1、Introduction,Percutaneous ASD closure (1974, King)Closure of atrial septal communications,ASD and PFOfrom an open surgical technique to percutaneous, catheter-based, closure devices,Currently available devices within the United States for percutaneous closure of atrial-level defects within randomize
2、d controlled trials,Interventional Catheterization in Adult Congenital Heart Disease. Circulation 2007; 115;1622-1633,Complications can be unknown or under-estimated prior to general userelatively small and carefull selected patient populationshort duration of follow-uplimited indications,To review
3、the rate of rare, but potentially serious complications highlighted 3 major complicationsdevice embolization (EM)device erosion (ER)thrombus formation,Device embolization,Embolization rate AGA device 0.5%,70% of the devices successfully retrieved percutaneouslyNMT device 4% in European studies12% wo
4、rld-wide.,Levi DS, Moore JW. Embolization and retrieval of the amplatzer septal occluder. Catheter Cardiovasc Interv. 2004;61:543547,Device erosion,NMT devicesonly 1 case reportAGA devices Numerous case reports In the United Statesestimated 9000 implants, 14 events were reported with confirmed erosi
5、ons and 3 deaths 0.1% incidence of this complication, but a 20% mortality risk with it occurs,Jeffrey W. Delaney, MD, Jennifer S. Li, MD, and John F. Rhodes, Congenit Heart Dis,2007,2:256264.,2-D and color Doppler TTE views of Aorto-atrial fistula. Am J Cardiol. 96: 16071609,Intraoperative photo, AG
6、A device in place and arrow to fistula. Am J Cardiol.96: 16071609,Thrombus formation,ASD/PFO封堵器血栓形成的临床诊断,封堵器血栓形成临床诊断主要依靠超声心动图，特别是经食管超声心动图（TEE）超声心动图特征为封堵器表面新出现的非平面性异常回声，并且该结构部分可随血流而飘动,Figure ATransesophagealechocardiographyfour-chamberview:left-sided mobile thrombus attached to a StarFLEX occluder de
7、tected four Weeks after catheter closure.Figure BTransesophagealechocardiography short axis: right-andleft-sided immobile thrombus surrounding an ASDOSOccluder detected four weeks after catheter closure. Figure C Transesophageal echocardio-graphy short-axis: large mobile thrombus (3018mm) Attached t
8、o the right atrial wall (without direct contact to the ASDOS device) detected one year after catheter closure.,J Am Coll Cardiol,2004,43:302-309,FigureA short transesophageal view of small mobile left-sided thrombion a StarFLEX occluder. During surgery,the absence of the left-sided thrombi. But dete
9、ction of a right-sided thrombus (8mm) not diagnosed before was removed together with the device.,J Am Coll Cardiol,2004,43:302-309,对成人患者，无论超声声窗条件，应常规进行经TEE检查，分别在术后4周、6个月、12个月进行对儿童患者随访，经胸超声心动图（TTE）已足够,ASD/PFO封堵器血栓形成的发生率,不同种类ASD/PFO封堵器血栓形成的发生率 La Rosee等描述38例ASD患者有3例（10.5%）血栓形成，60例PFO患者有8例（13.3 %）血栓形成L
10、ambert V等报道使用ASDOS封堵器139名患者中有9名血栓形成，血栓发病率6.5%Buttoned封堵器27名患者中有3名血栓形成，血栓发病率11.1%,表1 单中心不同类型封堵器术后4周和6个月时TEE检出血栓情况,J Am Coll Cardiol,2004,43:302-309,Amplatzer与CardioSEAL、Star FLEX 、PFO-Star之间血栓形成率有显著性差异（p0.05）（资料来自Cardiovascular Center Frankfurt,SanktKatharinen, Frankfurt, Germany）,最近Jeffrey 等为了回顾美国FD
11、A从2002年开始准入的种ASD/PFO封堵器（AGA和NMT）严重并发症发生情况搜索了2002-2004年MEDLINE和MAUDE的AGA和NMT公司的ASD/PFO封堵器的严重并发症文献与数据库资料 (MAUDE:制造商和用户的器械使用状况数字库),（资料来自Congenit Heart Dis. 2007;2:256264）,MEDLINE search,using the MeSH terms“Atrial septal defect closure,” “Amplatz,” “Device closure,” and “CardioSEAL”identified potential
12、 studies covering the 3-year period of device usage to be analyzedWe limited our search to articles written in Englishconcentrated on the larger case series, given that this would provide a more accurate complication rate. A total of 12 publications were selected reviewed for the incidence, type, an
13、d outcome of device closure complications,结果发现封堵器血栓形成及由此而引起的血栓栓塞是三大严重并发症之一在MAUDE中NMT公司的Star- FLEX及CardioSEAL，推算的发生率为0.2%AGA公司产的ASO仅为0.06%。MEDLINE文献中NMT公司的封堵器血栓形成发生率为： Star- FLEX5.7%、CardioSEAL7.122%AGA公司产的ASO仅了例,表2 美国FDA的MAUDE数据库(2002-2004年)两种封堵器并发症报告对比,EM, 封堵器栓塞/移位脱落； ER, 封堵器磨蚀心脏/心包积液； TE, 血栓栓塞；AR,
14、 心律失常；CVA, 脑卒中Amplatzer(R) Atrial Septal Occluder(ASO) (AGA Medical Corp., Golden Valley, MN, USA)CardioSEAL(R) Septal Occluder (CS) (NMT Medical, Inc., Boston, MA, USA)*来自厂家公布的数据，来自厂家内部的数据,表3 MEDLINE相关文献报道的并发症汇总,ASD/PFO封堵器血栓形成的临床危险因素,术前患者的临床因素Krumsdorf等大样本的临床研究表明，合并有心房颤动或房间隔瘤是ASD和PFO封堵术患者房间封堵器血栓形成最
15、显著的危险因素患者年龄、性别、合并凝血异常、冠心病、糖尿病或高血压均未发现与封堵器血栓形成有关患者术后有关因素术后预防感染使用的抗生素品种、术后残余分流及装置断裂等与封堵器血栓形成亦无关,表 单中心ASD/PFO封堵器血栓形成的潜在危险因素分析,封堵器血栓形成的临床转归,Krumsdorf等报道1000例ASD和PFO封堵术后出现封堵器血栓形成的病人20例17例患者血栓于周至个月内通过内科治疗溶解12例接受华法林，1例接受肝素，4例接受肝素和华法林3例需行外科摘除 1例患者的血栓粘附于Amplatzer伞的左侧面1例患者血栓粘附于Star- FLEX伞的右侧面例患者大血栓粘附于右房侧壁 (AS
16、DOS ),J Am Coll Cardiol 2004;43:3029,Thrombus on a CardioSeal occluder Left atrial thrombus formation was detected at 1 month follow-up in a 45 year old male without thrombophilia under an anticoagulation therapy with coumadine (arrow). After a short period of intravenously administered heparin, ant
17、icoagulation was changed to ASA plus Clopidogrel. At 2 months follow-up thrombus size had clearly regressed (arrows) and after additional 4 weeks it had completely resolved. (Current Pharmaceutical Design, 2006, 12, 1287-1291),images of large mobile thrombi on the left atrial (upper panel) and the r
18、ight atrial surface (lower panel) of a StarFlex occluder in a 47 year-old female2 months after implantation. Thrombus size had increased despite broad antithrombotic regimen using a combination of anticoagulant therapy (coumadine), ASA plus Clopidogrel. The occluder was explanted surgically 9 weeks
19、after implantation before an embolisation occurred.,迟发性血栓形成Krieg等报道1例62岁男性以Amplatzer进行PFO封堵术后8月时出现双下肢小腿动脉栓塞，随后并发急性心肌梗死，造影发现右侧冠状动脉血栓闭塞，超声心动图发现封堵器的左房面血栓形成，脑CT发现急性缺血性病灶。随即急诊取出封堵器及血栓，封闭PFO，并行冠脉搭桥术，后该病人病情好转出院Kawalsky 等报道1例29岁女性以Amplatzer行继发孔房缺封堵术2年后出现多发的大脑、小脑和脑干的栓塞，紧急予动脉内溶栓治疗而疗效欠佳，后经TEE发现封堵器的左房面有一巨大血栓形成，
20、这是迄今为止报道的第1例术后出现迟发的广泛脑栓塞形成病例,二、封堵器血栓形成的机制,封堵术后患者的凝血激活与植入封堵器的内皮化有关 动物实验研究发现，通常封堵器植入后一个月开始内皮化，三个月后则全部被内皮细胞覆盖 临床研究发现，封堵术后患者的凝血系统的活性曾一度增高,术后3个月时降至正常水平有报道Amplatzer封堵器的镍钛合金和聚酯纤维暴露于血液中时都会诱导血小板活性和凝血系统活性的增强,International Journal of Cardiology 98(2005)107112,International Journal of Cardiology 98(2005)107112,
21、内皮细胞是一个分泌多种活性物质的器官，封堵器表面内皮化初期，可能表达组织因子从而启动凝血过程，内皮下基底膜的暴露可促使血小板粘附和聚集，激活的血小板为凝血过程提供了反应平台(血小板第3因子)有报道认为，血流经过封堵器表面产生的湍流使凝血系统的活性增高。Josep Rodes-Cabau等13发现术后残余分流的存在亦提高凝血系统的活性。,防止封堵器血栓形成的临床策略,封堵术后随访,术后4周、6个月、12个月进行 TEE (成人)TTE(儿童 ),药物,血小板活化和凝血酶原激活是血栓形成中两个关键环节目前国内外在ASD/PFO封堵术后预防血栓形成主要是针对这两个环节即抗血小板治疗和抗凝血酶治疗,A
22、SD/PFO封堵术后预防封堵器血栓形成临床用药方案尚存在较大差异封堵术后预防封堵器血栓形成临床用药方案主要基于不多的生物学依据缺乏循证医学证据支持尚无前瞻性试验证明抗凝血酶和抗血小板哪种方案更理想 大多是基于临床试验的方案,常见方案有ASD封堵术后给予口服抗凝血酶药华法林，维持国际标准化比值（INR）在23之间ASD封堵术前即开始口服抗血小板聚集药，阿司匹林 35mg.kg-1.d-1至术后36个月ASD封堵术前即开始，先以阿司匹林(35mg.kg-1.d-1)联合氯吡格雷(75mg/d)口服68周甚至更长时间，再单独口服阿司匹林(35mg.kg-1.d-1)至术后6个月PFO封堵术后阿司匹林
23、联合氯吡格雷口服共6个月,国内先天性心脏病经导管介入治疗指南推荐ASD封堵术后肝素抗凝24小时按小儿35mg.kg-1.d-1及成人3mg.kg-1.d-1口服阿司匹林6个月对封堵器直径30mm成人酌情加服氯吡格雷75mg/d,尚无前瞻性试验证明抗凝血酶和抗血小板哪种方案更理想 1000例ASD/PFO封堵术资料回顾显示，980例无血栓形成患者中10%(95例)接受华法林治疗51%(505例)接受阿司匹林治疗39%(380例)接受阿司匹林联合氯吡格雷治疗20例血栓形成患者中15%(3例)口服华法林30%(6例)口服阿司匹林55%(11例)口服阿司匹林和氯吡格雷校正数据后不同用药方案血栓发生率差异无统计学意义,J Am Coll Cardiol 2004;43:3029,Cetta F报道1例以CardioSEAL成功进行PFO封堵病人，尽管服用华法林,INR达到22.8,排除合并凝血障碍性疾病及残余分流和心律失常,仍然形成了巨大的封堵器左房面血栓,Catheter Cardiovasc Interv,2003,59:396-398.,
