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Immune Thromobocytopenia旧名; Idiopathic thromocytopenic purpura
Immune Thrombocytopenia自己免疫機序による血小板破壊と産生障害発症率は10/100000-yr. 男女差無し.高齢者ほど多く, 小児では5-6/100000-yr程度.PLT減少のみのPrimaryと,HIV感染やSLEに...
PLTに対する自己抗体.GPIIb-IIIaに対する自己抗体が主で, IgGが最も多いが, 一部IgMやIgAのこともある.抗体が結合したPLTは急速に脾臓や肝臓でトラップされ,消失する.Cleveland Clinic Journal of ...
ITPは基本的に除外診断PLT以外のCBCに異常がないこと,末梢血所見に問題ないこと,出血以外の身体所見に問題がないこと(脾腫も無し),2次性のPLT低下(膠原病, 薬剤, 感染症, 血液腫瘍)が無いことを確認してITPと診断する.膠原病; S...
感染症とPLT減少小児では, IM, 風疹, 麻疹, 水痘などViral infectionでPLT減少合併が多い.その場合, PLT低下前(1-4wk)に感染症状を伴うため,判別は比較低容易. また2-8wkで改善する.成人例ではHCV, H...
HCV感染では肝硬変, 脾腫が無くてもPLT低下を来すことが知られている.成人例のITP患者のうち, 20%でHCV陽性との報告あり.またHCV感染者はITP発症リスクがHR 1.8[1.4-2.3].機序は様々. 脾機能亢進, 肝でのThro...
HIVのPLT低下はいつ生じても良い.HIV感染の初発症状としてもあり得る.HAARTが導入される前はPLT低下合併頻度は5-30%平均8.8%であった. 導入後の頻度は不明.免疫機序による低下,複合感染症(細菌, 寄生虫など)による低下悪性腫...
H pylori感染とITP成人ITP患者でH pylori陽性者は62.3%だが,ただ単に感染していただけな可能性もあるが,除菌後に52.7%でPLT上昇を認めた報告がある.日本からの報告では除菌施行した内56.2%でPLTが改善.CagA陽...
リンパ増殖性疾患とITPHematol Oncol Clin N Am 23 (2009) 1261–1274Table1Biologic background, treatment options, and prognostic implic...
PLT低下患者144名の骨髄所見MDS以外によるPLT低下を来す疾患 144例ITP, 感染由来(IAT), 脾機能亢進, 再生不良性貧血,Dimorphic anemia, 巨赤芽球性貧血, AML, ALL,Lymphoma-leukemi...
各骨髄所見のITP対する感度, 特異度was75%alongwithspecificityof49%.Thesensitiviemperipolesisincasesofdimorphicanemiawas44%[F2].Howevernopl...
正常の巨核球核は分葉し, 周囲に血小板産生を認める.
ちなみに, 感染症由来PLT低下に対しては,幼弱megakaryocyteは感度100%, 特異度61%.Cytoplasmic vacuolizationは感度40%, 特異度86%.Dysplastic fromは巨赤芽球性貧血に対するSn...
ITPの治療治療の目標は, 必要最低限の薬剤で,出血リスクが低いレベルまでPLTを上げ維持すること.成人例でPLT>3万で, 出血も軽度のみならば経過観察.PLT<3万で出血(+), もしくはPLT<1万といった出血リスクが大きい高度なPLT低...
ITPの初期治療はステロイド ± IVIGPSL 1mg/kg/dで開始し, 4-6wkかけてTapering.もしくは, Dexamethasone 40mg/d 4d/moのパルス療法.後者の方が効果は良好.効果は良好だが, ステロイドの中...
PSL, IVIGで効果乏しい場合は脾摘が適応となる.Rituximabも2nd-line treatmentとして用いられるが,平均効果持続期間は10.5mo程度しかない.近年Thrombopoietin-R agonistが効果高い報告があ...
13 RCTsのMeta-analysis(N=646)High-dose(HD) IVIG (総量2g/kg) とLow-dose IVIG (総量<2g/kg)で効果を比較.(投与方法としては0.2-0.4g/kg 5日間が最も多い方法. ...
副作用の頻度はLD-IVIGの方が少ない(OR0.39[0.18-0.83])他に, 慢性ITPへの移行率も有意差無し(OR 1.62[0.62-4.21])IVIGの投与量は0.2g/kg 5日間程度(総量<2g/kg)でOK.Blood C...
ITPの治療まとめ.再発性で, PLT <20kとなる場合は脾摘の適応となる脾摘後は2/3は再発無し.RituximabやThrombopoetin-R agonistsは,脾摘を回避可能な治療薬.decreases once the dose...
Thrombopoietinは主に肝臓で産生されるホルモン.MegakaryocyteのThrombopoietin-Rに結合しPLT産生を亢進させる作用を持つ.通常PLT低下患者ではThrombopoietin濃度が高くなるが,ITP患者では...
N Engl J Med 2011;365:734-41.
RomiplostimのRCTITP患者(PLT<3万/µL, 脾摘後63名, 脾摘未62名)Romiplostim SC vs Placeboに2:1で割り付け.薬剤はPLT 5-20万となるように調節. 24wk継続.OutcomeLanc...
RomiplostimのRCT脾摘されていないITP患者234名のOpen-labeled RCT.Romiplastim vs Placeboに割り付け52wk継続.Romiplastimは3µg/kgより開始し, PLT5-20万を目標に調...
EltrombopagのRCT既存の治療に不応性のITP患者118名のRCT. (PLT<3万/µL)Eltrombopag vs Placeboに割り付け, PLT上昇を比較.Eltrombopagは30mg, 50mg, 75mgを使用.D...
EltrombopagのRCTPLT<3万/µLの慢性ITP患者114名のDB-RCT.通常の治療 + Eltrombopag vs Placeboを6wk継続.50mg/dより開始し, 3wk目でPLT<5万ならば75mgに増量Outcome...
臨床での使用方法既存の治療で改善しないITPを対象とする.(レボレートは50mgで約5千円, ロミプレートは250µgで6万円也)Romiplostim; 初期投与量は1µg/kg SC. 1回/wk. PLT値に応じて調節し, 平均使用量は3...
RomiplostimのDose調節方法Lancet 2008; 371: 395–403より1µg/kg/wkより開始し, PLT 5-20万を達成する前は, PLT<1万/µL → 2µg/kg/wkで増量 PLT 1-5万/µL → 2µ...
Romiplostim, Eltrombopag使用中の患者では,Dose調節無しでPLT>5万が4wk以上持続するまで,毎週PLTをチェックする必要あり.その後は1ヶ月毎のチェックでOK.PLT 20-40万となるようならば治療は一時中断.P...
Thrombopoietin-R agonistの副作用最も多いのは頭痛, 悪心, 嘔吐, 怠感, 下痢, 関節痛, 鼻咽頭炎.薬剤中断後にITPが増悪するのは8-10%で認められる.中断後4wkは出血リスクが上昇し得る.中止時はTaperin...
Thrombopoietin-R agonistと血栓症リスクRomiplostimを使用した291名中,17名で25例の静脈, 動脈血栓症を併発.(8.6%)Eltrombopagを使用した299名中,16名で21例の静脈, 動脈血栓症を併発...
TABLE 3Newer therapies for immune thrombocytopeniarefractory to first-line treatment in adultsRITUXIMAB (RITUXAN) ROMIPLOST...
2nd lineでも効果が無い場合, 多剤併用療法を考慮する.Azathioprine, cyclosporine, cyclophosphamide,  mycophenolateといった免疫抑制剤を併用.もしくは幹細胞移植を考慮する.Cle...
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血小板 Itp

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血小板 Itp

  1. 1. Immune Thromobocytopenia旧名; Idiopathic thromocytopenic purpura
  2. 2. Immune Thrombocytopenia自己免疫機序による血小板破壊と産生障害発症率は10/100000-yr. 男女差無し.高齢者ほど多く, 小児では5-6/100000-yr程度.PLT減少のみのPrimaryと,HIV感染やSLEに合併するSecondaryがある.診断からの経過により, 新規診断, 一過性(診断から3mo),持続性(3-12mo), 慢性(>12mo)に分類される.N Engl J Med 2011;365:734-41.
  3. 3. PLTに対する自己抗体.GPIIb-IIIaに対する自己抗体が主で, IgGが最も多いが, 一部IgMやIgAのこともある.抗体が結合したPLTは急速に脾臓や肝臓でトラップされ,消失する.Cleveland Clinic Journal of Medicine 2012;79:641-650
  4. 4. ITPは基本的に除外診断PLT以外のCBCに異常がないこと,末梢血所見に問題ないこと,出血以外の身体所見に問題がないこと(脾腫も無し),2次性のPLT低下(膠原病, 薬剤, 感染症, 血液腫瘍)が無いことを確認してITPと診断する.膠原病; SLE, APS, 甲状腺疾患, Evans症候群.感染症; HIV, H pylori, HCV, CMV血液腫瘍; リンパ増殖性疾患Hematol Oncol Clin N Am 23 (2009) 1329–1341
  5. 5. 感染症とPLT減少小児では, IM, 風疹, 麻疹, 水痘などViral infectionでPLT減少合併が多い.その場合, PLT低下前(1-4wk)に感染症状を伴うため,判別は比較低容易. また2-8wkで改善する.成人例ではHCV, HIV, H pylori感染症が有名.感染症状を伴わないため, ITPと勘違いする可能性がある.Hematol Oncol Clin N Am 23 (2009) 1275–1297
  6. 6. HCV感染では肝硬変, 脾腫が無くてもPLT低下を来すことが知られている.成人例のITP患者のうち, 20%でHCV陽性との報告あり.またHCV感染者はITP発症リスクがHR 1.8[1.4-2.3].機序は様々. 脾機能亢進, 肝でのThrombopoietin産生低下,免疫機序によるPLT低下, IFNに伴うものなど.ステロイド, IVIGの効果はHCV-ITPとITPで同等.ただし, 免疫低下を考慮するとThrombopoietin-R agonistの方が良いかもしれないHematol Oncol Clin N Am 23 (2009) 1275–1297
  7. 7. HIVのPLT低下はいつ生じても良い.HIV感染の初発症状としてもあり得る.HAARTが導入される前はPLT低下合併頻度は5-30%平均8.8%であった. 導入後の頻度は不明.免疫機序による低下,複合感染症(細菌, 寄生虫など)による低下悪性腫瘍(Kaposi肉腫, NHLなど)に伴う低下薬剤に伴う低下など, 色々機序はある.PLT<5万となるような高度低下は少ない.HIVへの治療がPLT低下の治療となる.Hematol Oncol Clin N Am 23 (2009) 1275–1297
  8. 8. H pylori感染とITP成人ITP患者でH pylori陽性者は62.3%だが,ただ単に感染していただけな可能性もあるが,除菌後に52.7%でPLT上昇を認めた報告がある.日本からの報告では除菌施行した内56.2%でPLTが改善.CagA陽性H pyloriが関連している可能性があり,日本のH pyloriの殆どがCagA陽性.機序や関連性は未だ議論があるが,除菌でPLT改善すれば け物.Hematol Oncol Clin N Am 23 (2009) 1275–1297
  9. 9. リンパ増殖性疾患とITPHematol Oncol Clin N Am 23 (2009) 1261–1274Table1Biologic background, treatment options, and prognostic implications for ITP associated with LPDsOrigin ofAutoantibodiesCorrelationto LPDsPresentation/Activity/TumorBurdenEffect of ITPTreatmentEffect of LPDTreatmentPrognosticSignificanceCLL Normal B cells No Weak Good YesWM/MGUS Malignant BcellsNo No Good/weak UnknownMZL Bothmalignantand normalB cellsNot apparent Weak Good YesT-LGL Normal B cells Yes No Good UnknownHL Normal B cells No Good Unknown NoOther LPDs(DLBCL, FL,MCL, HCL)Normal B cells Yes Unknown Weak, maytrigger ITPUnknownAbbreviations: CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; FL, follic-ularlymphoma; HCL,hairycellleukemia;HL,Hodgkinlymphoma; LPD,lymphoproliferative disorder;ITP in Lymphoproliferative Disorders 1269
  10. 10. PLT低下患者144名の骨髄所見MDS以外によるPLT低下を来す疾患 144例ITP, 感染由来(IAT), 脾機能亢進, 再生不良性貧血,Dimorphic anemia, 巨赤芽球性貧血, AML, ALL,Lymphoma-leukemia syndrome, myeloma, 骨髄転移,Blast crisis of CMLMegakaryocyteの増減Indian Journal of Pathology and Microbiology 2009;52:490-4young forms of megakaryocytes with scant bluish cytoplasmand lacking lobulation of the nucleus which occupied mostof the cell.[1]Dysplastic megakaryocytes were defined as thosewith single/ multiple separate nuclei. Micromegakaryocyteswere defined as megakaryocytes whose size was that of a largelymphocyte/monocyte and which had a single/bilobed nucleus.The megakaryocytes were considered to show platelet budding ifthere was budding of cytoplasmic processes from their surfaces.Hypogranular forms were defined as megakaryocytes with palegrey or water clear cytoplasm and sparse or no granules. Thetype of cell seen within the megakaryocyte in emperipolesis wasalso documented.The number and morphology of the megakaryocytes in non-MDSrelated thrombocytopenia were assessed. Their significance wasstudied by comparing with the morphological changes in MDS.The distribution of morphological changes in cases of non-MDSconditions and MDS were compared using Fisher’s exact test. A Pvalue less than 0.05 was consideredsignificant. The sensitivity andspecificity for those morphological features which were significantin the relevant hematological disorders was also calculated.RESULTSThe commonest cause of thrombocytopenia for which bonemarrow examination was sought was AML (27 cases, 18.8%). Thesecondmost common cause wasITP (19 cases, 13.15%) which wasfollowed by ALL and dimorphic anemia (18 cases each, 12.5%).There were 17 casesof myeloma, 12 casesof megaloblastic anemia,eight cases of aplastic anemia, five cases of IAT and LLS, threecases of hypersplenism, two cases of bone marrow metastasis andone case of blast crisis of CML. Maximum number of cases (38cases, 26.4%) was seen in less than ten years of age group followedThe changes in number and morphology of megakaryocytes invarious hematological disorders are given in Tables 1 and 2. Therewas an increase in the number of megakaryocytes in 18 cases(94.7%) of ITP and immature megakaryocytes were seen in all thecases (sensitivity = 100%, specificity = 68%, Figure 1). Dysplasticforms were seen in 17 cases (89.5%), bare megakaryocytic nuclei in16 cases (84.2%) and micromegakaryocytes in eight cases (42.1%)of ITP, their sensitivity being 89%, 84% and 42% respectively andspecificity being 52%, 58% and 84% respectively. Emperipolesiswas seen in 13 cases (68.4%; sensitivity = 68%, specificity = 74%)with lymphocytes in five cases and lymphocytes and nucleated redblood cells in four cases.In cases of IAT, immature megakaryocytes were observed in all thefive cases (sensitivity = 100%, specificity = 61%) and cytoplasmicvacuolization was seen in two of the cases (sensitivity = 40%,specificity = 86%).Table 1: Incidence of changes in number of megakaryocytes in differenthematological disorders causing thrombocytopeniaBone marrow Number per low-power fieldImpression Normal Increased Decreased AbsentITP * 1 18IAT * 5Hypersplenism 3Aplasc anemia 2 6Dimorphic anemia 9 6 3Megaloblasc anemia 9 1 2MDS * 1 6 1 1ALL * 1 3 14AML * 3 1 17 6LLS * 1 1 3Myeloma 4 5 7 1Blast crisis of CML* 1Metastasis 2* ITP= Idiopathic thrombocytopenic purpura, IAT= Infecon-associated thrombocytopenia, MDS=
  11. 11. 各骨髄所見のITP対する感度, 特異度was75%alongwithspecificityof49%.Thesensitiviemperipolesisincasesofdimorphicanemiawas44%[F2].HowevernoplateletbuddingwasseeninanyofthecaIncasesofMDS,dysplasticforms,baremegakaryocyticnandmicromegakaryocyteswereseen.However,findimicromegakaryocyteswasmostsignificantwhencomptonon-MDScausesofthrombocytopenia(specificity-8Decreasedplateletbuddingandabsenceofcytoplasmicvacwasalsonoted.DISCUSSIONThrombocytopenia,eitherpersistent,isolatedorinassociwithpancytopeniarefractorytotreatmentisoneofthecommencounteredhematologicalproblemsforwhichabonemastudyissought.TheroutinelypreparedLeishmanstainedmarrowaspiratesmearscanhelptoobservethedyspofeaturesofthemegakaryocytesassociatedwiththenon-conditions.Thiscanimprovethediagnosticaccuracywiderangeofhematologicaldisorderstherebyenablingptherapeuticinterventions.Normalmaturationandplateletformationresultsmegakaryocyticdeoxyribonucleicacid(DNA)replicthatoccurswithoutcelldivisionresultinginlargelobupolypoidnucleus.Awidevarietyofgrowthfactorsthrombopoietinactsynergisticallywithotherhematopcytokinesandtranscriptionalfactorsstimulatingthematurandgrowthofmegakaryocytes.[3]Adefectinanyofthestamegakaryocytopoiesiscanleadtodysmegakaryocytopoiesithrombocytopenia.Ashifttoyoung,immature,lesspolypoidmegakaryoandfewermatureplatelet-producingmegakaryocyteswaoutstandingmorphologicalfeaturenotedinallthecasesointhepresentstudy(sensitivity=100%,specificity=6SimilarfindingswereobservedbyHouwerzijletal,[2]whtheysaiditisbecauseofapoptoticandpara-apoptotictyprogrammedcelldeath(PCD)ofmaturemegakaryocytes.oftheabnormalmegakaryocytesweresurroundedbyneutroandmacrophages,someinthestateofphagocytosis.InapproPCDofmaturemegakaryocytescandisruptplateletformandapoptosis-likePCD(para-apoptosis)occursinITP.findingisespeciallyusefulwhensomepatientsofMDSprwithisolatedthrombocytopenia,thusmimickingITP.Dyspformswereseenin17cases(89.5%),baremegakaryocyticnin16cases(84.2%)andmicromegakaryocytesineight(42.1%),theirsensitivitybeing89%,84%and42%respecandspecificity,52%,58%and84%respectively.Emperipolesis,seenin13ofthe19casesofITP(84sensitivity=68%,specificity=74%)withlymphocytesiandlymphocytesalongwithnucleatedredbloodcellsinTable 2: Incidence of changes in morphology of megakaryocytes in different hematological disorders causing thrombocytopeniaBone marrow Immature Dysplasc Bare Emperipolesis Platelet Cytoplasmic Micromegakaryocytes Hypogranular Number of nuclear lobesimpression megakaryocytes forms megakaryocyc budding vacuolizaon formsnuclei Normal DecreasedITP* 19 17 16 13 12 4 8 0 18 1IAT* 5 4 4 4 1 2 0 0 4 1Hypersplenism 0 0 0 1 1 1 0 0 3Aplasc anemia 2 1 2 2 1 1 0 0 1 1Dimorphic anemia 10 13 13 8 0 7 2 0 18Megaloblasc anemia 5 9 7 4 0 4 3 0 12MDS* 4 7 6 4 1 0 5 0 9ALL* 2 4 2 1 0 0 0 0 4AML* 2 8 8 4 0 0 5 0 19 2LLS* 1 2 1 1 0 0 0 0 2Myeloma 8 10 8 3 1 2 5 0 16 1* ITP= Idiopathic thrombocytopenic purpura, IAT= Infecon-associated thrombocytopenia, MDS= Myelodysplasc syndrome, ALL= Acute lymphoblasc lymphoma, AML= Acute myeloid leukemia, LLS= Leukemia-lymphoma syndromeIndian Journal of Pathology and Microbiology 2009;52:490-4感度 特異度Megakaryocyte増加 94.7%幼弱Megakaryocyte 100% 68%Dysplastic from 89.5% 52%Bare megakaryocytic nuclei 84.2% 58%micromegakaryocyte 42.1% 84%Emperipolesis 68.4% 74%I N D I A N J O U R N A L O F P A T H O L O G Y A N D M I C R O B I O L O G Y - 5 2 ( 4 ) , O C T O B E R - D E C E M B E R 2 0 0 9 491RESULTSThe commonest cause of thrombocytopenia for which bonemarrow examination was sought was AML (27 cases, 18.8%). Thesecondmost common cause wasITP (19 cases, 13.15%) which wasfollowed by ALL and dimorphic anemia (18 cases each, 12.5%).There were 17 casesof myeloma, 12 casesof megaloblastic anemia,eight cases of aplastic anemia, five cases of IAT and LLS, threecases of hypersplenism, two cases of bone marrow metastasis andone case of blast crisis of CML. Maximum number of cases (38cases, 26.4%) was seen in less than ten years of age group followedby 18.7% cases (27 cases) in 21-30 years of age. Least number ofcases was seen in more than 61 years of age (nine cases, 6.3%).Figure 1: An immature megakaryocyte with cytoplasmic vacuolization(arrow) in a case of idiopathic thrombocytopenic purpura (Leishmanstain, x 400)Figure 2: A megakaryocyte showing emperipolesis of neutrophils(arrows) in a case of dimorphic anemia (Leishman stain, x 400)Impression Normal Increased Decreased AbsentITP * 1 18IAT * 5Hypersplenism 3Aplasc anemia 2 6Dimorphic anemia 9 6 3Megaloblasc anemia 9 1 2MDS * 1 6 1 1ALL * 1 3 14AML * 3 1 17 6LLS * 1 1 3Myeloma 4 5 7 1Blast crisis of CML* 1Metastasis 2* ITP= Idiopathic thrombocytopenic purpura, IAT= Infecon-associated thrombocytopenia, MDS=Myelodysplasc syndrome, ALL= Acute lymphoblasc lymphoma, AML= Acute myeloid leukemia,LLS= Leukemia-lymphoma syndrome, CML= chronic myeloid leukemiaThe number and morphology of the megakaryocytes in non-MDSrelated thrombocytopenia were assessed. Their significance wasstudied by comparing with the morphological changes in MDS.The distribution of morphological changes in cases of non-MDSconditions and MDS were compared using Fisher’s exact test. A Pvalue less than 0.05 was consideredsignificant. The sensitivity andspecificity for those morphological features which were significantin the relevant hematological disorders was also calculated.RESULTSThe commonest cause of thrombocytopenia for which bonemarrow examination was sought was AML (27 cases, 18.8%). Thesecondmost common cause wasITP (19 cases, 13.15%) which wasfollowed by ALL and dimorphic anemia (18 cases each, 12.5%).There were 17 casesof myeloma, 12 casesof megaloblastic anemia,eight cases of aplastic anemia, five cases of IAT and LLS, threecases of hypersplenism, two cases of bone marrow metastasis andone case of blast crisis of CML. Maximum number of cases (38cases, 26.4%) was seen in less than ten years of age group followedby 18.7% cases (27 cases) in 21-30 years of age. Least number ofcases was seen in more than 61 years of age (nine cases, 6.3%).In cases of IAT, immature megakaryocytes were observed in alfive cases (sensitivity = 100%, specificity = 61%) and cytoplavacuolization was seen in two of the cases (sensitivity = 4specificity = 86%).Table 1: Incidence of changes in number of megakaryocytes in diffehematological disorders causing thrombocytopeniaBone marrow Number per low-power fieldImpression Normal Increased Decreased AbsenITP * 1 18IAT * 5Hypersplenism 3Aplasc anemia 2 6Dimorphic anemia 9 6 3Megaloblasc anemia 9 1 2MDS * 1 6 1 1ALL * 1 3 14AML * 3 1 17 6LLS * 1 1 3Myeloma 4 5 7 1Blast crisis of CML* 1Metastasis 2* ITP= Idiopathic thrombocytopenic purpura, IAT= Infecon-associated thrombocytopenia, MMyelodysplasc syndrome, ALL= Acute lymphoblasc lymphoma, AML= Acute myeloid leukemLLS= Leukemia-lymphoma syndrome, CML= chronic myeloid leukemia幼弱megakaryocyte通常megakaryocyteの周囲はPLTが多数認められるが, 幼弱では認めない. Emperipolesis
  12. 12. 正常の巨核球核は分葉し, 周囲に血小板産生を認める.
  13. 13. ちなみに, 感染症由来PLT低下に対しては,幼弱megakaryocyteは感度100%, 特異度61%.Cytoplasmic vacuolizationは感度40%, 特異度86%.Dysplastic fromは巨赤芽球性貧血に対するSn 75%, Sp 49%他にはDimorphic anemiaで認められる.EmperipolesisはDimorphic anemiaの44%で陽性.Indian Journal of Pathology and Microbiology 2009;52:490-4
  14. 14. ITPの治療治療の目標は, 必要最低限の薬剤で,出血リスクが低いレベルまでPLTを上げ維持すること.成人例でPLT>3万で, 出血も軽度のみならば経過観察.PLT<3万で出血(+), もしくはPLT<1万といった出血リスクが大きい高度なPLT低下では治療が推奨される.N Engl J Med 2011;365:734-41.
  15. 15. ITPの初期治療はステロイド ± IVIGPSL 1mg/kg/dで開始し, 4-6wkかけてTapering.もしくは, Dexamethasone 40mg/d 4d/moのパルス療法.後者の方が効果は良好.効果は良好だが, ステロイドの中止, 減量にてITPが再燃することが多く, 寛解持続するのは10-30%程度.N Engl J Med 2011;365:734-41.Cleveland Clinic Journal of Medicine 2012;79:641-650
  16. 16. PSL, IVIGで効果乏しい場合は脾摘が適応となる.Rituximabも2nd-line treatmentとして用いられるが,平均効果持続期間は10.5mo程度しかない.近年Thrombopoietin-R agonistが効果高い報告があり,期待されている.N Engl J Med 2011;365:734-41.
  17. 17. 13 RCTsのMeta-analysis(N=646)High-dose(HD) IVIG (総量2g/kg) とLow-dose IVIG (総量<2g/kg)で効果を比較.(投与方法としては0.2-0.4g/kg 5日間が最も多い方法. )効果(PLT上昇までの期間, 上昇量, 出血リスク)は両者有意差無し.急性ITPに対するIVIGの量Blood Coagulation and Fibrinolysis 2010, 21:713–721716 Blood Coagulation and Fibrinolysis 2010, Vol 21 No 8Fig. 20.1 0.2 0.5 1 2 5 10Studyor subcategoryXue [10]Zhang [14]Tang [15]Cao and Ji [18]Huang et al. [16]Zhu et al. [18]Ge [20]Yang [21]Total (95% Cl)Total events: 199 (low-IVIG), 188 (HD-IVIG)Test for heterogeneity: Chi2= 1.82, df = 7 (P = 0.97), I2= 0%Test for overall effect: Z = 0.00 (P = 1.00)23/2312/159/1023/3124/2838/5452/5518/25241 228 100.00 1.00 (0.61, 1.63)21/239/116/623/3024/2737/5349/5319/251.396.443.3618.7110.8334.328.4416.505.47 (0.25, 120.37)0.89 (0.12, 6.48)0.49 (0.02, 13.92)0.88 (0.27, 2.81)0.75 (0.15, 3.72)1.03 (0.45, 2.35)1.41 (0.30, 6.65)0.81 (0.23, 2.88)Low-IVIGn/NHD-IVIGn/NOR (fixed)95% ClWeight(%)OR (fixed)95% Cl
  18. 18. 副作用の頻度はLD-IVIGの方が少ない(OR0.39[0.18-0.83])他に, 慢性ITPへの移行率も有意差無し(OR 1.62[0.62-4.21])IVIGの投与量は0.2g/kg 5日間程度(総量<2g/kg)でOK.Blood Coagulation and Fibrinolysis 2010, 21:713–721
  19. 19. ITPの治療まとめ.再発性で, PLT <20kとなる場合は脾摘の適応となる脾摘後は2/3は再発無し.RituximabやThrombopoetin-R agonistsは,脾摘を回避可能な治療薬.decreases once the dose is tapered or stopped;remission is sustained in only 10% to 30% ofcases.30Continuation of corticosteroids is lim-ited by long-term complications such as op-portunistic infections, osteoporosis, and emo-tional lability.31Intravenous immunoglobulin andanti-D immunoglobulin are alternativesIntravenous immunoglobulin is recom-mended for patients who have not respondedto corticosteroids and is often used in preg-nancy. It is thought to act by blocking Fc re-ceptors in the reticuloendothelial system. In-travenous immunoglobulin rapidly increasesplatelet counts in 65% to 80% of patients,32but the effect is transient and the drug requiresfrequent administration. It is usually well tol-erated, although about 5% of patients expe-rience headache, chills, myalgias, arthralgias,and back pain. Rare, serious complicationsinclude thrombotic events, anaphylaxis (inIgA-deficient patients), and renal failure.Anti-D immunoglobulin, a pooled IgGproduct, is derived from the plasma of Rh(D)-negative donors and can be given only topatients who are Rh(D)-positive. Responserates as high as 70% have been reported, withplatelet effects lasting for more than 21 days.33Studies have shown better results at a highdose (75 µg/kg) than with the approved doseof 50 µg/kg.34Anti-D immunoglobulin can also be givenintermittently whenever the platelet countfalls below a specific level (ie, 30 × 109/L).This allows some patients to avoid splenec-tomy and may even trigger long-term remis-sion.32TABLE 2Treatment of immune thrombocytopeniaFirst-linePrednisone (1 mg/kg/day in tapering doses × 4–6 weeks)High-dose dexamethasone (Decadron) (40 mg daily × 4 days/month forseveral cycles)Intravenous immunoglobulin (0.8–1 g/kg)Intravenous anti-D immunoglobulin (50–75 µg/kg)Second-lineRituximab (Rituxan) (375 mg/m2weekly × 4 weeks)aSplenectomyaThrombopoietin receptor agonistsaRomiplostim (Nplate) (1–10 µg/kg subcutaneously weekly)Eltrombopag (Promacta) (25–75 mg orally daily)Azathioprine (Imuran)Cyclosporine A (Gengraf, Neoral, Sandimmune)Cyclophosphamide (Cytoxan)Danazol (Danocrine)DapsoneMycophenolate mofetil (CellCept)Vinca alkaloidsThird-lineCombination chemotherapyHematopoietic stem cell transplantationbaCommonly usedbWarranted only for severe refractory immune thrombocytopenia with bleedingcomplications unresponsive to other agentsCleveland Clinic Journal of Medicine 2012;79:641-650
  20. 20. Thrombopoietinは主に肝臓で産生されるホルモン.MegakaryocyteのThrombopoietin-Rに結合しPLT産生を亢進させる作用を持つ.通常PLT低下患者ではThrombopoietin濃度が高くなるが,ITP患者では原因は不明だが, 濃度が正常範囲のまま. >> 外から補うことでPLT上昇効果が見込める.RecombinantのThrombopoietinでは自己抗体誘導してしまったため,新しいRomiplostim(ロミプレート),Eltrombopag(レボレート®)が開発された.Thrombopoietin-RN Engl J Med 2011;365:734-41.
  21. 21. N Engl J Med 2011;365:734-41.
  22. 22. RomiplostimのRCTITP患者(PLT<3万/µL, 脾摘後63名, 脾摘未62名)Romiplostim SC vs Placeboに2:1で割り付け.薬剤はPLT 5-20万となるように調節. 24wk継続.OutcomeLancet 2008; 371: 395–403BA SplenectomisedNon-splenectomised2001501005000Number availablefor measurementPlaceboRomiplostim2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 2521 21 21 21 21 21 21RomiplostimPlacebo21 21 21 11 12 20 20 20 20 20 20 18 19 18 18 19 17 1942 42 42 42 42 42 41 42 41 41 40 39 41 39 40 40 39 40 39 39 40 38 38 39 4021 21 21 21 21 21 21 20 18 19 19 19 18 18 18 18 18 18 18 18 18 18 17 16 1741 41 41 41 41 41 40 41 41 40 40 37 40 38 40 38 39 39 38 39 38 36 38 39 39Number availablefor measurementPlaceboRomiplostim0 2 3 4 5 6 7 8 9 10 11 12Study weekMedianplateletcount(×109/L)Medianplateletcount(×109/L)13 14 15 16 17 18 19 20 21 22 23 24 25200150100500PLT上昇を認めたのは,Romiplostim投与群では脾摘群で78.6%脾摘未で87.8%Placebo群では7.1%のみ.
  23. 23. RomiplostimのRCT脾摘されていないITP患者234名のOpen-labeled RCT.Romiplastim vs Placeboに割り付け52wk継続.Romiplastimは3µg/kgより開始し, PLT5-20万を目標に調節. Max 10µg/kgOutcome; PLT>5万を達成したのはRomiplastim群で71-92%, Placebo群で26-51%.Treatment failureは11% vs 30%, OR 0.31[0.15-0.61]脾摘施行例は9% vs 36%, OR 0.17[0.08-0.35]N Engl J Med 2010;363:1889-99.
  24. 24. EltrombopagのRCT既存の治療に不応性のITP患者118名のRCT. (PLT<3万/µL)Eltrombopag vs Placeboに割り付け, PLT上昇を比較.Eltrombopagは30mg, 50mg, 75mgを使用.Day 43でのPLT>5万達成率; 28% vs 70% vs 81% vs 11%(PL)PLT数; 2.6万 vs 12.8万 vs 18.3万 vs 1.6万(PL)N Engl J Med 2007;357:2237­47.Eltrombopag for Chronic Idiopathic Thrombocytopenic Purpura10080907060403010502008 15 22 29 36 4340030020010001 8 15 22 29 4336Placebo Eltrombopag,30 mgEltrombopag,50 mgEltrombopag,75 mgPlaceboEltrombopag, 30 mgEltrombopag, 50 mgEltrombopag, 75 mg
  25. 25. EltrombopagのRCTPLT<3万/µLの慢性ITP患者114名のDB-RCT.通常の治療 + Eltrombopag vs Placeboを6wk継続.50mg/dより開始し, 3wk目でPLT<5万ならば75mgに増量Outcome; Day43において, PLT>5万達成率. Eltrombopag群で59% vs 16%, OR 9.61[3.31-27.86] 出血リスクはOR 0.49[0.26-0.89]投薬終了後2wkでPLTは基礎値まで低下.国内ではエボレート®12.5mg, 25mg錠が使用可能Lancet 2009; 373: 641–48
  26. 26. 臨床での使用方法既存の治療で改善しないITPを対象とする.(レボレートは50mgで約5千円, ロミプレートは250µgで6万円也)Romiplostim; 初期投与量は1µg/kg SC. 1回/wk. PLT値に応じて調節し, 平均使用量は3-4µg/kg. 最大投与量は10µg/kgEltrombopag; 初期投与量は50mg/d PO. PLT値に応じて調節し, 25-75mg/dの範囲で調節. 肝障害やアジア人では血中濃度が上昇するため, 初期投与量は25mg/dより開始する. また, 食事に影響されるため, 食後1-2hrで内服し, 制酸剤, Ca, Mgなど併用患者では 4hr以上あけて内服する必要あり.N Engl J Med 2011;365:734-41.
  27. 27. RomiplostimのDose調節方法Lancet 2008; 371: 395–403より1µg/kg/wkより開始し, PLT 5-20万を達成する前は, PLT<1万/µL → 2µg/kg/wkで増量 PLT 1-5万/µL → 2µg/kg/2wkで増量.PLT 5-20万を達成した後は, 維持アルゴリズムへ. PLT<1万/µL → 1µg/kg/wkで増量 PLT 1-5万/µL → 1µg/kg/2wkで増量. 2wk連続でPLT 20-40万/µL → 1µg/kg減量 PLT>40万/µL → 中断し, PLT<20万となってから         1µg/kg減量して再開 最大投与量は15µg/kg/wk
  28. 28. Romiplostim, Eltrombopag使用中の患者では,Dose調節無しでPLT>5万が4wk以上持続するまで,毎週PLTをチェックする必要あり.その後は1ヶ月毎のチェックでOK.PLT 20-40万となるようならば治療は一時中断.PLTを元に戻すことが目標ではない.Eltrombopagでは肝障害が報告されているため,Dose調節中は2wk毎に肝酵素チェック.その後は1ヶ月毎のチェックでOKN Engl J Med 2011;365:734-41.
  29. 29. Thrombopoietin-R agonistの副作用最も多いのは頭痛, 悪心, 嘔吐, 怠感, 下痢, 関節痛, 鼻咽頭炎.薬剤中断後にITPが増悪するのは8-10%で認められる.中断後4wkは出血リスクが上昇し得る.中止時はTaperingが他薬剤への切り替えが推奨される.Eltrombopagによる肝障害は11%(Placeboで7%).肝酵素が3ULN程度, Bilは1.6ULN程度上昇.薬剤継続しても改善することがあるが,ALT>3ULN, 4wk以上持続, 急速進行例では中断が必要.N Engl J Med 2011;365:734-41.
  30. 30. Thrombopoietin-R agonistと血栓症リスクRomiplostimを使用した291名中,17名で25例の静脈, 動脈血栓症を併発.(8.6%)Eltrombopagを使用した299名中,16名で21例の静脈, 動脈血栓症を併発.(7.0%)薬剤の使用期間で頻度は変わらず.また血栓症を来した患者は1つ以上の血栓リスクを有しており, リスクがある患者では要注意となる.骨髄線維症の合併も報告されている.N Engl J Med 2011;365:734-41.
  31. 31. TABLE 3Newer therapies for immune thrombocytopeniarefractory to first-line treatment in adultsRITUXIMAB (RITUXAN) ROMIPLOSTIM (NPLATE) ELTROMBOPAG (PROMACTA)Drug class Anti-CD20 monoclonalantibodyThrombopoietin receptoragonistThrombopoietin receptoragonistRoute Intravenous Subcutaneous OralDosing 375 mg/m2weekly × 4 1–10 mg/kg weekly 25–75 mg dailyApproximateplatelet countresponse rate*60%4179%(splenectomized patients)4788%(nonsplenectomized patients)4770%(receiving 50-mg dose)80%(receiving 75-mg dose) 51Approximate timeto response1–8 weeks351–4 weeks 2 weeksDurationof responseUp to 2 years(median 10.5 months) 43Platelet count returns to base-line 2 weeks after discontinuingtreatmentPlatelet count returns tobaseline 2 weeks afterdiscontinuing treatmentSafety concerns Mild infusion reactionRare: infections, serumsickness, bronchospasmBone marrow reticulinformation, thrombosisElevated liver enzymes,bone marrow reticulinformation, thrombosis*Platelet count > 50 x 109/LCleveland Clinic Journal of Medicine 2012;79:641-650
  32. 32. 2nd lineでも効果が無い場合, 多剤併用療法を考慮する.Azathioprine, cyclosporine, cyclophosphamide,  mycophenolateといった免疫抑制剤を併用.もしくは幹細胞移植を考慮する.Cleveland Clinic Journal of Medicine 2012;79:641-650

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