determined by purely obstetric The use of powerful non-steroidal anti-inflammatory indications (Bussel et al, 1991c; Burrows & Kelton, 1992; drugs for post-partum or post-operative analgesia should Letsky & Greaves, 1996). be avoided in women with platelet counts less than Following delivery, a cord blood platelet count should 100 109 l because of their anti-platelet activity which be determined in all cases (Level III evidence, Grade C may increase the risk of haemorrhage (Level IV Evidence, recommendation). Those infants with subnormal counts Grade C Recommendation). should be closely observed clinically and haematologically Venous thromboembolism (VTE) is the commonest cause as the platelet count tends to fall further to a nadir of maternal mortality in the UK and all women with ITP between d 2 and 5 after birth (Burrows & Kelton, 1992). should be considered for thromboprophylaxis if they are Treatment of the neonate is rarely required. In those with undergoing surgical delivery, are immobilized by other clinical haemorrhage or platelet counts < 20 109 l medical complications, have a congenital or acquired treatment with IVIg 1 g kg produces a rapid response. thrombophilia (especially the antiphospholipid syndrome) Life-threatening haemorrhage should be treated by platelet or recent venous thrombosis. In each case an individual transfusion combined with IVIg (Burrows & Kelton, risk assessment must be made about the desirability and 1992). safety of anticoagulant therapy taking into account factors Severe thrombocytopenia and clinical haemorrhage in such as age, obesity and personal and family history. neonates are sufficiently unusual in association with Although there are no published data to guide clinical maternal ITP that where they occur, neonatal alloimmune practice, treatment or prophylaxis with standard doses of thrombocytopenia should be excluded by laboratory testing. unfractionated heparin (UFH) or low-molecular-weight This is important not only for the appropriate management heparin (LMWH) should be used in women with platelet of the neonate, but also in relation to the antenatal counts > 50 109 l (Level IV Evidence, Grade C Recom- management of subsequent pregnancies. mendation) 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 OBSTETRIC ANAESTHETICS balance of risks would probably favour thromboprophylaxis Anaesthetic management options at platelet counts down to 50 109 l, especially if LMWH The obstetric anaesthetist is often called upon to make a with its more favourable therapeutic window is used. All decision regarding the advisability of regional analgesia and at-risk patients should use appropriate graduated compres- anaesthesia in these cases. Several textbooks and articles sion hosiery and be considered for intermittent mechanical offer guidance on this subject, and the general trend in pneumocompression of the calves during surgery (Level IV recent years has been to lower the cut-off point from a Evidence, Grade C Recommendation). platelet count of 80100 109 l (Beilin et al, 1997). In fact, there is no evidence to support this sort of all- Recommendation: or-nothing approach, and every case must therefore be considered on its own merits, with the risk of the procedure The mode of delivery in women with ITP should be decided by primarily obstetric indications. There is no (epidural spinal haematoma) balanced against the benefits evidence to support the routine use of caesarean (pain relief, better blood pressure control, avoidance of general anaesthesia). section (Grade B) When monitoring platelet levels, the trend as well as the Platelet counts > 50 109 l are safe for normal vaginal delivery if coagulation is otherwise normal absolute value is important, and the mother with a rapidly falling count should be regarded with more suspicion than Platelet counts > 80 109 l are safe for spinal epidu- the one with a low, but stable, platelet level (Greaves & ral anaesthesia or caesarean section if coagulation is otherwise normal Letsky, 1997). At the same time, the cause of the Women undergoing operative delivery should be thrombocytopenia must be taken into account since different pathologies have different effects upon the haemo- considered for thromboprophylaxis according to their individual clinical risk factors. Standard prophylactic static mechanism for a given platelet count. In general, doses of UFH or LMW heparin should be used if the patients with a platelet count of > 80 109 l in the absence of pre-eclampsia are unlikely to have significantly altered maternal platelet count is > 100 109 l (Grade C) Non-steroidal anti-inflammatory drugs should be avoi- platelet function. Tests of platelet function, such as bleeding ded for post-partum or post-operative analgesia in time, are operator-dependent and therefore of limited predictive value. Thromboelastography is a promising women with platelet counts < 100 109 l (Grade C) development in this field, but its place in clinical practice The risk of clinically dangerous thrombocytopenia in the neonate is very low but cannot be predicted by has yet to be determined, and will require further clinical clinical or laboratory parameters in the mother. trials (Gorton & Lyons, 1999). Routine coagulation studies are usually indicated in thrombocytopenia in case any other Attempts to measure the fetal platelet count by
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590 Guideline ACKNOWLEDGMENTS cordocentesis or fetal scalp blood sampling are not recommended as they carry more risks than potential The section on paediatric ITP is based on an article by Dr clinical benefits (Grade B) Bolton-Maggs (2002), written for Current Paediatrics and is Because of the risk of haemorrhagic complications in reproduced with permission by Elsevier Science Ltd. the neonate the application of scalp electrodes for monitoring in labour and fetal blood sampling should DISCLAIMER be avoided. The use of vacuum extraction (ventouse) is contraindicated and complicated instrumental delivery Although the advice and information contained in these (e.g. rotational forceps) should be avoided if possible guidelines is believed to be true and accurate at the time of (Grade C) going to press, neither the authors nor the publishers can Cord platelet counts should be measured in all accept any legal responsibility for any errors or omissions neonates of mothers with ITP and those with subnor- that may have been made. mal levels monitored clinically and with daily counts until after the nadir which usually occurs on d 25 British Committee for Standards in after delivery (Grade C) Haematology General Haematology Task Force Treatment of the thrombocytopenic neonate should be reserved for those with clinical evidence of haemor- WORKING PARTY rhage or a platelet count < 20 109 l when there is usually a prompt response to IVIg (1 g kg). Life- Dr Drew Provan, Barts & The London, Queen Marys School threatening haemorrhage should be treated with of Medicine and Dentistry, London, UK immediate platelet transfusion and IVIg (Grade C). Professor Adrian Newland, Barts & The London, Queen Marys School of Medicine and Dentistry, London UK Dr Derek Norfolk, Department of Haematology, General MANAGEMENT OF MENORRHAGIA Infirmary at Leeds, Leeds, UK For patients with ITP in whom heavy menstrual bleeding Dr Paula Bolton-Maggs, Department of Haematology, Alder Hey Childrens Hospital, Liverpool, UK occurs, symptom control may be achieved using tranexamic Professor John Lilleyman, Barts & The London, Queen acid and or oral contraceptives. The Mirena coil is a Marys School of Medicine and Dentistry, London, UK progestogen-loaded intrauterine contraceptive that induces Professor Ian Greer, Department of Obstetrics, University endometrial atrophy, and is effective in controlling menor- of Glasgow, Glasgow Royal Infirmary, Glasgow, UK rhagia. Dr Anne May, Department of Anaesthetics, Leicester Royal Infirmary, Leicester, UK PATIENT SUPPORT Dr Mike Murphy, National Blood Service, Department of The ITP Support Association was formed in 1995 to offer Haematology, Oxford Radcliffe Hospitals, and University of support to those with adult, childhood and maternal ITP. Oxford, UK Assisted by its medical advisors the Association publishes a Dr Willem Ouwehand, Department of Transfusion Medi- quarterly newsletter and a wealth of reader friendly booklets cine, Cambridge and NBS Cambridge and factsheets on ITP and its associated concerns, including Mrs Shirley Watson, ITP Support Association, Bedford, guidelines for schools, protocol for dentists of affected UK patients, splenectomy patients guide and holiday guide- lines. ITP HealthCare cards are supplied for a small fee, Classification of Evidence Levels giving personal details on a wallet-size laminated card in case of emergency. Ia Evidence obtained from meta-analysis of randomized Annual national conventions featuring ITP specialists controlled trials from the UK and USA allow patients to overcome their Ib Evidence obtained from at least one randomized feelings of isolation by meeting fellow sufferers. The controlled trial IIa Evidence obtained from at least one well-designed Association has funded research and part funded the controlled study without randomization National Register of Patients and the first ITP Specialist IIb Evidence obtained from at least one other type of Nurse. By sending an A5 SAE with 2x 1st class stamps to well-designed quasi-experimental study* The ITP Support Association, Synehurste, Kimbolton Road, III Evidence obtained from well-designed non-experimental Bolnhurst, Bedfordshire, MK44 2EW, UK, ITP suffer- descriptive studies, such as comparative studies, ers families can receive a free information pack. There is correlated studies and case studies no membership fee, the ITP Support Association is run by IV Evidence obtained from expert committee reports or volunteers and relies mainly on voluntary donations to fund opinions and or clinical experience of respected authorities its operation. Further information can be found on http:// www.itpsupport.org.uk and Where to Get Help patient *Refers to a situation in which implementation of an intervention leaflets can be ordered free of charge by e-mailing shirley@ is outwith the control of the investigators, but an opportunity exists itpsupport.org.uk. to evaluate its effect.
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Guideline 591 Classification of Grades of Recommendations Bellucci, S., Charpak, Y., Chastang, C. & Tobelem, G. (1988) Low doses v conventional doses of corticoids in immune thrombocy- A Requires at least one Evidence topenic purpura (ITP): results of a randomized clinical trial in randomized controlled trial levels Ia, Ib 160 children, 223 adults. Blood, 71, 11651169. as part of a body of literature Ben-Yehuda, D., Gillis, S. & Eldor, A. (1994) Clinical and ther- of overall good quality and apeutic experience in 712 Israeli patients with idiopathic consistency addressing specific thrombocytopenic purpura. Israeli ITP Study Group. Acta Hae- recommendation matologica, 91, 16. B Requires the availability of Evidence levels Berchtold, P. & McMillan, R. (1989) Therapy of chronic idiopathic well-conducted clinical IIa, IIb, III thrombocytopenic purpura in adults. Blood, 74, 23092317. studies but no randomized Berchtold, P. & Wenger, M. (1993) Autoantibodies against platelet clinical trials on the topic glycoproteins in autoimmune thrombocytopenic purpura: their of recommendation clinical significance and response to treatment. Blood, 81, 1246 C Requires evidence obtained Evidence 1250. from expert committee reports level IV Blanchette, V., Freedman, J. & Garvey, B. (1998) Management of or opinions and or clinical chronic immune thrombocytopenic purpura in children and experiences of respected adults. Seminars in Hematology, 35, 3651. authorities. Indicates an Blanchette, V., Imbach, P., Andrew, M., Adams, M., McMillan, J., absence of directly applicable Wang, E., Milner, R., Ali, K., Barnard, D., Bernstein, M., Chan, clinical studies of good quality K.W., Esseltine, D., deVeber, B., Israels, S., Kobrinsky, N. & Luke, B. (1994) Randomized trial of intravenous immunoglobulin G, intravenous anti-D, and oral prednisone in childhood acute immune thrombocytopenic purpura. Lancet, 344, 703707. 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592 Guideline an antigen- specific assay (MAIPA) in idiopathic thrombocyto- presenting with acute immune thrombocytopenic purpura (ITP). penic purpura and other immune thrombocytopenias. Blood, 88, Acta Paediatrica Suppl., 424, 7174. 194201. Carr, J.M., Kruskall, M.S., Kaye, J.A. & Robinson, S.H. (1986) Effi- Brox, A.G., Howson-Jan, K. & Fauser, A.A. (1988) Treatment of cacy of platelet transfusions in immune thrombocytopenia. idiopathic thrombocytopenic purpura with ascorbate. British American Journal of Medicine, 80, 10511054. Journal of Haematology, 70, 341344. Caulier, M.T., Rose, C., Roussel, M.T., Huart, C., Bauters, F. & Buchanan, G.R. & Adix, L. (2001) Outcome measures and treat- Fenaux, P. (1995) Pulsed high-dose dexamethasone in refractory ment endpoints other than platelet count in childhood idiopathic chronic idiopathic thrombocytopenic purpura. a report on 10 thrombocytopenic purpura. Seminars in Thrombosis and Hemos- cases. British Journal of Haematology, 91, 477479. tasis, 27, 277285. Cayco, A.V., Perazella, M.A. & Hayslett, J.P. (1997) Renal Buchanan, G.R. & Holtkamp, C.A. (1984) Prednisone therapy for insufficiency after intravenous immune globulin therapy: a children with newly diagnosed idiopathic thrombocytopenic report of two cases and an analysis of the literature. Journal of the purpura. A randomized clinical trial. American Journal of Pediatric American Society of Nephrology, 8, 17881794. Hematology Oncology, 6, 355361. CDC (1993) Recommendations of the advisory committee on Buchanan, G.R., de Alarcon, P.A., Feig, S.A., Gilchrist, G.S., Lukens, immunization practices: use of vaccines and immune globulins in J.N., Moertel, C.L., Cohen, A.R., Dickerman, J.D., Forman, E.N., persons with altered immunocompetence. Morbidity and Mortal- Glader, B.E. & Lusher, J.M. (1997) Acute idiopathic thrombocy- ity Weekly Report, 42, 112. topenic purpura management in childhood. 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Guideline 593 Duhem, C., Dicato, M.A. & Ries, F. (1994) Side-effects of Gereige, R.S. & Barrios, N.J. (2000) Treatment of childhood acute intravenous immune globulins. Clinical and Experimental immune thrombocytopenic purpura with high- dose methyl- Immunology, 97, 7983. prednisolone, intravenous immunoglobulin, or the combination Dwyer, J.M. (1992) Manipulating the immune system with immune of both. Puerto Rico Health Sciences Journal, 19, 1518. globulin. New England Journal of Medicine, 326, 107116. Gillis, S. & Eldor, A. (1998) Immune thrombocytopenic purpura: Eden, O.B. & Lilleyman, J.S. (1992) Guidelines for management of clinical aspects. Baillieres Clinical Haematology, 11, 361372. idiopathic thrombocytopenic purpura. The British Paediatric Godeau, B., Lesage, S., Divine, M., Wirquin, V., Farcet, J.P. & Haematology Group. Archives of Disease in Childhood, 67, 1056 Bierling, P. 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594 Guideline Kappers-Klunne, M.C. & vant Veer, M.B. (2001) Cyclosporin A for marrow examination have a role at presentation? Clinical and the treatment of patients with chronic idiopathic thrombocy- Laboratory Haematology, 22, 355358. topenic purpura refractory to corticosteroids or splenectomy. Makris, M., Greaves, M., Winfield, D.A., Preston, F.E. & Lilleyman, British Journal of Haematology, 114, 121125. J.S. (1994) Long-term management after splenectomy. Lifelong Karpatkin, S. (1997) Autoimmune (idiopathic) thrombocytopenic penicillin unproved in trials. British Medical Journal, 308, 131 purpura. Lancet, 349, 15311536. 132. Kattamis, A.C., Shankar, S. & Cohen, A.R. (1997) Neurologic Manoharan, A. (1991) Treatment of refractory idiopathic thromb- complications of treatment of childhood acute immune throm- ocytopenic purpura in adults. British Journal of Haematology, 79, bocytopenic purpura with intravenously administered immuno- 143147. globulin G. 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Guideline 595 Pizzuto, J. & Ambriz, R. (1984) Therapeutic experience on 934 in patients with idiopathic thrombocytopenic purpura. New adults with idiopathic thrombocytopenic purpura: Multicentric England Journal of Medicine, 337, 10871088. Trial of the Cooperative Latin American group on Hemostasis Scioscia, A.L., Grannum, P.A., Copel, J.A. & Hobbins, J.C. (1988) and Thrombosis. Blood, 64, 11791183. The use of percutaneous umbilical blood sampling in immune Porcelijn, L., Folman, C.C., Bossers, B., Huiskes, E., Overbeeke, M.A., thrombocytopenic purpura. American Journal of Obstetrics and v. d. Schoot, C.E., de Haas, M. & von dem Borne, A.E. (1998) The Gynecology, 159, 10661068. diagnostic value of thrombopoietin level measurements in Scott, J.R., Cruikshank, D.P., Kochenour, N.K., Pitkin, R.M. & thrombocytopenia. Thrombosis and Haemostasis, 79, 11011105. Warenski, J.C. 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