New article 3 years 10 months ago #59443
Immune thrombocytopenia (ITP) is a common hematologic disorder characterized by isolated thrombocytopenia. ITP presents as a primary form characterized by isolated thrombocytopenia (platelet count < 100 × 109/L) in the absence of other causes or disorders that may be associated with thrombocytopenia, or a secondary form in which immune thrombocytopenia develops in association with another disorder that is usually immune or infectious. ITP may affect individuals of all ages, with peaks during childhood and in the elderly, in whom the age specific incidence of ITP is greatest. Bleeding is the most common clinical manifestation of ITP, with the risk of bleeding and related morbidity increased in elderly patients. The pathogenesis of ITP is complex, involving alterations in humoral and cellular immunity. Thrombocytopenia is caused by antibodies that react with glycoproteins expressed on platelets and megakaryocytes (glycoprotein IIb/IIIa, Ib/IX and others), causing shortened survival of circulating platelets and impairing platelet production. Diminished numbers and function of regulatory T cells, as well as the effects of cytotoxic T cells also contribute to the pathogenesis of ITP. Corticosteroids remain the most common first line therapy for ITP, occasionally in conjunction with intravenous immunoglobulin (IVIg) and anti-Rh(D). However, these agents do not lead to durable remissions in the majority of adults with ITP, and considerable heterogeneity exists in the use of second line approaches, which may include splenectomy, Rituximab, or thrombopoietin receptor agonists (TRAs). This review summarizes the classification and diagnosis of primary and secondary ITP, as well as the pathogenesis and options for treatment. Remarkable advances in the understanding and management of ITP have been achieved over the last decade, though many questions remain.
New article 3 years 10 months ago #59447
Some interesting highlights:
The term “acute ITP” has been replaced by “newly-diagnosed ITP”, which refers to ITP diagnosed within the preceding 3 months1. Immune thrombocytopenia of 3-12 months duration is designated as “persistent ITP”, while “chronic ITP” is defined as disease of more than 12 months duration. “Severe ITP” refers to the presence of bleeding symptoms at presentation, or the development of new bleeding symptoms while on therapy, requiring additional intervention. “Refractory ITP” designates cases of immune thrombocytopenia that have not responded to splenectomy or have relapsed thereafter, and are severe or pose sufficient risk of bleeding to require ongoing therapy. Definitions to standardize criteria for responses to ITP therapy have also been proposed1.
Intracranial hemorrhage is the most feared complication of ITP. The incidence of intracranial hemorrhage in children has been estimated to be less than 0.2%, almost always occurring at platelet counts < 10 × 109/L 12;58. A recent report from the International Cooperative Study demonstrates that this complication occurs more frequently in adults than children, occurring in 10 of 1784 children and 6 of 340 adults with newly diagnosed ITP59. In a natural history study that enrolled 152 patients, 4 patients died of ITP-related causes in the first two years (1 due to hemorrhage, 3 due to infection), and 2 died of ITP related causes during long-term follow up (1 with post-splenectomy sepsis, 1 with refractory bleeding and a platelet count of 2 × 109/L)60. Patients with ITP may be at increased risk of hematologic malignancy, consistent with the demonstration of an increased frequency of CLL phenotype lymphocytes in patients with ITP.
Several risk factors for bleeding in ITP patients have been identified. Cohen et al identified 49 cases of fatal hemorrhage in 1718 patients from pooled ITP case series. The overall risk of fatal hemorrhage was between 0.0162 and 0.0389 cases per patient-year, with a risk of 0.004 in patients below 40 years increasing to 0.130 for patients above age 60. Cortelazzo et al observed an overall incidence of hemorrhagic events of 3.2% per patient-year in patients with ITP. Hemorrhagic events at similar platelet counts occurred in 10.4% of patients > 60 years, compared to 0.4 percent in patients under age 40. A previous history of hemorrhage also predicted bleeding (relative risk 27.5)64. Michel et al compared the incidence of bleeding and other outcomes in 55 ITP patients older than 70 years (mean age 77.8 ± 6.1 years) with those of a younger cohort (mean age 40.3 ± 14.9 years). The median platelet count at diagnosis did not differ between the two groups, though bleeding symptoms were more frequent in the older (82%) versus the younger (62%).
Recent studies suggest that patients with ITP have an increased risk of thrombosis. Aledort et al initially reported 18 thromboembolic events in 186 adults with chronic ITP70. Sarpatwari et al observed that the adjusted hazard ratio for venous, arterial or combined thromboembolic events in patients with ITP mined from the UK General Practice Research Database were 1.58 (95% CI, 1.01-2.48), 1.37 (95% CI, 0.94-2.00) and 1.41 (95% CI 1.04-1.91), respectively. The severity of thrombocytopenia correlated with the development of thrombosis. A study utilizing a matched ITP cohort from the Danish National Patient Registry observed an incidence rate ratio for venous thromboembolism in patients with ITP of 2.04 (95% CI: 1.45-2.87).
The mechanisms underlying the paradoxical development of thrombosis in patients with ITP are uncertain. The incidence of antiphospholipid antibodies (APLA) is increased in patients with ITP, and ITP patients with APLA may develop thrombosis more frequently. Though current guidelines do not recommend routine screening of ITP patients for APLA, this should be considered in patients who develop thrombosis. Other factors that may contribute to the development of thrombosis include elevated levels of prothrombotic, platelet-derived microparticles and complement activation on antibody-coated platelets.
The management of thrombosis in thrombocytopenic patients with ITP is not addressed by current guidelines. Many experts consider anticoagulation to be justified at platelet counts above approximately 40 × 109L, though this should be individualized depending upon the severity of the thrombotic event and characteristics of the patient. Aggressive treatment of ITP is warranted during anticoagulation therapy.
The diagnosis of primary ITP is one of exclusion. Both non-immune causes of thrombocytopenia and secondary immune thrombocytopenia must be considered (Table 3). Non-immune causes of thrombocytopenia include exposure to drugs or toxins that suppress platelet production (alcohol, chemotherapeutic agents), splenic sequestration of platelets, primary bone marrow disorders, prior radiation exposure (therapeutic or incidental), and inherited thrombocytopenias.
Corticosteroids remain the most commonly used first line therapy for ITP. At least 80% of patients with ITP initially respond to corticosteroids, although most of these individuals relapse when steroids are tapered. Several studies have examined whether more intensive dosing of steroids in newly-diagnosed ITP leads to more durable remissions. Cheng et al reported that treatment with a single course of dexamethasone (40 mg/day for four days) led to sustained responses (platelet count > 50 × 109/L at 6 months) in 50% of responders 88. Mazzucconi et al observed that treatment of newly-diagnosed ITP with 4-6 cycles of dexamethasone given at two week intervals led to relapse-free survival of 80-90% at 15 months. However, in a small, randomized study, a single course of high dose dexamethasone did not induce a greater percentage of sustained responses than standard doses of prednisolone89. Zaja et al compared a combination of dexamethasone and Rituximab with dexamethasone alone in the initial treatment of ITP, demonstrating a higher sustained response rate at 6 months in patients that received the combination (63% vs 36%, n = 52, P <0.004, 95% CI 0.079-0.455); however, these differences were lost on longer follow up.
Intravenous immunoglobulin is often used in conjunction with corticosteroids, particularly when a rapid rise in the platelet count is desired. IVIg is also used to support the platelet count until more definitive therapy can be delivered to patients whose platelets fall upon tapering of corticosteroids. IVIg increases the platelet count in 60-80% of treated patients, often within days, and is effective in both non-splenectomized and splenectomized patients, although responses are usually of short duration (1-3 weeks). Several IVIg regimens are employed, but many clinicians prefer the convenience of a 1 gm/kg/day infusion for 1 or 2 days. The activity of IVIg is mediated through several mechanisms, including modulation of Fcγ receptor expression and activity, inhibition of cytotoxic T cell activation, complement neutralization, cytokine modulation and inhibition of megakaryocyte apoptosis. Toxicities include aseptic meningitis, fluid overload, nephrotoxicity, thrombosis, and rarely, severe hemolytic anemia.
Several second line therapies exist for treatment of ITP resistant to corticosteroids, IVIg or anti-D. The use of older second-line agents has decreased significantly due to the emergence of Rituximab and thrombopoietin receptor agonists (TRAs), which offer greater efficacy with lower toxicity (Table 4). In this section we will focus on the use of newer agents in ITP; excellent reviews on the safety and efficacy of older agents are available.
Rituximab is a chimeric anti-CD20 antibody approved for treatment of lymphoma that is often used for ITP in patients who fail first line therapy. Whether it is best positioned before or after splenectomy or thrombopoietin receptor agonists (TRAs) is not established. In a systematic review of 313 ITP patients, half of whom were not splenectomized, 62.5% (95% CI, 52.6%–72.5%) of patients treated with Rituximab achieved a platelet count response (platelet increment of 50 × 109/L), with a median time to response of 5.5 weeks (range, 2–18 weeks) and a median duration of response of 10.5 months98. In another systematic review that included 364 non-splenectomized patients, the complete response rate was 41.5% with a mean time to response of 6.34 weeks and a median duration of response of 49 weeks99. In a single-arm prospective study of 60 non-splenectomized ITP patients, 40% achieved a platelet count at or above 50 × 109/L with at least a doubling from baseline at 1 year, and 33.3% of these responses were sustained at two years. However, a pilot, randomized, placebo-controlled trial that assessed a composite endpoint demonstrated only a non-significant trend toward superior responses to Rituximab within 6 months of therapy initiation101. An appealing aspect of Rituximab therapy is its ability to induce durable responses in approximately 21% of adults. Rituximab is usually administered at a dose of 375 mg/m2 weekly for four weeks, although a lower dose regimen of 100 mg/m2 may have similar efficacy. Despite targeting CD20 on B cells, the mechanism of Rituximab may involve more complex immunologic modulation. Successful therapy correlated in one report with normalization of T cell subset distribution103, and in another with reappearance of normal numbers and function of regulatory T cells.
Adverse effects of Rituximab include infusion reactions, serum sickness, and cardiac arrhythmias. Fatal reactivation of hepatitis B infection has occurred; thus, Rituximab is contraindicated in hepatitis B infected patients. Reactivation of latent JC virus leading to progressive multifocal leukoencephalopathy occurred in several patients treated with Rituximab, one of whom had ITP, though most were heavily pretreated with other immunosuppressive agents.
Splenectomy was the first successful treatment for ITP, and is still considered by some to be the “gold standard” since it provides the greatest opportunity for a durable remission105. Splenectomy may be offered to patients who fail to achieve sustained responses after steroid therapy, or may be used before or after a trial of Rituximab or TRAs. In a systematic review of 135 case series between 1966 and 2004, complete responses to splenectomy were observed in 66% of patients, with a median duration of follow-up of 28 months (range 1 to 153 months)106. In another systematic review of 1223 patients with ITP undergoing laparoscopic splenectomy, a 5-year success rate of 72% was reported107; most relapses occurred within the first 2 years after splenectomy. The use of splenectomy, especially in the United States and some European countries, has decreased from 50-60% to 20-25% in recent years. Laparoscopic splenectomy carries a mortality risk and complication rate of 0.2 and 9.6%, respectively (compared to 1.0 and 12.9% with open laparotomy)106. Splenectomy has been associated with an increased risk of infection and postsplenectomy sepsis, with an estimated mortality of 0.73 per 1000 patient years determined from a historical cohort undergoing splenectomy for hereditary spherocytosis109. However, whether patients with ITP experience an increased risk of postsplenectomy infection compared to other patients with ITP who have not undergone splenectomy has not been established. In a large Danish study, infection in patients splenectomized for ITP relative that in non-splenectomized individuals with a matched indication (ITP) was observed only within the first 90 days following splenectomy (RR 2.6, 95% CI 1.3-5.1). No significantly increased risk was seen thereafter, with relative risk of 1.0 between 91 and 365 days, and 1.4 (95% CI: 1.0-2.0) beyond the first year. Early infections result primarily from enteric pathogens. Nevertheless, immunization against encapsulated organisms and aggressive treatment of febrile illness may reduce long term infection-related morbidity and mortality post-splenectomy.
Current guidelines differ on the relative place of splenectomy in the management of ITP. While both the International Working Group and revised ASH guidelines consider splenectomy an acceptable second line option, the former group weights splenectomy similarly to several other options, while the ASH guidelines recommend splenectomy (Grade 1B evidence) for patients who fail corticosteroids, while only suggesting Rituximab or thrombopoietic agents (Grade 2C evidence). Given the lack of comparative data between splenectomy, Rituximab or TRA therapy, treatment decisions should be individualized and encompass both physician and patient preferences.
The position of thrombopoietin receptor agonists (TRAs) in ITP therapy continues to evolve. While some clinicians reserve these agents for patients with refractory ITP, others suggest their use in newly-diagnosed ITP with the goal of sustaining the platelet count for the first year after diagnosis in hopes of spontaneous remission. Neither of the two approved TRAs, Romiplostim and Eltrombopag, have direct sequence homology with thrombopoietin (Figure 2). Both enhance platelet production following binding to the thrombopoietin receptor, c-Mpl, on megakaryocytes, stimulating megakaryocyte proliferation and differentiation.