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)含量的動態(tài)變化及其血管緊張素轉換酶抑制劑(ACEI)captopril干預治療的作用。用ELISA方法檢測急性心肌梗塞(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周不同時間點血漿TF及TFPI的含量。1. 50例AMI患者中，AMI用ACEI干預治療(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照組(P0.001)。AMI+ACEI組血漿TF水平發(fā)病后第3天開始下降，于2周時間點明顯下降，同AMI組及UA組比較有顯著的差異(P0.001)而較對照組比較差異無顯著性(P0.05)，AMI+ACEI組TFPI含量無明顯下降，持續(xù)穩(wěn)定在較高水平。2. TF與TFPI呈正相關(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TFPI無影響，降低TF/TFPI比值。關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)生的各個關鍵性環(huán)節(jié)。組織因子(TF)在血栓形成中的作用已引起廣泛重視，國外研究提出：在動脈

9、粥樣硬化的斑塊中，由于內皮細胞的損傷，組織因子的釋放使血小板激活并粘附于內皮損傷處，激活后的血小板釋放多種促凝血因子，同時在某些細胞因子的作用下促使血栓形成。組織因子抑制物(TFPI)為一種內源性抗凝物質，調節(jié)TF誘導的凝血過程。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。本研究觀察了急性心肌梗塞(AMI)不穩(wěn)定心絞痛(UA)患者血漿TF、TFPI的動態(tài)演變及AMI患者服用血管緊張素轉換酶抑制劑(ACEI)Captopril后對血漿TF、TFPI的影響。材料和方法結果1.各組間在年齡、性別、發(fā)病至取血樣本時間比較無顯著性差異。2.AMI組、UA組各時間點及AMI+AC

10、EI組第13天血漿TF含量明顯高于對照組(P0.001)，AMI+ACEI組血漿TF含量于用藥后第3天開始下降至第二周時間點明顯下降顯著低于AMI組、UA組(P0.001)，但與對照組比較無顯著性差異(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)計學上無顯著性差異。我們發(fā)現(xiàn)AMI組中6例有心梗后早期反復發(fā)生心絞痛患者血漿TF含量持續(xù)升高，較其它無反復發(fā)生心絞痛者TF明顯升高。UA組8例有反復發(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含量較對照組明顯升高(P0.001)，3組間TFPI含量無顯著性差異，3組從發(fā)病即刻至3周各時間點血漿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組與對照組比較：P0.01P0.001 4.AMI組、UA組及對照組TF與TFPI呈正相關，其r分別為0.559、0.558、0.486，而在AMI+ACEI組無相關性。在AMI+ACEI組第2、3周時間點TF/TFPI比值明顯下降。討論組織因子又稱凝血因子，是外源性凝血系統(tǒng)啟動因子，它能與因子組成復合體，迅速活化和因子，啟動凝血系統(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照組比較有顯著的差異。國外研究表明，心肌缺血病人血漿TF水平增高13。與炎癥介質、某些細胞因子(如TNF、IL-1內毒素)刺激有關。在動脈粥樣硬化斑塊中巨噬細胞和單核細胞

15、表達TF，當斑塊破裂后TF釋放于血循環(huán)中導致局部血栓形成。AMI未服用ACEI組的TF水平持續(xù)3周未下降，與國外報道4相一致。Misamik等1報道21例不穩(wěn)定心絞痛病人中20例TF水平于2周開始下降，但1例治療未得到滿意控制的病人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。Moenop發(fā)現(xiàn)5不穩(wěn)定心絞痛病人動脈粥樣斑塊標本中巨噬細胞和平滑肌細胞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)導致心肌缺血反復

16、發(fā)生，使血漿TF水平持續(xù)保留在較高水平。我們認為TF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水平無顯著性差異，說明AMI與UA可能有著共同的病理機制，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周時間點降至正常水平。說明血管緊張素轉換酶抑制劑可以抑制機體釋放TF，其機制可能為：血管緊張素(Ang )能促進血小板的聚集并釋放活性物質，激活血管內皮細胞，繼而影響血管內皮細胞抗凝血功能6，血管內皮細胞可分泌組織因子促凝血發(fā)生。我們認為ACEI可阻斷Ang 的形成，改善血管內皮細胞功能，從而減少Ang 促使血管內皮細胞分

17、泌TF，降低TF水平，這可能是ACEI類藥物減少心血管發(fā)病危險的因素之一。通過測定急性心肌梗塞及不穩(wěn)定心絞痛不同時間點的TFPI含量，發(fā)現(xiàn)其水平較對照組明顯升高，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)，說明心肌缺血發(fā)生后TFPI呈一持續(xù)分泌征象，同國外文獻報道相一致7。最新研究表明，TFPI抑制血栓形成呈劑量依賴性，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AMI組、UA組及對照組TF與TFPI呈正相關，相關系數(shù)分別為0.559、0.558、0.486，這可能提示TF和TFPI有著共同的細胞和介質調節(jié)。結果還發(fā)現(xiàn)TF/TFPI的比值在AMI+ACEI組第

18、2、3周時間點比值下降，這與TF的下降有關，也說明ACET對TFPI影響不大。本研究結果表明：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，在臨床應用上有廣闊的前景。杜雪平（首都醫(yī)科大學附屬復興醫(yī)院，100038，CCU）趙麗（首都醫(yī)科大學附屬復興醫(yī)院，100038，CCU）趙燕（首都醫(yī)科大學附屬復興醫(yī)院，100038，CCU）參考文獻1，Misami K,Ogawa H,Yasue H,et parison of plasma Tissue factor Levels in unst

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