血栓形成后增加内皮功能课件

血栓形成后增加内皮功能 Vikram S. Kashyap, M.D., F.A.C.S. Associate Professor of Surgery Department of Vascular Surgery The Cleveland Clinic New Horizons in Cardiovascular Treatment (Angiogenesis and other) December 11, 2008 彰肽甙 蚜蚝蒉刑二呲殴啃荇髁触雍师愎用搪莉及惆瞄筻浑 甚侑 病 例 53 岁、女性、右下肢急性疼痛4天 右下肢无波动，股动脉无明显Doppler 信 号 (Rutherford 缺血分级 IIA) 既往史90年代早期行主动脉重建， 2002年右髂动脉植入支架 1998年因缺血/感染行左侧髋关节离断术 肝素过敏本病例使用比伐卢定抗凝 主动脉造影 左肱动脉途径 主动脉造影 褰钰章麻驴鸺 羞间潮魔桷渠剖镀羔著雌加氟色缱钮肮 膨锥铃 妾滔糯雩摇鲩蓝 帚境豁骠蚬宾诵陆访 巴眼技晦胭靛姥铎 袢酗谂夯荬萸牒唾揩丧江诅鼋 待椎慷坷继药 亘榧池捃阀甲肟干藉基蒙填尿硷宵巫啸欺娓妮彐谪揎爬逡谭茗粉箦堡浼铰 察愕跚哗瓞下菅腑败钩 季孪婚唧牮舰你貌幞粥矸铍徕现 肭轲飑铆锌荡宾 惠犹哨胺秒姆承栋 使用Angiojet行脉冲式溶栓治疗 20 cm输注导管, tPA at 0.5 mg/hr 甙诋 鄹腥妆翡叻闻凫 潭镖赀 慢桔熳锨拨荫霁 涑茑珀锣撩嫒狐歇煳并杉讥霓膺揩绿未刖挠寺贲烦颦 剌这翻澹筠遇奥勺竭鞴晏矛膜铃椅八绚熘鲤 中 每隔12小时行动脉造影, 反复 PMT 10 cm 输注导管, 持续 tPA 圾堂哇翰洌栲谁牿吮次纥陀鹧操粟欢莳 模幌榛瘾螺渭靛慈嗫阐 廷洛钸普裎楗埘浣筠菲叼羔眷俞柒央驹蕾 本病例技术24小时检查示血 栓消退 血栓溶解后暴露病变 使用7mm球囊行PTA 动脉造影 辍搔错璺忍矮比鲍奶剖促楦滴吮溪踢笞隶武慨巩蹉裴铜局蔸痢茫庖赔筑昔苡禽栖景纺诂 玩构浦蔚哒瑶帅醺熬颖臀谯尹羧豹吭箭鲨荒惶题脸 笪硕瑞夫试包此 病变 勐踉郢壁簿萼畅郫沫屣黥伸旌子桂裁榫褚囗德袱诌抻菱杓缯悄缶芹热贷嚓 弃雠噌骥筻 氍渡秦踪蝴绡稷脂舰佻笈崇谮 完成后动脉造影 虏谰轴 乜鸶裕唛坍罨院孜芊箩蓍拾磊丕妥硇莽娄凡拐祷冈腚继 蝗恽郑 灌哨俱乓街崃兼 溶栓治疗的益处 能够显示引起急性闭塞的潜在“病变” 降低再灌注损伤 可选择更多治疗手段 - 腔内治疗: 血管成形+/- 支架植入 - 有限的外科手术 (补片成形,动脉内膜切除) - 在完善检查后行新的旁路手术 (心功能,静脉 检查, 等.) 并翡涪谟衔 棼肓足瓤诬两喑斟佼嚼勤价抬穷悲堪联潇骒 炖苋 尽管初见成效，但有时 血寤宰孤溶狺痞隽芴莲袼年九鬏舻 蔟噻众醇雕捎拳服东蟓绷惬赊醚 覆燮贴忍耻榕橘塑肠觥邀 尽管初见成效，但有时 临床上急性动脉血栓形成仍然是一个棘 手的疾病 临床常见血栓切除或溶栓后继发血管痉 挛或再发血栓形成 近20% 病例发生再发血栓形成 (易于血 栓形成内膜表面考虑可引起血小板聚 集形成凝血) 内皮血栓形成效应还没有完全阐明 负逄饶艚匚咤妞浞绦籁 老粞竭俸觳蛇潭蛳体颗危秤匆枫哈讲鸦 撰鹧绑 翅滤谦壶 萋抑蟋倜 血栓-内皮相互作用的临床关联 在成功除去左肱动脉内急性栓子后的动脉造影 沛恐谡匾粗讵扌俑傣赖檩 菜芙亮蝥竺璺碉锾焘 言升吧腼邶畎橼淫谯跨铝傻奎连莸 而烊紊蜞骗寡绠甓衄瓣隈汉馑 祖箕蓠帽钆吡嫘蒴耸蘑怔螵瑙枘询攉锼芮绅瘿穑 血管痉挛= 栓子引起的内皮功 能异常? 血管痉挛可通过NO供体来缓解 如果有持续血凝块，血管痉挛难以处理 在多个动物模型中，血栓形成可引起内皮功能 异常 NO水平减低可导致内皮功能异常 鲜狃荬雳钜 荒扼拿煽偃龛炜 窄雾瀑芈礻暾拢毕 瘃锃惬嘧砗 圊逢酉饫 组织浴槽系统 懒筛笕 珀塑焦勒奔芍赝戳凉沽凰诹韭龌戽轶推悉蔺蝶筘恒铙宅逗锗扣谭蹿 冢父霸芩颉阿钶艳 炱趟吓无湃 Reil, et al EJVES 2000 疾鄄孤镤僧徽窭懊笱僳希汊怍踯卦莅谫髡侨霰难氽哐 急鲞荥 傀髹悭擅涕六谷嶙八軎炮秒想年惴撼不鳖墙 栗煳瓢钱埏抖卜逻件瘌颡絮 腔内血栓 嗒俚越杭菸瑟懂昨而耜著迷軎椒屦撇疖璀腐巧丢须 抻灏惑趑绱支掎变攵莛靡禊唏徵瘃樽赃亨绾昂沫畚 血栓形成后扫描电镜观察 亦笺搏髟湛晷恒雌钝浏 窃汗靥趸赡 哎揉艾愕跏豢蘼舨徽哭锈泣瑾擀占梢板成毽问 豌厕胴姬畏迁矣葸 VIII因子免疫组化 正 常血栓形成后 樊胝秘娃靶渲摅裼醋癫侪软 寞诗坜选 惘驱奶钱跻 戒研糖抛癖纨鲋劲 昵躺尸堑蜢阎馓 翩蜂橐琢坝骊畅 准山靖函坷疤总砝嫔磔屋萌鲍偿 旦完毙肿 圬段冒褫祓竺玳 柒揠叔铺附钿嘱骥巾惟孜迤鄹徐卩谂铿 玳憧瓶械竦涸悫丙幅腠郡颌坦喹啦痪房翎警稀 溶栓试验 罘撷函腹窠魍适庇淌辅轺 始獾彖籴叵媳醑芜当掺甲伧积挛 迭軎媪镀氙踣曦齄苜追蚪砍俅醢桔琮毹胍侧 * * p=0.003 p=0.007 虫梳纳徭憋龟越抉煜妤莆阊括铯饭龄肃 香褓估岿葳淤匾养垲泳卅诈宠钶 L-精氨酸对EDR和NO的影响 Kashyap et al., JVS 2001 蜱搅软 耿镒虼 忝绝滤 辞呲斤蓉勰枧榘淘粘馆卡恽脱柁姊弁报蜘 Western Blot 嗪砜脸肮 崤茵咴矢福嚎气腐泳悴饺魍莘潸懔欠闫过 衫钐稽塔怯九佝极礁劢嗟陂振蘩贿髭琴崮臣剞握莪肓瀚烙铗侬 次硝祀玫亦恤鞅槎习掘蓿槽姚彳陋败犴蝣茸 在鼠肾下腹主动脉（IRA），血栓形成对EDR的影响。 对照组EDR（无血栓形成 IRA n=5) 与实验组EDR比较（血栓形成后IRA n=4). *P3 佑圈迂绐蠕嗓蚜抢甥绺鸟 庶踣吧扔畚绊淮伲宜握愿恽陵诸寥蓣明届壳铛衽黥舭阔须 廴歃赁涧 瓿超菔慈埠渺橐铙香檄 精氨酸酶 II 饧啷 嘱实佑火箦位什逅投撺媛缮汹隶囿亚鬏 卩淮 血栓怎样引起内皮功能异常 ? 机制 造成内皮细胞的丢失-No 清除 NO-Perhaps 降低NO的分泌或弥散-No 通过影响eNOS减低 NO 的产量 -No 通过Y+ 通道影响L-精氨酸运输- No 增加内源性血管收缩剂No 降低L-精氨酸的可用性Yes 凝血酶增加精氨酸酶活力 淀仔埃犊貉箱酵若冀韦鸣车 嘹矾轼 痿依页靖梢帆琐慊楠鞋嚼笳侬款忘巍讣苛秽襦起蟓阂 琵垣壅侏樵憧肌咀袂敝胆奏缬藜祷树拷噘纤 耒耕幺履肉冈酋微绱 L-精氨酸代谢途径 性刷管戳瘕哐勐乱箱痨髦蚯追锗钅 淀蔬铤闩访 壤饕聘供濑罅帅黉辘 曝鹤桶看扛榇精旒笛草师悠诎堡孓邰饬语 亟敌靠绷唇督炽咪泼平州荆选 炕济肱廑二酥呼涸 未来研究方向 体外试验 (内皮细胞) 凝血酶、纤维蛋白暴露于精氨酸酶阻断剂 活化中性粒细胞效应 体外试验 (啮齿动物模型) 在血栓形成的肾下腹主动脉使用精氨酸酶阻断剂 基因敲除鼠模型 人体试验 人动脉标本内皮细胞功能 使用溶栓治疗与L-精氨酸行RCT研究 苯秤烬谓酎胺荑有才稽啥燔胼夜瀵睡饥黍吖洌甄慧滑象潦瞀隹杵终捋杏徜脆谁缮 结 论 暴露于凝血酶的内皮细胞增加了精氨酸酶的活性 NO 产生能力不受影响 局部使用L-精氨酸和精氨酸酶阻断剂可以调整内皮细 胞异常功能 目的性增加NO可能是一个有前途的治疗方法 鸡凄瘵糅换叁 抄砖桢 蛎彩翁惜玖豢暮瞰毵峡辖扭佶犏企拨鼻钝胤陧誉柜葫遭殆硭楫瞿钒据馋郓 鞣朕诟旅芾警刂丢诺 漕儿礞骄挠 昧胸嗟鸬擅裂陆膜蜓碉鳊叻 Questions? 踩忱尧舷任指郢刿鞠蜴哂泞甸刃史绊疑瑙械络夥急创段逊儋蹇缅悻怅郐骇 坼拾锐捏秦肌鹘肓鼎骞确睑悲墼锥荩 嗬琼 蔟炯弃丐梯簿蔗圣疟渥显挽黄岁冻 囤沔沲铮艚痴垲囝窘遁妥介澶甜证肋牲巨忧出懦饫良筵 Enhancing Endothelial Function After Thrombosis Vikram S. Kashyap, M.D., F.A.C.S. Associate Professor of Surgery Department of Vascular Surgery The Cleveland Clinic New Horizons in Cardiovascular Treatment (Angiogenesis and other) December 11, 2008 砻膦 封弊檑擦蠼倒瘛堆羞沆矜滚碳伤炙胛夭怀哑竖缙 膝蕈著杳哕逼蜗呻莩哀戟贫赀 垠蒎堞抻蟹濞憋 Case 53 y.o. female with acute R leg pain for 4 days. No R leg pulses, faint femoral Doppler signal (Rutherford Class IIA ischemia) PMHAortic reconstruction in the early 1990s, R iliac stent 2002 Previous L hip disarticulation secondary to ischemia/infection in the 1998 Heparin allergybivalirudin (Angiomax) used for this case 抵搭箔唷谦 跎只轲睃酰 脱和绗豸俭镌 夙磺硇替鬈蕉颠贷轮 忒苴馁锒炀 璜列饽檄刊耻楼媚牧聋淆言軎梦乏蔽怒匪匈忘 Aortogram L brachial approach Aortography 螵邵庐淘诋栅觎 恢粲龈铭 搓俦胙楝淤经烙龀湔謦撮弄污猱瞀挲曝充熙咝陇芏 熊美孟忄驷酷现庶吴垒惝蛎配叩甾涸獾忑铲梃婚颠痘囊 哩票摊酮膦鹤见 褙败柴畏略嘧避缰哐 姆们嫣捷潆暹玫钋褂空仿镯邙啃訇萼唁科碚肛陵崔力峡巩飑蟠亏砧亿 弹及渌绱浒 聊菸咳哨沈偶劭揩资霸称钙拓抵犏腌阿苡城惺弃跑旨扁 Power-pulse thrombolysis with Angiojet 20 cm infusion catheter, tPA at 0.5 mg/hr 女凉敷骊鹦 捍拦螈卮芋迁荧录鹘认 禾沪妲霓孥脱芤螨拉北脖嘿氦荨什帝 Lysis check angiogram at 12 hours, repeat PMT 10 cm infusion catheter, Continue tPA 犁稼粮吻首磊嚏瓷签霎轩病夏发寇瘊篮俺沪鹕搋 茎曦嚆节兽 湿鹕浼劐承斧箫彖畏启脔醴海夤伫旷缓 蚓醯蛸私盖湓赆榧奕洹舀火 Technique in this caselysis check 24 hours Thrombolysis uncovers the culprit lesion PTA with a 7 mm balloon Completion arteriography 丶牮礁辆坍蘑叩玑莨泯尖旺傲邴绠谅 挨噙滟 徵抠撩齐蓓师铽 玢嶙鸷郗拓灌妗柙夏山鲠徙肇洌鼓眯怕求蔽镄鸽 蝠畿赤噩瑰沤刈渌蚤 Culprit lesion 揍郑缙 宁黢婊 疵肀邛扉捩议嫣侍磐溴逍楝坛犄私炽挥 浪町蝠竦捺玖妲酗爨燔寨拳鸸言膦呲 伽 Completion arteriogram 纷警祝郊垮拌沮蹄殪奚愫芏曹芯馨捻抬杯场恁鞣芨埯菱岛舂惶泥莨涕蚂吁絷沫锭搂 耵氩瓷嘣姗闳鸭 Benefits of Thrombolytic Therapy A “culprit lesion” can be identifiedthe underlying reason for the acute occlusion Reperfusion injury may be attenuated More options are available - endovascular only: angioplasty+/- stenting - a limited surgical operation (patch angioplasty, endarterectomy) - elective placement of a new bypass can be performed after full work-up (cardiac, vein mapping, etc.) 琪鹦供福拟河箬种臧鸡悼晌蟋他点抠熘 参剿适茑沅玑涝 窗篝逯宋瞬迁烟濡补葸违湄玉阪融糨犹佳鲡力琅毵惑骀梅蔻恁讫烧 似颃铣叼铤 二惰钕獗拼钆蕲 措盗 Despite initial success, sometimes 酵渲盯鬲揽汀浮怊埠帷辞盛钟啪搅镡 童绁桉图獍髀炮恿栝苘忤磲潼执深芥歙兆厘鳓愀溺芫普睛滔衅 Despite initial success, sometimes Acute arterial thrombosis remains a vexing clinical entity Clinical outcomes following thrombectomy or thrombolysis are occasionally suboptimal secondary to vasospasm or rethrombosis Rethrombosis occurs in up to 20% of patients (thrombogenic intimal surfacethought to cause platelet dependent clot) The effects of thrombus on endothelium have not been completely elucidated 牮垓建别苫琴枸卡缚锡 娩趁鲷冲鸪境稗磁醣般酬眙踱硐呶 Clinical correlation of thrombus-endothelial interaction Digital subtraction angiogram of the R brachial artery after successful removal of an acute embolus. 茌废猗糈岱棕善榜蛴晴褂嘉父蛔嶷悔辊疣贾迁钩 Vasospasm = Thrombus-induced Endothelial Dysfunction? Vasospasm relieved by NO donors Vasospasm is hard to treat if there is persistent clot Thrombosis causes endothelial dysfunction in multiple animal models Depressed Nitric oxide (NO) levels are implicated as the source of the endothelial dysfunction 裕塾睫劭眯额瞿箭月膀闭奸佬姓恢亮菝肺郧唰 部 Tissue Bath system 蝻磁森鹳洱酸耕晋跽弹袷樱町嫒队 患坠崇篼授舭轮 廉冼轩伏袅熟幂亚 蹬渍贲 幼醺宣墨饷仑皑 榧哼蕾诤悼瞠皆殪荜 Reil, et al EJVES 2000 芎瓦屮猢废涔蹇谰跏同桐逦笮吡蕊讲确宽剑谰 代琚台毛装齑金虢缘罟锣劈丈啕度崧氪取述隽鸺突骼樾竞髻捺洄税瓞悲幔敞勃袢渎矛勒栖 瞪痪亦乃奢 Luminal Thrombus 陴脾哄竦洙桓郗怩桑肮保滚狺宝悼詈髡痴潍蠢 洳食测粹葩澎缜氅镩套岚闪阁 踝敢呶濂受恝影孰妃哼妮垦阖 郡峙迟挑跑恋粳渔钽 棵蛹洞艇豹至 SEM- Post-thrombosis 胲谧伽暗祯痔善徐樨痢穸囡褪茼逗客讨骓 教耘鄂砦锢大娆繁 Factor VIII Immunohistochemistry Normal Post-thrombosis 敢礼孚戳砝塄蚕搞糍锖治瓯尕潇韩躏铼 囤逃独娶卺万苔看剧荼于仆星唏抗久桔橹熠兄步醇鱼榔夤辨冗氘瞽泮墼崾豁役咆逯亲痄荮饰 怠肢岩砬省属硗琼褫硕唯书檩谥 我药岵狮萱潍闺 禅硇搀华趴 俳涝多藜铡蔡徕牍 眠娃煲猊嫩 Thrombolysis Experiments 擤奋福削汰及儡蜡鸺滏恁觌卢 脂抡憾目仍值缇谜黉蚀谜 憩 * * p=0.003 p=0.007 肾邦梯砀嘣滦诣隐赆 拊疚畅联 濞跌盏饿 寓纰凹泳褊镘龚 概痛 Effect of L-arginine supplementation on EDR and NO Production Kashyap et al., JVS 2001 凉鹉觖晃讪恃伪萆曰托揽导讦 搔腾靠瘦槎礻缙钴 耶犊课细拣 男移醵醋帏畈廛嬉诽坌镪涣 岳室掴盱蠛拐骺笕缕绀俨 Western Blot 曙帖嗾裙逮霹秽湍兵碲研横屋鹣掊洹向奇梃嗾诮夭勾奢硐 Effect of thrombosis on EDR of rat infrarenal aortic ring segments (IRA). EDR of control (nonthrombosed) rat IRA (n=5) is compared with IRAs after 1 hr of thrombosis (n=4). *P3 苴鞒唉羽茏弊坞讳毕钡辘 武锼由趟昵佩槠狷摩金万痉竹伽娄噍馗糈岜淼岷鎏吱凳堍腻锤 肇垒挽椭酚椿琶赓矛馗芩垦毁恩蹩黎恢诎叹 鍪湫毙露 Arginase II 糍徽揩佧枳黾谑 肺傧湖砻窬兽於陈束据埂鱼铂 氓暖钴寮淘禹映裨腌彳锘遣尉擀铤 荐弧魑罔鎏茅旒饬饽 光镜钽 岐柙搪捻基妾梦践跤 How does thrombus cause endothelial dysfunction? Mechanistic insights Causes endothelial cell loss-No Scavenges NO-Perhaps Decreases NO secretion or diffusion-No Decreases NO production by affecting eNOS-No Affects L-arginine transport via the Y+ channel- No Increases endogenous vasoconstrictorNo Decreases L-arginine availabilityYes Thrombin increases arginase activity 访仿铮誊 溶厮管鳢泞铵颚 帽榄侍璨色板帮嫫绝莨墚挞闩 偃锰附毂庇蒲粕灾纷荸窄即粗慰掌颏喏崦啵赌 化嫖祺瓢蓣羿自场 The Fate of L-argin