今日の臨床サポート

特発性血小板減少性紫斑病(ITP)

著者: 冨山佳昭 大阪大学医学部附属病院 輸血部

監修: 木崎昌弘 埼玉医科大学総合医療センター

著者校正/監修レビュー済:2021/02/10
参考ガイドライン:
  1. 厚生労働省難治性疾患政策研究事業 血液凝固異常症等に関する研究班 「ITP治療の参照ガイド」作成委員会:成人特発性血小板減少性紫斑病治療の参照ガイド 2019改訂版
患者向け説明資料

概要・推奨   

  1. ITP症例に対するヘリコバクター・ピロリ菌の除菌は、日本での有効率は高いが、欧米では低い傾向がある(推奨度1 OJ
  1. ITPに対する副腎資質ステロイド療法は約80%で有効である(推奨度1 O
  1. 副腎皮質ステロイドは減量により多くの症例で血小板数が低下し、中止できる症例は1025%である。しかしながら、維持量としてはプレドニゾロン10mg/日以下とする(推奨度1 OJ
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  1. 海外では、脾摘の前にワクチン接種(Streptococcus pneumoniaeHaemophilus influenzae type b、meningococcus)が推奨されている(推奨度2 G)。
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
冨山佳昭 : 未申告[2021年]
監修:木崎昌弘 : 講演料(ブリストル・マイヤーズスクイブ,ヤンセンファーマ,ノバルティスファーマ,セルジーン,MSD,小野薬品,武田薬品,大日本住友製薬),研究費・助成金など(武田薬品),奨学(奨励)寄付など(協和キリン,中外製薬,武田薬品,小野薬品,第一三共)[2021年]

改訂のポイント:
  1.  定期レビューを行い一部加筆するとともに、エビデンスランクを追記した。

病態・疫学・診察

疾患情報  
  1. 特発性血小板減少性紫斑病(ITP)は、抗血小板抗体によって、産生された血小板が破壊される、さらには抗血小板抗体によって巨核球造血・血小板造血が障害され、血小板数の低下を来している疾患である。
  1. ITPの診断は、血小板減少を来す原因疾患がないこと、血小板数の減少と骨髄での巨核球数が減少していないことが必要要件である。ただ、2011年の米国血液学会のガイドラインでは、骨髄検査は必ずしも必要であるとは記載されていない。
  1. わが国では、ITPは特定疾患として認定されているので、そのデータから推察すると、患者数は10万人あたり1.88人である。男性1.49人、女性2.25人と報告されている。
  1. ITPそのものは、それほど予後の悪い疾患ではない。しかし完全寛解になるのは、たかだか25%程度である。残りの症例はなんらかの治療が行われている。死亡の危険性は、血小板数が3万/μL未満の症例であれば、正常人に比べて4.2倍高くなり、かつ、60歳以上であれば致死的出血の危険性は約30倍高くなる。
  1. ITPとして診断を受けてから、緊急性を要さない場合はヘリコバクター・ピロリ(H. Pylori)の検査を行い、陽性であれば、除菌療法を行う。
  1. ITP治療の参照ガイド2019改訂版:図アルゴリズム
  1. 治療として血小板数が2~3万/μL以上で出血傾向がなければ、経過観察をする。それ未満で出血傾向があれば、副腎皮質ステロイドが第1選択薬である。第2選択として、TPO受容体作動薬、リツキシマブ、脾摘が挙げられる。
  1. 特発性血小板減少性紫斑病は、指定難病であり、研究班のITPの重症度分類を用いてStageⅡ以上の場合は申請し認定されると保険料の自己負担分の一部が公費負担として助成される。(平成27年1月施行
  1. 難病法に基づく医療費助成制度
問診・診察のポイント  
  1. 出血症状がどのようなものかを確認する。例えば、皮膚に点状出血、紫斑などが出現しているのか、鼻血がよく起きるのか、女性であれば生理の期間が延長するのか、筋肉内出血、関節内出血などが起きるのかなどを問診で確認する。

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文献 

著者: Francesco Rodeghiero, Roberto Stasi, Terry Gernsheimer, Marc Michel, Drew Provan, Donald M Arnold, James B Bussel, Douglas B Cines, Beng H Chong, Nichola Cooper, Bertrand Godeau, Klaus Lechner, Maria Gabriella Mazzucconi, Robert McMillan, Miguel A Sanz, Paul Imbach, Victor Blanchette, Thomas Kühne, Marco Ruggeri, James N George
雑誌名: Blood. 2009 Mar 12;113(11):2386-93. doi: 10.1182/blood-2008-07-162503. Epub 2008 Nov 12.
Abstract/Text Diagnosis and management of immune thrombocytopenic purpura (ITP) remain largely dependent on clinical expertise and observations more than on evidence derived from clinical trials of high scientific quality. One major obstacle to the implementation of such studies and in producing reliable meta-analyses of existing data is a lack of consensus on standardized critical definitions, outcome criteria, and terminology. Moreover, the demand for comparative clinical trials has dramatically increased since the introduction of new classes of therapeutic agents, such as thrombopoietin receptor agonists, and innovative treatment modalities, such as anti-CD 20 antibodies. To overcome the present heterogeneity, an International Working Group of recognized expert clinicians convened a 2-day structured meeting (the Vicenza Consensus Conference) to define standard terminology and definitions for primary ITP and its different phases and criteria for the grading of severity, and clinically meaningful outcomes and response. These consensus criteria and definitions could be used by investigational clinical trials or cohort studies. Adoption of these recommendations would serve to improve communication among investigators, to enhance comparability among clinical trials, to facilitate meta-analyses and development of therapeutic guidelines, and to provide a standardized framework for regulatory agencies.

PMID 19005182  Blood. 2009 Mar 12;113(11):2386-93. doi: 10.1182/blood-・・・
著者: Takuya Nishioka, Takahisa Yamane, Takayuki Takubo, Kensuke Ohta, Keunsik Park, Masayuki Hino
雑誌名: Cytometry B Clin Cytom. 2005 Nov;68(1):37-42. doi: 10.1002/cyto.b.20067.
Abstract/Text BACKGROUND: In 1975, Dixson reported that anti-platelet IgG on platelets from patients with idiopathic thrombocytopenic purpura (ITP) is greater than in normal people, by determining anti-platelet antibodies directly on the platelet surface with a quantitative complement lysis-inhibition-assay. Since then, platelet-associated IgG (PAIgG) has been thought of as evidence of ITP. Although platelets from ITP patients show significantly higher PAIgG values than from normal control individuals, PAIgG is not specific for autoantibody because it increases in other than immune ITP patients.
METHODS: We analyzed positive platelet percentage with various platelet-associated immunoglobulins: IgG, IgM, IgA, and total immunoglobulins, in the blood from 17 normal donors and 23 ITP patients.
RESULTS: The specificity for ITP disease was better in flow cytometry than in ELISA, because, other than ITP, only aplastic anemia was positive in flow cytometry; however, various disorders (aplastic anemia, chronic lymphocytic leukemia, acute myeloid leukemia, and myelodysplastic syndrome) showed positive in ELISA. Flow cytometry methods had the same sensitivity for ITP disease as ELISA. However, it is supposed that there was no nonimmune ITP in this study because the PAIgG negative patients (n = 1) showed positive results in flow cytometry.
CONCLUSION: Flow cytometry method was effective for ITP screening, especially for specificity.

(c) 2005 Wiley-Liss, Inc.
PMID 16184616  Cytometry B Clin Cytom. 2005 Nov;68(1):37-42. doi: 10.1・・・
著者: L T Romero-Guzmán, X López-Karpovitch, R Paredes, O Barrales-Benitez, J Piedras
雑誌名: Haematologica. 2000 Jun;85(6):627-31.
Abstract/Text BACKGROUND AND OBJECTIVE: Flow cytometry (FC) to identify platelet-associated (PA) immunoglobulin (Ig) is a potentially useful diagnostic test for idiopathic thrombocytopenic purpura (ITP). However, the restricted application of PAIg measurement to thrombocytopenic populations primarily comprised of ITP patients will artificially enhance the test's diagnostic specificity. For this reason, we performed a prospective study in which the results of a sensitive technique for detecting PAIg, as is FC, were correlated to the cause of the thrombocytopenia.
DESIGN AND METHODS: A total of 118 patients with platelet counts <100 x 10(9)/L and 30 normal donors with a platelet count >200 x 10(9)/L were studied for PAIg employing a flow cytometer. Forty-two children and 20 adults were diagnosed as having immune thrombocytopenia and 27 children and 29 adults had nonimmune thrombocytopenia of different etiology.
RESULTS: Raised levels of PAIg were found in 56/62 patients with immune thrombocytopenia and in 34/56 patients with non-immune thrombocytopenia. Diagnostic values of PAIg for the detection of immune thrombocytopenia were: sensitivity 90.3% and specificity 39. 3%. An enzyme-linked immunoabsorbant assay (ELISA) for the detection of autoantibodies to platelet glycoprotein (GP) complexes was used in adults, 9 with immune-related thrombocytopenia and 16 with non-immune thrombocytopenia, in order to determine the true non-specific nature of the positive PAIg test. By ELISA, 8/9 patients with immune thrombocytopenia and 7/16 with non-immune thrombocytopenic disorders showed autoantibodies to platelet GP complexes.
INTERPRETATION AND CONCLUSIONS: PAIg detection by FC constitutes a sensitive but non-specific assay thus making it unnecessary and inappropriate for establishing the diagnosis of ITP.

PMID 10878748  Haematologica. 2000 Jun;85(6):627-31.
著者: R Stasi, E Stipa, M Masi, M Cecconi, M T Scimò, F Oliva, A Sciarra, A P Perrotti, G Adomo, S Amadori
雑誌名: Am J Med. 1995 May;98(5):436-42.
Abstract/Text PURPOSE: To define response to therapy and ultimate outcome of adults with idiopathic thrombocytopenic purpura (ITP).
PATIENTS AND METHODS: We retrospectively analyzed patients with ITP diagnosed between 1978 and 1988, and reexamined them between June 1992 and March 1993. Data from 208 cases were collected. Median patient age was 44 years (range 14 to 78) at the time of diagnosis, and 51 years (range 19 to 86) at reexamination. Length of follow-up ranged from 48 to 151 months (median 92) and was longer than 10 years in 26 patients (12.5%). Reexamination included a careful interview, physical examination, complete blood count, screening for HIV infection, determination of platelet-bound IgG, and, in persistently thrombocytopenic patients, autoimmunity markers and routine laboratory investigations.
RESULTS: A total of 121 patients with fewer than 50 x 10(9) platelets per liter received an initial treatment with prednisone (PDN) at a dosage of 1 mg/kg of body weight for 1 month. Refractory or relapsed cases underwent splenectomy and/or other therapeutic modalities. In 87 patients with greater than 50 x 10(9) platelets per liter, no therapy was scheduled. An initial complete response to PDN was observed in 38.8% cases. A sustained complete remission (CR) lasting more than 6 months with no maintenance therapy was attained in 18.7%. At the time of last follow-up only 11 of these patients remained in CR. Sixty-three patients underwent splenectomy. Forty-seven (74.6%) had a CR, with 41 achieving a prolonged recovery (> 6 months). Twelve other cases attained a sustained partial remission. Long-lasting recoveries were observed in 7 other cases following alternative treatments. Spontaneous remissions occurred in 8 of 87 untreated cases after observation periods of 6 months or more. Eleven deaths were recorded (6 women and 5 men, median age 73), but only 5 were attributable to thrombocytopenia. At last control, 43 patients were in complete remission and free from therapy, and 52 were still on therapy. Four thrombocytopenic patients had laboratory features and a clinical history consistent with an autoimmune disease.
CONCLUSIONS: This analysis of ITP in adults suggests that splenectomy remains the most effective treatment. The majority of patients who undergo splenectomy can have a CR for many years, while only a minority of those who do not have this therapeutic modality or fail it are likely to attain similar results. The long-term prognosis of ITP is benign even in refractory cases. Spontaneous remissions can be observed in a significant percentage of untreated patients (about 9%). The development of overt autoimmune diseases is relatively uncommon. Particular attention should be given to the management of ITP in the elderly, where bleeding episodes of the central nervous system tend to occur more frequently.

PMID 7733121  Am J Med. 1995 May;98(5):436-42.
著者: Mansoor N Saleh, James B Bussel, Gregory Cheng, Oliver Meyer, Christine K Bailey, Michael Arning, Andres Brainsky, EXTEND Study Group
雑誌名: Blood. 2013 Jan 17;121(3):537-45. doi: 10.1182/blood-2012-04-425512. Epub 2012 Nov 20.
Abstract/Text Patients with chronic immune thrombocytopenia may have bleeding resulting from low platelet counts. Eltrombopag increases and maintains hemostatic platelet counts; however, to date, outcome has been reported only for treatment lasting ≤ 6 months. This interim analysis of the ongoing open-label EXTEND (Eltrombopag eXTENded Dosing) study evaluates the safety and efficacy of eltrombopag in 299 patients treated up to 3 years. Splenectomized and nonsplenectomized patients achieved platelets ≥ 50 000/μL at least once (80% and 88%, respectively). Platelets ≥ 50 000/μL and 2 × baseline were maintained for a median of 73 of 104 and 109 of 156 cumulative study weeks, respectively. Bleeding symptoms (World Health Organization Grades 1-4) decreased from 56% of patients at baseline to 20% at 2 years and 11% at 3 years. One hundred (33%) patients were receiving concomitant treatments at study entry, 69 of whom attempted to reduce them; 65% (45 of 69) had a sustained reduction or permanently stopped ≥ 1 concomitant treatment. Thirty-eight patients (13%) experienced ≥ 1 adverse events leading to study withdrawal, including patients meeting protocol-defined withdrawal criteria (11 [4%] thromboembolic events, 5 [2%] exceeding liver enzyme thresholds). No new or increased incidence of safety issues was identified. Long-term treatment with eltrombopag was generally safe, well tolerated, and effective in maintaining platelet counts in the desired range.

PMID 23169778  Blood. 2013 Jan 17;121(3):537-45. doi: 10.1182/blood-20・・・
著者: A Gasbarrini, F Franceschi, R Tartaglione, R Landolfi, P Pola, G Gasbarrini
雑誌名: Lancet. 1998 Sep 12;352(9131):878. doi: 10.1016/S0140-6736(05)60004-9.
Abstract/Text
PMID 9742983  Lancet. 1998 Sep 12;352(9131):878. doi: 10.1016/S0140-6・・・
著者: Kingo Fujimura, Masataka Kuwana, Yoshiyuki Kurata, Masahiro Imamura, Hiroshi Harada, Hisashi Sakamaki, Masanao Teramura, Kyuhei Koda, Shosaku Nomura, Sayaka Sugihara, Takeshi Shimomura, Tetsuro-Takahiro Fujimoto, Kazuma Oyashiki, Yasuo Ikeda
雑誌名: Int J Hematol. 2005 Feb;81(2):162-8.
Abstract/Text A retrospective study was performed to determine the prevalence of Helicobacter pylori (H pylori) infection, the effect of H pylori eradication on platelet counts, and the characteristic clinical features of chronic immune or idiopathic thrombocytopenic purpura (ITP) with H pylori infection. H pylori infection was found in 300 patients, a group that was significantly older (P < .005) and had more cases of hyperplastic megakaryocytes in the bone marrow (P = .01) than patients without H pylori infection. H pylori eradication therapy was performed in 207 H pylori-positive ITP cases, and the platelet count response was observed in 63% of the successful eradication group and in 33% of the unsuccessful eradication group (P < .005). In the successful group, the complete remission and partial remission rates were 23% and 42%, respectively, 12 months after eradication. In the majority of responders, the platelet count response occurred 1 month after eradication therapy, and the increased platelet count continued without ITP treatment for more than 12 months. H pylori eradication therapy was effective even in refractory cases, which were unresponsive to splenectomy. In conclusion, H pylori infection was involved in most ITP patients older than 40 years in Japan, and eradication therapy should be the first line of treatment in H pylori-positive ITP patients.

PMID 15765787  Int J Hematol. 2005 Feb;81(2):162-8.
著者: Atsuko Asahi, Masataka Kuwana, Hidekazu Suzuki, Toshifumi Hibi, Yutaka Kawakami, Yasuo Ikeda
雑誌名: Haematologica. 2006 Oct;91(10):1436-7. Epub 2006 Sep 7.
Abstract/Text Thirty-seven patients with idiopathic thrombocytopenic purpura (ITP) were treated with a standard Helicobacter pylori eradication regimen irrespective of H. pylori infection. Our results indicate that platelet recovery results from the disappearance of H. pylori itself, and is mediated, in part, through suppression of anti-platelet autoantibody production.

PMID 16963398  Haematologica. 2006 Oct;91(10):1436-7. Epub 2006 Sep 7.・・・
著者: Roberto Stasi, Ameet Sarpatwari, Jodi B Segal, John Osborn, Maria Laura Evangelista, Nichola Cooper, Drew Provan, Adrian Newland, Sergio Amadori, James B Bussel
雑誌名: Blood. 2009 Feb 5;113(6):1231-40. doi: 10.1182/blood-2008-07-167155. Epub 2008 Oct 22.
Abstract/Text Whether the eradication of Helicobacter pylori infection can increase the platelet count in patients with immune thrombocytopenic purpura (ITP) is still a controversial issue. To provide evidence-based guidance, we performed a systematic review of the literature published in English, selecting articles reporting 15 or more total patients. We identified 25 studies including 1555 patients, of whom 696 were evaluable for the effects of H pylori eradication on platelet count. The weighted mean complete response (platelet count > or = 100 x 10(9)/L) and overall response (platelet count > or = 30 x 10(9)/L and at least doubling of the basal count) were 42.7% (95% confidence interval [CI], 31.8%-53.9%) and 50.3% (95% CI, 41.6%-59.0%), respectively. In 222 patients with a baseline platelet count less than 30 x 10(9)/L, the complete response rate was 20.1% (95% CI, 13.5%-26.7%) and the overall response rate was 35.2% (95% CI, 28.0%-42.4%). The response rate tended to be higher in countries with a high background prevalence of H pylori infection and in patients with milder degrees of thrombocytopenia. These findings suggest that the detection and eradication of H pylori infection should be considered in the work-up of patients with seemingly typical ITP.

PMID 18945961  Blood. 2009 Feb 5;113(6):1231-40. doi: 10.1182/blood-20・・・
著者: J N George, S H Woolf, G E Raskob, J S Wasser, L M Aledort, P J Ballem, V S Blanchette, J B Bussel, D B Cines, J G Kelton, A E Lichtin, R McMillan, J A Okerbloom, D H Regan, I Warrier
雑誌名: Blood. 1996 Jul 1;88(1):3-40.
Abstract/Text
PMID 8704187  Blood. 1996 Jul 1;88(1):3-40.
著者: British Committee for Standards in Haematology General Haematology Task Force
雑誌名: Br J Haematol. 2003 Feb;120(4):574-96.
Abstract/Text
PMID 12588344  Br J Haematol. 2003 Feb;120(4):574-96.
著者: Cindy Neunert, Wendy Lim, Mark Crowther, Alan Cohen, Lawrence Solberg, Mark A Crowther, American Society of Hematology
雑誌名: Blood. 2011 Apr 21;117(16):4190-207. doi: 10.1182/blood-2010-08-302984. Epub 2011 Feb 16.
Abstract/Text Immune thrombocytopenia (ITP) is commonly encountered in clinical practice. In 1996 the American Society of Hematology published a landmark guidance paper designed to assist clinicians in the management of this disorder. Since 1996 there have been numerous advances in the management of both adult and pediatric ITP. These changes mandated an update in the guidelines. This guideline uses a rigorous, evidence-based approach to the location, interpretation, and presentation of the available evidence. We have endeavored to identify, abstract, and present all available methodologically rigorous data informing the treatment of ITP. We provide evidence-based treatment recommendations using the GRADE system in those areas in which such evidence exists. We do not provide evidence in those areas in which evidence is lacking, or is of lower quality--interested readers are referred to a number of recent, consensus-based recommendations for expert opinion in these clinical areas. Our review identified the need for additional studies in many key areas of the therapy of ITP such as comparative studies of "front-line" therapy for ITP, the management of serious bleeding in patients with ITP, and studies that will provide guidance about which therapy should be used as salvage therapy for patients after failure of a first-line intervention.

PMID 21325604  Blood. 2011 Apr 21;117(16):4190-207. doi: 10.1182/blood・・・
著者: Axel Matzdorff, Gabriele Arnold
雑誌名: Eur J Haematol. 2007 May;78(5):381-8. doi: 10.1111/j.1600-0609.2007.00829.x. Epub 2007 Feb 27.
Abstract/Text BACKGROUND: The 1996 ASH guidelines recommend glucocorticoids and splenectomy as standard treatment of chronic immune thrombocytopenic purpura (ITP). We sought to find out how many German ITP-patients were treated according to these guidelines and whether high-cost treatments were offered to the patients.
METHODS: We handed out a questionnaire at two self-help group meetings in 2004 and 2005 and to all patients who contacted the ITP self-help group until the end of 2005.
RESULTS: Eighty-five questionnaires were evaluated. Age (median 34 yr) and gender distribution (38% male, 62% female) were similar to other surveys. Median duration of disease was 5.2 yr. Seventy-five percent had platelets <20,000/microL at the time of diagnosis. Twenty-four percent still had <20,000 platelets/microL at the time of this survey. Forty-two percent had oropharyngeal mucosal bleeds, 28% gastrointestinal or urological bleeds, 11% bleedings in the eye with visual impairment or intracerebral bleeds. 96% had received a trial of glucocorticoid therapy. Seventy-five percent of the patients treated with glucocorticoids perceived this treatment as particularly bothersome. Seventy-five percent of the patients with low platelet count still had their spleen. Complementary and alternative medical treatments had been used by 46% of the patients. Only 33% of the patients had ever heard of rituximab.
CONCLUSION: Despite literature suggesting that patients wish to be well informed this survey shows that chronic ITP patients know little about their disease and the various treatment modalities. This and the frequent use of complementary and alternative medicines reflects inadequate communication between doctors and ITP patients.

PMID 17331128  Eur J Haematol. 2007 May;78(5):381-8. doi: 10.1111/j.16・・・
著者: Jacqueline A Guidry, James N George, Sara K Vesely, Shelia M Kennison, Deirdra R Terrell
雑誌名: Eur J Haematol. 2009 Sep;83(3):175-82. doi: 10.1111/j.1600-0609.2009.01265.x. Epub 2009 Apr 4.
Abstract/Text OBJECTIVES: The purpose of this study was to examine hematologist and patient perspectives about the side-effects of the corticosteroid treatment of immune thrombocytopenic purpura (ITP) and their perspectives about the patient's risk for bleeding. The specific aim was to compare patient and hematologist perspectives and, if a difference was documented, the implications of that difference. We hypothesized that patients with ITP may have more concern about corticosteroid side-effects and less concern about serious bleeding than hematologists.
METHODS: We surveyed 80 patients in the Oklahoma ITP Registry and all 83 hematologists in Oklahoma about the occurrence and severity of 18 corticosteroid side-effects and risks for serious bleeding.
RESULTS: Response rates were 80% (patients) and 71% (hematologists). Responses of patients and hematologists were significantly different from each other regarding both the frequency of severe corticosteroid side-effects and the risk of serious bleeding. For 13 of the 18 corticosteroid side-effects, patients reported more frequent occurrence of severe symptoms than hematologists (P < 0.05); physicians reported more frequent occurrence for one side-effect (P < 0.05). Conversely, 69% and 93% of hematologists reported being very worried about serious bleeding when responding to two case scenarios describing patients with platelet counts of 10 000/microL and 5000/microL (P < 0.05), compared with only 16 (31%) of 51 patients whose lowest platelet count had been <10 000/microL.
CONCLUSION: Awareness of the different opinions about corticosteroid side-effects and risk for bleeding between ITP patients and hematologists may improve management decisions.

PMID 19374704  Eur J Haematol. 2009 Sep;83(3):175-82. doi: 10.1111/j.1・・・
著者: Li Wei, Thomas M MacDonald, Brian R Walker
雑誌名: Ann Intern Med. 2004 Nov 16;141(10):764-70.
Abstract/Text BACKGROUND: Glucocorticoids have adverse systemic effects, including obesity, hypertension, and hyperglycemia, that may predispose to cardiovascular disease. The effect of glucocorticoid use on cardiovascular disease has not been quantified.
OBJECTIVE: To test the hypothesis that users of exogenous glucocorticoids have an increased risk for cardiovascular disease.
DESIGN: A cohort study using a record linkage database.
SETTING: Tayside, Scotland, United Kingdom.
PATIENTS: 68,781 glucocorticoid users and 82,202 nonusers without previous hospitalization for cardiovascular disease who were studied between 1993 and 1996.
MEASUREMENTS: The average daily dose of glucocorticoid exposure during follow-up was categorized as low (inhaled, nasal, and topical only), medium (oral, rectal, or parenteral <7.5 mg of prednisolone equivalent), or high (> or =7.5 mg of prednisolone equivalent). Poisson regression model, sensitivity analysis, and propensity score methods were used to investigate the association between glucocorticoid exposure and cardiovascular outcome.
RESULTS: 4383 cardiovascular events occurred in 257,487 person-years of follow-up for a rate of 17.0 (95% CI, 16.5 to 17.5) per 1000 person-years in the comparator group, and 5068 events occurred in 212,287 person-years for a rate of 23.9 (CI, 23.2 to 24.5) per 1000 person-years in the group exposed to glucocorticoids (22.1, 27.2, and 76.5 in low, medium, and high groups, respectively). The absolute risk difference was 6.9 (CI, 6.0 to 7.7) per 1000 person-years (5.1, 10.1, and 59.4, respectively). After adjustment for known covariates, the relative risk for a cardiovascular event in patients receiving high-dose glucocorticoids was 2.56 (CI, 2.18 to 2.99).
LIMITATIONS: Because the data were observational, residual confounding cannot be excluded.
CONCLUSION: Treatment with high-dose glucocorticoids seemed to be associated with increased risk for cardiovascular disease.

PMID 15545676  Ann Intern Med. 2004 Nov 16;141(10):764-70.
著者: Julian M Jenkins, Daphne Williams, Yanli Deng, Joanne Uhl, Valerie Kitchen, David Collins, Connie L Erickson-Miller
雑誌名: Blood. 2007 Jun 1;109(11):4739-41. doi: 10.1182/blood-2006-11-057968. Epub 2007 Feb 27.
Abstract/Text Eltrombopag (SB-497 115) is a first-in-class, oral, small-molecule, nonpeptide agonist of the thrombopoietin receptor (TpoR), being developed as a treatment for thrombocytopenia of various etiologies. In this phase 1 placebo-controlled clinical trial in 73 healthy male subjects, eltrombopag was administered as once-daily oral capsules for 10 days at doses of 5, 10, 25, 30, 50, and 75 mg. The pharmacokinetics of eltrombopag were dose dependent and linear, and eltrombopag increased platelet counts in a dose-dependent manner. There were no apparent differences in the incidence or severity of adverse events in subjects receiving active or placebo study medication. These observations indicate that eltrombopag is a once-daily, oral TpoR agonist with demonstrated thrombopoietic activity in human subjects, encouraging further studies in patients with thrombocytopenia.

PMID 17327409  Blood. 2007 Jun 1;109(11):4739-41. doi: 10.1182/blood-2・・・
著者: James B Bussel, Gregory Cheng, Mansoor N Saleh, Bethan Psaila, Lidia Kovaleva, Balkis Meddeb, Janusz Kloczko, Habib Hassani, Bhabita Mayer, Nicole L Stone, Michael Arning, Drew Provan, Julian M Jenkins
雑誌名: N Engl J Med. 2007 Nov 29;357(22):2237-47. doi: 10.1056/NEJMoa073275.
Abstract/Text BACKGROUND: The pathogenesis of chronic idiopathic thrombocytopenic purpura (ITP) involves antibody-mediated platelet destruction and reduced platelet production. Stimulation of platelet production may be an effective treatment for this disorder.
METHODS: We conducted a trial in which 118 adults with chronic ITP and platelet counts of less than 30,000 per cubic millimeter who had had relapses or whose platelet count was refractory to at least one standard treatment for ITP were randomly assigned to receive the oral thrombopoietin-receptor agonist eltrombopag (30, 50, or 75 mg daily) or placebo. The primary end point was a platelet count of 50,000 or more per cubic millimeter on day 43.
RESULTS: In the eltrombopag groups receiving 30, 50, and 75 mg per day, the primary end point was achieved in 28%, 70%, and 81% of patients, respectively. In the placebo group, the end point was achieved in 11% of patients. The median platelet counts on day 43 for the groups receiving 30, 50, and 75 mg of eltrombopag were 26,000, 128,000, and 183,000 per cubic millimeter, respectively; for the placebo group the count was 16,000 per cubic millimeter. By day 15, more than 80% of patients receiving 50 or 75 mg of eltrombopag daily had an increased platelet count. Bleeding also decreased during treatment in these two groups. The incidence and severity of adverse events were similar in the placebo and eltrombopag groups.
CONCLUSIONS: Eltrombopag increased platelet counts in a dose-dependent manner in patients with relapsed or refractory ITP. (ClinicalTrials.gov number, NCT00102739.)

2007 Massachusetts Medical Society
PMID 18046028  N Engl J Med. 2007 Nov 29;357(22):2237-47. doi: 10.1056・・・
著者: Adrian Newland, Marie T Caulier, Mies Kappers-Klunne, Martin R Schipperus, Francois Lefrere, Jaap J Zwaginga, Jenny Christal, Chien-Feng Chen, Janet L Nichol
雑誌名: Br J Haematol. 2006 Nov;135(4):547-53. doi: 10.1111/j.1365-2141.2006.06339.x.
Abstract/Text Abstract The objective of this open label, phase 1-2, multicentre trial was to evaluate the safety of AMG 531, a novel thrombopoiesis-stimulating peptibody, and its effect on platelet counts in adults with immune thrombocytopenic purpura. Four patients were assigned to each of four unit-dose cohorts: 30, 100, 300 or 500 microg, administered subcutaneously on days 1 and 15 (or day 22 if the day 15 platelet count was >50 x 10(9)/l). Safety was assessed by adverse event (AE) monitoring, clinical laboratory studies and antibody assays. Platelet response was defined as a platelet count double the baseline value and between 50 and 450 x 10(9)/l. Sixteen patients (10 women) were enrolled. The 500-microg cohort was discontinued because the first patient's platelet count became unacceptably high. AEs were generally expected and mild or moderate; the most frequent was headache (eight of 16 patients). Two patients experienced serious AEs related to AMG 531 (severe headache and elevated serum lactic dehydrogenase; thrombocytopenia). Platelet responses occurred with all doses and with a dose equivalent to >/=1 microg/kg in eight of 11 patients. In summary, patients tolerated AMG 531 well at the doses tested. No anti-AMG or antithrombopoietin antibodies were detected. Doses equivalent to >/=1 microg/kg increased platelet counts.

PMID 17061981  Br J Haematol. 2006 Nov;135(4):547-53. doi: 10.1111/j.1・・・
著者: David J Kuter, James B Bussel, Roger M Lyons, Vinod Pullarkat, Terry B Gernsheimer, Francis M Senecal, Louis M Aledort, James N George, Craig M Kessler, Miguel A Sanz, Howard A Liebman, Frank T Slovick, J Th M de Wolf, Emmanuelle Bourgeois, Troy H Guthrie, Adrian Newland, Jeffrey S Wasser, Solomon I Hamburg, Carlos Grande, François Lefrère, Alan Eli Lichtin, Michael D Tarantino, Howard R Terebelo, Jean-François Viallard, Francis J Cuevas, Ronald S Go, David H Henry, Robert L Redner, Lawrence Rice, Martin R Schipperus, D Matthew Guo, Janet L Nichol
雑誌名: Lancet. 2008 Feb 2;371(9610):395-403. doi: 10.1016/S0140-6736(08)60203-2.
Abstract/Text BACKGROUND: Chronic immune thrombocytopenic purpura (ITP) is characterised by accelerated platelet destruction and decreased platelet production. Short-term administration of the thrombopoiesis-stimulating protein, romiplostim, has been shown to increase platelet counts in most patients with chronic ITP. We assessed the long-term administration of romiplostim in splenectomised and non-splenectomised patients with ITP.
METHODS: In two parallel trials, 63 splenectomised and 62 non-splenectomised patients with ITP and a mean of three platelet counts 30x10(9)/L or less were randomly assigned 2:1 to subcutaneous injections of romiplostim (n=42 in splenectomised study and n=41 in non-splenectomised study) or placebo (n=21 in both studies) every week for 24 weeks. Doses of study drug were adjusted to maintain platelet counts of 50x10(9)/L to 200x10(9)/L. The primary objectives were to assess the efficacy of romiplostim as measured by a durable platelet response (platelet count > or =50x10(9)/L during 6 or more of the last 8 weeks of treatment) and treatment safety. Analysis was per protocol. These studies are registered with ClinicalTrials.gov, numbers NCT00102323 and NCT00102336.
FINDINGS: A durable platelet response was achieved by 16 of 42 splenectomised patients given romplostim versus none of 21 given placebo (difference in proportion of patients responding 38% [95% CI 23.4-52.8], p=0.0013), and by 25 of 41 non-splenectomised patients given romplostim versus one of 21 given placebo (56% [38.7-73.7], p<0.0001). The overall platelet response rate (either durable or transient platelet response) was noted in 88% (36/41) of non-splenectomised and 79% (33/42) of splenectomised patients given romiplostim compared with 14% (three of 21) of non-splenectomised and no splenectomised patients given placebo (p<0.0001). Patients given romiplostim achieved platelet counts of 50x10(9)/L or more on a mean of 13.8 (SE 0.9) weeks (mean 12.3 [1.2] weeks in splenectomised group vs 15.2 [1.2] weeks in non-splenectomised group) compared with 0.8 (0.4) weeks for those given placebo (0.2 [0.1] weeks vs 1.3 [0.8] weeks). 87% (20/23) of patients given romiplostim (12/12 splenectomised and eight of 11 non-splenectomised patients) reduced or discontinued concurrent therapy compared with 38% (six of 16) of those given placebo (one of six splenectomised and five of ten non-splenectomised patients). Adverse events were much the same in patients given romiplostim and placebo. No antibodies against romiplostim or thrombopoietin were detected.
INTERPRETATION: Romiplostim was well tolerated, and increased and maintained platelet counts in splenectomised and non-splenectomised patients with ITP. Many patients were able to reduce or discontinue other ITP medications. Stimulation of platelet production by romiplostim may provide a new therapeutic option for patients with ITP.

PMID 18242413  Lancet. 2008 Feb 2;371(9610):395-403. doi: 10.1016/S014・・・
著者: Bahareh Ghadaki, Ishac Nazi, John G Kelton, Donald M Arnold
雑誌名: Transfusion. 2013 Nov;53(11):2807-12. doi: 10.1111/trf.12139. Epub 2013 Mar 3.
Abstract/Text BACKGROUND: Thrombopoietin receptor agonists (TRAs) are effective treatments for immune thrombocytopenia (ITP). However, continuous therapy is generally required to maintain platelet (PLT) count responses.
STUDY DESIGN AND METHODS: In this case series, we describe ITP patients from our practice who achieved durable responses to the TRAs romiplostim and eltrombopag. Patients were classified as having a definite TRA-induced remission if PLT counts increased above 100 × 10(9) /L after TRA treatment and remained above 100 × 10(9) /L even after the medication was discontinued; or a possible TRA-induced remission if PLT counts increased above 100 × 10(9) /L, remained elevated for at least 3 months after the medication was discontinued, but a subsequent relapse occurred or the effect of other disease-modifying therapies could not be excluded.
RESULTS: Of 31 patients with chronic ITP treated with TRAs in our practice, nine patients achieved a PLT count response with either romiplostim (n = 6) or eltrombopag (n = 3) that was maintained even after the medications were discontinued. Three patients met criteria for a definite TRA-induced remission, each after exposure to romiplostim. Patients had ITP for a median of 7.8 years and had failed a median of four prior therapies including eight patients who had a splenectomy. We documented a progressive decline in anti-glycoprotein IIbIIIa PLT autoantibodies in one patient while on treatment.
CONCLUSION: Some patients with ITP can achieve sustained PLT count responses after the use of TRAs. This observation raises the possibility that these agents may restore immune tolerance to PLT antigens in some patients and supports the practice of down titrating the dose.

© 2013 American Association of Blood Banks.
PMID 23451917  Transfusion. 2013 Nov;53(11):2807-12. doi: 10.1111/trf.・・・
著者: Tomás José González-López, Cristina Pascual, María Teresa Álvarez-Román, Fernando Fernández-Fuertes, Blanca Sánchez-González, Isabel Caparrós, Isidro Jarque, María Eva Mingot-Castellano, José Angel Hernández-Rivas, Mónica Martín-Salces, Laura Solán, Paola Beneit, Reyes Jiménez, Silvia Bernat, Marcio M Andrade, Montserrat Cortés, Maria José Cortti, Susana Pérez-Crespo, Marta Gómez-Núñez, Pavel E Olivera, Gloria Pérez-Rus, Violeta Martínez-Robles, Rafael Alonso, Angeles Fernández-Rodríguez, María Carmen Arratibel, María Perera, Carmen Fernández-Miñano, Miguel Angel Fuertes-Palacio, Juan Andrés Vázquez-Paganini, Isabel Gutierrez-Jomarrón, Inés Valcarce, Erik de Cabo, Adriana Sainz, Rosa Fisac, Carlos Aguilar, María Paz Martínez-Badas, María Jesús Peñarrubia, María Calbacho, Carmen de Cos, Manuel González-Silva, Erika Coria, Arancha Alonso, Alberto Casaus, Armando Luaña, Pilar Galán, Cristina Fernández-Canal, Javier Garcia-Frade, José Ramón González-Porras
雑誌名: Am J Hematol. 2015 Mar;90(3):E40-3. doi: 10.1002/ajh.23900. Epub 2015 Jan 16.
Abstract/Text Eltrombopag is effective and safe in immune thrombocytopenia (ITP). Some patients may sustain their platelet response when treatment is withdrawn but the frequency of this phenomenon is unknown. We retrospectively evaluated 260 adult primary ITP patients (165 women and 95 men; median age, 62 years) treated with eltrombopag after a median time from diagnosis of 24 months. Among the 201 patients who achieved a complete remission (platelet count >100 × 10(9) /l), eltrombopag was discontinued in 80 patients. Reasons for eltrombopag discontinuation were: persistent response despite a reduction in dose over time (n = 33), platelet count >400 × 10(9) /l (n = 29), patient's request (n = 5), elevated aspartate aminotransferase (n = 3), diarrhea (n = 3), thrombosis (n = 3), and other reasons (n = 4). Of the 49 evaluable patients, 26 patients showed sustained response after discontinuing eltrombopag without additional ITP therapy, with a median follow-up of 9 (range, 6-25) months. These patients were characterized by a median time since ITP diagnosis of 46.5 months, with 4/26 having ITP < 1 year. Eleven patients were male and their median age was 59 years. They received a median of 4 previous treatment lines and 42% were splenectomized. No predictive factors of sustained response after eltrombopag withdrawal were identified. Platelet response following eltrombopag cessation may be sustained in an important percentage of adult primary ITP patients who achieved CR with eltrombopag. However, reliable markers for predicting which patients will have this response are needed.

© 2014 Wiley Periodicals, Inc.
PMID 25400215  Am J Hematol. 2015 Mar;90(3):E40-3. doi: 10.1002/ajh.23・・・
著者: Adrian Newland, Bertrand Godeau, Victor Priego, Jean-Francois Viallard, María F López Fernández, Amelia Orejudos, Melissa Eisen
雑誌名: Br J Haematol. 2016 Jan;172(2):262-73. doi: 10.1111/bjh.13827. Epub 2015 Nov 5.
Abstract/Text In anecdotal reports, some patients with immune thrombocytopenia (ITP) maintained platelet counts after discontinuing romiplostim. Here, we examined rates of platelet response (≥50 × 10(9) /l), remission, splenectomy and adverse events in patients with primary ITP duration ≤6 months who were treated with romiplostim for ≤12 months. The starting dose of romiplostim was 1 μg/kg; concomitant and rescue treatments were permitted to maintain platelet counts. Patients with platelet counts ≥50 × 10(9) /l at the end of 12 months entered a dose taper in which the romiplostim dose was decreased as long as platelet counts were maintained. Remission (platelet count ≥50 × 10(9) /l for 24 consecutive weeks with no ITP treatments) was evaluated in patients once romiplostim was discontinued. Over the 12 months, a high response rate (>90%) was observed. Platelet response occurred quickly (median, ~2 weeks) and was observed for a cumulative median of 11 months. Remission was observed in 24 patients (32%); there were no significantly predictors of remission. Most (20/24) patients had remission start before the forced taper. No new safety signals were identified. Thus, in patients with early-stage ITP, romiplostim was well tolerated and induced rapid responses, with remission occurring in approximately one-third of patients (NCT01143038, Amgen 20080435).

© 2015 John Wiley & Sons Ltd.
PMID 26537623  Br J Haematol. 2016 Jan;172(2):262-73. doi: 10.1111/bjh・・・
著者: Donald M Arnold, Francesco Dentali, Mark A Crowther, Ralph M Meyer, Richard J Cook, Christopher Sigouin, Graeme A Fraser, Wendy Lim, John G Kelton
雑誌名: Ann Intern Med. 2007 Jan 2;146(1):25-33.
Abstract/Text BACKGROUND: Rituximab, a monoclonal anti-CD20 antibody, is increasingly used to treat idiopathic thrombocytopenic purpura (ITP).
PURPOSE: To systematically review the literature on the efficacy and safety of rituximab for the treatment of adults with ITP.
DATA SOURCES: MEDLINE, EMBASE, the Cochrane Library, abstracts from the American Societies of Hematology and Clinical Oncology annual meetings, and bibliographies of relevant articles and reviews were searched in duplicate until April 2006.
STUDY SELECTION: Descriptive and comparative studies in any language that met predefined inclusion criteria were eligible. Efficacy analysis was restricted to studies enrolling 5 or more patients.
DATA EXTRACTION: Platelet count response, toxicities, dose, previous treatments, baseline platelet count, duration of ITP, study design, and sources of funding were extracted in duplicate.
DATA SYNTHESIS: We identified 19 eligible reports on efficacy (313 patients) and 29 on safety (306 patients). Weighted means for complete response (platelet count > 150 x 10(9) cells/L) and overall response (platelet count > 50 x 10(9) cells/L) with rituximab were 43.6% (95% CI, 29.5% to 57.7%) and 62.5% (CI, 52.6% to 72.5%), respectively. Responses lasted from 2 to 48 months. Nearly all patients had received corticosteroids, and 53.8% had undergone splenectomy. Nine patients (2.9%) died.
LIMITATIONS: There were no controlled studies, and no studies met all criteria for study quality. Reported deaths could not necessarily be attributed to rituximab. Overall, the number of rituximab-treated patients with ITP reported in the literature is small.
CONCLUSIONS: Rituximab resulted in an overall platelet count response in 62.5% of adults with ITP. However, this finding derives from uncontrolled studies that also reported significant toxicities, including death in 2.9% of cases. These data suggest that providers should avoid indiscriminate use of rituximab and that randomized, controlled trials of rituximab for ITP are urgently needed.

PMID 17200219  Ann Intern Med. 2007 Jan 2;146(1):25-33.
著者: Kiarash Kojouri, Sara K Vesely, Deirdra R Terrell, James N George
雑誌名: Blood. 2004 Nov 1;104(9):2623-34. doi: 10.1182/blood-2004-03-1168. Epub 2004 Jun 24.
Abstract/Text Splenectomy has been a standard treatment for adult patients with idiopathic thrombocytopenic purpura (ITP) for more than 50 years. However, the durability of responses, the ability to predict who will respond, and the frequency of surgical complications with splenectomy all remain uncertain. To better interpret current knowledge we systematically identified and reviewed all 135 case series, 1966 to 2004, that described 15 or more consecutive patients who had splenectomy for ITP and that had data for 1 of these 3 outcomes. Complete response was defined as a normal platelet count following splenectomy and for the duration of follow-up with no additional treatment. Forty-seven case series reported complete response in 1731 (66%) of 2623 adult patients with follow-up for 1 to 153 months; complete response rates did not correlate with duration of follow-up (r = -0.103, P = .49). None of 12 preoperative characteristics that have been reported consistently predicted response to splenectomy. Mortality was 1.0% (48 of 4955 patients) with laparotomy and 0.2% (3 of 1301 patients) with laparoscopy. Complication rates were 12.9% (318 of 2465) with laparotomy and 9.6% (88 of 921 patients) with laparoscopic splenectomy. Although the risk of surgery is an important consideration, splenectomy provides a high frequency of durable responses for adult patients with ITP.

PMID 15217831  Blood. 2004 Nov 1;104(9):2623-34. doi: 10.1182/blood-20・・・
著者: Nicola Vianelli, Francesca Palandri, Nicola Polverelli, Roberto Stasi, Joel Joelsson, Eva Johansson, Marco Ruggeri, Francesco Zaja, Silvia Cantoni, Angelo Emanuele Catucci, Anna Candoni, Enrica Morra, Magnus Björkholm, Michele Baccarani, Francesco Rodeghiero
雑誌名: Haematologica. 2013 Jun;98(6):875-80. doi: 10.3324/haematol.2012.075648. Epub 2012 Nov 9.
Abstract/Text The treatment of choice in steroid-resistant immune thrombocytopenia is still controversial due to the recent advent of new drugs (anti-CD20 antibodies and thrombopoietin mimetics) that have encouraged a generalized tendency to delay splenectomy. Consequently, it is extremely importance to define the efficacy and safety of splenectomy in the long term. We retrospectively analyzed the data of 233 patients affected by immune thrombocytopenia who underwent splenectomy between 1959 and 2001 in 6 European hematologic institutions and who have now a minimum follow up of ten years from surgery. Of the 233 patients, 180 (77%) achieved a complete response and 26 (11%) a response. Sixty-eight of 206 (33%) responsive patients relapsed, mostly (75%) within four years from first response. In 92 patients (39.5%), further treatment was required after splenectomy that was effective in 76 cases (83%). In 138 patients (59%), response was maintained free of any treatment at last contact. No significant association between baseline characteristics and likelihood of stable response was found. Overall, 73 (31%) and 58 (25%) patients experienced at least one infectious or hemorrhagic complication, which was fatal in 2 and 3 patients, respectively. A stable response to splenectomy was associated with a lower rate of infections (P=0.004) and hemorrhages (P<0.0001). Thrombosis developed in 18 patients (8%) and was fatal in 4. Splenectomy achieved a long-term stable response in approximately 60% of cases. Complications mainly affected non-responding patients and were fatal in a minority.

PMID 23144195  Haematologica. 2013 Jun;98(6):875-80. doi: 10.3324/haem・・・
著者: Soames Boyle, Richard H White, Ann Brunson, Ted Wun
雑誌名: Blood. 2013 Jun 6;121(23):4782-90. doi: 10.1182/blood-2012-12-467068. Epub 2013 May 1.
Abstract/Text Patients with immune thrombocytopenia (ITP) who relapse after an initial trial of corticosteroid treatment present a therapeutic challenge. Current guidelines recommend consideration of splenectomy, despite the known risks associated with surgery and the postsplenectomy state. To better define these risks, we identified a cohort of 9976 patients with ITP, 1762 of whom underwent splenectomy. The cumulative incidence of abdominal venous thromboembolism (AbVTE) was 1.6% compared with 1% in patients who did not undergo splenectomy; venous thromboembolism (VTE) (deep venous thrombosis and pulmonary embolus) after splenectomy was 4.3% compared with 1.7% in patients who did not undergo splenectomy. There was increased risk of AbVTE early (<90 days; hazard ratio [HR] 5.4 [confidence interval (CI), 2.3-12.5]), but not late (≥90 days; HR 1.5 [CI, 0.9-2.6]) after splenectomy. There was increased risk of VTE both early (HR 5.2 [CI, 3.2-8.5]) and late (HR 2.7 [CI, 1.9-3.8]) after splenectomy. The cumulative incidence of sepsis was 11.1% among the ITP patients who underwent splenectomy and 10.1% among the patients who did not. Splenectomy was associated with a higher adjusted risk of sepsis, both early (HR 3.3 [CI, 2.4-4.6]) and late (HR 1.6 or 3.1, depending on comorbidities). We conclude that ITP patients post splenectomy are at increased risk for AbVTE, VTE, and sepsis.

PMID 23637127  Blood. 2013 Jun 6;121(23):4782-90. doi: 10.1182/blood-2・・・
著者: Working Party of the British Committee for Standards in Haematology Clinical Haematology Task Force
雑誌名: BMJ. 1996 Feb 17;312(7028):430-4.
Abstract/Text Overwhelming postsplenectomy infection should be preventable if simple precautions are taken. An ad hoc working party of the British Committee for Standards in Haematology has reviewed recommendations for patients without a spleen and drawn up a consensus. Members of the working party were selected for their personal expertise and to represent relevant professional bodies. The guidelines, which are set out below, include and extend the chief medical officer's 1994 update.

PMID 8601117  BMJ. 1996 Feb 17;312(7028):430-4.
著者: J M Davies, R Barnes, D Milligan, British Committee for Standards in Haematology. Working Party of the Haematology/Oncology Task Force
雑誌名: Clin Med. 2002 Sep-Oct;2(5):440-3.
Abstract/Text Guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen were first published by the British Committee for Standards in Haematology in 1996. Key aspects of these guidelines related to anti-infective prophylaxis, immunisation schedules and treatment of proven or suspected infection. A recent review of the guidelines was undertaken, with a view to updating the recommendations where necessary The guideline review process did not reveal any major change in patient groups considered at risk. Occupational exposure to certain pathogens may, however, be a new risk factor for some infections. The recommendations for anti-infective prophylaxis remain unchanged. New recommendations for vaccination include the use of meningococcal group C vaccine in previously non-immunised hyposplenic patients and a need to consider the use of seven-valent pneumococcal vaccine. Recommendations for treatment of suspected or proven infection have not been significantly amended, but a local protocol should take into account relevant resistance patterns. There is an identified urgent need for further research into the effectiveness of varying vaccination strategies in the hyposplenic patient, and audit of infective episodes in this patient group should continue long term. Key guidelines are summarised below, together with grades of recommendation.

PMID 12448592  Clin Med. 2002 Sep-Oct;2(5):440-3.
著者: Joanne M Langley, Linda Dodds, Deshayne Fell, G Ross Langley
雑誌名: BMC Infect Dis. 2010 Jul 22;10:219. doi: 10.1186/1471-2334-10-219. Epub 2010 Jul 22.
Abstract/Text BACKGROUND: Splenectomy is associated with increased risk for bacteremia, due to impaired clearance of bloodborne agents and to altered phagocytosis and humoral immunity. We conducted a retrospective cohort study of patients at risk for splenectomy for a 13-year period to determine immunization coverage, and outcomes of those with and without splenectomy, and with or without receipt of influenza or pneumococcal vaccine.
METHODS: Data were extracted from the provincial Medical Services Insurance database for insured services rendered by a physician for 1990-2002, and from the Vital Statistics Death database. The eligible cohort was selected based on diagnostic codes for hematologic conditions for which splenectomy might be considered, such as immune thrombocytopenia. Each patient was followed longitudinally from the date of first diagnosis until 31 Dec, 2002, or death, or relocation out-of province. In addition, persons with splenectomy and no hematologic condition were identified and followed for 6 months post-surgery. Infectious illness rates per 100 person-years of observation and death rates were calculated with and without splenectomy. Death rates were determined using splenectomy status as a time-dependent covariate. The relationship between splenectomy and death according to immunization status was examined using Cox proportional hazard ratios.
RESULTS: Of 38,812 persons in the cohort 427 subjects with a hematologic diagnosis had splenectomy and another 452 subjects without a hematologic diagnosis had this surgery. 72% were > 18 years of age. Pneumococcal immunization was recorded in 16.5% of asplenic patients overall, and was not associated with reduced risk of death in these persons (adjusted Hazard Ratio [HR] = 1.07, 95% CI 0.70 - 1.65). Influenza immunization was recorded in 53.1% of asplenic patients overall, and was associated with reduced risk of death (adjusted HR = 0.46, 0.33-0.62). No pneumococcal or influenza immunization was recorded in patients with a hematologic diagnosis without splenectomy. Infectious illness visits were higher among all patients who had a splenectomy than among those without a splenectomy (151 visits/100 person-years of observation in the post-splenectomy period vs. 120 visits/100 person-years; p < 0.0001).
CONCLUSIONS: In asplenic patients, influenza immunization is associated with a 54% reduced risk of death compared to unimmunized asplenic persons; no reduction in risk was demonstrated with (polysaccharide) pneumococcal vaccine. Vaccine coverage in the entire cohort was less than routinely recommended. Improved delivery of infection prevention programs to this population is warranted. Conjugate pneumococcal vaccines should be urgently studied in this immunocompromised population.

PMID 20649965  BMC Infect Dis. 2010 Jul 22;10:219. doi: 10.1186/1471-2・・・
著者: C D Robinette, J F Fraumeni
雑誌名: Lancet. 1977 Jul 16;2(8029):127-9.
Abstract/Text A long-term follow-up of 740 American servicemen splenectomised because of trauma during the 1939-45 war showed a significant excess mortality from pneumonia and ischaemic heart-disease. Mortality from cirrhosis was also increased, but not significantly. The findings confirm that the risk of fatal infections is increased by asplenia; however, the risk of cancer was not increased, as it is in some other immunodeficiency states. Post-splenectomy thrombocytosis and hypercoagulability may account for the increased risk of fatal myocardial ischaemia in this group.

PMID 69206  Lancet. 1977 Jul 16;2(8029):127-9.
著者: R F Schilling
雑誌名: Lancet. 1997 Dec 6;350(9092):1677-8.
Abstract/Text
PMID 9400518  Lancet. 1997 Dec 6;350(9092):1677-8.
著者: R F Schilling, R E Gangnon, M I Traver
雑誌名: J Thromb Haemost. 2008 Aug;6(8):1289-95. doi: 10.1111/j.1538-7836.2008.03024.x. Epub 2008 May 15.
Abstract/Text BACKGROUND: It is probable that the variety and frequency of delayed adverse vascular events after splenectomy are underappreciated. Splenectomy is performed for a wide variety of conditions, and delayed postsplenectomy hazards are not often studied.
OBJECTIVE: To estimate the relative risk of adverse vascular events in members of hereditary spherocytosis families who have or have not had a splenectomy.
METHODS: Members of families in which hereditary spherocytosis exists were systematically questioned about adverse vascular events.
RESULTS: The cumulative incidence of arterial and venous events at age 70 years was greater in persons who had undergone a splenectomy for spherocytosis (arterial, 22% females, 32% males; venous, 20% females, 19% males) than in affected persons who did not undergo splenectomy (arterial, 3% females, 2% males; venous, 6% females, 4% males) or non-affected family members (arterial, 10% females, 17% males; venous, 4% females, 12% males). Affected subjects who undergo splenectomy are at greatly increased risk of arterial events as compared to affected subjects who do not undergo splenectomy [arterial, hazard ratio (HR) 7.2, 95% confidence interval (CI) 2.8-17.2; venous, HR 3.3, 95% CI 1.1-9.8].
CONCLUSION: There is a significant, long-lasting, increased risk of adverse arterial and venous thromboembolic events after splenectomy performed for hereditary spherocytosis. A review of the literature indicates that this is also true when splenectomy is performed for several other indications.

PMID 18485083  J Thromb Haemost. 2008 Aug;6(8):1289-95. doi: 10.1111/j・・・
著者: Drew Provan, Adrian Newland
雑誌名: Br J Haematol. 2002 Sep;118(4):933-44.
Abstract/Text
PMID 12199770  Br J Haematol. 2002 Sep;118(4):933-44.

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