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From bloodjournal.hematologylibrary.org by guest on March 26, 2014. For personal use only.

2005 106: 2244-2251 Prepublished online June 7, 2005; doi:10.1182/blood-2004-12-4598

How I treat idiopathic thrombocytopenic purpura (ITP)
Douglas B. Cines and James B. Bussel

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herbs. 525 E 68th St. 422 Curie Blvd. generally between 18 and 40 years of age. 2004. or if there is a concern about common variable immunodeficiency or IgA deficiency. or James B. and response to therapy were typical for ITP. including a bone marrow examination.7. e-mail: dcines@ mail. which confer a less favorable prognosis. proved to be compendia of opinions from panels of experienced physicians who concurred on some matters but not on others.edu.13. and the incidence of ITP increased with age and increased overall during the period of study. 2005. Payson 695.7 Two recent publications have questioned this perception.6 Gender disparity largely disappears among the elderly. Testing for HIV or hepatitis C infection (or both) is indicated in at-risk populations and the latter may occur more widely than previously appreciated. Submitted December 8. Weill Cornell Medical Center. Conversely.hematologylibrary. the age-specific incidence was highest among those older than 60 years. even if transient. laboratory testing. and it is likely that our own approach will change based on emerging data. and Departments of Pediatrics. NY. The first was a survey from a single county in Denmark using International Classification of Disease (ICD) codes at hospital discharge over a 22-year period.15 We neither perform the more sensitive breath testing nor treat empirically at presentation. or other substances (eg. severity of thrombocytopenia. Weill Cornell Medical Center. giant platelets. and Obstetrics and Gynecology. expert opinions differ for good reason. Comprehensive reviews on pathogenesis. How we diagnose ITP ITP remains a diagnosis of exclusion. family history consistent with inherited thrombocytopenia.From bloodjournal. Reprints: Douglas Cines. again. New York.12 Remissions induced by eradication of asymptomatic Haemophilus pylori infection have been reported in studies from Italy and Japan. pseudothrombocytopenia. We test for antiphospholipid antibodies if there is a history thrombosis.11 or drug-dependent antibodies. Bussel Introduction Our goal is to set forth our opinion of the best approach to managing adults with primary idiopathic (autoimmune) thrombocytopenic purpura (ITP). 2005. accepted April 14. experience from numerous centers over more than a half-century indicated that the typical adult with ITP is a woman.” The paucity of evidence-based medicine on this topic has been noted. especially intravenous immune globulin (IVIG) or intravenous anti-D (IV anti-D).10. 513A Stellar-Chance. quinine) associated with thrombocytopenia. Medicine. June 7. an otherwise unremarkable peripheral smear.8 The second was a prospective cohort analysis of newly presenting adults with platelet counts less than 50 000 ϫ 109/L in the Northern Health Region of the United Kingdom. The essential elements include an otherwise healthy individual who presents with isolated From the Departments of Pathology and Laboratory Medicine and Medicine.or third-trimester gestational failure. or symptoms/signs suggestive of an underlying disorder that may cause secondary immune thrombocytopenia. New York Presbyterian Hospital. the median age at diagnosis was 56 years. © 2005 by The American Society of Hematology 2244 BLOOD. Departments of Pathology and Laboratory Medicine and Medicine. and treatment are to be found elsewhere.1 Both the American Society of Hematology2 and the British Committee for Standards in Haematology General Haematology Task Force3 have issued “practice guidelines. We only perform bone marrow examinations as a matter of routine in otherwise typical patients if they are over 60 years of age when the incidence of MDS becomes significant. PA.upenn. and the exclusion of other causes of thrombocytopenia if grounds for suspicion exist. but much of what follows rests on our mutual experience treating patients. The female-male ratio was 1. 1 OCTOBER 2005 ⅐ VOLUME 106. Bussel. Many issues remain unresolved. New York Presbyterian Hospital.9 Presenting symptoms. or a prolonged activated partial thromboplastin time. if there is a reaction to IVIG or prior transfusions.14 but is not our experience. University of Pennsylvania School of Medicine. DOI 10. recurrent or second. and often prior to splenectomy if not previously performed. is the single best diagnostic test. secondary ITP. ITP in children. e-mail: jbussel@med. For personal use only.6. Departments of Pediatrics.edu.4.1182/blood-2004-12-4598.10 misdiagnosed myelodysplasia (MDS). Who develops ITP? Until recently. Cines and James B. and Obstetrics and Gynecology. University of Pennsylvania School of Medicine. Clonality and cytogenetics are assessed as part of the bone marrow evaluation.cornell. 2014. heavily referenced review.” These. We cite published evidence where we find it compelling and reproducible. New York. These include exposure to drugs. rather than an encyclopedic.and off-study.5 thrombocytopenia. How I treat How I treat idiopathic thrombocytopenic purpura (ITP) Douglas B. a physical examination that only shows evidence of bleeding consistent with the platelet count. PA 19104. The female-male ratio was 1. NY 10021.2 and. with emphasis on the word “opinion. in large part.16 Up to 5% to 10% of patients eventually meet criteria for systemic lupus erythematosus or another cause of secondary immune thrombocytopenia. Immunoglobulin levels are measured if there is a history of recurrent infection or allergy. a poor response to treatment may necessitate re-evaluation of the diagnosis. Philadelphia. but consider testing in chronic cases and those with gastrointestinal symptoms. Prepublished online as Blood First Edition Paper. Disturbances in thyroid function occur with sufficient frequency that we often measure thyroid-stimulating hormone levels if there are complaints of persistent fatigue and prior to splenectomy. both on. so these data do not simply reflect increased detection of mild cases based on automated platelet determinations.org by guest on March 26.17 Our approach to secondary immune thrombocytopenia. Medicine. in those who do not show a robust response (Ͼ 50 000 ϫ 109/L) to treatment. foods. Philadelphia.med. NUMBER 7 . Response to treatment. Approximately 1% of patients have coexisting immune hemolytic anemia (Evans syndrome) and a smaller percentage have immune neutropenia.

4 We do not rely on measuring antiplatelet antibodies to make or exclude a diagnosis of ITP. Our opinion is that it is as unreasonable to apply a “one-size fits all” threshold as it would be to attempt to normalize platelet counts in all patients.22 In a meta-analysis of 17 studies. including spontaneous intracerebral hemorrhage (ICH).org by guest on March 26. major bleeding has been reported at platelet counts between 20 000 and 30 000 ϫ 109/L. or even the extensive traveler. counts may drop suddenly at any time.24 at platelet counts between 10 000 and 20 000 ϫ 109/L. and patient preference. 40 to 60.8%. Figure 1 shows our treatment algorithm for initial management. Predicted 5-year mortality ranged from 2. antibodies have also been detected in 10% to 20% of patients with certain causes of “nonimmune” thrombocytopenias (eg. 2014.30 Therapy is indicated in all patients who present with bleeding and those with platelet counts less than 20 000 ϫ 109/L because fewer than 10% of adults rapidly attain spontaneous remission. and common side effects. the age-adjusted risk of fatal hemorrhage at platelet counts persistently less than 30 000 ϫ 109/L was estimated to be 0.24-26 Major bleeding. For personal use only. overt hematuria.hematologylibrary. In general. sedentary individuals die of hemorrhage over a 10-year period if they maintain a stable platelet count more than 20 000 ϫ 109/L and though we rarely treat patients with platelet counts more than 30 000 ϫ 109/L in the absence of extenuating circumstances that predispose to serious bleeding. expected response times. those in whom responsiveness to therapy has not been established—for example. gingival bleeding. Although rare. do patients present with bleeding disproportionate to the platelet count because of antibody-induced platelet dysfunction. NUMBER 7 ITP 2245 including systemic lupus erythematosus.From bloodjournal.23 Similar mortality rates have been reported by others depending on duration of followup. but not without precedence. prolonged epistaxis. when comorbid factors predisposing to bleeding or complications of therapy are present. These assays lack sufficient sensitivity to exclude a diagnosis of ITP18-20 and interlaboratory reproducibility is inadequate. Our usual practice is to maintain a somewhat higher platelet count initially (eg. Although some argue that current methods to detect platelet antigen-specific antibodies are now sufficiently specific to affirm the diagnosis.2% to 47. tolerance of treatment.3 We recommend maintaining platelet counts above 40 000 to 50 000 ϫ 109/L for patients requiring aspirin.29 Some patients experience untoward and otherwise unexplained fatigue when their platelet count is low. BLOOD.24 A worrisome number of patients who developed ICH did so after acute and often unpredictable Patients typically present with petechiae or purpura that develop over several days accompanied by platelet counts less than 20 000 ϫ 109/L. Furthermore. warfarin. and in some cases. chronic liver disease. among others. 1. Those with platelet counts more than 50 000 ϫ 109/L can almost always be observed. Spontaneous or posttraumatic ICH or bleeding at other internal sites is uncommon. nonsteroidal anti-inflammatory drugs. immediate therapy is not required for patients with platelet counts between 20 000 and 50 000 ϫ 109/L in the absence of bleeding or predisposing comorbid conditions such as uncontrolled hypertension. Rarely. Drugs that interfere with platelet function are discontinued. Treatment at presentation Principles of management Who we treat What is a hemostatic platelet count? Is the platelet count a reasonable surrogate marker for the risk of serious bleeding? In a recent 10-year study of 310 patients in whom treatment was generally used only at platelet counts less than 30 000 ϫ 109/L.27 We would argue that the goal of therapy must be individualized on the basis of signs and symptoms. although the onset is often more insidious than previously appreciated. The initial goal of treatment is to attain a hemostatic platelet count (Ն 30 000 ϫ 109/L) while minimizing the toxicity of treatment. There is room for disagreement in each of these cases. with the goal of establishing a track record of bleeding. a compelling case can be made to treat patients with platelet counts below 20 000 ϫ 109/L. active peptic ulcer disease. whereas platelet counts above 50 000 ϫ 109/L are usually discovered incidentally. those in whom there is a question about compliance. All others can be . and older than 60 years of age. but they illustrate the types of issues confronted in real practice. or after inadvertently taking medications that impair platelet function. compliance. Management is predicated primarily on the severity of thrombocytopenia and bleeding. anticoagulation. the 28 year-old hard-hat construction worker. Alternatives are substituted for drugs deemed necessary but potentially causal.2%. Some experts would apply this reasoning to recommendations for splenectomy. has been reviewed elsewhere. The reader is referred elsewhere for a more comprehensive tabulation of drug doses. the populations in which testing would be most helpful. 1 OCTOBER 2005 ⅐ VOLUME 106. MDS).4%. Hospitalization and emergency therapy We hospitalize (1) patients with profound mucocutaneous or internal bleeding and (2) those who present with platelet counts of less than 20 000 ϫ 109/L and a history of significant bleeding. the 26-year-old who feels completely drained of energy unless her platelet count approaches 50 000 ϫ 109/L. the policeman who routinely faces physical confrontation.2. and 13% per patient per year for those younger than 40. or menorrhagia may develop at platelet counts less than 10 000 ϫ 109/L.27 Thus. no published follow-up is of sufficient length or size to project risk over a life span. Is 20 000 to 30 000 ϫ 109/L a safe and appropriate platelet count for the 63-year-old man with angina who then suddenly requires clopidogrel and aspirin after a coronary stent is placed? What about the high school student able to afford college only if awarded a football scholarship. Although few otherwise healthy.24. generally less than 10 000 ϫ 109/L. or other antithrombotics. occurs predominantly in patients with platelet counts less than 20 000 ϫ 109/L. What is more contentious and requires individualization and considerable judgment is the wisdom of treating patients with platelet counts between 20 000 and 50 000 ϫ 109/L. although some (5 of 87 in one series7) require treatment later. respectively. only one hemorrhagic death occurred. antiphospholipid syndrome.21 events such as viral infection or head trauma. and HIV infection. lifestyle. Those with platelet counts between 30 000 and 50 000 ϫ 109/L may note easy bruising.10 Severe cutaneous bleeding. or head trauma. and risk management that allows us to modify the threshold for treatment over time. 30 000 ϫ 109/L) while we get to know the patient. B-cell malignancies (primarily chronic lymphocytic and large granular leukemias). the 19-year-old woman with marked menorrhagia unresponsive to hormonal management. recent surgery.28 although we use a higher threshold (see “Splenectomy”).

91 and the risk is lessened by avoiding treatment in those with a positive direct antiglobulin test unless attributable to prior IVIG or IV anti-D therapy. prn.0 mg/kg/day) orally as the initial approach. patients develop aseptic meningitis. Persistent ITP Thrombocytopenia recurs in most patients when corticosteroids are tapered. even those who enter remission often require additional or alternative therapy. our preference is to infuse IV anti-D as needed. including cessation of drugs that impair platelet function. NUMBER 7 occasion. Rarely.hematologylibrary.3 ␮g/kg). every. or hemolysis. Our practice is to continue full doses for 3 to 4 weeks. all 3 modalities given prior to transfusions may help preserve their longevity in the circulation.37 and platelet transfusions (bolus followed by continuous infusion as needed) for life.47 We taper prednisone slowly. to avoid adrenal insufficiency. topical thrombin.org by guest on March 26. 0.” We would generally treat for a minimum of 3 months and a maximum of 12 months. IV anti-D (50-75 ␮g/kg). thrombosis.From bloodjournal. (4) We recommend splenectomy for those clearly requiring therapy beyond 12 months to maintain a hemostatic platelet count and sooner in select individuals intolerant of therapy. on We treat most patients with prednisone (1. and progestational agents to manage menorrhagia. Rapid lasting responses to dexamethasone (40 mg orally daily for 4 d/mo) are reported. For those whose disease does not abate by 1 year after diagnosis. measures to minimize trauma. such as with ICH. including anti-CD20 (rituximab) or danazol are discussed (see “First-line therapy” and “Second-line therapy. who do not show a durable response. or IV methylprednisolone (1 g) if platelet counts remain below 20 000 ϫ 109/L or if there is another need for a more rapid response. cataracts.” respectively).38 Recombinant factor VIIa may be added in patients unresponsive to other modalities if an immediate response is necessary. Details of therapy and duration of treatment are discussed in text. which can be ameliorated by pretreatment with corticosteroids.or organ-threatening bleeding or after head trauma. and patient preference as discussed in “Initial therapy for nonemergent indications. Therapy of adult ITP before splenectomy. For those in whom the former is chosen. and it minimizes interference with a normal lifestyle. Failure to respond to prednisone.63 with vincristine and methylprednisolone. pulmonary insufficiency. In the largest series to date. repeated or continuous platelet transfusions may be required in urgent situations. before considering splenectomy. 2014.16 There is no consensus concerning the optimal duration of corticosteroid treatment. and fibrin glue to manage dental extractions. We treat patients with persistent ITP with the goal of maintaining the platelet count more than 20 000 to 30 000 ϫ 109/L while avoiding steroid-induced osteoporosis. treated as outpatients.” that is. (2) We generally initiate therapy with prednisone and add either IV anti-D (in Rhϩ.25. Common toxicities of IV anti-D include fever/chill reactions.40. po indicates orally. although the assertion that this approach increases long-term response compared with prednisone42 requires longer follow-up and confirmation. Proton pump inhibitors should be given when corticosteroids are used for more than a few weeks.39 IVIG is generally well tolerated other than for a postinfusion headache. IV anti-D can be substituted for prednisone in Rhϩ and direct antiglobulin-negative patients intolerant of corticosteroids or who have contraindications to their use. (3) Thrombocytopenia recurs in most adults as corticosteroids are tapered. and measures to reduce mucosal bleeding. We have used aspirin in patients at risk for thrombosis (even in the absence of antiphospholipid antibody) whose platelet counts increase rapidly to more than 600 000 ϫ 109/L.0 g/kg/d for 1-2 days). we recommend splenectomy.7. and q. intravascular hemolysis and disseminated intravascular coordination are rare33. 1 OCTOBER 2005 ⅐ VOLUME 106. 25% to 30% of patients showed responses lasting longer than 1 year. with active lifestyles or comorbid risk factors that make higher platelet counts desirable. one who is unlikely to need frequent monitoring or intervention. The treatment modality depends on the severity of the thrombocytopenia and bleeding. or who are intolerant of therapy. barring evidence of late improvement. direct antiglobulin-negative patients) or IVIG as needed for persistent severe thrombocytopenia with the goal of attaining a platelet count of greater than 30 000 ϫ 109/L and cessation of bleeding. but only 10% to 30% of patients enter stable remission once therapy is tapered or stopped1.47 Alternatives. and extravascular hemolysis. Response rates vary from 50% to 90% depending on intensity and duration of therapy. we have combined IVIG and IV anti-D. IV anti-D and platelet transfusions may be given as needed. to be performed.34-36. tolerance of treatment. collagen. desmopressin acetate (DDAVP. control of blood pressure. Initial therapy for nonemergent indications Figure 1. Urgent treatment is initiated with intravenous methylprednisolone (1. 2246 CINES and BUSSEL BLOOD. The major decision is whether to temporize with medical therapy or to proceed swiftly to splenectomy. The timing of the procedure depends on . dissolving lyophilized preparations in sterile water to lower osmolarity and slowing the infusion rate may lessen these risks. as needed. acute renal failure.41. especially once doses of 10 mg/d are reached. and/or IVIG should prompt the diagnosis to be reconsidered and a bone marrow evaluation. Splenectomy Splenectomy remains the single best option to convert a patient with ITP into a “nonpatient. such as ⑀-aminocaproic acid (100 mg/kg loading dose up to a maximum of 5 g given intravenously over 30-60 minutes followed by up to 5 g every 6 hours intravenously or orally [maximum dose ϭ 24 g/day]) and.41 Therapy with prednisone can be supplemented with IVIG (1. (1) Minimal emergent therapy includes IV methylprednisolone and IVIG. For personal use only. We use ⑀-aminocaproic acid or tranexamic acid swish and swallow to help control oral bleeding. at least initially. and other toxicities.0 g/d for 1-3 consecutive days) combined with IVIG (Figure 1).43-46. We also initiate general measures to reduce the risk of bleeding. including cytogenetics and flow cytometry. until a response is seen or side effects become intolerable. which act through different IgG-Fc␥ receptors. Before splenectomy in Rhϩ patients. IV anti-D.

54 The major known long-term risk of splenectomy is overwhelming bacterial sepsis. In the future. Alkylating agents should be avoided or minimized (total dose of cyclophosphamide Ͻ 2000 mg/m2) in younger adults and those wishing to have children. and patients are increasingly reluctant to have a healthy organ removed unless they have experienced significant bleeding or morbidity from prior therapy. Therapy of adult ITP following splenectomy.51 and perhaps those with an hepatic platelet sequestration pattern.90 It is our practice to look for an accessory spleen with magnetic resonance imaging or another sensitive scanning method (eg. Most patients achieve this goal.56. with the exception that few patients who have undergone splenectomy respond well to IV anti-D. prn indicates as needed. We reserve splenic irradiation for the rare patient in whom splenectomy is indicated but hazardous or as a diagnostic test.2%. This trend has been accelerated by evidence that IV anti-D and anti-CD20 may allow splenectomy to be deferred and possibly avoided. we have found that patients totally refractory to multiple prior treatments appear to fare less well. and complex orthopedic or plastic surgery. we often use these agents initially because the other suggested Figure 2.org by guest on March 26.26 There are no randomized trials to support the effectiveness of any specific approach. risk of trauma and of the procedure. more than 10 mg prednisone/d) is required to maintain a platelet count greater than 30 000 ϫ 109/L.52 although we have no direct experience on the latter. if possible.58 We concur with several of the recommendations of the British Haematology Task Force3 concerning platelet counts for minor surgery (Ͼ 50 000 ϫ 109/L) and most major surgery (Ͼ 80 000 ϫ 109/L). for example. responsiveness and side effects of therapy. whereas other medications may adversely affect comorbid conditions (eg. The goal of therapy in this setting is to attain a hemostatic platelet count rather than to achieve cure. a life expectancy of 8 to 12 years. Thus. nasal. the decision must be individualized. However. We do not recommend lifelong use of phenoyxmethylpenicillin (250-500 mg orally twice daily) or erythromycin (500 mg orally twice daily) in otherwise healthy adults. (1) The goal of therapy in this population is to maintain a hemostatic platelet count while minimizing druginduced toxicity. while minimizing drug-induced toxicity (Figure 2).3 Revaccination for pneumococcus is recommended every 5 to 10 years. which occurs in less than 1% of adults with uncomplicated ITP. 1 OCTOBER 2005 ⅐ VOLUME 106. because few patients can be managed with chronic low-dose (5-10 mg) or alternate day doses of prednisone or wish to be bound indefinitely to parenteral therapy with IVIG. However. nonresponders may experience bleeding problems after the procedure. IV anti-D. We suggest patients wear a MedAlert bracelet. For personal use only. H influenzae type b.48 The outcomes of the 2 approaches are comparable. as needed. we think the benefits of splenectomy outweigh the risks in the typical active young adult with easy bruising or significant menorrhagia. with splenectomy reserved for those with a platelet count consistently less than 20 000 ϫ 109/L or in the face of difficult-to-control bleeding. .0% and 0. and significant risks from surgery. a platelet count of 20 000 to 30 000 ϫ 109/L. with corticosteroids or IVIG or the emergent measures described (see “Hospitalization and emergency therapy”) depending on severity. 2014. Such preferences must be respected. and prostate surgery.49 First-line therapy We treat symptomatic relapses or severe recurrent thrombocytopenia in the same way as at initial presentation. a 75-year-old asymptomatic patient with a platelet count of 18 000 ϫ 109/L. some experts recommend a far more protracted period of watchful waiting. or pulse doses of corticosteroids in known responders to boost the platelet count prior to splenectomy.57 although our experience is that most patients respond to vaccination given more than 6 weeks after surgery. If the patient does not wish to temporize. whereas others are unable or unwilling to undergo the procedure. although it may take years25.50 patients with secondary forms of ITP. corticosteroids and bone density or danazol and prostate disease). and a life expectancy of 50 to 60 years whose disease shows no signs of abating.25. Mortality rates for open and laparoscopic splenectomy are 1.26 and therapy can be toxic17 if not used judiciously.53 although the former hastens recovery and offers better cosmesis. that is.55 We immunize our patients with polyvalent pneumoccocal.” (2) Our preference is to use anti-CD20 if not used previously and we consider reuse if a response was seen prior to splenectomy.47 We use IVIG.48 However. higher counts are advisable for cardiac bypass surgery. Alternatively. and use corticosteroids or IVIG (or both) in the interim. plastic. responses cannot be predicted through routinely available measures. heat-damaged red cells) if the response to splenectomy was durable.From bloodjournal. Approximately 85% of patients attain a hemostatic response after splenectomy and two thirds achieve a durable response (for reviews. neurosurgery. and quadrivalent meningococcal polysaccharide vaccines at least 2 weeks prior to splenectomy if possible. Our experience is consistent with the reported incidence of relapse of 15% to 25% within 10 years. we recommend splenectomy within 3 to 6 months if any therapy (eg.41. All febrile illnesses demand careful evaluation and intravenous antibiotics should be provided urgently at the onset of any systemic illness with fever of 38°C (101°F) or higher until bacterial sepsis can be excluded. select patients may require somewhat higher platelet counts because of comorbid risk factors as discussed in “Treatment of chronic ITP. Although splenectomy has been performed safely at exceedingly low platelet counts. BLOOD.hematologylibrary. Treatment of chronic ITP Principles of treatment Approximately 30% to 40% of patients have platelet counts less than 50 000 ϫ 109/L after splenectomy because they did not respond or they had a relapse.7. Prophylactic platelet transfusions are rarely warranted and their routine use should be discouraged. we combine danazol with either azathioprine or mycophenolate mofetil for a minimum of 4 months. respectively.25. long-term effects of the procedure on the incidence of occlusive cerebrovascular disease remain under study. and patient and doctor preference. see Kojouri et al48 and Schwartz et al49). as do the elderly. it is almost always wise to introduce additional medications. ⑀-Aminocaproic acid can be used as a supplement for oral. In contrast. thrombopoietic agents currently in clinical trials may be used both before and after splenectomy. in contrast to others.59 Although some patients who failed to respond to these measures on presentation do so after splenectomy. NUMBER 7 ITP 2247 disease severity.28 Although we might concur with this approach in. Elderly patients are more likely to have severe bleeding and to suffer debilitating side effects of therapy.25 In general.

org by guest on March 26. If the decision is made to treat. We generally treat patients in whom splenectomy fails with the anti-CD20 monoclonal antibody. rituximab.61 Side effects are mostly related to the first infusion (fever. For personal use only.67 A high fluid intake (3-4 L daily either orally or intravenously during and for at least 3 days after therapy) and frequent blood counts are necessary. but in our experience response rates are higher when danazol is combined with an immunosuppressant. Profound and prolonged peripheral B-cell depletion is universal. 1 OCTOBER 2005 ⅐ VOLUME 106.25 Although many patients tolerate extremely low platelet counts for years without serious bleeding even without treatment.62 This approach also permits the more problematic agent to be tapered first. we generally initiate therapy with at least 2 agents to avoid inducing multiple drug resistance genes. hirsutism. and morbidity and mortality are considerable. or immunosuppressants) and who have had serious morbidity or have extremely low platelet counts (eg. chills. but 30% of patients discontinued treatment due to side effects (hypertension. the doses of danazol and the immunosuppressant can be gradually lowered over a period of months. In our limited experience. Once a response is seen. If there is sufficient time. Responses are usually noted within 4 to 8 weeks after the first infusion but may occur as late as 4 months. patients who responded but had a relapse often respond to subsequent courses. the minority of patients respond. splenectomy. and headaches). danazol. adjusted based on drug and creatinine levels). as the first approach to chronic immunosuppression because the incidence of acute and serious side effects is lower than with cyclophosphamide and the frequency of lasting remissions is comparable (20%-40%).0-1. Some patients are intolerant or unwilling to continue danazol because of mood or menstrual changes. typically 600-800 mg per day. corticosteroids can be tapered and IVIG stopped. we give full doses for an additional 3 months and then strongly consider stopping treatment. Occasionally. Thrombocytopenia may worsen initially. bronchospasm. MDS) must be weighed against the potential benefits of resuming therapy. A complete or partial remission occurs in 25% to 50% of patients.70 Therapy should be stopped if there is no response after 2 courses and the literature is based on treating responders with at least 3 or more courses even if the platelet count has normalized. others suddenly develop ICH or other serious bleeding after infection or incidental trauma. We have less personal experience with the use of mycophenolate mofetil. 2248 CINES and BUSSEL BLOOD. Monitoring bone density or prophylactic treatment is indicated to avoid osteoporosis in patients treated chronically (Ͼ 6 months) with corticosteroids. Once a response is seen. approaching 10% to 15% in some series. The response to cyclophosphamide or azathioprine in patients who did or did not respond to the other agent is unknown. or transaminase elevations. Should relapse occur. like danazol. rash. many complete responses are durable (Ͼ 1 year). defined as the failure of any modality to keep the platelet count above 20 000 ϫ 109/L for an appreciable time without unacceptable toxicity.24-26 We generally reserve the treatments we describe for patients who are clearly refractory to previously mentioned modalities (ie. alternative therapies are toxic. We generally choose danazol and either azathioprine or mycophenolate mofetil. the decision to restart azathioprine must be balanced against the theoretical risk of complications from longterm use.64 Treatment is begun with 500 mg orally twice a day and the dose is increased to 1000 to 1500 mg orally twice a day after 2 weeks. The platelet count may fall before a response is seen and granulocyte colony-stimulating factor and prophylactic antibiotics may be needed. the long-term outcome of 12 patients (follow-up 35-150 months) included 5 complete and 1 partial remission. 5 complete and 5 partial remissions were noted in 18 patients who had undergone splenectomy. Treatment must be continued for 4 to 6 months to see its full effect. secondary malignancy. myalgias.68 Highdose cyclophosphamide (1. preferably in combination with danazol (10-15 mg/kg/d). Options are limited. . the response rate in refractory patients is undoubtedly lower. We rarely use vinca alkaloids except as adjunctive therapy because responses are almost always transient and treatment with vincristine is complicated by peripheral neuropathy.17.65 Danazol alone is unlikely to work in patients with profound thrombocytopenia unresponsive to corticosteroids or other measures. Dapsone (75-100 mg orally daily) provides results similar to danazol. The long-term effect of treatment on immune surveillance is unknown. hypotension. which appears low based on experience in renal transplantation. Optimal dosing for ITP and use in combination with other modalities is under investigation. is often stopped prematurely.63. rituximab (375 mg/m2 intravenously every week for 4 weeks).25-2. In one study responses lasting 1 to 39 months were noted in 15 of 23 patients with minimal toxicity64.From bloodjournal. Our preference is to use azathioprine (2 mg/kg orally every day adjusted to avoid severe neutropenia). 2014.58 However. NUMBER 7 treatments typically require weeks to months for their effect to become apparent.hematologylibrary.5 mg/kg/dose orally every 12 hours. the next step depends in part on the urgency of the situation. one option is cyclosporine (1. responses occur more slowly (typically 3-4 months) and this agent. but serious infection other than reactivation of hepatitis B in chronic carriers is rare and generally seen only in the context of additional immunosuppression.66 but should be avoided in patients with glucose-6-phosphate dehydrogenase deficiency. in one study. less than 10 000 ϫ 109/L).60. and the blood count should be monitored weekly. These recommendations may soon require modification based on the success of thrombopoietic agents (see “Experimental therapy”). Various combinations of chemotherapeutic agents have been used successfully in small numbers of heavily pretreated patients. If a response occurs. etc). therapy should be continued at full doses for at least 12 months and then discontinued gradually. An alternative is to use cyclophosphamide either intravenously (2 or 3 courses of 500-1000 mg/m2 at 3-4–week intervals)67 or orally (1-2 mg/kg daily adjusted to avoid severe neutropenia). Approximately 50% of patients unresponsive to splenectomy but not refractory to other treatments can be managed using either danazol alone or combined with low doses of steroids. Treatment of chronic refractory ITP Approximately 5% of patients have chronic refractory ITP. the long-term risks (eg. Responses typically require 1 to 3 months. Patients should drink at least 2 L liquids daily to prevent hemorrhagic cystitis.5 g/m2 intravenously) given at 4-week intervals may act more rapidly. patients can be maintained with periodic doses of vinblastine. We have seen rare dramatic responses to ex vivo perfusion of plasma over staphylococcal protein A columns. liver function tests should initially be monitored monthly and then every 1 to 3 months. If a complete response occurs to oral therapy. myalgias. but its efficacy is far less than reported and its use is limited by potentially severe side effects. In the event of relapse. but rarely discontinued entirely. Second-line therapy For patients who do not respond to rituximab.69 In one study.

hematologylibrary.88 However. see McCrae et al77). BLOOD.3 ITP is not a contraindication to breast-feeding. but the distinction from gestational thrombocytopenia may occasionally be problematic in the absence of a prenatal platelet count as both entities are diagnoses of exclusion. NUMBER 7 ITP 2249 Experimental therapy A new approach is the use of thrombopoietic factors. ITP should be suspected any time during pregnancy if isolated thrombocytopenia of less than 50 000 ϫ 109/L is detected. The mode of delivery is based almost entirely on obstetric considerations. unpublished data. but sepsis was common and 2 of the 6 complete responders died within a year.3. and deferred to the second trimester when necessary. In the absence of symptoms or treatment.75 ITP occurs in 1 per 1000 to 1 per 10 000 pregnancies. we tend to rely more on IVIG together with low-dose prednisone (20 mg every day) than in nonparous patients. even in women with severe thrombocytopenia. ITP and pregnancy Women with ITP may consult their physician as to the safety of becoming pregnant or the diagnosis may be considered for the first time during pregnancy because years may have passed since a complete blood count was performed. Approximately 4% of ITP neonates are born with severe thrombocytopenia (platelet counts Ͻ 20 000 ϫ 109/L). The largest reported experience involves 14 patients with refractory ITP who were more than 6 months after transplantation at the time of publication. but this can induce or exacerbate gestational diabetes.80 For this reason. 4 of 6 women who previously delivered severely thrombocytopenic infants treated with IVIG weekly for the last 6 weeks of pregnancy delivered less affected neonates (J. Sonography. finding a “silent” ICH demands immediate management and has implications for subsequent pregnancies.2.92 Thrombocytopenia is generally mild (platelet counts Ͼ 70 000 ϫ 109/L in 95% of cases) and there seems to be no impact on maternal or fetal health. especially during the first 2 trimesters. and close monitoring of the fetus with sonograms and the newborn with hemoglobin and bilirubin determinations is warranted. among others (for a review.89 We measure cord platelet counts in all newborns and serial platelet counts should be obtained during the first week postpartum because the onset of severe thrombocytopenia may be delayed. Only prior neonatal outcome provides a useful predictor of neonatal platelet count in subsequent pregnancies. it is also important to point out that precipitous falls are seen on occasion and demand more intensive therapy with its attendant complications.75.3. or magnetic resonance imaging of the head should be performed in all neonates born with platelet counts less than 50 000 ϫ 109/L even in the absence of symptoms. but importantly few have platelet counts that are less than 5000 ϫ 109/L unless alloantibodies are also present. hypertension. Ideally. We generally use corticosteroids as initial therapy.2. women requiring considerable therapy to manage their platelet count should not assume their neonate has an inordinate risk of bleeding. 6 attained stable platelet counts that were greater than 100 000 ϫ 109/L and 2 had partial responses (follow-up 9-42 months).From bloodjournal. and gestational thrombocytopenia.72. 1 OCTOBER 2005 ⅐ VOLUME 106. but we explain that maternal and fetal complications may occur and additional monitoring and therapy may be needed. maternal platelet counts should be maintained above 20 000 ϫ 109/L throughout pregnancy and above 50 000 ϫ 109/L near term to minimize the need for platelet transfusions in the event an emergency cesarean section is required.. 8 of 12 patients in one study and 7 of 8 in the other showed temporary but substantial increases in platelet counts at a dose of 3. There is limited experience with chemotherapy for neoplastic diseases in pregnant women that may be helpful in managing the truly exceptional case (for reviews. which we think is less than that of percutaneous umbilical vein sampling in severely thrombocytopenic fetuses. including pregnancy-induced hypertension and related conditions such as hemolysis. is found in 5% to 8% of healthy women with an uneventful pregnancy and accounts for at least 75% of all cases of thrombocytopenia at term. microangiopathic hemolytic processes. The latter. We do not use danazol. and other potentially teratogenic therapy (with the possible exception of azathioprine for which a registry exists for renal transplant recipients83). . consideration should be given to causes of thrombocytopenia confined to or more common during pregnancy. 2014. There were no procedural deaths. we find practice patterns are set by obstetricians and anestheologists. obstetric causes of disseminated intravascular coagulation. weekly as term approaches and more often.76 Postpartum bleeding is uncommon after vaginal delivery. and perhaps abruption and prematurity. For personal use only. anti-CD20. also referred to as incidental or benign thrombocytopenia of pregnancy. We have recently found IV anti-D to be safe (including for the newborn) and effective. caution is indicated. truncated form of human thrombopoietin. computed tomography scanning. we monitor platelet counts at least monthly through the first 2 trimesters. a molecule that activates the thrombopoietin receptor.80 Blood loss during cesarean section varies inversely with platelet counts. nor does the maternal response to treatment guarantee a favorable neonatal outcome.org by guest on March 26. a nonglycosylated. bone loss. and low platelet count (HELLP). vinca alkaloids. Although we think that a platelet count of 50 000 ϫ 109/L is generally sufficient for epidural anesthesia. Studies of anti–tumor necrosis factor ␣ receptor and anti– interleukin 2 receptor antagonists are too preliminary to evaluate. In one study. However. and a woman with ITP may start from a lower baseline. see Koren et al84 and Weisz et al85). The patient should be informed that no antenatal maternal measurements reliably predict the neonatal platelet count.3.73 We have used autologous stem cell transplantation as a measure of last resort in young patients with recurrent life-threatening bleeding.76 In addition to the differential diagnosis common to all patients with possible ITP. cyclophosphamide.81 Splenectomy should be avoided if possible. to avoid abortion. 2005).87 The severity of neonatal thrombocytopenia is often most marked 1 to 3 days after birth. Marked discrepancies between the neonatal and maternal platelet count are not uncommon. elevated liver enzymes. biweekly in the third. although experience is limited.3. The risk of ICH is estimated to be less than 1%.76 We are not aware of evidence that the risk of ICH can be reduced by cesarean section.B. discourage pregnancy in women with known ITP. if indicated.B. conversely.0 ␮g/kg or higher.71 In recently published phase 2 placebo-controlled trials of AMG 531.74 Of these. Several comprehensive reviews have been published. We explain that platelet counts commonly fall even during normal pregnancy.79 but a higher platelet count may be required for epidural anesthesia. We rarely. Platelet counts generally return to normal within 2 months after delivery. 2 of 4 patients developed temporary thrombocytosis after receiving marrow growth and development factor. if ever.78.86 Criteria for heparin prophylaxis after cesarean section have been reviewed. accounting for approximately 3% of women who are thrombocytopenic at delivery.

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