ITP in Adults
Mayo Clin Proc, April 2004, Vol 79
Management of Immune Thrombocytopenic Purpura in Adults
Primary immune thrombocytopenic purpura (ITP), also
counts (<10 × 109/L). Treatment of patients with ITP re-
referred to as idiopathic thrombocytopenic purpura, is an
fractory to corticosteroids and splenectomy requires care-
organ-specific autoimmune disorder in which antibody-
ful evaluation of disease severity, patient characteristics
coated or immune complex–coated platelets are destroyed
related to risk of bleeding, and adverse effects associated
prematurely by the reticuloendothelial system, resulting in
with treatment. Clinical trials with numerous new agents
peripheral blood thrombocytopenia. The disease is hetero-
are under way, which we hope will add more effective and
geneous with regard to its severity and clinical course and
targeted strategies to our therapeutic armamentarium.
is unpredictable in its response to therapy. Although the
We describe a logical and structured approach to the clini-
basic underlying pathophysiology of ITP has been known
cal management of ITP in adults, based on a literature
for more than 50 years, current treatment guidelines are
review and our personal experience.
based on expert opinion rather than on evidence because
Mayo Clin Proc. 2004;79:504-522
of a lack of high-quality clinical trials and research. The
ITP = immune thrombocytopenic purpura; IVIg = intrave-
only patients for whom treatment is clearly required are
nous immunoglobulin
those with severe bleeding and/or extremely low platelet
Primary immune thrombocytopenic purpura (ITP), also The results of the Danish study have been confirmed known as idiopathic thrombocytopenic purpura, is an recently in another setting. A British group3 published the immune-mediated disorder in which platelets are op- results of a prospective study in a population-based cohort sonized by autoreactive antibodies and prematurely de- of newly presenting adults (≥16 years of age) with ITP and stroyed by the reticuloendothelial system. No consistent platelet counts of less than 50 × 109/L. The study took place epidemiological data exist relating to ITP in adults. George between January 1, 1993, and December 31, 1999, in the et al1 reviewed the data of several reports and extrapolated former Northern Health Region in the United Kingdom an incidence of 66 cases per million persons per year. A (population, 3.08 million). The diagnosis of ITP in 245 pa- Danish survey2 from 1973 to 1995 estimated the annual tients (134 females to 111 males [1.2:1]) was confirmed by incidence of ITP among adults to be 32 cases per million bone marrow examination, and the median follow-up was per year, using a lower-threshold platelet count of 50 × 109/ 60 months (range, 6-78 months). The overall incidence was L. The incidence rate increased during the study period, 1.6 cases per 100,000 per year. The absolute incidence was primarily because of increased recognition of asymptom- similar for both sexes, with the highest age-specific inci- atic patients. This study confirmed that, in keeping with dence in those older than 60 years. The median age in this 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 andmiddle-aged people, the median age in this study was 56.4 The clinical features of ITP in adults are different from years, and the incidence in people older than 60 years the clinical features seen in childhood (Table 14). In children, was more than twice that of people younger than 60 years ITP is usually an acute, self-limiting disease, often occurring (4.62 vs 1.94 cases per 100,000 per year). Also, the sex 2 to 3 weeks after a viral infection (varicella, rubella, bias difference was almost completely eliminated in older mumps, upper respiratory tract infection, gastroenteritis, flu- like illnesses, etc) or immunization. In contrast, ITP in adultstypically has an insidious onset, with no preceding viral orother illness, and has a chronic course. Many cases of ITP in From the Department of Medical Sciences, “Regina Apostolorum”Hospital, Albano Laziale, Italy (R.S.); and Department of Haematol- adults are diagnosed incidentally after a routine complete ogy, St Bartholomew’s and The Royal London Hospital, London, blood cell count. In adults, the symptoms and signs are highly variable and range from the fairly common asymp- Individual reprints of this article are not available. Address corre- tomatic patient with mild bruising and mucosal bleeding spondence to Roberto Stasi, MD, Department of Medical Sciences, (eg, oral or gastrointestinal tract) to frank hemorrhage from “Regina Apostolorum” Hospital, Via S. Francesco, 50, 00041Albano Laziale, Italy (e-mail: [email protected]).
any site, the most serious of which is intracranial.
2004 Mayo Foundation for Medical Education and Research Mayo Clin Proc, April 2004, Vol 79
ITP in Adults
The diagnosis of ITP remains one of exclusion, requir- Table 1. Immune Thrombocytopenic Purpura
in Children and Adults
ing that all other conditions or factors that can cause throm-bocytopenia be ruled out.4 These causes include collagen vascular diseases, lymphoproliferative disorders, agamma- globulinemia, therapy with certain drugs, alloimmune thrombocytopenia, congenital or hereditary thrombocy- topenia, myelodysplasia, von Willebrand disease type IIB, human immunodeficiency virus infection, and other infec- tions. The history and physical examination are aimed at detecting these various causes of thrombocytopenia and are supported by ancillary laboratory tests (Table 2).
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.4,5Unfortunately, even among experts there is only little tomoderate agreement regarding the best treatment for these During the follow-up period, 6 patients died, 2 of hemor- patients. In this article, we illustrate current treatment op- rhage and 4 of infections, which were probably treatment tions for ITP that are based on a literature review and related. In another study, 3 of 6 adults died of infections, and only 2 died of hemorrhage.12 A recent report by Neylonet al3 indicates that 27 of 245 patients (11%) died during the WHICH PATIENTS WITH ITP SHOULD BE TREATED? study period, but only 3 (1.2%) of these deaths were attrib- The answer to the seemingly “innocent” question of which utable to ITP (bleeding) and only 1 (0.4%) to overwhelm- patients with ITP should be treated is complex and under- ing sepsis after splenectomy. The other deaths were appar- lines the heterogeneity of ITP. Disease-related and patient- ently unrelated to either ITP or its treatment. Considering related factors should be considered and treatment tailored these data together, it appears that the treatment of ITP is to the individual patient. Considering the chronic nature of almost as dangerous as the disease itself and that some the disease, the goal of treatment should be to provide a safe platelet count to prevent major bleeding while mini- The peripheral blood platelet count is obviously the major parameter for predicting the risk of bleeding, but few An understanding of the natural history of untreated ITP studies have described the risk of clinically important provides part of the rationale for deciding which patients bleeding at varying levels of thrombocytopenia. A platelet should be treated. Although 80% to 90% of children have a count of greater than 30 × 109/L is usually considered spontaneous remission of the disease within 2 to 8 weeks,6,7 “safe” for people leading a sedentary lifestyle.4,5 However, spontaneous remissions in adults are much rarer. However, only 1 prospective study supports this cut-off level.
in many adults presenting with mild and asymptomatic Cortelazzo et al9 described 49 untreated patients (of 117 thrombocytopenia, the disease appears to have a stable and total patients with ITP) with platelet counts greater than 30 benign course without treatment.8-10 Possibly less than 10% × 109/L and no symptomatic bleeding. No adverse events of such patients develop a more severe thrombocytopenia were reported among these 49 patients during a mean fol- and require treatment at 3- to 7-year follow-up.8 In our study low-up period of 30 months. A recent retrospective study of 208 adults with chronic ITP, 9% of patients remitted indicated that patients with ITP who achieved platelet spontaneously or required some form of therapy to support counts greater than 30 × 109/L while not being treated or the platelet count.8 In other series, the incidence of spontane- while receiving maintenance therapy had a long-term mor- ous remissions may have been underestimated because all tality rate identical to or only slightly greater than that of patients were treated initially with corticosteroids.4 the general population.10 Therefore, these studies support Only a few studies have addressed the mortality risk the contention that a platelet count of greater than 30 × 109/ attributable to ITP. Cohen et al11 reviewed data from 17 L is reasonably safe, but they do not indicate whether the case series involving 1817 patients with ITP and showed critical threshold is 30 × 109/L or a lower value. An early that the rate of fatal hemorrhage is between 0.0162 and investigation by Lacey and Penner13 showed that spontane- 0.0389 cases per patient-year at risk (the time at risk was ous major bleeding in adults with ITP is rare (<5% of defined as the time during which the platelet count is <30 × patients) with platelet counts of greater than 10 × 109/L and 109/L). The relationship between disease-related and treat- occurs in about 40% of patients with platelet counts of less ment-related mortality was specified by Portielje et al.10 than 10 × 109/L. These findings are in agreement with ITP in Adults
Mayo Clin Proc, April 2004, Vol 79
Table 2. Principal Elements of the Initial Work-up in
higher platelet counts bleed excessively. In fact, in the Adult Patients With Suspected
previously mentioned report by Neylon et al,3 only 1 of the Immune Thrombocytopenic Purpura*
3 deaths due to bleeding occurred at a platelet count of less Older studies have suggested that bleeding manifesta- tions in patients with ITP are expected to be less severe at equivalent platelet counts than in patients with thrombocy- Systemic symptoms, including weight loss, fever, headache, and topenia due to a hyporegenerative bone marrow.15 This is symptoms of autoimmune disorders such as arthralgias, rash, 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 Medications, including heparin, alcohol, quinidine/quinine, and greater hemostatic activity.16 Nevertheless, platelet dys- sulphonamides, which may cause thrombocytopenia, and aspirin,which may exacerbate bleeding function in ITP has been well described in the literature, Family history of thrombocytopenia, including bleeding symptoms indicating that antiplatelet antibodies can affect platelet function.17-21 For example, antibodies may bind to adhesion Comorbid conditions that may increase the risk of bleeding such as gastrointestinal disease, chronic liver diseases, chronic kidney molecules or other receptors on platelets to alter platelet function. They may impair adhesion and aggregation of platelets, inducing features of Glanzmann thrombasthenia19 or Bernard-Soulier–like syndromes20 or various other plate- let dysfunctions. In contrast, some antibodies may activate platelets, promoting thrombotic complications in ITP.21 Evidence for infection, particularly bacteremia or HIV infectionEvidence for autoimmune disease, such as arthritis, nephritis, or It is apparent from the results of several studies that factors other than the peripheral blood platelet count influ- ence 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, Peripheral blood smear observationBone marrow aspirate (if older than 60 years or another respectively.9 Similar rates of 13.0% and 0.4% per patient hematologic disorder is suspected, and in patients for whom per year, respectively, were noted in the previously men- tioned meta-analysis by Cohen et al.11 The presence of HIV test (in patients with risk factors for HIV infection) 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 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 recom-mendations can be given. We consider a platelet count of *HIV = human immunodeficiency virus.
Adapted from George et al,4 with permission from The American Society 50 × 109/L a reasonable threshold for people engaged in “physical” jobs, such as carpenters and farmers, whereasathletes who perform contact sports probably would re- observations of patients with chemotherapy-induced bone quire a platelet count of greater than 80 × 109/L. The British marrow suppression, indicating that clinically important Committee for Standards in Haematology5 has recently bleeding is less likely with platelet counts of greater than suggested the values of the platelet counts that are consid- 10 × 109/L unless the patient is febrile or has a serious ered safe for patients who are undergoing procedures likely to induce blood loss, including surgery, dental extraction, The degree of thrombocytopenia per se does not always or obstetric delivery (Table 3). Once again, note that these accurately predict bleeding risk, however, and experienced recommendations are based on opinion and that many phy- hematologists are aware that in many patients with ITP, the sicians would not agree with them on the basis of their own platelet count appears to have little bearing on the bleeding diathesis. Some individuals with severe ITP (platelets In summary, the critical elements in the decision-mak- counts of <10 × 109/L) do not bleed, whereas others with ing process include the presence of active bleeding; platelet Mayo Clin Proc, April 2004, Vol 79
ITP in Adults
count; patient age; patient’s lifestyle related to risk of Table 3. Recommendation for “Safe” Platelet Counts
in Adults
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 pa- tients 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 plate- From the British Committee for Standards in Haematology General let counts between 10 × 109/L and 30 × 109/L but with Haematology Task Force,5 with permission from Blackwell Publishing.
no active bleeding, for whom the decision to treat ismade after a thorough evaluation of the patient’s charac-teristics (age, lifestyle, etc) (Table 4); and (4) those for bleeding, irrespective of the increase in platelet counts.
whom treatment is not needed or is required in special Nevertheless, it has been shown that 42% of platelet trans- circumstances, which includes patients with platelet fusions result in a platelet increase of at least 20 × 109/L.22 counts of greater than 30 × 109/L and no bleeding ten- Aminocaproic acid (5 g initially and then 1 g every 5 hours given orally or intravenously) has been reported to be Although this categorization is widely accepted for the effective in controlling severe bleeding in ITP after failure initial treatment of adults, it may not be fully appropriate in of corticosteroids and platelet transfusions.23 Given the patients for whom several treatments have failed and efficacy of these interventions, plasmapheresis has been whose platelet counts are persistently less than 10 × 109/L.
used rarely in emergency settings but may play a role in In some of these patients, particularly in younger individu- als who have no bleeding symptoms, a wait-and-see policymay be preferable to avoid the long-term toxicities associ- 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.4 Intrave- Patients with internal or widespread mucocutaneous bleed- nous immunoglobulins are generally recommended for ing or in need of emergency surgery require urgent aggres- patients with critical bleeding and for those unresponsive sive therapy. Hospitalization is required, and general mea- to corticosteroids.4 The platelet count also can be sup- sures should be instituted to reduce the risk of bleeding, ported by anti-D immunoglobulin, which is active in the including avoidance of drugs that inhibit platelet function, presplenectomy setting.4 Results of treatments in the ma- control of blood pressure, and other factors. Although no jor series reported thus far are summarized in Table systematic studies have evaluated the efficacy of different regimens, there is general agreement that appropriate inter-ventions should include the following4,5: Table 4. Factors That Should Be Considered in
Deciding When to Treat Patients With
• Intravenous immunoglobulin (IVIg), 1 g/kg per day Immune Thrombocytopenic Purpura
• Intravenous methylprednisolone, 1 g/d for 3 days Presence of active bleedingPlatelet count • Platelet transfusions (either 5 U every 4-6 hours or Lifestyle (participation in activities that predispose to trauma) Management of intracranial bleeding should include all these interventions. When the platelet count is greater than Untreated or poorly controlled hypertension 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 de- struction, transfused platelets may provide temporary criti- cal hemostatic support. Platelet transfusions usually are given after IVIg and are often effective in controlling ITP in Adults
Mayo Clin Proc, April 2004, Vol 79
Table 5. Treatment Categories in
prednisone). No data were published on the long-term out- Immune Thrombocytopenic Purpura
come of these 2 studies. One study assessed the efficacy of high-dose methylprednisolone as first-line therapy for 21adults with severe thrombocytopenia and severe or persis- tent mucosal or vaginal bleeding; the results were com- pared with 36 patients with a less severe presentation who were treated with conventional doses of prednisone.44 Pa- tients treated with high-dose methylprednisolone re- sponded 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 *Treatment may be required in special circumstances, eg, in preparation shown between the 2 groups in the frequency of complete for major surgery or obstetric delivery.
or persistent remission. Oral dexamethasone at a dosageof 40 mg/d for 4 consecutive days has been used recently as initial treatment in 125 patients with ITP.25 The re- Corticosteroids have not been shown to alter the natural sponse rate was extremely high (85%), and with a median history of ITP; however, they allow the physician to “buy follow-up of 30.5 months, 50% of responders had a con- time” to determine which patients have acute ITP (lasting tinuous complete remission at the time this manuscript less than 6 months) and which patients will develop was written. Nevertheless, this was not a randomized chronic ITP and thus potentially need additional therapy.
trial, and whether or not initial high-dose therapy has a Approximately two thirds of patients achieve a complete or positive effect on the rate of sustained remissions is an partial response with corticosteroids, and most responses occur within the first week of treatment.4 The standard A few studies have evaluated the long-term outcome practice is to initiate treatment with oral prednisolone or of patients receiving corticosteroid treatment alone.8,10,45 prednisone, 1 to 2 mg/kg per day, given as single or divided These studies indicate that there is a high early relapse doses. However, major variations exist in treatment regi- rate (within 6 months) and thereafter a slower but con- mens in reference to the duration of full-dose treatment (2- tinuous relapse rate up to 6 years. Less than 20% of 6 weeks) and the mode of tapering (fast or slow). In our patients were in complete remission at the last follow-up.
practice, we taper and discontinue prednisone over 4 weeks Various factors for predicting the response (short term after achieving a normal platelet count because this period and/or long term) to corticosteroid therapy also have been includes the time during which most spontaneous remis- analyzed. A shorter duration of symptoms has been asso- ciated with a better response to corticosteroids in 2 stud- To date, only 2 randomized studies have compared con- ies,26,45 whereas age of patients older than those in the 45- ventional with low doses of prednisone as initial ther- to 60-year range was associated with a poorer response in apy.42,43 There was no difference in the likelihood of remis- sion at 6-month follow-up in either study. However, the If prednisone is resumed when thrombocytopenia re- larger study observed a trend toward an increased fre- curs, it is important to avoid the consequences of prolonged quency of complete remission (46% vs 35%) in the group corticosteroid therapy. The risk for corticosteroid-induced given the larger doses of prednisone. Moreover, a faster osteoporosis is of particular concern,47 and it is generally increase in platelet count was observed in the group receiv- recommended that patients treated with prednisone for ing the larger dose of prednisone (77% vs 51% having a more than 3 months receive calcium and vitamin D supple- platelet count greater than 50 × 109/L after 14 days of mentation and monitoring of bone mineral density.
Table 6. Response to First-Line Treatments
and Splenectomy*
*IVIg = intravenous immunoglobulin; NA = not available.
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ITP in Adults
The mechanisms of action of corticosteroids in ITP diagnosis. A few patients also experience rigidity, drowsi- have not been completely elucidated. It has been suggested ness or lethargy, fever, photophobia, and painful eye move- that corticosteroids impair the clearance of antibody- ments simulating meningitis.57 Renal impairment or failure coated platelets by tissue macrophages,48 inhibit antibody has been reported with some preparations.58,59 Intravenous production,49 and increase platelet production possibly by immunoglobulin products containing sucrose may present inhibiting phagocytosis of platelets by bone marrow mac- a greater risk for this complication.59 In fact, a dispro- rophages.48 In addition, cutaneous bleeding may resolve portionate amount of renal impairment or failure in pa- before an increase in the platelet count is seen, suggesting a tients with ITP (approximately 90%, according to US direct effect of corticosteroids on vascular integrity.50 reports) has been associated with sucrose-containingproducts,60 including (1) one product manufactured by the Intravenous Pooled Normal Human Immunoglobulin Central Laboratory Blood Transfusion Service, Swiss Red Intravenous immunoglobulin has been studied primarily Cross (Bern, Switzerland) (Sandoglobulin, distributed by in patients who were unresponsive to corticosteroids and Novartis, and Panglobulin, distributed by the American other therapies. Intravenous immunoglobulin is effective in Red Cross), and (2) IVIg products manufactured by elevating the platelet count in approximately 85% of pa- Centeon L.L.C. (Bradley, Ill) (Gammar-P I.V./Gammar- tients, with 65% achieving normal platelet counts (>100 × 109/L).51 Platelet counts may begin to increase after 1 day To minimize adverse effects, the infusion of IVIg is and usually reach peak levels within 1 week after treat- given slowly over several hours. Particular caution should ment.52 However, responses are generally transient, lasting be exercised in the administration of sucrose-containing no longer than 3 to 4 weeks, after which the platelet counts IVIg products in patients at increased risk for developing decrease to pretreatment levels.51,52 The dose of IVIg has acute renal failure, which includes those with any degree of been the subject of several studies. A single randomized preexisting renal insufficiency, diabetes mellitus, and age study showed no difference in efficacy between the 2 dos- ing schedules of 0.4 g/kg per day for 5 days and 1 g/kg per The mechanisms of action of IVIg in ITP are complex day as a single infusion.53 A multicenter trial randomly and not fully elucidated. Some studies suggest blockade of assigned 35 consecutive adult patients with ITP to receive Fc receptors on reticuloendothelial cells33,62 and suppres- IVIg at an initial total dosage of 0.5 g/kg or 1.0 g/kg over a sion of antibody production and binding,37,63 which may be period of 4 to 12 hours on day 1.32 Nonresponders received the result of anti-idiotype antibodies that bind antiplatelet additional IVIg in divided doses on days 4 and 5 to reach a antibodies and modulate immune response.64 total dose of 2.0 g/kg. This study suggested that initial The relative efficacy of high-dose methylprednisolone treatment with 1 g/kg of IVIg appeared to be more effective (15 mg/kg per day intravenously on days 1 to 3) vs IVIg than 0.5 g/kg and that some adults who did not respond to 1 (0.7 g/kg per day intravenously on days 1 to 3) was studied g/kg responded to a higher dose. On the basis of these in a prospective randomized trial of 122 patients with pre- studies, the standard regimen for IVIg is now 1 g/kg per viously untreated severe acute ITP.38 In a second random- ization, patients received either placebo or oral prednisone Intravenous immunoglobulin is prepared by ethanol (1 mg/kg per day) on days 4 to 21. The percentage of precipitation of pooled plasma, followed by techniques to patients with a platelet count greater than 50 × 109/L on minimize self-aggregation.54 Preparations of IVIg are stabi- days 2 and 5 was slightly greater for those receiving IVIg lized with glucose, maltose, glycine, sucrose, sorbitol, or (7% and 79%, respectively) than for those receiving meth- albumin. At least 90% to 95% of the IVIg preparation is ylprednisolone (2% and 60%; P=.04). The use of pred- composed of monomeric IgG. The IgG retains normal Fab nisone was significantly more effective than placebo for all and Fc functions required for antigen binding and phago- short-term study end points (eg, days with platelet count of cytic cell interaction, respectively. IgG aggregates, IgA, >50 × 109/L, highest platelet count, platelet count at 21 and other contaminants constitute a negligible fraction.
days, and time to relapse). However, remission rate at 1 Intravenous immunoglobulin has a normal IgG half-life in year was not affected by the initial treatment (IVIg vs vivo, with a physiological subclass distribution.54 The adverse effects of IVIg are generally mild. Approxi- Because of its high cost, IVIg generally is used when mately one half of patients have headaches, usually during resistance to corticosteroids develops, when there is a con- the first infusion. Occasionally, the headache is severe and traindication to the use of corticosteroids, or during preg- associated with nausea and vomiting.55,56 These symptoms nancy when potentially teratogenic drugs must be avoided.
can mimic intracranial hemorrhage, and a computed tomo- The rapid nature of the response to treatment makes it an graphic scan of the head may be required to determine the ideal agent for treatment of life-threatening bleeding or ITP in Adults
Mayo Clin Proc, April 2004, Vol 79
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 de-crease in hemoglobin of 1.0 g/dL, occasionally accompa-nied by chills and nausea. Anti-D appears to have minimal The spleen is the organ primarily responsible for the de- struction of antibody-sensitized platelets, and splenectomyis 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 op-timal time for performing splenectomy, the prediction of Figure 1. Kaplan-Meier plot of relapse-free survival after sple- response, the selection of the surgical procedure (standard nectomy in patients with immune thrombocytopenic purpura vs laparoscopic method), and the long-term efficacy of this (N=62) who were monitored at our institution.
procedure. No randomized trial has compared the efficacyand risks of drug treatment with splenectomy, and it is before surgery, although corticosteroids also may increase unlikely that such a trial will ever be performed. As with the platelet count with sufficient rapidity.
other treatment modalities, the decision to recommendsplenectomy should be individualized, taking into account the age of the patient, duration of the disease, comorbid The anti-D immunoglobulin is effective only in Rh D- conditions, efficacy and adverse effects of corticosteroid positive nonsplenectomized patients, in whom the antibody treatment, and preferences of the patient.
binds to the erythrocyte D antigen. The mechanism of About 75% of patients who undergo splenectomy action involves immune-mediated clearance of the op- achieve a complete remission (platelet count of >100-150 × sonized erythrocytes via the Fc receptors of the reticuloen- 109/L).8,30,31,34,65-68 Most relapses occur during the first 2 dothelial system, thereby minimizing removal of antibody- years after splenectomy, but even after that, a small per- coated platelets.39 Anti-D can be administered safely by centage of patients continue to relapse. In our series, ap- intravenous injection over a few minutes. The response rate proximately 60% of responders remained in remission at in one series was 70%, and the increase in platelet count 10 years (Figure 1), which is in keeping with most pub- lasted more than 3 weeks in 50% of the responders.27 The lished reports. However, in another study with a large toxicity profile of anti-D is similar to that of IVIg. The number of patients and long-term follow-up, most splenec- standard dosage of 50 mg/kg per day of intravenous anti-D tomized patients had relapsed,41 although the conclusions requires 72 hours to produce a clinically significant platelet of this study were not supported by a detailed presentation increase.40 Therefore, anti-D has not been recommended as of primary data. In some patients who relapse after splenec- first-line therapy to rapidly elevate the platelet count in tomy, an additional (accessory) spleen may be detected and patients with severe thrombocytopenia. In a prospective a second complete remission may be achieved after its randomized trial, 27 Rh D-positive patients with a diagno- removal.45,69,70 However, there are no studies of accessory sis of ITP in whom initial treatment with corticosteroids splenectomy that document efficacy by long-term com- had failed and who had platelet counts of 30 × 109/L or less plete remissions. Numerous methods can be used to look received intermittent treatment with anti-D at a dose of 50 for an accessory spleen, including computed tomographic to 75 µg/kg intravenously whenever their platelet count scanning, ultrasonography, and radionuclide imaging. If was 30 × 109/L or less.28 The higher dose resulted in greater radionuclide methods are used, the intraoperative use of a median day 1 (43 × 109/L vs 7.5 × 109/L; P=.01) and day 7 hand-held isotope detector probe can help locate an acces- (153 × 109/L vs 64.5 × 109/L; P=.001) platelet increases despite no greater hemoglobin decrease. The results also Most experts agree that splenectomy should be seriously indicated that 68% of patients repeatedly responded to anti- considered for patients in whom ITP is primarily refractory D infusion and that in some patients, splenectomy may to corticosteroid treatment, at 4 to 6 weeks after diagnosis, have been delayed or completely avoided.29 The substantial or in patients for whom a daily dose of 10 mg or more of Mayo Clin Proc, April 2004, Vol 79
ITP in Adults
prednisone is required to keep the platelet count at a “safe”level.4 In contrast, some suggest that this procedure shouldbe performed only after all other therapeutic modalitieshave been exhausted and the patient has a platelet count ofless than 25 × 109/L and is bleeding.41 In fact, it appears thatthe timing of splenectomy is delayed in most medical cen-ters. The median time to splenectomy was 11 months(range, 3-156 months), 3 years (range, 3 weeks to 19years), and 8 to 51 months in 3 different studies.8,31,71 Themost likely explanation for this observation is that thedecision to recommend splenectomy to many patients isdifficult because they may do well on low-dose corticoste-roids and splenectomy is an invasive procedure with poten-tial risks. For example, in a series of 78 patients whounderwent splenectomy, 26 (33%) experienced postopera-tive complications resulting in prolonged hospitalization orreadmission.10 The risk appeared particularly increased inelderly or obese patients with comorbid conditions. There-fore, identification of patients who may benefit from sple-nectomy 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 272).35,37,72-75 In the large study by Najean et al,72 Figure 2. Indium 111–labeled platelet scanning to determine the patients with hepatic sequestration had a response rate of site of platelet destruction. 1 = spleen; 2 = liver; 3 = heart; 4 = only 1%, whereas in other studies,35,76 the response rate was bladder; NA = not available. In this patient with immune throm- higher (≥28%). Thus, patients with hepatic sequestration bocytopenic purpura, intense uptake is seen in the spleen, with noactivity in other organs. The probability of achieving response is may still respond to splenectomy but to a lesser degree; the influenced by the pattern of uptake of the radionuclide.72 likelihood of achieving a complete response is lower thanin patients in whom platelet destruction is purely or pre-dominantly splenic. However, platelet sequestration stud- value when deciding about splenectomy, and of currently ies are difficult to perform and are available in only a few available methodology, the indium-labeled platelet study medical centers. Furthermore, the specificity of the test is appears to be the most accurate predictor of response to not high enough to recommend it routinely for patients in whom splenectomy has been considered.
Splenectomized patients have a small risk for over- Although it is generally agreed that increased age is a whelming infections, with an estimated mortality of 0.73 poor prognostic factor, this has not been reported consis- per 1000 patient-years.84 The risk for serious postsplenec- tently.31,35,36,45,72-75 Also, the literature is controversial con- tomy infection is greater in children younger than 5 years, cerning the prognostic value of the response to IVIg. Law who are therefore treated with prophylactic penicillin after et al77 reported a 90.5% positive predictive value and a splenectomy. Although there are no data on the efficacy of 100% negative predictive value of the response to IVIg. In vaccination, immunizations for Streptococcus pneumo- most subsequent studies, it was confirmed that patients niae, Hemophilus influenzae B, and Neisseria meningitides who responded to IVIg had a higher response rate to sple- are generally advised at least 2 weeks before splenectomy.4 nectomy, but the positive and negative predictive values The usefulness of postoperative antibiotic prophylaxis is a were not as high.71,73,75,78-82 Thus, patients who do not matter of controversy, and although it is not the standard of respond to IVIg still have a good chance of responding to care in the United States, lifelong prophylactic antibiotics splenectomy. Response to prednisone has been found to be a good prognostic factor in some studies,26,35,45,73 but not in There is no agreement on the minimal platelet count others.8,71 There is agreement that the time to splenectomy regarded as sufficient to perform splenectomy; in our prac- is not a prognostic factor.8,26,71,73-75 Presence of platelet anti- tice, we recommend a platelet count of at least 50 × 109/L, bodies had no prognostic value in 2 studies.73,83 Taken but often our patients must reach higher counts because together, “predictive” factors seem to have only limited surgeons are reluctant to operate on patients with throm- ITP in Adults
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bocytopenia. No data indicate whether preoperative treat- complete response in 1 patient, partial response in 4 pa- ment with corticosteroids or IVIg is more beneficial.
tients, and no response in 1 patient. However, in 6 of 19 Laparoscopic splenectomy has become popular during nonresponders, repeated embolization elicited a partial re- the past decade. The technique has the advantage of a sponse in only 1 patient. The remission rate of 51% was reduced risk of postoperative complications (which allows maintained by means of repeated embolization for a me- the procedure to be performed in patients who cannot un- dian follow-up period of 76 months after the initial embo- dergo open surgery) and a shorter hospital stay. Potential lization. Because a small accessory spleen can almost cer- problems associated with the laparoscopic approach are tainly cause relapse, leaving a residual quantity of spleen technical difficulties necessitating conversion to open sur- (as in partial splenic embolization) can cause any long-term gery and the inability to identify additional spleens and remission to fail. On the basis of this consideration, bleeding. Furthermore, the operation time with laparo- Martinez Lagares et al95 prospectively performed total scopic splenectomy is greater than with standard open splenic embolization in 13 patients, of whom 5 were depen- surgery. No randomized trials have been conducted to dent on high doses of corticosteroids to maintain a safe compare laparoscopic with conventional open surgery, al- platelet count (>30 × 109/L) and 8 were corticosteroid though numerous studies have shown that laparoscopic resistant with a sustained low platelet count (<30 × 109/L).
splenectomy is safe when performed by a surgeon experi- Complete embolization was achieved in 12 patients, and a enced in this procedure.86-90 Despite the lack of scientific partial embolization was achieved in 1 patient with an evidence, it may be the preferred method in patients with a aberrant splenic artery. Of the 12 patients, 10 had a com- high risk of postoperative complications, such as elderly plete and sustained response (median, 27 months; range, patients, those with cardiovascular disease, and/or those 22-38 months), with peak platelet counts greater than 400 × with a high risk of postoperative infection or thrombosis.
In patients at high risk for surgery, splenic irradiation91,92 or partial splenic embolization87-89 have been used with reports of success. Calverley et al91 reported that of 11 patients with ITP who were treated with splenic irradiation, Patients can be defined as having chronic refractory ITP if 8 responded. Three patients had a sustained (>52 weeks) splenectomy fails and the patients require additional increase in platelet count to safe levels after therapy was therapy. About 30% of adult patients with ITP may belong discontinued. An additional patient had a sustained response to this category. The goals of therapy for refractory ITP are but required intermittent low-dose corticosteroids. Four clearly different from those for patients at initial presenta- other patients had increased platelet counts that lasted from 8 tion because the chance of inducing a durable, complete, to 25 weeks. The total radiation dose was 6 Gy in 6 doses and unmaintained remission is much lower. Again, the over 3 weeks without renal shielding. In another study, 8 actual necessity for treatment should always be considered, patients with chronic ITP received a radiation dose of 15 and the risks and adverse effects of treatment should be Gy.92 One patient had a good durable response (>1 year); 2 weighed against the risks of no treatment.
patients had a good transient response; 2 patients had only A common strategy is to try treatment with low-dose partial response but required no other treatments for 2 years; corticosteroids. In fact, some patients require low doses of and 3 patients had no response. The radiation was adminis- prednisone, 5 to 10 mg/d or even less, that are comparable tered at a dosage of 1.5 Gy 2 times per week for 5 weeks with to physiological glucocorticoid secretion, approximately left kidney shielding but with 20% to 25% of the splenic 7.5 mg/d of prednisone. For these patients, experimenting volume undertreated. Splenic irradiation may result in the with new drugs does not seem necessary, although even at development of adhesions between the spleen and surround- these low doses, the risk of osteoporotic fractures is in- ing tissues, complicating splenectomy if it is performed later.
creased.96 However, many other patients require higher Therefore, splenic irradiation should be recommended only doses of prednisone to maintain a safe platelet count. For for those with contraindications to splenectomy.
these patients, alternative approaches are warranted, but no Partial splenic embolization was first used by Miyazaki treatments have been shown to be effective in randomized et al,93 who reported a 35% prolonged response rate in clinical trials assessing outcomes of bleeding and death.
patients with ITP. In a recent study, 20 (51%) of 39 patients Therefore, no algorithm based on evidence can be pro- responded to the initial embolization (complete response in posed for standard care of chronic refractory ITP.97 Many 11 and partial response in 9).94 One of the 11 complete agents, combination therapies, and procedures have been responders and 5 of the 9 partial responders relapsed after a proposed, some of which should be considered experimen- median follow-up period of 34 months (range, 15-23 tal (Table 7). The order in which they are cited in this months) and underwent repeated embolization, resulting in review does not imply a judgment of ranking or efficacy of Mayo Clin Proc, April 2004, Vol 79
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these therapies. Figure 3 shows an approach to therapy Table 7. Treatment Options for Patients With
Chronic Refractory Immune Thrombocytopenic Purpura
Eradication of Helicobacter pylori Infection A simple measure that can be adopted before other treatments are initiated is the detection and eventual eradi- cation of Helicobacter pylori infection. Recent reports sug- gest that this infection is associated with the development of autoimmune diseases including ITP and that its eradica- tion 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 al98 to 71.4% in the Spanish study by Jarque et al.99 These discrepancies can be explained perhaps by the different socioeconomic con- ditions of the patient populations investigated.100 The re- sults of H pylori eradication in ITP have been reviewed recently.98 Responses were extremely variable (reported range, 7%-100%). In total, 56 (46%) of 122 patients in whom the bacterium had been eradicated experienced sub- stantial improvement of thrombocytopenia. However, only a few of these patients had severe chronic ITP.
Oral or intravenous dexamethasone, at a dosage of 40 mg/d for 4 days and repeated every 4 weeks, has been usedsince the publication of an uncontrolled series of 10 pa- detailed analysis of the data reveals that extremely few tients. Splenectomy had failed in 6 of these patients.101 All patients with severe chronic refractory ITP responded to 10 patients in this series experienced a complete, durable this agent. In most negative studies, danazol was used in a response. However, subsequent studies have not produced small number of patients as a single agent and was discon- such favorable results in terms of response rate, with sus- tinued after 2 to 4 months. However, in some patients, tained responses achieved only in sporadic cases.102-105 response was delayed for as long as 10 months. Therefore, One study reported on 9 adult patients with platelet therapy should be continued for at least 6 months, prefer- counts of less than 50 × 109/L who were all treated initially ably for 1 year, if no serious adverse effects occur. Remis- with oral corticosteroids (prednisolone or prednisone at 1 sions induced by long-term danazol can last for years, even mg/kg per day). Methylprednisolone was given at 30 mg/ after discontinuation of the drug.107 Pharmacokinetic stud- kg per day for 3 days, 20 mg/kg per day for 4 days, and then ies indicate that danazol concentrations in plasma and in 5, 2, and 1 mg/kg per day each for 1 week. Platelet counts blood cell membranes are extremely variable.108,109 Some returned to normal within 3.5 days in all patients, although patients in whom standard dosage (400-800 mg/d) failed in 7, the response lasted only a few weeks before decreas- responded to a low dose (50 mg/d),110 suggesting that ex- cessively high blood concentrations may have adverse ef-fects on platelets. The mechanisms of action of danazol are unclear but involve impairment of macrophage-mediated Danazol, an attenuated androgen initially formulated for clearance of antibody-coated platelets via decreased Fc the treatment of endometriosis, can be used in male patients receptor expression.111 Danazol is generally well tolerated; and nonpregnant female patients with ITP. Ahn and Horst- the most frequent adverse effects include headache, nau- man107 recently reviewed 25 publications about danazol sea, breast tenderness, maculopapular rash, weight gain, therapy in chronic ITP. Favorable outcomes were reported hair loss, myalgia, amenorrhea, and liver dysfunction.
in 21 and negative outcomes in 4. Pooled data show that Long-term study of patients with angioneurotic edema danazol produces a sustained platelet increase in 30% of have shown the safety of danazol therapy given over a 10- patients. The platelet counts of an additional 10% of pa- year period.112 Rare cases of hepatic peliosis and hepatomas tients increased to 50 × 109/L to 100 × 109/L. However, a ITP in Adults
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Mucocutaneous non–life-threateningbleeding or planned procedure likely IVIg, 0.4 g/kg per day for 5 days or anti-D, 50 µg/kg once, repeat as necessary or Obser ve or azathioprine orcyclosporin A or vincristine rituximab or anti-CDC40 ligand or etanercept or daclizumab or Figure 3. Treatment options in adults with severe refractory immune thrombocytopenic purpura. IVIg = intra-venous immunoglobulin.
additional 30% to 40% may have partial responses.1 Me- Azathioprine is one of the most commonly used immu- dian time to response ranges between 2 and 4 months, and nosuppressive agents. Approximately 20% of patients may treatment should be continued for up to 6 months before achieve a normal platelet count with this agent. Responses being deemed a failure. Azathioprine may be given orally may be sustained for several months to years and, at least in at a dosage of 1 to 4 mg/kg per day, which should be some patients, persist after treatment is discontinued. An modified according to the leukocyte count. A major con- Mayo Clin Proc, April 2004, Vol 79
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cern, particularly in younger patients, is the risk of develop- had a complete response, which was sustained in 4 patients ing a malignancy. Kyle and Gertz113 reported the occur- for 60 to 150 months, and 2 had a partial response.
rence of acute leukemias and myelodysplastic syndromesin 30 patients treated with azathioprine. The teratogenic risk of azathioprine has not been documented.
Cyclosporin A has been shown to increase platelet counts when given either alone or with prednisolone.
Emilia et al119 reported 12 patients with chronic ITP treated Cyclophosphamide can be given as a daily oral dose or with cyclosporin A (2.5-3.0 mg/kg per day). Complete an intermittent (usually every 3-4 weeks) intravenous pulse responses were seen in 9 patients and a partial response in dose (1.0-1.5 g/m2). Oral cyclophosphamide is usually ini- 1. Adverse effects were moderate but transient. Most pa- tiated at a dosage of 1 to 2 mg/kg per day and should be tients had a sustained response after treatment was discon- adjusted with the aim of maintaining mild neutropenia.
tinued. In another study, 20 patients with ITP refractory to Responses occur within 2 to 10 weeks and, as with azathio- corticosteroids, half of whom had undergone splenectomy, prine, can persist after therapy is stopped.114 In an uncon- were treated with cyclosporin A for at least 4 weeks.120 The trolled case series of 20 patients, the intermittent intrave- dosage was reduced by 50 mg/d every 2 weeks in those nous regimen produced 65% complete responses and 20% showing responses. Five patients remained in complete partial responses.115 Five of the 13 responders relapsed at 4 remission for at least 2 years after discontinuing cyclo- months to 3 years. Responses occurred within 1 to 6 sporin A, and another 6 showed partial responses.
months after treatment. Adverse effects of cyclophospha- Cyclosporin A was discontinued in 6 patients because of mide include bone marrow suppression, hemorrhagic cysti- tis, infertility, teratogenicity, and development of second-ary malignancy. Therefore, the use of this agent should be carefully evaluated among younger patients.
Several small studies have investigated the use of rituximab, a monoclonal antibody directed against the B- cell antigen CD20.121-123 The regimen used was identical to Both vincristine and vinblastine have been used for that used in follicular lymphomas, ie, 375 mg/m2 weekly refractory ITP, and the response appears to be independent for 4 consecutive weeks. The results were variable, but of the agent used and the mode of delivery (intravenous when the data were combined, the overall response rate bolus or a more prolonged infusion).116 Responses have was slightly greater than 50%, with 25% to 30% sustained been described in 50% to 70% of patients. However, only a complete responses. Responses were observed both early few patients have a sustained remission, and most require during treatment and several weeks after the last rituximab maintenance injections. A common regimen for vincristine infusion. Splenectomized and nonsplenectomized patients is 2 mg/wk intravenously for several weeks. Adverse ef- responded equally well. The toxicity profile of rituximab fects include peripheral neuropathy, which is common and appears favorable, and most adverse effects are grade 1 to 2 may be persistent, and constipation. The mechanism of first-infusion reactions. The mechanisms of action of action of the vinca alkaloids is uncertain but may be related rituximab have not been investigated thoroughly. Rituximab to inhibition of phagocytic cell function.
induces a profound B-cell depletion that may involve theautoreactive B-cell clone. However, a mechanism of mac- rophage blockade by opsonized B cells also has been pro- The use of aggressive lymphomalike chemotherapy posed, which may account for the early responses.
regimens for chronic refractory ITP has been reported inone series.117,118 Immune thrombocytopenic purpura was associated with Hodgkin disease in one case and with Campath-1H is a humanized monoclonal antibody chronic lymphocytic leukemia in another. All 12 patients against CD52, a molecule expressed by both B and T had prior treatment with corticosteroids, and all had under- lymphocytes. Lim et al124 treated 6 patients with refractory gone splenectomy. The duration of thrombocytopenia ITP (3 patients had an underlying lymphoproliferative dis- ranged from 5 to 110 months, and all patients had platelet ease). A response was seen in 4 of 5 evaluable patients, and counts of less than 5 × 109/L unless they were receiving in 3 of these, the response lasted more than 4.9 months. In some form of platelet-enhancing therapy. The chemo- most patients, between 4 and 6 weeks were needed for a therapy regimen consisted of up to 6 cycles of cyclophos- response to occur. Adverse effects were notable and in- phamide and prednisone plus 1 or more other agents (vin- cluded rigors and fever during the infusion and marked cristine, procarbazine, and/or etoposide). Seven patients lymphopenia (<0.1 × 109/L) in all patients treated. Worsen- ITP in Adults
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ing of thrombocytopenia was noted in 2 patients during In one study, staphylococcal protein A immunoadsorp- therapy. A more recent study has investigated the use of tion was reported to be a highly effective method of im- Campath-1H in patients with various cytopenias. A re- proving platelet count. Snyder et al140 reported the effects sponse was obtained in 15 and maintained in 6 patients at of this treatment in 72 patients with chronic ITP. Forty-nine the expense of notable adverse effects.125 patients had undergone splenectomy, and most had re-ceived other platelet-enhancing therapies. All 72 patients Autologous Hematopoietic Stem Cell Transplantation were treated with an initial regimen of 6 immunoadsorption In recent years, autologous peripheral blood stem cell treatments for 2 to 3 weeks. Twenty-nine patients contin- transplantation has been used for severe unresponsive au- ued taking concomitant low-dose corticosteroids (<30 mg/ toimmune disorders. The results of a clinical trial using d), 9 of whom also received other platelet-enhancing medi- high-dose cyclophosphamide followed by autologous lym- cations. Twenty-five percent of patients had good re- phocyte-depleted peripheral blood stem cell transplanta- sponses (platelet counts of >100 × 109/L), 21% had fair tion have been reported by investigators at the National responses (platelet counts of >50-100 × 109/L and at least Institutes of Health Clinical Center in Bethesda, Md.126 The double the baseline count), and 54% had poor responses. In patient group comprised 14 adults with chronic refractory 36% of patients, responses were maintained for 2 months ITP, including 5 patients who had Evans syndrome (au- or longer. Other studies have documented much less favor- toimmune hemolytic anemia in addition to autoimmune able results and considerably greater toxicity.141,142 The thrombocytopenic purpura). At a median follow-up of 42 mechanisms of this therapy are unknown, but reduction in months, durable complete remissions were observed in 6 platelet-binding immunoglobulin and in circulating im- patients, durable partial responses in 2, and no response in mune complex levels has been the postulated mechanism 6; there were no transplant-related deaths. This trial has by which protein A immunoadsorption elicits its clinical been extended to recruit other patients. Another ongoing effects. Protein A immunoadsorption may decrease platelet trial at Fairview University Medical Center, Minneapolis, activation, and this may be an additional mechanism under- Minn, is evaluating the combination of timed plasmaphe- lying its efficacy.142 Approximately one third of the patients resis, high-dose cyclophosphamide and total lymphoid ir- developed an acute hypersensitivity-type reaction. A few radiation, and posttransplantation immunosuppression cases of severe vasculitis also have been reported.141,142 with cyclosporin A (
Thrombopoietin and Thrombopoietin-like Agents Clinical trials with numerous new agents are under way.
An alternative to increasingly intensive immunosup- More specific information about these trials can be found at pression may be to stimulate platelet production with the Web sites and http:// thrombopoietin or its analogues. In fact, in addition to Preliminary results for markedly shortened platelet survival, impaired platelet pro- most of these studies are either unavailable or have been duction may be responsible for thrombocytopenia in ITP.127 The pathogenetic mechanisms of this phenomenon prob- A response to etanercept, a recombinant fusion protein ably involve autoantibodies that affect megakaryocyte de- of the extracellular portion of the P75 tumor necrosis factor velopment. On the basis of these observations, it has been α receptor and the Fc portion of human IgG1, has been postulated that stimulation by thrombopoietin may result in documented in 3 patients with severe, chronic, refractory safe platelet counts. A report involving 4 patients docu- ITP.143 A clinical trial to evaluate the efficacy and toxicity mented increased platelet counts in 3 patients, with throm- of this agent in children and adults with chronic ITP is bocytosis resulting in platelet counts of up to approxi- A humanized monoclonal antibody to FcγRI receptors on monocytes and macrophages, MDX-33, has been inves- tigated in a multicenter phase 2 study by Terjanian et al.144 Several other therapies have been used in chronic ITP, A dose-dependent transient response in 30 patients with including dapsone,129,130 interferon α,131,132 colchicine,133 ascorbic acid,134 low-molecular-weight heparin,135 myco- A humanized monoclonal antibody to CD40 ligand has phenolate mofetil,136,137 2-chlorodeoxyadenosine,138 and li- been used in 2 groups of patients with ITP. This agent binds posomal doxorubicin.139 The number of patients in all these specifically to CD40 ligand (expressed by T cells) and studies was small, and the responses were mostly unim- blocks its ability to bind to CD40, thus preventing stimula- pressive, inconsistent, and transient, often occurring in pa- tion of the B lymphocytes and inhibiting antibody produc- tion. Of 29 patients treated, 7 showed an increase in platelet Mayo Clin Proc, April 2004, Vol 79
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count to greater than 30 × 109/L; at least 2 of these patients greater than 20 × 109/L do not require treatment until have since relapsed. Three additional patients with ITP, delivery is imminent but should be carefully monitored, with extremely low platelet counts and clinical bleeding, received the highest dose initially (rather than by dose Although a consensus has not been reached, most ex- escalation) and all responded.145 However, this trial was perts agree that platelet counts of greater than 50 × 109/L stopped because of adverse thrombotic events. Another are safe for normal vaginal delivery and are safe for ce- multicenter trial with a different humanized monoclonal sarean section, whereas epidural anesthesia is used only when platelet counts are greater than 80 × 109/L because of Daclizumab, a humanized monoclonal antibody di- the potential risk of hematoma formation and neurologic rected against CD25 (interleukin 2 receptor), which has been used primarily to prevent rejection of solid organ The major treatment options for maternal ITP are corti- transplants, is being tested at the Warren Grant Magnuson costeroids or IVIg. Vinca alkaloids, androgens, and most Clinical Center of Bethesda, Md, in patients with ITP who immunosuppressive drugs should not be used during preg- do not respond to initial prednisone treatment.147-150 nancy, although azathioprine has been used safely in pa- A phase 1/2 open-label dose-escalation clinical trial to tients who underwent transplantation. If the duration of evaluate the safety and efficacy of cytotoxic T-lympho- treatment is likely to be short, ie, starting in the third cyte-associated antigen 4 immunoglobulin (CTLA-4-Ig) in trimester, corticosteroids are a cost-effective option. An patients with refractory ITP has been launched in the initial dosage of 1 mg/kg per day (based on prepregnancy United Kingdom. The fusion immunoglobulin CTLA-4-Ig weight) is recommended153,154 and should be tapered subse- combines the first extracellular domain of human CD152 quently to the minimum hemostatically effective dose. Pa- and the Fc portion of human IgG1; CTLA-4-Ig probably tients must be monitored carefully for major adverse ef- blocks T-cell activation by competing for the costimulatory fects such as hypertension, hyperglycemia, osteoporosis, excessive weight gain, and psychosis. Because 90% of theadministered dose of prednisone is metabolized in the pla- centa, serious fetal adverse effects such as adrenal suppres- Mild to moderate thrombocytopenia is common in healthy sion are unlikely. If corticosteroid therapy is likely to be women with an apparently normal pregnancy.152 Most of prolonged, or notable adverse effects occur, or an unac- these women have gestational thrombocytopenia, a benign ceptably high maintenance dosage is required (>10 mg/d of self-limiting condition with no notable bleeding risk to prednisone), IVIg therapy should be considered.5 The re- either mother or infant.4,5 Gestational thrombocytopenia is sponse rate (80%) and duration of response (2-3 weeks) to characterized by mild thrombocytopenia (platelets rarely IVIg is similar to those of nonpregnant patients.
decrease to less than 80 × 109/L), occurrence in healthy The ability of maternal IVIg therapy to improve fetal women with otherwise normal blood counts, normal plate- platelet counts remains controversial.155 Intravenous immu- let counts before and after pregnancy, and no association noglobulin has the same potential risks and adverse effects with fetal or neonatal thrombocytopenia. However, distin- as in the nonpregnant patient, and the financial cost is much guishing gestational thrombocytopenia from ITP may be higher than that of corticosteroids. Therapeutic options for difficult or impossible when the thrombocytopenia is iden- women with severely symptomatic ITP refractory to oral tified for the first time during pregnancy and no previous corticosteroids or IVIg include high-dose intravenous meth- ylprednisolone (1 g), alone or combined with IVIg or aza- Proper management of ITP in pregnancy requires con- thioprine,154 which, from available data, appears to cause sideration of both the mother and the fetus because IgG no serious problems to either mother or fetus.156 Splenec- antiplatelet antibodies cross the placenta and may produce tomy during pregnancy is performed rarely; if absolutely profound thrombocytopenia in the neonate. No high-qual- essential, it is best carried out in the second trimester and ity prospective studies or randomized clinical trials exist may be successfully performed laparoscopically, although about preferred treatment of the mother or neonate or about this may be technically difficult after 20 weeks’ gestation.
optimal delivery procedure. The decision to treat the preg- More recently, intravenous anti-D has been shown to be nant woman with ITP is based on assessment of the risk of both effective and safe during pregnancy with no adverse hemorrhage. The platelet count usually decreases as preg- effects experienced by either the mother or fetus.157 nancy progresses, the greatest rate of decline and nadir The major concern is at delivery because the incidence occurring in the third trimester.153 Therefore, careful plan- of fetal thrombocytopenia with platelet counts of less than ning is required to ensure a safe platelet count at the time of 50 × 109/L is approximately 10% to 15% and with platelet delivery. Asymptomatic patients with platelet counts of counts of less than 20 × 109/L is approximately 5%.158-163 ITP in Adults
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No accurate, risk-free method of determining fetal platelet which should describe consecutive patients with clear in- count is currently available, and both cordocentesis and clusion and exclusion criteria as well as long follow-up fetal scalp blood sampling are rarely used in the treatment data to document clinical outcomes and platelet responses, of ITP during pregnancy. The only characteristics that have could help clinicians to delineate more precise treatment been consistently correlated with an increased incidence of fetal thrombocytopenia are prior splenectomy and throm-bocytopenia in the first or preceding sibling.160,161,164 In oneseries of 64 pregnant women with chronic ITP, the inci- George JN, El-Harake MA, Aster RH. Thrombocytopenia due to dence of severe neonatal thrombocytopenia (platelet count enhanced platelet destruction by immunologic mechanisms. In: of <50 × 109/L) was 57% when mothers had prior splenec- Beutler E, Lichtman MA, Coller BS, Kipps TJ, eds. Williams tomy and a gestational platelet count of less than 50 × 109/ Hematology. 5th ed. New York, NY: McGraw-Hill; 1995:1315-1355.
L; the incidence was 0% when mothers had neither of these Frederiksen H, Schmidt K. The incidence of idiopathic thrombo- cytopenic purpura in adults increases with age. Blood. 1999;94: It has been postulated that trauma during vaginal deliv- Neylon AJ, Saunders PW, Howard MR, Proctor SJ, Taylor PR, ery may precipitate central nervous system bleeding in the Northern Region Haematology Group. Clinically significant neonate and that cesarean section may obviate this prob- newly presenting autoimmune thrombocytopenic purpura in lem; however, this hypothesis has been questioned.162 In adults: a prospective study of a population-based cohort of 245patients. Br J Haematol. 2003;122:966-974.
fact, the incidence of fetal hemorrhage is less than 1%, and George JN, Woolf SH, Raskob GE, et al. Idiopathic thrombocy- there are no differences in the rate of complications with topenic purpura: a practice guideline developed by explicit cesarean section compared with vaginal delivery. Thus, it methods for the American Society of Hematology. Blood. 1996;88:3-40.
is now generally agreed that the mode of delivery in ITP British Committee for Standards in Haematology General should be determined purely by obstetric indications.
Haematology Task Force. Guidelines for the investigation and After delivery, the infant’s platelet count often declines management of idiopathic thrombocytopenic purpura in adults,children and in pregnancy. Br J Haematol. 2003;120:574-596.
during the first week and should be monitored carefully.165 Dickerhoff R, von Ruecker A. The clinical course of immune For severe thrombocytopenia or mucosal bleeding in the thrombocytopenic purpura in children who did not receive neonate, intravenous IVIg is the treatment of choice. Plate- intravenous immunoglobulins or sustained prednisone treatment.
J Pediatr. 2000;137:629-632.
let transfusions that are cytomegalovirus negative and irra- Kuhne T, Imbach P, Bolton-Maggs PH, Berchtold W, Blanchette diated can be added in the event of severe bleeding.5 V, Buchanan GR, Intercontinental Childhood ITP Study Group.
Newly diagnosed idiopathic thrombocytopenic purpura inchildhood: an observational study. Lancet. 2001;358:2122-2125.
Stasi R, Stipa E, Masi M, et al. Long-term observation of 208 Because of the general lack of randomized studies, man- adults with chronic idiopathic thrombocytopenic purpura. Am J agement options for ITP are not based on evidence but on a Cortelazzo S, Finazzi G, Buelli M, Molteni A, Viero P, Barbui T.
rational approach to the individual patient that includes High risk of severe bleeding in aged patients with chronic assessment of disease severity, patient’s characteristics re- idiopathic thrombocytopenic purpura. Blood. 1991;77:31-33.
lated to risk of bleeding, and the risks and adverse effects of Portielje JE, Westendorp RG, Kluin-Nelemans HC, Brand A.
Morbidity and mortality in adults with idiopathic thrombocyto- treatment. The toxicity profiles of many of the newer treat- penic purpura. Blood. 2001;97:2549-2554.
ments underline the need for appropriate choices and for Cohen YC, Djulbegovic B, Shamai-Lubovitz O, Mozes B. The trials designed to incorporate end points such as quality-of- bleeding risk and natural history of idiopathic thrombocytopenicpurpura in patients with persistent low platelet counts. Arch Intern life measures and economic analyses. Real evidence-based guidelines for this disease are not likely to be developed Schattner E, Bussel J. Mortality in immune thrombocytopenic soon. Considering the low incidence of mortality and major purpura: report of seven cases and consideration of prognosticindicators. Am J Hematol. 1994;46:120-126.
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THE COSTED NORMS APPROACH AS APPLIED TO THE SOCIAL SECTORIn this section, prototype formulae are presented for the socialsector components of the provincial equitable share allocation,namely education, welfare, and health. It is necessary, over time, to define more precisely whatconstitutes “basic services” in education, welfare, and health. Asnoted in Section 4, in many instances national

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