組織因子及其抑制物在急性冠脈綜合征中的作用研究

1、    組織因子及其抑制物在急性冠脈綜合征中的作用研究        摘要探討急性冠脈綜合征發(fā)生中血漿組織因子(TF)及其抑制物(TFPI)含量的動(dòng)態(tài)變化及其血管緊張素轉(zhuǎn)換酶抑制劑(ACEI)captopril干預(yù)治療的作用。用ELISA方法檢測(cè)急性心肌梗塞(AMI)不穩(wěn)定心絞痛(UA)患者入院后即刻、第1天、2天、3天、1周、2周、3周不同時(shí)間點(diǎn)血漿TF及TFPI的含量。1. 50例AMI患者中，AMI用ACEI干預(yù)治療(AMI+ACEI組)25例，常規(guī)治療組(AMI組)2

2、5例，UA組28例，血漿TF、TFPI水平均明顯高于正常對(duì)照組(P0.001)。AMI+ACEI組血漿TF水平發(fā)病后第3天開(kāi)始下降，于2周時(shí)間點(diǎn)明顯下降，同AMI組及UA組比較有顯著的差異(P0.001)而較對(duì)照組比較差異無(wú)顯著性(P0.05)，AMI+ACEI組TFPI含量無(wú)明顯下降，持續(xù)穩(wěn)定在較高水平。2. TF與TFPI呈正相關(guān)(P0.01)(r=0.549)。組織因子及其抑制物在急性冠脈綜合征中起重要作用。ACEI藥物降低血漿TF水平對(duì)TFPI無(wú)影響，降低TF/TFPI比值。關(guān)鍵詞急性心肌梗塞不穩(wěn)定心絞痛組織因子組織因子途徑抑制物血管緊張素轉(zhuǎn)換酶抑制劑 The Effect of Ti

3、ssue Factor and Tissue Factor Pathway Inhibitor in Acute Coronary SyndromeDu Xueping,Zhao Li,Zhao Yan（Fuxing Hospital-Affiliate of Capital University of Medical Sciences，100038）AbstractThe purpose of this investigation was to discover the plasma levels of TF and TFPI and their changing levels in acu

4、te coronary syndrome and to assess the efficacy of angiotansin converting enzyme inhibitor captopril in patients with acute myocardial infarction.The plasma levels of TF and TFPI were measured in patients suffered from acute myocardial infarction、unstable angina and control subjects on immediate tim

5、e、the first、second、third day and first、second、third week after hospitalization.The plasma concentration was assayed With ELISA method.Results:(1)The plasma level of TF and TFPI in 50 patients with AMI including 25 cases who were treated with usual therapy、25 patients treated with captopril and in 28

6、 patients with UA was higher than that in control group significantly(P0.001).The plasma level of TF in patients with AMI who were treated with captopril was decreased on the third day after hospitalization and was decreased significantly on the second week(P0.001)compared with usual therapy and was

7、 not significantly different with control group(P0.05).However,the plasma level of TFPI in patients with AMI who were treated with captopril didn't change respectively and was in a steady high level.(2)TF level correlated positively to TFPI level(P0.01,r=0.549).Conclusion:TF and TFPI play an imp

8、ortant role in acute coronary syndrome.ACEI is able to decrease the plasma level of TF、TF/TFPI ratio.Key words：Acute myocardial infarction; Unstable angina; Tissue factor; Tissue factor pathway inhibitor; Angiotension converting enzyme inhibitor血栓形成參與冠心病發(fā)生的各個(gè)關(guān)鍵性環(huán)節(jié)。組織因子(TF)在血栓形成中的作用已引起廣泛重視，國(guó)外研究提出：在動(dòng)脈

9、粥樣硬化的斑塊中，由于內(nèi)皮細(xì)胞的損傷，組織因子的釋放使血小板激活并粘附于內(nèi)皮損傷處，激活后的血小板釋放多種促凝血因子，同時(shí)在某些細(xì)胞因子的作用下促使血栓形成。組織因子抑制物(TFPI)為一種內(nèi)源性抗凝物質(zhì)，調(diào)節(jié)TF誘導(dǎo)的凝血過(guò)程。最近研究表明，在缺血性心臟病人中發(fā)現(xiàn)TF，TFPI升高，二者呈正相關(guān)。本研究觀(guān)察了急性心肌梗塞(AMI)不穩(wěn)定心絞痛(UA)患者血漿TF、TFPI的動(dòng)態(tài)演變及AMI患者服用血管緊張素轉(zhuǎn)換酶抑制劑(ACEI)Captopril后對(duì)血漿TF、TFPI的影響。材料和方法結(jié)果1.各組間在年齡、性別、發(fā)病至取血樣本時(shí)間比較無(wú)顯著性差異。2.AMI組、UA組各時(shí)間點(diǎn)及AMI+AC

10、EI組第13天血漿TF含量明顯高于對(duì)照組(P0.001)，AMI+ACEI組血漿TF含量于用藥后第3天開(kāi)始下降至第二周時(shí)間點(diǎn)明顯下降顯著低于A(yíng)MI組、UA組(P0.001)，但與對(duì)照組比較無(wú)顯著性差異(P0.05)。AMI與UA 2組之間從數(shù)據(jù)上顯示AMI組高于UA組，但統(tǒng)計(jì)學(xué)上無(wú)顯著性差異。我們發(fā)現(xiàn)AMI組中6例有心梗后早期反復(fù)發(fā)生心絞痛患者血漿TF含量持續(xù)升高，較其它無(wú)反復(fù)發(fā)生心絞痛者TF明顯升高。UA組8例有反復(fù)發(fā)生心絞痛，藥物治療效果不顯著，血漿TF含量于第三周仍在較高水平(表1)。表1各組TF含量變化(pg/ml)即刻1天2天3天1周2周3周AMI+ACEI124.5±40

11、.6118.5±41.5116.3±53.3109.0±65.9102.5±54.774.4±48.8()/(*)70.1±34.7()/(*)AMI122.9±41.5128.8±41.3131.7±46.8127.0±38.9125.1±55.5137.4±65.8(*)/()124.1±68.7(*)/()UA112.2±53.2114.4±58.2108.2±43.7116.5±45.5112.4±46.31

12、22.3±55.1()/()123.1±49.1()/()C64.9±34.9注：AMI+ACEI AMI UA組與C組比較P0.01，P0.001；*AMI+ACEI組與AMI組比較*P0.01，*P0.001；AMI+ACEI組與UA組比較P0.01，P0.0013.AMI+ACEI組、AMI組、UA組3組血漿TFPI含量較對(duì)照組明顯升高(P0.001)，3組間TFPI含量無(wú)顯著性差異，3組從發(fā)病即刻至3周各時(shí)間點(diǎn)血漿TFPI升高持續(xù)穩(wěn)定在較高水平(表2)。表2各組TFPI含量變化(ng/m)即刻1天2天3天1周2周3周AMI+ACEI67.6±14

13、.184.5±41.257.8±22.271.8±26.659.0±14.463.5±14.866.3±90.3AMI69.0±23.671.5±23.475.7±26.870.0±22.275.8±40.977.7±42.368.1±38.5UA61.5±39.463.0±35.262.9±22.362.7±26.265.3±30.066.0±32.268.9±27.3C32.8±16

14、.2注：AMI+ACEI、AMI、UA組與對(duì)照組比較：P0.01P0.001 4.AMI組、UA組及對(duì)照組TF與TFPI呈正相關(guān)，其r分別為0.559、0.558、0.486，而在A(yíng)MI+ACEI組無(wú)相關(guān)性。在A(yíng)MI+ACEI組第2、3周時(shí)間點(diǎn)TF/TFPI比值明顯下降。討論組織因子又稱(chēng)凝血因子，是外源性凝血系統(tǒng)啟動(dòng)因子，它能與因子組成復(fù)合體，迅速活化和因子，啟動(dòng)凝血系統(tǒng)。本研究發(fā)現(xiàn)：AMI及UA組血漿TF水平明顯增高與正常對(duì)照組比較有顯著的差異。國(guó)外研究表明，心肌缺血病人血漿TF水平增高13。與炎癥介質(zhì)、某些細(xì)胞因子(如TNF、IL-1內(nèi)毒素)刺激有關(guān)。在動(dòng)脈粥樣硬化斑塊中巨噬細(xì)胞和單核細(xì)胞

15、表達(dá)TF，當(dāng)斑塊破裂后TF釋放于血循環(huán)中導(dǎo)致局部血栓形成。AMI未服用ACEI組的TF水平持續(xù)3周未下降，與國(guó)外報(bào)道4相一致。Misamik等1報(bào)道21例不穩(wěn)定心絞痛病人中20例TF水平于2周開(kāi)始下降，但1例治療未得到滿(mǎn)意控制的病人TF水平仍保留在較高水平。本研究也發(fā)現(xiàn)UA組28例中8例反復(fù)發(fā)作心絞痛，TF持續(xù)保留在較高水平，致使總體TF水平3周仍未下降可能與此有關(guān)。Moenop發(fā)現(xiàn)5不穩(wěn)定心絞痛病人動(dòng)脈粥樣斑塊標(biāo)本中巨噬細(xì)胞和平滑肌細(xì)胞TF含量增高，斑塊破裂釋放TF，活化因子和因子，激活外源性凝血系統(tǒng)，導(dǎo)致血小板聚集和纖維蛋白沉積，形成血栓。不穩(wěn)定心絞痛病人由于血栓不穩(wěn)定狀態(tài)導(dǎo)致心肌缺血反復(fù)

16、發(fā)生，使血漿TF水平持續(xù)保留在較高水平。我們認(rèn)為T(mén)F水平可以間接反映血栓的不穩(wěn)定狀態(tài)。AMI組和UA組比較血漿TF水平無(wú)顯著性差異，說(shuō)明AMI與UA可能有著共同的病理機(jī)制，外源性凝血系統(tǒng)在疾病的發(fā)生中起了一定的作用。AMI+ACEI組，血漿TF含量于服藥后第3天下降，第2、3周時(shí)間點(diǎn)降至正常水平。說(shuō)明血管緊張素轉(zhuǎn)換酶抑制劑可以抑制機(jī)體釋放TF，其機(jī)制可能為：血管緊張素(Ang )能促進(jìn)血小板的聚集并釋放活性物質(zhì)，激活血管內(nèi)皮細(xì)胞，繼而影響血管內(nèi)皮細(xì)胞抗凝血功能6，血管內(nèi)皮細(xì)胞可分泌組織因子促凝血發(fā)生。我們認(rèn)為ACEI可阻斷Ang 的形成，改善血管內(nèi)皮細(xì)胞功能，從而減少Ang 促使血管內(nèi)皮細(xì)胞分

17、泌TF，降低TF水平，這可能是ACEI類(lèi)藥物減少心血管發(fā)病危險(xiǎn)的因素之一。通過(guò)測(cè)定急性心肌梗塞及不穩(wěn)定心絞痛不同時(shí)間點(diǎn)的TFPI含量，發(fā)現(xiàn)其水平較對(duì)照組明顯升高，從發(fā)病即刻到發(fā)病后3周，血漿TFPI水平維持在較高狀態(tài)，說(shuō)明心肌缺血發(fā)生后TFPI呈一持續(xù)分泌征象，同國(guó)外文獻(xiàn)報(bào)道相一致7。最新研究表明，TFPI抑制血栓形成呈劑量依賴(lài)性，并可抑制血小板的激活，拮抗重組TF(rTF)引起的血小板活化8。在A(yíng)MI組、UA組及對(duì)照組TF與TFPI呈正相關(guān)，相關(guān)系數(shù)分別為0.559、0.558、0.486，這可能提示TF和TFPI有著共同的細(xì)胞和介質(zhì)調(diào)節(jié)。結(jié)果還發(fā)現(xiàn)TF/TFPI的比值在A(yíng)MI+ACEI組第

18、2、3周時(shí)間點(diǎn)比值下降，這與TF的下降有關(guān)，也說(shuō)明ACET對(duì)TFPI影響不大。本研究結(jié)果表明：TF在冠脈血栓形成中起了一定的作用。ACEI藥物可降低TF水平，減少外源性凝血系統(tǒng)引起血栓形成。TF的單克隆抗體、重組TFPI，可作為一種抗血栓形成的藥物，在臨床應(yīng)用上有廣闊的前景。杜雪平（首都醫(yī)科大學(xué)附屬?gòu)?fù)興醫(yī)院，100038，CCU）趙麗（首都醫(yī)科大學(xué)附屬?gòu)?fù)興醫(yī)院，100038，CCU）趙燕（首都醫(yī)科大學(xué)附屬?gòu)?fù)興醫(yī)院，100038，CCU）參考文獻(xiàn)1，Misami K,Ogawa H,Yasue H,et parison of plasma Tissue factor Levels in unst

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