《急性腦梗死出血性轉(zhuǎn)化的危險(xiǎn)因素研究的國(guó)內(nèi)外文獻(xiàn)綜述》7300字

急性腦梗死出血性轉(zhuǎn)化的危險(xiǎn)因素研究的國(guó)內(nèi)外文獻(xiàn)綜述目錄TOC\o"1-2"\h\u21710急性腦梗死出血性轉(zhuǎn)化的危險(xiǎn)因素研究的國(guó)內(nèi)外文獻(xiàn)綜述 1259191.1.1出血性轉(zhuǎn)化的定義 1222571.1.2出血性轉(zhuǎn)化的流行病學(xué) 1144621.1.3出血性轉(zhuǎn)化的分類 2206991）出血性腦梗死（HI）和腦實(shí)質(zhì)血腫（PH） 3281322）癥狀性腦出血(sICH)和無癥狀性腦出血 3196763）早期和晚期出血性轉(zhuǎn)化 452301.1.4出血性轉(zhuǎn)化的病理生理機(jī)制 4154171）缺血損傷 514132）再灌注損傷 5294523）凝血功能紊亂 5276204）血腦屏障破壞 69222參考文獻(xiàn) 8出血性轉(zhuǎn)化的定義Fisher和Adams于1951年首次明確地提出了腦梗死后出血性轉(zhuǎn)化的基本概念A(yù)DDINEN.CITE<EndNote><Cite><Author>Fisher</Author><Year>1951</Year><RecNum>162</RecNum><DisplayText><styleface="superscript">[17]</style></DisplayText><record><rec-number>162</rec-number><foreign-keys><keyapp="EN"db-id="22x9t9xporwr26e5stuvres4d0d025wf90r0"timestamp="1617030135">162</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Fisher,M.</author><author>Adams,R.D.</author></authors></contributors><titles><title>Observationsonbrainembolismwithspecialreferencetothemechanismofhemorrhagicinfarction</title><secondary-title>JNeuropatholExpNeurol</secondary-title><alt-title>Journalofneuropathologyandexperimentalneurology</alt-title></titles><periodical><full-title>JNeuropatholExpNeurol</full-title><abbr-1>Journalofneuropathologyandexperimentalneurology</abbr-1></periodical><alt-periodical><full-title>JNeuropatholExpNeurol</full-title><abbr-1>Journalofneuropathologyandexperimentalneurology</abbr-1></alt-periodical><pages>92-4</pages><volume>10</volume><number>1</number><edition>1951/01/01</edition><keywords><keyword>*CerebralArteries</keyword><keyword>*CerebralVeins</keyword><keyword>*Embolism</keyword><keyword>*Infarction</keyword><keyword>*IntracranialEmbolism</keyword><keyword>*cerebralarteriesandveins</keyword></keywords><dates><year>1951</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0022-3069(Print) 0022-3069</isbn><accession-num>14804137</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[17]，出血性轉(zhuǎn)化是指急性腦梗死發(fā)生后缺血區(qū)內(nèi)恢復(fù)血流灌注而引起的出血，它既是腦梗死自然病演變的組成部分，也是采取干預(yù)措施（溶栓、抗凝、抗血小板、介入等治療）后的風(fēng)險(xiǎn)之一，目前常采用的定義是：腦梗死發(fā)生后第一次行顱腦CT或MRI檢查時(shí)并未發(fā)現(xiàn)有腦內(nèi)出血，而再次檢查時(shí)發(fā)現(xiàn)有腦內(nèi)出血ADDINEN.CITEADDINEN.CITE.DATA[18]，或根據(jù)首次頭顱CT或MRI就可以確診梗死合并出血ADDINEN.CITEADDINEN.CITE.DATA[19]。出血性轉(zhuǎn)化的流行病學(xué)出血性轉(zhuǎn)化的流行病學(xué)由于各研究在研究設(shè)計(jì)、研究對(duì)象及出血性轉(zhuǎn)化的定義等方面存在一定的差異，所得到的出血性轉(zhuǎn)化的發(fā)生率有所不同。自發(fā)性出血性轉(zhuǎn)化在尸檢研究中的發(fā)生率介于38%至71%之間，而CT檢出率在13%至43%之間，其中癥狀性顱內(nèi)出血（symptomaticintracranialhemorrhage，sICH）約占0.6%至20%ADDINEN.CITEADDINEN.CITE.DATA[20,21]。一項(xiàng)隊(duì)列研究發(fā)現(xiàn)，出血性腦梗死型(hemorrhagicinfarction，HI）的發(fā)生率高于腦實(shí)質(zhì)血腫型（parenchymalhemorrhage，PH），HI的發(fā)生率約為9%，而PH的發(fā)生率約為3%ADDINEN.CITEADDINEN.CITE.DATA[22]，PH2型與早期惡化和3個(gè)月死亡率相關(guān)，但PH1或HI型與其無明顯相關(guān)性ADDINEN.CITEADDINEN.CITE.DATA[23]。早期的一項(xiàng)系統(tǒng)評(píng)價(jià)表明ADDINEN.CITE<EndNote><Cite><Author>Lindley</Author><Year>2004</Year><RecNum>113</RecNum><DisplayText><styleface="superscript">[7]</style></DisplayText><record><rec-number>113</rec-number><foreign-keys><keyapp="EN"db-id="22x9t9xporwr26e5stuvres4d0d025wf90r0"timestamp="1617025868">113</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Lindley,R.I.</author><author>Wardlaw,J.M.</author><author>Sandercock,P.A.</author><author>Rimdusid,P.</author><author>Lewis,S.C.</author><author>Signorini,D.F.</author><author>Ricci,S.</author></authors></contributors><auth-address>DepartmentofGeriatricMedicine,WestmeadHospital,Westmead,Australia.</auth-address><titles><title>Frequencyandriskfactorsforspontaneoushemorrhagictransformationofcerebralinfarction</title><secondary-title>JStrokeCerebrovascDis</secondary-title><alt-title>Journalofstrokeandcerebrovasculardiseases:theofficialjournalofNationalStrokeAssociation</alt-title></titles><periodical><full-title>JStrokeCerebrovascDis</full-title><abbr-1>Journalofstrokeandcerebrovasculardiseases:theofficialjournalofNationalStrokeAssociation</abbr-1></periodical><alt-periodical><full-title>JStrokeCerebrovascDis</full-title><abbr-1>Journalofstrokeandcerebrovasculardiseases:theofficialjournalofNationalStrokeAssociation</abbr-1></alt-periodical><pages>235-46</pages><volume>13</volume><number>6</number><edition>2007/10/02</edition><dates><year>2004</year><pub-dates><date>Nov-Dec</date></pub-dates></dates><isbn>1052-3057</isbn><accession-num>17903981</accession-num><urls></urls><electronic-resource-num>10.1016/j.jstrokecerebrovasdis.2004.03.003</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[7]，在未經(jīng)任何治療的患者中，CT掃描發(fā)現(xiàn)的HT的發(fā)生率約7%到10%，sICH約占1%到2%。當(dāng)患者使用阿司匹林和肝素治療時(shí)，這一比例增加到約8%到22%，sICH的風(fēng)險(xiǎn)相應(yīng)增加(2%到9%)，溶栓治療發(fā)生HT的風(fēng)險(xiǎn)最大，其比例為10%至48%，發(fā)生sICH的比例為1%至20%。其中，rt-PA靜脈溶栓最令人擔(dān)心的并發(fā)癥是sICH，其發(fā)病率高且死亡率接近50％ADDINEN.CITEADDINEN.CITE.DATA[11]。但是一些主要的溶栓試驗(yàn)報(bào)告的發(fā)生率僅為0.6％至7％，這很可能是由于使用了嚴(yán)格的納入標(biāo)準(zhǔn)ADDINEN.CITEADDINEN.CITE.DATA[24-26]。在NINDS溶栓試驗(yàn)中，急性腦梗死患者使用rt-PA靜脈溶栓后有3%的患者出現(xiàn)無癥狀性顱內(nèi)出血（asymptomaticintracranialhemorrhage），6%的患者在前36小時(shí)內(nèi)出現(xiàn)sICH，其中50%死亡ADDINEN.CITE<EndNote><Cite><Year>1995</Year><RecNum>133</RecNum><DisplayText><styleface="superscript">[27]</style></DisplayText><record><rec-number>133</rec-number><foreign-keys><keyapp="EN"db-id="22x9t9xporwr26e5stuvres4d0d025wf90r0"timestamp="1617027857">133</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors></contributors><titles><title>Tissueplasminogenactivatorforacuteischemicstroke</title><secondary-title>NEnglJMed</secondary-title><alt-title>TheNewEnglandjournalofmedicine</alt-title></titles><periodical><full-title>NEnglJMed</full-title><abbr-1>TheNewEnglandjournalofmedicine</abbr-1></periodical><alt-periodical><full-title>NEnglJMed</full-title><abbr-1>TheNewEnglandjournalofmedicine</abbr-1></alt-periodical><pages>1581-7</pages><volume>333</volume><number>24</number><edition>1995/12/14</edition><keywords><keyword>ActivitiesofDailyLiving</keyword><keyword>Aged</keyword><keyword>BrainIschemia/drugtherapy</keyword><keyword>CerebralHemorrhage/chemicallyinduced</keyword><keyword>CerebrovascularDisorders/complications/*drugtherapy/mortality</keyword><keyword>DisabilityEvaluation</keyword><keyword>Double-BlindMethod</keyword><keyword>DrugAdministrationSchedule</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Infusions,Intravenous</keyword><keyword>Male</keyword><keyword>MiddleAged</keyword><keyword>TissuePlasminogenActivator/adverseeffects/*therapeuticuse</keyword><keyword>TreatmentOutcome</keyword></keywords><dates><year>1995</year><pub-dates><date>Dec14</date></pub-dates></dates><isbn>0028-4793(Print) 0028-4793</isbn><accession-num>7477192</accession-num><urls></urls><electronic-resource-num>10.1056/nejm199512143332401</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[27]。在ECASSIII試驗(yàn)中，rt-PA組的腦出血發(fā)生率達(dá)到27%，其中sICH發(fā)生率為2.4%。在第三次國(guó)際中風(fēng)試驗(yàn)(IST-3)中，rt-PA治療使sICH病例數(shù)量顯著增加7倍，致命性sICH病例增加8倍ADDINEN.CITEADDINEN.CITE.DATA[28]。2012年，Wardlaw等人對(duì)ACI患者靜脈注射rt-PA的12項(xiàng)RCT進(jìn)行薈萃分析發(fā)現(xiàn)，sICH發(fā)生率為7.7%，致命性HT的發(fā)生率為3.6%，表明溶栓后早期死亡與致命腦出血之間存在強(qiáng)烈關(guān)聯(lián)ADDINEN.CITEADDINEN.CITE.DATA[29]。一項(xiàng)對(duì)7項(xiàng)臨床試驗(yàn)的薈萃分析顯示，在急性心源性腦卒中發(fā)作后48小時(shí)內(nèi)開始使用抗凝劑或抗血小板藥物治療，接受抗凝的患者出血性轉(zhuǎn)化的風(fēng)險(xiǎn)增加2.5%ADDINEN.CITE<EndNote><Cite><Author>Paciaroni</Author><Year>2007</Year><RecNum>136</RecNum><DisplayText><styleface="superscript">[30]</style></DisplayText><record><rec-number>136</rec-number><foreign-keys><keyapp="EN"db-id="22x9t9xporwr26e5stuvres4d0d025wf90r0"timestamp="1617028019">136</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Paciaroni,M.</author><author>Agnelli,G.</author><author>Micheli,S.</author><author>Caso,V.</author></authors></contributors><auth-address>StrokeUnit,DepartmentofInternalMedicine,UniversityofPerugia,Perugia,Italy.mpaciaroni@libero.it</auth-address><titles><title>Efficacyandsafetyofanticoagulanttreatmentinacutecardioembolicstroke:ameta-analysisofrandomizedcontrolledtrials</title><secondary-title>Stroke</secondary-title><alt-title>Stroke</alt-title></titles><periodical><full-title>Stroke</full-title><abbr-1>Stroke</abbr-1></periodical><alt-periodical><full-title>Stroke</full-title><abbr-1>Stroke</abbr-1></alt-periodical><pages>423-30</pages><volume>38</volume><number>2</number><edition>2007/01/06</edition><keywords><keyword>Anticoagulants/*adverseeffects/*therapeuticuse</keyword><keyword>Embolism/*drugtherapy/epidemiology</keyword><keyword>Humans</keyword><keyword>MyocardialIschemia/*drugtherapy/epidemiology</keyword><keyword>*RandomizedControlledTrialsasTopic/methods</keyword><keyword>Stroke/*drugtherapy/epidemiology</keyword></keywords><dates><year>2007</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0039-2499</isbn><accession-num>17204681</accession-num><urls></urls><electronic-resource-num>10.1161/01.STR.0000254600.92975.1f</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[30]。機(jī)械性血栓切除術(shù)(MT)已成為治療急性缺血性卒中(AIS)合并大血管閉塞(LVO)的標(biāo)準(zhǔn)方法ADDINEN.CITEADDINEN.CITE.DATA[31,32]，在最近的薈萃分析中，Sadeh-Gonik等人發(fā)現(xiàn)，無論是否聯(lián)合靜脈溶栓，機(jī)械取栓術(shù)后腦出血和癥狀性出血的發(fā)生率分別為24％和8％ADDINEN.CITEADDINEN.CITE.DATA[33]。一項(xiàng)多中心的前瞻性研究表明ADDINEN.CITEADDINEN.CITE.DATA[34]，連續(xù)前循環(huán)串聯(lián)大血管閉塞性卒中患者接受血栓切除術(shù)后，24.7%發(fā)生HI型出血性轉(zhuǎn)化，14.2%發(fā)生PH型出血轉(zhuǎn)化，未發(fā)現(xiàn)HI型對(duì)90天臨床結(jié)果的不利影響，而PH的發(fā)生與死亡率的增加顯著相關(guān)。出血性轉(zhuǎn)化的分類急性腦梗死后HT的分類在各個(gè)研究中有所不同，并且不是CT或MRI檢測(cè)到的顱內(nèi)出血都會(huì)使神經(jīng)癥狀惡化并損害預(yù)后。因此，腦梗死和再灌注治療后的顱內(nèi)出血根據(jù)影像學(xué)特征和與臨床惡化的相關(guān)性進(jìn)行分類。單純的放射學(xué)分類使用出血的部位、形式和程度及其與缺血性損傷的關(guān)系來區(qū)分不同的出血亞型，這些亞型可能在神經(jīng)功能損害和預(yù)后方面有所不同?；旌戏派鋵W(xué)-臨床分類在放射學(xué)發(fā)現(xiàn)腦出血的基礎(chǔ)上增加了臨床癥狀，將腦梗死后出血型轉(zhuǎn)化按照有無臨床神經(jīng)功能惡化可以分為癥狀性的腦出血和無癥狀性的腦出血。1）出血性腦梗死（HI）和腦實(shí)質(zhì)血腫（PH）目前最常用的分類方法是ECASS分型，它純粹是放射學(xué)的分類，其包括HI型和PH型，HI型又分為兩種亞型（HI1型和HI2型），PH型也分為兩種亞型（PH1型和PH2型），如圖1-1ADDINEN.CITEADDINEN.CITE.DATA[35]。在CT上，具體的影像學(xué)表現(xiàn)見表1-1ADDINEN.CITEADDINEN.CITE.DATA[36]表1-1ECASS分型-出血性轉(zhuǎn)化的分類分型說明HI1型梗死灶局部存在小的瘀點(diǎn)HI1型局部存在更多的融合性瘀斑而無占位效應(yīng)PH1型梗死組織內(nèi)血腫體積小于30%梗死體積，無大的占位效應(yīng)PH2型血應(yīng)圖1-1出血性轉(zhuǎn)化的影像學(xué)分型2）癥狀性腦出血(sICH)和無癥狀性腦出血根據(jù)有無臨床神經(jīng)功能惡化分為癥狀性腦出血和無癥狀性腦出血，sICH通常與急性腦梗死治療相關(guān)，是HT的一個(gè)亞型，具有最顯著的臨床后果。sICH中的分類方案有助于預(yù)測(cè)臨床預(yù)后和指導(dǎo)治療。sICH的定義來源于歐洲和美國(guó)的主要溶栓試驗(yàn)，所有這些試驗(yàn)都要求在溶栓治療后的腦CT上存在出血表現(xiàn)ADDINEN.CITEADDINEN.CITE.DATA[23,37]。具體定義見表1-2。表1-2癥狀性顱內(nèi)出血（sICH）的定義臨床研究CT掃描時(shí)間定義NINDS發(fā)病24小時(shí)，7-10天或臨床癥狀提示有出血時(shí)隨時(shí)掃描以前的CT掃描中沒有發(fā)現(xiàn)出血，隨后懷疑出血或神經(jīng)功能減退ECASSII治療后22-36h，7天或臨床癥狀加重時(shí)CT上任何部位的出血，NIHSS評(píng)分增加≥4分ECASSIIICT或MRI治療后22-36小時(shí)掃描任何出血+NIHSS評(píng)分增加≥4分或死亡,明確出血是病情惡化的主要原因SITS-MOST治療后22-36小時(shí)表現(xiàn)為PH2型，并伴有神經(jīng)功能惡化，NIHSS評(píng)分增加≥4分3）早期和晚期出血性轉(zhuǎn)化HT是腦梗死自然史的一部分，其發(fā)生時(shí)間差異很大ADDINEN.CITE<EndNote><Cite><Author>Hornig</Author><Year>1986</Year><RecNum>70</RecNum><DisplayText><styleface="superscript">[38]</style></DisplayText><record><rec-number>70</rec-number><foreign-keys><keyapp="EN"db-id="22x9t9xporwr26e5stuvres4d0d025wf90r0"timestamp="1617022057">70</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Hornig,C.R.</author><author>Dorndorf,W.</author><author>Agnoli,A.L.</author></authors></contributors><titles><title>Hemorrhagiccerebralinfarction--aprospectivestudy</title><secondary-title>Stroke</secondary-title><alt-title>Stroke</alt-title></titles><periodical><full-title>Stroke</full-title><abbr-1>Stroke</abbr-1></periodical><alt-periodical><full-title>Stroke</full-title><abbr-1>Stroke</abbr-1></alt-periodical><pages>179-85</pages><volume>17</volume><number>2</number><edition>1986/03/01</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Albumins/cerebrospinalfluid</keyword><keyword>Blood-BrainBarrier</keyword><keyword>CerebralHemorrhage/*etiology</keyword><keyword>CerebralInfarction/complications/*physiopathology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>MiddleAged</keyword><keyword>ProspectiveStudies</keyword><keyword>Risk</keyword><keyword>SerumAlbumin/analysis</keyword><keyword>Tomography,X-RayComputed</keyword><keyword>Ultrasonography</keyword></keywords><dates><year>1986</year><pub-dates><date>Mar-Apr</date></pub-dates></dates><isbn>0039-2499(Print) 0039-2499</isbn><accession-num>3515635</accession-num><urls></urls><electronic-resource-num>10.1161/01.str.17.2.179</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[38]，人們對(duì)與急性腦梗死遲發(fā)性HT相關(guān)的因素了解甚少，可能由治療干預(yù)導(dǎo)致的HT往往在可預(yù)測(cè)的時(shí)間內(nèi)發(fā)生。根據(jù)HT的發(fā)生時(shí)間是否超過24小時(shí)，將它分為早期和晚期出血性轉(zhuǎn)化。如NINDSrt-PA試驗(yàn)ADDINEN.CITE<EndNote><Cite><Year>1997</Year><RecNum>69</RecNum><DisplayText><styleface="superscript">[39]</style></DisplayText><record><rec-number>69</rec-number><foreign-keys><keyapp="EN"db-id="22x9t9xporwr26e5stuvres4d0d025wf90r0"timestamp="1617022009">69</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors></contributors><titles><title>Intracerebralhemorrhageafterintravenoust-PAtherapyforischemicstroke.TheNINDSt-PAStrokeStudyGroup</title><secondary-title>Stroke</secondary-title><alt-title>Stroke</alt-title></titles><periodical><full-title>Stroke</full-title><abbr-1>Stroke</abbr-1></periodical><alt-periodical><full-title>Stroke</full-title><abbr-1>Stroke</abbr-1></alt-periodical><pages>2109-18</pages><volume>28</volume><number>11</number><edition>1997/11/22</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>BrainIschemia/*drugtherapy</keyword><keyword>CerebralHemorrhage/*chemicallyinduced/diagnosticimaging/therapy</keyword><keyword>CerebrovascularDisorders/*drugtherapy</keyword><keyword>Double-BlindMethod</keyword><keyword>Forecasting</keyword><keyword>Humans</keyword><keyword>Incidence</keyword><keyword>Injections,Intravenous</keyword><keyword>MiddleAged</keyword><keyword>PlasminogenActivators/*adverseeffects/therapeuticuse</keyword><keyword>RiskFactors</keyword><keyword>TimeFactors</keyword><keyword>TissuePlasminogenActivator/*adverseeffects/therapeuticuse</keyword><keyword>Tomography,X-RayComputed</keyword><keyword>TreatmentOutcome</keyword></keywords><dates><year>1997</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0039-2499(Print) 0039-2499</isbn><accession-num>9368550</accession-num><urls></urls><electronic-resource-num>10.1161/01.str.28.11.2109</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[39]所述，溶栓后的HT通常是早期事件（<24h），其中所有致命的PH均發(fā)生在該時(shí)間段內(nèi)，80％發(fā)生在治療后12h內(nèi)。當(dāng)急性腦梗死患者接受靜脈抗凝治療時(shí)，HT發(fā)生的時(shí)間會(huì)延遲，這種時(shí)機(jī)的差異可能取決于達(dá)到抗凝作用所需的時(shí)間，尤其在使用普通肝素時(shí)，若在治療開始時(shí)未選擇靜脈注射，則其抗凝作用會(huì)延遲1至2小時(shí)ADDINEN.CITE<EndNote><Cite><Author>Paciaroni</Author><Year>2007</Year><RecNum>136</RecNum><DisplayText><styleface="superscript">[30]</style></DisplayText><record><rec-number>136</rec-number><foreign-keys><keyapp="EN"db-id="22x9t9xporwr26e5stuvres4d0d025wf90r0"timestamp="1617028019">136</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Paciaroni,M.</author><author>Agnelli,G.</author><author>Micheli,S.</author><author>Caso,V.</author></authors></contributors><auth-address>StrokeUnit,DepartmentofInternalMedicine,UniversityofPerugia,Perugia,Italy.mpaciaroni@libero.it</auth-address><titles><title>Efficacyandsafetyofanticoagulanttreatmentinacutecardioembolicstroke:ameta-analysisofrandomizedcontrolledtrials</title><secondary-title>Stroke</secondary-title><alt-title>Stroke</alt-title></titles><periodical><full-title>Stroke</full-title><abbr-1>Stroke</abbr-1></periodical><alt-periodical><full-title>Stroke</full-title><abbr-1>Stroke</abbr-1></alt-periodical><pages>423-30</pages><volume>38</volume><number>2</number><edition>2007/01/06</edition><keywords><keyword>Anticoagulants/*adverseeffects/*therapeuticuse</keyword><keyword>Embolism/*drugtherapy/epidemiology</keyword><keyword>Humans</keyword><keyword>MyocardialIschemia/*drugtherapy/epidemiology</keyword><keyword>*RandomizedControlledTrialsasTopic/methods</keyword><keyword>Stroke/*drugtherapy/epidemiology</keyword></keywords><dates><year>2007</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0039-2499</isbn><accession-num>17204681</accession-num><urls></urls><electronic-resource-num>10.1161/01.STR.0000254600.92975.1f</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[30]。在得出治療干預(yù)對(duì)HT時(shí)機(jī)的影響的結(jié)論時(shí)，應(yīng)考慮一系列影響HT影像學(xué)檢查時(shí)機(jī)的因素,這些因素包括在臨床試驗(yàn)干預(yù)后的特定時(shí)間、臨床神經(jīng)功能惡化后或在HT自然史觀察研究的任意間隔后行影像學(xué)檢查，檢測(cè)的時(shí)機(jī)還受所用成像方式（例如帶有或不帶有梯度回波或磁敏感加權(quán)成像序列的CT或MRI）的準(zhǔn)確性的影響，這些序列對(duì)出血的檢測(cè)更為敏感ADDINEN.CITEADDINEN.CITE.DATA[40]。出血性轉(zhuǎn)化的病理生理機(jī)制HT是一種動(dòng)態(tài)和復(fù)雜的現(xiàn)象，其病理生理學(xué)尚不清楚，它的發(fā)生發(fā)展需要多個(gè)相互關(guān)聯(lián)的病理過程，目前認(rèn)為可能由血腦屏障（bloodbrainbarrier,BBB）破壞，凝血功能紊亂和缺血再灌注損傷等介導(dǎo)。1）缺血損傷在腦缺血發(fā)作后的早期，細(xì)胞內(nèi)ATP水平大幅下降，從而嚴(yán)重?fù)p害了Na+-K+-ATP酶的活性ADDINEN.CITE<EndNote><Cite><Author>Rossi</Author><Year>2007</Year><RecNum>154</RecNum><DisplayText><styleface="superscript">[41]</style></DisplayText><record><rec-number>154</rec-number><foreign-keys><keyapp="EN"db-id="22x9t9xporwr26e5stuvres4d0d025wf90r0"timestamp="1617029596">154</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Rossi,D.J.</author><author>Brady,J.D.</author><author>Mohr,C.</author></authors></contributors><auth-address>NeurologicalSciencesInstitute,OregonHealth&ScienceUniversity,505NW185thAvenue,Beaverton,Oregon97232,USA.rossid@</auth-address><titles><title>Astrocytemetabolismandsignalingduringbrainischemia</title><secondary-title>NatNeurosci</secondary-title><alt-title>Natureneuroscience</alt-title></titles><periodical><full-title>NatNeurosci</full-title><abbr-1>Natureneuroscience</abbr-1></periodical><alt-periodical><full-title>NatNeurosci</full-title><abbr-1>Natureneuroscience</abbr-1></alt-periodical><pages>1377-86</pages><volume>10</volume><number>11</number><edition>2007/10/30</edition><keywords><keyword>Animals</keyword><keyword>Astrocytes/*metabolism</keyword><keyword>*BrainIschemia/metabolism/pathology/physiopathology</keyword><keyword>Humans</keyword><keyword>Models,Biological</keyword><keyword>SignalTransduction/*physiology</keyword></keywords><dates><year>2007</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1097-6256(Print) 1097-6256</isbn><accession-num>17965658</accession-num><urls></urls><electronic-resource-num>10.1038/nn2004</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[41]，這會(huì)造成細(xì)胞和代謝功能的一系列失衡，導(dǎo)致血腦屏障破壞ADDINEN.CITE<EndNote><Cite><Author>Warach</Author><Year>2004</Year><RecNum>155</RecNum><DisplayText><styleface="superscript">[42]</style></DisplayText><record><rec-number>155</rec-number><foreign-keys><keyapp="EN"db-id="22x9t9xporwr26e5stuvres4d0d025wf90r0"timestamp="1617029655">155</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Warach,S.</author><author>Latour,L.L.</author></authors></contributors><auth-address>NationalInstituteofNeurologicalDisorders&Stroke,10CenterDrive,MSC1063,Building10,RoomB1D733,Bethesda,MD20892-1063,USA.warachs@</auth-address><titles><title>Evidenceofreperfusioninjury,exacerbatedbythrombolytictherapy,inhumanfocalbrainischemiausinganovelimagingmarkerofearlyblood-brainbarrierdisruption</title><secondary-title>Stroke</secondary-title><alt-title>Stroke</alt-title></titles><periodical><full-title>Stroke</full-title><abbr-1>Stroke</abbr-1></periodical><alt-periodical><full-title>Stroke</full-title><abbr-1>Stroke</abbr-1></alt-periodical><pages>2659-61</pages><volume>35</volume><number>11Suppl1</number><edition>2004/10/09</edition><keywords><keyword>*Blood-BrainBarrier</keyword><keyword>BrainIschemia/*drugtherapy/physiopathology</keyword><keyword>CerebralHemorrhage/etiology</keyword><keyword>FibrinolyticAgents/*adverseeffects</keyword><keyword>Humans</keyword><keyword>MagneticResonanceImaging</keyword><keyword>ReperfusionInjury/*physiopathology</keyword><keyword>ThrombolyticTherapy/*adverseeffects</keyword></keywords><dates><year>2004</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0039-2499</isbn><accession-num>15472105</accession-num><urls></urls><electronic-resource-num>10.1161/01.Str.0000144051.32131.09</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[42]。此外，缺血造成劇烈的急性炎癥反應(yīng)ADDINEN.CITE<EndNote><Cite><Author>Komotar</Author><Year>2008</Year><RecNum>156</RecNum><DisplayText><styleface="superscript">[43]</style></DisplayText><record><rec-number>156</rec-number><foreign-keys><keyapp="EN"db-id="22x9t9xporwr26e5stuvres4d0d025wf90r0"timestamp="1617029718">156</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Komotar,R.J.</author><author>Kim,G.H.</author><author>Otten,M.L.</author><author>Hassid,B.</author><author>Mocco,J.</author><author>Sughrue,M.E.</author><author>Starke,R.M.</author><author>Mack,W.J.</author><author>Ducruet,A.F.</author><author>Merkow,M.B.</author><author>Garrett,M.C.</author><author>Connolly,E.S.</author></authors></contributors><auth-address>DepartmentofNeurologicalSurgery,ColumbiaUniversity,NewYork,NY10032,USA.</auth-address><titles><title>Theroleofcomplementinstroketherapy</title><secondary-title>AdvExpMedBiol</secondary-title><alt-title>Advancesinexperimentalmedicineandbiology</alt-title></titles><periodical><full-title>AdvExpMedBiol</full-title><abbr-1>Advancesinexperimentalmedicineandbiology</abbr-1></periodical><alt-periodical><full-title>AdvExpMedBiol</full-title><abbr-1>Advancesinexperimentalmedicineandbiology</abbr-1></alt-periodical><pages>23-33</pages><volume>632</volume><edition>2008/11/26</edition><keywords><keyword>BrainIschemia/physiopathology</keyword><keyword>ComplementSystemProteins/*therapeuticuse</keyword><keyword>Humans</keyword><keyword>Inflammation/drugtherapy</keyword><keyword>Neurons/pathology</keyword><keyword>ReperfusionInjury/drugtherapy/physiopathology</keyword><keyword>Stroke/*drugtherapy</keyword></keywords><dates><year>2008</year></dates><isbn>0065-2598(Print) 0065-2598</isbn><accession-num>19025111</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[43]，進(jìn)一步破壞了正常的腦血管解剖結(jié)構(gòu)和生理機(jī)能，導(dǎo)致血管壁的通透性大大增加，使得血液外滲。另外，研究表明，出血性轉(zhuǎn)化與基底膜（細(xì)胞外基質(zhì)）的降解相關(guān)，其機(jī)制尚未明確，可能與細(xì)胞外基質(zhì)蛋白質(zhì)水解失調(diào)有關(guān)ADDINEN.CITE<EndNote><Cite><Author>Wang</Author><Year>2003</Year><RecNum>157</RecNum><DisplayText><styleface="superscript">[44]</style></DisplayText><record><rec-number>157</rec-number><foreign-keys><keyapp="EN"db-id="22x9t9xporwr26e5stuvres4d0d025wf90r0"timestamp="1617029775">157</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Wang,X.</author><author>Lo,E.H.</author></authors></contributors><auth-address>NeuroprotectionResearchLaboratory,DepartmentsofNeurologyandRadiology,MassachusettsGeneralHospital,Boston,MA.Wangxi@</auth-address><titles><title>Triggersandmediatorsofhemorrhagictransformationincerebralischemia</title><secondary-title>MolNeurobiol</secondary-title><alt-title>Molecularneurobiology</alt-title></titles><periodical><full-title>MolNeurobiol</full-title><abbr-1>Molecularneurobiology</abbr-1></periodical><alt-periodical><full-title>MolNeurobiol</full-title><abbr-1>Molecularneurobiology</abbr-1></alt-periodical><pages>229-44</pages><volume>28</volume><number>3</number><edition>2004/01/08</edition><keywords><keyword>Animals</keyword><keyword>Apoptosis/physiology</keyword><keyword>Blood-BrainBarrier/physiology</keyword><keyword>BrainIschemia/*complications/*physiopathology</keyword><keyword>CerebralHemorrhage/*etiology/*physiopathology</keyword><keyword>ExtracellularFluid/metabolism</keyword><keyword>Humans</keyword><keyword>InflammationMediators/metabolism</keyword><keyword>Microcirculation/metabolism/pathology/physiopathology</keyword><keyword>ReperfusionInjury/etiology/physiopathology</keyword></keywords><dates><year>2003</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0893-7648(Print) 0893-7648</isbn><accession-num>14709787</accession-num><urls></urls><electronic-resource-num>10.1385/mn:28:3:229</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[44]，腦缺血的動(dòng)物模型中發(fā)現(xiàn)，腦缺血發(fā)作后，幾種基質(zhì)金屬蛋白（matrixmetalloproteinase，MMP）的表達(dá)顯著增加ADDINEN.CITEADDINEN.CITE.DATA[45,46]，MMP可降解血管細(xì)胞外基質(zhì)，削弱血管，使其易于滲漏和破裂ADDINEN.CITEADDINEN.CITE.DATA[47]，從而導(dǎo)致出血性轉(zhuǎn)化的發(fā)生。腦微血管是缺血性損傷的重要靶點(diǎn)，也是血液滲漏的主要部位ADDINEN.CITE<EndNote><Cite><Author>Wang</Author><Year>2003</Year><RecNum>157</RecNum><DisplayText><styleface="superscript">[44]</style></DisplayText><record><rec-number>157</rec-number><foreign-keys><keyapp="EN"db-id="22x9t9xporwr26e5stuvres4d0d025wf90r0"timestamp="1617029775">157</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Wang,X.</author><author>Lo,E.H.</author></authors></contributors><auth-address>NeuroprotectionResearchLaboratory,DepartmentsofNeurologyandRadiology,MassachusettsGeneralHospital,Boston,MA.Wangxi@</auth-address><titles><title>Triggersandmediatorsofhemorrhagictransformationincerebralischemia</title><secondary-title>MolNeurobiol</secondary-title><alt-title>Molecularneurobiology</alt-title></titles><periodical><full-title>MolNeurobiol</full-title><abbr-1>Molecularneurobiology</abbr-1></periodical><alt-periodical><full-title>MolNeurobiol</full-title><abbr-1>Molecularneurobiology</abbr-1></alt-periodical><pages>229-44</pages><volume>28</volume><number>3</number><edition>2004/01/08</edition><keywords><keyword>Animals</keyword><keyword>Apoptosis/physiology</keyword><keyword>Blood-BrainBarrier/physiology</keyword><keyword>BrainIschemia/*complications/*physiopathology</keyword><keyword>CerebralHemorrhage/*etiology/*physiopathology</keyword><keyword>ExtracellularFluid/metabolism</keyword><keyword>Humans</keyword><keyword>InflammationMediators/metabolism</keyword><keyword>Microcirculation/metabolism/pathology/physiopathology</keyword><keyword>ReperfusionInjury/etiology/physiopathology</keyword></keywords><dates><year>2003</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0893-7648(Print) 0893-7648</isbn><accession-num>14709787</accession-num><urls></urls><electronic-resource-num>10.1385/mn:28:3:229</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[44]，在局灶性腦缺血實(shí)驗(yàn)中，腦微血管的基底膜顯著喪失，結(jié)果顯示，血管壁完整性的喪失與點(diǎn)狀出血的發(fā)生有關(guān)，這種微血管損傷的機(jī)制可能包括纖溶酶產(chǎn)生的層粘連蛋白降解、基質(zhì)金屬蛋白酶的大量激活、白細(xì)胞通過血管壁的遷移等ADDINEN.CITE<EndNote><Cite><Author>Hamann</Author><Year>1999</Year><RecNum>160</RecNum><DisplayText><styleface="superscript">[48]</style></DisplayText><record><rec-number>160</rec-number><foreign-keys><keyapp="EN"db-id="22x9t9xporwr26e5stuvres4d0d025wf90r0"timestamp="1617030053">160</key></for