《急性脑梗死出血性转化的危险因素研究的国内外文献综述》7300字

急性脑梗死出血性转化的危险因素研究的国内外文献综述目录TOC\o"1-2"\h\u21710急性脑梗死出血性转化的危险因素研究的国内外文献综述 1259191.1.1出血性转化的定义 1222571.1.2出血性转化的流行病学 1144621.1.3出血性转化的分类 2206991）出血性脑梗死（HI）和脑实质血肿（PH） 3281322）症状性脑出血(sICH)和无症状性脑出血 3196763）早期和晚期出血性转化 452301.1.4出血性转化的病理生理机制 4154171）缺血损伤 514132）再灌注损伤 5294523）凝血功能紊乱 5276204）血脑屏障破坏 69222参考文献 8出血性转化的定义Fisher和Adams于1951年首次明确地提出了脑梗死后出血性转化的基本概念ADDINEN.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]，出血性转化是指急性脑梗死发生后缺血区内恢复血流灌注而引起的出血，它既是脑梗死自然病演变的组成部分，也是采取干预措施（溶栓、抗凝、抗血小板、介入等治疗）后的风险之一，目前常采用的定义是：脑梗死发生后第一次行颅脑CT或MRI检查时并未发现有脑内出血，而再次检查时发现有脑内出血ADDINEN.CITEADDINEN.CITE.DATA[18]，或根据首次头颅CT或MRI就可以确诊梗死合并出血ADDINEN.CITEADDINEN.CITE.DATA[19]。出血性转化的流行病学出血性转化的流行病学由于各研究在研究设计、研究对象及出血性转化的定义等方面存在一定的差异，所得到的出血性转化的发生率有所不同。自发性出血性转化在尸检研究中的发生率介于38%至71%之间，而CT检出率在13%至43%之间，其中症状性颅内出血（symptomaticintracranialhemorrhage，sICH）约占0.6%至20%ADDINEN.CITEADDINEN.CITE.DATA[20,21]。一项队列研究发现，出血性脑梗死型(hemorrhagicinfarction，HI）的发生率高于脑实质血肿型（parenchymalhemorrhage，PH），HI的发生率约为9%，而PH的发生率约为3%ADDINEN.CITEADDINEN.CITE.DATA[22]，PH2型与早期恶化和3个月死亡率相关，但PH1或HI型与其无明显相关性ADDINEN.CITEADDINEN.CITE.DATA[23]。早期的一项系统评价表明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]，在未经任何治疗的患者中，CT扫描发现的HT的发生率约7%到10%，sICH约占1%到2%。当患者使用阿司匹林和肝素治疗时，这一比例增加到约8%到22%，sICH的风险相应增加(2%到9%)，溶栓治疗发生HT的风险最大，其比例为10%至48%，发生sICH的比例为1%至20%。其中，rt-PA静脉溶栓最令人担心的并发症是sICH，其发病率高且死亡率接近50％ADDINEN.CITEADDINEN.CITE.DATA[11]。但是一些主要的溶栓试验报告的发生率仅为0.6％至7％，这很可能是由于使用了严格的纳入标准ADDINEN.CITEADDINEN.CITE.DATA[24-26]。在NINDS溶栓试验中，急性脑梗死患者使用rt-PA静脉溶栓后有3%的患者出现无症状性颅内出血（asymptomaticintracranialhemorrhage），6%的患者在前36小时内出现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试验中，rt-PA组的脑出血发生率达到27%，其中sICH发生率为2.4%。在第三次国际中风试验(IST-3)中，rt-PA治疗使sICH病例数量显著增加7倍，致命性sICH病例增加8倍ADDINEN.CITEADDINEN.CITE.DATA[28]。2012年，Wardlaw等人对ACI患者静脉注射rt-PA的12项RCT进行荟萃分析发现，sICH发生率为7.7%，致命性HT的发生率为3.6%，表明溶栓后早期死亡与致命脑出血之间存在强烈关联ADDINEN.CITEADDINEN.CITE.DATA[29]。一项对7项临床试验的荟萃分析显示，在急性心源性脑卒中发作后48小时内开始使用抗凝剂或抗血小板药物治疗，接受抗凝的患者出血性转化的风险增加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]。机械性血栓切除术(MT)已成为治疗急性缺血性卒中(AIS)合并大血管闭塞(LVO)的标准方法ADDINEN.CITEADDINEN.CITE.DATA[31,32]，在最近的荟萃分析中，Sadeh-Gonik等人发现，无论是否联合静脉溶栓，机械取栓术后脑出血和症状性出血的发生率分别为24％和8％ADDINEN.CITEADDINEN.CITE.DATA[33]。一项多中心的前瞻性研究表明ADDINEN.CITEADDINEN.CITE.DATA[34]，连续前循环串联大血管闭塞性卒中患者接受血栓切除术后，24.7%发生HI型出血性转化，14.2%发生PH型出血转化，未发现HI型对90天临床结果的不利影响，而PH的发生与死亡率的增加显著相关。出血性转化的分类急性脑梗死后HT的分类在各个研究中有所不同，并且不是CT或MRI检测到的颅内出血都会使神经症状恶化并损害预后。因此，脑梗死和再灌注治疗后的颅内出血根据影像学特征和与临床恶化的相关性进行分类。单纯的放射学分类使用出血的部位、形式和程度及其与缺血性损伤的关系来区分不同的出血亚型，这些亚型可能在神经功能损害和预后方面有所不同。混合放射学-临床分类在放射学发现脑出血的基础上增加了临床症状，将脑梗死后出血型转化按照有无临床神经功能恶化可以分为症状性的脑出血和无症状性的脑出血。1）出血性脑梗死（HI）和脑实质血肿（PH）目前最常用的分类方法是ECASS分型，它纯粹是放射学的分类，其包括HI型和PH型，HI型又分为两种亚型（HI1型和HI2型），PH型也分为两种亚型（PH1型和PH2型），如图1-1ADDINEN.CITEADDINEN.CITE.DATA[35]。在CT上，具体的影像学表现见表1-1ADDINEN.CITEADDINEN.CITE.DATA[36]表1-1ECASS分型-出血性转化的分类分型说明HI1型梗死灶局部存在小的瘀点HI1型局部存在更多的融合性瘀斑而无占位效应PH1型梗死组织内血肿体积小于30%梗死体积，无大的占位效应PH2型血应图1-1出血性转化的影像学分型2）症状性脑出血(sICH)和无症状性脑出血根据有无临床神经功能恶化分为症状性脑出血和无症状性脑出血，sICH通常与急性脑梗死治疗相关，是HT的一个亚型，具有最显著的临床后果。sICH中的分类方案有助于预测临床预后和指导治疗。sICH的定义来源于欧洲和美国的主要溶栓试验，所有这些试验都要求在溶栓治疗后的脑CT上存在出血表现ADDINEN.CITEADDINEN.CITE.DATA[23,37]。具体定义见表1-2。表1-2症状性颅内出血（sICH）的定义临床研究CT扫描时间定义NINDS发病24小时，7-10天或临床症状提示有出血时随时扫描以前的CT扫描中没有发现出血，随后怀疑出血或神经功能减退ECASSII治疗后22-36h，7天或临床症状加重时CT上任何部位的出血，NIHSS评分增加≥4分ECASSIIICT或MRI治疗后22-36小时扫描任何出血+NIHSS评分增加≥4分或死亡,明确出血是病情恶化的主要原因SITS-MOST治疗后22-36小时表现为PH2型，并伴有神经功能恶化，NIHSS评分增加≥4分3）早期和晚期出血性转化HT是脑梗死自然史的一部分，其发生时间差异很大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]，人们对与急性脑梗死迟发性HT相关的因素了解甚少，可能由治疗干预导致的HT往往在可预测的时间内发生。根据HT的发生时间是否超过24小时，将它分为早期和晚期出血性转化。如NINDSrt-PA试验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均发生在该时间段内，80％发生在治疗后12h内。当急性脑梗死患者接受静脉抗凝治疗时，HT发生的时间会延迟，这种时机的差异可能取决于达到抗凝作用所需的时间，尤其在使用普通肝素时，若在治疗开始时未选择静脉注射，则其抗凝作用会延迟1至2小时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]。在得出治疗干预对HT时机的影响的结论时，应考虑一系列影响HT影像学检查时机的因素,这些因素包括在临床试验干预后的特定时间、临床神经功能恶化后或在HT自然史观察研究的任意间隔后行影像学检查，检测的时机还受所用成像方式（例如带有或不带有梯度回波或磁敏感加权成像序列的CT或MRI）的准确性的影响，这些序列对出血的检测更为敏感ADDINEN.CITEADDINEN.CITE.DATA[40]。出血性转化的病理生理机制HT是一种动态和复杂的现象，其病理生理学尚不清楚，它的发生发展需要多个相互关联的病理过程，目前认为可能由血脑屏障（bloodbrainbarrier,BBB）破坏，凝血功能紊乱和缺血再灌注损伤等介导。1）缺血损伤在脑缺血发作后的早期，细胞内ATP水平大幅下降，从而严重损害了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]，这会造成细胞和代谢功能的一系列失衡，导致血脑屏障破坏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，缺血造成剧烈的急性炎症反应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]，进一步破坏了正常的脑血管解剖结构和生理机能，导致血管壁的通透性大大增加，使得血液外渗。另外，研究表明，出血性转化与基底膜（细胞外基质）的降解相关，其机制尚未明确，可能与细胞外基质蛋白质水解失调有关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]，脑缺血的动物模型中发现，脑缺血发作后，几种基质金属蛋白（matrixmetalloproteinase，MMP）的表达显着增加ADDINEN.CITEADDINEN.CITE.DATA[45,46]，MMP可降解血管细胞外基质，削弱血管，使其易于渗漏和破裂ADDINEN.CITEADDINEN.CITE.DATA[47]，从而导致出血性转化的发生。脑微血管是缺血性损伤的重要靶点，也是血液渗漏的主要部位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]，在局灶性脑缺血实验中，脑微血管的基底膜显著丧失，结果显示，血管壁完整性的丧失与点状出血的发生有关，这种微血管损伤的机制可能包括纤溶酶产生的层粘连蛋白降解、基质金属蛋白酶的大量激活、白细胞通过血管壁的迁移等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