封堵器血栓形成的認(rèn)識

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 with

2、in the United States for percutaneous closure of atrial-level defects within randomized controlled trials,Interventional Catheterization in Adult Congenital Heart Disease. Circulation 2007; 115;1622-1633,,?,Complicati

3、ons can be unknown or under-estimated prior to general userelatively small and carefull selected patient populationshort duration of follow-uplimited indications,,?,To review the rate of rare, but potentially serious

4、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 percu

5、taneouslyNMT device 4% in European studies1–2% world-wide.,Levi DS, Moore JW. Embolization and retrieval of the amplatzer septal occluder. Catheter Cardiovasc Interv. 2004;61:543–547,,?,Device erosion,NMT devicesonly

6、 1 case reportAGA devices Numerous case reports In the United Statesestimated 9000 implants, 14 events were reported with confirmed erosions and 3 deaths 0.1% incidence of this complication, but a 20% mortality risk

7、 with it occurs,Jeffrey W. Delaney, MD, Jennifer S. Li, MD, and John F. Rhodes, Congenit Heart Dis,2007,2:256–264.,,?,2-D and color Doppler TTE views of Aorto-atrial fistula. Am J Cardiol. 96: 1607–1609,Intraoperative ph

8、oto, AGA device in place and arrow to fistula. Am J Cardiol.96: 1607–1609,,?,Thrombus formation,,?,ASD/PFO封堵器血栓形成的臨床診斷,封堵器血栓形成臨床診斷主要依靠超聲心動圖，特別是經(jīng)食管超聲心動圖（TEE）超聲心動圖特征為封堵器表面新出現(xiàn)的非平面性異?；芈?，并且該結(jié)構(gòu)部分可隨血流而飄動,,?,Figure ATransesoph

9、agealechocardiographyfour-chamberview:left-sided mobile thrombus attached to a StarFLEX occluder detected four Weeks after catheter closure.Figure BTransesophagealechocardiography short axis: right-andleft-sided immo

10、bile thrombus surrounding an ASDOSOccluder detected four weeks after catheter closure. Figure C Transesophageal echocardio-graphy short-axis: large mobile thrombus (30×18mm) Attached to the right atrial wall (w

11、ithout 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. Duri

12、ng surgery,the absence of the left-sided thrombi. But detection of a right-sided thrombus (8mm) not diagnosed before was removed together with the device.,J Am Coll Cardiol,2004,43:302-309,,?,對成人患者，無論超聲聲窗條件，應(yīng)常規(guī)進(jìn)行經(jīng)TEE檢查，分

13、別在術(shù)后4周、6個月、12個月進(jìn)行對兒童患者隨訪，經(jīng)胸超聲心動圖（TTE）已足夠,,?,ASD/PFO封堵器血栓形成的發(fā)生率,不同種類ASD/PFO封堵器血栓形成的發(fā)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Lambert V等報(bào)道使用ASDOS封堵器139名患者中有9名血栓形成，血栓發(fā)病率6.5%Buttoned封堵器27名患者中有3名血栓形成，血栓

14、發(fā)病率11.1%,,?,表1 單中心不同類型封堵器術(shù)后4周和6個月時TEE檢出血栓情況,J Am Coll Cardiol,2004,43:302-309,,?,Amplatzer與CardioSEAL、Star FLEX 、PFO-Star之間血栓形成率有顯著性差異（p<0.05）（資料來自Cardiovascular Center Frankfurt,SanktKatharinen, Frankfurt, Germany

15、）,,?,最近Jeffrey 等為了回顧美國FDA從2002年開始準(zhǔn)入的２種ASD/PFO封堵器（AGA和NMT）嚴(yán)重并發(fā)癥發(fā)生情況搜索了2002-　2004年MEDLINE和MAUDE的AGA和NMT公司的ASD/PFO封堵器的嚴(yán)重并發(fā)癥文獻(xiàn)與數(shù)據(jù)庫資料 (MAUDE:制造商和用戶的器械使用狀況數(shù)字庫),（資料來自Congenit Heart Dis. 2007;2:256–264[７]）,,?,MEDLINE search,

16、using the MeSH terms“Atrial septal defect closure,” “Amplatz,” “Device closure,” and “CardioSEAL”identified potential studies covering the 3-year period of device usage to be analyzedWe limited our search to articles

17、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, and outcome of devi

18、ce closure complications,,?,結(jié)果發(fā)現(xiàn)封堵器血栓形成及由此而引起的血栓栓塞是三大嚴(yán)重并發(fā)癥之一在MAUDE中NMT公司的Star- FLEX及CardioSEAL，推算的發(fā)生率為0.2%AGA公司產(chǎn)的ASO僅為0.06%。MEDLINE文獻(xiàn)中NMT公司的封堵器血栓形成發(fā)生率為： Star- FLEX5.7%、CardioSEAL7.1–22%AGA公司產(chǎn)的ASO僅了１例,,?,表2 美國F

19、DA的MAUDE數(shù)據(jù)庫(2002-2004年)兩種封堵器并發(fā)癥報(bào)告對比,EM, 封堵器栓塞/移位脫落； ER, 封堵器磨蝕心臟/心包積液； TE, 血栓栓塞；AR, 心律失常；CVA, 腦卒中Amplatzer(R) Atrial Septal Occluder(ASO) (AGA Medical Corp., Golden Valley, MN, USA)CardioSEAL(R) Septal Occluder (CS) (N

20、MT Medical, Inc., Boston, MA, USA)*來自廠家公布的數(shù)據(jù)，?來自廠家內(nèi)部的數(shù)據(jù),,?,表3 　MEDLINE相關(guān)文獻(xiàn)報(bào)道的并發(fā)癥匯總,,?,,?,ASD/PFO封堵器血栓形成的臨床危險(xiǎn)因素,術(shù)前患者的臨床因素Krumsdorf等大樣本的臨床研究表明，合并有心房顫動或房間隔瘤是ASD和PFO封堵術(shù)患者房間封堵器血栓形成最顯著的危險(xiǎn)因素患者年齡、性別、合并凝血異常、冠心病、糖尿病或高血壓均未發(fā)現(xiàn)與封堵器

21、血栓形成有關(guān)患者術(shù)后有關(guān)因素術(shù)后預(yù)防感染使用的抗生素品種、術(shù)后殘余分流及裝置斷裂等與封堵器血栓形成亦無關(guān),,?,表４ 單中心ASD/PFO封堵器血栓形成的潛在危險(xiǎn)因素分析,,?,封堵器血栓形成的臨床轉(zhuǎn)歸,Krumsdorf等報(bào)道1000例ASD和PFO封堵術(shù)后出現(xiàn)封堵器血栓形成的病人20例17例患者血栓于４周至６個月內(nèi)通過內(nèi)科治療溶解12例接受華法林，1例接受肝素，4例接受肝素和華法林3例需行外科摘除 1例患者的血栓粘附于A

22、mplatzer傘的左側(cè)面1例患者血栓粘附于Star- FLEX傘的右側(cè)面１例患者大血栓粘附于右房側(cè)壁 (ASDOS ),J Am Coll Cardiol 2004;43:302–9,,?,Thrombus on a CardioSeal occluder Left atrial thrombus formation was detected at 1 month follow-up in a 45 year old

23、male without thrombophilia under an anticoagulation therapy with coumadine (arrow). After a short period of intravenously administered heparin, anticoagulation was changed to ASA plus Clopidogrel. At 2 months fol

24、low-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 (u

25、pper panel) and the right 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 combinat

26、ion of anticoagulant therapy (coumadine), ASA plus Clopidogrel. The occluder was explanted surgically 9 weeks after implantation before an embolisation occurred.,,?,遲發(fā)性血栓形成Krieg等報(bào)道1例62歲男性以Amplatzer進(jìn)行PFO封堵術(shù)后8月時出現(xiàn)雙下肢小腿動脈

27、栓塞，隨后并發(fā)急性心肌梗死，造影發(fā)現(xiàn)右側(cè)冠狀動脈血栓閉塞，超聲心動圖發(fā)現(xiàn)封堵器的左房面血栓形成，腦CT發(fā)現(xiàn)急性缺血性病灶。隨即急診取出封堵器及血栓，封閉PFO，并行冠脈搭橋術(shù)，后該病人病情好轉(zhuǎn)出院Kawalsky 等報(bào)道1例29歲女性以Amplatzer行繼發(fā)孔房缺封堵術(shù)2年后出現(xiàn)多發(fā)的大腦、小腦和腦干的栓塞，緊急予動脈內(nèi)溶栓治療而療效欠佳，后經(jīng)TEE發(fā)現(xiàn)封堵器的左房面有一巨大血栓形成，這是迄今為止報(bào)道的第1例術(shù)后出現(xiàn)遲發(fā)的廣泛腦栓塞

28、形成病例,,?,二、封堵器血栓形成的機(jī)制,封堵術(shù)后患者的凝血激活與植入封堵器的內(nèi)皮化有關(guān) 動物實(shí)驗(yàn)研究發(fā)現(xiàn)，通常封堵器植入后一個月開始內(nèi)皮化，三個月后則全部被內(nèi)皮細(xì)胞覆蓋 臨床研究發(fā)現(xiàn)，封堵術(shù)后患者的凝血系統(tǒng)的活性曾一度增高,術(shù)后3個月時降至正常水平有報(bào)道Amplatzer封堵器的鎳鈦合金和聚酯纖維暴露于血液中時都會誘導(dǎo)血小板活性和凝血系統(tǒng)活性的增強(qiáng),,?,International Journal of Cardiology 9

29、8(2005)107–112,,?,International Journal of Cardiology 98(2005)107–112,,?,內(nèi)皮細(xì)胞是一個分泌多種活性物質(zhì)的器官，封堵器表面內(nèi)皮化初期，可能表達(dá)組織因子從而啟動凝血過程，內(nèi)皮下基底膜的暴露可促使血小板粘附和聚集，激活的血小板為凝血過程提供了反應(yīng)平臺(血小板第3因子)有報(bào)道認(rèn)為，血流經(jīng)過封堵器表面產(chǎn)生的湍流使凝血系統(tǒng)的活性增高。Josep Rode´s-C

30、abau等[13]發(fā)現(xiàn)術(shù)后殘余分流的存在亦提高凝血系統(tǒng)的活性。,,?,防止封堵器血栓形成的臨床策略,,?,封堵術(shù)后隨訪,術(shù)后4周、6個月、12個月進(jìn)行 TEE (成人)TTE(兒童 ),,?,藥物,血小板活化和凝血酶原激活是血栓形成中兩個關(guān)鍵環(huán)節(jié)目前國內(nèi)外在ASD/PFO封堵術(shù)后預(yù)防血栓形成主要是針對這兩個環(huán)節(jié)即抗血小板治療和抗凝血酶治療,,?,ASD/PFO封堵術(shù)后預(yù)防封堵器血栓形成臨床用藥方案尚存在較大差異封堵術(shù)后預(yù)防封堵

31、器血栓形成臨床用藥方案主要基于不多的生物學(xué)依據(jù)缺乏循證醫(yī)學(xué)證據(jù)支持尚無前瞻性試驗(yàn)證明抗凝血酶和抗血小板哪種方案更理想 大多是基于臨床試驗(yàn)的方案,,?,常見方案有①ASD封堵術(shù)后給予口服抗凝血酶藥華法林，維持國際標(biāo)準(zhǔn)化比值（INR）在2～3之間②ASD封堵術(shù)前即開始口服抗血小板聚集藥，阿司匹林 3～5mg.kg-1.d-1至術(shù)后3～6個月③ASD封堵術(shù)前即開始，先以阿司匹林(3～5mg.kg-1.d-1)聯(lián)合氯吡格雷(75mg

32、/d)口服6～8周甚至更長時間，再單獨(dú)口服阿司匹林(3～5mg.kg-1.d-1)至術(shù)后6個月④PFO封堵術(shù)后阿司匹林聯(lián)合氯吡格雷口服共6個月,,?,國內(nèi)《先天性心臟病經(jīng)導(dǎo)管介入治療指南》推薦ASD封堵術(shù)后肝素抗凝24小時按小兒3～5mg.kg-1.d-1及成人3mg.kg-1.d-1口服阿司匹林6個月對封堵器直徑＞30mm成人酌情加服氯吡格雷75mg/d,,?,尚無前瞻性試驗(yàn)證明抗凝血酶和抗血小板哪種方案更理想 1000例A

33、SD/PFO封堵術(shù)資料回顧顯示，980例無血栓形成患者中10%(95例)接受華法林治療51%(505例)接受阿司匹林治療39%(380例)接受阿司匹林聯(lián)合氯吡格雷治療20例血栓形成患者中15%(3例)口服華法林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數(shù)據(jù)后不同用藥方案血栓發(fā)生率差異無統(tǒng)計(jì)學(xué)意義,J Am Coll Cardiol 2004;43:302–9,,?,Cetta F報(bào)道1例以Ca