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Home , Hematology, Serum sickness, Thrombocytopenia

Immune thrombocytopenic The diagnosis and management of chronic immune in adults

A. Newland ABSTRACT

Barts and the London School Primary immune thrombocytopenia (ITP) is a complex autoimmune disorder involving - and cell-mediated destruction of and suppression of production. The definition of ITP of and , 9 Queen Mary University of London, requires an isolated thrombocytopenia with a platelet count below 100×10 /L, and with no other obvi- London, United Kingdom ous cause or clinically evident secondary form of immune thrombocytopenia. There is no “gold stan- dard” test for ITP, but the diagnosis is based on exclusion. ITP is a minor disease for many patients; however, the natural history is variable and unpredictable. Many patients who are in otherwise good health can be left untreated, especially if their platelet Education: 9 the education program for the counts are close to or above 20×10 /L. The overall mortality rate for ITP is less than 1%, and the mor- annual congress of the European bidity and mortality associated with treatment can be worse than the disease. Hematology Association While there is general agreement over treatment of the newly presenting adult with ITP, few evi- dence-based studies direct in the relapsed and refractory patient. There is an understanding 2011;5:184-190 that the patient should be treated for their clinical state rather than their platelet count but not what second line treatment should be used and in what order. The options will be considered in this review.

disease duration, the term “newly diagnosed Introduction ITP” has been adopted for all cases at diag- Primary immune thrombocytopenia (ITP) nosis. A new category, called “persistent is an autoimmune disorder typified by a ITP,” was introduced for patients with ITP to platelet count below the normal range. define the period lasting between 3 and 12 Clinical manifestations are related to the months from diagnosis. This category severity of thrombocytopenia and include includes patients not achieving spontaneous purpura and episodes, which can be remission or not maintaining their response potentially life-threatening and require after stopping treatment between 3 and 12 emergency treatment. In the past, “acute months from diagnosis. The term “chronic ITP” has been used to describe a self-limited ITP” is used for patients with ITP lasting for form of the disease (e.g., secondary to viral more than 12 months. illness) and “chronic ITP” identified ITP last- Acute abrupt-onset ITP, with duration of ing for more than 6 months. This definition less than 6 months, occurs mainly in chil- was felt to be unsatisfactory, and a more dren, often following viral or coherent staging scheme was felt necessary immunization, with boys and girls being in order to compare studies and define the equally affected. Chronic ITP is typically disease. seen in adults, more often affecting women The terminology was agreed and defini- of childbearing age. In Europe, the incidence tions published in 2009 by Rodeghiero et al. of ITP in adults has been estimated to be on behalf of an International Working between 1 and 4 per 100,000 persons.2–4 Group.1 The abbreviation ITP now stands for When a cut-off platelet count of less than 50 immune thrombocytopenia and not immune x 109/L was applied, the annual incidence of . It is defined as a ITP was estimated to be 2.25 per 100,000 in platelet count of under 100×109/L without Denmark2 and 1.6 per 100,000 in the UK.4 any other cause of thrombocytopenia. A In up to 30% of patients with immune new staging scheme was also proposed, thrombocytopenia, the cause may be sec- which defines the following stages of ITP: ondary to infection (HIV, HCV, CMV, or • Newly diagnosed ITP: months 0–3 after EBV), drugs, another autoimmune disorder presentation (e.g., SLE) or in association with a malignan- • Persistent ITP: months 4–12 cy (malignant or chronic lympho- • Chronic ITP: greater than 12 months cytic ; CLL). • Refractory ITP: patient has failed splenec- The natural history of ITP is variable and tomy unpredictable. For patients who are in other- • Severe ITP: patient has had major clinical wise good health, many can be left untreat- bleeding. ed, especially if their platelet counts are close In the absence of reliable predictive clinical to or above 20×109/L. The overall mortality or laboratory tests, variables parameters of rate for ITP is less than 1%, and the morbid-

| 184 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) London, United Kingdom, June 9-12, 2011 ity and mortality associated with treatment – often ), disease, alcohol abuse, med- related to – can be worse than the disease. ications (prescription or non-prescription), environmen- Thus, platelet count and risk for bleeding events should tal toxins, exposure, primary dis- be considered before treatment of ITP is initiated. A eases, and recent transfusions or immunizations should guideline describing the consensus of management in all be considered and where possible, excluded. Europe was published in 2003.5 These guidelines fol- There is much controversy over the incidence and lowed those of the American Society of Hematology in importance of immunizations, which are infrequently 1996.6 It was generally felt that these needed updating but clearly associated with thrombocytopenia. Measles, due, in part, to the introduction of new classes of thera- mumps, (MMR) is typical, and it is estimated peutic agents and a greater understanding of the disease that one in 40,000 children given MMR will develop pathophysiology. The International Consensus Report severe thrombocytopenia about 1–2 weeks post vacci- on the diagnosis and treatment of ITP were published in nation. It is associated with platelet-reactive anti-glyco- 2010.7 The writing committee reviewed over 1000 man- , and is self limited in 80% of uscripts written in the last 20 years to try to establish patients. In the remaining 20%, thrombocytopenia per- working guidelines, evidence based where possible, that sists but is responsive to ITP specific therapy, and recur- could subsequently be used, in conjunction with the rence is rare.9 new terminology, to review practice and provide future Inherited thrombocytopenias should be considered in audited treatment advice. ASH have subsequently patients who have a life-long history of thrombocytope- updated their guidelines with broadly similar recom- nia or suggestive family history. mendations. The main difference is the recommenda- tion that remains the main second line treatment of chronic ITP, which in the light of newer Anti-platelet and other auto-antibodies options and patient preference, is increasingly contro- and their role in the pathogenesis of ITP versial.8 In early 1980 it was noted that sera or eluates of platelets from patients with ITP would bind to normal Diagnosis platelets but only about one-quarter would bind to the platelets of patients with Glanzmann’s thrombasthe- There is no “gold standard” test for ITP, but the diag- nia.10 It was speculated that ITP patients produced auto- nosis is one based on exclusion of other causes of isolat- antibodies against either platelet glycoprotein (GP) IIb ed thrombocytopenia. The essential investigations or GPIIIa since thrombasthenic patients lack these pro- include history and physical examination, full teins. Since that time, several laboratories have provided count, and examination of the blood smear. A bone direct evidence for the presence of auto-antibodies marrow examination is now considered to be necessary against GPIIb/IIIA and other platelet in ITP.11–14 in only a few selected groups of patients: those over 60 In the meantime, platelet kinetic studies using radio- years of age, those who fail to respond to therapy or labeling methods had reignited the debate about the have relapsed after therapy, or non-responding patients mechanisms of thrombocytopenia in ITP. These studies being considered for splenectomy, and some of these showed shortened platelet survival, and high rates of remain debatable. All adult patients should be screened platelet production ranging from 4 to 9 times normal in for HIV and , and in appropriate countries, patients with ITP.15–17 With the introduction of 111In, the for H. pylori. small numbers of autologous platelets in ITP could be Some tests should be considered in special circum- adequately labeled, and it became evident that there stances. In patients who might go on to receive intra- was considerable heterogeneity in platelet turnover venous immunoglobulin, an underlying immunoglobu- between patients, with a substantial proportion having lin deficiency should be considered and the IgG level platelet production within normal limits even though checked. This is particularly important in children to the mean cell life of platelets was significantly reduced exclude Common Variable Immune deficiency, but compared with that in healthy subjects.18–20 If platelet should also be considered in adults. In patients being destruction were the only mechanism to cause throm- considered for anti-RhD, the Rh group and direct bocytopenia, then platelet production would be expect- antiglobulin test (DAT) should also be evaluated. ed to increase to offset low platelet counts. It was, should also be screened for in those who therefore, proposed once again that thrombocytopenia may receive the anti-CD20 monoclonal antibody ritux- may result not only from platelet destruction, but also imab. from antibody-mediated damage to . Testing for glycoprotein-specific antibodies may con- Evidence to support this hypothesis has accumulated firm the diagnosis but the tests lack sensitivity and are over time. rarely used routinely. Testing for anti-phospholipid anti- The infections most closely linked with ITP are HIV, bodies and other auto-antibodies is not useful diagnos- HCV, and H. pylori.21–23 It has been demonstrated, at least tically but may be important to exclude associated con- in vitro, that patients may have antibodies that bind to ditions. antigens on these organisms and that cross react with an It is important to exclude secondary thrombocytope- epitope of GPIIIa or other unspecified epitopes on the nia, and the following should be considered prior to platelet surface suggesting molecular mimicry and epi- diagnosing primary ITP: In addition to the viral infec- tope spread. tions mentioned above other immune or autoimmune As has been seen in the exclusion of secondary causes disorders (including SLE), malignancy (especially non- of thrombocytopenia, an ITP-like presentation occurs in

Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 185 | 16th Congress of the European Hematology Association diverse other clinical contexts. These are often seen in patients with platelet counts greater than 30 x 109/L do conditions also affecting aspects of the not require treatment unless they are undergoing proce- and durable complete remission are rare (SLE, ALPS - dures likely to result in blood loss (e.g., , dental autoimmune lymphoproliferative syndrome, Evans syn- extraction or parturition).5,6 drome, anti-phospholipid syndrome) or uncommon Most of the available treatments for ITP are aimed (CLL, common variable immune deficiency, post-trans- primarily at attenuating excessive platelet destruction. plantation/). Even patients who (e.g., prednisolone) are the standard present with primary ITP often express or develop anti- first-line treatment. They are cheap and effective in bodies to phospholipids, thyroid antigens, nuclear anti- approximately two-thirds of patients, although most gens, and RBCs,24 and some develop clinical manifesta- will relapse. tions associated with these antibodies. Prednisolone is usually given at a dose of 0.5–2 mg/kg Even among patients that have no overt signs of sec- for 2–4 weeks, and if there was no response, then the ondary forms of the syndrome, ITP is still heteroge- therapy should be stopped and alternates considered. neous, and a varying proportion of patients express Recent data indicates that Dexamethasone at a dose of other autoantibodies. Anti-nuclear antibodies are found 40 mg daily for 4 days every 4 weeks for 1–4 cycles can in approximately 20% of patients with ITP, but less than lead to sustained responses,26 but many patients find the 2% develop systemic .9,24 The incidence of anti- side-effects intolerable, and unless used in a clinical trial, phospholipid antibodies is approximately 40–50%, evidence is not strong enough to recommend this as the reaching 70% in some series.9,24 Available evidence is major form of first line therapy for most patients. In conflicting as to whether the presence of antiphospho- addition to the well-recognized short term effects of lipid antibodies predisposes to after success- hyperactivity, anxiety, and appetite stimulation, there ful treatment. Thus, there are many clinical scenarios are well-recognized long-term of steroids, where it is not at all clear whether or not the patient has including infections, hypertension, glaucoma, cushin- primary or secondary ITP.25 goid appearance, hypertension, diabetes mellitus, osteo- These include: porosis, and the occasional development of avascular • positive serology but no clinical evidence of HCV or necrosis of the hip, and their use should be strictly con- H. pylori with failure to respond to antimicrobial ther- trolled and time limited. apies Intravenous (IV) immunoglobulin is usually reserved • positive ANA, but not lupus for “rescue” treatment of acute bleeding episodes and • anti-phospholipid binding protein antibodies, but no for patients who are refractory to steroids, or require history of thrombosis or loss unacceptably high doses of these agents to maintain a • antimicrosomal or antithyrogobulin antibodies, but safe platelet count. Anti-D is no longer available in normal TSH Europe, but is still used in North America despite the • positive DAT, but no haemolytic risk of DIC and the associated increase in mortality. It • paraprotein or a clone on , which remains an option in patients who are Rh(D) positive is becoming increasingly apparent in older patients and who are not splenectomized. It is an appropriate with ITP, but no clinical evidence of a clonal disorder initial therapy in patients who are not candidates for • low IgG, but no history of recurrent infection. corticosteroids (e.g., insulin-dependent diabetes) or who are acutely bleeding and require a rapid elevation in platelet count. Management of immune thrombocytopenia Vinca alkaloids are also a useful, but short-lived, treat- ment for ITP. In a number of small studies, short-term In general, the treatment should be tailored to the elevation in platelet counts is seen in nearly 50% of individual patient; there is no standard therapy that all patients, especially those who have not responded to patients ought to undergo. Factors to be considered corticosteroids. include whether the patient is bleeding, other medical Patients who fail to respond to such first-line thera- problems (including diabetes), activity and lifestyle, pies or whose conditions relapse face the options of individual tolerance of side effects, patient preferences undergoing treatment with second-line drug therapy or and concerns, and finally the platelet count. Treatment splenectomy; however, there is a lack of evidence based should not be based solely on platelet counts, but con- clinical data to confirm the efficacy and safety of any of sidered with the totality of the patient’s medical issues these second-line treatments. In some patients with and preferences. Treatment is not indicated in patients chronic disease, it is worth looking for, and treating H. with a platelet count above 50 x 109/L, except in the fol- pylori see previous comment infection which may be all lowing situations: that is necessary. A recent article by Psaila and Bussel • platelet dysfunction or another haemostatic defect has reviewed the current treatment options in refractory • trauma or surgery disease.27 • comorbidities for bleeding, e.g., dialysis A number of different immunosuppressive agents • mandatory requirement for therapy have been used in ITP. In general, the evidence comes • profession or lifestyle that exposes the individual to from controlled clinical studies, without randomization, trauma. or from descriptive studies. The evidence for azathio- In chronic ITP, the goal of treatment is to achieve a prine and cyclophosphamide falls into this category but platelet count that prevents major bleeding, rather than the consensus is that these drugs remain an important to raise platelet count to the normal range. Management option for treating ITP patients. An increased risk of is tailored to the individual patient and in general, leukemia has not been reported in ITP patients exposed

| 186 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) London, United Kingdom, June 9-12, 2011 to azathioprine, and is particularly useful if they have and/or immunosuppressives. The role of , associated haemolytic anemia. There is reasonable therefore, is not clearly established at this time. In the Grade B evidence for the use of cyclosporin A, past 5 years, a registry has been set up by rheumatolo- mycophenolate, and rituximab as alternate immuno- gists in France looking at the safety of rituximab in suppressive options. Mycophenolate produces a outside a clinical trial setting.39 This response in about a quarter to a half of all patients and registry has included more than 1000 patients, some of is well tolerated by the majority of patients.28 It should whom have received up to eight courses of rituximab be remembered, however, that suppression of the over years. The overall incidence of infection was slight- immune system can predispose patients to infection, ly higher than the one reported in clinical trials was, which is a major cause of death in ITP patients.29,30 The reflecting that some patients treated with rituximab long term use of immune suppressive agents, particular- would have not been not included in clinical trials ly in patients who have failed splenectomy, is an espe- because of comorbidities, but not a single case of PML cial risk. has been reported. Overall, 5% of patients acquired sec- ondary . Rituximab In 2001, Stasi et al. reported for the first time in an Splenectomy observational study the efficacy of rituximab in adults Splenectomy has proved an effective therapy in the with chronic ITP.31 A number of other studies have con- management of primary ITP, with a systematic review firmed the efficacy of rituximab in patients with ITP. In of 135 reported series from 1966 to 2004 finding a com- 2007 Arnold et al. published a meta-analysis combining plete response (CR), defined by a platelet count of at some of these studies including at least five patients least 150 x 109/L and 30 days or longer on no treatment, treated.32 The overall response rate (platelet count in 66% of patients.40 However, the procedure is not >50×109/L) correct was estimated to be 60%, with an without risk, including intra-abdominal hemorrhage,41 overall complete response rate (platelet count thromboembolic events,42 and overwhelming post- >15×109/L) correct of approximately 46%. The study by splenectomy infections (OPSI).43 Although the risks of Cooper et al. in 200433 showed that rituximab could be these complications in patients with primary ITP is esti- equally effective both pre-splenectomy and post- mated to be low,44 when coupled with the risk of failure splenectomy. The better the initial response was, the to achieve CR in one-third of patients, limited data on longer the response was. The only factor correlated long-term relapse risk, and increasing awareness of the with a lower likelihood of response was the duration of pathogenic heterogeneity of the disease,45–47 they pro- ITP. The multicentre prospective French study of vide sufficient impetus to investigate potential pre-oper- Godeau et al.34 in chronic ITP (over 6 months’ duration) ative predictive variables of response. showed similar results and after 2 years of follow-up, A number of such clinical predictors have been sug- the overall response rate was 33%. gested, including i) response to and IVIg The study by Zaja in Italy35 was a prospective, ran- ; ii) platelet turnover; iii) platelet lifespan; iv) domized comparison between a single course of dexam- patient age; v) duration of disease; vi) platelet-bound ethasone 40 mg/m2 correct for four consecutive days immunoglobulin; and vii) site of platelet destruction as and dexamethasone followed by rituximab 375 mg/m2 determined by radionuclide labeling techniques. In a weekly for 4 weeks. The study in previously untreated systematic review of the effectiveness of splenectomy patients showed a rate of sustained response (platelet among adult patients with primary ITP, Kojouri et al. count >50×109/L at 6 months) of 63% in the dexametha- report inconclusive evidence in support of this last vari- sone plus rituximab arm compared with only 36% in able.40 the dexamethasone arm. After a median follow-up of 20 However, past investigations into platelet sequestra- months, approximately 75% of the initial responders in tion studies have adopted heterogeneous methods and both arms had a lasting response. varied widely with regard to power. Utilizing patients All these studies used rituximab at a conventional with primary ITP who underwent 111In-labelled, autolo- dose of 375 mg/m2. Other studies from Italy and the gous platelet sequestration studies at Barts and The UK36,37 suggest that a lower dosage of rituximab (i.e., 100 London NHS Trust between 1994 and 2008, we evalu- mg weekly for 4 weeks) can be sufficient to achieve a ated the effectiveness of sequestration site in predicting response in the ITP setting. short, medium, and long-term surgical failure through No serious adverse events were reported in the initial multivariable logistic regression modeling. In total 256 studies in ITP. However, infusion reactions are not infre- patients with primary ITP underwent scanning, with 91 quent, and both and hypogammaglobu- (35.5%) proceeding to splenectomy. Logistic regression linemia have been reported.34 More recently, there has revealed adjusted, statistically significant odds ratios been concern about the possible induction of progres- (ORs) for surgical failure of 7.47 (95% CI, 1.89–29.43) at sive multifocal leucoencephalopathy (PML), an oppor- 1–3 months post-splenectomy, 4.85 (95% CI, 1.04– tunistic infection of the brain, which is fatal in almost 22.54) at 6–12 months post-splenectomy, and 5.39 (95% 100% of cases. A review of adverse events associated CI, 1.34–21.65) at last follow-up (median: 3.8 years with rituximab38 reported 57 cases of PML in patients [range: 0.5–13.1 years]) in patients with mixed or hepat- treated with rituximab; the majority of these patients ic versus purely or predominantly splenic platelet had been treated for a lymphoma, whereas only a few sequestration. These findings support adoption of a cau- had autoimmune disorders, including two with ITP. tious approach to splenectomy in patients exhibiting Most of these patients had received not only rituximab mixed or hepatic sequestration.48 but also or long-term corticosteroids

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erned by signaling through the Mpl and the lig- Thrompopoietin receptor agonists and for this receptor, known as (TPO), Initially ITP was thought to be a disease of increased has a pivotal role in the regulation of platelet produc- platelet destruction, which is why current standard tion. Following the cloning of the molecule, two recom- treatments are either of a non-specific immunosuppres- binant thrombopoietin molecules were developed: sant nature or targeted solely at decreasing platelet recombinant human thrombopoietin (rhTPO) and pegy- destruction. Recent evidence suggests that suboptimal lated human recombinant growth and platelet production by suppression of megakaryocyte development factor (PEG-rHuMGDF). These agents production and maturation may also have a role in ITP. underwent extensive clinical testing for a range of Therefore, it was postulated that treatment aimed at thrombocytopenic disorders. The clinical development increasing platelet production may provide an opportu- of these recombinant growth factors was halted in 1998 nity to improve outcomes in patients with this chronic with reports that patients receiving PEG-rHuMGDF disease.49 (which has significant sequence homology with Megakaryopoiesis and platelet production are gov- endogenous TPO) developed severe thrombocytopenia

Table 1. Investigation of suspected ITP.

Basic evaluation Tests in selected cases Tests of unproven benefit

Patient history Antiphospholipid antibody (including ACL and Lupus) Glycoprotein-Specific Ab Family history Anti thyroid antibody and thyroid function Thrombopoitein Assay Physical examination Pregnancy test Reticulated platelet count Full blood count Antinuclear antibodies Indirect PaIgG Peripheral Viral PCR for parvovirus and CMV Blood group (Rh) and reticulocyte count Platelet survival DAGT Serum complement levels Quantitative Ig measurement * H. pylori HIV and HCV

Table 2. Summary of treatment options.

Clinical situation Therapy option

First line – Anti-D (initial treatment for newly diagnosed ITP) – Corticosteroids: dexamethasone, , prednis(ol)one – IVIg Second line – Azathioprine – Cyclosporin A – Cyclophosphamide – Danazol – Dapsone – Mycophenolate mofetil – Rituximab – Splenectomy – TPO-receptor agonists – Vinca alkaloids

Treatment for refractory ITP patients Category A: (patients failing first and second-line therapies) Treatment options with sufficient data – TPO-receptor agonists Category B: Treatment options with minimal data and considered to have potential for considerable toxicity – Campath-1H – Combination of first- and second-line therapies – Combination chemotherapy – Haemopoietic stem cell transplantation (HSCT)

Modified from7

| 188 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) London, United Kingdom, June 9-12, 2011 stemming from antibodies against PEG-rHuMgDF that results shown with Rituximab first described by Stasi in cross-reacted with endogenous TPO (eTPO), neutraliz- 2001.31 Future treatment options have been recently ing its biologic activity. reviewed.57 Despite safety concerns raised by autoantibody cross- reactivity, the success of the first-generation throm- bopoietic growth factors in stimulating platelet produc- Conclusion tion led to the development of a second generation of thrombopoietic growth factors that had no sequence While there is general agreement over treatment of homology with native TPO. Clinical trials with these, the newly presenting adult with ITP, few evidence the TPO peptide mimetic AMG 531 (also known as based studies direct therapy in the relapsed and refrac- Nplate or , Amgen, Thousand Oaks, tory patient. There is an understanding that the patient California) and the nonpeptide mimetic should be treated for their clinical state rather than their (also known as Promacta, GlaxoSmithKline, Research platelet count but not what second line treatment Triangle Park, North Carolina) have both resulted in should be used and in what order. In order to develop a dose-dependent increases in platelets in healthy subjects rational approach, an international group produced a and in significant increases in platelets in patients with consensus report on investigation and management giv- chronic ITP.50 ing (where possible) evidence based advice on treat- The extensive clinical studies have shown that ment pathways. It is hoped that by following such an platelet responses are seen in approximately 80%, a approach, treatment in the future can be audited and much greater percentage than in other second line stud- authoritative guidelines developed7 and the place of the ies and the response is maintained while the drugs con- newer treatments understood. tinue to be administered. They are almost as effective in splenectomized patients as in the nonsplenectomized ones.51 Recent phase III studies have confirmed the effi- References cacy and safety following long-term usage of both of the currently available products.52,53 The licenses for 1. Rodeghiero F, Stasi R, Gernsheimer T, et al. (2009) Standard - ization of terminology, definitions and outcome criteria in these agents vary throughout the world. In some (USA immune thrombocytopenic purpura of adults and children: and Canada) the license covers pre-splenectomy use report from an international working group. Blood. 2009; whereas in Europe, this is only covered for patients in 113:2386-93. 2. Frederiksen H, Schmidt K. The incidence of idiopathic throm- whom the surgery is contraindicated. bocytopenic purpura in adults increases with age. Blood. These agents appear to be well tolerated without the 1999;94:909-913. formation of autoantibodies that were seen in the stud- 3. Kaye J, Schoonen M, Fryzek J. ITP incidence and mortality in UK general practice database. Haematologica. 2007;92(Suppl ies with the first generation of thrombopoietins. 1):280. Increases in marrow reticulin have been reported, but 4. Neylon AJ, Saunders PW, Howard MR, Proctor SJ, Taylor PR. these appear to be a reversible phenomenon and not Clinically significant newly presenting autoimmune thrombocy- associated with formation of collagen fibrosis. The inci- topenic purpura in adults: a prospective study of a population- based cohort of 245 patients. Br J Haematol. 2003;122:966-74. dence of increase in marrow reticulin is unknown but is 5. Provan D, Newland AC, et al. British Committee for likely to be higher in patients treated with high doses, Standards in Haematology, General Haematology Task Force. which should therefore be used with caution. There Guidelines for the investigation and management of idiopath- ic thrombocytopenic purpura in adults, children and in preg- appears to be no increased incidence of thrombotic nancy. Br J Haematol. 2003;120:574-96. events in patients who achieve normal platelet counts 6. George JN, Woolf SH, Raskob GE, et al. Idiopathic thrombo- compared with those receiving placebo, however, cytopenic purpura: A practice guideline developed by explicit methods for the American Society of Hematology. Blood. thrombotic events have been reported in patients with 1996;88:3-40. other risk factors of cardiovascular disease, and a recent 7. Provan D, Stasi R, Newland AC, et al. (2010) International report has shown an increased of venous and arterial consensus report on the investigation and management of pri- thrombo-embolism in any patient with ITP, suggesting mary immune thrombocytopenia. Blood. 115:168-86. 54 8. Neunert C, Lim W, Crowther M, Cohen A, Solberg L, Crowther that ITP is a pro-thrombotic condition. M. Clinical guideline update on “Immune thrombocytopenia: an evidence based practiceguideline developed by the American Society of Hematology”. Blood. Feb 16, 2011. (Epub ahead of print as doi:10.1182/blood-2010-08-302984] New developments 9. Cines DB, Bussel JB, Liebman HA, Luning Prak ET. The ITP syndrome: Pathogenic and clinical diversity. Blood. 2009;113: With the increasing understanding of molecular path- 6511-21. 10. van Leeuwen EF, van der Ven JT, Engelfriet CP, von dem Borne ways in ITP and of the aetiology of the disease, more AE. Specificity of autoantibodies in autoimmune thrombocy- targeted and immune based therapies are under study. topenia. Blood. 1982;59:23-6. Ongoing clinical trials in ITP involve antibodies against 11. Kiefel V, Santoso S, Weisheit M, Mueller-Eckhardt C. Monoclonal the Fc receptor, such as MDX-33, a humanized anti- antibody--specific immobilization of platelet antigens (MAIPA): a new tool for the identification of platelet-reactive antibodies. FcgRI monoclonal, and GMA-161, a humanized anti- Blood. 1987;70:1722-6. FcgRIII monoclonal.55 Investigation of inhibition of FcR 12. McMillan R, Tani P, Millard F, Berchtold P, Renshaw L, Woods signaling mechanisms is currently under investigation VL. Platelet-associated and plasma anti-glycoprotein autoanti- 56 bodies in chronic ITP. Blood. 1987;70:1040-5. with R788, a small molecule prodrug of the biologically 13. Woods VL, Kurata Y, Montgomery RR, et al. Autoantibodies active R406. This is a potent and relatively selective against platelet glycoprotein Ib in patients with chronic orally available inhibitor of Syk ( tyrosine kinase). immune thrombocytopenic purpura. Blood. 1984; 64;156-60. 14. Woods VL, Oh EH, Mason D, McMillan R. Autoantibodies There are also a number of anti-CD20 monoclonal anti- against the platelet glycoprotein IIb/IIIa complex in patients bodies attempting to duplicate and improve on the with chronic ITP. Blood. 1984;63:368-75.

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15. Branehog I, Kutti J, Weinfeld A. (1974) Platelet survival and profile of low-dose rituximab for the treatment of autoim- platelet production in idiopathic thrombocytopenic purpura mune cytopenias in adults. Haematologica. 2007;92:1695-8. (ITP). Br J Haematol. 1974;27:127-43. 38. Carson KR, Focosi D, Major EO, et al. Monoclonal antibody- 16. Harker LA. Thrombokinetics in idiopathic thrombocytopenic associated progressive multifocal leucoencephalopathy in purpura. Br J Haematol. 1970;19:95-104. patients treated with rituximab, natalizumab, and efalizumab: 17. Harker LA, Finch CA. Thrombokinetics in man. J Clin Invest. A Review from the Research on Adverse Drug Events and 1969;48:963-74. Reports (RADAR) Project. Lancet Oncol. 2009;10:816-24. 18. Ballem PJ, Segal GM, Stratton JR, Gernsheimer T, Adamson 39. Gottenberg J, Ravaud P, Bardin T, et al. Risk factors of severe JW, Slichter SJ. Mechanisms of thrombocytopenia in chronic infections in patients with rheumatoid arthritis treated with autoimmune thrombocytopenic purpura. Evidence of both rituximab in the and Rituximab (AIR) registry. impaired platelet production and increased platelet clearance. Arthritis Rheum. 2010;62:2625-32. J Clin Invest. 1987;80:33-40 40. Kojouri K, Vesely SK, Terrell DR, George JN. Splenectomy for 19. Heyns AdP, Badenhorst PN, Lotter MG, Pieters H, Wessels P, adult patients with idiopathic thrombocytopenic purpura: A Kotze HF. Platelet turnover and kinetics in immune thrombo- cytopenic purpura: results with autologous 111In-labeled systematic review to assess long-term platelet count respons- platelets and homologous 51Cr-labeled platelets differ. Blood. es, prediction of response, and surgical complications. Blood. 1986;67:86-92. 2004;104:2623-34. 20. Stoll D, Cines DB, Aster RH, Murphy S. (1985) Platelet kinet- 41. Wanachiwanawin W, Visudhiphan S, Pinankijagum A, ics in patients with idiopathic thrombocytopenic purpura and Vatanavicharn S. Therapy of chronic idiopathic thrombocy- moderate thrombocytopenia. Blood. 1985;65:584-88. topenic purpura in adults: Experiences from Thailand. Southeast 21. Li Z, Nardi MA, Karpatkin S. Role of molecular mimicry to Asian J Trop Med . 1993;24(Suppl 1):71-5. HIV-1 peptides in HIV-1-related immunologic thrombocy- 42. Robinette CD, Fraumeni JF. Splenectomy and subsequent mor- topenia. Blood. 2005;106:572–6. tality in veterans of the 1939-45 war. Lancet .1977;ii:127-9. 22. Zhang W, Nardi MA, Borkowsky W, et al. Role of molecular 43. Bisharat N, Omari H, Lavi I, Raz R. Risk of infection and death mimicry of hepatitis C protein with platelet GPIIIa in among post-splenectomy patients. J Infect. 2001;43:182-6. hepatitis C-related immunologic thrombocytopenia. Blood. 44. Schwartz J, Leber MD, Gillis S, et al. Long term follow-up 2009;113:4086-93. after splenectomy performed for immune thrombocytopenic 23. Takahashi T, Yujiri T, Shinohara K, et al. Molecular mimicry purpura (ITP). Am J Hematol. 2003;72:94-8. by Helicobacter pylori CagA protein may be involved in the 45. McMillan R, Wang L, Tomer A, Nichol J, Pistillo J. Suppression pathogenesis of H. pylori-associated chronic idiopathic of in vitro megakaryocyte production by antiplatelet autoanti- thrombocytopenic purpura. Br J Haematol. 2004;124:91-6. bodies from adult patients with chronic ITP. Blood. 24. Cines DB, Liebman H, Stasi R. Pathobiology of secondary 2004;103:1364-1369. immune thrombocytopenia. Semin Hematol. 2009;46:S2-14. 46. Olsson B, Andersson PO, Jernas M, et al. T-cell-mediated cyto- 25. Cines DB. Pathogenesis of ITP. In Cines DB, Kuter DJ, toxicity toward platelets in chronic idiopathic thrombocy- Newland AC, Provan D, Semple, JW, editors. Immune topenic purpura. Nat Med. 2003;9:1123-4. Thrombocytopenia: The Handbook. 2011ESH Forum Service 47. Yu J, Heck S, Patel V, et al. Defective circulating CD25 regula- Editore. P. 77-89 tory T cells in patients with chronic immune thrombocy- 26. Mazzucconi NG, Fazi P, Bernasconi S, et al. Therapy with topenic purpura. Blood. 2008;112:1325-8. high-dose dexamethasone (HDDXM) in previously untreated 48. Sarpatwari A, Provan D, Erquo S, Sobnack R, Tai FWD, patients affected by idiopathic thrombocytopenic purpura. A GIMEMA experience. Blood. 2007;109:1401-7. Newland AC. Autologous 111 In-labelled platelet sequestra- 27. Psaila B, Bussel J. Refractory idiopathic thrombocytopenic pur- tion studies in patients with primary immune thrombocytope- pura: current strategies for investigation and management. Br nia (ITP) prior to splenectomy: a report from the United J Haematol. 2008;143:16-26. Kingdom ITP Registry. Br J Haematol. 2010;151:477-87. 28. Provan D, Moss AJ, Newland AC, Bussel JB. Efficacy of 49. Molineux G, Newland A. Development of romiplostim for the mycophenolate mofetil as single-agent therapy for refractory treatment of patients with chronic immune thrombocytope- immune thrombocytopenic purpura. Am J Hematol. 2006 nia: from bench to bedside. Br J Haematol. 2010;150:9-20. Jan;81(1):19-25. 50. Newland, A. Thrombopoietin mimetic agents in the manage- 29. Portielje JE, Westendorp RG, Kluin-Nelemans HC, Brand A. ment of immune thrombocytopenic purpura. Semin Hematol. Morbidity and mortality in adults with idiopathic thrombocy- 2007;44:35-45. topenic purpura. Blood. 2001;97:2549-54. 51. Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim 30. Stasi R, Stipa E, Masi M, et al. Long-term observation of 208 in patients with chronic immune thrombocytopenic purpura: adults with chronic idiopathic thrombocytopenic purpura. a double blind randomized controlled trial. Lancet. 2008 Feb Am J Med. 1995;98:436-42. 2;371(9610):395-403. 31. Stasi R, Pagano A, Stipa E, Amadori S. Rituximab chimeric 52. Bussel JB, Kuter DJ, Pullarkat V, Lyons RM, Guo M, Nichol JL. anti-CD20 monoclonal antibody treatment for adults with Safety and Efficacy of long-term treatment with romiplostim in chronic idiopathic thrombocytopenic purpura. Blood. 2001; thrombocytopenic patients with ITP. Blood. 2009;113:2161-71. 98:952-7. 53. Cheng G, Saleh MN, Marcher C, et al. Eltrombopag for the 32. Arnold DM, Dentali F, Crowther MA, et al. Systematic review: management of chronic immune thrombocytopenia (RAISE): Efficacy and safety of rituximab for adults with idiopathic throm- a 6 month, randomised phase 3 study. Lancet. 2011 Jan bocytopenic purpura. Ann Intern Med. 2007;146:25-33. 29;377(9763):393-402. Erratum in: Lancet. 2011 Jan 29;377 33. Cooper N, Stasi R, Cunningham-Rundles S, et al. The efficacy (9763):382. and safety of B-cell depletion with anti-CD20 monoclonal 54. Sarpatwari A, Bennett D, Logie JW, Shukla A, Beach KJ, antibody in adults with chronic immune thrombocytopenic Newland AC. Thromboembolic events among adult patients purpura. Br J Haematol. 2004;125:232-239. with primary immune thrombocytopenia in the United 34. Godeau B, Porcher R, Fain O, et al. Rituximab efficacy and safety in adult splenectomy candidates with chronic immune Kingdom General Practice Research Database. Haematologica. thrombocytopenic purpura - results of a prospective multicen- 2010;95:1167-75. ter phase 2 study. Blood. 2008;112:999-1004. 55. Li X, Hou M. Emerging drugs for idiopathic thrombocytopenic 35. Zaja F, Baccarani M, Mazza P, et al. Dexamethasone plus rit- purpura in adults. Expt Opin Emerg Drugs. 2008;13:237-54. uximab yields higher sustained response rates than dexam- 56. Podolanczuk A, Lazarus AH, Crow AR, Grossbard E, Bussel ethasone monotherapy in adults with primary immune JB. Of mice and men: an open-label pilot study for treatment thrombocytopenia. Blood. 2010 Feb 3. [Epub ahead of print as of immune thrombocytopenic purpura by an inhibitor of Syk. doi: 10.1182/blood-2009-07-229815]. Blood. 2009;113:3154-60. 36. Zaja F, Vianelli N, Volpetti S, et al. Low-dose rituximab in adult 57. Newland AC. Future managements of ITP; in Immune patients with primary immune thrombocytopenia. Eur J Thrombocytopenia: The Handbook. Cines DB, Kuter DJ, Haematol. 2010 Jun 10. [Epub ahead of print as doi:]. Newland AC, Provan D, Semple JW, editors.2011. ESH Forum 37. Provan D, Butler T, Evangelista ML, et al. Activity and safety Service Editore P. 227-242.

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