肝硬化伴脾亢患者血小板減少癥臨床研究進(jìn)展-感染科

血小板減少癥臨床研究進(jìn)展齊魯制藥有限公司

于海玲2010年12月7日血小板減少癥病因血小板數(shù)量減少是出血性疾病最常見(jiàn)的病因。血小板減少癥按病因分為：血小板破壞增加：免疫性血小板減少性紫癜（ITP）彌散性血管內(nèi)凝血（DIC）肝素誘發(fā)的血小板減少癥其他藥物誘發(fā)血小板減少癥血小板生成減少AA，AL，放化療骨髓抑制，感染干擾素治療慢性乙型病毒性肝炎所致骨髓抑制，白細(xì)胞及血小板減少是其常見(jiàn)的不良反應(yīng)之一，約有25%~30%的患者因此原因須暫?；蛑兄怪委焄

血小板分布異常：脾亢阮長(zhǎng)耿.血小板減少癥的研究進(jìn)展.中華醫(yī)學(xué)會(huì)第八次全國(guó)血液學(xué)學(xué)術(shù)會(huì)議論文匯編;2004年血小板計(jì)數(shù)與出血程度Gaydosla,Freirichej,Manteln.Thequantitativerelationbetweenplateletcountandhemorrhageinpatientswithacuteleukemia.NEnglJMed.1962May3;266:905-9.102030400.5151050100Plateletcount(x109/L)%Dayswithhemorrhage血小板減少癥的治療病因治療：如ITP應(yīng)用糖皮質(zhì)激素、丙種球蛋白等2007年美國(guó)ASH血小板輸注指南介紹：預(yù)防性血小板輸注的閾值為患者血小板計(jì)數(shù)10×109/L?；?、骨髓移植、骨髓自身因素(如再生障礙性貧血或骨髓增生異常綜合征)引起的血小板減少腦部手術(shù)時(shí)要求血小板計(jì)數(shù)不低于100×109/L其他侵入性操作或是創(chuàng)傷手術(shù)時(shí)要求血小板計(jì)數(shù)在50～100×109/L水平血小板生長(zhǎng)因子：刺激造血細(xì)胞的增殖和分化其它血小板生長(zhǎng)因子IL-1IL-3IL-6白細(xì)胞介素-11（rhIL-11，巨和粒）血小板生成素（rHuTPO，特比澳）羅米司亭（Romiplostim，Nplate）艾曲波帕（Eltrombopag，Promacta）巨核細(xì)胞生長(zhǎng)因子（MGDF）血小板生長(zhǎng)因子白細(xì)胞介素（IL-11）白介素-11(interleukin11，IL-11)是由造血微環(huán)境基質(zhì)細(xì)胞和部分間葉細(xì)胞產(chǎn)生的多效性細(xì)胞因子：成熟的IL-11編碼178個(gè)氨基酸，分子量為19.2kDa為4-螺旋束型結(jié)構(gòu)，每個(gè)功能域由7個(gè)反平行的β折疊片層組成IL-11通過(guò)與受體(IL-11R)結(jié)合促進(jìn)信號(hào)傳導(dǎo)DimitriHARMEGNIES,el.Characterizationofapotenthumaninterleukin-11agonist.Biochem.J.(2003)375,23–32NC位點(diǎn)I位點(diǎn)III位點(diǎn)IIIL-11介導(dǎo)的信號(hào)傳導(dǎo)通路IL-11通過(guò)復(fù)雜的信號(hào)通路介導(dǎo)，通過(guò)一系列的信號(hào)級(jí)聯(lián)反應(yīng)，作用于細(xì)胞核內(nèi)特異的DNA片段，調(diào)控靶基因的轉(zhuǎn)錄，直接影響細(xì)胞的增殖、分化和凋亡GP130IL-11RIL-11RSypJAK2GRB2SOSRASSTATsMAPKpp90rskPhospholipaseDPhosphatidicAcidPrimaryResponseGenes(geneexpression)IL-11STAT：信號(hào)傳導(dǎo)和轉(zhuǎn)錄活化因子MAPK：促進(jìn)細(xì)胞分裂蛋白激酶IL-11縮短造血干細(xì)胞G0期IL-11——多能細(xì)胞因子GP130IL-11RIL-11促進(jìn)造血祖細(xì)胞分化成熟信號(hào)級(jí)聯(lián)反應(yīng)維持上皮細(xì)胞動(dòng)態(tài)平衡基因活化刺激肝臟產(chǎn)生急性期抗炎反應(yīng)蛋白抑制巨噬細(xì)胞分泌炎性介質(zhì),抑制免疫反應(yīng)骨髓脂肪生長(zhǎng)抑制王震,等.白介素在骨髓造血微環(huán)境調(diào)控中的作用.國(guó)外醫(yī)學(xué)輸血及血液學(xué)分冊(cè)2002,25:160-163.血小板生成過(guò)程IL-11促進(jìn)造血干細(xì)胞和巨核祖細(xì)胞的增殖誘導(dǎo)巨核細(xì)胞成熟，促進(jìn)高倍性巨核細(xì)胞生成成熟的巨核細(xì)胞胞質(zhì)伸向骨髓竇腔，裂解脫落為血小板進(jìn)入血流SaitohM,etal.Recombinanthumaninterleukin-11improvedcarboplatininducedthrombocytopeniawithoutaffectingantitumoractivetiesinmicebearing.Lewislungcarcinomacells.CancerChemotherPharmacol,2002,49:161-l66.rhIL-11劑量耐受性試驗(yàn)16例乳腺癌患者入組，接受大劑量化療IL-11療效呈劑量依賴(lài)性，劑量越高，療效越好（p<0.05）外周血骨髓巨核細(xì)胞染色體倍數(shù)檢測(cè)顯示，劑量≥25μg/kg時(shí)，巨核細(xì)胞倍數(shù)大大增加，血小板數(shù)明顯增多IL-11藥物最大耐受劑量(MDT)為75μg/kg，推薦劑量為25μg/kg-50μg/kgMichaelS.Gordon,WortaJ.etal.APhaseITrialofRecombinantHumanInterleukin-11inWomenWithBreastCancerReceivingChemotherapy.Blood,Vol87,No9(May1).1996:pp3615-3624daysoftreatment（circle0）mg/dl3pts75μg6pts50μg3pts25μg3pts10μgAdministrationsatDay1-14白介素-11治療肝硬化伴脾功能亢進(jìn)患者血小板減少I(mǎi)L-11不僅可以提升肝硬化患者的血小板，同時(shí)對(duì)患者可能存在的肝功能損害和黏膜糜爛有好處IL-11對(duì)肝炎患者肝臟炎癥和纖維化過(guò)程有保護(hù)作用[1]在內(nèi)毒素血癥中可減少肝臟損傷[2]肝硬化引起的血小板減少癥患者每天皮下注射rhlL-113mg，不僅使得患者血小板計(jì)數(shù)提高，同時(shí)ALT、AST在治療期間也有明顯下降[3]ongJP，YounossiZM．ManagingthehematologicsideeffectsofantiviraltherapyforchronichepatitisC：anemia。neutropenia，andthmmbocytopenia[J]．CleveClinJMed，2004，71(Suppl3)：S17-21．halibR．Recombinanthumaninterleukin·11improvesthromboeytopeniainpatientswithcirrhosis[J]．Hepatology，2003，37：1165-1171．MaeshimaK,TakahashiT,NakahiraK,eta1．Aprotectiveroleofinterleukin11onhepaticinjuryinacuteendotoxemia[J]．Shock,2004，21(2):134-138．Interleukin-11forTreatmentof

HepatitisC-AssociatedITP

WallaceH.CoulterPlateletLaboratory,Divisionofematology/Oncology,DepartmentofMedicine,UniversityofMiami,MillerSchoolofMedicine,Miami,Fla.,USAVincenzoFontanaPamelaDudkiewiczWencheJyLarryHorstmanYeonS.AhnActaHaematol2008;119:126-132.Interleukin-11forTreatmentof

HepatitisC-AssociatedITPPatientswithHepatitisC-AssociatedITPGroup1rhIL-1150μg/kgd,week1-8initially,thenweeklyfor4weeks,thenmonthlyWhenpatientsobtainedgoodresultsandtoleratedtherapy,theywereallowedtocontinueitonceaweekasmaintenancetherapytoprolongremissionVincenzoFontana,etal.Interleukin-11forTreatmentofHepatitisC-AssociatedITP.ActaHaematol2008;119:126-132.Group2rhIL-1115-35μg/kg,3daysperweek,week1-6initially,thenweeklyfor4weeks,thenmonthly)Results:plateletcountTreatmentpre-post-pre-post-Ingroup1,meanplateletcountsrosefrom54×109/lto103×109/l

(p=0.02)in6/7patients1-2weeksafterrhIL-11Ingroup2,meanplateletcountsrosefrom51×109/lto74×109/l(p=0.04)in4/5patientsin1-2weeksPlateletresponsestorhIL-11weredose-dependent:

athighdose,improvementofplateletcountswasmorepronouncedResults:LiverFunctionTreatmentpre-post-pre-post-VincenzoFontana,etal.Interleukin-11forTreatmentofHepatitisC-AssociatedITP.ActaHaematol2008;119:126-132.Results:HepatitisCViralLoadLiverTreatmentpre-post-pre-post-VincenzoFontana,etal.Interleukin-11forTreatmentofHepatitisC-AssociatedITP.ActaHaematol2008;119:126-132.Ingroup1,theHCV-RNAtiterdecreasedwithtreatmentinallpatients,fallingtomeanof16%ofinitialvaluein1-10weeksIngroup2,thechangeofHCV-RNAwasnotstatisticallysignificantResults:Anti-PlateletAntibodies(aPlt-Ab)Treatmentpre-post-pre-post-VincenzoFontana,etal.Interleukin-11forTreatmentofHepatitisC-AssociatedITP.ActaHaematol2008;119:126-132.Ingroup1,meanIgGdecreasedfrom4.01to2.04(p=0.05),after4–8weeksIngroup2,thechangeswerenotstatisticallysignificant(p=0.68)重組人白介素-11在肝硬化脾功能亢進(jìn)患者中的術(shù)前應(yīng)用溫州醫(yī)學(xué)院附屬第二醫(yī)院朱寶玲姚榮欣夏軼姿金栗名實(shí)用醫(yī)學(xué)雜志2008年第24卷第10期重組人白介素-11在肝硬化脾功能亢進(jìn)患者中的術(shù)前應(yīng)用繼發(fā)性脾功能亢進(jìn)患者N=22rhIL-1150μg/kgd,d1-1020例患者為乙型肝炎后肝硬化，2例為酒