Immune Thrombocytopenia (ITP)

39

Immune Thrombocytopenia (ITP) Jenny M. Despotovic* and James B. Bussel† *

Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States, †Department of Pediatrics, Weill Medical College of Cornell University, New York, NY, United States

INTRODUCTION 707 INCIDENCE 707 ETIOLOGY AND PATHOPHYSIOLOGY 707 Factors Involving B-Cells 709 Factors Involving T-Cells 709 Factors Involving Platelet Production 710 Factors Affecting the Development of ITP 710 Infection 710 Immunodeficiency 711 Other 711 DIAGNOSIS AND CLINICAL ASSESSMENT 711 MANAGEMENT 712 When to Initiate Treatment 713 First-Line Treatments Aiming to Increase Platelet Counts Rapidly 715 Second-Line Treatment Options 717 Management of ITP During Pregnancy 719 PROGNOSIS 719 Improvement With Time 719 Morbidity and Mortality 719 SUMMARY 719 REFERENCES 719

INTRODUCTION Primary Immune Thrombocytopenia (ITP) is an autoimmune condition characterized by an isolated low platelet count (<100  109/L) in the absence of underlying causes.1 The pathophysiology of ITP is complex and incompletely understood, but involves rapid platelet clearance due to antibody-mediated destruction, a shift in T-cell balance, and immune-mediated megakaryocyte abnormalities leading to altered platelet production.2–4 The extent to which each mechanism affects an individual patient’s platelet count is unpredictable and likely varies. ITP is classified by duration as newly diagnosed (3 months), persistent (3–12 months) and chronic (12 months).1 ITP is a diagnosis of exclusion, as there is no clinical test with appropriate sensitivity and specificity to confirm the diagnosis and reliably exclude other causes.5,6 Additionally, treatment decisions remain a great challenge for physicians. There is much heterogeneity among the ITP patient population in bleeding manifestations even at equivalent platelet counts,7–10 and particularly in response to specific treatments.6,11 As understanding of ITP disease biology improves, so does the repertoire of therapeutic options. However, direct comparisons of treatments in randomizedcontrolled clinical trials are lacking and there are important differences between reports of single treatment studies in terms of clinical evaluation, patient populations, and measurements Platelets. https://doi.org/10.1016/B978-0-12-813456-6.00039-4 Copyright © 2019 Elsevier Inc. All rights reserved.

of treatment response. These issues make it difficult to determine the optimal approach to the treatment of individual patients with ITP. These issues have been partially clarified by clinical guidelines that will soon be updated,6,11 the content of which form much of the basis of the recommendations in the clinical section of this chapter. To summarize the current understanding of the background, pathophysiology and management of ITP, this chapter is divided into the following sections: incidence (II), etiology and pathophysiology (III), diagnosis and clinical assessment (IV), management (V), and prognosis (VI). The new developments section at the end of the chapter will highlight new and emerging therapies for ITP.

INCIDENCE The true incidence of ITP is unknown, as those with a more mild form of the disease may never come to medical attention. However, there are published data on the reported incidence and prevalence of ITP in different parts of the world without substantial differences. Clearly, the incidence varies according to age and sex. For childhood ITP, the incidence is estimated at 5 cases/100,000 children12 with prevalence estimates ranging from 4.6/100,000 children in European reports13 to 7.2/ 100,000 in North American studies.14 In prepubertal children, the peak age is 2–5 years, and there appears to be a small but statistically significant male predominance.15 Postpubertal adolescents appear to transition toward an adult form of ITP, and a female predominance. In adults, the annual incidence is 3/100,000 with a 1.9 female: male ratio in middle age but a male predominance emerges in those over the age of 60 years.15,16 The age-adjusted prevalence in one early study was 9.5/100,000,14 reflecting a higher rate of chronicity in the older population. An important issue in considering this data is that epidemiological studies of ITP vary in their definitions and eligibility criteria. Furthermore, there are likely to be a large number of asymptomatic cases that go unrecognized; as many as half of 185 adults with ITP followed at tertiary care centers had their initial thrombocytopenia discovered while they were asymptomatic and on a routine visit to their primary care physician.17 In addition, there may be a bias toward recognizing ITP in women of childbearing age because platelet counts may be routinely obtained during pregnancy.

ETIOLOGY AND PATHOPHYSIOLOGY The pathophysiology of ITP is incompletely understood, but most likely results from an interplay of multiple factors. Given the highly variable presentation, disease severity and duration, as well as response to treatment, it is likely that the predominant factor(s) driving the thrombocytopenia varies considerably among patients. Understanding of the complex immune abnormalities driving ITP has improved over time, and the proposed mechanisms involved are described in this section. See Figs. 39.1 and 39.2 for hypothesized mechanisms of ITP development.

707

708

IL-10

T reg B reg Decreased T reg function and number

Inability to regulate APC, Effector T cells, B cells

=

GpIIb/IIIa

Platelet phagocytosis

Lack of B regs lead to decreased T reg function

APC Megakaryocyte

= CD4+ T cell GpIb/IX

Epitope Spreading

x

GpIIb/IIIa antibodies

Megakaryocyte targeting

GpIb/IX antibodies

Direct T Cell mediated destruction

Abnormal megakaryocyte morphology and maturation

CD4+ T cell

B cell

B cell

Cytotoxic T cell

Fig. 39.1 Summary of ITP pathogenesis. (1) Auto-antibodies targeting platelet glycoproteins, most commonly glycoprotein IIb/IIIa. Opsonized platelets bind Fcγ receptors on antigen presenting cells. Once phagocytosed, platelets are degraded and cryptic epitopes to additional platelet glycoproteins are exposed. Antigen presenting cells then express glycoprotein IIb/IIIa as well as other platelet glycoproteins in the cell surfaces, which are recognized by CD4-postive T cells. T cell clones interact with B-cells thereby propagating antibody production. (2) Antibodies target platelets and also megakaryocytes resulting in decreased number of mature megakaryocytes and abnormal megakaryocyte maturation. (3) Cytotoxic T cells can directly target platelets independent of antibody-mediated destruction. (4) T regulatory cells promote self-tolerance are both decreased in number and function in ITP. (5) B regulatory cells act to inhibit T-cell activation and promote self-tolerance via IL-10 secretion. B regulatory cells are reduced in number and are less responsive to regulatory cytokine signaling in ITP. The direct interaction with T regulatory cells is not fully understood. (6) There are increased pro-inflammatory T cell responses in ITP. The balance is shifted toward CD4+ Th0/Th1 and Th17 activation and decreased Th2 responses.

PART IV Disorders of Platelet Number and/or Function

Th2

Th17 Th1 Th0

Immune Thrombocytopenia (ITP)

709

39

TPO

Mpl

Hepatocyte

Aging platelets undergo desialylation

ITP: platelet destruction and TPO loss overwhelmes TPO production

Senescent platelets trigger TPO production via JAK2/STAT3 in hepatocytes

Fig. 39.2 Platelet desialylation leads to insufficient TPO levels. Aging platelets in circulation constitutively undergo desialylation, a process where terminal sialic acids are cleaved from platelet glycoproteins. Desialylated platelets bind hepatic Ashwell-Morell receptors and then undergo phagocytosis and are removed from circulation. Platelet phagocytosis stimulates hepatic TPO production via the JAK-STAT pathway. TPO bound to platelets is cleared when platelets are destroyed in the setting of ITP. This loss of TPO overcomes hepatic compensatory TPO production.

Factors Involving B-Cells The early descriptions of “thrombocytopenic purpura” were hypothesized to be due to pathogenic autoantibodies targeting platelets. William Harrington’s classic experiments involved infusing whole blood or plasma from patients with ITP into healthy persons; he noted prompt and often profound thrombocytopenia in approximately 60% of those infused, demonstrating for the first time an “antiplatelet” substance in the plasma of affected patients.18 The following decade, Shulman et al. reported the plasma factor to be immunoglobulin.19 Subsequently Karpatkin and McMillan confirmed in separate studies that this plasma factor was an IgG autoantibody.20,21 The most common antigenic epitopes identified are platelet surface glycoprotein (GP) IIb-IIIa and GPIb-IX receptors.22 Binding of antibodies to these sites opsonizes platelets for clearance in the reticuloendothelial system (primarily the spleen and liver) via FcγR-bearing phagocytic cells (Fig. 39.1).2,3 It is hypothesized that the target antigen may have relevance to disease severity and treatment response. Specifically, both murine and human studies have demonstrated that anti-GPIb antibodies are associated with more severe and treatment refractory disease.23,24 Animal studies have demonstrated that anti-GPIb antibodies may lead to platelet clearance through hepatic Ashwell-Morell receptors (FcR independent) as a result of deglycosylation, which could explain the differential response to therapies aimed at interfering with FcR mediated clearance (Fig. 39.2).25

Furthermore, studies in mice have demonstrated unique effects of anti-GPIb to block megakaryocyte release of platelets.24 B-cell biology-related abnormalities described in ITP include increased levels of B-cell activating factor (BAFF) leading to increased B cell proliferation and survival, and abnormal regulatory B cell (Breg, CD19+24+Foxp3+) number and function which results in reduced self-tolerance via reduction in regulatory T cells (Treg).26,27 Also Audia et al. have highlighted the interactions of Th21 cells and B cells in the spleen that likely contribute to existence of long-lived plasma cells. B cell abnormalities described above and the resultant autoantibodies have been demonstrated to affect marrow megakaryocyte production and maturation including damaging megakaryocytes.4,24,28 Diseases resulting in abnormal B-cells (CVID) are associated with high rates of ITP29 perhaps explained by loss of function of checkpoints.30

Factors Involving T-Cells Only approximately 60% of patients with ITP have detectable anti-platelet antibodies.31 Although there are limitations to sensitivity and specificity of available assays,5 this also suggests alternative mechanisms may play an important role in the development of ITP. In fact, a very large number of T cell abnormalities have been described in this disorder. One key development in understanding the pathophysiology of ITP has been identification of an abnormal T cell subset profile in affected

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PART IV Disorders of Platelet Number and/or Function

patients. An increased ratio of Th1:Th2 profile suggests an immune pattern shifted toward immune activation and away from self-tolerance. This may be due in large part to abnormalities in the regulatory T cell compartment (Treg, CD4 + CD25 + Foxp3 + cells) which have been consistently found to be reduced in the circulation in patients with ITP as well as being dysfunctional (Fig. 39.1). Treg abnormalities may be due to altered cytokine secretion, including interferon gamma and IL10, resulting from altered T cell number and function. These cells play a critical role in self-tolerance, and when Treg number or function is abnormal, auto-reactive subpopulations are not regulated as efficiently. Recently, data has emerged demonstrating that autoantibody production by B-cells is promoted by clonal T-helper cells that are not suppressed by Tregs.32,33 Notably, these Treg abnormalities may revert to “normal” with response to treatments including rituximab, corticosteroids and TPO agonists.34–38 Another role of T-cells of uncertain clinical significance is that of CD8 cytotoxic T-cells, which may attack splenic platelets and megakaryocytes. While two studies from the same group have demonstrated that this can occur,39,40 it remains unclear how often this is found in patients with ITP, where it occurs, and whether it mediates lack of response to certain treatments. Additionally, cytotoxic CD8 + T cells may be able to directly lyse circulating platelets in the spleen and have effects on marrow megakaryocyte maturation.40 ITP has been reported in T-cell disorders including DiGeorge syndrome (thymic hypoplasia)/velocardiofacial syndrome and fas (CD95) or fas pathway deficiency syndromes including autoimmune lymphoproliferative (ALPS, Canale-Smith) syndrome.41–43 Defects in the classical pathway of complement (C) may result in a failure to clear immune complexes, resulting in longer persistence of an “enhanced” immunogen. Low C4 has been associated with ITP and low levels of all of the components of the classical pathway have been linked to systemic lupus erythematosus (SLE).44 Studies of Fc receptors in patients with ITP have not been conclusive, but one study suggested a major effect of an FcγRIIA polymorphism in children with newly diagnosed ITP both in placebo patients and those receiving IVIG. Polymorphisms of these and other receptors may at least partially determine response to some treatments including IVIG (FcγRIIB), IV anti-D (FcγRIIA) and rituximab (FcγRIIIA).45–48

Factors Involving Platelet Production Early studies of platelet production in ITP performed in the 1970s and 1980s suggested that platelet production was lower than might be anticipated given the degree of accelerated platelet destruction.49,50 Subsequently, platelet survival studies using autologous Indium111-labeled platelets confirmed that platelet turnover in ITP was minimally increased or normal in a proportion of patients, demonstrating impaired platelet production.51–53 Following the cloning of thrombopoietin (TPO) (Chapter 61), a number of studies demonstrated that the serum levels of TPO in patients with ITP were either normal or minimally increased.54,55 Two independent investigations have demonstrated that antibodies from the sera of patients with ITP were capable of inhibiting the maturation and differentiation of immature megakaryocyte precursors to megakaryocytes (Fig. 39.1).28,56 Both the platelet lifespan studies and measurement of reticulated platelets (Chapter 32) have suggested that platelet production is often reduced. Finally, the ability of a majority of patients with refractory ITP to respond to TPO receptor stimulation (see Management section later) provides further evidence that thrombopoiesis is insufficient in many patients with ITP. Recent studies reviewed by Grozovsky et al. have suggested that in addition to constitutive

production of TPO57and increase in TPO secondary to inflammation via interaction of IL6 with its hepatic receptor, desialated platelets cleared by the Ashwell-Morell receptor signal via the same pathway as IL-6 to increase TPO levels (Fig. 39.2) (see also Chapter 4).58,59

Factors Affecting the Development of ITP ITP is an acquired disorder, and the initiating trigger is generally thought to immunologic such as an infection or other environmental exposure, a vaccination, with or without a preexisting immunologic dysregulation. ITP can also develop during pregnancy. Despite these hypothesized triggers, the etiology of ITP development in an individual patient is typically unknown. As with other autoimmune disorders, it is hypothesized that genetic variants may contribute to the development of ITP in a non-Mendelian pattern. A description of the proposed mechanisms of events that can trigger ITP follow. Since ITP is identified at higher counts in asymptomatic patients17 and may slowly progress to actionable levels of disease, it appears that there is an under-recognized form of ITP in which platelet counts fall slowly over months to years before “presenting” with hemorrhagic symptoms.

Infection Acute infections, even vaccinations, appear to precede many cases of ITP in children. The infection is thought to serve merely as an initiator of the disease, and viral persistence is not required, except for specific infections to be discussed later. The mechanism for viral precipitation of ITP is incompletely understood. Antibodies that cross-react with an antigen on the platelet membrane have been demonstrated in children with varicella-induced ITP and in patients with HIV.60,61 It is possible that viral infection may inadvertently disrupt the immunoregulatory network in a transient but strategic way that allows an antiplatelet autoantibody to be produced. Another theory proposes that the viral infection leads to oxidative damage to the platelet surface resulting in neoantigens, with the resulting immune response cross-reacting with normal platelet membrane perpetuating the ITP.62 This latter hypothesis has been promulgated to explain development of chronic ITP in children given the relatively rapid resolution of ITP in most pediatric cases. It is also possible that viral infection merely exacerbates a preexisting thrombocytopenia and thereby precipitates clinical presentation rather than directly contributing to the autoimmune pathogenesis. These issues are discussed in more detail in other published reviews.24,63 In certain situations, the role of infection appears to be different: the chronicity and severity of ITP may be strongly linked to the persistence of the underlying infection, for example in HIV, Hepatitis C (HCV), cytomegalovirus (CMV) and Helicobacter (H) Pylori infections. While one could (and we would) consider these secondary ITP, without specific testing these cases are usually indistinguishable on clinical grounds from primary ITP. Thrombocytopenia occurs in up to one third of HIV patients and may result from autoimmune dysregulation secondary to severe T-cell depletion and also from direct viral cytotoxicity, as megakaryocytes express the HIV receptors CD4, CXCR4 (monocytic or early viral subtype) and CCR5 (T cell or late subtype).64 Thrombocytopenia usually correlates with detectable viral load and thus almost always responds to highly active antiretroviral therapy (HAART). IV anti-D has been shown to be superior to IVIG in these patients in a small crossover study if a rapid platelet increase is required.65 Similarly, a percentage of patients with chronic HCV develop thrombocytopenia, although the mechanisms are not as straightforward as for HIV.66 Hypersplenism, low thrombopoietin (TPO) production

Immune Thrombocytopenia (ITP)

due to hepatic impairment, disseminated intravascular coagulation (DIC), cryoglobulinemia, and the effects of interferon treatment may all contribute to hepatitis C-induced thrombocytopenia.66 These patients may bleed at higher platelet counts than primary idiopathic ITP patients as a result of vascular damage mediated by cryoglobulins.66 Successful eradication of HCV may now be possible in a high proportion of patients given the current ability to treat thrombocytopenic HCV-infected patients with newer, less toxic agents but it remains unclear how often elimination of Hepatitis C virus will result in a substantial increase in basal platelet count in these patients. Many reports describe interactions between Helicobacter pylori colonization and development and/or persistence of ITP.67–70 Numerous reports suggest that H. pylori eradication can ameliorate ITP and routine testing for H. pylori with urea breath test or stool antigen test in adult patients with ITP (but not children) in whom eradication would be appropriate has been recommended by the American Society of Hematology and expert consensusbased guidelines.6,11 However, thus far, platelet response has been geographically based with a high rate of response to eradication in Japan and Italy and a low rate in the United States (for unknown reasons, perhaps related to variation in H. pylori strain). Other chronic infections associated with thrombocytopenia include CMV,71 parvovirus, and other dormant viruses that may be activated by potent immunosuppressive therapy such as high-dose steroids. Eradication of CMV greatly improved the severity of the ITP in a small series.71

Immunodeficiency One approach to understanding the immune mechanisms underlying ITP is to consider diseases of altered immunity with which secondary ITP is associated.2,3 For example, chronic lymphocytic leukemia (CLL, a B cell proliferative disease), common variable immunodeficiency (CVID, hypogammaglobulinemia), IgA deficiency, and IgG2 deficiency, disorders in which there is abnormal antibody production secondary to abnormal B cells, are all associated with an incidence of ITP far higher than would be expected in the normal population.72 In contrast, Bruton’s X-linked agammaglobulinemia in which mature B cells are lacking, antibodies are absent, and T-cell function is essentially normal is not associated with ITP.2,3 In summary, an assortment of genetic predispositions, immune pathways and environmental insults including infections may underlie ITP in children and adults and variability in the relative importance of each pathway may contribute to the considerable heterogeneity that is apparent among patients with ITP. Delineating differences could potentially better define subgroups with varying prognoses, hemorrhagic tendency and health related quality of life impact, and could optimize treatment approaches.

Other An ever-increasing number of diseases are associated with ITP including ALPS and ALPS-like lymphoproliferative syndromes, chronic lymphocytic leukemia, and Hodgkin and nonHodgkin lymphomas, among others. Some of inherited syndromes such as DiGeorge syndrome and Wiskott-Aldrich syndrome may have autoimmune components. In most of these cases, treatment of the underlying condition will improve the platelet count; temporizing measures can be used in the beginning.

DIAGNOSIS AND CLINICAL ASSESSMENT As there is no specific diagnostic test for ITP, the diagnosis continues to be made presumptively on clinical grounds when

711

TABLE 39.1 Secondary Causes of ITP and Differential Diagnoses Classification

Examples

Infections

Viral infections including HIV, HCV, parvovirus, CMV, and H. pylori Systemic lupus erythematosus, Evans syndrome, antiphospholipid syndrome, common variable immunodeficiency, IgA deficiency, autoimmune lymphoproliferative syndrome (ALPS) Lymphoproliferative disorders (CLL, Hodgkin disease, and non-Hodgkin lymphoma), leukemias Quinine, heparin, alcohol, valproate, estrogen, etc. (see Chapter 40 for details) Myelodysplasia, megaloblastic anemia, aplastic anemia Viral hepatitis, cirrhosis, and alcohol-associated MYH9-related disorders, Wiskott-Aldrich syndrome, Type IIb von Willebrand disease, thrombocytopenia with absent radius (TAR), RUNX1, Bernard-Soulier syndrome (see Chapter 46)

Other autoimmune and immunodeficiency conditions

Malignancy

Drugs

Bone marrow failure disorders Liver disease Inherited thrombocytopenias

patient history (including the identification of a previously normal platelet count, if available), physical examination, complete blood count and examination of the blood smear do not identify an alternative etiology for the thrombocytopenia. Examples of differential diagnoses and secondary causes of ITP that should be considered when evaluating patients with thrombocytopenia are presented in Table 39.1. The suggested initial evaluation of children and adults with suspected ITP remains controversial as of this writing due to limited evidence-based data to drive decisions. The recommendations of the international expert consensus group report and the 2011 American Society of Hematology (ASH) guidelines are presented in Table 39.2,6,11 but these are currently undergoing revisions. If a child with thrombocytopenia has an acute onset of bleeding symptoms and signs, an otherwise normal complete blood count and blood smear, and a normal physical examination (except for signs of hemorrhage), including absence of hepatosplenomegaly and lymphadenopathy or other abnormalities that could suggest an alternative diagnosis (Table 39.1), then the diagnosis is highly likely to be ITP, and almost certainly not leukemia.73 The presence of certain features may complicate the diagnosis in some cases, such as the presence of hepatosplenomegaly in a post-Epstein-Barr or other virus induced ITP or in Gaucher disease; the existence of anemia that is not readily explained by thrombocytopenia-induced bleeding such as epistaxis or menorrhagia (if the MCV is low suggesting iron deficiency anemia or thalassemia trait supporting the diagnosis of ITP); or the presence of features suggestive of underlying autoimmune or immunodeficiency states. In contrast to children, the diagnosis of ITP is often considerably more difficult in adult patients. For example, an elderly patient on numerous medications who is hospitalized, has multiple medical problems including possibly infection, and then develops a progressive thrombocytopenia presents a very difficult diagnostic challenge. In addition to the tests listed in Table 39.2, other investigations that may be considered on a case by case basis include medication elimination (rarely with antibody testing); antiphospholipid and antinuclear antibodies; CMV, EBV, HHV6, and parvovirus PCRs; thyroid

39

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PART IV Disorders of Platelet Number and/or Function

TABLE 39.2 Evaluation of Children and Adults With Suspected ITP Features Supportive of ITP

Features Suggestive of Alternative Diagnosis

Patient history

■ Classical bleeding symptoms include petechiae, ecchymoses, mouth blisters, epistaxis, menorrhagia, hematuria, GI bleeding ■ Evidence of preceding viral illness or immunization (e.g., MMR), especially in children ■ Otherwise well ■ Previously normal platelet count

Family history

Typically none

Physical examination

Normal except for bleeding manifestations

Complete blood count and blood smear

Normal except for thrombocytopenia, variable to large (but not giant) platelets, microcytic anemia may be present as a consequence of chronic bleeding

Reticulocyte count

Assists in evaluation of anemia, if present

HIV and HCV testinga H. pylori (urea breath test or stool antigen test, not antibody test)b Quantitative immunoglobulin measurements (IgG, IgA, IgM)c Blood group and directantiglobulin test (DAT)d

Negative Negative (may be positive and unrelated to ITP)

■ Symptoms or history of SLE or other systemic autoimmune disorders: joint symptoms, rash, fever, iritis, etc. ■ Nonplatelet-type bleeding symptoms such as joint bleeds ■ Thrombocytopenia developing coincidently with initiation of new medications ■ Family history of thrombocytopenia suggests inherited condition ■ Splenomegaly ■ Lymphadenopathy ■ Radiological abnormalities of the radius (suggestive of TAR or Fanconi syndrome) ■ Spurious low platelet counts due to platelet clumping or satellitism (see Chapter 48) ■ Excessive numbers of large or small platelets or abnormal platelet morphology suggest nonimmune/ inherited platelet disorders ■ Neutrophil inclusions (MYH9-related disorders) ■ Red cell fragments (thrombotic thrombocytopenic purpura, TTP) or spherocytes (Evans syndrome) ■ Blasts (leukemia) Increased in hemolytic anemia (Evans syndrome, TTP) Decreased in production defects (malignancy and marrow failure) Positive Positive (in which case eradication to be pursued)

Bone marrow examinatione

Normal to increased numbers of megakaryocytes typically seen with no other abnormalities

Normal

Abnormal (including monoclonal spikes in adults suggestive of plasma cell dyscrasia)

Rh-status is useful to indicate whether treatment with anti-D may be considered; negative DAT

Positive DAT may indicate more generalized immune dysregulation, or if combined with AIHA, Evans syndrome May identify patients with malignant, lymphoproliferative, myelodysplastic, or marrow failure syndromes

a

Recommended in all patients as treatment of these conditions may result in resolution of the thrombocytopenia. Recommended in adults in whom eradication therapy would be given if test positive. Not recommended in children. Recommended to identify patients with immunodeficiency in whom immunosuppressive agents are relatively contraindicated. Ideally, measurement should be performed prior to IVIG therapy. d The significance of a positive DAT alone is unclear but in combination with evidence of hemolysis suggests Evans syndrome. e May be indicated in older patients (>60 years) and those who fail to respond to treatment; not recommended in children with typical ITP. A major change in the 2011 ASH guideline as compared to the previous guideline is that routine bone marrow examination in is no longer recommended above a threshold age in “typical” ITP. In practice, bone marrow studies are often performed in patients >60 years to exclude CLL and MDS. If bone marrow examination is performed, ideally a trephine biopsy as well as an aspirate, immunophenotyping and cytogenetics should be performed. b c

function and antibody testing; antiplatelet antibody testing, TPO levels, bone marrow aspirate and biopsy (the latter to exclude hypoplasia), and pregnancy testing (if appropriate). As discussed in detail in Chapter 32, measurement of reticulated (newly produced) platelets can now be part of the automated complete blood count using for example a Sysmex analyzer which quantifies the immature platelet fraction (IPF%).74 IPF% can differentiate between aplastic and consumptive thrombocytopenic states and provide insight into mechanisms of treatment effect and response or nonresponse.75–77 Response to treatment is a useful diagnostic indicator. A platelet increase in response to IVIG or IV anti-D treatment is suggestive of immune platelet destruction, although it does not exclude secondary ITP and lack of response does not exclude the diagnosis. Responses to steroids and to splenectomy are less specific to ITP but still useful. Conversely if a

patient has a sustained marked rise in platelet count following a platelet transfusion lasting > 12–24 h, ITP is unlikely. In summary, the diagnosis of ITP remains one of exclusion and the search for possible secondary or alternative diagnoses must be tailored according to specific patient circumstances but needs to be considered since many underlying causes may not be readily apparent. Response to specific therapies remains the only way to include ITP (as opposed to excluding other diagnoses). In the future, molecular testing in several forms may be useful for diagnosis, prognosis, and approach to treatment.

MANAGEMENT The goal of treatment in ITP is to provide adequate hemostasis to control bleeding symptoms, avoid potentially catastrophic hemorrhage, minimize treatment-related toxicities, and maximize quality of life including individualizing treatment to

Immune Thrombocytopenia (ITP)

713

TABLE 39.3 First-Line Therapies for ITP

Treatment Corticosteroids Prednis(ol)one

Dexamethasone

Methylprednisolone Intravenous immunoglobulin (IVIG)

Intravenous anti-D

Recommended Dose

Expected Time to Platelet Response

39 Expected Response Rate

Issues Well-documented potentially severe toxicities and tolerability issues limit long-term use

0.5–2 mg/kg/day for 2–4 weeks or until platelet count 30–50  109/L 40 mg/day for 4 days every 2–4 weeks for 1–4 cycles 30 mg/kg/day for 7 days 1 g/kg/day for 1–2 days

Several days to weeks

70%–80% initial response

1–7 days

As high as 90% initial response, with 20%–80% achieving durable response

1–4 days

As high as 80% initial response

24 h to 4 days

Up to 80% achieve significant platelet increase but for the majority of patients response is usually transient with platelet counts returning to pretreatment levels in 2–4 weeks

50–75 mg/kg

2–5 days

As for IVIG

optimize it for the patient’s lifestyle and activities. This is achieved through use of first, second, and even third line and emergency “rescue” treatments balanced with cautious observation in appropriate patients (Tables 39.3–39.5).

When to Initiate Treatment Deciding when and in whom treatment is indicated remains a challenge, especially in children. This is largely because of the difficulty in predicting which patients are at most risk of serious hemorrhage, which patients will spontaneously improve, and especially because a reliable method of anticipating response and toxicity to different treatments is currently unavailable. The majority of patients with ITP suffer no or relatively minor bleeding symptoms including petechiae, bruising and epistaxis. Fortunately, more significant hemorrhage such as intracranial or major organ bleeding is relatively rare, with ICH occurring in <1% of children and 1.4% of adults with ITP.78–81 However, ICH may occur in 4%–13% of adults over the age of 60, especially in those with comorbidities.82,83 Predicting which patients are at risk of severe bleeding is a major yet unresolved goal of ITP research. While bleeding is not directly related to the platelet count, maintaining a count of >30,000 reduces the risk of serious bleeding in high-risk patients. Some small preliminary studies have suggested that platelet function is stable over time84 and measurements could potentially predict bleeding risk,83 although clinically available platelet function tests such as aggregometry or platelet function analyzer (PFA-100) cannot be performed in severe thrombocytopenia and therefore are generally not useful in patients with ITP.85 Single platelet assessment by whole blood flow cytometry has been extensively studied in the research setting and may be useful to predict bleeding in the future.76 Future approaches

Mild fever-chill reactions and headaches common and can be severe. IgA-depleted preparations necessary in IgA-deficiency to avoid anaphylaxis Two FDA boxed warnings (thrombosis and renal failure) As for IVIG plus hemolytic anemia may be dose-limiting FDA boxed warning (intravascular hemolysis, renal failure, and DIC) WinRho SDF was removed from the European market due to safety concerns Only used in Rh D-positive, DAT-negative patients who have not been splenectomized

might utilize molecular testing if markers of increased likelihood of bleeding are identified. The low incidence of major bleeding is largely explained by the fact that patients with ITP appear to have adequate platelet function due to larger, younger, more hemostatic platelets compared to other causes of thrombocytopenia.85–88 The IPF has been shown in two studies to be inversely correlated with bleeding risk,77,210 although larger studies are needed. Nonetheless, platelet count is the traditional surrogate marker for bleeding risk despite considerable variability in bleeding tendency between patients with similarly low platelet counts. Though the vast majority of catastrophic bleeding events occur in patients with platelet counts of <10–20  109/L, these events are still rare, even in patients with the lowest platelet counts.10,81 Therefore, the decision to treat involves a number of important factors with important differences in adults and children with ITP which will be discussed separately. Careful assessment of bleeding symptoms, both present and historical, is paramount in determining bleeding risk and need for treatment, more important than the platelet count. Certain types of bleeding, namely wet purpura and possibly hematuria, signify a higher risk of intracranial hemorrhage.81,89 Several bleeding score systems have been developed to standardize bleeding assessments and to systematically quantify response to treatment,79,90–93 although to date none has been universally adopted. The most widely used has been the World Health Organization (WHO) bleeding scale,94 although this has limited applicability to ITP and may be the least suitable because it focuses on severe bleeding (rare in ITP) and depends heavily on interventions such as transfusions rarely used in ITP. Quality of life is increasingly important in monitoring the impact of disease and effects of therapies. A specific scoring

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PART IV Disorders of Platelet Number and/or Function

TABLE 39.4 Second-Line Therapies for ITP

Treatment

Expected Time to Platelet Response

Dose

Thrombopoietin receptor agonist (TPO-RA) Romiplostim

Issues

<8–12 weeks

Up to 80% respond initially with 2/3 achieving sustained response 40%–60% CR and PR, with primarily CR’s durable at 1 year. Only 20% persisting CR rate at 3 years

7–14 days

60%–90%

Postoperative hemorrhage, thromboembolism and infection with encapsulated organisms Infusion reactions common, occasionally severe hypersensitivity. Rarely associated with progressive multifocal leukoencephalopathy. Prolonged hypogammaglobulinemia in some patients Thrombosis, rebound TP, marrow reticulin fibrosis

<1 month

Splenectomy

Rituximab

Expected Response Rate

Typically used at 375 mg/m2  4 weekly doses (lower doses reported to be effective in small studies)

1–10 μg/kg SC weekly

Eltrombopag

25–75 mg PO daily (start lower in East Asians)

Fostamatinib

100–150 mg BID

1–10 weeks depending upon dose required to achieve response 2–4 weeks depending upon dosing 2–8 weeks

Abnormal liver function tests

20%–40% of highly refractory patients

Abnormal liver function tests Effects on cartilage limit pediatric use

Others Azathioprine Cyclosporine Cyclophosphamide Danazol Dapsone Mycophenolate mofetil Vinca alkaloids 6-Mercaptopurine Abbreviations: CR, complete remission; PR, partial remission; SC, subcutaneously; TP, thrombocytopenia.

TABLE 39.5 Emergency Therapies to Consider in ITP Treatment

Dose

Issues

Platelet transfusion

May need to be given as continuous infusion and following IVIG 400–1000 mg/kg/dose and 50–75 μg/kg, respectively Dexamethasone 40 mg/ day  4 days  3– 4 cycles and IV methylprednisolone 1 g IV over 10–30 min 0.03 mg/kg to max of 1–2 mg IV push

Only for major ongoing hemorrhage

IVIG, IV anti-D

High dose steroids

Vincristine Emergency splenectomy Supportive therapies

Short-term solution Both need high dose IV steroid premedication Variable efficacy and better as part of combination and when used close to diagnosis Good IV access required

Antifibrinolytics, progestational agents, cautery, rVIIa

system has been developed for ITP, the ITP-PAQ. The SF-36 has also been extensively used (as has the ITP-KIT for children).95–97 Substantial decreases in HRQoL in adults and children with ITP have been demonstrated. Patients, especially with chronic disease, may be so acclimated to their reduced HRQoL that they do not realize it may be disease and treatment-related; considering it their natural state. HRQoL is probably insufficiently considered in treatment decisions. Initial optimism that increasing the platelet count would dramatically improve HRQoL has been limited by recognition

that platelet improvement may improve HRQoL but not to “normal control” levels. Studies of mechanism are required to advance this area for patients. Other factors that ideally would be considered in deciding to treat, as well as which treatment to use, include activity risks such as sports and work, comorbidities, other medications, other patient medical conditions, family history, accessibility of medical care, requirements for frequent visits with certain treatments, out of pocket expense, and the degree of family/ caregiver participation.98–100

Treatment Considerations for Children Given the low rate of serious bleeding and high rate of spontaneous resolution, the ASH 2011 guidelines recommend observation without treatment for nonbleeding children regardless of platelet count.11 The ICIS studies have found (P. Imbach, personal communication) that there is an increased frequency of treatment of children when the platelet count is lower, especially when it is <10  109/L. Reasons to consider treatment for a nonbleeding child with ITP are similar in category to those of adults but manifest differently. They include reduced HRQoL (which may be subtle in smaller children), bleeding risk, distance from and access to emergency services and outpatient follow up, concomitant medical conditions or medications (comorbidities), parent/caregiver anxiety including age and ability to control activity, impact of and compliance with activity modifications, and likelihood of spontaneous remission. Whether cautious observation of the nonbleeding child with ITP should extend beyond the first 3–6 months has never been adequately studied but the general philosophy behind it is largely driven by the

Immune Thrombocytopenia (ITP)

likelihood of spontaneous improvement.101 There is no clear age cutoff at which older children and adolescents are treated more like adults, but the bleeding risk appears to remain low up to around age 40 years.102 The upcoming 2018 ASH guidelines may make more specific recommendations in this area.

Treatment Considerations for Adults Older adults are likely to have comorbid conditions, be on medications, and have an overall higher bleeding risk, so treatment is usually initiated at platelet counts of <30  109/L, but rarely indicated at platelet counts >50  109/L in the absence of other factors.1,102 There is emerging data that suggest it may be safe to observe a select group of low risk adults with newly diagnosed ITP,103,104 but this has not become standard practice. In contrast, it appears clear that patients over the age of 60 are more likely to have serious bleeding and may require more aggressive treatment. At the same time, these patients may be at highest risk of treatment related toxicity including risk of thrombosis if the TPO agents are used.105 A widely accepted solution to this quandary has not yet been forthcoming. In summary, given the toxicities associated with the available therapies, approaches to care must be individualized including identifying patients not needing treatment. If/when treatment is initiated, the goal should be to achieve adequate hemostasis and ideally improve HRQoL, but not achieve a normal platelet count.

First-Line Treatments Aiming to Increase Platelet Counts Rapidly The goal of first-line therapy in ITP is rapidly to address ongoing bleeding or imminent bleeding risk. First-line treatments for ITP include corticosteroids (dexamethasone, prednisone or prednisolone, or intravenous methylprednisolone), intravenous immunoglobulin (IVIG) and IV anti-D (Tables 39.3–39.5). Fig. 39.3 highlights the theorized mechanism of action of these agents. These agents are not expected to provide durable platelet response, with the possible exception of dexamethasone. Prednisone (prednisolone) is the standard first-line therapy for adults, and is a commonly used first-line agent in children. Although there is no standard dosing regimen, adults typically receive doses of 1 mg/kg (or 60mg) for 14–28days before tapering. IVIG may possibly also be given to achieve a more rapid increase in platelet counts.106 Approximately two-thirds of patients treated with corticosteroids have reduction in bleeding and improvement in platelet counts; however, these effects are usually transient and reverse upon tapering or discontinuation of treatment.107 Initial response rates and especially durability of response may be higher for pulse dexamethasone therapy than for daily oral prednisolone,108 although a metaanalysis revealed discrepancies across different studies.109 In children, a shorter course of prednisone is favored, typically 1–2 mg/kg/day although some prefer a short course of 4 mg/kg for 4 days with taper. Multiple mechanisms for the beneficial effects of steroids have been reported, but it is unclear which predominate. The most important immediate effects of steroids are likely inhibition of Fcγ-mediated phagocytosis, more rapid clearance of autoantibodies via effects on the neonatal Fc receptor (FcRn),110,111 reduction of antibody production, suppression of immune cell reactivity including normalizing circulating regulatory T-cell numbers, improved endothelial stability,112 and increased platelet production via interference with antibodymediated binding to megakaryocytes and possibly a direct effect on thrombopoiesis.35,52,113–116 Toxicity greatly limits use of steroids, most commonly mood changes, disordered sleep, and weight gain, and, worsening with longer use,

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increasing rates of growth retardation, hypertension, hyperglycemia, immune suppression, osteoporosis, gastritis and duodenal ulcer, pancreatitis, and cataracts, among others. Intravenous immunoglobulin (IVIG) is a pooled plasma preparation consisting of predominantly polyclonal IgG antibodies.117 Numerous studies have demonstrated the beneficial effect on platelet count and bleeding symptoms in both adults and children with ITP.100,118,119 Approximately 75%–80% of patients show a bleeding and/or platelet response to IVIG at standard dosing of 1 g/kg/day as a single dose or two daily doses, or 0.4–0.5 g/kg/day for 2–5 days administered via a 2to 6-h IV infusion. The response is more rapid than corticosteroids,120–122,205 and the peak platelet response is generally seen within 3 days post treatment.6,121 For this reason, IVIG is the first choice treatment for an acutely bleeding patient with ITP. The complete mechanism of action of IVIG remains poorly understood, but the acute effect involves inhibition of immune-mediated platelet clearance.75,117,118,123 How platelet clearance is reduced is debated. Upregulation of macrophage FcyRIIB, as proposed by Ravetch, is the most widely accepted mechanism.124,125 There are a number of different immunoglobulin preparations available, and each has a slightly different composition, which may explain subtle variabilities in response and toxicity. Each product is composed of pooled plasma from at least several thousand donors. The donors are carefully screened and the products treated to minimize risk of infectious transmission.117 However, infusion reactions and other adverse events occur in over 25% of treated patients. Infusion reactions include fever, chills, nausea, hypotension, headache, and tachycardia, and can be managed (at least in part) by reducing the rate of infusion and with premedication with antihistamines, antipyretics and occasionally corticosteroids.126 Headache is the most troubling adverse effect of high dose IVIG treatment, and occurs in up to 30%–40% of treated patients. This can be particularly challenging if a patient with ITP develops severe headache soon after IVIG infusion, resulting in re-presentation to medical care and potential evaluation for ICH often including CT scan.127 More severe toxicities are rare and include anaphylactic reactions, aseptic meningitis, and hemolytic anemia. Additionally, the US FDA label carries two boxed warnings for most IVIG preparations, for thrombosis and renal failure; the latter was primarily associated with one brand no longer in use. These more severe events are now exceptionally rare. Anti-D immune globulin is a plasma-derived, polyclonal anti-D derived from hyperimmunized Rh negative volunteers.117 The beneficial effect of IV anti-D in ITP was initially demonstrated during studies attempting to determine the mechanism of IVIG effect.128 Since then, studies have confirmed that IV anti-D immune globulin treatment results in rapid improvement in bleeding symptoms and increased platelet count in approximately 75% of Rh positive, nonsplenectomized patients with ITP at doses of 50–75 μg/kg.129 A study in children at diagnosis of ITP directly compared IVIG (0.8 g/kg) with IV anti-D 75 μg/kg and IV anti-D 50 μg/kg, and showed that 75 μg/kg of IV anti-D was equivalent to IVIG in terms of frequency of response, speed and depth of effect.130 The mechanism of anti-D effect in ITP is similar to IVIG, in decreasing platelet destruction but by interference with FcγRIIA receptor on splenic macrophages.131 These and other data suggest that IVIG and anti-D act by different mechanisms. Further evidence in support of this theory is provided by Bussel and colleagues, who found that patients who fail treatment with one may respond to the other,132 and that use of both together may be at least additive.133 Anti-D immune globulin has a similar side effect profile to IVIG, with some important differences. Anti-D is derived from hyperimmune donors, so donor exposure is dramatically less than IVIG (hundreds of donors per dose compared to more

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PART IV Disorders of Platelet Number and/or Function

Corticosteroids Intravenous immune globulin Anti-D immune globulin

APC

GpIIb/IIIa

T cell

GpIb/IX

GpIb/IX antibodies

GpIIb/IIIa antibodies

Immunomodulators

Splenectomy B cell

x x

Rituximab

x Megakaryocyte Spleen

x x

x x

Thrombopoetin agonists

Increased production over platelet destruction

Fig. 39.3 Mechanisms of ITP treatments. (1) IVIG and anti-D immune globulin decrease platelet clearance by impeding Fc-receptor binding of opsonized platelets by the reticuloendothelial system, thereby allowing platelets to remain in circulation. (2) Splenectomy reduces clearance of opsonized platelets and may also lead to decreased antibody production. (3) Immunomodulatory drugs nonspecifically impede T cell mediated platelet destruction. (4) Rituximab is a monoclonal antibody targeting CD20 positive B cells. Loss of B cells reduces antiplatelet antibody production. (5) TPO agonists stimulate megakaryocyte production of new platelets.

than ten thousand with IVIG). Infusion reactions occur commonly with anti-D, with a much lower rate of headache, depending upon the dose (50 vs. 75 micrograms/kg). Premedications as described above for IVIG are also commonly administered prior to anti-D.117,130,134 Extravascular (splenic) hemolysis is an expected result of anti-D administration; treatment results in an average decrease in hemoglobin of 1–2 g/dL with return to baseline in 3–4 weeks.129 IV anti-D is currently of limited availability in much of Europe due to safety concerns following reports of severe intravascular hemolysis, acute renal insufficiency and occasionally death,129,135,136 although these events occur in <1:1000 infusions and occur in patients with identifiable predispositions including evidence of hemolysis, cytokine storm, renal impairment, or high fever with concern for EBV infection.134 The US FDA label for anti-D carries a boxed warning regarding the risk of life-threatening

intravascular hemolysis, organ failure, and respiratory distress, and recommended implementation of a postadministration monitoring period.134 Baseline evaluation prior to treatment must include reticulocyte count, blood type, and direct antiglobulin test (DAT) to screen for preexisting hemolysis or hemolytic tendency. Patients over 65 years of age, anemic, and/or those with an acute febrile illness or evidence of renal dysfunction should be treated with caution; splenectomized patients are unlikely to respond. Platelet transfusions are rarely necessary in patients even with a high likelihood of bleeding; rapidly acting alternatives such as IVIG, anti-D, and steroids should be considered instead. Platelet transfusion may be useful if an immediate increase in platelet count is required while awaiting the effect of a more definitive or lasting treatment; but are generally not indicated for the typical patient with minor bleeding. Other indications

Immune Thrombocytopenia (ITP)

for platelet transfusion may include severe trauma, or prior to an emergent surgical procedure. Other treatments, such as IVIG, can be surprisingly effective in the short term (hours) after infusion if needed. Concomitant immunosuppression with corticosteroids and/or especially IVIG may prolong the lifespan of transfused platelets. Bolus of very high platelet doses followed by continuous platelet infusion may be necessary in difficult cases.

Second-Line Treatment Options Although 70%–80% of patients will respond to corticosteroids and/or IVIG or IV anti-D, a proportion of children and a high proportion of adults will be unresponsive or relapse after initial treatment, and in these patients second-line therapy may need to be considered (Table 39.4). In some patients, especially children, “maintenance therapy” (if needed) is often initially attempted with repeated infusions of IVIG or IV anti-D or boluses of high dose steroids. Long-term immunosuppressive agents such as azathioprine or mycophenolate mofetil can be considered. However, management of persistent, chronic, refractory or relapsed ITP has dramatically changed over the last decade with development of rituximab and thrombopoietin receptor agonists. The place of these agents in relation to splenectomy remains controversial; there is insufficient evidence to determine the correct sequence of treatments.103,137 See Fig. 39.3 for hypothesized mechanisms for the described second-line therapies.

Splenectomy Splenectomy was the primary treatment for chronic ITP from the early to late 1900s.138 Splenectomy is often not the first second-line treatment offered139; currently, it is usually not performed until at least 12 months from diagnosis (except in emergency or very difficult settings) to allow time for spontaneous remission. Surgical removal of the spleen, the primary site of platelet clearance in a majority of patients, results in normalization of platelet counts in up to 80% of adults with a longterm (at least 5–10 years) response in around two-thirds of all patients; relapses usually occur within 2 years after surgery. Limited data in children is similar to slightly better.80,140–142 However, splenectomy carries risks of hemorrhage, postoperative complications including thromboembolism (stroke), and lifetime increased risk of infection with encapsulated organisms. Laparoscopic splenectomy is the current state of the art. Predicting which patients are likely to respond to splenectomy in ITP remains challenging. Despite limited availability, determining the primary site of platelet destruction using Indium (In)111 platelet-labeling studies is arguably the most reliable predictor of response.143–146 In a published evaluation of just under 100 patients who had In111-labeled platelet scans to evaluate splenic versus hepatic platelet sequestration prior to surgery, those patients with purely splenic destruction were significantly more likely to respond to surgery than those with mixed or predominantly hepatic destruction with an odds ratio of over 7 for immediate response and over 5 for persisting response at 4 years.146 The large number of conflicting reports on whether response to IVIG or corticosteroids is associated with higher likelihood of response to splenectomy132,147 emphasize the inability to rely on these parameters. Response rates are lower in older patients (age ill-defined), and patients in whom platelet underproduction is predominant may be less likely to respond.53 In addition, patients with secondary ITP including due to Evans syndrome or SLE are less likely to have a sustained response148,149 (the former especially in children) and patients with ITP secondary to immunodeficiency are likely to have a higher risk of infections complications and therefore may be better managed with IVIG therapy.

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Long-term consequences of splenectomy remain hard to quantify. Postsplenectomy sepsis due to encapsulated bacteremia is a risk that can be mitigated, but not eliminated, by vaccination for encapsulated organisms, patient education, and availability of antibiotics. Pneumococcal conjugate and polysaccharide as well as meningococcal conjugates and haemophilus influenzae vaccines should be verified up to date or ideally administered prior to splenectomy, and prophylactic antibiotics should be administered at least during the first 90 days, during which time there is up to 30 fold increased risk of sepsis. After this time, the continued administration of prophylactic antibiotic use is controversial and highly variable, despite evidence of a slight increased risk of sepsis that remains lifelong; risk appears higher in young children.150,151 In addition, infection with intracellular organisms, including malaria, dengue, and babesia, is substantially more severe in splenectomized patients; frequent exposure to these infections could be considered a strong relative contraindication to the procedure. Portal vein thrombosis and other thromboembolic complications are rare in children and more common in older patients, especially stroke102.152 Unresolved possibilities include whether there is an increased incidence of accelerated atherosclerosis, pulmonary hypertension, and/or dementia.153,154

Rituximab Rituximab (Rituxan, Mabthera) is a chimeric murine/human monoclonal anti-CD20 antibody that causes depletion of Blymphocytes for approximately 4–12 months after administration.155 Widely used in treatment of hematologic malignancies and autoimmune conditions, it can be employed as a secondline agent in ITP, inducing a platelet response to a platelet count 50  109/L in 40%–60% of patients with full normalization of platelet counts ( 150  109/L) in 20%–40%.155,156 Responses typically develop by 8 weeks following therapy and are maintained for 1 year in almost all patients who have achieved complete remission.157 However, 3–5 year responses occur only in approximately 20%–25%.157 Repeat courses may be given if relapses occur in patients who have had a durable response. The great majority of studies have used 4 weekly infusions of 375 mg/m2. However, alternative dosing regimens including lower dose therapy (100 mg weekly  4 weeks)158 or 1 g  2 doses 2 weeks apart159 have also been shown to be effective. Two studies in untreated adult patients demonstrated superiority of dexamethasone combined with rituximab as compared to that seen with dexamethasone alone.158 Rituximab is associated with manageable side effects including first infusion reactions, serum sickness, fever, chills, and rashes that may be prevented using premedication. Carriers of hepatitis B are at risk of viral activation. Vaccine responses are impaired until B cells return. A small percentage of patients develop hypogammaglobulinemia,160 especially with three cycles of dexamethasone161 and rarely increased infections.162,163 The long-term immunological effects of repeated courses of rituximab are not well known. A primary concern is acquisition of the JC virus resulting in progressive multifocal leukoencephalopathy (PML); thus far only one unequivocal case has been identified in ITP, presumably because of the lack of concomitant immunosuppressive medications.164 Two recent studies have shown a much higher durable response rate in women either within 1 year of ITP diagnosis or <40 years of age; the latter may be a surrogate for active menstruation since only adolescent females had a similarly high durable rate among children.207 Overall, rituximab appears to be a reasonably safe and well-tolerated treatment option for patients not responding to first-line agents; and it may delay or prevent splenectomy. Some centers recommend concomitant dexamethasone.208

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PART IV Disorders of Platelet Number and/or Function

Thrombopoietin Receptor (TPO-R) Agonists The advent of TPO-R agonists has revolutionized ITP treatment, both because of high efficacy rates in patients previously classified as having difficult disease, the apparently low rate of toxicity, and because of insights provided into ITP pathogenesis and platelet kinetics (see also Chapter 61). Following cloning and identification of TPO in the early 1994,165–168 the first generation of TPO-R agonists were developed. These were recombinant proteins bearing close resemblance to endogenous thrombopoietin and primarily were used in chemotherapyinduced thrombocytopenia.169,170 However, clinical development was abruptly halted when recipients (including healthy platelet donors) developed severe thrombocytopenia (in some cases pancytopenia) due to anti-TPO antibodies that crossreacted with endogenous TPO.171,172 Following this, a second generation of nonimmunogenic agents was developed, two of which were approved in 2008 by the U.S. Food and Drug Administration (FDA) for the treatment of ITP and subsequently in over 100 countries. Romiplostim is a “peptibody” administered by once-weekly, subcutaneous injection at 1–10 μg/kg/dose. In parallel randomized controlled trials in splenectomized and nonsplenectomized patients (63 patients in each), overall platelet responses to counts >50  109/L in 4 of 24 study weeks were achieved in 79% and 88% of treated patients, respectively, compared with 0% and 14% in the placebo groups respectively; however, a durable response (>50  109 for 6 of 8 weeks) in splenectomized patients was only identified in 39%.173 Treatment with eltrombopag, an oral small-molecule therapy given at 25, 50, or 75 mg daily, had similar single-platelet response rates (81% of patients treated with 75 mg daily).174 Data from long-term trials in adults are now available, and show continuation of response in a similar proportion of patients on longterm therapy.105,175–178 Both agents have reduced both bleeding and need for rescue medications in responders, as well as allowed concomitant medications to be tapered and improved health-related quality of life. In children, due to their high rates of efficacy and favorable safety profiles relative to other agents, experienced physicians are using thrombopoietin agonists commonly and even prior to the diagnosis of chronic ITP.179 Data in adults suggest that patients unresponsive to one TPO agonist may successfully switch to the other,180 emphasizing the possible different mechanisms of action. Avatrombopag, a second oral nonpeptide TPO-R, recently completed a phase 3 trial after a previous phase 2 trial.181 Though some studies have demonstrated that a small percentage of patients treated with TPO-R agents experienced a sustained remission off therapy, the mechanism for this uncertain phenomenon is unclear.182 The percentage of patients in whom this might be expected, in which patients this might occur, and whether any curative effects exist, for example via the induction of Tregs, remains to be determined in trials designed to specifically assess these endpoints. The TPO-R agonists appear to have only minor side effects in the great majority of patients. Mild headache, nasopharyngitis, and gastrointestinal symptoms appear most common, although the overall incidence of adverse effects has been relatively similar in treatment and placebo groups. In the 10 years since the FDA approval of the TPO-R agonists, long-term safety data has emerged that have provided additional insight into the previous concerns associated with long-term use of these agents, specifically bone marrow fibrosis, thrombosis, cataract formation with eltrombopag, and neutralizing antibodies with romiplostim. A reversible and mild increase in bone marrow reticulin has been identified in a small number of patients. This has been evaluated in animal studies183 and in retrospective and prospective reviews of bone marrow examinations. It has not been shown to be of clinical

significance, as a result of ongoing monitoring in patients treated for long periods.184–188 There has also been concern over the possible increase in thromboembolic events which totaled 6% of subjects in each of two long-term TPO-RA studies105. The available data, including long-term studies, have not found evidence of increased rates of ongoing thromboembolic events in treated patients as most cases have occurred in the first year of treatment.105,185,188,189 The mechanism underlying the small increase in thromboembolic events in these patients remains elusive. In light of these concerns, it is recommended that a minimally effective dose be used to aim for a hemostatic platelet count (usually 50–100  109/L) rather than aiming for a normal or even near normal count. Finally, abrupt cessation of therapy may be associated with rebound thrombocytopenia and therefore tapering of doses and/or careful monitoring of platelet counts for 2–4 weeks after discontinuation is typically recommended.190 Adverse events specific to eltrombopag include elevated transaminases in approximately 8%–10% of adult patients, which are reversible with continued treatment or upon transient discontinuation; 3% of children and of adults cannot tolerate eltrombopag for this reason.188 Dietary modifications are required to ensure optimal absorption and efficacy of eltrombopag, as it binds strongly to divalent cations such as calcium, magnesium, and iron. Care must be taken to avoid these dietary interactions by administering eltrombopag on an empty stomach or separated by around 2 h before or after meals, and by 4 h after meals, vitamins, or medications containing significant amounts of these minerals. Iron deficiency has been reported in children taking eltrombopag, possibly due to iron chelation.191 The early eltrombopag clinical trials included ophthalmologic assessments to screen for cataract formation/worsening based on findings from 1 juvenile murine study. While long-term studies have not shown a significantly increased risk of cataract in treated patients, screening can be considered for patients with additional risk factors such as prolonged steroid exposure.188,192,193,209 Romiplostim is a peptibody with no sequence homology to endogenous thrombopoietin. Neutralizing antibodies specific to romiplostim have developed in 1% or less of patients, with no cross-reactive antibodies against endogenous thrombopoietin identified. This may be a reason for abrupt loss in response to romiplostim; testing is available through the manufacturer. TPO-R agonists are discussed in more detail in Chapter 61.

Novel Therapies Fostamatinib is an oral spleen tyrosine kinase (syk) inhibitor in clinical trials for adults with chronic ITP. It was approved by the FDA in the United States in 2018 to be used after failure of one other treatment of ITP.194 Efficacy ranged from 18% to 43% depending upon endpoint definition; patients on the open label extension study have been on treatment for over 2 years in a number of cases with preserved responses.206 Toxicities include hypertension, diarrhea, and transaminitis. There are no current plans for pediatric use because of adverse effects on growing cartilage. Rozanolixizumab is an agent that is active by blocking the neonatal Fc receptor from recycling IgG; it is in phase 2 trials for adults with chronic ITP.

Multiagent Treatments for Acute and Maintenance Therapy For treatments aiming to rapidly increase the platelet count in the acute setting, combinations of therapies can be used. IVIG

Immune Thrombocytopenia (ITP)

1 g/kg and IV methylprednisolone 30 mg/kg (up to 1000 mg) are commonly combined in the setting of serious bleeding or with any need to urgently increase the platelet count. Additional treatments that may be considered include the addition of vincristine up to 1.5 mg IV (0.03 mg/kg) and IV anti-D 75 μg/ kg (in Rh-positive, DAT-negative patients). Two, three, or all four agents can be infused together in <6–8 h in an experienced outpatient department. In responders, the combination is usually required only one to four times while a more lasting therapy has time to take effect.133 Medications used as combination therapy for maintenance of a stable increase in platelet count include danazol (400– 800 mg/day) and azathioprine (2 mg/kg/day).133,195 Of the 17 evaluable patients in the study by Boruchov et al. who subsequently started on danazol plus azathioprine as oral maintenance therapy, 76% achieved platelet counts over 50  109/ L.133 The multiagent regimen was well tolerated. Danazol may cause mild facial hair growth and acne but relatively little edema; it can lead to aggressive behavior. It will suppress menses completely, which may be clinically advantageous. Azathioprine may cause mild diarrhea and leukopenia, but the latter infrequently occurs at the above dose and can be used as the dose-limiting toxicity. Clinically relevant immunosuppression (infections, induction of malignancy) has not been reported with this agent in patients with ITP. Liver function tests should be followed routinely with both danazol and azathioprine— for example, monthly at first, and then 2–3 monthly. Other combination therapies have been reported in the treatment of ITP. Figueroa et al. used CHOP therapy and had lasting responses in a number of patients.196 Arnold et al. tried prednisone, cyclosporine and mycophenolate mofetil, all in lower doses than are typically used in single-agent therapy, and reported good responses in a small group of patients without frequent or major infectious complications.197

Management of ITP During Pregnancy The management of ITP during pregnancy is discussed in Chapter 43. The management of neonatal autoimmune thrombocytopenia as a result of maternal ITP is discussed in Chapters 44 and 45. The usual treatments of pregnant women with ITP include steroids and IVIG. IV anti-D may be helpful. A recent study of the use of the Chinese SSS TPO agent in 31 women with ITP in pregnancy suggested not only efficacy but safety with this approach including for the fetus; additional studies are required but of great interest.198

PROGNOSIS Improvement With Time Whereas the rate of spontaneous remission in children is at least 70%–80% by 1-year duration of disease, adults are more likely to have persistent and then chronic thrombocytopenia. Many studies have shown that 10%–30% of adults with ITP improve with an initial course of prednisone.199 Furthermore, even in adults with persistent and chronic ITP, there is a rate, albeit low per unit time, of spontaneous improvement and remission. Studies have suggested that if treatment is given to support the platelet count, then by 1–2 years from diagnosis, perhaps 50% of adult patients will no longer require any treatment, allowing them to avoid splenectomy indefinitely.200–203 These studies include (a) a trial of dexamethasone,200 (b) repeated infusions of IV anti-D,201 (c) a controlled trial comparing prednisone to IV anti-D in which >50% of patients in both arms were able to discontinue all treatment at around 12 months,202 and (d) a natural history study following a large cohort of treated patients.

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Morbidity and Mortality Chronic ITP in adults carries significant morbidity, both due to the disease itself and to toxicities of treatments. In addition to severe hemorrhagic complications, chronic ITP in adults is associated with an increased risk of infections, hematological malignancies, mortality, and development of comorbidities.199,204 One study reported that the mortality rate of adult patients with chronic ITP was 30% higher than the general population although much of this came from chronic overuse of steroids.80 A recent Danish study reported that patients with chronic ITP had a 5-year mortality of 24% as compared to 14% for the comparison control cohort, and these deaths were equally attributable to hemorrhage and infection.199 Although ITP in children is typically benign, a very small number of children suffer substantial morbidity and mortality. The incidence of intracranial hemorrhage (ICH) in children with ITP is estimated at 0.5%.81 Of those children with ITP who experience ICH, only 50% make a full recovery while 25% have neurological sequelae and 25% of cases are fatal.81 ITP and its treatment may also have a psychosocial and educational impact, especially in children and young adults, who may not fully participate in school or sports.

SUMMARY ITP is a complex and heterogeneous autoimmune disease resulting in often profound thrombocytopenia and variable bleeding symptoms. Treatment is directed at minimizing bleeding and/or bleeding risk. Areas ripe for further research in the field of ITP include: (1) development of a specific diagnostic test(s), (2) better understanding of the autoimmune response; and methods for predicting, (3) bleeding risk, (4) chronicity to distinguish high- and low-risk ITP patients, specifically in whom early aggressive treatment would be desirable to improve long-term outcomes, and (5) response to specific treatments. In addition, comparative trials of available agents would be very useful to better delineate choices of treatments. REFERENCES 1. Rodeghiero F, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenia of adults and children: report from an international working group. Blood 2009;113:2386–93. 2. Cines D, Bussel J, Liebman H, Luning Prak E. The ITP syndrome: pathogenic and clinical diversity. Blood 2009;113:6511–21. 3. Cines D, Liebman H, Stasi R. Pathobiology of secondary immune thrombocytopenia. Semin Hematol 2009;46:S2–S14. 4. Houwerzijl E, et al. Ultrastructural study shows morphologic features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura. Blood 2004;103:500–6. 5. Heikal N, Smock K. Laboratory testing for platelet antibodies. Am J Hematol 2013;88:818–21. 6. Provan D, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 2010;115:168–86. 7. Altomare I, Cetin K, Wetten S, Wasser J. Rate of bleeding-related episodes in adult patients with primary immune thrombocytopenia: a retrospective cohort study using a large administrative medical claims database in the US. Clin Epidemiol 2016;8:231–9. 8. Li S, et al. Rate of bleeding-related episodes in elderly patients with primary immune thrombocytopenia: a retrospective cohort study. Curr Med Res Opin 2018;34:209–16. 9. Neunert C, et al. Bleeding manifestations and management of children with persistent and chronic immune thrombocytopenia: data from the Intercontinental Cooperative ITP Study Group (ICIS). Blood 2013;121:4457–62.

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