Immune Thrombocytopenia, previously known as Idiopathic or Immune Thrombocytopenic Purpura is a nosographic entity characterised mainly by two elements: isolated thrombocytopenia, meaning there are no alterations in other haematological parameters, and absence of clinical manifestations and symptoms which cannot be directly linked to thrombocytopenia. Bleeding symptoms, when present, generally correlate with severity of the thrombocytopenia. Overall mortality is less than 1-2%, however the morbidity can be severe in the individual patient, both due to bleeding events and/or limitations given by the bleeding risk and to the toxicity of treatments.

The variety of names given to ITP in the past reflect the somewhat troubled history of the disease. An International Working Group (IWG) recently has suggested a clear name that respects the acquired clinical knowledge (Rodeghiero F et al, 2009)PubMed, putting an end to the unacceptable terminological confusion (Ruggeri M et al, 2008)PubMed. IWG decided to keep the acronym ITP previously referred to Idiopathic or Immune Thrombocytopenic Purpura, considering its spread in the literature. IWG has also clearly distinguished the primitive forms (primary ITP) from the secondary ones (secondary ITP), in which thrombocytopenia is caused by the presence of an underlying disease which can be observed at diagnosis. Where not further specified, the term ITP generally refers to the primary form. The choice of using the terms immune or idiopathic for thrombocytopenia is based on the evidence that there is a common autoimmune pathogenic mechanism to all acquired primary and secondary forms, except for thrombocytopenia due to megakaryocytic hypoplasia. Rare alloimmune forms exist such as neonatal alloimmune thrombocytopenia and post-transfusion purpura but will not be developed in the text.

 

DEFINITIONS AND TERMINOLOGY

The lack of a common terms to define ITP and its different phases and the absence of a response criteria to therapy have hindered the efforts in developing comparative analysis between different clinical experiences, so during diagnosis and therapy there are some grey areas without any scientific evidence (Ruggeri M et al, 2008)PubMed. The need to standardize the terminology and the response criteria is even more necessary with the introduction of new therapeutic proposals, such as anti CD-20 monoclonal antibodies and the thrombopoietin receptor agonists (TPO-RAs), and moreover in the prospect of new therapies still in the experimental phase.
A summary of the new terminology classification is presented in Table I.


 Rodeghiero_Immune_thrombocytopenia_Table_

Table I. Immune Thrombocytopenia (ITP): definitions and terminology

 

The term purpura, previously included in the name of the disease, is considered inappropriate by the IWG taking into account that the bleeding symptoms can be absent or minimal in up to 50% of cases. The secondary forms are clearly separated from primary ITP as the therapy often has to target the baseline disease or, in the case of drug-induced ITP, consist in avoiding the exposition to the drug that causes the symptoms. The main secondary forms will be discussed in the paragraph dedicated to diagnosis.

Moreover, a clear distinction between the primary and secondary forms is not always easy or possible and most likely the primary forms will become less with the progress of knowledge and of diagnostic methods (Cines DB et al, 2009)PubMed. Furthermore, when ITP coexists with the presence of lupus anticoagulant, high-titre anticardiolipin antibodies or anti-nuclear antibodies, even if clinical manifestations are not present such as recurrent miscarriage, thrombosis or development of collagenopathy, the natural progress could be worsened by a high complication rate. However the IWG believe that there is not enough evidence to classify these forms of ITP as secondary. Further research is necessary.

The platelet threshold of 100 x 109/L, which is below the lower limit of the normal range (generally between 120-150 x 109/L) has been used to avoid inappropriate diagnosis of many cases without a clinically significant disease and of relatively frequent cases of thrombocytopenia in pregnancy, a completely benign phenomenon. Furthermore, a prospective study of otherwise healthy people with a platelet count between 100-150 x 109/L has demonstrated that the probability to develop more severe thrombocytopenia (< 100 x 109/L) after 10 years of observation was only 6.9% (Neylon AJ et al, 2003)PubMed.

 

CLINICAL PRESENTATION AND PHASES OF THE DISEASE

The hemorrhagic manifestations of ITP are those typical to primary hemostatic defects, with a prevalence of petechiae and ecchymoses. Spontaneous hemorrhagic manifestations generally occur with platelet levels below 20-30 x 109/L yet with great variability from patient to patient. These can also occur with higher platelet levels (> 50-60 x 109/L) even in the event of minor trauma or in subjects with other hemostatic defects, including the acquired type, such as those linked to consumption of aspirin and other antiplatelet drugs or anticoagulants.

Petechiae are mainly located on the lower limbs or on other parts of the body with increased venous pressure. They may extend over the entire body, mainly during the acute onset phase, with a not so rare subsequent recurrence. Based on the number of petechiae which can range from a few dozens to several thousands, the overall picture can be remarkable and if, as is often the case, there is a concomitant presence of ecchimoses, this fits with the appearance of “morbus maculosus hemorrhagicus” described by Werlhof in 1735. Petechiae or hemorrhagic bullae may be seen inside the mouth. At times subconjunctival hemorrhages are present. This scenario is more common in the acute form of the disorder, typical in children, often appearing after a viral illness, which generally resolve spontaneously within a few weeks. Alongside these manifestations (dry purpura), gingival bleeding and epistaxis, bleedings in the gastrointestinal or genitourinary tracts with hematuria and/or metrorrhagia (wet purpura) and, very rarely, intracranial hemorrhages may manifest although more rarely and when more severe forms are present (platelet count below 5-10 x 109/L). The terms dry and wet purpura are not used consistently by different authors and should not be applied. Hematomas are reported very rarely and hemarthrosis only in exceptional cases.

Some patients are practically asymptomatic although platelet counts are extremely low (below 10 x 109/L) for long periods. It is not clear whether the severity of the symptoms has a prognostic significance related to the risk of life-threatening bleedings. These occur however generally in patients with a platelet count that is usually below 20 x 109/L. There is a lack of epidemiological data on the incidence of bleeding symptoms. From a study by Neylon et al, bleeding episodes at onset in patients with platelet counts below 30 x 109/L have approximately the following distribution: external hemorrhages 15%; bleedings into the skin 46%; asymptomatic patients between 20% and 39%. Patients with platelets between 30 and 50 x 109/L: wet purpura 4%; dry purpura 43%; aymptomatic patients 53% (Neylon AJ et al, 2003)PubMed. Furthermore, generally symptoms occur more frequently in women rather than in men, mainly regarding external hemorrhages.


Stages of the disease

The stages of the disease are presented in Figure I.

 

Rodeghiero_Immune_thrombocytopenia_Figure_

Figure I. Stages of the disease (Immune Thrombocytopenia)

 

Without clinical or laboratory parameters to define the duration of the disease, IWG recommends to use the term “newly diagnosed ITP” for all of those cases that are observed for the first time. In this category the forms that were previously defined “acute” are included which are typical in children and often secondary to confirmed or expected viral infections, in which a spontaneous remission is often observed. However, when an active infectious form is confirmed at the diagnosis of ITP associated to thrombocytopenia and not drug-induced, this will be referred to as a secondary form, specifying the concomitant infectious disease. Besides the classical distinction between the acute and the chronic forms, a new category has been introduced namely “persistent ITP” that includes patients who do not go into spontaneous remission in the period between 3 and 12 months following diagnosis or whose complete response at the end of the initial therapy is not maintained over time. In fact, during this stage, as we will see, splenectomy is indicated only rarely due to the occurrence of spontaneous remissions also in adults. The term “chronic ITP” is currently used for those patients with ITP that lasts more than 12 months. In these patients spontaneous remission is considered an exceptional event and treatments such as immunosuppressive drugs or splenectomy, often worsened by a significant toxicity can be justified only when a high bleeding risk is present or when thrombocytopenia has a significant impact on the quality of life.

The severity of the disease – usually classified in mild, moderate, severe – is moderately correlated, although with significant deviations in different patients, with the degree of thrombocytopenia. This is generally defined as the main bleeding risk factor. However IWG has preferred to follow the clinical manifestations defining ITP as severe only if the patients have significant symptoms (Table I). Although it is not always possible to perform splenectomy in all patients, IWG however consider the definition of refractoriness as not applicable to non-splenectomised patients. The demonstrated curative potential of splenectomy in more than 60% of cases is a result that currently is not obtainable with any other medical treatment (Kojouri K et al, 2004)PubMed. The definition is not applicable to the paediatric population, in which splenectomy is suggested only in exceptional cases due to its higher risk of infections.

 

PATHOGENESIS AND ETIOLOGY

The autoimmune pathogenesis of ITP, whether primary or secondary, is demonstrated by many studies carried out in the last few decades. Harrington in the early 1950s (Harrington WJ et al, 1953)PubMed had already proven that if plasma from patients affected by severe thrombocytopenia without an apparent cause was infused into healthy volunteers (Harrington himself volunteered) a marked transitory thrombocytopenia manifested. The “antiplatelet factor” in the patients’ plasma was subsequently identified as the class G autoantibodies produced by the patients against (public) antigens present on the membrane of platelets.

The antiplatelet autoantibodies represent the final effector of the autoimmune process. They are mainly produced by the spleen, have a limited antigenic repertoire and are mainly IgG type, generally targeting the glycoproteins (GP) GP IIb/IIIa or GP Ib/IX types present on the patients’ platelet membranes, in particular the epitopes of the N-terminal region of GP IIb. Since these are public epitopes, the autoantibodies are active against heterologous platelets obtained from donors, thus explaining the shortened half-life of the transfused platelets in subjects with ITP  (McMillan R, 2000)PubMed. With the current diagnostic techniques the presence of autoantibodies is detectable in just over 80% of cases: anti GP IIb/IIIa in 60% and anti GP Ib/IX in approximately 20%. The pathogenetic mechanisms of undetectable autoantibodies either on the platelet surface or in the serum in subjects are still widely unknown, even though technical limitations in demonstrating the presence of specific autoantibodies (false negatives) cannot be excluded. Among these alternative mechanisms, that could also coexist in the forms with autoantibodies, the mechanism that seems to have great importance is the one dependent on the cytotoxic activity CD 8+ T lymphocytes autoreactive towards platelets able to cause intravascular lysis (Olsson B et al, 2003)PubMed. Cytotoxic autoreactive T lymphocytes, like autoantibodies, destroy platelets and inhibit magakaryocytopoeisis reducing platelet production.

While many experimental data have clarified the effector mechanisms of immune-mediated thrombocytopenia, the onset of autoimmunity is still not clear. For secondary forms to infection, the onset could consist in a molecular mimicry mechanism, clearly demonstrated in some forms associated with HIV, HCV or Helicobacter pylori, in which the antibodies against the pathogen agent cross-react with GP IIIa epitopes of the platelets of the infected patient (Takahashi T et al, 2004PubMedNardi M et al, 2004PubMedZhang W et al, 2009PubMed). These cross-reactive antibodies generally disappear with the resolution of the infection and consequently a normalization of the thrombocytopenia is obtained. However in many cases the cause of the loss of immunotolerance towards self antigens remains unknown and a genetic predisposition is brought into consideration, for which some data can indicate the association of ITP with specific class I and II HLA alleles or with polymorphisms of genes coding for the Fcy receptors (Kuhne T, 2010).

The first abnormality is detectable in the effector response of the T helper 1 lymphocytes (Th 1), capable of producing pro inflammatory cytokines (interferone-α, interleukina 2, tumor necrosis factor). Once the Th 1 lymphocytes become autoreactive, they stimulate the B lymphocytes to produce autoantibodies. The autoreactivity of Th 1 lymphocytes seems to be connected to a reduction in number and a dysfunction of regulatory T (T reg) cells (Sakakura M et al, 2007PubMedZhang XL et al, 2009PubMedStasi R et al, 2008PubMed). Table II summarises the pathogenic and etiological concepts described.

 

Rodeghiero_Immune_thrombocytopenia_Table_2

Table II. Etiopathogenesis of ITP

 

Mechanisms of thrombocytopenia: peripheral destruction and reduced production

The classic notion of ITP, as described in the first kinetic studies based on an analysis of the survival of homologous platelets marked with transfused 51Cr in the circulation, is a disease due exclusively to increased platelet destruction (Harker LA, Finch CA, 1969)PubMed, which cannot be compensated by a high production of platelets. In apparent contrast with this classic definition of ITP, more recent kinetic studies with autologous platelets marked with 111In have shown that platelet production is definitely normal or reduced (Ballem PJ et al, 1987).

Thrombocytopenia in primary and secondary ITP is therefore caused by two main factors: destruction of the circulating platelets and suppression of platelet production.

The destruction is caused by phagocytosis of the monocyte-macrophage system, mediated by the Fc receptor of the autoantibodies present on the patients’ platelet membrane, together with the contribution, albeit marginal, of platelet lysis mediated by the complement or by the cytotoxic lymphocytes  (Stasi R et al, 2008bPubMedCooper N, Bussel J, 2006PubMed).

Reduced or insufficient platelet production compared with the increased peripheral consumption is due to two factor orders:

  • The first is due to damage of megakaryocytes at different phases of maturation, on the membrane of which the main targets of antiplatelet autoantibodies, GP IIb-IIIa and Ib-IX, are present, as documented by morphological and functional studies carried out by the McMillan group (Chang M et al, 2003)PubMed. Furthermore the cytotoxic autoreactive lymphocytes hinder an optimal platelet production applying a cytotoxic action on the megacariocytes.
  • The second factor involves thrombopoietin (TPO), the main regulator of megacariopoiesis. The TPO serum levels in ITP are in fact reduced in proportion to the thrombocytopenia, in evident contrast with other conditions such as aplastic anaemia (Mukai HY et al, 1996PubMedKuter DJ, 2009PubMed). To understand the mechanism which involves a reduced circulating level of free TPO in ITP it is necessary to remember that the level of this cytokine, produced constantly by the liver, depends on the quantity that is bound by the receptors present on the megacariocytes and on the platelets. Therefore, when the megacariocyte and platelet mass is reduced the level of free TPO is reduced to re-establish a homeostatic balance. In ITP, the increased megacariocyte mass generally binds and removes TPO from the circulation, generating a non-efficient megacariocytopoiesis. Furthermore, the increased platelet turnover contributes to removing free TPO from the circulation.

 

EPIDEMIOLOGY

The epidemiological data available about the incidence of ITP are generally unreliable due to systematic inclusion and accuracy errors and due to errors in defining the population. They also only refer to two European Countries (Denmark and Great Britain) and the threshold value to define a subject with thrombocytopenia varies from study to study either ranging from 50 to 150 x 109/L or is simply not reported.

Recently results of the available studies and their methods have been accurately analysed and critically assessed (Terrell DR et al, 2010)PubMed..

The incidence in adults is estimated between 1.6 and 3.9 per 100.000 inhabitants/year. The lowest incidence is found with a very conservative method used to diagnose ITP (Neylon AJ et al, 2003)PubMed with the mandatory presence of a bone biopsy or a bone marrow examination, not obligatory according to the diagnostic criteria currently in use (George JN et al, 1996PubMedBritish Committee for Standards in Haematology General Haematology Task Force, 2003PubMedProvan D et al, 2010PubMedNeunert C et al, 2011PubMed). The Frederiksen and Schmidt study seems to have the least methodological biases and provides an adjusted estimate based on sex and age which is of 2.68 new cases of ITP a year every 100,000 adult subjects; by limiting the analysis to cases with less than 50 x 109/L, the incidence decreases to 2.25 (Frederiksen H, Schmidt K, 1999)PubMed. For the first time the mean age of the population with ITP is documented as fairly older (56 years) and the prevalence has a strong tendency to increase after 60 but not in females on the contrary to what is described in the clinical series of the literature.

The incidence of ITP in children is estimated between 1.9 and 6.4 per 100,000 children a year (Terrell DR et al, 2010)PubMed. The only reliable estimate of the incidence of chronic ITP in children is the one reported by Reid et al for the north England health area which is estimated at 0.46 new cases every 100,000 children a year (Reid MM, 1995)PubMed.

The prevalence of adult cases is estimated between 9 and 20 per 100,000. These estimates are related only to the American population and are entirely based on databases produced exclusively for administrative purposes with all the consequent limitations on reliability (Segal JB, Powe NR, 2006PubMedFeudjo-Tepie MA et al, 2008PubMed).

The only study on the prevalence of chronic ITP in children (from 0.5 to 15.5 years) was performed in Sweden with a national questionnaire, the result of which was of 4.6 cases per 100,000 children a year.

 

DIAGNOSIS

ITP is still a diagnosis of exclusion in patients with thrombocytopenia which is not associated with other hematochemical disorders and with no evidence of concomitant diseases at the time of manifestation.

Table III reports the recommendations formulated recently by an International group of experts about clinical and laboratory studies considered essential, useful or without demonstrated use and therefore not recommended (Provan D et al, 2010)PubMed.

 

Rodeghiero_Immune_thrombocytopenia_Table_3

Table III. Recommendations for the diagnosis of primary ITP in children and adults

 

As reported in the notes below Table III, the morphological exam of peripheral blood is crucial for a correct diagnosis and therefore has to be performed by an expert haematologist directly involved in the final diagnosis.

The presence of anaemia can co-exist with the diagnosis of ITP as long as it is secondary to chronic hemorrhagic loss or however due to iron deficiency or to a haemolytic autoimmune process such as the Fischer-Evans syndrome.

The myelodysplastic syndrome with isolated deletion of chromosome 20q presents an indolent form of myelodyplasia that can be associated with the isolated thrombocytopenia with values at times below 30 x 109/L without evident morphologic anomalies or significant anaemia. The exclusion of this disease – mainly in refractory cases to therapy – is made possible with the research of this chromosome anomaly through cytogenetic findings or preferably with FISH (Gupta R et al, 2007)PubMed.

The measurement of the baseline immunoglobulin levels (IgG, IgA, IgM) is appropriate as low values can lead to a diagnosis of common variable immunodeficiency, a condition that can be associated to ITP while selective IgA deficiency is a contraindication to the use of immunoglobulins due to the risk of anaphylaxis. Tests for Helicobacter pylori, preferably performed by measuring the antigen in the faeces or with the urea test, have to be taken into consideration in those adult subjects whose therapy could change if present.

The complete conduct of morphological and laboratory clinical investigations, reported in table III, generally permit the exclusion of secondary forms of ITP. However, different forms of thrombocytopenia listed in tables IV and V as well as hereditary forms indicated in table VI should be excluded by performing appropriate investigations particularly in children who do not respond to corticosteroids or with chronic ITP and in adults with ITP who do not respond to intravenous administration of IgG. Molecular investigations that have to be performed in specialized laboratories are often essential to correctly diagnose suspected hereditary forms, which are apparently isolated cases of thrombocytopenia evident at birth or in the first few months of life (Neven B et al, 2011PubMedVisco C, Rodeghiero F, 2009PubMedVisco C et al, 2008PubMed).

Tables IV, V and VI show the different forms of thrombocytopenia to should be considered during evaluation.

 

Rodeghiero_Immune_thrombocytopenia_Table_4

Table IV. Approximate rate of primary ITP and secondary ITP in general and classified in different forms

 

Rodeghiero_Immune_thrombocytopenia_Table_5

Table V. Acquired thrombocytopenia identified as distinct nosographic entities

 

Rodeghiero_Immune_thrombocytopenia_Table_6

Table VI. Hereditary thrombocytopenia classified according to platelet volume

 

The secondary forms are reported in table IV. The incidence and the prevalence of the secondary forms of ITP are approximate as they have not been properly investigated in appropriate studies.

Apart from the forms reported in table IV, other types of thrombocytopenia are carefully taken into consideration by the haematologist for differential diagnosis such as the autoimmune drug-induced forms, the post-transfusion purpura and the autoimmune forms in the course of myelodysplasia. Non-autoimmune thrombocytopenia or thrombocytopenia named after the peculiar clinical features also need to be considered. Some of these forms can manifest in apparently isolated ways and can be confused with ITP. Table V reports a list of the main forms of immune and non-immune thrombocytopenia to consider in the differential diagnosis of ITP.

Finally, the hereditary forms reported in table VI need to be taken into consideration mainly in children (Lambert MP, 2011)PubMed. The presence of ALPS will be excluded in case of lymphocytosis due to its frequent onset in the first years of life.

 

THERAPY

Newly diagnosed ITP

Which patients need to be treated

Although the risk of severe hemorrhage during ITP is generally minor (less than 5%), with a prevalence of mortality caused by bleeding events, in particular brain haemorrhages, that is no higher than 1-2%, many cohort studies show that morbidity and mortality are higher in patients with platelet counts below 20-30 x 109/L and even more so in subjects who are refractory to treatment with values below 10 x 109/L (Portielje JE et al, 2001PubMedMcMillan R, Durette C, 2004PubMed). Mortality is lower in children with severe bleedings, including intracranial hemorrhage representing less than 0.5% of cases (Kuhne T et al, 2003PubMed   Bolton-Maggs PH, Moon I, 1997PubMedDonato H et al, 2009PubMedNeunert CE et al, 2008PubMed), while in elderly patients these type of bleedings are significantly higher rising above 10% (Cortelazzo S et al, 1991PubMedCohen YC et al, 2000PubMed). Therefore severe thrombocytopenia in adults and in the elderly should be treated to reduce the bleeding risk. All traditional and recent guidelines are consistent in reporting that the objective of the treatment is to prevent bleeding episodes and not to increase the platelet count (George JN et al, 1996PubMedBritish Committee for Standards in Haematology General Haematology Task Force, 2003PubMedProvan D et al, 2010PubMedNeunert C et al, 2011PubMed). However, without predictive clinical parameters and based on a sufficiently reliable correlation between the platelet count and the hemorrhagic risk (as previously discussed), a platelet count above 20-30 x 109/L is considered an acceptable safe level for subjects who do not perform particularly risky activities or who do not suffer from congenital or acquired concomitant haemostatic disorders therefore receiving antithrombotic therapy. When bleeding symptoms are present, treatment is indicated even with higher platelet counts. Most paediatricians in oncohematological centres with experience in this field believe that treatment of infantile ITP is inappropriate at onset if wet purpura is not present whatever the platelet level. However, every decision needs to be put into context and made case-by-case.

Response criteria and objective of the therapy

In the absence of standardised assessment criteria and due to the lack of prospective studies, especially in adults, in whom treatment efficacy was evaluated in terms of reduction of hemorrhagic morbidity, the response criterion commonly adopted consists of increasing the platelet count and its duration over time. This is the best surrogate end point currently available. The response criteria reported by IWG are summarised in table VII.

 

Rodeghiero_Immune_thrombocytopenia_Table_7

Table VII. Objectives, indications and response criteria in the treatment of newly diagnosed ITP
Treatment

Table VIII summarises the available treatments that are used most frequently for newly diagnosed forms and the expected results which, as we can see, are generally short-term (Stasi R, Provan D, 2004PubMedAlpdogan O et al, 1998PubMedCheng Y et al, 2003PubMedMazzucconi MG et al, 2007PubMedSchiavotto C et al, 1993PubMed).

The treatments used for newly diagnosed patients such as corticosteroids, IVIg and anti-D Ig are often called first-line therapy.

 

Rodeghiero_Immune_thrombocytopenia_Table_8

Table VIII. Treatment of newly diagnosed ITP, expected results and side effects (first line therapy)

 

Treatment of persistent or chronic ITP

The objective of treating cases that do not respond to first-line therapy or who relapse after an initial response consists of postponing splenectomy or other more toxic treatments to after the first 12 months from diagnosis (chronic ITP). In this phase of the disease, partial or complete (spontaneous or induced by first line therapy) long-term remissions are rare, certainly less than 10% of cases. A prolonged use of corticosteroid therapy has not been demonstrated to improve the natural course of ITP. Furthermore, the continuous use of corticosteroids, even at minimum doses (around 5 mg a day) is strongly discouraged due to cumulative toxicity with severe metabolic alterations and increased risk of infection. Second-line drugs (see Table IX) show significant toxicity and may lack in curative potential. The risk/benefit ratio of treatment with second-line drugs against no treatment (except for severe hemorrhage or high bleeding risk) is critical in every therapeutic decision, considering that in refractory cases over time mortality caused by toxicity is similar to that caused by haemorrhage (Portielje JE et al, 2001)PubMed. Splenectomy, as we will see, is the first choice therapy in chronic ITP. However, recently special attention to short and long term risks connected to asplenia and to the reluctance of many patients and doctors – mainly in North Europe and in the U.S.A. – have lead to proposals of therapeutic attempts aimed at avoiding this surgical procedure, among which the first-line use of anti-CD20 monoclonal antibodies (rituximab) or thrombopoietin receptor agonists (TPO-ra) (Rodeghiero F, Ruggeri M, 2008)PubMed. However, the attempts to put rituximab among the first-line therapy treatments, in association with dexamethasone or deltacortene, have not been demonstrated as efficient in the long-term. Considering the significant toxicity of rituximab, first-line use is not recommended (Zaja F et al, 2010PubMedArnold DM et al, 2012PubMed). In Table IX, rituximab appears among the pre-splenectomy treatments and among the second-line treatments usually given to patients that have failed splenectomy (refractory patients) or who could not have surgery due to medical reasons (comorbidity) or refusal of consent.
About 50 – 60% of patients do not respond to traditional first or second line medical therapy in the long term with increasing exposition to an unacceptable toxicity of treatment. In these patients, if there is still a significant hemorrhagic risk, the clinician needs to evaluate treatment with a curative potential (splenectomy or rituximab) or a continuous therapy for an indefinite period of time such as treatment with recently marketed TPO receptor agonists.

 

Rodeghiero_Immune_thrombocytopenia_Table_9

Table IX. Main therapies for the treatment of persistent and chronic ITP (second-line therapy)

 

Persistent ITP therapy

The objective of persistent ITP therapy is not clear. Avoiding or at least postponing toxic treatments for the patient is fundamental. Therefore, in the absence of an important hemorrhagic risk, a conservative approach is to treat the patient only when at great risk or when skin or mucosal haemorrhages are present, administering intravenous Ig on demand. Short-term therapy with a medium/low dosage of corticosteroids – frequently prescribed in general practice – should be discouraged. If the patient shows a tendency to bleed, or requires a safety platelet threshold (usually > 30-50 x 109/L) due to the patient’s life style, second-line medical treatments can be used, for example danazol or dapsone for men or for infertile women due to age. However, even with no bleeding episodes, it is difficult to apply a conservative approach only based on surveillance of patients with persistent ITP with a platelet count below 10-20 x 109/L. The conservative approach is applied to children and special cases in which the patient has complete awareness and acceptance of the therapeutic program. Helicobacter pylori screening is recommended in all patients, if not already performed, to attempt eradication therapy when tests are positive.

Chronic ITP therapy

During this phase of the disease a spontaneous improvement is generally not encountered. The main aim is to induce a long-term response (splenectomy, rituximab, immunosuppressive drugs) or to establish a chronic therapy with TPO-RAs at least in cases with platelet counts below 20-30 x 109/L, with bleeding symptoms, or with life styles or antithrombotic therapy which require a higher platelet count. Doses, main results and adverse events to medical therapy are reported in Table IX (Stasi R et al, 2009PubMedEmilia G et al,2007PubMed;  Vesely SK et al, 2004PubMedCarson KR et al, 2009PubMed).

Splenectomy

Surgical therapy is the first therapeutic option in patients with persistent or chronic ITP who require a continuous treatment and in whom splenectomy is not contraindicated for medical reasons (British Committee for Standards in Haematology General Haematology Task Force, 2003PubMedRodeghiero F, Ruggeri M, 2011). Generally it is recommended to wait for the chronic phase of the disease. However, rather than turning to toxic treatments with poor efficacy, it may be appropriate to anticipate surgical procedures, aiming to avoid immunosuppression that would overlap immunodeficiency produced by splenectomy. Naturally the refusal of the patient is always respected, in which case the applicable therapeutic guidelines are those of patients refractory to splenectomy.
Splenectomy, initially proposed in 1916 by Kaznelson, is considered the highest curative potential treatment (although in operational terms) for ITP (Cooper N, Bussel J, 2006)PubMed. The systematic review of 135 series of patients, treated between 1996 and 2004 including 2623 adult patients (Kojouri K et al, 2004)PubMed, allows a global evaluation of the obtainable results and of the possible medium to long term side effects (Table X). An Italian multi-centric study on a cohort of 402 cases (53 cases aged < 16 years) confirmed the excellent results that can be achieved with splenectomy: 86% with partial or complete response; 14% refractory cases; 23% with relapse mainly within 2 years from the surgical procedure; the latter cases responded to medical treatment or improved spontaneously in at least 50% of cases. Fatal cases due to infection were not reported.
A possible increase in short and long term risks connected to splenectomy could hinder the wider use of this procedure. A recent revision demonstrated however that the death rate connected to laparoscopic splenectomy is close to zero and the infection risk – present throughout the whole life of the patient – is correlated to a global mortality rate of less than 0.5-1%, which is lower than the value of patients with ITP and the indication to splenectomy in whom the operation has not yet been performed (Rodeghiero F, Ruggeri M, 2012)PubMed. The immediate and long term (well demonstrated in cases of splenectomy for chronic anaemia) thrombotic risk seems lower in ITP. Patients should be monitored for the rare but possible cases of thrombosis of the splenoportal venous system. The use of post-operative LMWH at prophylactic doses (or also before surgery when platelet values are above 30-50 x 109/L) is generally recommended even if their efficacy is not demonstrated. A correct patient management is able to reduce concomitant illnesses due to splenectomy.

 

Rodeghiero_Immune_thrombocytopenia_Table_10

Table X. Efficacy and adverse events in the short and long term after splenectomy

 

Rituximab

The use of the recombinant chimeric monoclonal humanized anti CD20 antibody (Fc portion of human origin and Fab portions of murine origin) was proposed in the early 2000s, after its proven efficacy in the treatment of CD20 positive non-Hodgkin lymphoma and also in autoimmune diseases characterized by autoantibody production. The infusion of the monoclonal antibody (Table IX) administered according to the standard doses used for the treatment of lymphomas (1 weekly doses of 375 mg/m2 for 4 weeks) causes a prolonged depletion of CD20 positive lymphocytes in peripheral blood, lymph node, spleen and bone marrow with consequent immunosuppression and potential elimination of auto-reactive B lymphocytes. The use of rituximab for ITP has not been approved by the Italian Medicines Agency (AIFA). In 2011 rituximab was included in table three of the list of treatments that are regulated by Law n° 648/96 and are therefore reimbursed by the Italian National Health System. The drugs included in the list are innovative off-label treatments that are supported by scientific evidence that may be used when no therapeutic alternatives exist. The use of this drug can be justified in cases where standard medical therapies are not applicable due to ineffectiveness or excessive toxicity of other treatments (for example corticosteroids and immunosuppressants) or due to unsustainable long term costs (for example high doses of IVIg). Rituximab can be administered when splenectomy is contraindicated or refused by the patient however it has not been demonstrated that the use of the drug in patients considered for splenectomy significantly reduces the subsequent need to carry out the surgical procedure, since the long term efficacy of the treatment is lower than 20% of cases  (Patel V et al, 2006). These data have been confirmed by a recent randomized study performed by a French group. In this study, in which 60 patients with chronic ITP indicated for splenectomy were treated with rituximab, only 33% still had a satisfactory response after 2 years while over 40% still had to have a splenectomy (Godeau B et al, 2008)PubMed. Considering the demonstrated or potential toxicity (Arnold DM, Kelton JG, 2007)PubMed, acceptable in an oncological disease but not in benign disease such as ITP, the use of rituximab is not justified apart from rare cases, especially since specific treatments are available such as TPO-RAs. The use of rituximab should be limited only to TPO-RAs non responders or when their administration is contraindicated. The use of rituximab with the intent to cure before splenectomy has not been confirmed. Furthermore, vaccinations which are required before splenectomy as well as other ones such as influenza vaccinations are ineffective in patients treated with rituximab.

TPO receptor agonists

Two agents are available with agonist activity on the thrombopoietin receptors: romiplostim (Nplate®), a peptibody that is given by subcutaneous injection weekly, and eltrombopag (Revolade®), constituted of a small organic molecule that can be administered orally. The two treatments do not contain an amino acid sequence or a molecular structure present in the endogenous thrombopoietin and therefore exclude that antibodies against these agents may neutralize the endogenous thrombopoietin. The summary of the product characteristics and briefing notes should be consulted before using these agents.

In particular, for romiplostim:

Summary of product characteristics, http://www.agenziafarmaco.gov.it/sites/default/files/it_nplate_pi_v10_aifa_final_0.pdf

AIFA briefing note, http://www.agenziafarmaco.gov.it/sites/default/files/-_nii_nplate_dhcp_ii__17_versione_italiana_finale.pdf

And for eltrombopag:

Summary of product characteristics, http://aifa-emato.agenziafarmaco.it/revolade_indicazioni_gen.pdf

Romiplostim and eltrombopag represent the only treatments with high quality evidence, demonstrated by randomized prospective clinical trials and by a grade A recommendation(Provan D et al, 2010)PubMed. The efficacy in non splectomized and splectomized patients is around 80%, a success rate that is not obtainable with other treatments (Bussel JB et al, 2009PubMedBussel JB et al, 2009bPubMedKuter DJ et al, 2008PubMedKuter DJ et al, 2010PubMedKuter DJ et al, 2009PubMedCheng G et al, 2011PubMed). However, when administration is interrupted, except for very rare cases, the patient’s platelet levels return to the baseline value or even lower (rebound thrombopenia) in 1 to 2 weeks. Patients in treatment should be monitored by specialized centers with frequent adjustments of the dose, due to the fact that the platelet count has important variations in time pushing towards even severe thrombocytopenia or towards marked thrombocytosis for causes that do not depend on the administered dose.
Safety data are reassuring for treatments that last between three to five years (see Table IX) even if development of bone marrow fibrosis in very long-term treatment has still not been excluded. Prospective studies are ongoing to evaluate this side effect with an observation period of no longer than three years. Furthermore, in clinical trials and in extension studies performed without control subjects, thromboembolic events seemed to occur with higher frequency in subjects treated with placebo or standard therapy. Further studies are necessary to draw final conclusions. Considering the data available so far, the use of TPO-RAs seems appropriate mainly in the following situations:

1. With the aim to postpone splenectomy if delay is possible due to inter-current factors or the need to follow the patient’s choice;

2. To prepare the patient with severe thrombocytopenia for splenectomy to reduce hemorrhage risk;

3. To give patients effective therapy with low toxicity while waiting for splenectomy generally scheduled after twelve months from diagnosis. In Europe their use in patients before splenectomy is considered an off-label indication;

4. Considering recent evidence on the efficacy of TPO receptor agonists, patients who are refractory to multiple standard therapies and/or to splenectomy or with a contraindication or motivated refusal to undergo splenectomy are perfect candidates for the administration of these agents for an indefinite period of time according to the official indications. After one to two years of continuous treatment the dose should be cautiously tapered even if this approach is not supported by evidence of specific clinical trials.

Therapeutic algorithm proposal based on the curative potential of splenectomy

This algorithm (Figure 2) takes into consideration the recommendations present in the recent ASH guidelines and also represents the therapeutic strategy adopted by the author (Neunert C et al, 2011)PubMed.

 

Rodeghiero_Immune_thrombocytopenia_Figure_2

Figure II. Proposal of a therapeutic algorithm focusing on the curative potential of splenectomy

 

ITP patients refractory or with a contraindication to splenectomy or non responders to first and second line treatment

The highest mortality rate due to hemorrhage is found in multi-refractory patients (around 3-5% of patients who start treatment) (McMillan R, Durette C, 2004)PubMed. None of the treatments listed in Table IX, which include corticosteroids, immunosuppressants, TPO-RAs are effective even for short term treatments. IVIg often do not marginally increase circulating platelets for a brief period. Therapeutic attempts that have no valid experimentation or with an uncertain cost/benefit ratio are justified in these patients if significant hemorrhage or very severe thrombocytopenia are present. These attempts include polychemiotherapy with anti-CD52 (alemtuzumab) or tumor necrosis factor (TNFα) inhibitor (etanercept) monoclonal antibodies, or high dose chemiotherapy followed by emopoietic stem cell transplant. The fragmented nature of the available data does not allow to formulate any recommendations. Recently the Bussel group reported positive results administering a multiple therapy consisting of at least three different drugs (immunoglobulins, steroids and vinca alkaloids) in a small cohort of patients completely refractory to individual agents (in particular to corticosteroids, immunoglobulins and splenectomy) obtaining clinically significant increases in platelet counts (Boruchov DM et al, 2007)PubMed. The following maintenance treatment with an association of danazol and azathioprine was equally effective. However these patients had not been tested with rituximab and TPO receptor agonists and could have been responsive to these agents.

Emergency treatment

The hospitalization of the patient is necessary if a new or a relapse case concomitantly has a life-threatening or organ-damaging hemorrhage, if the patient has significant thrombocytopenia (< 10 x 109/L) associated with purpura manifestations or if a mucosal bleeding is present. Corticosteroids should be administered immediately preferring high-dose dexamethasone associated with immunoglobulins. Transfusion of one or more apheresis platelet units is indicated. Menorrhagia when present is treated with hormonal therapy.

Overview of treatment during pregnancy and in the new-born

ITP is not a common cause for thrombocytopenia during pregnancy and can occur in approximately one in every 1000/10,000 pregnancies with symptoms that can manifest at any time during the pregnancy. Gestational thrombocytopenia should be distinguished from ITP as the risk is low, with platelet counts rarely going below 80 x 109/L. Differential diagnosis during pregnancy should be considered as there are so many gestational secondary non-specific thrombocytopenia cases, as mentioned previously, and some specific thrombocytopenia cases such as those that manifest during pre-eclampsia, the HELLP syndrome (Hemolysis, Elevated Liver function tests and Low Platelet count) and acute fatty liver impairment. The aim of the therapy is to prevent maternal bleeding and generally treatment is not required in asymptomatic pregnant woman with platelet counts above 20-30 x 109/L, a level that is sufficient for a vaginal delivery. A platelet count of at least 70-80 x 109/L is recommended to be able to insert an epidural catheter if pain control is required during labour. Furthermore, if a caesarean delivery is scheduled a platelet count of at least 50 x 109/L is recommended during the last weeks of pregnancy. If it is not possible to program the caesarean section the platelet count should not be below this value before the delivery. Corticosteroids, in particular, prednisone and prednisolone are considered safe treatments. IVIg are also considered acceptable drugs during pregnancy. If there is no response to these drugs, in exceptional cases azathioprine and rituximab can be used. Women who received rituximab during or twelve months before pregnancy seemed to have an increased number of maternal and fetal complications (Chakravarty EF et al, 2011)PubMed. According to the Author laparoscopic splenectomy is recommended during the second trimester of pregnancy. TPO-RAs are contraindicated as absence of teratogenicity has not yet been confirmed. The use of corticosteroids is associated with premature rupture of the fetal membranes and placental abruption or teratogenicity when exposed to high doses during the first trimester, in particular incomplete closure of the upper lip and the palate (cleft lip and palate). These risks do not seem to be included in recent literature. Furthermore, due to the fact that the fetal liver is not capable of converting prednisone to its active metabolite prednisolone and the placenta is able to inactivate prednisolone by 11-beta-hydroxylase, prednisolone and prednisone are first choice drugs in pregnant women that require corticosteroid therapy. Corticosteroids do not cause congenital malformations and multiple abortions are unlikely to be induced by the administration of these drugs. Perinatal infections and adrenal insufficiency are rarely reported in the literature, that are based on the analysis of over 1000 pregnancies (Ostesen M, 1994)PubMed. However corticosteroids should be used with caution for the least time possible to obtain the lowest effective dose, generally not above 20 mg a day of prednisolone, to avoid toxicity such as osteoporosis, hypertension, diabetes and psychiatric disorders which are more frequent during pregnancy.
Corticosteroids have not been detected in breast milk if not at concentrations with no biological effect so they have no contraindication during breast-feeding (Berlin CM, Briggs GG, 2005)PubMed. The antiplatelet antibodies cross the placenta and can cause thrombocytopenia in the fetus. Thrombocytopenia with platelets below 100 x 109/L can manifest in 15% of the new-born with mothers with ITP. 10% of new-borns can develop a more severe thrombocytopenia with platelet counts below 50 x 109/L while counts below 20 x 109/L can be experienced in 4% of new-borns. In these cases hemorrhagic complications can manifest with intracranial hemorrage reporting the highest risk. Cordocentesis or fetal scalp sampling to obtain platelet counts in the new-born are not recommended. However, caesarean sections should be performed only if there is an obstetric indication regardless to maternal ITP. Platelet counts should be monitored in the new-born, in the umbilical cord and at birth and then for at least five days in venous blood. When thrombocytopenia is detected transcranial ultrasound is performed to exclude intracranial hemorrhage.

 

CONCLUSIONS

Regardless of the progress obtained during the last decade in physio-pathological knowledge, primary ITP is still a diagnosis of exclusion. The re-evaluation of the diagnosis is necessary in first-line therapy non responders, often performing a bone marrow biopsy when not available, before proceeding to more challenging therapies such as splenectomy, TPO-RAs and immunosuppressant agents. Experimental procedures including the use of TPO-RAs were introduced for the treatment of refractory patients to splenectomy or with contraindication to this procedure. Scientific level one evidence was obtained with a grade A recommendation for the use of these new agents strictly based on an experimental design that involved the comparison with placebo or a blinded standard therapy. The position in the sequential treatment algorithm however is still not established. In particular, their use during the persistent phase of ITP, even when evaluated appropriate, requires specific clinical trials. As underlined, important limitations remain in traditional therapies, mainly for their long term toxicity, that limits their systematic long-term use. New treatment options require a redefinition of the ITP treatment paradigm that bring into consideration the new physio-pathological knowledge and the new available treatment options. Further studies are necessary to identify treatments to cure ITP more than to control thrombocytopenia.

 

Acknowledgements

I would like to thank Dr. Sophia Campbell-Davies, BPharm (Hematology Project Foundation, Vicenza and University of Milan, Italy) for her skilful assistance in the English translation.

 

 

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