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Management of Immune Thrombocytopenic Purpura in Adults

  • Roberto Stasi
    Correspondence
    Individual reprints of this article are not available. Address correspondence to Roberto Stasi, MD, Department of Medical Sciences, “Regina Apostolorum” Hospital, Via S. Francesco, 50, 00041 Albano Laziale, Italy
    Affiliations
    Department of Medical Sciences, “Regina Apostolorum” Hospital, Albano Laziale, Italy
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  • Drew Provan
    Affiliations
    Department of Haematology, St Bartholomew's and The Royal London Hospital, London, United Kingdom
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      Primary immune thrombocytopenic purpura (ITP), also referred to as idiopathic thrombocytopenic purpura, is an organ-specific autoimmune disorder in which antibodycoated or immune complex-coated platelets are destroyed prematurely by the reticuloendothelial system, resulting in peripheral blood thrombocytopenia. The disease is heterogeneous with regard to its severity and clinical course and is unpredictable in its response to therapy. Although the basic underlying pathophysiology of ITP has been known for more than 50 years, current treatment guidelines are based on expert opinion rather than on evidence because of a lack of high-quality clinical trials and research. The only patients for whom treatment is clearly required are those with severe bleeding and/or extremely low platelet counts (<10 × 109/L). Treatment of patients with ITP refractory to corticosteroids and splenectomy requires careful evaluation of disease severity, patient characteristics related to risk of bleeding, and adverse effects associated with treatment. Clinical trials with numerous new agents are under way, which we hope will add more effective and targeted strategies to our therapeutic armamentarium. We describe a logical and structured approach to the clinical management of ITP in adults, based on a literature review and our personal experience.

      Abbreviations:

      ITP (immune thrombocytopenic purpura), IVIg (intravenous immunoglobulin)
      Primary immune thrombocytopenic purpura (ITP), also known as idiopathic thrombocytopenic purpura, is an immune-mediated disorder in which platelets are opsonized by autoreactive antibodies and prematurely destroyed by the reticuloendothelial system. No consistent epidemiological data exist relating to ITP in adults. George et al
      • George JN
      • El-Harake MA
      • Aster RH
      Thrombocytopenia due to enhanced platelet destruction by immunologic mechanisms.
      reviewed the data of several reports and extrapolated an incidence of 66 cases per million persons per year. A Danish survey
      • Frederiksen H
      • Schmidt K
      The incidence of idiopathic thrombocytopenic purpura in adults increases with age.
      from 1973 to 1995 estimated the annual incidence of ITP among adults to be 32 cases per million per year, using a lower-threshold platelet count of 50 × 109/L. The incidence rate increased during the study period, primarily because of increased recognition of asymptomatic patients. This study confirmed that, in keeping with other autoimmune disorders, adult ITP is more common in women (female-male ratio, 1.7). However, in contrast to the common belief that ITP is a disorder of younger and middle-aged people, the median age in this study was 56.4 years, and the incidence in people older than 60 years was more than twice that of people younger than 60 years (4.62 vs 1.94 cases per 100,000 per year). Also, the sex bias difference was almost completely eliminated in older patients.
      The results of the Danish study have been confirmed recently in another setting. A British group
      • Neylon AJ
      • Saunders PW
      • Howard MR
      • Proctor SJ
      • Taylor PR
      • Northern Region Haematology Group
      Clinically significant newly presenting autoimmune thrombocytopenic purpura in adults: a prospective study of a population-based cohort of 245 patients.
      published the results of a prospective study in a population-based cohort of newly presenting adults (≥16 years of age) with ITP and platelet counts of less than 50 × 109/L. The study took place between January 1, 1993, and December 31, 1999, in the former Northern Health Region in the United Kingdom (population, 3.08 million). The diagnosis of ITP in 245 patients (134 females to 111 males [1.2:1]) was confirmed by bone marrow examination, and the median follow-up was 60 months (range, 6-78 months). The overall incidence was 1.6 cases per 100,000 per year. The absolute incidence was similar for both sexes, with the highest age-specific incidence in those older than 60 years. The median age in this survey was 56 years.
      The clinical features of ITP in adults are different from the clinical features seen in childhood (Table 1
      • George JN
      • Woolf SH
      • Raskob GE
      • et al.
      Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology.
      ). In children, ITP is usually an acute, self-limiting disease, often occurring 2 to 3 weeks after a viral infection (varicella, rubella, mumps, upper respiratory tract infection, gastroenteritis, flulike illnesses, etc) or immunization. In contrast, ITP in adults typically has an insidious onset, with no preceding viral or other illness, and has a chronic course. Many cases of ITP in adults are diagnosed incidentally after a routine complete blood cell count. In adults, the symptoms and signs are highly variable and range from the fairly common asymptomatic patient with mild bruising and mucosal bleeding (eg, oral or gastrointestinal tract) to frank hemorrhage from any site, the most serious of which is intracranial.
      Table 1Immune Thrombocytopenic Purpura in Children and Adults
      ChildrenAdults
      Peak age incidence (y)2-650
      Sex incidence (M:F)1:11:1.7
      OnsetAcuteInsidious
      Preceding infectionCommonUnusual
      Platelet count (× 109/L)Often <20Often >20
      Usual duration2-4 wkYears
      Course
      Data from George et al. 4
      (%)
       Spontaneous remissions>802
       Chronic disease2443
       Response to splenectomy7166
       Complete recovery8964
      * Data from George et al.
      • George JN
      • Woolf SH
      • Raskob GE
      • et al.
      Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology.
      The diagnosis of ITP remains one of exclusion, requiring that all other conditions or factors that can cause thrombocytopenia be ruled out.
      • George JN
      • Woolf SH
      • Raskob GE
      • et al.
      Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology.
      These causes include collagen vascular diseases, lymphoproliferative disorders, agammaglobulinemia, therapy with certain drugs, alloimmune thrombocytopenia, congenital or hereditary thrombocytopenia, myelodysplasia, von Willebrand disease type IIB, human immunodeficiency virus infection, and other infections. The history and physical examination are aimed at detecting these various causes of thrombocytopenia and are supported by ancillary laboratory tests (Table 2).
      Table 2Principal Elements of the Initial Work-up in Adult Patients With Suspected Immune Thrombocytopenic Purpura
      HIV = human immunodeficiency virus.
      Adapted from George et al,
      • George JN
      • Woolf SH
      • Raskob GE
      • et al.
      Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology.
      with permission from The American Society of Hematology.
      • History
        • Bleeding symptoms
          • Type of bleeding
          • Severity of bleeding
          • Duration of bleeding
        • Systemic symptoms, including weight loss, fever, headache, and symptoms of autoimmune disorders such as arthralgias, rash, alopecia, and venous thrombosis
        • Risk factors for HIV infection
        • Pregnancy status
        • Medications, including heparin, alcohol, quinidine/quinine, and sulphonamides, which may cause thrombocytopenia, and aspirin, which may exacerbate bleeding
        • Family history of thrombocytopenia, including bleeding symptoms and symptoms of autoimmune disorders
        • Comorbid conditions that may increase the risk of bleeding such as gastrointestinal disease, chronic liver diseases, chronic kidney diseases
      • Physical examination
        • Bleeding signs
          • Type of bleeding
          • Severity of bleeding
        • Liver, spleen, lymph nodes, and jaundice
        • Evidence for infection, particularly bacteremia or HIV infection
        • Evidence for autoimmune disease, such as arthritis, nephritis, or cutaneous vasculitis
        • Evidence for thrombosis
        • Neurologic function
      • Laboratory tests
        • Necessary and/or appropriate
          • Repeated hemograms
          • Peripheral blood smear observation
          • Bone marrow aspirate (if older than 60 years or another hematologic disorder is suspected, and in patients for whom splenectomy is considered)
          • HIV test (in patients with risk factors for HIV infection)
        • Unnecessary, but may be appropriate
          • Lupus anticoagulant
          • Platelet antigen-specific antibody
          • Direct antiglobulin test
          • Chest x-ray
          • Mean platelet volume
          • Reticulocyte count
          • Urinalysis
          • Thyroid function tests
      * HIV = human immunodeficiency virus.
      Few high-quality studies are available with which to assess the efficacy of ITP treatments; existing guidelines are based more on expert opinion than on evidence.
      • George JN
      • Woolf SH
      • Raskob GE
      • et al.
      Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology.
      • British Committee for Standards in Haematology General Haematology Task Force
      Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy.
      Unfortunately, even among experts there is only little to moderate agreement regarding the best treatment for these patients. In this article, we illustrate current treatment options for ITP that are based on a literature review and personal experience.

      WHICH PATIENTS WITH ITP SHOULD BE TREATED?

      The answer to the seemingly “innocent” question of which patients with ITP should be treated is complex and underlines the heterogeneity of ITP. Disease-related and patientrelated factors should be considered and treatment tailored to the individual patient. Considering the chronic nature of the disease, the goal of treatment should be to provide a safe platelet count to prevent major bleeding while minimizing adverse effects.
      An understanding of the natural history of untreated ITP provides part of the rationale for deciding which patients should be treated. Although 80% to 90% of children have a spontaneous remission of the disease within 2 to 8 weeks,
      • Dickerhoff R
      • von Ruecker A
      The clinical course of immune thrombocytopenic purpura in children who did not receive intravenous immunoglobulins or sustained prednisone treatment.
      • Kuhne T
      • Imbach P
      • Bolton-Maggs PH
      • Berchtold W
      • Blanchette V
      • Buchanan GR
      • Intercontinental Childhood ITP Study Group
      Newly diagnosed idiopathic thrombocytopenic purpura in childhood: an observational study.
      spontaneous remissions in adults are much rarer. However, in many adults presenting with mild and asymptomatic thrombocytopenia, the disease appears to have a stable and benign course without treatment.
      • Stasi R
      • Stipa E
      • Masi M
      • et al.
      Long-term observation of 208 adults with chronic idiopathic thrombocytopenic purpura.
      • Cortelazzo S
      • Finazzi G
      • Buelli M
      • Molteni A
      • Viero P
      • Barbui T
      High risk of severe bleeding in aged patients with chronic idiopathic thrombocytopenic purpura.
      • Portielje JE
      • Westendorp RG
      • Kluin-Nelemans HC
      • Brand A
      Morbidity and mortality in adults with idiopathic thrombocytopenic purpura.
      Possibly less than 10% of such patients develop a more severe thrombocytopenia and require treatment at 3- to 7-year follow-up.
      • Stasi R
      • Stipa E
      • Masi M
      • et al.
      Long-term observation of 208 adults with chronic idiopathic thrombocytopenic purpura.
      In our study of 208 adults with chronic ITP, 9% of patients remitted spontaneously or required some form of therapy to support the platelet count.
      • Stasi R
      • Stipa E
      • Masi M
      • et al.
      Long-term observation of 208 adults with chronic idiopathic thrombocytopenic purpura.
      In other series, the incidence of spontaneous remissions may have been underestimated because all patients were treated initially with corticosteroids.
      • George JN
      • Woolf SH
      • Raskob GE
      • et al.
      Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology.
      Only a few studies have addressed the mortality risk attributable to ITP. Cohen et al
      • Cohen YC
      • Djulbegovic B
      • Shamai-Lubovitz O
      • Mozes B
      The bleeding risk and natural history of idiopathic thrombocytopenic purpura in patients with persistent low platelet counts.
      reviewed data from 17 case series involving 1817 patients with ITP and showed that the rate of fatal hemorrhage is between 0.0162 and 0.0389 cases per patient-year at risk (the time at risk was defined as the time during which the platelet count is <30 × 109/L). The relationship between disease-related and treatment-related mortality was specified by Portielje et al.
      • Portielje JE
      • Westendorp RG
      • Kluin-Nelemans HC
      • Brand A
      Morbidity and mortality in adults with idiopathic thrombocytopenic purpura.
      During the follow-up period, 6 patients died, 2 of hemorrhage and 4 of infections, which were probably treatment related. In another study, 3 of 6 adults died of infections, and only 2 died of hemorrhage.
      • Schattner E
      • Bussel J
      Mortality in immune thrombocytopenic purpura: report of seven cases and consideration of prognostic indicators.
      A recent report by Neylon et al
      • Neylon AJ
      • Saunders PW
      • Howard MR
      • Proctor SJ
      • Taylor PR
      • Northern Region Haematology Group
      Clinically significant newly presenting autoimmune thrombocytopenic purpura in adults: a prospective study of a population-based cohort of 245 patients.
      indicates that 27 of 245 patients (11%) died during the study period, but only 3 (1.2%) of these deaths were attributable to ITP (bleeding) and only 1 (0.4%) to overwhelming sepsis after splenectomy. The other deaths were apparently unrelated to either ITP or its treatment. Considering these data together, it appears that the treatment of ITP is almost as dangerous as the disease itself and that some patients are clearly overtreated.
      The peripheral blood platelet count is obviously the major parameter for predicting the risk of bleeding, but few studies have described the risk of clinically important bleeding at varying levels of thrombocytopenia. A platelet count of greater than 30 × 109/L is usually considered “safe” for people leading a sedentary lifestyle.
      • George JN
      • Woolf SH
      • Raskob GE
      • et al.
      Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology.
      • British Committee for Standards in Haematology General Haematology Task Force
      Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy.
      However, only 1 prospective study supports this cut-off level. Cortelazzo et al
      • Cortelazzo S
      • Finazzi G
      • Buelli M
      • Molteni A
      • Viero P
      • Barbui T
      High risk of severe bleeding in aged patients with chronic idiopathic thrombocytopenic purpura.
      described 49 untreated patients (of 117 total patients with ITP) with platelet counts greater than 30 × 109/L and no symptomatic bleeding. No adverse events were reported among these 49 patients during a mean follow-up period of 30 months. A recent retrospective study indicated that patients with ITP who achieved platelet counts greater than 30 × 109/L while not being treated or while receiving maintenance therapy had a long-term mortality rate identical to or only slightly greater than that of the general population.
      • Portielje JE
      • Westendorp RG
      • Kluin-Nelemans HC
      • Brand A
      Morbidity and mortality in adults with idiopathic thrombocytopenic purpura.
      Therefore, these studies support the contention that a platelet count of greater than 30 × 109/ L is reasonably safe, but they do not indicate whether the critical threshold is 30 × 109/L or a lower value. An early investigation by Lacey and Penner
      • Lacey JV
      • Penner JA
      Management of idiopathic thrombocytopenic purpura in the adult.
      showed that spontaneous major bleeding in adults with ITP is rare (<5% of patients) with platelet counts of greater than 10 × 109/L and occurs in about 40% of patients with platelet counts of less than 10 × 109/L. These findings are in agreement with observations of patients with chemotherapy-induced bone marrow suppression, indicating that clinically important bleeding is less likely with platelet counts of greater than 10 × 109/L unless the patient is febrile or has a serious systemic illness.
      • Wandt H
      • Frank M
      • Ehninger G
      • et al.
      Safety and cost effectiveness of a 10 × 109/L trigger for prophylactic platelet transfusions compared with the traditional 20 × 109/L trigger: a prospective comparative trial in 105 patients with acute myeloid leukemia.
      The degree of thrombocytopenia per se does not always accurately predict bleeding risk, however, and experienced hematologists are aware that in many patients with ITP, the platelet count appears to have little bearing on the bleeding diathesis. Some individuals with severe ITP (platelets counts of <10 × 109/L) do not bleed, whereas others with higher platelet counts bleed excessively. In fact, in the previously mentioned report by Neylon et al,
      • Neylon AJ
      • Saunders PW
      • Howard MR
      • Proctor SJ
      • Taylor PR
      • Northern Region Haematology Group
      Clinically significant newly presenting autoimmune thrombocytopenic purpura in adults: a prospective study of a population-based cohort of 245 patients.
      only 1 of the 3 deaths due to bleeding occurred at a platelet count of less than 10 × 109/L.
      Older studies have suggested that bleeding manifestations in patients with ITP are expected to be less severe at equivalent platelet counts than in patients with thrombocytopenia due to a hyporegenerative bone marrow.
      • Harker LA
      • Slichter SJ
      The bleeding time as a screening test for evaluation of platelet function.
      This is likely to be related to the fact that the circulating platelets in patients with ITP are younger because the platelet lifespan is reduced, and these younger platelets possess greater hemostatic activity.
      • Peng J
      • Friese P
      • Heilmann E
      • George JN
      • Burstein SA
      • Dale GL
      Aged platelets have an impaired response to thrombin as quantitated by P-selectin expression.
      Nevertheless, platelet dysfunction in ITP has been well described in the literature, indicating that antiplatelet antibodies can affect platelet function.
      • Clancy R
      • Jenkins E
      • Firkin B
      Qualitative platelet abnormalities in idiopathic thrombocytopenic purpura.
      • Yanabu M
      • Suzuki M
      • Soga T
      • et al.
      Influences of antiplatelet autoantibodies on platelet function in immune thrombocytopenic purpura.
      • Balduini CL
      • Bertolino G
      • Noris P
      • et al.
      Defect of platelet aggregation and adhesion induced by autoantibodies against platelet glycoprotein IIIa.
      • Varon D
      • Gitel SN
      • Varon N
      • et al.
      Immune Bernard Soulier-like syndrome associated with anti-glycoprotein-IX antibody [letter].
      • Pfueller SL
      • David R
      • Firkin BG
      • Bilston RA
      • Cortizo WF
      • Raines G
      Platelet aggregating IgG antibody to platelet surface glycoproteins associated with thrombosis and thrombocytopenia.
      For example, antibodies may bind to adhesion molecules or other receptors on platelets to alter platelet function. They may impair adhesion and aggregation of platelets, inducing features of Glanzmann thrombasthenia
      • Balduini CL
      • Bertolino G
      • Noris P
      • et al.
      Defect of platelet aggregation and adhesion induced by autoantibodies against platelet glycoprotein IIIa.
      or Bernard-Soulier-like syndromes
      • Varon D
      • Gitel SN
      • Varon N
      • et al.
      Immune Bernard Soulier-like syndrome associated with anti-glycoprotein-IX antibody [letter].
      or various other platelet dysfunctions. In contrast, some antibodies may activate platelets, promoting thrombotic complications in ITP.
      • Pfueller SL
      • David R
      • Firkin BG
      • Bilston RA
      • Cortizo WF
      • Raines G
      Platelet aggregating IgG antibody to platelet surface glycoproteins associated with thrombosis and thrombocytopenia.
      It is apparent from the results of several studies that factors other than the peripheral blood platelet count influence the risk of bleeding, the most important of which is probably age. In one report, the rates of severe hemorrhagic complications in patients older than 60 years and younger than 40 years were 10.4% and 0.4% per patient per year, respectively.
      • Cortelazzo S
      • Finazzi G
      • Buelli M
      • Molteni A
      • Viero P
      • Barbui T
      High risk of severe bleeding in aged patients with chronic idiopathic thrombocytopenic purpura.
      Similar rates of 13.0% and 0.4% per patient per year, respectively, were noted in the previously mentioned meta-analysis by Cohen et al.
      • Cohen YC
      • Djulbegovic B
      • Shamai-Lubovitz O
      • Mozes B
      The bleeding risk and natural history of idiopathic thrombocytopenic purpura in patients with persistent low platelet counts.
      The presence of conditions such as fever, uremia, or chronic liver disorders is known to be associated with impaired platelet function and an increased risk of bleeding, but specific data for patients with ITP are unavailable.
      Safe platelet counts differ between sedentary persons and those with active lifestyles, but to date this finding has not been investigated systematically, and no precise recommendations can be given. We consider a platelet count of 50 × 109/L a reasonable threshold for people engaged in “physical” jobs, such as carpenters and farmers, whereas athletes who perform contact sports probably would require a platelet count of greater than 80 × 109/L. The British Committee for Standards in Haematology
      • British Committee for Standards in Haematology General Haematology Task Force
      Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy.
      has recently suggested the values of the platelet counts that are considered safe for patients who are undergoing procedures likely to induce blood loss, including surgery, dental extraction, or obstetric delivery (Table 3). Once again, note that these recommendations are based on opinion and that many physicians would not agree with them on the basis of their own experience.
      Table 3Recommendation for “Safe” Platelet Counts in Adults
      From the British Committee for Standards in Haematology General Haematology Task Force,
      • British Committee for Standards in Haematology General Haematology Task Force
      Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy.
      with permission from Blackwell Publishing.
      ProcedurePlatelet count (× 109/L)
      Dentistry≥10
      Extractions≥30
      Regional dental block≥30
      Minor surgery≥50
      Major surgery≥80
      Vaginal delivery≥50
      Cesarean section≥80
      Spinal or epidural anesthesia≥80
      In summary, the critical elements in the decision-making process include the presence of active bleeding; platelet count; patient age; patient's lifestyle related to risk of bleeding; presence of additional risk factors for bleeding, such as uremia, chronic liver diseases, etc; predictable adverse effects of the offered treatment; and patient's preferences (Table 4). Accordingly, we believe that patients with ITP can be grouped into 1 of 4 treatment categories: (1) those who must be treated, which includes all patients with active bleeding; (2) those who should be treated, which includes patients with a platelet count of less than 10 × 109/L and no active bleeding; (3) those who might be treated, which includes patients with platelet counts between 10 × 109/L and 30 × 109/L but with no active bleeding, for whom the decision to treat is made after a thorough evaluation of the patient's characteristics (age, lifestyle, etc) (Table 4); and (4) those for whom treatment is not needed or is required in special circumstances, which includes patients with platelet counts of greater than 30 × 109/L and no bleeding tendency (Table 5).
      Table 4Factors That Should Be Considered in Deciding When to Treat Patients With Immune Thrombocytopenic Purpura
      • Presence of active bleeding
      • Platelet count
      • Age
      • Lifestyle (participation in activities that predispose to trauma)
      • Additional risk factors for bleeding
        • Uremia
        • Untreated or poorly controlled hypertension
        • Fever
        • Infections
        • Alcoholism
        • Aneurysms
        • History of peptic ulcer disease
        • Chronic liver diseases
      • Adverse effects of treatment
      • Patient's preferences
      Table 5Treatment Categories in Immune Thrombocytopenic Purpura
      CategoryIndication for treatment
      1. Presence of active bleeding Platelet count: anyYes
      2. Platelet count <10 × 109/L No active bleedingYes
      3. Platelet count 10-30 × 109/L No active bleedingOnly after evaluation of all the factors in Table 4
      4. Platelet count >30 × 109/L No active bleedingNo
      Treatment may be required in special circumstances, eg, in preparation for major surgery or obstetric delivery.
      * Treatment may be required in special circumstances, eg, in preparation for major surgery or obstetric delivery.
      Although this categorization is widely accepted for the initial treatment of adults, it may not be fully appropriate in patients for whom several treatments have failed and whose platelet counts are persistently less than 10 × 109/L. In some of these patients, particularly in younger individuals who have no bleeding symptoms, a wait-and-see policy may be preferable to avoid the long-term toxicities associated with treatment.

      EMERGENCY TREATMENT

      Patients with internal or widespread mucocutaneous bleeding or in need of emergency surgery require urgent aggressive therapy. Hospitalization is required, and general measures should be instituted to reduce the risk of bleeding, including avoidance of drugs that inhibit platelet function, control of blood pressure, and other factors. Although no systematic studies have evaluated the efficacy of different regimens, there is general agreement that appropriate interventions should include the following
      • George JN
      • Woolf SH
      • Raskob GE
      • et al.
      Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology.
      • British Committee for Standards in Haematology General Haematology Task Force
      Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy.
      :
      • Intravenous immunoglobulin (IVIg), 1 g/kg per day for 2 days
      • Intravenous methylprednisolone, 1 g/d for 3 days
      • Platelet transfusions (either 5 U every 4-6 hours or 2 U/h)
      Management of intracranial bleeding should include all these interventions. When the platelet count is greater than 100 × 109/L, craniotomy may be considered. Emergency splenectomy may be considered in individual patients who do not respond and require additional treatment. Although patients with ITP are assumed to have rapid platelet destruction, transfused platelets may provide temporary critical hemostatic support. Platelet transfusions usually are given after IVIg and are often effective in controlling bleeding, irrespective of the increase in platelet counts. Nevertheless, it has been shown that 42% of platelet transfusions result in a platelet increase of at least 20 × 109/L.
      • Carr JM
      • Kruskall MS
      • Kaye JA
      • Robinson SH
      Efficacy of platelet transfusions in immune thrombocytopenia.
      Aminocaproic acid (5 g initially and then 1 g every 5 hours given orally or intravenously) has been reported to be effective in controlling severe bleeding in ITP after failure of corticosteroids and platelet transfusions.
      • Bartholomew JR
      • Salgia R
      • Bell WR
      Control of bleeding in patients with immune and nonimmune thrombocytopenia with aminocaproic acid.
      Given the efficacy of these interventions, plasmapheresis has been used rarely in emergency settings but may play a role in refractory cases.
      • Flick JT
      • Grush O
      • Morgan S
      • Walls C
      • Lazarchick J
      The role of apheresis in the support of life-threatening ITP relapse.

      INITIAL TREATMENT

      Once the decision to treat a patient with ITP has been made, and provided the patient's situation is not life threatening, corticosteroids are the standard initial treatment.
      • George JN
      • Woolf SH
      • Raskob GE
      • et al.
      Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology.
      Intravenous immunoglobulins are generally recommended for patients with critical bleeding and for those unresponsive to corticosteroids.
      • George JN
      • Woolf SH
      • Raskob GE
      • et al.
      Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology.
      The platelet count also can be supported by anti-D immunoglobulin, which is active in the presplenectomy setting.
      • George JN
      • Woolf SH
      • Raskob GE
      • et al.
      Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology.
      Results of treatments in the major series reported thus far are summarized in Table 6.
      • Stasi R
      • Stipa E
      • Masi M
      • et al.
      Long-term observation of 208 adults with chronic idiopathic thrombocytopenic purpura.
      • Portielje JE
      • Westendorp RG
      • Kluin-Nelemans HC
      • Brand A
      Morbidity and mortality in adults with idiopathic thrombocytopenic purpura.
      • Cheng Y
      • Wong RS
      • Soo YO
      • et al.
      Initial treatment of immune thrombocytopenic purpura with high-dose dexamethasone.
      • Pizzuto J
      • Ambriz R
      Therapeutic experience on 934 adults with idiopathic thrombocytopenic purpura: Multicentric Trial of the Cooperative Latin American Group on Hemostasis and Thrombosis.
      • Scaradavou A
      • Woo B
      • Woloski BM
      • et al.
      Intravenous anti-D treatment of immune thrombocytopenic purpura: experience in 272 patients.
      • Newman GC
      • Novoa MV
      • Fodero EM
      • Lesser ML
      • Woloski BM
      • Bussel JB
      A dose of 75 microg/kg/d of i.v. anti-D increases the platelet count more rapidly and for a longer period of time than 50 microg/kg/d in adults with immune thrombocytopenic purpura.
      • Cooper N
      • Woloski BM
      • Fodero EM
      • et al.
      Does treatment with intermittent infusions of intravenous anti-D allow a proportion of adults with recently diagnosed immune thrombocytopenic purpura to avoid splenectomy?.
      • Kumar S
      • Diehn FE
      • Gertz MA
      • Tefferi A
      Splenectomy for immune thrombocytopenic purpura: long-term results and treatment of postsplenectomy relapses.
      • Winde G
      • Schmid KW
      • Lugering N
      • et al.
      Results and prognostic factors of splenectomy in idiopathic thrombocytopenic purpura.
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      • Caulier MT
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      • Schaeffer A
      • Bierling P
      Intravenous immunoglobulin for adults with autoimmune thrombocytopenic purpura: results of a randomized trial comparing 0.5 and 1 g/kg b.w..
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      • Baslar Z
      • et al.
      Overview of 321 patients with idiopathic thrombocytopenic purpura: retrospective analysis of the clinical features and response to therapy.
      • Lamy T
      • Moisan A
      • Dauriac C
      • Ghandour C
      • Morice P
      • Le Prise PY
      Splenectomy in idiopathic thrombocytopenic purpura: its correlation with the sequestration of autologous indium-111-labeled platelets.
      • Fabris F
      • Tassan T
      • Ramon R
      • et al.
      Age as the major predictive factor of long-term response to splenectomy in immune thrombocytopenic purpura.
      • Winiarski J
      • Kreuger A
      • Ejderhamn J
      • Holm G
      High dose intravenous IgG reduces platelet associated immunoglobulins and complement in idiopathic thrombocytopenic purpura.
      • Godeau B
      • Chevret S
      • Varet B
      • French ATIP Study Group
      • et al.
      Intravenous immunoglobulin or high-dose methylprednisolone, with or without oral prednisone, for adults with untreated severe autoimmune thrombocytopenic purpura: a randomised, multicentre trial.
      • Ware RE
      • Zimmerman SA
      Anti-D: mechanisms of action.
      • Bussel JB
      • Graziano JN
      • Kimberly RP
      • Pahwa S
      • Aledort LM
      Intravenous anti-D treatment of immune thrombocytopenic purpura: analysis of efficacy, toxicity, and mechanism of effect.
      • Bell Jr, WR
      Long-term outcome of splenectomy for idiopathic thrombocytopenic purpura.
      Table 6Response to First-Line Treatments and Splenectomy
      IVIg = intravenous immunoglobulin; NA = not available.
      ReferenceType of treatmentNo. of patientsNo. (%) of responses
      InitialLong-term
      • Stasi R
      • Stipa E
      • Masi M
      • et al.
      Long-term observation of 208 adults with chronic idiopathic thrombocytopenic purpura.
      • Cheng Y
      • Wong RS
      • Soo YO
      • et al.
      Initial treatment of immune thrombocytopenic purpura with high-dose dexamethasone.
      • Pizzuto J
      • Ambriz R
      Therapeutic experience on 934 adults with idiopathic thrombocytopenic purpura: Multicentric Trial of the Cooperative Latin American Group on Hemostasis and Thrombosis.
      • Scaradavou A
      • Woo B
      • Woloski BM
      • et al.
      Intravenous anti-D treatment of immune thrombocytopenic purpura: experience in 272 patients.
      • Newman GC
      • Novoa MV
      • Fodero EM
      • Lesser ML
      • Woloski BM
      • Bussel JB
      A dose of 75 microg/kg/d of i.v. anti-D increases the platelet count more rapidly and for a longer period of time than 50 microg/kg/d in adults with immune thrombocytopenic purpura.
      • Cooper N
      • Woloski BM
      • Fodero EM
      • et al.
      Does treatment with intermittent infusions of intravenous anti-D allow a proportion of adults with recently diagnosed immune thrombocytopenic purpura to avoid splenectomy?.
      • Kumar S
      • Diehn FE
      • Gertz MA
      • Tefferi A
      Splenectomy for immune thrombocytopenic purpura: long-term results and treatment of postsplenectomy relapses.
      • Winde G
      • Schmid KW
      • Lugering N
      • et al.
      Results and prognostic factors of splenectomy in idiopathic thrombocytopenic purpura.
      Corticosteroids16851107 (66)202/1296 (16)
      • Godeau B
      • Caulier MT
      • Decuypere L
      • Rose C
      • Schaeffer A
      • Bierling P
      Intravenous immunoglobulin for adults with autoimmune thrombocytopenic purpura: results of a randomized trial comparing 0.5 and 1 g/kg b.w..
      • Kimberly RP
      • Salmon JE
      • Bussel JB
      • Crow MK
      • Hilgartner MW
      Modulation of mononuclear phagocyte function by intravenous gamma-globulin.
      • Pamuk GE
      • Pamuk ON
      • Baslar Z
      • et al.
      Overview of 321 patients with idiopathic thrombocytopenic purpura: retrospective analysis of the clinical features and response to therapy.
      • Lamy T
      • Moisan A
      • Dauriac C
      • Ghandour C
      • Morice P
      • Le Prise PY
      Splenectomy in idiopathic thrombocytopenic purpura: its correlation with the sequestration of autologous indium-111-labeled platelets.
      • Fabris F
      • Tassan T
      • Ramon R
      • et al.
      Age as the major predictive factor of long-term response to splenectomy in immune thrombocytopenic purpura.
      IVIg259193 (75)NA
      • Winiarski J
      • Kreuger A
      • Ejderhamn J
      • Holm G
      High dose intravenous IgG reduces platelet associated immunoglobulins and complement in idiopathic thrombocytopenic purpura.
      • Godeau B
      • Chevret S
      • Varet B
      • French ATIP Study Group
      • et al.
      Intravenous immunoglobulin or high-dose methylprednisolone, with or without oral prednisone, for adults with untreated severe autoimmune thrombocytopenic purpura: a randomised, multicentre trial.
      Anti-D immunoglobulin165115 (70)NA
      • Stasi R
      • Stipa E
      • Masi M
      • et al.
      Long-term observation of 208 adults with chronic idiopathic thrombocytopenic purpura.
      • Portielje JE
      • Westendorp RG
      • Kluin-Nelemans HC
      • Brand A
      Morbidity and mortality in adults with idiopathic thrombocytopenic purpura.
      • Pizzuto J
      • Ambriz R
      Therapeutic experience on 934 adults with idiopathic thrombocytopenic purpura: Multicentric Trial of the Cooperative Latin American Group on Hemostasis and Thrombosis.
      • Scaradavou A
      • Woo B
      • Woloski BM
      • et al.
      Intravenous anti-D treatment of immune thrombocytopenic purpura: experience in 272 patients.
      • Newman GC
      • Novoa MV
      • Fodero EM
      • Lesser ML
      • Woloski BM
      • Bussel JB
      A dose of 75 microg/kg/d of i.v. anti-D increases the platelet count more rapidly and for a longer period of time than 50 microg/kg/d in adults with immune thrombocytopenic purpura.
      • Cooper N
      • Woloski BM
      • Fodero EM
      • et al.
      Does treatment with intermittent infusions of intravenous anti-D allow a proportion of adults with recently diagnosed immune thrombocytopenic purpura to avoid splenectomy?.
      • Kumar S
      • Diehn FE
      • Gertz MA
      • Tefferi A
      Splenectomy for immune thrombocytopenic purpura: long-term results and treatment of postsplenectomy relapses.
      • Winde G
      • Schmid KW
      • Lugering N
      • et al.
      Results and prognostic factors of splenectomy in idiopathic thrombocytopenic purpura.
      • Ware RE
      • Zimmerman SA
      Anti-D: mechanisms of action.
      • Bussel JB
      • Graziano JN
      • Kimberly RP
      • Pahwa S
      • Aledort LM
      Intravenous anti-D treatment of immune thrombocytopenic purpura: analysis of efficacy, toxicity, and mechanism of effect.
      • Bell Jr, WR
      Long-term outcome of splenectomy for idiopathic thrombocytopenic purpura.
      Splenectomy13221059 (80)819/1287 (64)
      * IVIg = intravenous immunoglobulin; NA = not available.

      Corticosteroids

      Corticosteroids have not been shown to alter the natural history of ITP; however, they allow the physician to “buy time” to determine which patients have acute ITP (lasting less than 6 months) and which patients will develop chronic ITP and thus potentially need additional therapy. Approximately two thirds of patients achieve a complete or partial response with corticosteroids, and most responses occur within the first week of treatment.
      • George JN
      • Woolf SH
      • Raskob GE
      • et al.
      Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology.
      The standard practice is to initiate treatment with oral prednisolone or prednisone, 1 to 2 mg/kg per day, given as single or divided doses. However, major variations exist in treatment regimens in reference to the duration of full-dose treatment (2-6 weeks) and the mode of tapering (fast or slow). In our practice, we taper and discontinue prednisone over 4 weeks after achieving a normal platelet count because this period includes the time during which most spontaneous remissions would occur.
      To date, only 2 randomized studies have compared conventional with low doses of prednisone as initial therapy.
      • Bellucci S
      • Charpak Y
      • Chastang C
      • Tobelem G
      Low doses v conventional doses of corticoids in immune thrombocytopenic purpura (ITP): results of a randomized clinical trial in 160 children, 223 adults.
      • Mazzucconi MG
      • Francesconi M
      • Fidani P
      • et al.
      Treatment of idiopathic thrombocytopenic purpura (ITP): results of a multicentric protocol.
      There was no difference in the likelihood of remission at 6-month follow-up in either study. However, the larger study observed a trend toward an increased frequency of complete remission (46% vs 35%) in the group given the larger doses of prednisone. Moreover, a faster increase in platelet count was observed in the group receiving the larger dose of prednisone (77% vs 51% having a platelet count greater than 50 × 109/L after 14 days of prednisone). No data were published on the long-term outcome of these 2 studies. One study assessed the efficacy of high-dose methylprednisolone as first-line therapy for 21 adults with severe thrombocytopenia and severe or persistent mucosal or vaginal bleeding; the results were compared with 36 patients with a less severe presentation who were treated with conventional doses of prednisone.
      • Alpdogan O
      • Budak-Alpdogan T
      • Ratip S
      • et al.
      Efficacy of high-dose methylprednisolone as a first-line therapy in adult patients with idiopathic thrombocytopenic purpura.
      Patients treated with high-dose methylprednisolone responded more rapidly (4.7 vs 8.4 days) and had a higher overall response rate (80% vs 53%) despite presenting with more severe disease clinically. However, no difference was shown between the 2 groups in the frequency of complete or persistent remission. Oral dexamethasone at a dosage of 40 mg/d for 4 consecutive days has been used recently as initial treatment in 125 patients with ITP.
      • Cheng Y
      • Wong RS
      • Soo YO
      • et al.
      Initial treatment of immune thrombocytopenic purpura with high-dose dexamethasone.
      The response rate was extremely high (85%), and with a median follow-up of 30.5 months, 50% of responders had a continuous complete remission at the time this manuscript was written. Nevertheless, this was not a randomized trial, and whether or not initial high-dose therapy has a positive effect on the rate of sustained remissions is an unresolved issue.
      A few studies have evaluated the long-term outcome of patients receiving corticosteroid treatment alone.
      • Stasi R
      • Stipa E
      • Masi M
      • et al.
      Long-term observation of 208 adults with chronic idiopathic thrombocytopenic purpura.
      • Portielje JE
      • Westendorp RG
      • Kluin-Nelemans HC
      • Brand A
      Morbidity and mortality in adults with idiopathic thrombocytopenic purpura.
      • DiFino SM
      • Lachant NA
      • Kirshner JJ
      • Gottlieb AJ
      Adult idiopathic thrombocytopenic purpura: clinical findings and response to therapy.
      These studies indicate that there is a high early relapse rate (within 6 months) and thereafter a slower but continuous relapse rate up to 6 years. Less than 20% of patients were in complete remission at the last follow-up. Various factors for predicting the response (short term and/or long term) to corticosteroid therapy also have been analyzed. A shorter duration of symptoms has been associated with a better response to corticosteroids in 2 studies,
      • Pizzuto J
      • Ambriz R
      Therapeutic experience on 934 adults with idiopathic thrombocytopenic purpura: Multicentric Trial of the Cooperative Latin American Group on Hemostasis and Thrombosis.
      • DiFino SM
      • Lachant NA
      • Kirshner JJ
      • Gottlieb AJ
      Adult idiopathic thrombocytopenic purpura: clinical findings and response to therapy.
      whereas age of patients older than those in the 45- to 60-year range was associated with a poorer response in another study.
      • Guthrie Jr, TH
      • Brannan DP
      • Prisant LM
      Idiopathic thrombocytopenic purpura in the older adult patient.
      If prednisone is resumed when thrombocytopenia recurs, it is important to avoid the consequences of prolonged corticosteroid therapy. The risk for corticosteroid-induced osteoporosis is of particular concern,
      • Laan RF
      • van Riel PL
      • van de Putte LB
      • van Erning LJ
      • van't Hof MA
      • Lemmens JA
      Low-dose prednisone induces rapid reversible axial bone loss in patients with rheumatoid arthritis: a randomized, controlled study.
      and it is generally recommended that patients treated with prednisone for more than 3 months receive calcium and vitamin D supplementation and monitoring of bone mineral density.
      The mechanisms of action of corticosteroids in ITP have not been completely elucidated. It has been suggested that corticosteroids impair the clearance of antibodycoated platelets by tissue macrophages,
      • Gernsheimer T
      • Stratton J
      • Ballem PJ
      • Slichter SJ
      Mechanisms of response to treatment in autoimmune thrombocytopenic purpura.
      inhibit antibody production,
      • Fujisawa K
      • Tani P
      • Piro L
      • McMillan R
      The effect of therapy on platelet-associated autoantibody in chronic immune thrombocytopenic purpura.
      and increase platelet production possibly by inhibiting phagocytosis of platelets by bone marrow macrophages.
      • Gernsheimer T
      • Stratton J
      • Ballem PJ
      • Slichter SJ
      Mechanisms of response to treatment in autoimmune thrombocytopenic purpura.
      In addition, cutaneous bleeding may resolve before an increase in the platelet count is seen, suggesting a direct effect of corticosteroids on vascular integrity.
      • Kitchens CS
      • Pendergast JF
      Human thrombocytopenia is associated with structural abnormalities of the endothelium that are ameliorated by glucocorticosteroid administration.

      Intravenous Pooled Normal Human Immunoglobulin

      Intravenous immunoglobulin has been studied primarily in patients who were unresponsive to corticosteroids and other therapies. Intravenous immunoglobulin is effective in elevating the platelet count in approximately 85% of patients, with 65% achieving normal platelet counts (>100 × 109/L).
      • Bussel JB
      • Pham LC
      Intravenous treatment with gammaglobulin in adults with immune thrombocytopenic purpura: review of the literature.
      Platelet counts may begin to increase after 1 day and usually reach peak levels within 1 week after treatment.
      • Carroll RR
      • Noyes WD
      • Kitchens CS
      High-dose intravenous immunoglobulin therapy in patients with immune thrombocytopenic purpura.
      However, responses are generally transient, lasting no longer than 3 to 4 weeks, after which the platelet counts decrease to pretreatment levels.
      • Bussel JB
      • Pham LC
      Intravenous treatment with gammaglobulin in adults with immune thrombocytopenic purpura: review of the literature.
      • Carroll RR
      • Noyes WD
      • Kitchens CS
      High-dose intravenous immunoglobulin therapy in patients with immune thrombocytopenic purpura.
      The dose of IVIg has been the subject of several studies. A single randomized study showed no difference in efficacy between the 2 dosing schedules of 0.4 g/kg per day for 5 days and 1 g/kg per day as a single infusion.
      • Godeau B
      • Lesage S
      • Divine M
      • Wirquin V
      • Farcet JP
      • Bierling P
      Treatment of adult chronic autoimmune thrombocytopenic purpura with repeated high-dose intravenous immunoglobulin.
      A multicenter trial randomly assigned 35 consecutive adult patients with ITP to receive IVIg at an initial total dosage of 0.5 g/kg or 1.0 g/kg over a period of 4 to 12 hours on day 1.
      • Godeau B
      • Caulier MT
      • Decuypere L
      • Rose C
      • Schaeffer A
      • Bierling P
      Intravenous immunoglobulin for adults with autoimmune thrombocytopenic purpura: results of a randomized trial comparing 0.5 and 1 g/kg b.w..
      Nonresponders received additional IVIg in divided doses on days 4 and 5 to reach a total dose of 2.0 g/kg. This study suggested that initial treatment with 1 g/kg of IVIg appeared to be more effective than 0.5 g/kg and that some adults who did not respond to 1 g/kg responded to a higher dose. On the basis of these studies, the standard regimen for IVIg is now 1 g/kg per day for 1 to 2 days.
      Intravenous immunoglobulin is prepared by ethanol precipitation of pooled plasma, followed by techniques to minimize self-aggregation.
      • Boshkov LK
      • Kelton JG
      Use of intravenous gammaglobulin as an immune replacement and an immune suppressant.
      Preparations of IVIg are stabilized with glucose, maltose, glycine, sucrose, sorbitol, or albumin. At least 90% to 95% of the IVIg preparation is composed of monomeric IgG. The IgG retains normal Fab and Fc functions required for antigen binding and phagocytic cell interaction, respectively. IgG aggregates, IgA, and other contaminants constitute a negligible fraction. Intravenous immunoglobulin has a normal IgG half-life in vivo, with a physiological subclass distribution.
      • Boshkov LK
      • Kelton JG
      Use of intravenous gammaglobulin as an immune replacement and an immune suppressant.
      The adverse effects of IVIg are generally mild. Approximately one half of patients have headaches, usually during the first infusion. Occasionally, the headache is severe and associated with nausea and vomiting.
      • Blanchette V
      • Imbach P
      • Andrew M
      • et al.
      Randomised trial of intravenous immunoglobulin G, intravenous anti-D, and oral prednisone in childhood acute immune thrombocytopenic purpura.
      • Kattamis AC
      • Shankar S
      • Cohen AR
      Neurologic complications of treatment of childhood acute immune thrombocytopenic purpura with intravenously administered immunoglobulin G.
      These symptoms can mimic intracranial hemorrhage, and a computed tomographic scan of the head may be required to determine the diagnosis. A few patients also experience rigidity, drowsiness or lethargy, fever, photophobia, and painful eye movements simulating meningitis.
      • Sekul EA
      • Cupler EJ
      • Dalakas MC
      Aseptic meningitis associated with high-dose intravenous immunoglobulin therapy: frequency and risk factors.
      Renal impairment or failure has been reported with some preparations.
      • Schiavotto C
      • Ruggeri M
      • Rodeghiero F
      Adverse reactions after high-dose intravenous immunoglobulin: incidence in 83 patients treated for idiopathic thrombocytopenic purpura (ITP) and review of the literature.
      • Cayco AV
      • Perazella MA
      • Hayslett JP
      Renal insufficiency after intravenous immune globulin therapy: a report of two cases and an analysis of the literature.
      Intravenous immunoglobulin products containing sucrose may present a greater risk for this complication.
      • Cayco AV
      • Perazella MA
      • Hayslett JP
      Renal insufficiency after intravenous immune globulin therapy: a report of two cases and an analysis of the literature.
      In fact, a disproportionate amount of renal impairment or failure in patients with ITP (approximately 90%, according to US reports) has been associated with sucrose-containing products,
      • Centers for Disease Control and Prevention
      Renal insufficiency and failure associated with immune globulin intravenous therapy—United States, 1985-1998.
      including (1) one product manufactured by the Central Laboratory Blood Transfusion Service, Swiss Red Cross (Bern, Switzerland) (Sandoglobulin, distributed by Novartis, and Panglobulin, distributed by the American Red Cross), and (2) IVIg products manufactured by Centeon L.L.C. (Bradley, Ill) (Gammar-P I.V./Gammar-I.V.b).
      To minimize adverse effects, the infusion of IVIg is given slowly over several hours. Particular caution should be exercised in the administration of sucrose-containing IVIg products in patients at increased risk for developing acute renal failure, which includes those with any degree of preexisting renal insufficiency, diabetes mellitus, and age older than 70 years.
      • Sati HI
      • Ahya R
      • Watson HG
      Incidence and associations of acute renal failure complicating high-dose intravenous immunoglobulin therapy.
      The mechanisms of action of IVIg in ITP are complex and not fully elucidated. Some studies suggest blockade of Fc receptors on reticuloendothelial cells
      • Kimberly RP
      • Salmon JE
      • Bussel JB
      • Crow MK
      • Hilgartner MW
      Modulation of mononuclear phagocyte function by intravenous gamma-globulin.
      • Saleh M
      • Court W
      • Huster W
      • Shaw D
      • LoBuglio A
      Effect of commercial immunoglobulin G preparation on human monocyte Fc-receptor dependent binding of antibody coated platelets.
      and suppression of antibody production and binding,
      • Winiarski J
      • Kreuger A
      • Ejderhamn J
      • Holm G
      High dose intravenous IgG reduces platelet associated immunoglobulins and complement in idiopathic thrombocytopenic purpura.
      • Delfraissy JF
      • Tchernia G
      • Laurian Y
      • Wallon C
      • Galanaud P
      • Dormont J
      Suppressor cell function after intravenous gammaglobulin treatment in adult chronic idiopathic thrombocytopenic purpura.
      which may be the result of anti-idiotype antibodies that bind antiplatelet antibodies and modulate immune response.
      • Berchtold P
      • Dale GL
      • Tani P
      • McMillan R
      Inhibition of auto-antibody binding to platelet glycoprotein IIb/IIIa by anti-idiotypic antibodies in intravenous gammaglobulin.
      The relative efficacy of high-dose methylprednisolone (15 mg/kg per day intravenously on days 1 to 3) vs IVIg (0.7 g/kg per day intravenously on days 1 to 3) was studied in a prospective randomized trial of 122 patients with previously untreated severe acute ITP.
      • Godeau B
      • Chevret S
      • Varet B
      • French ATIP Study Group
      • et al.
      Intravenous immunoglobulin or high-dose methylprednisolone, with or without oral prednisone, for adults with untreated severe autoimmune thrombocytopenic purpura: a randomised, multicentre trial.
      In a second randomization, patients received either placebo or oral prednisone (1 mg/kg per day) on days 4 to 21. The percentage of patients with a platelet count greater than 50 × 109/L on days 2 and 5 was slightly greater for those receiving IVIg (7% and 79%, respectively) than for those receiving methylprednisolone (2% and 60%; P=.04). The use of prednisone was significantly more effective than placebo for all short-term study end points (eg, days with platelet count of >50 × 109/L, highest platelet count, platelet count at 21 days, and time to relapse). However, remission rate at 1 year was not affected by the initial treatment (IVIg vs methylprednisolone).
      Because of its high cost, IVIg generally is used when resistance to corticosteroids develops, when there is a contraindication to the use of corticosteroids, or during pregnancy when potentially teratogenic drugs must be avoided. The rapid nature of the response to treatment makes it an ideal agent for treatment of life-threatening bleeding or before surgery, although corticosteroids also may increase the platelet count with sufficient rapidity.

      Anti-D Immunoglobulin

      The anti-D immunoglobulin is effective only in Rh D-positive nonsplenectomized patients, in whom the antibody binds to the erythrocyte D antigen. The mechanism of action involves immune-mediated clearance of the opsonized erythrocytes via the Fc receptors of the reticuloendothelial system, thereby minimizing removal of antibody-coated platelets.
      • Ware RE
      • Zimmerman SA
      Anti-D: mechanisms of action.
      Anti-D can be administered safely by intravenous injection over a few minutes. The response rate in one series was 70%, and the increase in platelet count lasted more than 3 weeks in 50% of the responders.
      • Scaradavou A
      • Woo B
      • Woloski BM
      • et al.
      Intravenous anti-D treatment of immune thrombocytopenic purpura: experience in 272 patients.
      The toxicity profile of anti-D is similar to that of IVIg. The standard dosage of 50 mg/kg per day of intravenous anti-D requires 72 hours to produce a clinically significant platelet increase.
      • Bussel JB
      • Graziano JN
      • Kimberly RP
      • Pahwa S
      • Aledort LM
      Intravenous anti-D treatment of immune thrombocytopenic purpura: analysis of efficacy, toxicity, and mechanism of effect.
      Therefore, anti-D has not been recommended as first-line therapy to rapidly elevate the platelet count in patients with severe thrombocytopenia. In a prospective randomized trial, 27 Rh D-positive patients with a diagnosis of ITP in whom initial treatment with corticosteroids had failed and who had platelet counts of 30 × 109/L or less received intermittent treatment with anti-D at a dose of 50 to 75 µg/kg intravenously whenever their platelet count was 30 × 109/L or less.
      • Newman GC
      • Novoa MV
      • Fodero EM
      • Lesser ML
      • Woloski BM
      • Bussel JB
      A dose of 75 microg/kg/d of i.v. anti-D increases the platelet count more rapidly and for a longer period of time than 50 microg/kg/d in adults with immune thrombocytopenic purpura.
      The higher dose resulted in greater median day 1 (43 × 109/L vs 7.5 × 109/L; P=.01) and day 7 (153 × 109/L vs 64.5 × 109/L; P=.001) platelet increases despite no greater hemoglobin decrease. The results also indicated that 68% of patients repeatedly responded to anti-D infusion and that in some patients, splenectomy may have been delayed or completely avoided.
      • Cooper N
      • Woloski BM
      • Fodero EM
      • et al.
      Does treatment with intermittent infusions of intravenous anti-D allow a proportion of adults with recently diagnosed immune thrombocytopenic purpura to avoid splenectomy?.
      The substantial advantages of anti-D compared with IVIg are lower costs (although still much more expensive than corticosteroids) and more convenient administration. The dose-limiting toxicity of anti-D is hemolytic anemia, with a mean decrease in hemoglobin of 1.0 g/dL, occasionally accompanied by chills and nausea. Anti-D appears to have minimal efficacy in splenectomized patients.
      • Bussel JB
      • Graziano JN
      • Kimberly RP
      • Pahwa S
      • Aledort LM
      Intravenous anti-D treatment of immune thrombocytopenic purpura: analysis of efficacy, toxicity, and mechanism of effect.

      SECOND-LINE TREATMENT

      The spleen is the organ primarily responsible for the destruction of antibody-sensitized platelets, and splenectomy is traditionally considered to be the second-line treatment in adults with ITP in whom achieving a safe platelet count with initial prednisone therapy has failed. However, there are many uncertainties and controversies regarding the optimal time for performing splenectomy, the prediction of response, the selection of the surgical procedure (standard vs laparoscopic method), and the long-term efficacy of this procedure. No randomized trial has compared the efficacy and risks of drug treatment with splenectomy, and it is unlikely that such a trial will ever be performed. As with other treatment modalities, the decision to recommend splenectomy should be individualized, taking into account the age of the patient, duration of the disease, comorbid conditions, efficacy and adverse effects of corticosteroid treatment, and preferences of the patient.
      About 75% of patients who undergo splenectomy achieve a complete remission (platelet count of >100-150 × 109/L).
      • Stasi R
      • Stipa E
      • Masi M
      • et al.
      Long-term observation of 208 adults with chronic idiopathic thrombocytopenic purpura.
      • Kumar S
      • Diehn FE
      • Gertz MA
      • Tefferi A
      Splenectomy for immune thrombocytopenic purpura: long-term results and treatment of postsplenectomy relapses.
      • Winde G
      • Schmid KW
      • Lugering N
      • et al.
      Results and prognostic factors of splenectomy in idiopathic thrombocytopenic purpura.
      • Pamuk GE
      • Pamuk ON
      • Baslar Z
      • et al.
      Overview of 321 patients with idiopathic thrombocytopenic purpura: retrospective analysis of the clinical features and response to therapy.
      • Schwartz J
      • Leber MD
      • Gillis S
      • Giunta A
      • Eldor A
      • Bussel JB
      Long term follow-up after splenectomy performed for immune thrombocytopenic purpura (ITP).
      • Schiavotto C
      • Rodeghiero F
      Twenty years experience with treatment of idiopathic thrombocytopenic purpura in a single department: results in 490 cases.
      • Vianelli N
      • Valdre L
      • Fiacchini M
      • et al.
      Long-term follow-up of idiopathic thrombocytopenic purpura in 310 patients.
      • Ben-Yehuda D
      • Gillis S
      • Eldor A
      • Israeli ITP Study Group
      Clinical and therapeutic experience in 712 Israeli patients with idiopathic thrombocytopenic purpura.
      Most relapses occur during the first 2 years after splenectomy, but even after that, a small percentage of patients continue to relapse. In our series, approximately 60% of responders remained in remission at 10 years (Figure 1), which is in keeping with most published reports. However, in another study with a large number of patients and long-term follow-up, most splenectomized patients had relapsed,
      • Bell Jr, WR
      Long-term outcome of splenectomy for idiopathic thrombocytopenic purpura.
      although the conclusions of this study were not supported by a detailed presentation of primary data. In some patients who relapse after splenectomy, an additional (accessory) spleen may be detected and a second complete remission may be achieved after its removal.
      • DiFino SM
      • Lachant NA
      • Kirshner JJ
      • Gottlieb AJ
      Adult idiopathic thrombocytopenic purpura: clinical findings and response to therapy.
      • Akwari OE
      • Itani KM
      • Coleman RE
      • Rosse WF
      Splenectomy for primary and recurrent immune thrombocytopenic purpura (ITP): current criteria for patient selection and results.
      • Fabris F
      • Zanatta N
      • Casonato A
      • Randi ML
      • Luzzatto G
      • Girolami A
      Response to splenectomy in idiopathic thrombocytopenic purpura: prognostic value of the clinical and laboratory evaluation.
      However, there are no studies of accessory splenectomy that document efficacy by long-term complete remissions. Numerous methods can be used to look for an accessory spleen, including computed tomographic scanning, ultrasonography, and radionuclide imaging. If radionuclide methods are used, the intraoperative use of a hand-held isotope detector probe can help locate an accessory spleen during surgery.
      Figure thumbnail gr1
      Figure 1Kaplan-Meier plot of relapse-free survival after splenectomy in patients with immune thrombocytopenic purpura (N=62) who were monitored at our institution.
      Most experts agree that splenectomy should be seriously considered for patients in whom ITP is primarily refractory to corticosteroid treatment, at 4 to 6 weeks after diagnosis, or in patients for whom a daily dose of 10 mg or more of prednisone is required to keep the platelet count at a “safe” level.
      • George JN
      • Woolf SH
      • Raskob GE
      • et al.
      Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology.
      In contrast, some suggest that this procedure should be performed only after all other therapeutic modalities have been exhausted and the patient has a platelet count of less than 25 × 109/L and is bleeding.
      • Bell Jr, WR
      Long-term outcome of splenectomy for idiopathic thrombocytopenic purpura.
      In fact, it appears that the timing of splenectomy is delayed in most medical centers. The median time to splenectomy was 11 months (range, 3-156 months), 3 years (range, 3 weeks to 19 years), and 8 to 51 months in 3 different studies.
      • Stasi R
      • Stipa E
      • Masi M
      • et al.
      Long-term observation of 208 adults with chronic idiopathic thrombocytopenic purpura.
      • Winde G
      • Schmid KW
      • Lugering N
      • et al.
      Results and prognostic factors of splenectomy in idiopathic thrombocytopenic purpura.
      • Ruivard M
      • Caulier MT
      • Vantelon JM
      • et al.
      The response to high-dose intravenous immunoglobulin or steroids is not predictive of outcome after splenectomy in adults with autoimmune thrombocytopenic purpura.
      The most likely explanation for this observation is that the decision to recommend splenectomy to many patients is difficult because they may do well on low-dose corticosteroids and splenectomy is an invasive procedure with potential risks. For example, in a series of 78 patients who underwent splenectomy, 26 (33%) experienced postoperative complications resulting in prolonged hospitalization or readmission.
      • Portielje JE
      • Westendorp RG
      • Kluin-Nelemans HC
      • Brand A
      Morbidity and mortality in adults with idiopathic thrombocytopenic purpura.
      The risk appeared particularly increased in elderly or obese patients with comorbid conditions. Therefore, identification of patients who may benefit from splenectomy would be helpful when making this decision.
      Not unexpectedly, observing splenic sequestration of indium-labeled platelets was a good prognostic factor in many studies in which this scanning method was applied (Figure 2
      • Najean Y
      • Rain JD
      • Billotey C
      The site of destruction of autologous 111In-labelled platelets and the efficiency of splenectomy in children and adults with idiopathic thrombocytopenic purpura: a study of 578 patients with 268 splenectomies.
      ).
      • Lamy T
      • Moisan A
      • Dauriac C
      • Ghandour C
      • Morice P
      • Le Prise PY
      Splenectomy in idiopathic thrombocytopenic purpura: its correlation with the sequestration of autologous indium-111-labeled platelets.
      • Winiarski J
      • Kreuger A
      • Ejderhamn J
      • Holm G
      High dose intravenous IgG reduces platelet associated immunoglobulins and complement in idiopathic thrombocytopenic purpura.
      • Najean Y
      • Rain JD
      • Billotey C
      The site of destruction of autologous 111In-labelled platelets and the efficiency of splenectomy in children and adults with idiopathic thrombocytopenic purpura: a study of 578 patients with 268 splenectomies.
      • Radaelli F
      • Faccini P
      • Goldaniga M
      • et al.
      Factors predicting response to splenectomy in adult patients with idiopathic thrombocytopenic purpura.
      • Fenaux P
      • Caulier MT
      • Hirschauer MC
      • Beuscart R
      • Goudemand J
      • Bauters F
      Reevaluation of the prognostic factors for splenectomy in chronic idiopathic thrombocytopenic purpura (ITP): a report on 181 cases.
      • Naouri A
      • Feghali B
      • Chabal J
      • et al.
      Results of splenectomy for idiopathic thrombocytopenic purpura: review of 72 cases.
      In the large study by Najean et al,
      • Najean Y
      • Rain JD
      • Billotey C
      The site of destruction of autologous 111In-labelled platelets and the efficiency of splenectomy in children and adults with idiopathic thrombocytopenic purpura: a study of 578 patients with 268 splenectomies.
      patients with hepatic sequestration had a response rate of only 1%, whereas in other studies,
      • Lamy T
      • Moisan A
      • Dauriac C
      • Ghandour C
      • Morice P
      • Le Prise PY
      Splenectomy in idiopathic thrombocytopenic purpura: its correlation with the sequestration of autologous indium-111-labeled platelets.
      • Rossi G
      • Cattaneo C
      • Motta M
      • Pizzocaro C
      • Lanzi S
      • Pouche A
      Platelet kinetic study in patients with idiopathic thrombocytopenic purpura (ITP) refractory or relapsing after corticosteroid treatment.
      the response rate was higher (≥28%). Thus, patients with hepatic sequestration may still respond to splenectomy but to a lesser degree; the likelihood of achieving a complete response is lower than in patients in whom platelet destruction is purely or predominantly splenic. However, platelet sequestration studies are difficult to perform and are available in only a few medical centers. Furthermore, the specificity of the test is not high enough to recommend it routinely for patients in whom splenectomy has been considered.
      Figure thumbnail gr2
      Figure 2Indium 111-labeled platelet scanning to determine the site of platelet destruction. 1 = spleen; 2 = liver; 3 = heart; 4 = bladder; NA = not available. In this patient with immune thrombocytopenic purpura, intense uptake is seen in the spleen, with no activity in other organs. The probability of achieving response is influenced by the pattern of uptake of the radionuclide.
      • Najean Y
      • Rain JD
      • Billotey C
      The site of destruction of autologous 111In-labelled platelets and the efficiency of splenectomy in children and adults with idiopathic thrombocytopenic purpura: a study of 578 patients with 268 splenectomies.
      Although it is generally agreed that increased age is a poor prognostic factor, this has not been reported consistently.
      • Winde G
      • Schmid KW
      • Lugering N
      • et al.
      Results and prognostic factors of splenectomy in idiopathic thrombocytopenic purpura.
      • Lamy T
      • Moisan A
      • Dauriac C
      • Ghandour C
      • Morice P
      • Le Prise PY
      Splenectomy in idiopathic thrombocytopenic purpura: its correlation with the sequestration of autologous indium-111-labeled platelets.
      • Fabris F
      • Tassan T
      • Ramon R
      • et al.
      Age as the major predictive factor of long-term response to splenectomy in immune thrombocytopenic purpura.
      • DiFino SM
      • Lachant NA
      • Kirshner JJ
      • Gottlieb AJ
      Adult idiopathic thrombocytopenic purpura: clinical findings and response to therapy.
      • Najean Y
      • Rain JD
      • Billotey C
      The site of destruction of autologous 111In-labelled platelets and the efficiency of splenectomy in children and adults with idiopathic thrombocytopenic purpura: a study of 578 patients with 268 splenectomies.
      • Radaelli F
      • Faccini P
      • Goldaniga M
      • et al.
      Factors predicting response to splenectomy in adult patients with idiopathic thrombocytopenic purpura.
      • Fenaux P
      • Caulier MT
      • Hirschauer MC
      • Beuscart R
      • Goudemand J
      • Bauters F
      Reevaluation of the prognostic factors for splenectomy in chronic idiopathic thrombocytopenic purpura (ITP): a report on 181 cases.
      • Naouri A
      • Feghali B
      • Chabal J
      • et al.
      Results of splenectomy for idiopathic thrombocytopenic purpura: review of 72 cases.
      Also, the literature is controversial concerning the prognostic value of the response to IVIg. Law et al
      • Law C
      • Marcaccio M
      • Tam P
      • Heddle N
      • Kelton JG
      High-dose intravenous immune globulin and the response to splenectomy in patients with idiopathic thrombocytopenic purpura.
      reported a 90.5% positive predictive value and a 100% negative predictive value of the response to IVIg. In most subsequent studies, it was confirmed that patients who responded to IVIg had a higher response rate to splenectomy, but the positive and negative predictive values were not as high.
      • Ruivard M
      • Caulier MT
      • Vantelon JM
      • et al.
      The response to high-dose intravenous immunoglobulin or steroids is not predictive of outcome after splenectomy in adults with autoimmune thrombocytopenic purpura.
      • Radaelli F
      • Faccini P
      • Goldaniga M
      • et al.
      Factors predicting response to splenectomy in adult patients with idiopathic thrombocytopenic purpura.
      • Naouri A
      • Feghali B
      • Chabal J
      • et al.
      Results of splenectomy for idiopathic thrombocytopenic purpura: review of 72 cases.
      • Bussel JB
      • Kaufmann CP
      • Ware RE
      • Woloski BM
      Do the acute platelet responses of patients with immune thrombocytopenic purpura (ITP) to IV anti-D and to IV gammaglobulin predict response to subsequent splenectomy?.
      • Kondo H
      • Imamura T
      High-dose intravenous immune globulin and the response to splenectomy monitoring with platelet-associated IgG in patients with idiopathic thrombocytopenic purpura [letter].
      • Hemmila MR
      • Foley DS
      • Castle VP
      • Hirschl RB
      The response to splenectomy in pediatric patients with idiopathic thrombocytopenic purpura who fail high-dose intravenous immune globulin.
      • Choi CW
      • Kim BS
      • Seo JH
      • et al.
      Response to high-dose intravenous immune globulin as a valuable factor predicting the effect of splenectomy in chronic idiopathic thrombocytopenic purpura patients.
      • Schneider P
      • Wehmeier A
      • Schneider W
      High-dose intravenous immune globulin and the response to splenectomy in patients with idiopathic thrombocytopenic purpura [letter].
      Thus, patients who do not respond to IVIg still have a good chance of responding to splenectomy. Response to prednisone has been found to be a good prognostic factor in some studies,
      • Pizzuto J
      • Ambriz R
      Therapeutic experience on 934 adults with idiopathic thrombocytopenic purpura: Multicentric Trial of the Cooperative Latin American Group on Hemostasis and Thrombosis.
      • Lamy T
      • Moisan A
      • Dauriac C
      • Ghandour C
      • Morice P
      • Le Prise PY
      Splenectomy in idiopathic thrombocytopenic purpura: its correlation with the sequestration of autologous indium-111-labeled platelets.
      • DiFino SM
      • Lachant NA
      • Kirshner JJ
      • Gottlieb AJ
      Adult idiopathic thrombocytopenic purpura: clinical findings and response to therapy.
      • Radaelli F
      • Faccini P
      • Goldaniga M
      • et al.
      Factors predicting response to splenectomy in adult patients with idiopathic thrombocytopenic purpura.
      but not in others.
      • Stasi R
      • Stipa E
      • Masi M
      • et al.
      Long-term observation of 208 adults with chronic idiopathic thrombocytopenic purpura.
      • Ruivard M
      • Caulier MT
      • Vantelon JM
      • et al.
      The response to high-dose intravenous immunoglobulin or steroids is not predictive of outcome after splenectomy in adults with autoimmune thrombocytopenic purpura.
      There is agreement that the time to splenectomy is not a prognostic factor.
      • Stasi R
      • Stipa E
      • Masi M
      • et al.
      Long-term observation of 208 adults with chronic idiopathic thrombocytopenic purpura.
      • Pizzuto J
      • Ambriz R
      Therapeutic experience on 934 adults with idiopathic thrombocytopenic purpura: Multicentric Trial of the Cooperative Latin American Group on Hemostasis and Thrombosis.
      • Ruivard M
      • Caulier MT
      • Vantelon JM
      • et al.
      The response to high-dose intravenous immunoglobulin or steroids is not predictive of outcome after splenectomy in adults with autoimmune thrombocytopenic purpura.
      • Radaelli F
      • Faccini P
      • Goldaniga M
      • et al.
      Factors predicting response to splenectomy in adult patients with idiopathic thrombocytopenic purpura.
      • Fenaux P
      • Caulier MT
      • Hirschauer MC
      • Beuscart R
      • Goudemand J
      • Bauters F
      Reevaluation of the prognostic factors for splenectomy in chronic idiopathic thrombocytopenic purpura (ITP): a report on 181 cases.
      • Naouri A
      • Feghali B
      • Chabal J
      • et al.
      Results of splenectomy for idiopathic thrombocytopenic purpura: review of 72 cases.
      Presence of platelet antibodies had no prognostic value in 2 studies.
      • Radaelli F
      • Faccini P
      • Goldaniga M
      • et al.
      Factors predicting response to splenectomy in adult patients with idiopathic thrombocytopenic purpura.
      • Kernoff M
      • Malan E
      Platelet antibody levels do not correlate with response to therapy in idiopathic thrombocytopenic purpura.
      Taken together, “predictive” factors seem to have only limited value when deciding about splenectomy, and of currently available methodology, the indium-labeled platelet study appears to be the most accurate predictor of response to splenectomy.
      Splenectomized patients have a small risk for overwhelming infections, with an estimated mortality of 0.73 per 1000 patient-years.
      • Schilling RF
      Estimating the risk for sepsis after splenectomy in hereditary spherocytosis.
      The risk for serious postsplenectomy infection is greater in children younger than 5 years, who are therefore treated with prophylactic penicillin after splenectomy. Although there are no data on the efficacy of vaccination, immunizations for Streptococcus pneumoniae, Hemophilus influenzae B, and Neisseria meningitides are generally advised at least 2 weeks before splenectomy.
      • George JN
      • Woolf SH
      • Raskob GE
      • et al.
      Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology.
      The usefulness of postoperative antibiotic prophylaxis is a matter of controversy, and although it is not the standard of care in the United States, lifelong prophylactic antibiotics are recommended in UK guidelines.
      • Davies JM
      • Barnes R
      • Milligan D
      • British Committee for Standards in Haematology
      • Working Party of the Haematology/Oncology Task Force
      Update of guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen.
      There is no agreement on the minimal platelet count regarded as sufficient to perform splenectomy; in our practice, we recommend a platelet count of at least 50 × 109/L, but often our patients must reach higher counts because surgeons are reluctant to operate on patients with thrombocytopenia.
      No data indicate whether preoperative treatment with corticosteroids or IVIg is more beneficial.
      Laparoscopic splenectomy has become popular during the past decade. The technique has the advantage of a reduced risk of postoperative complications (which allows the procedure to be performed in patients who cannot undergo open surgery) and a shorter hospital stay. Potential problems associated with the laparoscopic approach are technical difficulties necessitating conversion to open surgery and the inability to identify additional spleens and bleeding. Furthermore, the operation time with laparoscopic splenectomy is greater than with standard open surgery. No randomized trials have been conducted to compare laparoscopic with conventional open surgery, although numerous studies have shown that laparoscopic splenectomy is safe when performed by a surgeon experienced in this procedure.
      • Katkhouda N
      • Mavor E
      Laparoscopic splenectomy.
      • Cordera F
      • Long KH
      • Nagorney DM
      • et al.
      Open versus laparoscopic splenectomy for idiopathic thrombocytopenic purpura: clinical and economic analysis.
      • Pace DE
      • Chiasson PM
      • Schlachta CM
      • Mamazza J
      • Poulin EC
      Laparoscopic splenectomy for idiopathic thrombocytopenic purpura (ITP).
      • Brodsky JA
      • Brody FJ
      • Walsh RM
      • Malm JA
      • Ponsky JL
      Laparoscopic splenectomy.
      • Bresler L
      • Guerci A
      • Brunaud L
      • et al.
      Laparoscopic splenectomy for idiopathic thrombocytopenic purpura: outcome and long-term results.
      Despite the lack of scientific evidence, it may be the preferred method in patients with a high risk of postoperative complications, such as elderly patients, those with cardiovascular disease, and/or those with a high risk of postoperative infection or thrombosis.
      In patients at high risk for surgery, splenic irradiation
      • Calverley DC
      • Jones GW
      • Kelton JG
      Splenic radiation for corticosteroid-resistant immune thrombocytopenia.
      • Caulier MT
      • Darloy F
      • Rose C
      • et al.
      Splenic irradiation for chronic autoimmune thrombocytopenic purpura in patients with contra-indications to splenectomy.
      or partial splenic embolization
      • Cordera F
      • Long KH
      • Nagorney DM
      • et al.
      Open versus laparoscopic splenectomy for idiopathic thrombocytopenic purpura: clinical and economic analysis.
      • Pace DE
      • Chiasson PM
      • Schlachta CM
      • Mamazza J
      • Poulin EC
      Laparoscopic splenectomy for idiopathic thrombocytopenic purpura (ITP).
      • Brodsky JA
      • Brody FJ
      • Walsh RM
      • Malm JA
      • Ponsky JL
      Laparoscopic splenectomy.
      have been used with reports of success. Calverley et al
      • Calverley DC
      • Jones GW
      • Kelton JG
      Splenic radiation for corticosteroid-resistant immune thrombocytopenia.
      reported that of 11 patients with ITP who were treated with splenic irradiation, 8 responded. Three patients had a sustained (>52 weeks) increase in platelet count to safe levels after therapy was discontinued. An additional patient had a sustained response but required intermittent low-dose corticosteroids. Four other patients had increased platelet counts that lasted from 8 to 25 weeks. The total radiation dose was 6 Gy in 6 doses over 3 weeks without renal shielding. In another study, 8 patients with chronic ITP received a radiation dose of 15 Gy.
      • Caulier MT
      • Darloy F
      • Rose C
      • et al.
      Splenic irradiation for chronic autoimmune thrombocytopenic purpura in patients with contra-indications to splenectomy.
      One patient had a good durable response (>1 year); 2 patients had a good transient response; 2 patients had only partial response but required no other treatments for 2 years; and 3 patients had no response. The radiation was administered at a dosage of 1.5 Gy 2 times per week for 5 weeks with left kidney shielding but with 20% to 25% of the splenic volume undertreated. Splenic irradiation may result in the development of adhesions between the spleen and surrounding tissues, complicating splenectomy if it is performed later. Therefore, splenic irradiation should be recommended only for those with contraindications to splenectomy.
      Partial splenic embolization was first used by Miyazaki et al,
      • Miyazaki M
      • Itoh H
      • Kaiho T
      • et al.
      Partial splenic embolization for the treatment of chronic idiopathic thrombocytopenic purpura.
      who reported a 35% prolonged response rate in patients with ITP. In a recent study, 20 (51%) of 39 patients responded to the initial embolization (completeresponse in 11 and partial response in 9).
      • Kimura F
      • Itoh H
      • Ambiru S
      • et al.
      Long-term results of initial and repeated partial splenic embolization for the treatment of chronic idiopathic thrombocytopenic purpura.
      One of the 11 complete responders and 5 of the 9 partial responders relapsed after a median follow-up period of 34 months (range, 15-23 months) and underwentrepeated embolization, resulting in complete response in 1 patient, partial response in 4 patients, and no response in 1 patient. However, in 6 of 19 nonresponders, repeated embolization elicited a partial response in only 1 patient. The remission rate of 51% was maintained by means of repeated embolization for a median follow-up period of 76 months after the initial embolization. Because a small accessory spleen can almost certainly cause relapse, leaving a residual quantity of spleen (as in partial splenic embolization) can cause any long-term remission to fail. On the basis of this consideration, Martinez Lagares et al
      • Martinez Lagares F
      • Fernandez Fuertes F
      • Hernandez Cabrero T
      • et al.
      Complete splenic embolization in the treatment of immune thrombocytopenic purpura [letter].
      prospectively performed total splenic embolization in 13 patients, of whom 5 were dependent on high doses of corticosteroids to maintain a safe platelet count (>30 × 109/L) and 8 were corticosteroid resistant with a sustained low platelet count (<30 × 109/L). Complete embolization was achieved in 12 patients, and a partial embolization was achieved in 1 patient with an aberrant splenic artery. Of the 12 patients, 10 had a complete and sustained response (median, 27 months; range, 22-38 months), with peak platelet counts greater than 400 × 109/L between days 8 and 13.

      TREATMENT OF PATIENTS IN WHOM SPLENECTOMY FAILS

      Patients can be defined as having chronic refractory ITP if splenectomy fails and the patients require additional therapy. About 30% of adult patients with ITP may belong to this category. The goals of therapy for refractory ITP are clearly different from those for patients at initial presentation because the chance of inducing a durable, complete, and unmaintained remission is much lower. Again, the actual necessity for treatment should always be considered, and the risks and adverse effects of treatment should be weighed against the risks of no treatment.
      A common strategy is to try treatment with low-dose corticosteroids. In fact, some patients require low doses of prednisone, 5 to 10 mg/d or even less, that are comparable to physiological glucocorticoid secretion, approximately 7.5 mg/d of prednisone. For these patients, experimenting with new drugs does not seem necessary, although even at these low doses, the risk of osteoporotic fractures is increased.
      • van Everdingen AA
      • Jacobs JW
      • Siewertsz Van Reesema DR
      • Bijlsma JW
      Low-dose prednisone therapy for patients with early active rheumatoid arthritis: clinical efficacy, disease-modifying properties, and side effects: a randomized, double-blind, placebo-controlled clinical trial.
      However, many other patients require higher doses of prednisone to maintain a safe platelet count. For these patients, alternative approaches are warranted, but no treatments have been shown to be effective in randomized clinical trials assessing outcomes of bleeding and death. Therefore, no algorithm based on evidence can be proposed for standard care of chronic refractory ITP.
      • Provan D
      • Newland A
      Fifty years of idiopathic thrombocytopenic purpura (ITP): management of refractory ITP in adults.
      Many agents, combination therapies, and procedures have been proposed, some of which should be considered experimental (Table 7). The order in which they are cited in this review does not imply a judgment of ranking or efficacy of these therapies. Figure 3 shows an approach to therapy based on our personal experience.
      Table 7Treatment Options for Patients With Chronic Refractory Immune Thrombocytopenic Purpura
      Type of treatmentAdverse effects
      Conventional agents
       Oral dexamethasoneOsteoporosis, psychosis, avascular necrosis of femoral head (idiosyncratic)
       Intravenous methylprednisolone
      Diabetes, fluid retention
       DanazolWeight gain, hirsutism, liver function disturbances
       AzathioprineImmunosuppression, neutropenia, liver function disturbances
       Intravenous cyclophosphamideLeukemia, cytopenia, teratogenicity
       Vinca alkaloidsNeuropathy
       Combination chemotherapyLeukemia, cytopenia, teratogenicity
       Cyclosporin ANephrotoxicity, immunosuppression
       DapsoneHemolysis, nausea, abdominal pain
       Staphylococcal protein A columnAcute hypersensitivity-type reaction, vasculitis
       Interferon αFlu-like syndrome, fatigue, neuropathy
      Experimental therapies
       RituximabFirst-infusion reactions
       Campath-1HRigors, fever, lymphopenia
       Mycophenolate mofetilNausea, abdominal pain
       Megakaryocyte growth and development factorHypertension, vomiting, headache
       Autologous stem cell transplantationHemorrhagic cystitis, vaginal bleeding, gastrointestinal bleeding, epistaxis, febrile neutropenia
      Figure thumbnail gr3
      Figure 3Treatment options in adults with severe refractory immune thrombocytopenic purpura. IVIg = intravenous immunoglobulin.

      Eradication of Helicobacter pylori Infection

      A simple measure that can be adopted before other treatments are initiated is the detection and eventual eradication of Helicobacter pylori infection. Recent reports suggest that this infection is associated with the development of autoimmune diseases including ITP and that its eradication may result in clinical responses. Studies describing the prevalence of H pylori infection in patients with ITP have generated conflicting results. Prevalences ranged from 21.6% in the American study by Michel et al
      • Michel M
      • Cooper N
      • Jean C
      • Frissora C
      • Bussel JB
      Does Helicobacter pylori initiate or perpetuate immune thrombocytopenic purpura?.
      to 71.4% in the Spanish study by Jarque et al.
      • Jarque I
      • Andreu R
      • Llopis I
      • et al.
      Absence of platelet response after eradication of Helicobacter pylori infection in patients with chronic idiopathic thrombocytopenic purpura.
      These discrepancies can be explained perhaps by the different socioeconomic conditions of the patient populations investigated.
      • Suerbaum S
      • Michetti P
      Helicobacter pylori infection.
      The results of H pylori eradication in ITP have been reviewed recently.
      • Michel M
      • Cooper N
      • Jean C
      • Frissora C
      • Bussel JB
      Does Helicobacter pylori initiate or perpetuate immune thrombocytopenic purpura?.
      Responses were extremely variable (reported range, 7%-100%). In total, 56 (46%) of 122 patients in whom the bacterium had been eradicated experienced substantial improvement of thrombocytopenia. However, only a few of these patients had severe chronic ITP.

      High-Dose Corticosteroids

      Oral or intravenous dexamethasone, at a dosage of 40 mg/d for 4 days and repeated every 4 weeks, has been used since the publication of an uncontrolled series of 10 patients. Splenectomy had failed in 6 of these patients.
      • Andersen JC
      Response of resistant idiopathic thrombocytopenic purpura to pulsed high-dose dexamethasone therapy [published correction appears in N Engl J Med. 1994;331:283].
      All 10 patients in this series experienced a complete, durable response. However, subsequent studies have not produced such favorable results in terms of response rate, with sustained responses achieved only in sporadic cases.
      • Schiavotto C
      • Ruggeri M
      • Castaman G
      • Rodeghiero F
      High-dose dexamethasone in adult refractory idiopathic thrombocytopenic purpura [letter].
      • Demiroglu H
      • Dundar S
      High-dose pulsed dexamethasone for immune thrombocytopenia [letter].
      • Stasi R
      • Brunetti M
      • Pagano A
      • Stipa E
      • Masi M
      • Amadori S
      Pulsed intravenous high-dose dexamethasone in adults with chronic idiopathic thrombocytopenic purpura.
      • Caulier MT
      • Rose C
      • Roussel MT
      • Huart C
      • Bauters F
      • Fenaux P
      Pulsed high-dose dexamethasone in refractory chronic idiopathic thrombocytopenic purpura: a report on 10 cases.
      One study reported on 9 adult patients with platelet counts of less than 50 × 109/L who were all treated initially with oral corticosteroids (prednisolone or prednisone at 1 mg/kg per day). Methylprednisolone was given at 30 mg/ kg per day for 3 days, 20 mg/kg per day for 4 days, and then 5, 2, and 1 mg/kg per day each for 1 week. Platelet counts returned to normal within 3.5 days in all patients, although in 7, the response lasted only a few weeks before decreasing to pretreatment levels.
      • Akoglu T
      • Paydas S
      • Bayik M
      • Lawrence R
      • Firatli T
      Megadose methylprednisolone pulse therapy in adult idiopathic thrombocytopenic purpura [letter].

      Danazol

      Danazol, an attenuated androgen initially formulated for the treatment of endometriosis, can be used in male patients and nonpregnant female patients with ITP. Ahn and Horstman
      • Ahn YS
      • Horstman LL
      Idiopathic thrombocytopenic purpura: pathophysiology and management.
      recently reviewed 25 publications about danazol therapy in chronic ITP. Favorable outcomes were reported in 21 and negative outcomes in 4. Pooled data show that danazol produces a sustained platelet increase in 30% of patients. The platelet counts of an additional 10% of patients increased to 50 × 109/L to 100 × 109/L. However, a detailed analysis of the data reveals that extremely few patients with severe chronic refractory ITP responded to this agent. In most negative studies, danazol was used in a small number of patients as a single agent and was discontinued after 2 to 4 months. However, in some patients, response was delayed for as long as 10 months. Therefore, therapy should be continued for at least 6 months, preferably for 1 year, if no serious adverse effects occur. Remissions induced by long-term danazol can last for years, even after discontinuation of the drug.
      • Ahn YS
      • Horstman LL
      Idiopathic thrombocytopenic purpura: pathophysiology and management.
      Pharmacokinetic studies indicate that danazol concentrations in plasma and in blood cell membranes are extremely variable.
      • Horstman LL
      • Jy W
      • Arce M
      • Ahn YS
      Danazol distribution in plasma and cell membranes as related to altered cell properties: implications for mechanism.
      • Potts GO
      • Schane HP
      • Edelson J
      Pharmacology and pharmacokinetics of danazol.
      Some patients in whom standard dosage (400-800 mg/d) failed responded to a low dose (50 mg/d),
      • Ahn YS
      • Mylvaganam R
      • Garcia RO
      • Kim CI
      • Palow D
      • Harrington WJ
      Low-dose danazol therapy in idiopathic thrombocytopenic purpura.
      suggesting that excessively high blood concentrations may have adverse effects on platelets. The mechanisms of action of danazol are unclear but involve impairment of macrophage-mediated clearance of antibody-coated platelets via decreased Fc receptor expression.
      • Schreiber AD
      • Chien P
      • Tomaski A
      • Cines DB
      Effect of danazol in immune thrombocytopenic purpura.
      Danazol is generally well tolerated; the most frequent adverse effects include headache, nausea, breast tenderness, maculopapular rash, weight gain, hair loss, myalgia, amenorrhea, and liver dysfunction. Long-term study of patients with angioneurotic edema have shown the safety of danazol therapy given over a 10-year period.
      • Hosea SW
      • Santaella ML
      • Brown EJ
      • Berger M
      • Katusha K
      • Frank MM
      Long-term therapy of hereditary angioedema with danazol.
      Rare cases of hepatic peliosis and hepatomas have been reported.
      • Ahn YS
      • Horstman LL
      Idiopathic thrombocytopenic purpura: pathophysiology and management.

      Azathioprine

      Azathioprine is one of the most commonly used immunosuppressive agents. Approximately 20% of patients may achieve a normal platelet count with this agent. Responses may be sustained for several months to years and, at least in some patients, persist after treatment is discontinued. An additional 30% to 40% may have partial responses.
      • George JN
      • El-Harake MA
      • Aster RH
      Thrombocytopenia due to enhanced platelet destruction by immunologic mechanisms.
      Median time to response ranges between 2 and 4 months, and treatment should be continued for up to 6 months before being deemed a failure. Azathioprine may be given orally at a dosage of 1 to 4 mg/kg per day, which should be modified according to the leukocyte count. A major concern, particularly in younger patients, is the risk of developing a malignancy. Kyle and Gertz
      • Kyle RA
      • Gertz MA
      Second malignancies after chemotherapy.
      reported the occurrence of acute leukemias and myelodysplastic syndromes in 30 patients treated with azathioprine. The teratogenic risk of azathioprine has not been documented.

      Cyclophosphamide

      Cyclophosphamide can be given as a daily oral dose or an intermittent (usually every 3-4 weeks) intravenous pulse dose (1.0-1.5 g/m2). Oral cyclophosphamide is usually initiated at a dosage of 1 to 2 mg/kg per day and should be adjusted with the aim of maintaining mild neutropenia. Responses occur within 2 to 10 weeks and, as with azathioprine, can persist after therapy is stopped.
      • Verlin M
      • Laros Jr, RK
      • Penner JA
      Treatment of refractory thrombocytopenic purpura with cyclophosphamide.
      In an uncontrolled case series of 20 patients, the intermittent intravenous regimen produced 65% complete responses and 20% partial responses.
      • Reiner A
      • Gernsheimer T
      • Slichter SJ
      Pulse cyclophosphamide therapy for refractory autoimmune thrombocytopenic purpura.
      Five of the 13 responders relapsed at 4 months to 3 years. Responses occurred within 1 to 6 months after treatment. Adverse effects of cyclophosphamide include bone marrow suppression, hemorrhagic cystitis, infertility, teratogenicity, and development of secondary malignancy. Therefore, the use of this agent should be carefully evaluated among younger patients.

      Vinca Alkaloids

      Both vincristine and vinblastine have been used for refractory ITP, and the response appears to be independent of the agent used and the mode of delivery (intravenous bolus or a more prolonged infusion).
      • Facon T
      • Caulier MT
      • Wattel E
      • Jouet JP
      • Bauters F
      • Fenaux P
      A randomized trial comparing vinblastine in slow infusion and by bolus i.v. injection in idiopathic thrombocytopenic purpura: a report on 42 patients.
      Responses have been described in 50% to 70% of patients. However, only a few patients have a sustained remission, and most require maintenance injections. A common regimen for vincristine is 2 mg/wk intravenously for several weeks. Adverse effects include peripheral neuropathy, which is common and may be persistent, and constipation. The mechanism of action of the vinca alkaloids is uncertain but may be related to inhibition of phagocytic cell function.

      Combination Chemotherapy

      The use of aggressive lymphomalike chemotherapy regimens for chronic refractory ITP has been reported in one series.
      • Figueroa M
      • Gehlsen J
      • Hammond D
      • et al.
      Combination chemotherapy in refractory immune thrombocytopenic purpura.
      • McMillan R
      Long-term outcomes after treatment for refractory immune thrombocytopenic purpura [letter].
      Immune thrombocytopenic purpura was associated with Hodgkin disease in one case and with chronic lymphocytic leukemia in another. All 12 patients had prior treatment with corticosteroids, and all had undergone splenectomy. The duration of thrombocytopenia ranged from 5 to 110 months, and all patients had platelet counts of less than 5 × 109/L unless they were receiving some form of platelet-enhancing therapy. The chemotherapy regimen consisted of up to 6 cycles of cyclophosphamide and prednisone plus 1 or more other agents (vincristine, procarbazine, and/or etoposide). Seven patients had a complete response, which was sustained in 4 patients for 60 to 150 months, and 2 had a partial response.

      Cyclosporin A

      Cyclosporin A has been shown to increase platelet counts when given either alone or with prednisolone. Emilia et al
      • Emilia G
      • Morselli M
      • Luppi M
      • et al.
      Long-term salvage therapy with cyclosporin A in refractory idiopathic thrombocytopenic purpura.
      reported 12 patients with chronic ITP treated with cyclosporin A (2.5-3.0 mg/kg per day). Complete responses were seen in 9 patients and a partial response in 1. Adverse effects were moderate but transient. Most patients had a sustained response after treatment was discontinued. In another study, 20 patients with ITP refractory to corticosteroids, half of whom had undergone splenectomy, were treated with cyclosporin A for at least 4 weeks.
      • Kappers-Klunne MC
      • van't Veer MB
      Cyclosporin A for the treatment of patients with chronic idiopathic thrombocytopenic purpura refractory to corticosteroids or splenectomy.
      The dosage was reduced by 50 mg/d every 2 weeks in those showing responses. Five patients remained in complete remission for at least 2 years after discontinuing cyclosporin A, and another 6 showed partial responses. Cyclosporin A was discontinued in 6 patients because of adverse effects.

      Rituximab

      Several small studies have investigated the use of rituximab, a monoclonal antibody directed against the B-cell antigen CD20.
      • Stasi R
      • Pagano A
      • Stipa E
      • Amadori S
      Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura.
      • Giagounidis AA
      • Anhuf J
      • Schneider P
      • et al.
      Treatment of relapsed idiopathic thrombocytopenic purpura with the anti-CD20 monoclonal antibody rituximab: a pilot study.
      • Zaja F
      • Vianelli N
      • Sperotto A
      • et al.
      B-cell compartment as the selective target for the treatment of immune thrombocytopenias.
      The regimen used was identical to that used in follicular lymphomas, ie, 375 mg/m2 weekly for 4 consecutive weeks. The results were variable, but when the data were combined, the overall response rate was slightly greater than 50%, with 25% to 30% sustained complete responses. Responses were observed both early during treatment and several weeks after the last rituximab infusion. Splenectomized and nonsplenectomized patients responded equally well. The toxicity profile of rituximab appears favorable, and most adverse effects are grade 1 to 2 first-infusion reactions. The mechanisms of action of rituximab have not been investigated thoroughly. Rituximab induces a profound B-cell depletion that may involve the autoreactive B-cell clone. However, a mechanism of macrophage blockade by opsonized B cells also has been proposed, which may account for the early responses.

      Campath-1H

      Campath-1H is a humanized monoclonal antibody against CD52, a molecule expressed by both B and T lymphocytes. Lim et al
      • Lim SH
      • Hale G
      • Marcus RE
      • Waldmann H
      • Baglin TP
      CAMPATH-1 monoclonal antibody therapy in severe refractory autoimmune thrombocytopenic purpura.
      treated 6 patients with refractory ITP (3 patients had an underlying lymphoproliferative disease). A response was seen in 4 of 5 evaluable patients, and in 3 of these, the response lasted more than 4.9 months. In most patients, between 4 and 6 weeks were needed for a response to occur. Adverse effects were notable and included rigors and fever during the infusion and marked lymphopenia (<0.1 × 109/L) in all patients treated. Worsening of thrombocytopenia was noted in 2 patients during therapy. A more recent study has investigated the use of Campath-1H in patients with various cytopenias. A response was obtained in 15 and maintained in 6 patients at the expense of notable adverse effects.
      • Willis F
      • Marsh JC
      • Bevan DH
      • et al.
      The effect of treatment with Campath-1H in patients with autoimmune cytopenias.

      Autologous Hematopoietic Stem Cell Transplantation

      In recent years, autologous peripheral blood stem cell transplantation has been used for severe unresponsive autoimmune disorders. The results of a clinical trial using high-dose cyclophosphamide followed by autologous lymphocyte-depleted peripheral blood stem cell transplantation have been reported by investigators at the National Institutes of Health Clinical Center in Bethesda, Md.
      • Huhn RD
      • Fogarty PF
      • Nakamura R
      • et al.
      High-dose cyclophosphamide with autologous lymphocyte-depleted peripheral blood stem cell (PBSC) support for treatment of refractory chronic autoimmune thrombocytopenia.
      The patient group comprised 14 adults with chronic refractory ITP, including 5 patients who had Evans syndrome (autoimmune hemolytic anemia in addition to autoimmune thrombocytopenic purpura). At a median follow-up of 42 months, durable complete remissions were observed in 6 patients, durable partial responses in 2, and no response in 6; there were no transplant-related deaths. This trial has been extended to recruit other patients. Another ongoing trial at Fairview University Medical Center, Minneapolis, Minn, is evaluating the combination of timed plasmapheresis, high-dose cyclophosphamide and total lymphoid irradiation, and posttransplantation immunosuppression with cyclosporin A (http://www.clinicaltrials.gov).

      Thrombopoietin and Thrombopoietin-like Agents

      An alternative to increasingly intensive immunosuppression may be to stimulate platelet production with thrombopoietin or its analogues. In fact, in addition to markedly shortened platelet survival, impaired platelet production may be responsible for thrombocytopenia in ITP.
      • Ballem PJ
      • Segal GM
      • Stratton JR
      • Gernsheimer T
      • Adamson JW
      • Slichter SJ
      Mechanisms of thrombocytopenia in chronic autoimmune thrombocytopenic purpura: evidence of both impaired platelet production and increased platelet clearance.
      The pathogenetic mechanisms of this phenomenon probably involve autoantibodies that affect megakaryocyte development. On the basis of these observations, it has been postulated that stimulation by thrombopoietin may result in safe platelet counts. A report involving 4 patients documented increased platelet counts in 3 patients, with thrombocytosis resulting in platelet counts of up to approximately 800 × 109/L in 2 patients.
      • Nomura S
      • Dan K
      • Hotta T
      • Fujimura K
      • Ikeda Y
      Effects of pegylated recombinant human megakaryocyte growth and development factor in patients with idiopathic thrombocytopenic purpura.

      Other Treatments

      Several other therapies have been used in chronic ITP, including dapsone,
      • Hernandez F
      • Linares M
      • Colomina P
      • et al.
      Dapsone for refractory chronic idiopathic thrombocytopenic purpura.
      • Godeau B
      • Oksenhendler E
      • Bierling P
      Dapsone for autoimmune thrombocytopenic purpura.
      interferon α,
      • Proctor SJ
      • Jackson G
      • Carey P
      • et al.
      Improvement of platelet counts in steroid-unresponsive idiopathic immune thrombocytopenic purpura after short-course therapy with recombinant alpha 2b interferon.
      • Dubbeld P
      • Hillen HF
      • Schouten HC
      Interferon treatment of refractory idiopathic thrombocytopenic purpura (ITP).
      colchicine,
      • Blanchette V
      • Freedman J
      • Garvey B
      Management of chronic immune thrombocytopenic purpura in children and adults.
      ascorbic acid,
      • Godeau B
      • Bierling P
      Treatment of chronic autoimmune thrombocytopenic purpura with ascorbate [letter].
      low-molecular-weight heparin,
      • Shen ZX
      • Li JM
      • Wang ZY
      • Han ZC
      • Caen JP
      • Bellucci SA
      Thrombocytopoietic effect of heparin given in chronic immune thrombocytopenic purpura.
      mycophenolate mofetil,
      • Howard J
      • Hoffbrand AV
      • Prentice HG
      • Mehta A
      Mycophenolate mofetil for the treatment of refractory auto-immune haemolytic anaemia and auto-immune thrombocytopenia purpura.
      • Hou M
      • Peng J
      • Shi Y
      • et al.
      Mycophenolate mofetil (MMF) for the treatment of steroid-resistant idiopathic thrombocytopenic purpura.
      2-chlorodeoxyadenosine,
      • Figueroa M
      • McMillan R
      2-Chlorodeoxyadenosine in the treatment of chronic refractory immune thrombocytopenic purpura [letter].
      and liposomal doxorubicin.
      • Cosgriff TM
      • Black ML
      • Stein III, W
      Successful treatment of severe refractory idiopathic thrombocytopenic purpura with liposomal doxorubicin.
      The number of patients in all these studies was small, and the responses were mostly unimpressive, inconsistent, and transient, often occurring in patients with less severe ITP.
      In one study, staphylococcal protein A immunoadsorption was reported to be a highly effective method of improving platelet count. Snyder et al
      • Snyder Jr, HW
      • Cochran SK
      • Balint Jr, JP
      • et al.
      Experience with protein A-immunoadsorption in treatment-resistant adult immune thrombocytopenic purpura.
      reported the effects of this treatment in 72 patients with chronic ITP. Forty-nine patients had undergone splenectomy, and most had received other platelet-enhancing therapies. All 72 patients were treated with an initial regimen of 6 immunoadsorption treatments for 2 to 3 weeks. Twenty-nine patients continued taking concomitant low-dose corticosteroids (<30 mg/ d), 9 of whom also received other platelet-enhancing medications. Twenty-five percent of patients had good responses (platelet counts of >100 × 109/L), 21% had fair responses (platelet counts of >50-100 × 109/L and at least double the baseline count), and 54% had poor responses. In 36% of patients, responses were maintained for 2 months or longer. Other studies have documented much less favorable results and considerably greater toxicity.
      • Kabisch A
      • Kroll H
      • Wedi B
      • Kiefel V
      • Pralle H
      • Mueller-Eckhardt C
      Severe adverse effects of protein A immunoadsorption [letter].
      • Cahill MR
      • Macey MG
      • Cavenagh JD
      • Newland AC
      Protein A immunoadsorption in chronic refractory ITP reverses increased platelet activation but fails to achieve sustained clinical benefit.
      The mechanisms of this therapy are unknown, but reduction in platelet-binding immunoglobulin and in circulating immune complex levels has been the postulated mechanism by which protein A immunoadsorption elicits its clinical effects. Protein A immunoadsorption may decrease platelet activation, and this may be an additional mechanism underlying its efficacy.
      • Cahill MR
      • Macey MG
      • Cavenagh JD
      • Newland AC
      Protein A immunoadsorption in chronic refractory ITP reverses increased platelet activation but fails to achieve sustained clinical benefit.
      Approximately one third of the patients developed an acute hypersensitivity-type reaction. A few cases of severe vasculitis also have been reported.
      • Kabisch A
      • Kroll H
      • Wedi B
      • Kiefel V
      • Pralle H
      • Mueller-Eckhardt C
      Severe adverse effects of protein A immunoadsorption [letter].
      • Cahill MR
      • Macey MG
      • Cavenagh JD
      • Newland AC
      Protein A immunoadsorption in chronic refractory ITP reverses increased platelet activation but fails to achieve sustained clinical benefit.

      INVESTIGATIONAL THERAPIES

      Clinical trials with numerous new agents are under way. More specific information about these trials can be found at the Web sites http://www.clinicaltrials.gov and http://www.itppeople.com/clinical.htm. Preliminary results for most of these studies are either unavailable or have been published only in abstract form.
      A response to etanercept, a recombinant fusion protein of the extracellular portion of the P75 tumor necrosis factor α receptor and the Fc portion of human IgG1, has been documented in 3 patients with severe, chronic, refractory ITP.
      • McMinn Jr, JR
      • Cohen S
      • Moore J
      • et al.
      Complete recovery from refractory immune thrombocytopenic purpura in three patients treated with etanercept.
      A clinical trial to evaluate the efficacy and toxicity of this agent in children and adults with chronic ITP is ongoing.
      A humanized monoclonal antibody to FcγRI receptors on monocytes and macrophages, MDX-33, has been investigated in a multicenter phase 2 study by Terjanian et al.
      • Terjanian T
      • Sher H
      • Vemuri R
      • et al.
      A proof-of-concept phase 2 study of monoclonal antibody MDX-33 in adult subjects with chronic stable ITP [abstract].
      A dose-dependent transient response in 30 patients with mild adverse effects was recorded.
      A humanized monoclonal antibody to CD40 ligand has been used in 2 groups of patients with ITP. This agent binds specifically to CD40 ligand (expressed by T cells) and blocks its ability to bind to CD40, thus preventing stimulation of the B lymphocytes and inhibiting antibody production. Of 29 patients treated, 7 showed an increase in platelet count to greater than 30 × 109/L; at least 2 of these patients have since relapsed. Three additional patients with ITP, with extremely low platelet counts and clinical bleeding, received the highest dose initially (rather than by dose escalation) and all responded.
      • Bussel J
      • Wissert M
      • Oates B
      • Scaramucci J
      • Nadeau K
      • Adelman B
      Humanized monoclonal anti-CD40 ligand antibody (hu5c8) rescue therapy of 15 adults with severe chronic refractory ITP [abstract].
      However, this trial was stopped because of adverse thrombotic events. Another multicenter trial with a different humanized monoclonal antibody to CD40 ligand is ongoing.
      • Kuwana M
      • Kawakami Y
      • Ikeda Y
      Suppression of autoreactive T-cell response to glycoprotein IIb/IIIa by blockade of CD40/CD154 interaction: implications for treatment of immune thrombocytopenic purpura.
      Daclizumab, a humanized monoclonal antibody directed against CD25 (interleukin 2 receptor), which has been used primarily to prevent rejection of solid organ transplants, is being tested at the Warren Grant Magnuson Clinical Center of Bethesda, Md, in patients with ITP who do not respond to initial prednisone treatment.
      • Carswell CI
      • Plosker GL
      • Wagstaff AJ
      Daclizumab: a review of its use in the management of organ transplantation.
      • Billaud EM
      Clinical pharmacology of immunosuppressive drugs: year 2000—time for alternatives.
      • Ponticelli C
      • Tarantino A
      Promising new agents in the prevention of transplant rejection.
      • Berard JL
      • Velez RL
      • Freeman RB
      • Tsunoda SM
      A review of interleukin-2 receptor antagonists in solid organ transplantation.
      A phase 1/2 open-label dose-escalation clinical trial to evaluate the safety and efficacy of cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin (CTLA-4-Ig) in patients with refractory ITP has been launched in the United Kingdom. The fusion immunoglobulin CTLA-4-Ig combines the first extracellular domain of human CD152 and the Fc portion of human IgG1; CTLA-4-Ig probably blocks T-cell activation by competing for the costimulatory molecules.
      • Abrams JR
      • Lebwohl MG
      • Guzzo CA
      • et al.
      CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris.

      ITP IN PREGNANCY

      Mild to moderate thrombocytopenia is common in healthy women with an apparently normal pregnancy.
      • Burrows RF
      • Kelton JG
      Incidentally detected thrombocytopenia in healthy mothers and their infants.
      Most of these women have gestational thrombocytopenia, a benign self-limiting condition with no notable bleeding risk to either mother or infant.
      • George JN
      • Woolf SH
      • Raskob GE
      • et al.
      Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology.
      • British Committee for Standards in Haematology General Haematology Task Force
      Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy.
      Gestational thrombocytopenia is characterized by mild thrombocytopenia (platelets rarely decrease to less than 80 × 109/L), occurrence in healthy women with otherwise normal blood counts, normal platelet counts before and after pregnancy, and no association with fetal or neonatal thrombocytopenia. However, distinguishing gestational thrombocytopenia from ITP may be difficult or impossible when the thrombocytopenia is identified for the first time during pregnancy and no previous platelet counts have been documented.
      • George JN
      • Woolf SH
      • Raskob GE
      • et al.
      Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology.
      • British Committee for Standards in Haematology General Haematology Task Force
      Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy.
      Proper management of ITP in pregnancy requires consideration of both the mother and the fetus because IgG antiplatelet antibodies cross the placenta and may produce profound thrombocytopenia in the neonate. No high-quality prospective studies or randomized clinical trials exist about preferred treatment of the mother or neonate or about optimal delivery procedure. The decision to treat the pregnant woman with ITP is based on assessment of the risk of hemorrhage. The platelet count usually decreases as pregnancy progresses, the greatest rate of decline and nadir occurring in the third trimester.
      • Burrows RF
      • Kelton JG
      Thrombocytopenia during pregnancy.
      Therefore, careful planning is required to ensure a safe platelet count at the time of delivery. Asymptomatic patients with platelet counts of greater than 20 × 109/L do not require treatment until delivery is imminent but should be carefully monitored, both clinically and hematologically.
      • Letsky EA
      • Greaves M
      • Maternal and Neonatal Haemostasis Working Party of the Haemostasis and Thrombosis Task Force of the British Society for Haematology
      Guidelines on the investigation and management of thrombocytopenia in pregnancy and neonatal alloimmune thrombocytopenia.
      Although a consensus has not been reached, most experts agree that platelet counts of greater than 50 × 109/L are safe for normal vaginal delivery and are safe for cesarean section, whereas epidural anesthesia is used only when platelet counts are greater than 80 × 109/L because of the potential risk of hematoma formation and neurologic damage.
      • George JN
      • Woolf SH
      • Raskob GE
      • et al.
      Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology.
      The major treatment options for maternal ITP are corticosteroids or IVIg. Vinca alkaloids, androgens, and most immunosuppressive drugs should not be used during pregnancy, although azathioprine has been used safely in patients who underwent transplantation. If the duration of treatment is likely to be short, ie, starting in the third trimester, corticosteroids are a cost-effective option. An initial dosage of 1 mg/kg per day (based on prepregnancy weight) is recommended
      • Burrows RF
      • Kelton JG
      Thrombocytopenia during pregnancy.
      • Letsky EA
      • Greaves M
      • Maternal and Neonatal Haemostasis Working Party of the Haemostasis and Thrombosis Task Force of the British Society for Haematology
      Guidelines on the investigation and management of thrombocytopenia in pregnancy and neonatal alloimmune thrombocytopenia.
      and should be tapered subsequently to the minimum hemostatically effective dose. Patients must be monitored carefully for major adverse effects such as hypertension, hyperglycemia, osteoporosis, excessive weight gain, and psychosis. Because 90% of the administered dose of prednisone is metabolized in the placenta, serious fetal adverse effects such as adrenal suppression are unlikely. If corticosteroid therapy is likely to be prolonged, or notable adverse effects occur, or an unacceptably high maintenance dosage is required (>10 mg/d of prednisone), IVIg therapy should be considered.
      • British Committee for Standards in Haematology General Haematology Task Force
      Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy.
      The response rate (80%) and duration of response (2-3 weeks) to IVIg is similar to those of nonpregnant patients.
      The ability of maternal IVIg therapy to improve fetal platelet counts remains controversial.
      • Nicolini U
      • Tannirandorn Y
      • Gonzalez P
      • et al.
      Continuing controversy in alloimmune thrombocytopenia: fetal hyperimmunoglobulinemia fails to prevent thrombocytopenia.
      Intravenous immunoglobulin has the same potential risks and adverse effects as in the nonpregnant patient, and the financial cost is much higher than that of corticosteroids. Therapeutic options for women with severely symptomatic ITP refractory to oral corticosteroids or IVIg include high-dose intravenous methylprednisolone (1 g), alone or combined with IVIg or azathioprine,
      • Letsky EA
      • Greaves M
      • Maternal and Neonatal Haemostasis Working Party of the Haemostasis and Thrombosis Task Force of the British Society for Haematology
      Guidelines on the investigation and management of thrombocytopenia in pregnancy and neonatal alloimmune thrombocytopenia.
      which, from available data, appears to cause no serious problems to either mother or fetus.
      • Alstead EM
      • Ritchie JK
      • Lennard-Jones JE
      • Farthing MJ
      • Clark ML
      Safety of azathioprine in pregnancy in inflammatory bowel disease.
      Splenectomy during pregnancy is performed rarely; if absolutely essential, it is best carried out in the second trimester and may be successfully performed laparoscopically, although this may be technically difficult after 20 weeks' gestation. More recently, intravenous anti-D has been shown to be both effective and safe during pregnancy with no adverse effects experienced by either the mother or fetus.
      • Michel M
      • Novoa MV
      • Bussel JB
      Intravenous anti-D as a treatment for immune thrombocytopenic purpura (ITP) during pregnancy.
      The major concern is at delivery because the incidence of fetal thrombocytopenia with platelet counts of less than 50 × 109/L is approximately 10% to 15% and with platelet counts of less than 20 × 109/L is approximately 5%.
      • Yamada H
      • Kato EH
      • Kishida T
      • Negishi H
      • Makinoda S
      • Fujimoto S
      Risk factors for neonatal thrombocytopenia in pregnancy complicated by idiopathic thrombocytopenic purpura.
      • Iyori H
      • Fujisawa K
      • Akatsuka J
      Thrombocytopenia in neonates born to women with autoimmune thrombocytopenic purpura.
      • Christiaens GC
      • Nieuwenhuis HK
      • Bussel JB
      Comparison of platelet counts in first and second newborns of mothers with immune thrombocytopenic purpura.
      • Payne SD
      • Resnik R
      • Moore TR
      • Hedriana HL
      • Kelly TF
      Maternal characteristics and risk of severe neonatal thrombocytopenia and intracranial hemorrhage in pregnancies complicated by autoimmune thrombocytopenia.
      • Burrows RF
      • Kelton JG
      Pregnancy in patients with idiopathic thrombocytopenic purpura: assessing the risks for the infant at delivery.
      • Cook RL
      • Miller RC
      • Katz VL
      • Cefalo RC
      Immune thrombocytopenic purpura in pregnancy: a reappraisal of management.
      No accurate, risk-free method of determining fetal platelet count is currently available, and both cordocentesis and fetal scalp blood sampling are rarely used in the treatment of ITP during pregnancy. The only characteristics that have been consistently correlated with an increased incidence of fetal thrombocytopenia are prior splenectomy and thrombocytopenia in the first or preceding sibling.
      • Christiaens GC
      • Nieuwenhuis HK
      • Bussel JB
      Comparison of platelet counts in first and second newborns of mothers with immune thrombocytopenic purpura.
      • Payne SD
      • Resnik R
      • Moore TR
      • Hedriana HL
      • Kelly TF
      Maternal characteristics and risk of severe neonatal thrombocytopenia and intracranial hemorrhage in pregnancies complicated by autoimmune thrombocytopenia.
      • Valat AS
      • Caulier MT
      • Devos P
      • et al.
      Relationships between severe neonatal thrombocytopenia and maternal characteristics in pregnancies associated with autoimmune thrombocytopenia.
      In one series of 64 pregnant women with chronic ITP, the incidence of severe neonatal thrombocytopenia (platelet count of <50 × 109/L) was 57% when mothers had prior splenectomy and a gestational platelet count of less than 50 × 109/ L; the incidence was 0% when mothers had neither of these 2 findings.
      • Valat AS
      • Caulier MT
      • Devos P
      • et al.
      Relationships between severe neonatal thrombocytopenia and maternal characteristics in pregnancies associated with autoimmune thrombocytopenia.
      It has been postulated that trauma during vaginal delivery may precipitate central nervous system bleeding in the neonate and that cesarean section may obviate this problem; however, this hypothesis has been questioned.
      • Burrows RF
      • Kelton JG
      Pregnancy in patients with idiopathic thrombocytopenic purpura: assessing the risks for the infant at delivery.
      In fact, the incidence of fetal hemorrhage is less than 1%, and there are no differences in the rate of complications with cesarean section compared with vaginal delivery. Thus, it is now generally agreed that the mode of delivery in ITP should be determined purely by obstetric indications.
      After delivery, the infant's platelet count often declines during the first week and should be monitored carefully.
      • Burrows RF
      • Kelton JG
      Fetal thrombocytopenia and its relation to maternal thrombocytopenia.
      For severe thrombocytopenia or mucosal bleeding in the neonate, intravenous IVIg is the treatment of choice. Platelet transfusions that are cytomegalovirus negative and irradiated can be added in the event of severe bleeding.
      • British Committee for Standards in Haematology General Haematology Task Force
      Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy.

      CONCLUSIONS

      Because of the general lack of randomized studies, management options for ITP are not based on evidence but on a rational approach to the individual patient that includes assessment of disease severity, patient's characteristics related to risk of bleeding, and the risks and adverse effects of treatment. The toxicity profiles of many of the newer treatments underline the need for appropriate choices and for trials designed to incorporate end points such as quality-of-life measures and economic analyses. Real evidence-based guidelines for this disease are not likely to be developed soon. Considering the low incidence of mortality and major morbidity of ITP, prospective trials probably would require the enrollment of several hundred patients to show the superiority of a particular agent or management protocol. The availability of a biological surrogate marker, such as the detection of autoreactive B-cell clones, would obviously be a major step forward. Unfortunately, such markers have not yet been identified. Basic research needs to be intensified to unravel the pathogenetic mechanisms underlying ITP, which we hope would lead to more individualized, targeted, and possibly less toxic treatment regimens. Meanwhile, a stronger methodology of clinical reports, which should describe consecutive patients with clear inclusion and exclusion criteria as well as long follow-up data to document clinical outcomes and platelet responses, could help clinicians to delineate more precise treatment strategies.

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