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NEJM
James N. George, M.D., and Sara K. Vesely, Ph.D. Recognition of immune thrombocytopenic purpura is increasing because of the increasing frequency of routine blood counts that reveal unexpected thrombocytopenia. For patients who may have immune thrombocytopenic purpura, the essential decisions are whether to perform additional diagnostic studies and whether to initiate any treatment. The diagnosis of immune thrombocytopenic purpura is established only by ruling out other causes of thrombocytopenia. The patient's history, the findings on physical examination, the blood counts, and the findings on examination of the blood smear are usually sufficient.1,2 Examination of the blood smear is essential to rule out in vitro platelet clumping that can cause a falsely low platelet count and to ensure that there are no abnormalities of the white cells or red cells. A bone marrow biopsy may be appropriate in older patients to rule out occult myelodysplasia; tests for antiplatelet antibodies are not helpful.1,2 Most important is a thorough history taking to rule out drug-induced thrombocytopenia.3 Merely asking patients what medicines they are taking is not sufficient; physicians must explicitly ask about any use of over-the-counter drugs, vitamins, supplements, or herbal remedies. For example, a patient may assume that his or her physician is not interested in quinine, commonly taken for leg cramps, but quinine is one of the most frequent causes of severe drug-induced thrombocytopenia.3 Herbal remedies can also cause severe thrombocytopenia.4 Once immune thrombocytopenic purpura has been diagnosed, the essential decision is whether any treatment, beyond counseling and careful observation, is necessary. The goal is not to achieve a normal platelet count, but rather to prevent bleeding. Initial management in children differs from that in adults. Immune thrombocytopenic purpura in children is typically an acute disease that improves in several weeks and resolves in several months. Therefore, many pediatric hematologists recommend only observation for children who do not have serious bleeding, even if the thrombocytopenia is severe.2 In adults, because immune thrombocytopenic purpura is typically a persistent disease, treatment is routinely initiated if the thrombocytopenia is severe, even if the bleeding is negligible. Therefore, in adults, the decision either to treat or to observe is made by assessing the platelet count. A reasonable estimate of a safe platelet count, and therefore a reasonable basis for observation without specific treatment, is a platelet count greater than 30,000 per cubic millimeter. This value is far below normal, but it seems to be sufficient to prevent serious bleeding. In two case series, 49 of 117 patients (42 percent)5 and 28 of 152 patients (18 percent)6 had initial platelet counts that were greater than 30,000 per cubic millimeter. Most of these patients were observed without treatment, and none had serious bleeding. For the past 50 years, the initial treatment in adults with severe thrombocytopenia has been oral prednisone, usually at a dose of 1 mg per kilogram of body weight per day.1,2 In most patients, the platelet count increases in response to this regimen but then falls when the dose of prednisone is tapered. There is no agreement on the appropriate duration of treatment; typically, the administration of prednisone is started with no plan for when to stop. Prolonged treatment with prednisone may cause many problems, such as opportunistic infections, osteoporosis, the formation of cataracts, and emotional lability, which is often intolerable. Therefore, the regimen proposed by Cheng et al. in this issue of the Journal7 � a much higher dose of glucocorticoid for only four days � is appealing. Cheng et al.7 describe 125 consecutive adults who had a new diagnosis of immune thrombocytopenic purpura and who were followed for a median of 30.5 months. All the patients received initial treatment with 40 mg of dexamethasone (equivalent to 250 mg of prednisone) daily for four consecutive days. Cheng et al. report that the platelet count in 85 percent of the patients was at least 50,000 per cubic millimeter within one week after the completion of treatment with dexamethasone and that half of these patients had a sustained response for at least six months with no further treatment. The authors' definition of a response is consistent with the goal of achieving a safe, though not necessarily normal, platelet count. Cheng et al. report that no patients had side effects severe enough to prompt the discontinuation of treatment. The appeal of this regimen is the short duration of treatment as well as its low cost ($12.20 in our pharmacy). Emotional lability, hyperglycemia, and hypertension are severe side effects that may occur with such a high dose of a glucocorticoid, but the devastating toxic effects that can result from prolonged treatment can be avoided. It is impressive that 50 percent of the patients with an initial response had a sustained response after only four days of treatment. Short pulses of a high dose of a glucocorticoid, an approach similar to the traditional method of treatment for severe autoimmune disorders,8 may provide more intensive and more sustained immunosuppression than a regimen of prednisone given at a lower dose. Should this report change our initial treatment of adults with severe immune thrombocytopenic purpura? Not until more experience provides greater confidence. If the results are repeated and confirmed, with documentation of a response rate similar to that with conventional prednisone treatment2 and an acceptable rate of side effects, then this regimen of dexamethasone may be safer because the risks associated with prolonged prednisone treatment can be avoided. This approach to the treatment of immune thrombocytopenic purpura is not new. Pulsed, high-dose dexamethasone therapy was proposed nine years ago as a monthly regimen for patients with immune thrombocytopenic purpura who did not have a response to initial treatment.9 All 10 patients described in that report had sustained responses, and none had serious side effects. However, the results were not confirmed; lack of confirmation is the fate of many optimistic reports based on uncontrolled observations in few patients. Some subsequent reports of studies in which high-dose pulses of dexamethasone were used described poor efficacy and serious toxicity. Glucocorticoid treatment in adults who have a new diagnosis of immune thrombocytopenic purpura and severe thrombocytopenia is appropriate even in the absence of serious bleeding, because the course of the disease and the attendant risk of bleeding are not yet known. However, the indications for subsequent treatment, which may be associated with greater risks than the initial glucocorticoid treatment, must be more stringent. Splenectomy is the traditional treatment approach for patients in whom initial glucocorticoid therapy fails; it provides sustained responses with safe platelet counts in more than 80 percent of patients but is associated with a substantial risk of complications.6 For patients who do not have a response to splenectomy, many treatments have been proposed, including various immunosuppressive and chemotherapeutic agents. Initial optimistic reports were followed by a number of reports describing less success and greater toxicity. However, the success rate of these agents in patients who have the greatest need for treatment (e.g., patients who have had immune thrombocytopenic purpura for several months or longer, who have not had a response to splenectomy, and who have a platelet count that is less than 10,000 per cubic millimeter with serious bleeding) is not known. These severely affected patients may have lower response rates than others, and most patients are not so severely affected. Since the potential benefits of treatment are uncertain, severe thrombocytopenia that is not accompanied by serious bleeding may not be a sufficient reason to assume the risks of intensive immunosuppressive treatment. The risks associated with immunosuppressive treatment were well documented in a recent case series6; death from bleeding occurred in 2 of 152 patients (1 percent), but death from infectious complications of treatment occurred in 4 patients (3 percent). Many patients with immune thrombocytopenic purpura say that the treatment is worse than the disease; most never have serious bleeding, but treatment commonly has side effects that can be severe. A lesson may be learned from the Mikado in Gilbert and Sullivan's operetta, who says, "Let the punishment fit the crime." For immune thrombocytopenic purpura, "Let the treatment fit the patient."
From the Departments of Medicine and Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City. References
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