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Immune Thrombocytopenia: A Complex Autoimmune Disease
C H A P T E R
48 Immune Thrombocytopenia: A Complex Autoimmune Disease Eun-Ju Lee1 and James B. Bussel2 1
Department of Medicine, New York Presbyterian Hospital, Weill Cornell Medical Center, New York, NY, United States 2Departments of Pediatrics, Medicine, and Obstetrics and Gynecology, New York Presbyterian Hospital, Weill Cornell Medical Center, New York, NY, United States
O U T L I N E Introduction
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First-Line Therapies
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Epidemiology
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Second-Line Therapies
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Diagnosis
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Splenectomy
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Pathogenesis
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Rituximab
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Platelet Autoantibodies
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Thrombopoietin Receptor Agonists
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T-Cell Involvement
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Conclusion
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Megakaryopoiesis
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References
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Treatment
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INTRODUCTION ITP is an acquired autoimmune disorder characterized by a platelet count ,100 3 109 L21 due to accelerated platelet destruction and impaired platelet production (McMillan, 1981; Heyns Adu et al., 1986). It is generally believed that the autoimmune response is mediated by both antiplatelet antibodies and T cell mediated cytotoxicity. Platelets are derived from megakaryocytes (MKs), whose production and maturation in the bone marrow are regulated by thrombopoietin (TPO) (Kaushansky, 1995). Normal platelet values range from 150 to 450 3 109 L21. Bleeding due to impaired primary hemostasis and platelet plug formation is a major clinical consequence of thrombocytopenia. ITP occurs in both children and adults. The incidence of ITP is estimated at 3.3/100,000 adults per year and between 1.9 and 6.4/100,000 children per year (Terrell et al., 2010). Adults and children have similar platelet counts at diagnosis and bleeding symptoms with severe thrombocytopenia. However, the underlying disease processes are likely distinct as the majority of children with ITP achieve spontaneous remission while most adults face a chronic disorder (Terrell et al., 2010; Lambert and Gernsheimer, 2017; Stasi et al., 1995).
The Autoimmune Diseases, 6th. DOI: https://doi.org/10.1016/B978-0-12-812102-3.00048-8
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Copyright © 2020 Elsevier Inc. All rights reserved.
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TABLE 48.1
Causes of Secondary Immune Thrombocytopenia
Infection
HIV, HCV, H. pylori, CMV, Varicella zoster
Autoimmune disorders
SLE, APS, Evans syndrome
Immunodeficiency
CVID, ALPS, mild SCID
Lymphoproliferative disorders
CLL, HD, LGL, NHL
Postvaccination
Especially MMR
Drug-induced
Depakote, quinine, quinidine
Bone marrow transplantation side effect HIV, Human immunodeficiency virus; HCV, hepatitis C virus; H. pylori, Helicobacter pylori; CMV, cytomegalovirus; SLE, systemic lupus erythematosus; APS, antiphospholipid syndrome; CVID, common variable immune deficiency; ALPS, autoimmune lymphoproliferative syndrome; SCID, severe combined immunodeficiency; CLL, chronic lymphocytic leukemia; HD, Hodgkin disease; LGL, large granular Tlymphocyte leukemia; NHL, non-Hodgkin lymphoma; MMR, measles-mumps-rubella. Adapted from Neunert, C., Lim, W., Crowther, M., et al., 2011. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood 117 (16), 4190 4207; Cines, D.B., Bussel, J.B., Liebman, H.A., et al., 2009. The ITP syndrome: pathogenic and clinical diversity. Blood 113 (26), 6511 6521.
According to the 2010 International Working Group (IWG) consensus of ITP experts, the acronym ITP represents immune thrombocytopenia, avoiding the terms “idiopathic” and “purpura” that had been included in the past. This reflects the enhanced understanding of the pathophysiology of ITP and lack of purpura in many cases. The IWG defines primary ITP as an isolated thrombocytopenia in the absence of other identified conditions and secondary if occurring in the context of drug exposures or other disorders associated with immune dysregulation (Table 48.1) (Rodeghiero et al., 2009). This chapter reviews the epidemiology, diagnosis, pathogenesis, and treatment of ITP with specific emphasis on the autoimmune aspects of the disease.
EPIDEMIOLOGY Studies indicate a slightly higher prevalence of ITP in males in childhood and in older adulthood with increased incidence in women in the middle (child-bearing) adult years (30 60 years age group) (Segal and Powe, 2006; Moulis et al., 2014). Peak incidence occurs during childhood and in adults greater than 60 years of age (Moulis et al., 2014). Though limited, there are some data suggesting decreased incidence among black populations and seasonal variation with a peak in the winter and spring months (Moulis et al., 2014, 2017). Severe spontaneous or posttraumatic bleeding, such as gastrointestinal, genitourinary, and gynecologic hemorrhage, skin and mucosal hemorrhage, or intracranial hemorrhage (ICH), may occur with platelet values ,10 3 109 L21 and can occur but is less frequent in patients with platelets between 10 3 109 and 20 3 109 L21 (Cortelazzo et al., 1991; Cines and Bussel, 2005). Factors associated with increased risk of bleeding include lower platelet counts, male gender, older age, and prior hemorrhage (Lambert and Gernsheimer, 2017; Cortelazzo et al., 1991; Neunert et al., 2011, 2015). Adults have a higher overall rate of intracranial bleeding than children, 1.4% versus 0.4% (Neunert et al., 2015) potentially reflecting the presence of medical comorbidities. ICH is especially prevalent in patients over the age of 60 (Cortelazzo et al., 1991). Although bleeding is a significant concern with thrombocytopenia, recent reports indicate an increased risk of thromboembolism in ITP patients with a relative risk of 1.6 compared to the general population (Doobaree et al., 2016). The reasons behind this remain unclear but could be related to increased platelet activation and to cellderived microparticles (Bidot et al., 2008; Sewify et al., 2013; Psaila et al., 2011) with possibly some contribution of treatment effect. For example, patients who have undergone splenectomy have a higher rate of thromboembolism than nonsplenectomized ITP patients (Doobaree et al., 2016; Boyle et al., 2013). Patients receiving TPO receptor agonists (TPO-RAs) also have a higher risk of thromboembolic events (6% over several years of treatment) (Wong et al., 2017).
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DIAGNOSIS
In the US population, there was greater in-hospital mortality for ITP patients compared to non-ITP hospitalizations (Danese et al., 2009). This increased mortality also exists in ITP patients compared with the general population along with higher rates of cardiovascular disease, thromboembolic events, bleeding, and infection (Norgaard et al., 2011; Frederiksen et al., 2014).
DIAGNOSIS An isolated platelet count ,100 3 109 L21 in the absence of other underlying disorders characterizes ITP. Current guidelines recommend a thorough evaluation of a patient’s history, physical examination, complete blood count (CBC), and peripheral blood smear (Neunert et al., 2011; Provan et al., 2010). In taking the history, particular attention should be given to the presence of systemic diseases, infections, chronicity, and severity of bleeding/bruising events, medications, vaccinations, and personal or family history of thrombocytopenia or easy bleeding/bruising. The physical exam should be unremarkable save for manifestations of bleeding or bruising. Careful examination of the liver, the spleen, the lymph nodes, and the radial ray is particularly warranted. Detection of a significantly enlarged spleen should prompt evaluation for disorders other than ITP. The CBC should show intact hemoglobin and white blood cell count. Abundant platelet clumping and signs of hemolysis (schistocytes) should be absent on the peripheral blood smear. The IWG consensus report from 2010 recommends checking for human immunodeficiency virus (HIV), hepatitis C virus, Helicobacter pylori, quantitative immunoglobulin levels, and a direct antiglobulin test (DAT) (Provan et al., 2010). The evaluation of antiphospholipid antibodies, antinuclear antibodies, antiplatelet antibodies, thyroid function testing, and cytomegalovirus could be helpful but are not routinely recommended, unless guided by symptoms or history (Neunert et al., 2011; Provan et al., 2010). Both the IWG consensus report (2010) and the American Society of Hematology (ASH) 2011 practice guidelines advise against routine bone marrow biopsy in the evaluation of children and younger adults (Neunert et al., 2011; Provan et al., 2010; Jubelirer and Harpold, 2002; Mak et al., 2000). The IWG suggests consideration of bone marrow biopsy in certain situations such as patients older than 60 years of age, presence of systemic symptoms, or prior to splenectomy (Provan et al., 2010). Bone marrow aspirate and biopsy are important tools in patients with refractory disease to rule out other causes of thrombocytopenia. Note that both documents may be revised in the near future with the next rendition of the ASH guidelines expected by early 2018. ITP remains a diagnosis of exclusion. The majority of ITP cases are primary and around 20% are secondary (Table 48.1), the most common causes varying by location. In the United States, the most common causes of secondary ITP are common variable immune deficiency (CVID), systemic lupus erythematosus, hepatitis C infection, and chronic lymphocytic leukemia (Moulis et al., 2014; Cines et al., 2009). Whether ITP is primary or secondary, transient substantial response to intravenous immunoglobulin (IVIG) is supportive of the diagnosis. The phases of ITP are defined as acute, persistent, and chronic (Table 48.2). Once diagnosed, most adults will go on to have chronic ITP (Cuker et al., 2015). Those with clinically significant bleeding and very low platelet counts requiring initiation of treatment, additional therapies, or increased doses of medications are described as having “severe” ITP (Rodeghiero et al., 2009). Severe ITP can occur during any phase of ITP. “Refractory” ITP describes disease not responsive to splenectomy with severe ITP or significant risk of bleeding to warrant treatment (Rodeghiero et al., 2009).
TABLE 48.2 Phases of Immune Thrombocytopenia Acute
Diagnosis to 3 months
Persistent
3 12 months from diagnosis
Chronic
More than 12 months from diagnosis
Adapted from Rodeghiero, F., Stasi, R., Gernsheimer, T., et al., 2009. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood 113 (11), 2386 2393.
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PATHOGENESIS Primary ITP is a complicated acquired autoimmune condition with thrombocytopenia broadly resulting from pathologic antiplatelet autoantibodies (Shulman et al., 1965), T cell mediated platelet destruction (Olsson et al., 2003), and impaired MK production (Khodadi et al., 2016). It is a very heterogeneous disease whereby immune dysregulation of many causes results in the antiplatelet response described above. It is worth noting that initially in the first stage of B-cell development, 50% or so are autoantibodies which, given the marrow milieu, are directed against blood cells especially platelets. Therefore with preformed antibodies that can be stimulated, ITP can develop as a loss of control (Nemazee et al., 1991).
PLATELET AUTOANTIBODIES Autoantibodies, typically IgG, are produced against single or multiple platelet surface antigens particularly components of the glycoprotein (GP) IIb/IIIa and GPIb/IX complexes but also others that may have been underestimated in the past such as anti-GPVI (He et al., 1995; Woods et al., 1984; Audia et al., 2017). IgA and IgM antiplatelet antibodies are seen less often and typically in conjunction with IgG autoantibodies (He et al., 1994); their role is largely unclear. B lymphocytes may secrete autoreactive antibodies and are present in increased frequency in patients with ITP (Kuwana et al., 2014; Chen et al., 2012). The spleen is the main site of antiplatelet antibody production with the peripheral blood, bone marrow, and probably lymph nodes serving as secondary sources of antibody-producing B and plasma cells (McMillan et al., 1974). Phagocytes with Fcγ-receptors recognize antiplatelet antibody bound to platelets, facilitating their phagocytosis and destruction. Given the local production of antibodies and the constant presence of about one-third of the intravascular platelet mass, the spleen is the primary site of platelet destruction with usually a smaller contribution via the reticuloendothelial system of the liver (Ballem et al., 1987; Zufferey et al., 2017; McMillan, 2007). In addition to antibody-mediated destruction via phagocytosis, antibody binding can activate complement-mediated platelet lysis (Tsubakio et al., 1986), though this has been poorly studied and the significance of complement components is not completely clear. Currently, neither the IWG nor the ASH practice guidelines recommend routine testing for platelet autoantibodies (Neunert et al., 2011; Provan et al., 2010). No detectable antibodies are found in up to 30% 40% of the patients (Zufferey et al., 2017), and this is reflected in the low sensitivity (i.e., percent of patients with ITP with positive antibodies) of 49% 66% of platelet antibody testing in ITP. In addition, a specificity of only 78% 93% leads to a significant number of false-positive tests (Warner et al., 1999; Brighton et al., 1996; McMillan et al., 2003). Possible reasons behind the absence of detectable antibodies in a substantial percent of ITP patients include suppression of antibody levels due to preceding treatment, the presence of antibodies to other platelet antigens that are not being assayed, and a significant contribution of antibody-independent mechanisms of disease such as T cell mediated platelet destruction and/or suppression of platelet production (Zufferey et al., 2017; McMillan, 2007). In addition to the production of autoreactive antibodies, other mechanisms of immune dysregulation involving B cells may also participate in the pathogenesis ITP. B cell activating factor (BAFF or B lymphocyte stimulator) is a cytokine that plays a critical role in regulating B-cell survival, maturation, and stimulation (Schneider et al., 1999). Elevated levels of BAFF in ITP may contribute to disease activity by rescuing autoreactive B and T cells from apoptosis and by promoting survival of long-lived splenic plasma cells (Audia et al., 2017; Zhu et al., 2009; Mahevas et al., 2013). A subset of IL-10 producing B-regulatory cells (Bregs) helps to maintain intact immune tolerance by promoting the differentiation of T-regulatory cells (Tregs), regulating T helper 1 (Th1)/T helper 2 (Th2) balance, and suppressing activation of monocytes, thus playing a vital role in immune suppression (Li et al., 2012; Semple, 2012; Lemoine et al., 2011). Not only are Bregs decreased in patients with ITP but they are also functionally impaired (Li et al., 2012).
T-CELL INVOLVEMENT T cells and dysregulation of T-cell populations are involved in the pathogenesis of ITP through a variety of mechanisms. A change in T-helper cell balance occurs with decreased Th2 polarization resulting in an increased Th1/Th2 ratio (Ogawara et al., 2003; Wang et al., 2005) and with an inverse correlation of the Th1/Th2 ratio with
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platelet count in ITP (Takahashi et al., 2017; Panitsas et al., 2004). The significance of this altered T-cell balance is not yet known but as Th1 polarization is required for macrophage stimulation, this may result in increased platelet phagocytosis (Audia et al., 2017). The most discussed mechanism, possibly due to the current lack of clarity, involves the role of cytotoxic T cells. CD81 cytotoxic T cells can directly lyse platelets (Zhao et al., 2008) and accumulate in the bone marrow inhibiting platelet production (Olsson et al., 2008). T cells can also enhance antibody formation as demonstrated by a population of autoreactive GPIIb/IIIa CD41 T cells that promote the production of antiplatelet antibodies (Kuwana et al., 1998). The latter may involve the CD40 CD40 ligand (CD154) interaction (Audia et al., 2014). Tregs suppress self-reactive lymphocytes and preserve immunological self-tolerance (Hori et al., 2003; Sakaguchi et al., 2009). The spontaneous development of severe autoimmune disease in animal models with depleted Treg populations, and in humans with specific deficiency of Tregs, highlights the importance of Tregs in maintaining immune homeostasis (Kim et al., 2007; Yu et al., 2017). As shown in multiple studies, both decreased number and impaired function of Tregs characterize the abnormal immune environment of ITP (Sakakura et al., 2007; Liu et al., 2007). Why all of these mechanisms result in ITP, rather than perhaps other autoimmune diseases, remains to be clarified. Possibilities include the preexistence of autoantiplatelet antibodies or the resemblance of platelets to lymphocytes with multiple immunologically active molecules. The latter may lead to platelet participation in the immune response resulting in the presentation of platelet GPs to antigen-presenting cells. Another largely unresolved issue is why ITP resolves in certain cases and not in others. Several approaches have been explored. In children, if the initial inciting infection results in oxidative damage to the platelet membrane, then this increases the chance of developing chronic ITP (Zhang and Zehnder, 2013). In support of this hypothesis is an Egyptian study randomizing addition of antioxidative therapy showing a benefit to this form of treatment (Elalfy et al., 2015). Another study of children with chronic ITP suggested a number of polymorphisms in T-cell pathways contributed to chronic ITP (Zhang et al., 2014). One appeal of these findings is that they strongly support a polygenic instead of monogenic etiology of chronic disease. A corroborative set of findings comes from the study of a B cell directed treatment (rituximab plus dexamethasone). Nonresponders had a significantly increased frequency of monoclonal and oligoclonal T-cell repertoires compared to responders (Chapin et al., 2016). This suggests that the persistence of abnormal T cells relates to the persistence of ITP. The majority of patients with ITP gradually improve but certain patients worsen over time. One of the reasons behind this appears to include processes such as epitope spreading whereby epitopes distinct from the initial inciting epitope become major targets of the ongoing immune response (Cornaby et al., 2015). But, as with many of the discussed immunologic phenomena, this has been shown to occur but to be of unclear clinical significance.
MEGAKARYOPOIESIS Despite the normal or increased number of MKs seen in bone marrow biopsies of ITP patients, the platelet production is actually impaired (Louwes et al., 1999; Dameshek and Miller, 1946). Abnormalities in MK development contribute to insufficient platelet production. Early microscopy studies demonstrated extensive damage to 50% 75% of MKs (Stahl et al., 1986). More recent studies confirm these findings showing features of apoptosis and para-apoptosis in the majority of mature MKs with surrounding neutrophils and macrophages (Houwerzijl et al., 2004). Since MKs express platelet surface antigens (i.e., GPIIb/IIIa, GPIb/IX), these antiplatelet antibodies, and potentially autoreactive T cells, can affect MK maturation/platelet production in the bone marrow (Houwerzijl et al., 2004; McMillan et al., 2004; Chang et al., 2003). Another reason for the suboptimal platelet production involves TPO, produced by the liver and the main growth factor for MKs (de Sauvage et al., 1996). After TPO binds to its receptor, c-Mpl, on platelets and MKs, it is internalized and eventually destroyed along with the platelet (Kuter and Rosenberg, 1995; Debili et al., 1995). Thus the total cell mass of c-Mpl expressing cells regulates circulating TPO levels; the same is true of granulocyte colony-stimulating factor although not erythropoietin (Corbacioglu et al., 2000). While patients with ITP have low absolute platelet number, TPO levels remain low due to uptake by the increased population of MKs and platelets with a short lifespan (Chang et al., 1999). An additional pathway leading to TPO production has recently been discovered. Desialylation of membrane proteins occurs as platelets age, leading to their binding by the hepatic Ashwell Morell receptor which induces platelet phagocytosis and TPO production (Audia et al., 2017; Grozovsky et al., 2015). However, in ITP, the majority of antibody-coated platelets are believed to be destroyed via FcR-mediated phagocytosis and not in this
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fashion. These findings of low circulating TPO levels in ITP may partly explain why TPO-RA is an often effective treatment. Reduced proplatelet formation in patients with undetectable antiplatelet antibodies suggests a nonimmune, inherent defect in late megakaryopoiesis (Riviere et al., 2015). As mentioned briefly above, CD81 cytotoxic T cells accumulate in the bone marrow (Olsson et al., 2008) where they suppress proper MK apoptosis, a step required for platelet production (Li et al., 2007). In one study, nonresponders to TPO-RAs had increased MKs in the marrow but reduced platelet reticulocytes suggesting that their lack of response was due to impaired ability of proplatelets to release platelets (Barsam et al., 2011). Responders to TPO-RAs had clearly increased platelet reticulocytes compared to those patients who responded to treatments such as IVIG, IV anti-D, and even an antiFcR III antibody, demonstrating their unique mechanism of effect, that is, stimulation of platelet production (Barsam et al., 2011).
TREATMENT Generally, patients with platelets above 30 3 109 L21 are not at risk for serious bleeding and may be followed by observation alone. Patients with platelets ,10 3 109 L21 are treated, and the decision to treat those with platelets between 10 3 109 and 30 3 109 L21 depends on factors such as bleeding/bruising symptoms, medical comorbidities, and fatigue (Cooper, 2017); most adults with platelet counts in this range are likely to be treated. The goal of treatment is to achieve a durably improved platelet count without the need for ongoing therapy.
FIRST-LINE THERAPIES Historically, first-line treatments include steroids, IVIG, and IV anti-D. The overall aim of these therapies is to decrease autoantibody-mediated platelet destruction, although which of their multiple potential mechanisms of action are most significant is not completely understood (Zufferey et al., 2017). IVIG slows platelet destruction and increases platelet half-life but exactly how this occurs remains controversial. There are various types and doses of steroids used in ITP but no consensus regarding the optimal regimen. Some studies suggest improved response rates using one or multiple rounds of high-dose dexamethasone (40 mg/day 3 4 days) compared to a prolonged prednisone taper (Wei et al., 2016; Mazzucconi et al., 2007). In patients with contraindications to high doses of steroids, IVIG 1 g/kg may be used for 1 or 2 days depending on platelet response (Cooper, 2017). The primary common toxicity is headache, which can be severe. Patients who are RhD antigen positive, are DAT negative, and have intact spleens are candidates for treatment with IV anti-D (Scaradavou et al., 1997; Cooper et al., 2002). IV anti-D has been shown to be particularly efficacious in children and in HIV-related ITP (Scaradavou et al., 1997), though all treated patients must be monitored for intravascular hemolysis. Intravascular hemolysis and fever chill nausea vomiting cytokine-driven reactions to IV anti-D can both be ameliorated substantially by premedication with high dose IV steroids, for example, methylprednisolone 30 mg/kg up to 1 g.
SECOND-LINE THERAPIES If the initial attempt at therapy does not result in lasting improvement and/or clinical remission, multiple agents are available as second-line treatments. The selection among these agents is very difficult and the only clear, unequivocal tenet is not to continue steroids.
SPLENECTOMY Splenectomy remains a reasonable option with around 60% of the patients achieving a normal platelet count postsurgery and maintaining a sustained response at 5 years (Kojouri et al., 2004; Kumar et al., 2002; Ahmed et al., 2016). However, this potential benefit should be balanced with the surgical risk and long-term increased risk of infection/sepsis and thrombosis especially stroke (Ahmed et al., 2016). The decreased usage of splenectomy (Boyle et al., 2013) reflects the possibility of other treatment options, the long-term response in only 60%,
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the inability to predict the response except in very few centers, and the hope that the ITP will improve over 1 3 years such that no ongoing treatment will be necessary. If very good prediction of response were widely available, it would probably be selected more frequently.
RITUXIMAB Rituximab is an anti-CD-20 monoclonal antibody that depletes circulating CD-20-positive antibody-producing B cells. The overall response rate is around 50% 60% and about 20% 30% of the patients have a long-term (. 5 years) response (Patel et al., 2012; Arnold et al., 2007). Apparently, the population with the best response to the combination of rituximab and three cycles of dexamethasone is women with ITP of ,1 year’s duration (Chapin et al., 2016). Caution should be taken as B-cell depletion can lead to decreased vaccine response for up to 6 months (Nazi et al., 2013) and repeated courses of rituximab, especially in combination with dexamethasone, can lead to severe hypogammaglobulinemia (Cooper et al., 2009). Those with existing CVID, and patients who are on immunosuppressive medications, may be at greater risk for hypogammaglobulinemia and infection but those with CVID should already be on IVIG and they respond to rituximab particularly well (Gobert et al., 2011). Obtaining baseline immunoglobulin levels is recommended prior to treatment with rituximab (Cooper, 2017; Kado et al., 2016). In addition, patients should be tested for hepatitis B due to the risk of viral reactivation with rituximab. Overall, rituximab is generally well tolerated with toxicities including very occasional severe infusion reaction, serum sickness, prolonged immunosuppression, and rare reports of progressive multifocal leukoencephalopathy, only one or two of which occurred in patients with ITP (Carson et al., 2009; Cuker and Neunert, 2016).
THROMBOPOIETIN RECEPTOR AGONISTS TPO-RAs bind to the TPO receptor stimulating megakaryopoiesis and hence platelet production. Currently, there are two TPO-RAs, eltrombopag and romiplostim, approved by the US Food and Drug Administration (FDA) and European Medicines Agency. Both agents lack sequence or structural homology with endogenous TPO avoiding the risk of developing cross-reactive antibodies (Kuter, 2007). Eltrombopag is an orally available, small molecule, nonpeptide TPO-RA that binds the transmembrane domain of the TPO receptor (Kuter, 2007; Rodeghiero and Carli, 2017). It is FDA approved for the treatment of ITP in adults and children $ 1 year-old refractory to corticosteroids, IVIg, or splenectomy; adults with severe aplastic anemia; and thrombocytopenia due to chronic hepatitis C infection. Romiplostim is a recombinant fusion protein, a so-called peptibody, given weekly via subcutaneous injection that shares the same TPO receptor binding site as endogenous TPO (Rodeghiero and Carli, 2017). Romiplostim is FDA approved for the treatment of chronic ITP in adults refractory corticosteroids, IVIg, or splenectomy. In a double-blind randomized controlled trial of 63 splenectomized and 62 nonsplenectomized patients with ITP, Romiplostim had an overall response rate (4 of 24 weeks) of 80% 90% with durable platelet response rates (platelet count $ 50 3 109/L for at least 6 of the final 8 weeks of the study) of 38% in splenectomized and 61% in nonsplenectomized patients. The majority of patients who had been on concomitant treatment were able to reduce the dosage of or discontinue other ITP medications, and rescue treatments for low counts were reduced as was bleeding (Kuter et al., 2008). Longer term studies of up to 5 years demonstrated ongoing efficacy and safety of Romiplostim (Bussel et al., 2009a; Kuter et al., 2013). Randomized controlled trials of eltrombopag in adults and children show initial platelet response rates of 59% 79%, with a significant proportion of patients able to decrease or discontinue concomitant ITP therapies (Bussel et al., 2009b; Grainger et al., 2015; Cheng et al., 2011). Potential risks of both TPO-RAs include thrombosis, headaches, and myalgia and bone marrow fibrosis. Eltrombopag may result in cataracts and transaminitis or hyperbilirubinemia (Bussel et al., 2009a; Kuter et al., 2013). Romiplostim has a higher rate of cycling counts in some responders, and there appears to be a 1% incidence of neutralizing antibodies (which do not cross-react with native TPO) (Carpenedo et al., 2016). Should a patient not respond to or not tolerate one of the TPO-RAs switching to the other is a reasonable option (Khellaf et al., 2013). Although not meant as curative therapy, there are reports of patients sustaining adequate platelet counts after TPO-RA discontinuation (Cuker et al., 2015) but how to decide when to taper or stop a TPO-RA remains uncertain. The Sunshine Pharmaceutical Co., Ltd. has a TPO-RA that resembles native TPO which is licensed in China and several Asian countries (Zhao et al., 2004). Two additional TPO-RAs are in clinical trial at present.
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Multiple other agents are used as second-line treatments in ITP including mycophenolate mofetil, danazol, azathioprine, dapsone, vincristine, and cyclophosphamide. There are a number of single arm studies with each of these agents albeit with response rates mostly ,50% in difficult patients (Taylor et al., 2015; Hou et al., 2003; Maloisel et al., 2004; Provan et al., 2006; Quiquandon et al., 1990; Stirnemann et al., 2016). The latter two agents (vincristine and cyclophosphamide) have been used much less frequently in recent years because of their toxicities.
CONCLUSION ITP is a prototypic organ-specific autoimmune disease. Its relative frequency is attributed to the development of immature pre-B and B cells in the marrow where they are exposed to platelets. Studies of tolerance have shown that the most immature B cells have an autospecificity in approximately 50% of cells that steadily falls to ,1%. Rupture of tolerance in one of many areas can thus readily result in ITP. ITP is a final common pathway disease that can result from many different etiologies. The current inability to dissect out which one is occurring in a given patient has been one of the primary limitations in improving the management of ITP. With the increasing number of acceptable treatment options, it can be very difficult to decide which one to select in a given patient. Studies not only of various polymorphisms or mutations in patients linked to their outcomes of their ITP, for example, not only bleeding and fatigue but also response to different therapies and whether spontaneous improvement will occur are badly needed. If and when this happens, the information should allow a more rational approach to the management of ITP in the future. There is general agreement that curative therapies are more effective in patients very close to diagnosis so that prediction of outcome, for example, chronicity, would be very useful in the decision of minimal treatment, just enough to avoid bleeding, as compared to a rituximab and dexamethasone-based regimen intended to be curative.
References Ahmed, R., Devasia, A.J., Viswabandya, A., et al., 2016. Long-term outcome following splenectomy for chronic and persistent immune thrombocytopenia (ITP) in adults and children: Splenectomy in ITP. Ann. Hematol. 95 (9), 1429 1434. Arnold, D.M., Dentali, F., Crowther, M.A., et al., 2007. Systematic review: efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura. Ann. Intern. Med. 146 (1), 25 33. Audia, S., Rossato, M., Santegoets, K., et al., 2014. Splenic TFH expansion participates in B-cell differentiation and antiplatelet-antibody production during immune thrombocytopenia. Blood 124 (18), 2858 2866. Audia, S., Mahevas, M., Samson, M., et al., 2017. Pathogenesis of immune thrombocytopenia. Autoimmun. Rev. 16 (6), 620 632. Ballem, P.J., Segal, G.M., Stratton, J.R., et al., 1987. Mechanisms of thrombocytopenia in chronic autoimmune thrombocytopenic purpura. Evidence of both impaired platelet production and increased platelet clearance. J. Clin. Invest. 80 (1), 33 40. Barsam, S.J., Psaila, B., Forestier, M., et al., 2011. Platelet production and platelet destruction: assessing mechanisms of treatment effect in immune thrombocytopenia. Blood 117 (21), 5723 5732. Bidot, L., Jy, W., Bidot Jr, C., et al., 2008. Microparticle-mediated thrombin generation assay: increased activity in patients with recurrent thrombosis. J. Thromb. Haemost. 6 (6), 913 919. Boyle, S., White, R.H., Brunson, A., et al., 2013. Splenectomy and the incidence of venous thromboembolism and sepsis in patients with immune thrombocytopenia. Blood 121 (23), 4782 4790. Brighton, T.A., Evans, S., Castaldi, P.A., et al., 1996. Prospective evaluation of the clinical usefulness of an antigen-specific assay (MAIPA) in idiopathic thrombocytopenic purpura and other immune thrombocytopenias. Blood 88 (1), 194 201. Bussel, J.B., Kuter, D.J., Pullarkat, V., et al., 2009a. Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood 113 (10), 2161 2171. Bussel, J.B., Provan, D., Shamsi, T., et al., 2009b. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet 373 (9664), 641 648. Carpenedo, M., Cantoni, S., Coccini, V., et al., 2016. Response loss and development of neutralizing antibodies during long-term treatment with romiplostim in patients with immune thrombocytopenia: a case series. Eur. J. Haematol. 97 (1), 101 103. Carson, K.R., Evens, A.M., Richey, E.A., et al., 2009. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood 113 (20), 4834 4840. Chang, M., Qian, J.X., Lee, S.M., et al., 1999. Tissue uptake of circulating thrombopoietin is increased in immune-mediated compared with irradiated thrombocytopenic mice. Blood 93 (8), 2515 2524. Chang, M., Nakagawa, P.A., Williams, S.A., et al., 2003. Immune thrombocytopenic purpura (ITP) plasma and purified ITP monoclonal autoantibodies inhibit megakaryocytopoiesis in vitro. Blood 102 (3), 887 895. Chapin, J., Lee, C.S., Zhang, H., et al., 2016. Gender and duration of disease differentiate responses to rituximab-dexamethasone therapy in adults with immune thrombocytopenia. Am. J. Hematol. 91 (9), 907 911. Chen, J.F., Yang, L.H., Chang, L.X., et al., 2012. The clinical significance of circulating B cells secreting anti-glycoprotein IIb/IIIa antibody and platelet glycoprotein IIb/IIIa in patients with primary immune thrombocytopenia. Hematology 17 (5), 283 290.
VII. ORGAN SPECIFIC AUTOIMMUNE DISEASES
REFERENCES
919
Cheng, G., Saleh, M.N., Marcher, C., et al., 2011. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet 377 (9763), 393 402. Cines, D.B., Bussel, J.B., 2005. How I treat idiopathic thrombocytopenic purpura (ITP). Blood 106 (7), 2244 2251. Cines, D.B., Bussel, J.B., Liebman, H.A., et al., 2009. The ITP syndrome: pathogenic and clinical diversity. Blood 113 (26), 6511 6521. Cooper, N., 2017. State of the art - how I manage immune thrombocytopenia. Br. J. Haematol. 177 (1), 39 54. Cooper, N., Woloski, B.M., Fodero, E.M., et al., 2002. Does treatment with intermittent infusions of intravenous anti-D allow a proportion of adults with recently diagnosed immune thrombocytopenic purpura to avoid splenectomy? Blood 99 (6), 1922 1927. Cooper, N., Davies, E.G., Thrasher, A.J., 2009. Repeated courses of rituximab for autoimmune cytopenias may precipitate profound hypogammaglobulinaemia requiring replacement intravenous immunoglobulin. Br. J. Haematol. 146 (1), 120 122. Corbacioglu, S., Bux, J., Konig, A., et al., 2000. Serum granulocyte colony-stimulating factor levels are not increased in patients with autoimmune neutropenia of infancy. J. Pediatr. 137 (1), 96 99. Cornaby, C., Gibbons, L., Mayhew, V., et al., 2015. B cell epitope spreading: mechanisms and contribution to autoimmune diseases. Immunol. Lett. 163 (1), 56 68. Cortelazzo, S., Finazzi, G., Buelli, M., et al., 1991. High risk of severe bleeding in aged patients with chronic idiopathic thrombocytopenic purpura. Blood 77 (1), 31 33. Cuker, A., Neunert, C.E., 2016. How I treat refractory immune thrombocytopenia. Blood 128 (12), 1547 1554. Cuker, A., Prak, E.T., Cines, D.B., 2015. Can immune thrombocytopenia be cured with medical therapy? Semin. Thromb. Hemost. 41 (4), 395 404. Dameshek, W., Miller, E.B., 1946. The megakaryocytes in idiopathic thrombocytopenic purpura, a form of hypersplenism. Blood 1, 27 50. Danese, M.D., Lindquist, K., Gleeson, M., et al., 2009. Cost and mortality associated with hospitalizations in patients with immune thrombocytopenic purpura. Am. J. Hematol. 84 (10), 631 635. Debili, N., Wendling, F., Cosman, D., et al., 1995. The Mpl receptor is expressed in the megakaryocytic lineage from late progenitors to platelets. Blood 85 (2), 391 401. Doobaree, I.U., Nandigam, R., Bennett, D., et al., 2016. Thromboembolism in adults with primary immune thrombocytopenia: a systematic literature review and meta-analysis. Eur. J. Haematol. 97 (4), 321 330. Elalfy, M.S., Elhenawy, Y.I., Deifalla, S., et al., 2015. Oxidant/antioxidant status in children and adolescents with immune thrombocytopenia (ITP) and the role of an adjuvant antioxidant therapy. Pediatr. Blood Cancer 62 (5), 830 837. Frederiksen, H., Maegbaek, M.L., Norgaard, M., 2014. Twenty-year mortality of adult patients with primary immune thrombocytopenia: a Danish population-based cohort study. Br. J. Haematol. 166 (2), 260 267. Gobert, D., Bussel, J.B., Cunningham-Rundles, C., et al., 2011. Efficacy and safety of rituximab in common variable immunodeficiencyassociated immune cytopenias: a retrospective multicentre study on 33 patients. Br. J. Haematol. 155 (4), 498 508. Grainger, J.D., Locatelli, F., Chotsampancharoen, T., et al., 2015. Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial. Lancet 386 (10004), 1649 1658. Grozovsky, R., Begonja, A.J., Liu, K., et al., 2015. The Ashwell-Morell receptor regulates hepatic thrombopoietin production via JAK2-STAT3 signaling. Nat. Med. 21 (1), 47 54. He, R., Reid, D.M., Jones, C.E., et al., 1994. Spectrum of Ig classes, specificities, and titers of serum antiglycoproteins in chronic idiopathic thrombocytopenic purpura. Blood 83 (4), 1024 1032. He, R., Reid, D.M., Jones, C.E., et al., 1995. Extracellular epitopes of platelet glycoprotein Ib alpha reactive with serum antibodies from patients with chronic idiopathic thrombocytopenic purpura. Blood 86 (10), 3789 3796. Heyns Adu, P., Badenhorst, P.N., Lotter, M.G., et al., 1986. Platelet turnover and kinetics in immune thrombocytopenic purpura: results with autologous 111In-labeled platelets and homologous 51Cr-labeled platelets differ. Blood 67 (1), 86 92. Hori, S., Nomura, T., Sakaguchi, S., 2003. Control of regulatory T cell development by the transcription factor Foxp3. Science 299 (5609), 1057 1061. Hou, M., Peng, J., Shi, Y., et al., 2003. Mycophenolate mofetil (MMF) for the treatment of steroid-resistant idiopathic thrombocytopenic purpura. Eur. J. Haematol. 70 (6), 353 357. Houwerzijl, E.J., Blom, N.R., van der Want, J.J., et al., 2004. Ultrastructural study shows morphologic features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura. Blood 103 (2), 500 506. Jubelirer, S.J., Harpold, R., 2002. The role of the bone marrow examination in the diagnosis of immune thrombocytopenic purpura: case series and literature review. Clin. Appl. Thromb. Hemost. 8 (1), 73 76. Kado, R., Sanders, G., McCune, W.J., 2016. Suppression of normal immune responses after treatment with rituximab. Curr. Opin. Rheumatol. 28 (3), 251 258. Kaushansky, K., 1995. Thrombopoietin: the primary regulator of platelet production. Blood 86 (2), 419 431. Khellaf, M., Viallard, J.F., Hamidou, M., et al., 2013. A retrospective pilot evaluation of switching thrombopoietic receptor-agonists in immune thrombocytopenia. Haematologica 98 (6), 881 887. Khodadi, E., Asnafi, A.A., Shahrabi, S., et al., 2016. Bone marrow niche in immune thrombocytopenia: a focus on megakaryopoiesis. Ann. Hematol. 95 (11), 1765 1776. Kim, J.M., Rasmussen, J.P., Rudensky, A.Y., 2007. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 8 (2), 191 197. Kojouri, K., Vesely, S.K., Terrell, D.R., et al., 2004. Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet count responses, prediction of response, and surgical complications. Blood 104 (9), 2623 2634. Kumar, S., Diehn, F.E., Gertz, M.A., et al., 2002. Splenectomy for immune thrombocytopenic purpura: long-term results and treatment of postsplenectomy relapses. Ann. Hematol. 81 (6), 312 319. Kuter, D.J., 2007. New thrombopoietic growth factors. Blood 109 (11), 4607 4616. Kuter, D.J., Rosenberg, R.D., 1995. The reciprocal relationship of thrombopoietin (c-Mpl ligand) to changes in the platelet mass during busulfan-induced thrombocytopenia in the rabbit. Blood 85 (10), 2720 2730.
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Kuter, D.J., Bussel, J.B., Lyons, R.M., et al., 2008. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet 371 (9610), 395 403. Kuter, D.J., Bussel, J.B., Newland, A., et al., 2013. Long-term treatment with romiplostim in patients with chronic immune thrombocytopenia: safety and efficacy. Br. J. Haematol. 161 (3), 411 423. Kuwana, M., Kaburaki, J., Ikeda, Y., 1998. Autoreactive T cells to platelet GPIIb-IIIa in immune thrombocytopenic purpura. Role in production of anti-platelet autoantibody. J. Clin. Invest. 102 (7), 1393 1402. Kuwana, M., Okazaki, Y., Ikeda, Y., 2014. Detection of circulating B cells producing anti-GPIb autoantibodies in patients with immune thrombocytopenia. PLoS One 9 (1), e86943. Lambert, M.P., Gernsheimer, T.B., 2017. Clinical updates in adult immune thrombocytopenia. Blood 129 (21), 2829 2835. Lemoine, S., Morva, A., Youinou, P., et al., 2011. Human T cells induce their own regulation through activation of B cells. J. Autoimmun. 36 (3-4), 228 238. Li, S., Wang, L., Zhao, C., et al., 2007. CD81 T cells suppress autologous megakaryocyte apoptosis in idiopathic thrombocytopenic purpura. Br. J. Haematol. 139 (4), 605 611. Li, X., Zhong, H., Bao, W., et al., 2012. Defective regulatory B-cell compartment in patients with immune thrombocytopenia. Blood 120 (16), 3318 3325. Liu, B., Zhao, H., Poon, M.C., et al., 2007. Abnormality of CD4(1)CD25(1) regulatory T cells in idiopathic thrombocytopenic purpura. Eur. J. Haematol. 78 (2), 139 143. Louwes, H., Zeinali Lathori, O.A., Vellenga, E., et al., 1999. Platelet kinetic studies in patients with idiopathic thrombocytopenic purpura. Am. J. Med. 106 (4), 430 434. Mahevas, M., Patin, P., Huetz, F., et al., 2013. B cell depletion in immune thrombocytopenia reveals splenic long-lived plasma cells. J. Clin. Invest. 123 (1), 432 442. Mak, Y.K., Yu, P.H., Chan, C.H., et al., 2000. The management of isolated thrombocytopenia in Chinese adults: does bone marrow examination have a role at presentation? Clin. Lab. Haematol. 22 (6), 355 358. Maloisel, F., Andres, E., Zimmer, J., et al., 2004. Danazol therapy in patients with chronic idiopathic thrombocytopenic purpura: long-term results. Am. J. Med. 116 (9), 590 594. Mazzucconi, M.G., Fazi, P., Bernasconi, S., et al., 2007. Therapy with high-dose dexamethasone (HD-DXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura: a GIMEMA experience. Blood 109 (4), 1401 1407. McMillan, R., 1981. Chronic idiopathic thrombocytopenic purpura. N. Engl. J. Med. 304 (19), 1135 1147. McMillan, R., 2007. The pathogenesis of chronic immune thrombocytopenic purpura. Semin. Hematol. 44 (4Suppl 5), S3 S11. McMillan, R., Longmire, R.L., Yelenosky, R., et al., 1974. Quantitation of platelet-binding IgG produced in vitro by spleens from patients with idiopathic thrombocytopenic purpura. N. Engl. J. Med. 291 (16), 812 817. McMillan, R., Wang, L., Tani, P., 2003. Prospective evaluation of the immunobead assay for the diagnosis of adult chronic immune thrombocytopenic purpura (ITP). J. Thromb. Haemost. 1 (3), 485 491. McMillan, R., Wang, L., Tomer, A., et al., 2004. Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP. Blood 103 (4), 1364 1369. Moulis, G., Palmaro, A., Montastruc, J.L., et al., 2014. Epidemiology of incident immune thrombocytopenia: a nationwide population-based study in France. Blood 124 (22), 3308 3315. Moulis, G., Guenin, S., Limal, N., et al., 2017. Seasonal variations of incident primary immune thrombocytopenia in adults: an ecological study. Eur. J. Intern. Med. 37, e26 e28. Nazi, I., Kelton, J.G., Larche, M., et al., 2013. The effect of rituximab on vaccine responses in patients with immune thrombocytopenia. Blood 122 (11), 1946 1953. Nemazee, D., Russell, D., Arnold, B., et al., 1991. Clonal deletion of autospecific B lymphocytes. Immunol. Rev. 122, 117 132. Neunert, C., Lim, W., Crowther, M., et al., 2011. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood 117 (16), 4190 4207. Neunert, C., Noroozi, N., Norman, G., et al., 2015. Severe bleeding events in adults and children with primary immune thrombocytopenia: a systematic review. J. Thromb. Haemost. 13 (3), 457 464. Norgaard, M., Jensen, A.O., Engebjerg, M.C., et al., 2011. Long-term clinical outcomes of patients with primary chronic immune thrombocytopenia: a Danish population-based cohort study. Blood 117 (13), 3514 3520. Ogawara, H., Handa, H., Morita, K., et al., 2003. High Th1/Th2 ratio in patients with chronic idiopathic thrombocytopenic purpura. Eur. J. Haematol. 71 (4), 283 288. Olsson, B., Andersson, P.O., Jernas, M., et al., 2003. T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura. Nat. Med. 9 (9), 1123 1124. Olsson, B., Ridell, B., Carlsson, L., et al., 2008. Recruitment of T cells into bone marrow of ITP patients possibly due to elevated expression of VLA-4 and CX3CR1. Blood 112 (4), 1078 1084. Panitsas, F.P., Theodoropoulou, M., Kouraklis, A., et al., 2004. Adult chronic idiopathic thrombocytopenic purpura (ITP) is the manifestation of a type-1 polarized immune response. Blood 103 (7), 2645 2647. Patel, V.L., Mahevas, M., Lee, S.Y., et al., 2012. Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia. Blood 119 (25), 5989 5995. Provan, D., Moss, A.J., Newland, A.C., et al., 2006. Efficacy of mycophenolate mofetil as single-agent therapy for refractory immune thrombocytopenic purpura. Am. J. Hematol. 81 (1), 19 25. Provan, D., Stasi, R., Newland, A.C., et al., 2010. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 115 (2), 168 186. Psaila, B., Bussel, J.B., Frelinger, A.L., et al., 2011. Differences in platelet function in patients with acute myeloid leukemia and myelodysplasia compared to equally thrombocytopenic patients with immune thrombocytopenia. J. Thromb. Haemost. 9 (11), 2302 2310.
VII. ORGAN SPECIFIC AUTOIMMUNE DISEASES
REFERENCES
921
Quiquandon, I., Fenaux, P., Caulier, M.T., et al., 1990. Re-evaluation of the role of azathioprine in the treatment of adult chronic idiopathic thrombocytopenic purpura: a report on 53 cases. Br. J. Haematol. 74 (2), 223 228. Riviere, E., Viallard, J.F., Guy, A., et al., 2015. Intrinsically impaired platelet production in some patients with persistent or chronic immune thrombocytopenia. Br. J. Haematol. 170 (3), 408 415. Rodeghiero, F., Carli, G., 2017. Beyond immune thrombocytopenia: the evolving role of thrombopoietin receptor agonists. Ann. Hematol. 96 (9), 1421 1434. Rodeghiero, F., Stasi, R., Gernsheimer, T., et al., 2009. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood 113 (11), 2386 2393. Sakaguchi, S., Wing, K., Onishi, Y., et al., 2009. Regulatory T cells: how do they suppress immune responses? Int. Immunol. 21 (10), 1105 1111. Sakakura, M., Wada, H., Tawara, I., et al., 2007. Reduced Cd41 Cd251 T cells in patients with idiopathic thrombocytopenic purpura. Thromb. Res. 120 (2), 187 193. de Sauvage, F.J., Carver-Moore, K., Luoh, S.M., et al., 1996. Physiological regulation of early and late stages of megakaryocytopoiesis by thrombopoietin. J. Exp. Med. 183 (2), 651 656. Scaradavou, A., Woo, B., Woloski, B.M., et al., 1997. Intravenous anti-D treatment of immune thrombocytopenic purpura: experience in 272 patients. Blood 89 (8), 2689 2700. Schneider, P., MacKay, F., Steiner, V., et al., 1999. BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J. Exp. Med. 189 (11), 1747 1756. Segal, J.B., Powe, N.R., 2006. Prevalence of immune thrombocytopenia: analyses of administrative data. J. Thromb. Haemost. 4 (11), 2377 2383. Semple, J.W., 2012. Bregging rights in ITP. Blood 120 (16), 3169. Sewify, E.M., Sayed, D., Abdel Aal, R.F., et al., 2013. Increased circulating red cell microparticles (RMP) and platelet microparticles (PMP) in immune thrombocytopenic purpura. Thromb. Res. 131 (2), e59 e63. Shulman, N.R., Marder, V.J., Weinrach, R.S., 1965. Similarities between known antiplatelet antibodies and the factor responsible for thrombocytopenia in idiopathic purpura. Physiologic, serologic and isotopic studies. Ann. N. Y. Acad. Sci. 124 (2), 499 542. Stahl, C.P., Zucker-Franklin, D., McDonald, T.P., 1986. Incomplete antigenic cross-reactivity between platelets and megakaryocytes: relevance to ITP. Blood 67 (2), 421 428. Stasi, R., Stipa, E., Masi, M., et al., 1995. Long-term observation of 208 adults with chronic idiopathic thrombocytopenic purpura. Am. J. Med. 98 (5), 436 442. Stirnemann, J., Kaddouri, N., Khellaf, M., et al., 2016. Vincristine efficacy and safety in treating immune thrombocytopenia: a retrospective study of 35 patients. Eur. J. Haematol. 96 (3), 269 275. Takahashi, N., Saitoh, T., Gotoh, N., et al., 2017. The cytokine polymorphisms affecting Th1/Th2 increase the susceptibility to, and severity of, chronic ITP. BMC Immunol. 18 (1), 26. Taylor, A., Neave, L., Solanki, S., et al., 2015. Mycophenolate mofetil therapy for severe immune thrombocytopenia. Br. J. Haematol. 171 (4), 625 630. Terrell, D.R., Beebe, L.A., Vesely, S.K., et al., 2010. The incidence of immune thrombocytopenic purpura in children and adults: a critical review of published reports. Am. J. Hematol. 85 (3), 174 180. Tsubakio, T., Tani, P., Curd, J.G., et al., 1986. Complement activation in vitro by antiplatelet antibodies in chronic immune thrombocytopenic purpura. Br. J. Haematol. 63 (2), 293 300. Wang, T., Zhao, H., Ren, H., et al., 2005. Type 1 and type 2 T-cell profiles in idiopathic thrombocytopenic purpura. Haematologica 90 (7), 914 923. Warner, M.N., Moore, J.C., Warkentin, T.E., et al., 1999. A prospective study of protein-specific assays used to investigate idiopathic thrombocytopenic purpura. Br. J. Haematol. 104 (3), 442 447. Wei, Y., Ji, X.B., Wang, Y.W., et al., 2016. High-dose dexamethasone vs prednisone for treatment of adult immune thrombocytopenia: a prospective multicenter randomized trial. Blood 127 (3), 296 302. quiz 370. Wong, R.S.M., Saleh, M.N., Khelif, A., et al., 2017. Safety and efficacy of long-term treatment of chronic/persistent ITP with eltrombopag: final results of the EXTEND study. Blood 130, 2527 2536. Woods Jr, V.L., Oh, E.H., Mason, D., et al., 1984. Autoantibodies against the platelet glycoprotein IIb/IIIa complex in patients with chronic ITP. Blood 63 (2), 368 375. Yu, H., Paiva, R., Flavell, R.A., 2017. Harnessing the power of regulatory T cells to control autoimmune diabetes: overview and perspective. Immunology 153 (2), 161 170. Zhang, B., Zehnder, J.L., 2013. Oxidative stress and immune thrombocytopenia. Semin. Hematol. 50 (3), e1 e4. Zhang, D., Zhang, X., Ge, M., et al., 2014. The polymorphisms of T cell-specific TBX21 gene may contribute to the susceptibility of chronic immune thrombocytopenia in Chinese population. Hum. Immunol. 75 (2), 129 133. Zhao, Y.Q., Wang, Q.Y., Zhai, M., et al., 2004. [A multi-center clinical trial of recombinant human thrombopoietin in chronic refractory idiopathic thrombocytopenic purpura]. Zhonghua Nei Ke Za Zhi. 43 (8), 608 610. Zhao, C., Li, X., Zhang, F., et al., 2008. Increased cytotoxic T-lymphocyte-mediated cytotoxicity predominant in patients with idiopathic thrombocytopenic purpura without platelet autoantibodies. Haematologica 93 (9), 1428 1430. Zhu, X.J., Shi, Y., Peng, J., et al., 2009. The effects of BAFF and BAFF-R-Fc fusion protein in immune thrombocytopenia. Blood 114 (26), 5362 5367. Zufferey, A., Kapur, R., Semple, J.W., 2017. Pathogenesis and therapeutic mechanisms in immune thrombocytopenia (ITP). J. Clin. Med. 6 (2), pii: E16.
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48 Immune Thrombocytopenia: A Complex Autoimmune Disease Eun-Ju Lee1 and James B. Bussel2 1
Department of Medicine, New York Presbyterian Hospital, Weill Cornell Medical Center, New York, NY, United States 2Departments of Pediatrics, Medicine, and Obstetrics and Gynecology, New York Presbyterian Hospital, Weill Cornell Medical Center, New York, NY, United States
O U T L I N E Introduction
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First-Line Therapies
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Epidemiology
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Second-Line Therapies
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Diagnosis
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Splenectomy
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Pathogenesis
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Rituximab
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Platelet Autoantibodies
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Thrombopoietin Receptor Agonists
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T-Cell Involvement
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Conclusion
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Megakaryopoiesis
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References
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Treatment
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INTRODUCTION ITP is an acquired autoimmune disorder characterized by a platelet count ,100 3 109 L21 due to accelerated platelet destruction and impaired platelet production (McMillan, 1981; Heyns Adu et al., 1986). It is generally believed that the autoimmune response is mediated by both antiplatelet antibodies and T cell mediated cytotoxicity. Platelets are derived from megakaryocytes (MKs), whose production and maturation in the bone marrow are regulated by thrombopoietin (TPO) (Kaushansky, 1995). Normal platelet values range from 150 to 450 3 109 L21. Bleeding due to impaired primary hemostasis and platelet plug formation is a major clinical consequence of thrombocytopenia. ITP occurs in both children and adults. The incidence of ITP is estimated at 3.3/100,000 adults per year and between 1.9 and 6.4/100,000 children per year (Terrell et al., 2010). Adults and children have similar platelet counts at diagnosis and bleeding symptoms with severe thrombocytopenia. However, the underlying disease processes are likely distinct as the majority of children with ITP achieve spontaneous remission while most adults face a chronic disorder (Terrell et al., 2010; Lambert and Gernsheimer, 2017; Stasi et al., 1995).
The Autoimmune Diseases, 6th. DOI: https://doi.org/10.1016/B978-0-12-812102-3.00048-8
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TABLE 48.1
Causes of Secondary Immune Thrombocytopenia
Infection
HIV, HCV, H. pylori, CMV, Varicella zoster
Autoimmune disorders
SLE, APS, Evans syndrome
Immunodeficiency
CVID, ALPS, mild SCID
Lymphoproliferative disorders
CLL, HD, LGL, NHL
Postvaccination
Especially MMR
Drug-induced
Depakote, quinine, quinidine
Bone marrow transplantation side effect HIV, Human immunodeficiency virus; HCV, hepatitis C virus; H. pylori, Helicobacter pylori; CMV, cytomegalovirus; SLE, systemic lupus erythematosus; APS, antiphospholipid syndrome; CVID, common variable immune deficiency; ALPS, autoimmune lymphoproliferative syndrome; SCID, severe combined immunodeficiency; CLL, chronic lymphocytic leukemia; HD, Hodgkin disease; LGL, large granular Tlymphocyte leukemia; NHL, non-Hodgkin lymphoma; MMR, measles-mumps-rubella. Adapted from Neunert, C., Lim, W., Crowther, M., et al., 2011. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood 117 (16), 4190 4207; Cines, D.B., Bussel, J.B., Liebman, H.A., et al., 2009. The ITP syndrome: pathogenic and clinical diversity. Blood 113 (26), 6511 6521.
According to the 2010 International Working Group (IWG) consensus of ITP experts, the acronym ITP represents immune thrombocytopenia, avoiding the terms “idiopathic” and “purpura” that had been included in the past. This reflects the enhanced understanding of the pathophysiology of ITP and lack of purpura in many cases. The IWG defines primary ITP as an isolated thrombocytopenia in the absence of other identified conditions and secondary if occurring in the context of drug exposures or other disorders associated with immune dysregulation (Table 48.1) (Rodeghiero et al., 2009). This chapter reviews the epidemiology, diagnosis, pathogenesis, and treatment of ITP with specific emphasis on the autoimmune aspects of the disease.
EPIDEMIOLOGY Studies indicate a slightly higher prevalence of ITP in males in childhood and in older adulthood with increased incidence in women in the middle (child-bearing) adult years (30 60 years age group) (Segal and Powe, 2006; Moulis et al., 2014). Peak incidence occurs during childhood and in adults greater than 60 years of age (Moulis et al., 2014). Though limited, there are some data suggesting decreased incidence among black populations and seasonal variation with a peak in the winter and spring months (Moulis et al., 2014, 2017). Severe spontaneous or posttraumatic bleeding, such as gastrointestinal, genitourinary, and gynecologic hemorrhage, skin and mucosal hemorrhage, or intracranial hemorrhage (ICH), may occur with platelet values ,10 3 109 L21 and can occur but is less frequent in patients with platelets between 10 3 109 and 20 3 109 L21 (Cortelazzo et al., 1991; Cines and Bussel, 2005). Factors associated with increased risk of bleeding include lower platelet counts, male gender, older age, and prior hemorrhage (Lambert and Gernsheimer, 2017; Cortelazzo et al., 1991; Neunert et al., 2011, 2015). Adults have a higher overall rate of intracranial bleeding than children, 1.4% versus 0.4% (Neunert et al., 2015) potentially reflecting the presence of medical comorbidities. ICH is especially prevalent in patients over the age of 60 (Cortelazzo et al., 1991). Although bleeding is a significant concern with thrombocytopenia, recent reports indicate an increased risk of thromboembolism in ITP patients with a relative risk of 1.6 compared to the general population (Doobaree et al., 2016). The reasons behind this remain unclear but could be related to increased platelet activation and to cellderived microparticles (Bidot et al., 2008; Sewify et al., 2013; Psaila et al., 2011) with possibly some contribution of treatment effect. For example, patients who have undergone splenectomy have a higher rate of thromboembolism than nonsplenectomized ITP patients (Doobaree et al., 2016; Boyle et al., 2013). Patients receiving TPO receptor agonists (TPO-RAs) also have a higher risk of thromboembolic events (6% over several years of treatment) (Wong et al., 2017).
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DIAGNOSIS
In the US population, there was greater in-hospital mortality for ITP patients compared to non-ITP hospitalizations (Danese et al., 2009). This increased mortality also exists in ITP patients compared with the general population along with higher rates of cardiovascular disease, thromboembolic events, bleeding, and infection (Norgaard et al., 2011; Frederiksen et al., 2014).
DIAGNOSIS An isolated platelet count ,100 3 109 L21 in the absence of other underlying disorders characterizes ITP. Current guidelines recommend a thorough evaluation of a patient’s history, physical examination, complete blood count (CBC), and peripheral blood smear (Neunert et al., 2011; Provan et al., 2010). In taking the history, particular attention should be given to the presence of systemic diseases, infections, chronicity, and severity of bleeding/bruising events, medications, vaccinations, and personal or family history of thrombocytopenia or easy bleeding/bruising. The physical exam should be unremarkable save for manifestations of bleeding or bruising. Careful examination of the liver, the spleen, the lymph nodes, and the radial ray is particularly warranted. Detection of a significantly enlarged spleen should prompt evaluation for disorders other than ITP. The CBC should show intact hemoglobin and white blood cell count. Abundant platelet clumping and signs of hemolysis (schistocytes) should be absent on the peripheral blood smear. The IWG consensus report from 2010 recommends checking for human immunodeficiency virus (HIV), hepatitis C virus, Helicobacter pylori, quantitative immunoglobulin levels, and a direct antiglobulin test (DAT) (Provan et al., 2010). The evaluation of antiphospholipid antibodies, antinuclear antibodies, antiplatelet antibodies, thyroid function testing, and cytomegalovirus could be helpful but are not routinely recommended, unless guided by symptoms or history (Neunert et al., 2011; Provan et al., 2010). Both the IWG consensus report (2010) and the American Society of Hematology (ASH) 2011 practice guidelines advise against routine bone marrow biopsy in the evaluation of children and younger adults (Neunert et al., 2011; Provan et al., 2010; Jubelirer and Harpold, 2002; Mak et al., 2000). The IWG suggests consideration of bone marrow biopsy in certain situations such as patients older than 60 years of age, presence of systemic symptoms, or prior to splenectomy (Provan et al., 2010). Bone marrow aspirate and biopsy are important tools in patients with refractory disease to rule out other causes of thrombocytopenia. Note that both documents may be revised in the near future with the next rendition of the ASH guidelines expected by early 2018. ITP remains a diagnosis of exclusion. The majority of ITP cases are primary and around 20% are secondary (Table 48.1), the most common causes varying by location. In the United States, the most common causes of secondary ITP are common variable immune deficiency (CVID), systemic lupus erythematosus, hepatitis C infection, and chronic lymphocytic leukemia (Moulis et al., 2014; Cines et al., 2009). Whether ITP is primary or secondary, transient substantial response to intravenous immunoglobulin (IVIG) is supportive of the diagnosis. The phases of ITP are defined as acute, persistent, and chronic (Table 48.2). Once diagnosed, most adults will go on to have chronic ITP (Cuker et al., 2015). Those with clinically significant bleeding and very low platelet counts requiring initiation of treatment, additional therapies, or increased doses of medications are described as having “severe” ITP (Rodeghiero et al., 2009). Severe ITP can occur during any phase of ITP. “Refractory” ITP describes disease not responsive to splenectomy with severe ITP or significant risk of bleeding to warrant treatment (Rodeghiero et al., 2009).
TABLE 48.2 Phases of Immune Thrombocytopenia Acute
Diagnosis to 3 months
Persistent
3 12 months from diagnosis
Chronic
More than 12 months from diagnosis
Adapted from Rodeghiero, F., Stasi, R., Gernsheimer, T., et al., 2009. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood 113 (11), 2386 2393.
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PATHOGENESIS Primary ITP is a complicated acquired autoimmune condition with thrombocytopenia broadly resulting from pathologic antiplatelet autoantibodies (Shulman et al., 1965), T cell mediated platelet destruction (Olsson et al., 2003), and impaired MK production (Khodadi et al., 2016). It is a very heterogeneous disease whereby immune dysregulation of many causes results in the antiplatelet response described above. It is worth noting that initially in the first stage of B-cell development, 50% or so are autoantibodies which, given the marrow milieu, are directed against blood cells especially platelets. Therefore with preformed antibodies that can be stimulated, ITP can develop as a loss of control (Nemazee et al., 1991).
PLATELET AUTOANTIBODIES Autoantibodies, typically IgG, are produced against single or multiple platelet surface antigens particularly components of the glycoprotein (GP) IIb/IIIa and GPIb/IX complexes but also others that may have been underestimated in the past such as anti-GPVI (He et al., 1995; Woods et al., 1984; Audia et al., 2017). IgA and IgM antiplatelet antibodies are seen less often and typically in conjunction with IgG autoantibodies (He et al., 1994); their role is largely unclear. B lymphocytes may secrete autoreactive antibodies and are present in increased frequency in patients with ITP (Kuwana et al., 2014; Chen et al., 2012). The spleen is the main site of antiplatelet antibody production with the peripheral blood, bone marrow, and probably lymph nodes serving as secondary sources of antibody-producing B and plasma cells (McMillan et al., 1974). Phagocytes with Fcγ-receptors recognize antiplatelet antibody bound to platelets, facilitating their phagocytosis and destruction. Given the local production of antibodies and the constant presence of about one-third of the intravascular platelet mass, the spleen is the primary site of platelet destruction with usually a smaller contribution via the reticuloendothelial system of the liver (Ballem et al., 1987; Zufferey et al., 2017; McMillan, 2007). In addition to antibody-mediated destruction via phagocytosis, antibody binding can activate complement-mediated platelet lysis (Tsubakio et al., 1986), though this has been poorly studied and the significance of complement components is not completely clear. Currently, neither the IWG nor the ASH practice guidelines recommend routine testing for platelet autoantibodies (Neunert et al., 2011; Provan et al., 2010). No detectable antibodies are found in up to 30% 40% of the patients (Zufferey et al., 2017), and this is reflected in the low sensitivity (i.e., percent of patients with ITP with positive antibodies) of 49% 66% of platelet antibody testing in ITP. In addition, a specificity of only 78% 93% leads to a significant number of false-positive tests (Warner et al., 1999; Brighton et al., 1996; McMillan et al., 2003). Possible reasons behind the absence of detectable antibodies in a substantial percent of ITP patients include suppression of antibody levels due to preceding treatment, the presence of antibodies to other platelet antigens that are not being assayed, and a significant contribution of antibody-independent mechanisms of disease such as T cell mediated platelet destruction and/or suppression of platelet production (Zufferey et al., 2017; McMillan, 2007). In addition to the production of autoreactive antibodies, other mechanisms of immune dysregulation involving B cells may also participate in the pathogenesis ITP. B cell activating factor (BAFF or B lymphocyte stimulator) is a cytokine that plays a critical role in regulating B-cell survival, maturation, and stimulation (Schneider et al., 1999). Elevated levels of BAFF in ITP may contribute to disease activity by rescuing autoreactive B and T cells from apoptosis and by promoting survival of long-lived splenic plasma cells (Audia et al., 2017; Zhu et al., 2009; Mahevas et al., 2013). A subset of IL-10 producing B-regulatory cells (Bregs) helps to maintain intact immune tolerance by promoting the differentiation of T-regulatory cells (Tregs), regulating T helper 1 (Th1)/T helper 2 (Th2) balance, and suppressing activation of monocytes, thus playing a vital role in immune suppression (Li et al., 2012; Semple, 2012; Lemoine et al., 2011). Not only are Bregs decreased in patients with ITP but they are also functionally impaired (Li et al., 2012).
T-CELL INVOLVEMENT T cells and dysregulation of T-cell populations are involved in the pathogenesis of ITP through a variety of mechanisms. A change in T-helper cell balance occurs with decreased Th2 polarization resulting in an increased Th1/Th2 ratio (Ogawara et al., 2003; Wang et al., 2005) and with an inverse correlation of the Th1/Th2 ratio with
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platelet count in ITP (Takahashi et al., 2017; Panitsas et al., 2004). The significance of this altered T-cell balance is not yet known but as Th1 polarization is required for macrophage stimulation, this may result in increased platelet phagocytosis (Audia et al., 2017). The most discussed mechanism, possibly due to the current lack of clarity, involves the role of cytotoxic T cells. CD81 cytotoxic T cells can directly lyse platelets (Zhao et al., 2008) and accumulate in the bone marrow inhibiting platelet production (Olsson et al., 2008). T cells can also enhance antibody formation as demonstrated by a population of autoreactive GPIIb/IIIa CD41 T cells that promote the production of antiplatelet antibodies (Kuwana et al., 1998). The latter may involve the CD40 CD40 ligand (CD154) interaction (Audia et al., 2014). Tregs suppress self-reactive lymphocytes and preserve immunological self-tolerance (Hori et al., 2003; Sakaguchi et al., 2009). The spontaneous development of severe autoimmune disease in animal models with depleted Treg populations, and in humans with specific deficiency of Tregs, highlights the importance of Tregs in maintaining immune homeostasis (Kim et al., 2007; Yu et al., 2017). As shown in multiple studies, both decreased number and impaired function of Tregs characterize the abnormal immune environment of ITP (Sakakura et al., 2007; Liu et al., 2007). Why all of these mechanisms result in ITP, rather than perhaps other autoimmune diseases, remains to be clarified. Possibilities include the preexistence of autoantiplatelet antibodies or the resemblance of platelets to lymphocytes with multiple immunologically active molecules. The latter may lead to platelet participation in the immune response resulting in the presentation of platelet GPs to antigen-presenting cells. Another largely unresolved issue is why ITP resolves in certain cases and not in others. Several approaches have been explored. In children, if the initial inciting infection results in oxidative damage to the platelet membrane, then this increases the chance of developing chronic ITP (Zhang and Zehnder, 2013). In support of this hypothesis is an Egyptian study randomizing addition of antioxidative therapy showing a benefit to this form of treatment (Elalfy et al., 2015). Another study of children with chronic ITP suggested a number of polymorphisms in T-cell pathways contributed to chronic ITP (Zhang et al., 2014). One appeal of these findings is that they strongly support a polygenic instead of monogenic etiology of chronic disease. A corroborative set of findings comes from the study of a B cell directed treatment (rituximab plus dexamethasone). Nonresponders had a significantly increased frequency of monoclonal and oligoclonal T-cell repertoires compared to responders (Chapin et al., 2016). This suggests that the persistence of abnormal T cells relates to the persistence of ITP. The majority of patients with ITP gradually improve but certain patients worsen over time. One of the reasons behind this appears to include processes such as epitope spreading whereby epitopes distinct from the initial inciting epitope become major targets of the ongoing immune response (Cornaby et al., 2015). But, as with many of the discussed immunologic phenomena, this has been shown to occur but to be of unclear clinical significance.
MEGAKARYOPOIESIS Despite the normal or increased number of MKs seen in bone marrow biopsies of ITP patients, the platelet production is actually impaired (Louwes et al., 1999; Dameshek and Miller, 1946). Abnormalities in MK development contribute to insufficient platelet production. Early microscopy studies demonstrated extensive damage to 50% 75% of MKs (Stahl et al., 1986). More recent studies confirm these findings showing features of apoptosis and para-apoptosis in the majority of mature MKs with surrounding neutrophils and macrophages (Houwerzijl et al., 2004). Since MKs express platelet surface antigens (i.e., GPIIb/IIIa, GPIb/IX), these antiplatelet antibodies, and potentially autoreactive T cells, can affect MK maturation/platelet production in the bone marrow (Houwerzijl et al., 2004; McMillan et al., 2004; Chang et al., 2003). Another reason for the suboptimal platelet production involves TPO, produced by the liver and the main growth factor for MKs (de Sauvage et al., 1996). After TPO binds to its receptor, c-Mpl, on platelets and MKs, it is internalized and eventually destroyed along with the platelet (Kuter and Rosenberg, 1995; Debili et al., 1995). Thus the total cell mass of c-Mpl expressing cells regulates circulating TPO levels; the same is true of granulocyte colony-stimulating factor although not erythropoietin (Corbacioglu et al., 2000). While patients with ITP have low absolute platelet number, TPO levels remain low due to uptake by the increased population of MKs and platelets with a short lifespan (Chang et al., 1999). An additional pathway leading to TPO production has recently been discovered. Desialylation of membrane proteins occurs as platelets age, leading to their binding by the hepatic Ashwell Morell receptor which induces platelet phagocytosis and TPO production (Audia et al., 2017; Grozovsky et al., 2015). However, in ITP, the majority of antibody-coated platelets are believed to be destroyed via FcR-mediated phagocytosis and not in this
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fashion. These findings of low circulating TPO levels in ITP may partly explain why TPO-RA is an often effective treatment. Reduced proplatelet formation in patients with undetectable antiplatelet antibodies suggests a nonimmune, inherent defect in late megakaryopoiesis (Riviere et al., 2015). As mentioned briefly above, CD81 cytotoxic T cells accumulate in the bone marrow (Olsson et al., 2008) where they suppress proper MK apoptosis, a step required for platelet production (Li et al., 2007). In one study, nonresponders to TPO-RAs had increased MKs in the marrow but reduced platelet reticulocytes suggesting that their lack of response was due to impaired ability of proplatelets to release platelets (Barsam et al., 2011). Responders to TPO-RAs had clearly increased platelet reticulocytes compared to those patients who responded to treatments such as IVIG, IV anti-D, and even an antiFcR III antibody, demonstrating their unique mechanism of effect, that is, stimulation of platelet production (Barsam et al., 2011).
TREATMENT Generally, patients with platelets above 30 3 109 L21 are not at risk for serious bleeding and may be followed by observation alone. Patients with platelets ,10 3 109 L21 are treated, and the decision to treat those with platelets between 10 3 109 and 30 3 109 L21 depends on factors such as bleeding/bruising symptoms, medical comorbidities, and fatigue (Cooper, 2017); most adults with platelet counts in this range are likely to be treated. The goal of treatment is to achieve a durably improved platelet count without the need for ongoing therapy.
FIRST-LINE THERAPIES Historically, first-line treatments include steroids, IVIG, and IV anti-D. The overall aim of these therapies is to decrease autoantibody-mediated platelet destruction, although which of their multiple potential mechanisms of action are most significant is not completely understood (Zufferey et al., 2017). IVIG slows platelet destruction and increases platelet half-life but exactly how this occurs remains controversial. There are various types and doses of steroids used in ITP but no consensus regarding the optimal regimen. Some studies suggest improved response rates using one or multiple rounds of high-dose dexamethasone (40 mg/day 3 4 days) compared to a prolonged prednisone taper (Wei et al., 2016; Mazzucconi et al., 2007). In patients with contraindications to high doses of steroids, IVIG 1 g/kg may be used for 1 or 2 days depending on platelet response (Cooper, 2017). The primary common toxicity is headache, which can be severe. Patients who are RhD antigen positive, are DAT negative, and have intact spleens are candidates for treatment with IV anti-D (Scaradavou et al., 1997; Cooper et al., 2002). IV anti-D has been shown to be particularly efficacious in children and in HIV-related ITP (Scaradavou et al., 1997), though all treated patients must be monitored for intravascular hemolysis. Intravascular hemolysis and fever chill nausea vomiting cytokine-driven reactions to IV anti-D can both be ameliorated substantially by premedication with high dose IV steroids, for example, methylprednisolone 30 mg/kg up to 1 g.
SECOND-LINE THERAPIES If the initial attempt at therapy does not result in lasting improvement and/or clinical remission, multiple agents are available as second-line treatments. The selection among these agents is very difficult and the only clear, unequivocal tenet is not to continue steroids.
SPLENECTOMY Splenectomy remains a reasonable option with around 60% of the patients achieving a normal platelet count postsurgery and maintaining a sustained response at 5 years (Kojouri et al., 2004; Kumar et al., 2002; Ahmed et al., 2016). However, this potential benefit should be balanced with the surgical risk and long-term increased risk of infection/sepsis and thrombosis especially stroke (Ahmed et al., 2016). The decreased usage of splenectomy (Boyle et al., 2013) reflects the possibility of other treatment options, the long-term response in only 60%,
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the inability to predict the response except in very few centers, and the hope that the ITP will improve over 1 3 years such that no ongoing treatment will be necessary. If very good prediction of response were widely available, it would probably be selected more frequently.
RITUXIMAB Rituximab is an anti-CD-20 monoclonal antibody that depletes circulating CD-20-positive antibody-producing B cells. The overall response rate is around 50% 60% and about 20% 30% of the patients have a long-term (. 5 years) response (Patel et al., 2012; Arnold et al., 2007). Apparently, the population with the best response to the combination of rituximab and three cycles of dexamethasone is women with ITP of ,1 year’s duration (Chapin et al., 2016). Caution should be taken as B-cell depletion can lead to decreased vaccine response for up to 6 months (Nazi et al., 2013) and repeated courses of rituximab, especially in combination with dexamethasone, can lead to severe hypogammaglobulinemia (Cooper et al., 2009). Those with existing CVID, and patients who are on immunosuppressive medications, may be at greater risk for hypogammaglobulinemia and infection but those with CVID should already be on IVIG and they respond to rituximab particularly well (Gobert et al., 2011). Obtaining baseline immunoglobulin levels is recommended prior to treatment with rituximab (Cooper, 2017; Kado et al., 2016). In addition, patients should be tested for hepatitis B due to the risk of viral reactivation with rituximab. Overall, rituximab is generally well tolerated with toxicities including very occasional severe infusion reaction, serum sickness, prolonged immunosuppression, and rare reports of progressive multifocal leukoencephalopathy, only one or two of which occurred in patients with ITP (Carson et al., 2009; Cuker and Neunert, 2016).
THROMBOPOIETIN RECEPTOR AGONISTS TPO-RAs bind to the TPO receptor stimulating megakaryopoiesis and hence platelet production. Currently, there are two TPO-RAs, eltrombopag and romiplostim, approved by the US Food and Drug Administration (FDA) and European Medicines Agency. Both agents lack sequence or structural homology with endogenous TPO avoiding the risk of developing cross-reactive antibodies (Kuter, 2007). Eltrombopag is an orally available, small molecule, nonpeptide TPO-RA that binds the transmembrane domain of the TPO receptor (Kuter, 2007; Rodeghiero and Carli, 2017). It is FDA approved for the treatment of ITP in adults and children $ 1 year-old refractory to corticosteroids, IVIg, or splenectomy; adults with severe aplastic anemia; and thrombocytopenia due to chronic hepatitis C infection. Romiplostim is a recombinant fusion protein, a so-called peptibody, given weekly via subcutaneous injection that shares the same TPO receptor binding site as endogenous TPO (Rodeghiero and Carli, 2017). Romiplostim is FDA approved for the treatment of chronic ITP in adults refractory corticosteroids, IVIg, or splenectomy. In a double-blind randomized controlled trial of 63 splenectomized and 62 nonsplenectomized patients with ITP, Romiplostim had an overall response rate (4 of 24 weeks) of 80% 90% with durable platelet response rates (platelet count $ 50 3 109/L for at least 6 of the final 8 weeks of the study) of 38% in splenectomized and 61% in nonsplenectomized patients. The majority of patients who had been on concomitant treatment were able to reduce the dosage of or discontinue other ITP medications, and rescue treatments for low counts were reduced as was bleeding (Kuter et al., 2008). Longer term studies of up to 5 years demonstrated ongoing efficacy and safety of Romiplostim (Bussel et al., 2009a; Kuter et al., 2013). Randomized controlled trials of eltrombopag in adults and children show initial platelet response rates of 59% 79%, with a significant proportion of patients able to decrease or discontinue concomitant ITP therapies (Bussel et al., 2009b; Grainger et al., 2015; Cheng et al., 2011). Potential risks of both TPO-RAs include thrombosis, headaches, and myalgia and bone marrow fibrosis. Eltrombopag may result in cataracts and transaminitis or hyperbilirubinemia (Bussel et al., 2009a; Kuter et al., 2013). Romiplostim has a higher rate of cycling counts in some responders, and there appears to be a 1% incidence of neutralizing antibodies (which do not cross-react with native TPO) (Carpenedo et al., 2016). Should a patient not respond to or not tolerate one of the TPO-RAs switching to the other is a reasonable option (Khellaf et al., 2013). Although not meant as curative therapy, there are reports of patients sustaining adequate platelet counts after TPO-RA discontinuation (Cuker et al., 2015) but how to decide when to taper or stop a TPO-RA remains uncertain. The Sunshine Pharmaceutical Co., Ltd. has a TPO-RA that resembles native TPO which is licensed in China and several Asian countries (Zhao et al., 2004). Two additional TPO-RAs are in clinical trial at present.
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Multiple other agents are used as second-line treatments in ITP including mycophenolate mofetil, danazol, azathioprine, dapsone, vincristine, and cyclophosphamide. There are a number of single arm studies with each of these agents albeit with response rates mostly ,50% in difficult patients (Taylor et al., 2015; Hou et al., 2003; Maloisel et al., 2004; Provan et al., 2006; Quiquandon et al., 1990; Stirnemann et al., 2016). The latter two agents (vincristine and cyclophosphamide) have been used much less frequently in recent years because of their toxicities.
CONCLUSION ITP is a prototypic organ-specific autoimmune disease. Its relative frequency is attributed to the development of immature pre-B and B cells in the marrow where they are exposed to platelets. Studies of tolerance have shown that the most immature B cells have an autospecificity in approximately 50% of cells that steadily falls to ,1%. Rupture of tolerance in one of many areas can thus readily result in ITP. ITP is a final common pathway disease that can result from many different etiologies. The current inability to dissect out which one is occurring in a given patient has been one of the primary limitations in improving the management of ITP. With the increasing number of acceptable treatment options, it can be very difficult to decide which one to select in a given patient. Studies not only of various polymorphisms or mutations in patients linked to their outcomes of their ITP, for example, not only bleeding and fatigue but also response to different therapies and whether spontaneous improvement will occur are badly needed. If and when this happens, the information should allow a more rational approach to the management of ITP in the future. There is general agreement that curative therapies are more effective in patients very close to diagnosis so that prediction of outcome, for example, chronicity, would be very useful in the decision of minimal treatment, just enough to avoid bleeding, as compared to a rituximab and dexamethasone-based regimen intended to be curative.
References Ahmed, R., Devasia, A.J., Viswabandya, A., et al., 2016. Long-term outcome following splenectomy for chronic and persistent immune thrombocytopenia (ITP) in adults and children: Splenectomy in ITP. Ann. Hematol. 95 (9), 1429 1434. Arnold, D.M., Dentali, F., Crowther, M.A., et al., 2007. Systematic review: efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura. Ann. Intern. Med. 146 (1), 25 33. Audia, S., Rossato, M., Santegoets, K., et al., 2014. Splenic TFH expansion participates in B-cell differentiation and antiplatelet-antibody production during immune thrombocytopenia. Blood 124 (18), 2858 2866. Audia, S., Mahevas, M., Samson, M., et al., 2017. Pathogenesis of immune thrombocytopenia. Autoimmun. Rev. 16 (6), 620 632. Ballem, P.J., Segal, G.M., Stratton, J.R., et al., 1987. Mechanisms of thrombocytopenia in chronic autoimmune thrombocytopenic purpura. Evidence of both impaired platelet production and increased platelet clearance. J. Clin. Invest. 80 (1), 33 40. Barsam, S.J., Psaila, B., Forestier, M., et al., 2011. Platelet production and platelet destruction: assessing mechanisms of treatment effect in immune thrombocytopenia. Blood 117 (21), 5723 5732. Bidot, L., Jy, W., Bidot Jr, C., et al., 2008. Microparticle-mediated thrombin generation assay: increased activity in patients with recurrent thrombosis. J. Thromb. Haemost. 6 (6), 913 919. Boyle, S., White, R.H., Brunson, A., et al., 2013. Splenectomy and the incidence of venous thromboembolism and sepsis in patients with immune thrombocytopenia. Blood 121 (23), 4782 4790. Brighton, T.A., Evans, S., Castaldi, P.A., et al., 1996. Prospective evaluation of the clinical usefulness of an antigen-specific assay (MAIPA) in idiopathic thrombocytopenic purpura and other immune thrombocytopenias. Blood 88 (1), 194 201. Bussel, J.B., Kuter, D.J., Pullarkat, V., et al., 2009a. Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood 113 (10), 2161 2171. Bussel, J.B., Provan, D., Shamsi, T., et al., 2009b. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet 373 (9664), 641 648. Carpenedo, M., Cantoni, S., Coccini, V., et al., 2016. Response loss and development of neutralizing antibodies during long-term treatment with romiplostim in patients with immune thrombocytopenia: a case series. Eur. J. Haematol. 97 (1), 101 103. Carson, K.R., Evens, A.M., Richey, E.A., et al., 2009. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood 113 (20), 4834 4840. Chang, M., Qian, J.X., Lee, S.M., et al., 1999. Tissue uptake of circulating thrombopoietin is increased in immune-mediated compared with irradiated thrombocytopenic mice. Blood 93 (8), 2515 2524. Chang, M., Nakagawa, P.A., Williams, S.A., et al., 2003. Immune thrombocytopenic purpura (ITP) plasma and purified ITP monoclonal autoantibodies inhibit megakaryocytopoiesis in vitro. Blood 102 (3), 887 895. Chapin, J., Lee, C.S., Zhang, H., et al., 2016. Gender and duration of disease differentiate responses to rituximab-dexamethasone therapy in adults with immune thrombocytopenia. Am. J. Hematol. 91 (9), 907 911. Chen, J.F., Yang, L.H., Chang, L.X., et al., 2012. The clinical significance of circulating B cells secreting anti-glycoprotein IIb/IIIa antibody and platelet glycoprotein IIb/IIIa in patients with primary immune thrombocytopenia. Hematology 17 (5), 283 290.
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REFERENCES
919
Cheng, G., Saleh, M.N., Marcher, C., et al., 2011. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet 377 (9763), 393 402. Cines, D.B., Bussel, J.B., 2005. How I treat idiopathic thrombocytopenic purpura (ITP). Blood 106 (7), 2244 2251. Cines, D.B., Bussel, J.B., Liebman, H.A., et al., 2009. The ITP syndrome: pathogenic and clinical diversity. Blood 113 (26), 6511 6521. Cooper, N., 2017. State of the art - how I manage immune thrombocytopenia. Br. J. Haematol. 177 (1), 39 54. Cooper, N., Woloski, B.M., Fodero, E.M., et al., 2002. Does treatment with intermittent infusions of intravenous anti-D allow a proportion of adults with recently diagnosed immune thrombocytopenic purpura to avoid splenectomy? Blood 99 (6), 1922 1927. Cooper, N., Davies, E.G., Thrasher, A.J., 2009. Repeated courses of rituximab for autoimmune cytopenias may precipitate profound hypogammaglobulinaemia requiring replacement intravenous immunoglobulin. Br. J. Haematol. 146 (1), 120 122. Corbacioglu, S., Bux, J., Konig, A., et al., 2000. Serum granulocyte colony-stimulating factor levels are not increased in patients with autoimmune neutropenia of infancy. J. Pediatr. 137 (1), 96 99. Cornaby, C., Gibbons, L., Mayhew, V., et al., 2015. B cell epitope spreading: mechanisms and contribution to autoimmune diseases. Immunol. Lett. 163 (1), 56 68. Cortelazzo, S., Finazzi, G., Buelli, M., et al., 1991. High risk of severe bleeding in aged patients with chronic idiopathic thrombocytopenic purpura. Blood 77 (1), 31 33. Cuker, A., Neunert, C.E., 2016. How I treat refractory immune thrombocytopenia. Blood 128 (12), 1547 1554. Cuker, A., Prak, E.T., Cines, D.B., 2015. Can immune thrombocytopenia be cured with medical therapy? Semin. Thromb. Hemost. 41 (4), 395 404. Dameshek, W., Miller, E.B., 1946. The megakaryocytes in idiopathic thrombocytopenic purpura, a form of hypersplenism. Blood 1, 27 50. Danese, M.D., Lindquist, K., Gleeson, M., et al., 2009. Cost and mortality associated with hospitalizations in patients with immune thrombocytopenic purpura. Am. J. Hematol. 84 (10), 631 635. Debili, N., Wendling, F., Cosman, D., et al., 1995. The Mpl receptor is expressed in the megakaryocytic lineage from late progenitors to platelets. Blood 85 (2), 391 401. Doobaree, I.U., Nandigam, R., Bennett, D., et al., 2016. Thromboembolism in adults with primary immune thrombocytopenia: a systematic literature review and meta-analysis. Eur. J. Haematol. 97 (4), 321 330. Elalfy, M.S., Elhenawy, Y.I., Deifalla, S., et al., 2015. Oxidant/antioxidant status in children and adolescents with immune thrombocytopenia (ITP) and the role of an adjuvant antioxidant therapy. Pediatr. Blood Cancer 62 (5), 830 837. Frederiksen, H., Maegbaek, M.L., Norgaard, M., 2014. Twenty-year mortality of adult patients with primary immune thrombocytopenia: a Danish population-based cohort study. Br. J. Haematol. 166 (2), 260 267. Gobert, D., Bussel, J.B., Cunningham-Rundles, C., et al., 2011. Efficacy and safety of rituximab in common variable immunodeficiencyassociated immune cytopenias: a retrospective multicentre study on 33 patients. Br. J. Haematol. 155 (4), 498 508. Grainger, J.D., Locatelli, F., Chotsampancharoen, T., et al., 2015. Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial. Lancet 386 (10004), 1649 1658. Grozovsky, R., Begonja, A.J., Liu, K., et al., 2015. The Ashwell-Morell receptor regulates hepatic thrombopoietin production via JAK2-STAT3 signaling. Nat. Med. 21 (1), 47 54. He, R., Reid, D.M., Jones, C.E., et al., 1994. Spectrum of Ig classes, specificities, and titers of serum antiglycoproteins in chronic idiopathic thrombocytopenic purpura. Blood 83 (4), 1024 1032. He, R., Reid, D.M., Jones, C.E., et al., 1995. Extracellular epitopes of platelet glycoprotein Ib alpha reactive with serum antibodies from patients with chronic idiopathic thrombocytopenic purpura. Blood 86 (10), 3789 3796. Heyns Adu, P., Badenhorst, P.N., Lotter, M.G., et al., 1986. Platelet turnover and kinetics in immune thrombocytopenic purpura: results with autologous 111In-labeled platelets and homologous 51Cr-labeled platelets differ. Blood 67 (1), 86 92. Hori, S., Nomura, T., Sakaguchi, S., 2003. Control of regulatory T cell development by the transcription factor Foxp3. Science 299 (5609), 1057 1061. Hou, M., Peng, J., Shi, Y., et al., 2003. Mycophenolate mofetil (MMF) for the treatment of steroid-resistant idiopathic thrombocytopenic purpura. Eur. J. Haematol. 70 (6), 353 357. Houwerzijl, E.J., Blom, N.R., van der Want, J.J., et al., 2004. Ultrastructural study shows morphologic features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura. Blood 103 (2), 500 506. Jubelirer, S.J., Harpold, R., 2002. The role of the bone marrow examination in the diagnosis of immune thrombocytopenic purpura: case series and literature review. Clin. Appl. Thromb. Hemost. 8 (1), 73 76. Kado, R., Sanders, G., McCune, W.J., 2016. Suppression of normal immune responses after treatment with rituximab. Curr. Opin. Rheumatol. 28 (3), 251 258. Kaushansky, K., 1995. Thrombopoietin: the primary regulator of platelet production. Blood 86 (2), 419 431. Khellaf, M., Viallard, J.F., Hamidou, M., et al., 2013. A retrospective pilot evaluation of switching thrombopoietic receptor-agonists in immune thrombocytopenia. Haematologica 98 (6), 881 887. Khodadi, E., Asnafi, A.A., Shahrabi, S., et al., 2016. Bone marrow niche in immune thrombocytopenia: a focus on megakaryopoiesis. Ann. Hematol. 95 (11), 1765 1776. Kim, J.M., Rasmussen, J.P., Rudensky, A.Y., 2007. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 8 (2), 191 197. Kojouri, K., Vesely, S.K., Terrell, D.R., et al., 2004. Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet count responses, prediction of response, and surgical complications. Blood 104 (9), 2623 2634. Kumar, S., Diehn, F.E., Gertz, M.A., et al., 2002. Splenectomy for immune thrombocytopenic purpura: long-term results and treatment of postsplenectomy relapses. Ann. Hematol. 81 (6), 312 319. Kuter, D.J., 2007. New thrombopoietic growth factors. Blood 109 (11), 4607 4616. Kuter, D.J., Rosenberg, R.D., 1995. The reciprocal relationship of thrombopoietin (c-Mpl ligand) to changes in the platelet mass during busulfan-induced thrombocytopenia in the rabbit. Blood 85 (10), 2720 2730.
VII. ORGAN SPECIFIC AUTOIMMUNE DISEASES
920
48. IMMUNE THROMBOCYTOPENIA: A COMPLEX AUTOIMMUNE DISEASE
Kuter, D.J., Bussel, J.B., Lyons, R.M., et al., 2008. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet 371 (9610), 395 403. Kuter, D.J., Bussel, J.B., Newland, A., et al., 2013. Long-term treatment with romiplostim in patients with chronic immune thrombocytopenia: safety and efficacy. Br. J. Haematol. 161 (3), 411 423. Kuwana, M., Kaburaki, J., Ikeda, Y., 1998. Autoreactive T cells to platelet GPIIb-IIIa in immune thrombocytopenic purpura. Role in production of anti-platelet autoantibody. J. Clin. Invest. 102 (7), 1393 1402. Kuwana, M., Okazaki, Y., Ikeda, Y., 2014. Detection of circulating B cells producing anti-GPIb autoantibodies in patients with immune thrombocytopenia. PLoS One 9 (1), e86943. Lambert, M.P., Gernsheimer, T.B., 2017. Clinical updates in adult immune thrombocytopenia. Blood 129 (21), 2829 2835. Lemoine, S., Morva, A., Youinou, P., et al., 2011. Human T cells induce their own regulation through activation of B cells. J. Autoimmun. 36 (3-4), 228 238. Li, S., Wang, L., Zhao, C., et al., 2007. CD81 T cells suppress autologous megakaryocyte apoptosis in idiopathic thrombocytopenic purpura. Br. J. Haematol. 139 (4), 605 611. Li, X., Zhong, H., Bao, W., et al., 2012. Defective regulatory B-cell compartment in patients with immune thrombocytopenia. Blood 120 (16), 3318 3325. Liu, B., Zhao, H., Poon, M.C., et al., 2007. Abnormality of CD4(1)CD25(1) regulatory T cells in idiopathic thrombocytopenic purpura. Eur. J. Haematol. 78 (2), 139 143. Louwes, H., Zeinali Lathori, O.A., Vellenga, E., et al., 1999. Platelet kinetic studies in patients with idiopathic thrombocytopenic purpura. Am. J. Med. 106 (4), 430 434. Mahevas, M., Patin, P., Huetz, F., et al., 2013. B cell depletion in immune thrombocytopenia reveals splenic long-lived plasma cells. J. Clin. Invest. 123 (1), 432 442. Mak, Y.K., Yu, P.H., Chan, C.H., et al., 2000. The management of isolated thrombocytopenia in Chinese adults: does bone marrow examination have a role at presentation? Clin. Lab. Haematol. 22 (6), 355 358. Maloisel, F., Andres, E., Zimmer, J., et al., 2004. Danazol therapy in patients with chronic idiopathic thrombocytopenic purpura: long-term results. Am. J. Med. 116 (9), 590 594. Mazzucconi, M.G., Fazi, P., Bernasconi, S., et al., 2007. Therapy with high-dose dexamethasone (HD-DXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura: a GIMEMA experience. Blood 109 (4), 1401 1407. McMillan, R., 1981. Chronic idiopathic thrombocytopenic purpura. N. Engl. J. Med. 304 (19), 1135 1147. McMillan, R., 2007. The pathogenesis of chronic immune thrombocytopenic purpura. Semin. Hematol. 44 (4Suppl 5), S3 S11. McMillan, R., Longmire, R.L., Yelenosky, R., et al., 1974. Quantitation of platelet-binding IgG produced in vitro by spleens from patients with idiopathic thrombocytopenic purpura. N. Engl. J. Med. 291 (16), 812 817. McMillan, R., Wang, L., Tani, P., 2003. Prospective evaluation of the immunobead assay for the diagnosis of adult chronic immune thrombocytopenic purpura (ITP). J. Thromb. Haemost. 1 (3), 485 491. McMillan, R., Wang, L., Tomer, A., et al., 2004. Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP. Blood 103 (4), 1364 1369. Moulis, G., Palmaro, A., Montastruc, J.L., et al., 2014. Epidemiology of incident immune thrombocytopenia: a nationwide population-based study in France. Blood 124 (22), 3308 3315. Moulis, G., Guenin, S., Limal, N., et al., 2017. Seasonal variations of incident primary immune thrombocytopenia in adults: an ecological study. Eur. J. Intern. Med. 37, e26 e28. Nazi, I., Kelton, J.G., Larche, M., et al., 2013. The effect of rituximab on vaccine responses in patients with immune thrombocytopenia. Blood 122 (11), 1946 1953. Nemazee, D., Russell, D., Arnold, B., et al., 1991. Clonal deletion of autospecific B lymphocytes. Immunol. Rev. 122, 117 132. Neunert, C., Lim, W., Crowther, M., et al., 2011. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood 117 (16), 4190 4207. Neunert, C., Noroozi, N., Norman, G., et al., 2015. Severe bleeding events in adults and children with primary immune thrombocytopenia: a systematic review. J. Thromb. Haemost. 13 (3), 457 464. Norgaard, M., Jensen, A.O., Engebjerg, M.C., et al., 2011. Long-term clinical outcomes of patients with primary chronic immune thrombocytopenia: a Danish population-based cohort study. Blood 117 (13), 3514 3520. Ogawara, H., Handa, H., Morita, K., et al., 2003. High Th1/Th2 ratio in patients with chronic idiopathic thrombocytopenic purpura. Eur. J. Haematol. 71 (4), 283 288. Olsson, B., Andersson, P.O., Jernas, M., et al., 2003. T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura. Nat. Med. 9 (9), 1123 1124. Olsson, B., Ridell, B., Carlsson, L., et al., 2008. Recruitment of T cells into bone marrow of ITP patients possibly due to elevated expression of VLA-4 and CX3CR1. Blood 112 (4), 1078 1084. Panitsas, F.P., Theodoropoulou, M., Kouraklis, A., et al., 2004. Adult chronic idiopathic thrombocytopenic purpura (ITP) is the manifestation of a type-1 polarized immune response. Blood 103 (7), 2645 2647. Patel, V.L., Mahevas, M., Lee, S.Y., et al., 2012. Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia. Blood 119 (25), 5989 5995. Provan, D., Moss, A.J., Newland, A.C., et al., 2006. Efficacy of mycophenolate mofetil as single-agent therapy for refractory immune thrombocytopenic purpura. Am. J. Hematol. 81 (1), 19 25. Provan, D., Stasi, R., Newland, A.C., et al., 2010. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 115 (2), 168 186. Psaila, B., Bussel, J.B., Frelinger, A.L., et al., 2011. Differences in platelet function in patients with acute myeloid leukemia and myelodysplasia compared to equally thrombocytopenic patients with immune thrombocytopenia. J. Thromb. Haemost. 9 (11), 2302 2310.
VII. ORGAN SPECIFIC AUTOIMMUNE DISEASES
REFERENCES
921
Quiquandon, I., Fenaux, P., Caulier, M.T., et al., 1990. Re-evaluation of the role of azathioprine in the treatment of adult chronic idiopathic thrombocytopenic purpura: a report on 53 cases. Br. J. Haematol. 74 (2), 223 228. Riviere, E., Viallard, J.F., Guy, A., et al., 2015. Intrinsically impaired platelet production in some patients with persistent or chronic immune thrombocytopenia. Br. J. Haematol. 170 (3), 408 415. Rodeghiero, F., Carli, G., 2017. Beyond immune thrombocytopenia: the evolving role of thrombopoietin receptor agonists. Ann. Hematol. 96 (9), 1421 1434. Rodeghiero, F., Stasi, R., Gernsheimer, T., et al., 2009. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood 113 (11), 2386 2393. Sakaguchi, S., Wing, K., Onishi, Y., et al., 2009. Regulatory T cells: how do they suppress immune responses? Int. Immunol. 21 (10), 1105 1111. Sakakura, M., Wada, H., Tawara, I., et al., 2007. Reduced Cd41 Cd251 T cells in patients with idiopathic thrombocytopenic purpura. Thromb. Res. 120 (2), 187 193. de Sauvage, F.J., Carver-Moore, K., Luoh, S.M., et al., 1996. Physiological regulation of early and late stages of megakaryocytopoiesis by thrombopoietin. J. Exp. Med. 183 (2), 651 656. Scaradavou, A., Woo, B., Woloski, B.M., et al., 1997. Intravenous anti-D treatment of immune thrombocytopenic purpura: experience in 272 patients. Blood 89 (8), 2689 2700. Schneider, P., MacKay, F., Steiner, V., et al., 1999. BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J. Exp. Med. 189 (11), 1747 1756. Segal, J.B., Powe, N.R., 2006. Prevalence of immune thrombocytopenia: analyses of administrative data. J. Thromb. Haemost. 4 (11), 2377 2383. Semple, J.W., 2012. Bregging rights in ITP. Blood 120 (16), 3169. Sewify, E.M., Sayed, D., Abdel Aal, R.F., et al., 2013. Increased circulating red cell microparticles (RMP) and platelet microparticles (PMP) in immune thrombocytopenic purpura. Thromb. Res. 131 (2), e59 e63. Shulman, N.R., Marder, V.J., Weinrach, R.S., 1965. Similarities between known antiplatelet antibodies and the factor responsible for thrombocytopenia in idiopathic purpura. Physiologic, serologic and isotopic studies. Ann. N. Y. Acad. Sci. 124 (2), 499 542. Stahl, C.P., Zucker-Franklin, D., McDonald, T.P., 1986. Incomplete antigenic cross-reactivity between platelets and megakaryocytes: relevance to ITP. Blood 67 (2), 421 428. Stasi, R., Stipa, E., Masi, M., et al., 1995. Long-term observation of 208 adults with chronic idiopathic thrombocytopenic purpura. Am. J. Med. 98 (5), 436 442. Stirnemann, J., Kaddouri, N., Khellaf, M., et al., 2016. Vincristine efficacy and safety in treating immune thrombocytopenia: a retrospective study of 35 patients. Eur. J. Haematol. 96 (3), 269 275. Takahashi, N., Saitoh, T., Gotoh, N., et al., 2017. The cytokine polymorphisms affecting Th1/Th2 increase the susceptibility to, and severity of, chronic ITP. BMC Immunol. 18 (1), 26. Taylor, A., Neave, L., Solanki, S., et al., 2015. Mycophenolate mofetil therapy for severe immune thrombocytopenia. Br. J. Haematol. 171 (4), 625 630. Terrell, D.R., Beebe, L.A., Vesely, S.K., et al., 2010. The incidence of immune thrombocytopenic purpura in children and adults: a critical review of published reports. Am. J. Hematol. 85 (3), 174 180. Tsubakio, T., Tani, P., Curd, J.G., et al., 1986. Complement activation in vitro by antiplatelet antibodies in chronic immune thrombocytopenic purpura. Br. J. Haematol. 63 (2), 293 300. Wang, T., Zhao, H., Ren, H., et al., 2005. Type 1 and type 2 T-cell profiles in idiopathic thrombocytopenic purpura. Haematologica 90 (7), 914 923. Warner, M.N., Moore, J.C., Warkentin, T.E., et al., 1999. A prospective study of protein-specific assays used to investigate idiopathic thrombocytopenic purpura. Br. J. Haematol. 104 (3), 442 447. Wei, Y., Ji, X.B., Wang, Y.W., et al., 2016. High-dose dexamethasone vs prednisone for treatment of adult immune thrombocytopenia: a prospective multicenter randomized trial. Blood 127 (3), 296 302. quiz 370. Wong, R.S.M., Saleh, M.N., Khelif, A., et al., 2017. Safety and efficacy of long-term treatment of chronic/persistent ITP with eltrombopag: final results of the EXTEND study. Blood 130, 2527 2536. Woods Jr, V.L., Oh, E.H., Mason, D., et al., 1984. Autoantibodies against the platelet glycoprotein IIb/IIIa complex in patients with chronic ITP. Blood 63 (2), 368 375. Yu, H., Paiva, R., Flavell, R.A., 2017. Harnessing the power of regulatory T cells to control autoimmune diabetes: overview and perspective. Immunology 153 (2), 161 170. Zhang, B., Zehnder, J.L., 2013. Oxidative stress and immune thrombocytopenia. Semin. Hematol. 50 (3), e1 e4. Zhang, D., Zhang, X., Ge, M., et al., 2014. The polymorphisms of T cell-specific TBX21 gene may contribute to the susceptibility of chronic immune thrombocytopenia in Chinese population. Hum. Immunol. 75 (2), 129 133. Zhao, Y.Q., Wang, Q.Y., Zhai, M., et al., 2004. [A multi-center clinical trial of recombinant human thrombopoietin in chronic refractory idiopathic thrombocytopenic purpura]. Zhonghua Nei Ke Za Zhi. 43 (8), 608 610. Zhao, C., Li, X., Zhang, F., et al., 2008. Increased cytotoxic T-lymphocyte-mediated cytotoxicity predominant in patients with idiopathic thrombocytopenic purpura without platelet autoantibodies. Haematologica 93 (9), 1428 1430. Zhu, X.J., Shi, Y., Peng, J., et al., 2009. The effects of BAFF and BAFF-R-Fc fusion protein in immune thrombocytopenia. Blood 114 (26), 5362 5367. Zufferey, A., Kapur, R., Semple, J.W., 2017. Pathogenesis and therapeutic mechanisms in immune thrombocytopenia (ITP). J. Clin. Med. 6 (2), pii: E16.
VII. ORGAN SPECIFIC AUTOIMMUNE DISEASES