Pathophysiology and therapeutic options in primary immunethrombocytopenia Department of Haematology, St George's Hospital, London, United Kingdom The acronym ITP stands for primary immune mechanisms leading to thrombocytopenia and the evolving therapeutic modalities for chronic refractory thrombocytopenic purpura), an acquired autoimmune disorder characterised by isolated thrombocytopeniain the absence of conditions known to cause thrombocytopenia, such as infections, other autoimmune disorders, drugs, etc1. Manifestations of ITP can be localised haemorrhaging in skin or mucous observed a child with purpura born to a mother with membranes that are usually of little to no clinical chronic ITP6. Purpura in the child resolved 3 weeks consequence (petechiae, purpura, ecchymoses, later, although the mother still had ITP. The existence epistaxis); more rarely, ITP can be associated with of a humoral anti-platelet factor that had been passed severe bleeding events such as intracranial from mother to child was advanced. To test this haemorrhage (ICH). However, most ITP patients are hypothesis, Harrington received 500 mL of blood from asymptomatic in the presence of platelet counts greater a patient with ITP. Within three hours, his platelet counts dropped below 10x109/L as he developed ITP can be classified based on patient age (adult chills, fever, headache, confusion and petechiae7. His or childhood ITP), and duration of thrombocytopenia: platelet count remained extremely low for four days, newly diagnosed, up to 3 months from diagnosis; finally returning back to normal levels by the fifth persistent, 3-12 months from the time of diagnosis; day8. He performed a similar experiment on chronic, >12 months from the time of diagnosis1. The volunteers, confirming his original finding.
clinical features of ITP in adults are usually different Harrington's seminal experiment provided the first from those seen in childhood. ITP in children usually evidence that platelet destruction in ITP is caused by has an abrupt ("acute") onset, often occurring 1 to 2 a plasma-derived factor9, later identified as anti- weeks after a viral infection or 2 to 6 weeks after platelet antibodies10,11. The most commonly identified immunization with the measles, mumps and rubella antigenic targets of these autoantibodies are platelet (MMR) vaccine3,4, and recovers spontaneously in a glycoproteins (GP) IIb/IIIa and Ib/IX, with a number few weeks regardless of treatment. In contrast, ITP in of ITP patients having antibodies directed to multiple adults typically has an insidious onset, with no platelet antigens12. Antibodies against GP IIb/IIIa show preceding viral or other illness, and has frequently a clonal restriction in light-chain use13, and antibodies derived from phage-display libraries show selective Design of prospective, controlled clinical trials has usage of a single Ig heavy-chain variable region gene been particularly difficult, since patients with the chronic disease needing treatment are less than 10% regions of these antibodies suggests that they originate of all ITP patients5. Nevertheless, randomised trials from a limited number of B-cell clones by antigen- with several new pharmacologic agents have recently driven affinity selection and somatic mutation14. It should be noted, however, that autoantibodies are not In this review we shall summarize the current detectable in up to 50% of ITP patients12,15 and that Blood Transfus DOI 10.2450/2010.0080-10 SIMTI Servizi Srl remission in ITP can occur despite the continued Fc receptors (FcR), may also be launched to maintain presence of platelet autoantibodies16. Reasons for these findings may include technical factors (current The role of antigen-presenting cells (APCs) for monoclonal-based assays only detect antibodies with the loss of tolerance in ITP remains unclear, but a known specificity, typically GPIIb-IIIa and GPIb- model has been advanced in which APCs are crucial IX; variable sensitivity of the assays), removal of in generating a number of new or cryptic epitopes autoantibodies by megakaryocytes, and the presence from platelet glycoproteins27. In this model, APCs of alternative mechanisms of the thrombocytopenia.
expressing these novel peptides, along with co- As a matter of fact, several lines of evidence also stimulatory molecules, induce the activation of T-cells link T-cells to the pathogenic process in ITP. Platelet- that recognize these additional platelet antigens. Thus, reactive T-cells have been found in the blood of this acquired recognition of new self-determinants, patients with this disorder, with the major target or epitope spreading, may play an important role in antigen being GP IIb/IIIa17. In these patients, T-cells the initiation and perpetuation of ITP. T-cell clones stimulate the synthesis of antibody after exposure to that react with cryptic epitopes may escape the fragments of GP IIb/IIIa but not after exposure to negative selection in the thymus when self- native proteins18. The derivation of these cryptic determinants are present at a sub-threshold epitopes in vivo and the reason for sustained T-cell activation are unknown. It has been hypothesised that Thrombocytopenia may accompany or follow a cryptic epitopes, normally not exposed in a self- variety of infections from which ITP must be antigen, may become exposed and recognised by the differentiated. In adults, the most prevalent infections immune system under certain circumstances, for associated with thrombocytopenia are those from example, an infection19. Other studies have shown that hepatitis C virus (HCV), human immunodeficiency patients with chronic ITP often have increased virus (HIV), and Helicobacter pylori (H. pylori)28. In Th1/Th2 ratio, expansion of oligoclonal T-cells20,21, typical cases the thrombocytopenia presents with an and the presence of cytotoxic T-cells against insidious onset, has no tendency to remit spontaneously (although its severity may parallel the The emergence of anti-platelet autoantibodies and stage of the infectious disease), and may closely mimic anti-platelet cytotoxic T-cells is a consequence of a chronic ITP. Response to infection may generate loss of the immunological tolerance for self antigens.
antibodies that cross-react with platelet antigens or Filion et al. have shown that autoreactive T-cells directed against GPIIb/IIIa are present in the peripheral blood of all healthy individuals23, implying thatperipheral tolerance mechanisms are crucial to prevent Mechanisms leading to the thrombocytopenia autoreactive T-cells from becoming activated. Several Both in vitro and clinical studies have shown that other T cell abnormalities have emerged from the the spleen is the primary site of antibody investigation of immune regulation in ITP patients.
production33,34 and is also the dominant organ for the Among these, CD4+CD25+ regulatory T-cells have clearance of IgG-coated platelets35,36. In a minority of an impaired suppressive activity when compared to patients, hepatic clearance predominates. Human healthy subjects24. Also, CD3+ T-lymphocytes from macrophages express several Fc receptors that bind patients with active ITP present an altered expression IgG specifically37. Functionally, there are two different of genes associated with apoptosis and are classes of Fc receptors: the activation and the significantly more resistant to dexamethasone-induced inhibitory receptors, which transmit their signals via suppression compared to normal lymphocytes22,25.
immunoreceptor tyrosine-based activation (ITAM) or As far as B-cells are concerned, the expansion of inhibitory motifs (ITIM), respectively. Clinical data, autoreactive clones is suppressed in the bone marrow.
along with information gained from animal models, If some B-cells escape this suppression or deletion, suggest that the FcγRI, the high affinity receptor, does peripheral mechanisms, most importantly the not play a relevant role in ITP38,39. On the other hand, functional balance between activating and inhibitory evidence has accumulated to indicate that the low- affinity receptors FcγRIIA and FcγRIIIA are primarily marrow megakaryocytes from patients with ITP.
responsible for removal of opsonised platelets40.
Extensive megakaryocytic abnormalities were Engagement of FcγRIIA on the surface of human consistently present in a significant percentage of all macrophages by anti-GPIIb/IIIa-coated platelets stages of ITP megakaryocyte50,51. In the most recent triggers intracellular signaling through the tyrosine of these studies, Houwerzijl et al. the described kinase Syk, that leads to engulfment of the opsonised features characteristic of nonclassic apoptosis, including mitochondrial swelling with cytoplasmic The presence of antibodies against GP Ib/IX has vacuolisation, distention of demarcation membranes, been associated with resistance to intravenous and condensation of nuclear chromatin51. Para- immunoglobulin therapy both in a mouse model41 and in retrospective series of ITP patients42. These findings megakaryocytes derived from CD34+ cells grown in suggest the possibility of direct cytotoxicity or ITP plasma, suggesting that autoantibodies may complement fixation as a mechanism of platelet initiate the cascade of programmed cell death. In destruction rather than antibody-dependent, Fc addition, megakaryocytes may be surrounded by receptor-mediated phagocytosis by macrophages.
neutrophils and macrophages, suggesting an Interestingly, platelet kinetic studies using indium- inflammatory response against these cells.
111 (111In)-labelled autologous platelets have shown A role for direct T-cell-mediated cytotoxicity considerable heterogeneity in platelet turnover in against platelets has been demonstrated in vitro22.
patients with chronic ITP35,36,43,44. While the platelet Whether this effect occurs in vivo and its relative lifespan is often markedly decreased in most patients, importance in determining platelet destruction has not in some it is only mildly reduced; furthermore, platelet been elucidated. There is also evidence that ITP is turnover (a measure of platelet production) is associated with accumulation and activation of T-cells frequently subnormal. Overall, approximately 40% in the bone marrow that occurs through increased of patients with ITP were found to have a reduced VLA-4 and CX3CR1 expression52. It has been advanced that these activated T-cells may mediate the If platelet destruction were the only mechanism to destruction of platelets in the bone marrow52.
cause thrombocytopenia, then platelet production Thrombocytopenia associated with infectious would be expected to increase and offset low platelet diseases is characterised by antibody-mediated platelet destruction. However, platelet production may be thrombocytopenia may result not only from platelet impaired by infection of megakaryocytes (HCV and destruction, but also from antibody-mediated damage HIV), decreased production of thrombopoietin to megakaryocytes. Evidence to support this (HCV), and splenic sequestration of platelets hypothesis has accumulated over time.
secondary to portal hypertension (HCV)28.
McMillan et al. reported that IgG produced by cells (grown in vitro) from the spleens of patients with ITP would bind to megakaryocytes, whereas IgG produced ITP is considered a benign disorder with an by cells from the spleens of healthy controls did not approximately 60% higher rate of mortality than bind to megakaryocytes45. A few years later other gender- and age-matched comparison subjects without investigators demonstrated that antibodies against ITP53. This increased risk of death is largely platelet antigens would bind to megakaryocytes as concentrated in patients 60 years of age or older54.
well46,47. More recent in vitro experiments have further However, fatal bleeding occurs only with severe defined the role of autoantibodies in patients with ITP.
thrombocytopenia and specific therapy may not be Two studies in particular, by Chang et al.48 and necessary unless the platelet count is <20x109/L or McMillan et al.49 support the view that autoantibodies there is extensive bleeding. Another important in ITP suppress megakaryocyte production and consideration is that for some patients the morbidity from side effects of therapy may exceed any problems Electron microscopy studies have clarified some caused by the ITP5,54. The management of patients aspects of the autoantibody-induced damage in bone with ITP must therefore take into account the age of the patient, the severity of the illness, and the immunoglobulin, which is efficacious only in Rh- anticipated natural history. Current guidelines consider positive patients and in the presplenectomy setting65.
treatment for ITP appropriate for symptomatic patients Anti-D binds to the Rhesus D erythrocyte antigen.
and for those at significant risk of bleeding55-59.
The mechanisms of action of anti-D have not beencompletely elucidated. A widely accepted model involves immune-mediated clearance of the sensitised If the clinical presentation is not that of a life- erythrocytes in the reticuloendothelial system, threatening bleeding corticosteroids are considered the competing with antibody-coated platelets for the Fc standard initial treatment55. The current practice in receptors66. The response rate to intravenous anti-D many countries is to initiate treatment with oral at the dose of 50 µg/kg, defined as a platelet increase prednisolone or prednisone, 1 to 2 mg/kg per day, ≥20x109/L, was 78% in the largest series (156 patients) given as single or divided doses. Approximately two published to date65. The increase in platelet count thirds of patients achieve a complete or partial (95±114x109/L) was seen after 72 hours, and lasted response with corticosteroids at these "standard" more than 21 days in 50% of the responders. At doses doses, with most responses occurring within the first of 75 µg/kg, anti-D increases the platelet count more week of treatment56. However, only 10% to 15% of rapidly, and for a longer duration compared with the all adult patients with ITP who receive predniso(lo)ne standard dose of 50 µg/kg67. Furthermore, platelet therapy have a durable remission56. Two large responses occurring within 24 hours are comparable nonrandomised studies have shown that a short course to those reported with IVIG68. Subcutaneous anti-D of treatment with high-dose oral dexamethasone (40 has been tried in a few patients suffering from chronic mg/d for 4 consecutive days) was well tolerated and ITP69. None of the patients treated with this alternate with higher response rates compared to published route of administration developed haemolysis or any studies with standard-dose corticosteroids60,61. An other significant reaction. In addition, subcutaneous ongoing randomised trial of the Italian group delivery of anti-D seemed to produce largely the same GIMEMA will define the relative efficacy of the two beneficial effect observed with intravenous delivery.
In two different studies from the same center, the repeated use of either maintenance IVIG69 or generally recommended for patients with critical maintenance anti-D globulin70 allowed approximately bleeding and for those unresponsive to corticosteroids 40% of adults with ITP to avoid splenectomy. A or for whom corticosteroids are contraindicated55.
randomised, controlled trial has subsequently tested Several regimens for IVIG have been used with the potential of anti-D to avoid or defer the need for comparable clinical outcomes. In current practice the splenectomy in newly diagnosed adults with ITP and standard dose is 1 g/kg per day for one to two days56.
a platelet count <30,000/µL. There were no differences Intravenous immunoglobulin is effective in elevating in the rates of spontaneous remission or the need for the platelet count to more than 50×109/L in splenectomy between the anti-D group and the routine approximately 80% of patients. In more than half of care group71. However, splenectomy was performed responders, the platelet count becomes normal prematurely, not according to protocol in 11 of 14 (>100×109/L)63. Platelet counts may begin to increase patients. This may have affected the inability to show after 1 day and usually reach peak levels within 1 a difference between the two groups with regard to week after treatment64. However, responses are generally transient, lasting no longer than 3 to 4 weeks, IVIG and particularly anti-D can cause mild after which the platelet counts decrease to pretreatment alloimmune haemolysis and IVIG may also cause levels. Thus, IVIG therapy is ideal when a rapid headache, nausea, and vomiting, symptoms that may increase in platelet count is desired in patients with cause concern for the possible occurrence of life-threatening bleeding and can also be combined intracranial haemorrhage72. Some sucrose-containing with steroids and platelet transfusions in these products may also be associated with acute renal failure73. Although evidence of haemolysis is present A convenient alternative to IVIG is anti-D in most patients treated with anti-D, the decline in haemoglobin concentration rarely exceeds 2 g/dL65.
treatment algorithm. Generally accepted criteria for Rare cases of massive intravascular haemolysis and splenectomy include a severe thrombocytopenia disseminated intravascular coagulation have been (<10-20x109/L), a high risk of bleeding for platelet reported75. It has been conjectured that a coexisting counts less than 30x109/L, or the requirement of autoimmune haemolytic anaemia (Evan's syndrome) continuous glucocorticoid therapy to maintain safe could have contributed to these complications75. For all these reasons anti-D should not be used, or used with extreme care, in patients with a positive direct splenectomy in chronic ITP. The initial complete anti-globulin test (risk of intravascular haemolysis) response (platelet count >150×109/L) rate is 65-70% and in those with a haemoglobin level that is less than and the long term response rate is 60-70%85,86. In other 10 g/dL (risk of developing symptomatic anaemia words, approximately 50% of patients with chronic Considering the substantially lower costs and No preoperative characteristic has been reported shorter infusion time (minutes compared with hours) to predict response to splenectomy consistently.
of anti-D compared to IVIG, the former is preferred Splenic sequestration of 111In-labelled platelets was a for the long-term use. However, anti-D for use in ITP good prognostic factor in many studies in which this is currently not licensed in many countries, including scanning method was applied. In the large study by Najean et al., a splenic pattern of platelet destruction Emergency treatment is indicated for internal or had a positive predictive value of 93%, whereas a profound mucocutaneous bleeding. Hospitalization is hepatic or diffuse pattern of platelet destruction had a required, and general measures should be instituted negative predictive value of 77%87. However, platelet to reduce the risk of bleeding, including avoidance of sequestration studies are difficult to standardise and drugs that inhibit platelet function, control of blood are available in only a few medical centers.
pressure, and other factors. Although no systematic Occasionally, patients may fail to respond to studies have evaluated the efficacy of different splenectomy because of the failure to remove an regimens, there is general agreement that appropriate accessory spleen. Accessory spleens are found in 12% interventions should include the following55,56,76: to 43% of post-splenectomy patients with recurrent platelet transfusions (either one therapeutic dose or persistent ITP. Recurrence has been reported as late every 4-6 hours or half therapeutic dose/h); as 21 years after splenectomy, and up to 66% of these IVIG (1 g/kg, repeated the following day if the patients achieve a complete remission after accessory intravenous methylprednisolone, 1 g/d for 3 days.
The presence of residual splenic tissue can be Platelet transfusions may be given without diagnosed by examination of the blood smear for concomitant therapy and can usually stop bleeding Howell-Jolly bodies that appear in the red cells of irrespective of the increase in platelet counts77,78. IVIG asplenic individuals. Persistent splenic tissue can be and methylprednisolone may be effective both as initial treatment and if bleeding continues after platelet An alternative to conventional open splenectomy transfusions79-83. A limited number of reports suggest is laparoscopic splenectomy. Several studies have intravenous recombinant human factor VIIa can be shown reduced blood loss with this procedure and beneficial in patients with critical bleeding refractory more rapid recovery time, and suggested a lower mortality rate compared with open splenectomy (0.2%and 1.0%, respectively)85.
Splenectomised patients have a small risk for For decades splenectomy has been considered the overwhelming infections, with an estimated mortality second-line treatment in adults with ITP unresponsive of 0.73 per 1,000 patient-years89. The risk for serious to initial corticosteroid therapy. Recently, however, post-splenectomy infection is greater in children the availability of effective pharmacological agents younger than 5 years, who are rarely candidates for has challenged the position of splenectomy in the splenectomy. Although there are no data on the efficacy of vaccination, immunisations against experimental approaches include campath-1H, encapsulated bacteria (Streptococcus pneumoniae, liposomal doxorubicin, protein A immunoadsorption meningitidis) are generally advised at least 2 weeks transplantation56. The toxicities associated with these before splenectomy55. The usefulness of postoperative agents should be carefully evaluated when further antibiotic prophylaxis remains a matter of debate.
While it is not the standard of care in the United States,lifelong prophylactic antibiotics are recommended in Thrombopoietin receptor agonists for the treatment As previously discussed, impaired platelet Treatment of patients with refractory ITP Patients are considered to have refractory ITP if thrombocytopenia in several patients with ITP.
splenectomy fails (either no initial response or relapse Growth factor stimulation of megakaryopoiesis might after splenectomy) and they require additional therefore be a rational approach to increase the platelet therapy1. No curative approach is currently available for refractory ITP, and the objective of treatment is to First-generation thrombopoietin receptor agonists achieve haemostatically safe platelet counts included recombinant human TPO (rhTPO), and (>20 to 30x109/L) while minimising the adverse side megakaryocyte growth and differentiation factor (MGDF), a non-glycosylated, truncated form of TPO Relapsed patients generally have a poor response coupled to polyethylene glycol94. Clinical trials with to repeat challenge with corticosteroids in the face of these agents were stopped after the development of substantial toxicity. In recent years, several studies IgG4 antibodies to PEG-MGDF was observed in have reported significant response rates both prior to healthy volunteers95. Such antibodies cross-reacted and after splenectomy with the use of rituximab, an with endogenous TPO neutralizing its activity and thereby led to thrombocytopenia. Clinical trial activity specifically targets B-cells, including those producing was resumed with second-generation thrombopoietic anti-platelet antibodies91. B-cell depletion is transient growth factors that have no sequence homology with (lasting 6 to 12 months, in most cases) and has few endogenous TPO, but still bind and activate the TPO side effects or toxicities91. A systematic analysis of receptor. Two of these new agents, romiplostim and the published literature suggests that rituximab eltrombopag, are now licensed for use in patients with produces an initial response in approximately 60% (range, 25% to 75%) of cases, with no significant Romiplostim is a recombinant protein defined as difference between splenectomised and non- a "peptibody". It is made of 2 disulphide-bonded splenectomised patients92. The median response immunoglobulin Fc fragments each of which is duration is 10.5 months (range, 2-48 months), with a covalently bound at residue 228 with 2 identical 15-20% rate of long-term complete responses. A peptide sequences linked via polyglycine96.
French study indicates that the use of rituximab allows Eltrombopag is a small, orally available, hydrazone to defer splenectomy for at least 1 year in 40% of organic compound. This molecule was identified from high-throughput screening of small-molecule Several other drugs have been reported to have some activity (although not consistently) in refractory Patients enrolled in the trials with the TPO receptor ITP. These include the attenuated androgen danazol, agonists were required to have a platelet count dapsone, azathioprine, cyclophosphamide, vinca < 30×109/L and to have failed a prior ITP therapy, alkaloids, recombinant IFN-α2B, cyclosporin A, and which might have included splenectomy. Response mycophenolate mofetil, alone or in combinations56.
to therapy was variably defined in the various studies.
Responses with these agents are variable and for some Romiplostim has been the first agent to receive of them, such as azathioprine or danazol, they may marketing approval thanks to the results of two pivotal only be apparent after several weeks or months. More randomised, placebo-controlled, phase III studies98.
The trials had a 24-week duration; one was in randomised, double-blind, placebo-controlled studies splenectomised and one in nonsplenectomised have been published recently. In the first, adults with patients. Patients were randomised (2:1) to receive chronic ITP received standard care plus once-daily romiplostim or placebo once weekly by subcutaneous eltrombopag 50 mg (n=76) or placebo (n=38) for up injection over the study period. The initial romiplostim to 6 weeks100. After 3 weeks, patients with platelet dose was 1 µg/kg and subsequent doses were adjusted counts less than 50×109/L could increase the dose to based on platelet response to achieve target counts of 75 mg. The primary endpoint was the proportion of 50x109 to 200x109/L. The maximum permitted dose patients achieving platelet counts 50×109/L or more at day 43. The response rate was 59% in eltrombopag Responses, defined as a platelet count rise to patients and 16% in placebo patients (odds ratio 9.61, ≥50×109/L during four or more weeks during the 24 95% CI 3.31-27.86; P<0.0001). Of 34 patients who weeks study, were observed in 79% (33/42) of increased their dose of eltrombopag, 10 (29%) responded. No pre-treatment variable was associated splenectomised patients, compared with only 14% (3/ with the achievement of response. Platelet counts 21) of nonsplenectomised and 0% (0) splenectomised generally returned to baseline values within 2 weeks placebo recipients (P<0.001). The majority of the after the end of treatment. The frequency of bleeding romiplostim-treated patients (87%) were able to events at any time during the study was lower in discontinue concomitant treatments or substantially patients receiving eltrombopag than did those reduce dosage (by >25%) compared with only 38% receiving placebo (odds ratio 0.49, 95% CI 0.26-0.89; of placebo recipients. Moreover, fewer romiplostim- P=0.021); however, the frequency of grade 3-4 treated patients required rescue medications compared adverse events during treatment and adverse events with placebo subjects (26.2 versus 57.1% of leading to study discontinuation were similar in both In the second phase III trial, called RAISE, 197 patients with previously-treated chronic ITP and romiplostim study were allowed to enroll in an open- platelets <30×109/L were randomised 2:1 to standard label extension study of romiplostim with doses of care plus eltrombopag or placebo101. Each patient adjusted weekly depending on the platelet count. Data was evaluated for response (platelet count from 142 patients treated for periods of up to 3 years 50-400×109/L) over the 6-month period, the primary are available99. Altogether, 87% of patients (n=124) endpoint being the odds of responding to eltrombopag achieved a platelet response, defined as a platelet count versus placebo. Irrespective of splenectomy status, >50x109/L and at least double the baseline value in more eltrombopag-treated patients responded during the absence of rescue medication in the previous 8 the entire 6-month period compared with placebo weeks. On average, this response occurred for 67% (odds ratio 8.2, 99% CI 3.59-18.73; P<0.001). A post- of the weeks on study in patients who responded.
hoc analysis using the same response criteria of the Bleeding events during treatment were reduced romiplostim studies (response defined as platelet count compared to baseline. Long-term romiplostim elevations =50 and =400×109/L for at least 4 treatment was generally well tolerated and treatment- consecutive weeks at any time during the 6-month related serious events occurred in 13 patients (9%).
treatment period) indicated a response rate of 70% in Thromboembolic events occurred in seven (5%) patients, six of whom had pre-existing risk factors splenectomised patients102. Eltrombopag also such as cardiovascular disease and/or a history of significantly reduced the odds of bleeding by 76% thrombosis. One patient transiently developed (p<0.001). More patients reduced concomitant ITP neutralizing antibodies to romiplostim (absent on medications (predominantly corticosteroids) on retesting approximately 4 months after discontinuation eltrombopag than placebo (59% vs 32%; P=0.02), and of treatment), but these did not cross-react with fewer patients required rescue medication on endogenous TPO or affect the platelet response.
eltrombopag than placebo (18% vs 40%; P=0.001).
With regard to eltrombopag, the results of two Eltrombopag was well tolerated. Nausea and vomiting were reported more frequently on eltrombopag, development of a myelofibrosis-like disease105.
whereas serious bleeding events (P=0.03), peripheral Interestingly, a germline activating mutation of MPL, edema (P=0.01), and dyspepsia (P=0.01) were MPLSer505Asn, has been identified in patients with reported more frequently on placebo. Three hereditary thrombocytosis106. Affected patients exhibit eltrombopag patients experienced thromboembolic a significant risk of thrombosis, splenomegaly and events; none were observed on placebo. A mild, bone marrow fibrosis, with reduced life expectancy transient, elevation of alanine aminotransferase and in comparison with wild-type relatives. Splenomegaly total bilirubin levels was observed in 9 (7%) and 5 (4%) of eltrombopag-treated patients, respectively.
predominantly in patients with an age of 20 years old Results from the EXTEND study (Eltrombopag or greater, suggesting that these manifestations Extended Dosing Study) have been reported in develop over several years. It is therefore necessary abstract form103. Patients were maintained on their to monitor closely ITP patients on chronic treatment concomitant medication and commenced on 50 mg with TPO receptor agonists for the potential eltrombopag. Following response, concomitant therapy was reduced and eltrombopag tapered to splenomegaly. It is also uncertain whether treatment maintain a platelet count of more than 50x109/L.
with thrombopoietic agents can sustain platelet counts Evaluable individuals (n=299) had a median treatment over several years in chronic ITP, or will eventually duration of 204 days (2-861 days). Overall, 86% of lead to stem cell depletion and bone marrow failure.
patients (257/299) achieved a platelet count ≥50x109/L. Splenectomised and non-splenectomised patients responded equally well (89% and 82%, The pathophysiology of ITP is complex and respectively). Patients on treatment for ≥6 months or abnormalities of both the B-cell and the T-cell ≥12 months achieved platelet counts of ≥50x109/L compartments have been identified. The mechanisms and 2x baseline for 69% (18/26 weeks) and 71% of the thrombocytopenia involve both increased (37/52 weeks) of the time on treatment, respectively.
platelet destruction and, in a significant proportion of Treatment was generally well tolerated. However, 13 cases, impaired platelet production.
patients (4%) experienced 16 thromboembolic events; New therapeutic approaches, such as rituximab, 11/13 (85%) experienced the event at a platelet count have been evaluated in adult patients with ITP. These lower than the maximum platelet count achieved findings have been particularly important for those during eltrombopag treatment. The clinical patients who would prefer to postpone or avoid significance of these thromboembolic events is splenectomy. Thrombopoietin receptor agonists uncertain, as most of the patients had a well defined appear to be very effective in a high percentage of refractory patients and very tolerable. The potential Some considerations about the potential risk of long term side effects of these agents is currently a chronic therapy with these agents are appropriate.
major limitation in shifting them to second line Thrombosis is clearly a major concern, but published data do not suggest a difference in either arterial orvenous thrombotic events between treatment and placebo groups. Reversible increase of bone marrow Rodeghiero F, Stasi R, Gernsheimer T, et al.
reticulin has been observed in a few patients in the Standardization of terminology, definitions andoutcome criteria in immune thrombocytopenic clinical trials with romiplostim104. This also requires purpura of adults and children: report from an patient monitoring and a prospective bone marrow international working group. Blood 2009; 113: 2386- study in a larger number of patients to provide a clearer view of the frequency, reversibility, and clinical Stasi R, Evangelista ML, Stipa E, et al. Idiopathicthrombocytopenic purpura: current concepts in consequences of bone marrow changes associated pathophysiology and management. Thromb Haemost with these new agents in patients with ITP. In a mouse model, expression of a constitutively active mutant Black C, Kaye JA, Jick H. MMR vaccine and TPO receptor (MPL), MPL W515A, resulted in the idiopathic thrombocytopaenic purpura. Br J Clin recognized by autoreactive T cells in patients with Miller E, Waight P, Farrington CP, et al. Idiopathic immune thrombocytopenic purpura. Blood 2001; 98: thrombocytopenic purpura and MMR vaccine. Arch Portielje JE, Westendorp RG, Kluin-Nelemans HC, dysfunctional pathophysiology in ITP. Crit Rev Oncol Brand A. Morbidity and mortality in adults with idiopathic thrombocytopenic purpura. Blood 2001; Fogarty PF, Rick ME, Zeng W, et al. T cell receptor VB repertoire diversity in patients with immune Imbach P, Kuhne T, Signer E. Historical aspects and thrombocytopenia following splenectomy. Clin Exp present knowledge of idiopathic thrombocytopenic purpura. Br J Haematol 2002; 119: 894-900.
Stasi R, Del Poeta G, Stipa E, et al. Response to B- Ahn YS, Horstman LL. Idiopathic thrombocytopenic cell depleting therapy with rituximab reverts the purpura: pathophysiology and management. Int J abnormalities of T cell subsets in patients with idiopathic thrombocytopenic purpura. Blood 2007; Schwartz RS. Immune thrombocytopenic purpura- from agony to agonist. N Engl J Med 2007; 357: 2299- Olsson B, Andersson PO, Jernas M, et al. T-cell- mediated cytotoxicity toward platelets in chronic Harrington WJ, Minnich V, Hollingsworth JW, Moore idiopathic thrombocytopenic purpura. Nat Med 2003; CV. Demonstration of a thrombocytopenic factor in the blood of patients with thrombocytopenic purpura.
Filion MC, Proulx C, Bradley AJ, et al. Presence in peripheral blood of healthy individuals of autoreactive Shulman NR, Marder VJ, Weinrach RS. Similarities T cells to a membrane antigen present on bone between known antiplatelet antibodies and the factor marrow-derived cells. Blood 1996; 88: 2144-50.
responsible for thrombocytopenia in idiopathic Liu B, Zhao H, Poon MC, et al. Abnormality of purpura. Physiologic, serologic and isotopic studies.
CD4(+)CD25(+) regulatory T cells in idiopathic Ann N Y Acad Sci 1965; 124: 499-542.
thrombocytopenic purpura. Eur J Haematol 2007; 78: van Leeuwen EF, van der Ven JT, Engelfriet CP, von dem Borne AE. Specificity of autoantibodies in Olsson B, Andersson PO, Jacobsson S, et al. Disturbed apoptosis of T-cells in patients with active idiopathic thrombocytopenic purpura. Thromb Haemost 2005; McMillan R, Wang L, Tani P. Prospective evaluation of the immunobead assay for the diagnosis of adult Takai T. Roles of Fc receptors in autoimmunity. Nat chronic immune thrombocytopenic purpura (ITP). J Cines DB, Blanchette VS. Immune thrombocytopenic McMillan R, Lopez-Dee J, Bowditch R. Clonal purpura. N Engl J Med 2002; 346: 995-1008.
restriction of platelet-associated anti-GPIIb/IIIa Stasi R, Willis F, Shannon MS, Gordon-Smith EC.
autoantibodies in patients with chronic ITP. Thromb thrombocytopenia. Hematol Oncol Clin North Am Roark JH, Bussel JB, Cines DB, Siegel DL. Genetic Nardi MA, Liu LX, Karpatkin S. GPIIIa-(49-66) is a thrombocytopenic purpura reveals evidence of clonal major pathophysiologically relevant antigenic expansion and somatic mutation. Blood 2002; 100: determinant for anti-platelet GPIIIa of HIV-1-related immunologic thrombocytopenia. Proc Natl Acad Sci Brighton TA, Evans S, Castaldi PA, et al. Prospective evaluation of the clinical usefulness of an antigen- Li Z, Nardi MA, Karpatkin S. Role of molecular mimicry to HIV-1 peptides in HIV-1-related thrombocytopenic purpura and other immune immunologic thrombocytopenia. Blood 2005; 106: thrombocytopenias. Blood 1996; 88: 194-201.
Stockelberg D, Hou M, Jacobsson S, et al. Detection Zhang W, Nardi MA, Borkowsky W, et al. Role of of platelet antibodies in chronic idiopathic molecular mimicry of hepatitis C virus protein with thrombocytopenic purpura (ITP). A comparative study platelet GPIIIa in hepatitis C-related immunologic using flow cytometry, a whole platelet ELISA, and thrombocytopenia. Blood 2009; 113: 4086-93.
an antigen capture ELISA. Eur J Haematol 1996; 56: Takahashi T, Yujiri T, Shinohara K, et al. Molecular mimicry by Helicobacter pylori CagA protein may Kuwana M, Kaburaki J, Ikeda Y. Autoreactive T cells be involved in the pathogenesis of H. pylori-associated to platelet GPIIb-IIIa in immune thrombocytopenic chronic idiopathic thrombocytopenic purpura. Br J purpura. Role in production of anti-platelet autoantibody. J Clin Invest 1998; 102: 1393-402.
McMillan R, Longmire RL, Yelenosky R, et al.
Kuwana M, Kaburaki J, Kitasato H, et al.
Immunoglobulin synthesis in vitro by splenic tissue Immunodominant epitopes on glycoprotein IIb-IIIa in idiopathic thrombocytopenic purpura. N Engl J Med Chang M, Nakagawa PA, Williams SA, et al. Immune Kuwana M, Okazaki Y, Kaburaki J, et al. Spleen is a thrombocytopenic purpura (ITP) plasma and purified primary site for activation of platelet-reactive T and B cells in patients with immune thrombocytopenic megakaryocytopoiesis in vitro. Blood 2003; 102: purpura. J Immunol 2002; 168: 3675-82.
Siegel RS, Rae JL, Barth S, et al. Platelet survival McMillan R, Wang L, Tomer A, et al. Suppression of and turnover: important factors in predicting response in vitro megakaryocyte production by antiplatelet to splenectomy in immune thrombocytopenic purpura.
autoantibodies from adult patients with chronic ITP.
Louwes H, Zeinali Lathori OA, Vellenga E, de Wolf Stahl CP, Zucker-Franklin D, McDonald TP.
JT. Platelet kinetic studies in patients with idiopathic Incomplete antigenic cross-reactivity between thrombocytopenic purpura. Am J Med 1999; 106: platelets and megakaryocytes: relevance to ITP. Blood Nimmerjahn F, Ravetch JV. Fcgamma receptors: old Houwerzijl EJ, Blom NR, van der Want JJ, et al.
friends and new family members. Immunity 2006; 24: Ultrastructural study shows morphologic features of apoptosis and para-apoptosis in megakaryocytes from Ericson SG, Coleman KD, Wardwell K, et al.
patients with idiopathic thrombocytopenic purpura.
Monoclonal antibody 197 (anti-Fc gamma RI) infusion in a patient with immune thrombocytopenia Olsson B, Ridell B, Carlsson L, et al. Recruitment of purpura (ITP) results in down-modulation of Fc T cells into bone marrow of ITP patients possibly due gamma RI on circulating monocytes. Br J Haematol to elevated expression of VLA-4 and CX3CR1. Blood Crow AR, Lazarus AH. Role of Fcgamma receptors Schoonen WM, Kucera G, Coalson J, et al.
in the pathogenesis and treatment of idiopathic Epidemiology of immune thrombocytopenic purpura thrombocytopenic purpura. J Pediatr Hematol Oncol in the General Practice Research Database. Br J Crow AR, Song S, Siragam V, Lazarus AH.
Cohen YC, Djulbegovic B, Shamai-Lubovitz O, Mechanisms of action of intravenous immunoglobulin Mozes B. The bleeding risk and natural history of in the treatment of immune thrombocytopenia.
idiopathic thrombocytopenic purpura in patients with Pediatric blood & cancer 2006; 47: 710-3.
persistent low platelet counts. Arch Intern Med 2000; Webster ML, Sayeh E, Crow M, et al. Relative efficacy of intravenous immunoglobulin G in ameliorating George JN, Woolf SH, Raskob GE, et al. Idiopathic thrombocytopenia induced by antiplatelet GPIIbIIIa thrombocytopenic purpura: a practice guideline versus GPIbalpha antibodies. Blood 2006; 108: developed by explicit methods for the American Society of Hematology. Blood 1996; 88: 3-40.
Go RS, Johnston KL, Bruden KC. The association between platelet autoantibody specificity and response thrombocytopenic purpura in adults. Mayo Clin Proc to intravenous immunoglobulin G in the treatment of patients with immune thrombocytopenia.
Cines DB, Bussel JB. How I treat idiopathic thrombocytopenic purpura (ITP). Blood 2005; 106: Heyns AD, Lotter MG, Badenhorst PN, et al. Kinetics and sites of destruction of 111Indium-oxine-labeled George JN. Management of patients with refractory platelets in idiopathic thrombocytopenic purpura: a immune thrombocytopenic purpura. J Thromb quantitative study. Am J Hematol 1982; 12: 167-77.
Ballem PJ, Segal GM, Stratton JR, et al. Mechanisms Bussel J. Treatment of immune thrombocytopenic of thrombocytopenia in chronic autoimmune purpura in adults. Semin Hematol 2006; 43: S3-10; thrombocytopenic purpura. Evidence of both impaired platelet production and increased platelet clearance. J Cheng Y, Wong RS, Soo YO, et al. Initial treatment of immune thrombocytopenic purpura with high-dose McMillan R, Luiken GA, Levy R, et al. Antibody dexamethasone. N Engl J Med 2003; 349: 831-6.
Mazzucconi MG, Fazi P, Bernasconi S, et al. Therapy thrombocytopenic purpura. JAMA 1978; 239: previously untreated patients affected by idiopathic Rabellino EM, Levene RB, Leung LL, Nachman RL.
thrombocytopenic purpura: a GIMEMA experience.
Human megakaryocytes. II. Expression of platelet proteins in early marrow megakaryocytes. J Exp Med Gruppo Italiano Malattie EMatologiche dell'Adulto.
Prednisone or Dexamethasone in Treating Patients Vinci G, Tabilio A, Deschamps JF, et al.
With Newly Diagnosed, Previously Untreated Primary Immunological study of in vitro maturation of human Immune Thrombocytopenic Purpura. Clinical megakaryocytes. Br J Haematol 1984; 56: 589-605.
Bussel JB, Pham LC. Intravenous treatment with British Committee for Standards in Haematology General Haematology Task Force. Guidelines for the thrombocytopenic purpura: review of the literature.
investigation and management of idiopathic thrombocytopenic purpura in adults, children and in Godeau B, Lesage S, Divine M, et al. Treatment of pregnancy. Br J Haematol 2003; 120: 574-96.
adult chronic autoimmune thrombocytopenic purpura Carr JM, Kruskall MS, Kaye JA, Robinson SH.
with repeated high-dose intravenous immunoglobulin.
Efficacy of platelet transfusions in immune thrombocytopenia. The American journal of medicine Scaradavou A, Woo B, Woloski BM, et al. Intravenous anti-D treatment of immune thrombocytopenic Salama A, Kiesewetter H, Kalus U, et al. Massive purpura: experience in 272 patients. Blood 1997; 89: platelet transfusion is a rapidly effective emergency treatment in patients with refractory autoimmune Lazarus AH, Crow AR. Mechanism of action of IVIG and anti-D in ITP. Transfus Apher Sci 2003; 28: 249- Culic S. Recombinant factor VIIa for refractive Newman GC, Novoa MV, Fodero EM, et al. A dose of 75 microg/kg/d of i.v. anti-D increases the platelet thrombocytopenic purpura. Br J Haematol 2003; 120: count more rapidly and for a longer period of time than 50 microg/kg/d in adults with immune Barnes C, Blanchette V, Canning P, Carcao M.
thrombocytopenic purpura. Br J Haematol 2001; 112: intracerebral haemorrhage in severe thrombocytopenia Meyer O, Kiesewetter H, Hermsen M, et al.
unresponsive to platelet-enhancing treatment. Transfus Replacement of intravenous administration of anti-D by subcutaneous administration in patients with Busani S, Marietta M, Pasetto A, Girardis M. Use of autoimmune thrombocytopenia. Pediatr Blood Cancer recombinant factor VIIa in a thrombocytopenic patient with spontaneous intracerebral haemorrhage. Thromb Bussel JB, Pham LC, Aledort L, Nachman R.
Maintenance treatment of adults with chronic Savani BN, Dunbar CE, Rick ME. Combination refractory immune thrombocytopenic purpura using therapy with rFVIIa and platelets for hemorrhage in repeated intravenous infusions of gammaglobulin.
patients with severe thrombocytopenia and alloimmunization. Am J Hematol 2006; 81: 218-9.
Cooper N, Woloski BM, Fodero EM, et al. Does Wrobel G, Dobaczewski G, Patkowski D, et al.
treatment with intermittent infusions of intravenous Experiences with recombinant activated factor VII in anti-D allow a proportion of adults with recently the treatment of severe refractory thrombocytopenia.
diagnosed immune thrombocytopenic purpura to Pediatr Blood Cancer 2006; 47: 729-30.
avoid splenectomy? Blood 2002; 99: 1922-7.
Salama A, Rieke M, Kiesewetter H, von Depka M.
George JN, Raskob GE, Vesely SK, et al. Initial Experiences with recombinant FVIIa in the emergency management of immune thrombocytopenic purpura in adults: a randomized controlled trial comparing thrombocytopenia: a review of the literature. Ann intermittent anti-D with routine care. American journal Kojouri K, Vesely SK, Terrell DR, George JN.
Kattamis AC, Shankar S, Cohen AR. Neurologic Splenectomy for adult patients with idiopathic complications of treatment of childhood acute immune thrombocytopenic purpura: a systematic review to thrombocytopenic purpura with intravenously assess long-term platelet count responses, prediction administered immunoglobulin G. The Journal of of response, and surgical complications. Blood 2004; Katz U, Achiron A, Sherer Y, Shoenfeld Y. Safety of Vianelli N, Galli M, de Vivo A, et al. Efficacy and intravenous immunoglobulin (IVIG) therapy.
safety of splenectomy in immune thrombocytopenic purpura: long-term results of 402 cases.
Gaines AR. Disseminated intravascular coagulation Najean Y, Rain JD, Billotey C. The site of destruction hemoglobinuria following Rh(0)(D) immune globulin of autologous 111In-labelled platelets and the efficiency of splenectomy in children and adults with thrombocytopenic purpura. Blood 2005; 106: idiopathic thrombocytopenic purpura: a study of 578 patients with 268 splenectomies. Br J Haematol 1997; Tarantino MD, Bussel JB, Cines DB, et al. A closer look at intravascular hemolysis (IVH) following Akwari OE, Itani KM, Coleman RE, Rosse WF.
intravenous anti-D for immune thrombocytopenic Splenectomy for primary and recurrent immune purpura (ITP). Blood 2007; 109: 5527; author reply thrombocytopenic purpura (ITP). Current criteria for patient selection and results. Ann Surg 1987; 206: 529-41.
Schilling RF. Estimating the risk for sepsis after 101) Cheng G, Saleh MN, Marcher C, et al. Eltrombopag splenectomy in hereditary spherocytosis. Ann Intern for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study.
Davies JM, Barnes R, Milligan D. Update of guidelines for the prevention and treatment of 102) Stasi R, Cheng G, Saleh MN, et al. Durable and infection in patients with an absent or dysfunctional Overall Platelet Responses in Patients With Chronic Idiopathic Thrombocytopenic Purpura (ITP) During Stasi R, Pagano A, Stipa E, Amadori S. Rituximab Long-term Treatment With Oral Eltrombopag by chimeric anti-CD20 monoclonal antibody treatment Splenectomy Status: the RAISE Study. Haematologica for adults with chronic idiopathic thrombocytopenic 103) Saleh MN, Bussel JB, Cheng G, et al. Long-Term Arnold DM, Dentali F, Crowther MA, et al.
Treatment of Chronic Immune Thrombocytopenic Systematic review: efficacy and safety of rituximab Purpura with Oral Eltrombopag: Results From the for adults with idiopathic thrombocytopenic purpura.
EXTEND Study. ASH Annual Meeting Abstracts Godeau B, Fain O, Porcher R, et al. Rituximab Is an 104) Kuter DJ, Mufti GJ, Bain BJ, et al. Evaluation of bone Alternative to Splenectomy in Adults with Chronic marrow reticulin formation in chronic immune Immune Thrombocytopenic Purpura: Results of a thrombocytopenia patients treated with romiplostim.
Multicenter Prospective Phase 2 Study. Blood 2006; 105) Pecquet C, Staerk J, Chaligne R, et al. Induction of Kuter DJ. New thrombopoietic growth factors. Blood myeloproliferative disorder and myelofibrosis by thrombopoietin receptor W515 mutants is mediated Li J, Yang C, Xia Y, et al. Thrombocytopenia caused by cytosolic tyrosine 112 of the receptor. Blood 2010; by the development of antibodies to thrombopoietin.
106) Teofili L, Giona F, Torti L, et al. Hereditary Wang B, Nichol JL, Sullivan JT. Pharmacodynamics associated with a high thrombotic risk, splenomegaly thrombopoietin receptor ligand. Clin Pharmacol Ther and progression to bone marrow fibrosis.
Erickson-Miller CL, DeLorme E, Tian SS, et al.
Discovery and characterization of a selective,nonpeptidyl thrombopoietin receptor agonist. ExpHematol 2005; 33: 85-93.
Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy ofromiplostim in patients with chronic immunethrombocytopenic purpura: a double-blindrandomised controlled trial. Lancet 2008; 371:395-403.
Bussel JB, Kuter DJ, Pullarkat V, et al. Safety andefficacy of long-term treatment with romiplostim inthrombocytopenic patients with chronic ITP. Blood2009; 113: 2161-71.
Received: 12 September 2010 - Accepted: 11 October 2010Correspondence: Roberto Stasi 100) Bussel JB, Provan D, Shamsi T, et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic Blackshaw RoadSW17 0QT London, United Kingdom purpura: a randomised, double-blind, placebo- controlled trial. Lancet 2009; 373: 641-8.

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