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Bone Marrow Examination in adults

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

SPECIALIZED LABORATORY ASSAYS IN THE DIAGNOSIS OF ITP

Assays for anti-platelet antibodies

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

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

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

Investigation of platelet autoantibodies may be of value in adults with

♦  Combination of bone marrow failure associated with immune-mediated thrombocytopenia

♦  ITP patients refractory to ?rst and second line treatment

♦  Drug-dependent immune thrombocytopenia (DDITP)

♦ Miscellaneous disorders (rare), e.g. monoclonal gammopathies and acquired autoantibody-mediated thrombasthenia

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

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

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

Thrombopoietin (TPO) assays

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

Reticulated platelets

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

Helicobacter pylori infection

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

Recommendation for adults:
The diagnosis of ITP is based principally on the exclusion of other causes of thrombocytopenia using the history, physical examination, blood count, peripheral blood film, autoimmune pro?le and other investigations. Further investigations are not indicated in the routine work-up of patients with suspected ITP if the history, examination, blood count and ?lm are typical of the diagnosis of ITP and do not include unusual features that are uncommon in ITP, or suggestive of other causes (Evidence IIb–IV; Grade B, C).
A bone marrow examination is unnecessary in adults unless there are atypical features, or the patient is over the age of 60 years, or the patient relapses following complete remission, on or off therapy, or splenectomy is being considered (Evidence Level III).
PAIg is elevated in both immune and non-immune thrombocytopenia and therefore has no role in the diagnosis of uncomplicated ITP (Evidence level III).
It is worth determining the presence of H. pylori in patients refractory to therapy since some patients have shown improvement in platelet counts following eradication therapy (Evidence level III, Grade B recommendation).

MANAGEMENT OF ADULT ITP

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

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

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