dxy

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

Patients failing first and second line therapies

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

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

Anti-CD20 antibody. Rituximab (chimaeric anti-CD20 monoclonal antibody) has been evaluated in a single study (Stasi et al, 2001) in which 25 patients with ITP resistant to 2–5 therapeutic options were treated with 375 mg/m² rituximab weekly for 4 weeks. Five patients showed a complete response and a partial response was seen in a further five. In seven patients the responses were sustained for over 6 months. There was a suggestion that younger patients showed better response rates.
Campath-1H. Lim et al (1993) treated six patients with refractory ITP (three patients had underlying CLL/nonHodgkin's lymphoma and one had Hodgkin's disease). A response was seen in four of five evaluable patients, and in three of these the response lasted more than 4–9 months. In most cases it took between 4 and 6 weeks for a response to occur. Side effects were significant and included rigors and fever during the infusion, and marked lymphopenia (< 0.1×10⁹/ l) in all patients treated. Worsening of thrombocytopenia was noted in two patients during therapy. A more recent study of the use of Campath-1H in patients with a variety of cytopenias has shown that it was well tolerated with encouraging responses (Willis et al, 2001).
Mycophenolate mofetil. This antiproliferative immunosuppressant, licensed for the prophylaxis of acute renal, cardiac or liver transplant rejection, has been shown to be of value in some patients with autoimmune cytopenias including refractory ITP (Evidence Level IV). However, the numbers of patients treated to date are small and larger studies are required (Zimmer-Molsberger et al, 1997; Allison & Eugui, 2000; Howard et al, 2002).

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

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

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

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

Recommendation for therapy in adults failing first and second line therapies:
Campath-1H and rituximab are agents that may be of value for patients in whom there is no response to other therapies and in whom there is a de?nite requirement to elevate the platelet count (e.g. active bleeding). Mycophenolate mofetil appears to be effective in some patients with severe refractory ITP but larger studies are required to con?rm its ef?cacy and safety. In terms of the risk: bene?t ratio, treatments with interferon-a, protein A columns, plasmapheresis and liposomal doxorubicin are not recommended.

Emergency treatment in adult patients

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

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

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

INVESTIGATION AND MANAGEMENT OF ITP IN CHILDREN

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

Diagnosis

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

Differential diagnosis

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

Congenital disorders that may resemble ITP

(a) In a young child (within a few weeks or months of birth)
Wiskott Aldrich syndrome
Bernard Soulier syndrome
Other occasional families with isolated congenital or hereditary thrombocytopenias of unspecified type

(b) In older children
Evolving Fanconi anaemia
von Willebrand’s disease type IIB (Donner et al, 1987)
Serious marrow disorders
Acute leukaemia (NB especially Down syndrome)
Aplastic anaemia


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