老年不稳定性心绞痛患者血浆TAFI的变化及低分子量肝素对其影响
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摘要
背景：不稳定性心绞痛(unstable angina，UA)严重危害老年人身体健康，局部冠状动脉粥样硬化斑块由稳定转为不稳定，继而破裂导致血栓形成是UA的主要发病机理。明确不稳定性斑块发生的分子机制以及识别不稳定性斑块，进而采取有效的干预措施，已成为冠心病研究领域的热点。
近年来，凝血纤溶系统的变化与冠心病发生、发展的关系越来越受到人们的重视。凝血酶激活的纤溶抑制物(thrombin-activatable fibrinolysis Inhibitor，TAFI)作为凝血纤溶活性的调节因子，在心脑血管血栓性疾病发生、发展中起重要作用。研究发现心绞痛的发生、UA的顽固性与血浆TAFI水平相关。因此，TAFI在UA发生、发展中可能发挥一定作用，并且TAFI水平的调节可能对UA病情的控制具有重要意义。
由于不稳定性心绞痛患者存在凝血纤溶活性的失调，因此抗凝治疗在其防治措施中占有重要地位。低分子量肝素(low-molecular-weight heparin，LMWH)和普通肝素(standard unfractionated heparin，UFH)能有效降低UA患者心肌梗死等严重心脏事件。LMWH较UFH有许多优点，作为UFH的替代品逐渐为临床所接受。既往研究表明，LMWH通过增强抗凝血酶活性、促进组织因子通道抑制剂释放、降低血管假性血友病因子浓度、促进纤溶功能等途径发挥抗凝作用。TAFI作为连接凝血和纤溶两大系统的活性调节分子，可能是LWMH治疗UA过程中抗凝作用途径之一。
Background: Unstable angina (UA) is a common and multi-onset disease, which has serious effects on the health of the aged. The major pathogenesis of UA is the instability of local coronary atherosclerotic plaque and arterial thrombogenesis secondary to the plaque disruption. It has become a hot spot of precaution and therapy in coronary heart disease (CHD) that identifying and recognizing molecular mechanism of the plaque instability, then taking effective measures on prevention and cure.
The more and more close attentions are paid to association between the development of CHD and active variance in the system of thrombosis and fibrinolysis. Recently, thrombin-activatable fibrinolysis Inhibitor (TAFI) has attached more importance as a factor regulatory to activity of thrombosis and fibrinolysis in cardiovascular and cerebrovascular diseases. Clinical studies have indicated plasma TAFI levels were related to development of angina pectoris and refractory UA Therefore, TAFI is likely to play a partial role in the development of UA, and the regulation of TAFI levels is potential significant to improve UA patients' clinical
近年来，凝血纤溶系统的变化与冠心病发生、发展的关系越来越受到人们的重视。凝血酶激活的纤溶抑制物(thrombin-activatable fibrinolysis Inhibitor，TAFI)作为凝血纤溶活性的调节因子，在心脑血管血栓性疾病发生、发展中起重要作用。研究发现心绞痛的发生、UA的顽固性与血浆TAFI水平相关。因此，TAFI在UA发生、发展中可能发挥一定作用，并且TAFI水平的调节可能对UA病情的控制具有重要意义。
由于不稳定性心绞痛患者存在凝血纤溶活性的失调，因此抗凝治疗在其防治措施中占有重要地位。低分子量肝素(low-molecular-weight heparin，LMWH)和普通肝素(standard unfractionated heparin，UFH)能有效降低UA患者心肌梗死等严重心脏事件。LMWH较UFH有许多优点，作为UFH的替代品逐渐为临床所接受。既往研究表明，LMWH通过增强抗凝血酶活性、促进组织因子通道抑制剂释放、降低血管假性血友病因子浓度、促进纤溶功能等途径发挥抗凝作用。TAFI作为连接凝血和纤溶两大系统的活性调节分子，可能是LWMH治疗UA过程中抗凝作用途径之一。
Background: Unstable angina (UA) is a common and multi-onset disease, which has serious effects on the health of the aged. The major pathogenesis of UA is the instability of local coronary atherosclerotic plaque and arterial thrombogenesis secondary to the plaque disruption. It has become a hot spot of precaution and therapy in coronary heart disease (CHD) that identifying and recognizing molecular mechanism of the plaque instability, then taking effective measures on prevention and cure.
The more and more close attentions are paid to association between the development of CHD and active variance in the system of thrombosis and fibrinolysis. Recently, thrombin-activatable fibrinolysis Inhibitor (TAFI) has attached more importance as a factor regulatory to activity of thrombosis and fibrinolysis in cardiovascular and cerebrovascular diseases. Clinical studies have indicated plasma TAFI levels were related to development of angina pectoris and refractory UA Therefore, TAFI is likely to play a partial role in the development of UA, and the regulation of TAFI levels is potential significant to improve UA patients' clinical
引文
1. Morange PE, Juhan-Vague I, Scarabin PY, et al. Association between TAFI antigen and Ala147Thr polymorphism of the TAFI gene and the angina pectoris incidence. The PRIME Study (Prospective Epidemiological Study of MI)[J]. Thromb Haemost, 2003, 89(3): 554-60.
2. Brouwers GJ, Leebeek FW, Tanck MW, et al. Association between thrombin-activatable fibrinolysis inhibitor (TAFI) and clinical outcome in patients with unstable angina pectoris[J]. Thromb Haemost, 2003, 90(1): 92-100.
3. Wallentin. Low molecular weight heparin in unstable coronary artery disease[J]. Expert Opin Investig Drugs, 2000, 9(3): 581-592.
4. Nagashima M, Yin ZF, et al. Thrombin-aetivatable fibrinolysis inhibitor (TAFI) defieient mice[J]. Front Biosci, 2002, 7: d556-68.
5. Kokichi Suzuki, Yuko Muto, et al. enhancement of fibrinolysis by EF6265[(S)-7-Amino-2-[[[(R)-2-methyl-1-(3-phenylpropanoylamino)propyl] hydroxypho sphinoyl] methyl] heptanoie Acid], a specific inhibitor of plasma carboxypeptidase B[J]. J Pharmacol Exp Ther, 2004, 309:607-615.
6. Silveira A, Schatteman K, Goossens F, et al. Plasma procarboxypepfidase U in men with symptomatic coronary artery disease[J]. Thromb Haemost, 2000, 84(3): 364-8.
7．中华医学会心血管病分会，中华心血管病杂志编辑委员会．不稳定性心绞痛诊断治疗建议．中华心血管病杂志，2000，28：409-412．
8. Chalmers J, et al.WHO-ISO hypertension guidelines commitee. 1999 world healthy organization-international society hypertension guidelines for management of hypertension[J]. J Hypertens, 1999, 17: 151-185.
9．中华心血管病杂志编委会血脂异常防治对策专题组．血脂异常防治建议．中华心血管病杂志，1997，25：169-175．
10. Report of the expert commitee on the diagnosis and classification of diabetes mellitus[J]. Diabetes Care, 2002, 25(Suppl 1): S5-20.
11. Herrick JB. Clinical features of sudden obstruction of the coronary arteries[J]. JAMA, 1912, 59: 2015-2020.
12. Constantinides P. Plaque fissures in human coronary thrombosis[J]. J Athero Res, 1966, 6: 1-17.
13. Davies MJ, Thomas AC. Plaque fissuring: the cause of acute myocardial infarction, sudden ischemic death and crescendo angina[J]. Br Heart J, 1985, 53: 363-373.
14. Naghavi M, Libby P, Falk E, et al. From vulnerable plaque to vulnerable patient.A call for new definition and risk assessment strategies: part Ⅰ and part Ⅱ[J]. Circulation, 2003, 108: 1664-1778.
15．胡大一．急性冠状动脉综合征的治疗新对策和新模式[J]．中国介入心脏病学杂志，2002，10(1)：3．
16．杨曙光．不稳定性心绞痛的诊断与治疗进展[J]．中国全科医学杂志，1998，1(3)：190．
17．陈纪林．无NA段抬高的急性冠状动脉综合征[J]．中华心血管病杂志，2000，29(8)：501．
18. Salomaa V, Stinson JD, Kark JD, et al. Association of fibrinolytic parameters with early atheroselerosis: The ARIC Study[J]. Circulation, 1995, 91: 284.
19. Heinrich J, Schulte H, Sehonfeld R, et al. Association of variables of coagulation, fibrinolysis and acute-phase with atheroselerosis in coronary and peripheral arteries and those arteries supplying the brain[J]. Thromb Haemost, 1995, 73(3): 374-9.
20. Hoffmeister HM, Jur M, Wendel HP, et al. Alterations of coagulation and fibrinolytic and kallikrein-kinin systems in the acute and postacute phases in patients with unstable angina pectoris[J]. Circulation, 1995, 91: 2520.
21. Toss H, Lindahl B, Siegbahn A, Wallentin L, and for the FRISC Study Group. Prognostic influence of increased fibrinogen and C-reactive protein levels in unstable coronary artery disease[J]. Circulation, 1997, 96: 4204.
22. Wang W, Boffa MB, Bajzar L, et al. A study of the mechanism of inhibition of fibrinolysis by activated thrombin-activable fibrinolysis inhibitor[J]. J Biol Chem, 1998,273: 27176 - 27181.
23. Klement P, Liao P, Bajzar L. A novel approach to arterial thrombolysis [J]. Blood, 1999,94:2735 - 2743.
24. Hosaka Y, Takahashi Y, Ishii H. Thrombomodulin in human plasma contributes to inhibit fibnnolysis through acceleration of thrombin-dependent activation of plasma procarboxypeptidase B [J]. Thromb Haemost, 1998,79(2): 371-7.
25. Boffa MB, Wang W, Bajzar L, et al. Plasma and recombinant thrombin-activable fibrinolysis inhibitor (TAFI) and activated TAFI compared with respect to glycosylation, thrombin/thrombomodulin-dependent activation, thermal stability, and enzymatic properties [J]. J Biol Chem, 1998,273: 2127 - 2135.
26. Leurs J, Wissing BM, Nerme V, et al. Different mechanisms contribute to the biphasic pattern of carboxypeptidase U (TAFIa) generation during in vitro clot lysis in human plasma [J]. Thromb Haemost, 2003, 89(2): 264-71.
27. Bajzar L, Morser J; Nesheim M. TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex [J]. J Biol Chem, 1996,271:16603 -16608.
28. Marx PF, Hackeng TM, Dawson PE, et al. Inactivation of active thrombin-activable fibrinolysis inhibitor takes place by a process that involves conformational instability rather than proteolytic cleavage [J]. J Biol Chem, 2000, 275:12410 -12415.
29. Marx PF, Dawson PE, Bouma BN, et al. Plasmin-mediated activation and inactivation of thrombin-activatable fibrinolysis inhibitor [J]. Biochemistry, 2002, 41(21): 6688-96.
30. Boffa MB, Bell R, Stevens WK, et al. Roles of Thermal Instability and Proteolytic Cleavage in Regulation of Activated Thrombin-activable Fibrinolysis Inhibitor [J]. J Biol Chem, 2000,275:12868 -12878.
31. Lau HK, Segev A, Hegele RA, et al. Thrombin-activatable fibrinolysis inhibitor (TAFI): a novel predictor of angiographic coronary restenosis [J]. Thromb Haemost. 2003, 90(6): 1187-91.
32. Juhan-Vague I, Morange PE, Aubert H, et al. Plasma thrombin-activatable fibrinolysis inhibitor antigen concentration and genotype in relation to myocardial infarction in the north and south of europe[J]. Arterioscler Thromb Vasc Biol. 2002, 22: 867-73.
33. Juhan-Vague I, Morange PE, PRIME Study Group. Very high TAFI antigen levels are associated with a lower risk of hard coronary events: the PRIME Study[J]. J Thromb Haemost. 2003, 1(10): 2243-4.
34. Fuster V, Fallon JT, Nemerson Y. Coronary thrombosis[J]. Lancet, 1996, 348 Suppl 1: s7-10.
35. Klein W, Buchwald A, Hillis SE, et al. Comparison of low-molecular-weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease: Fragrnin in Unstable Coronary Artery Disease Study (FRIC)[J]. Circulation, 1997, 96: 61—68.
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1 Wang W, Boffa MB, Bajzar L, et al. A study of the mechanism of inhibition of fibrinolysis by activated thrombin-activable fibrinolysis inhibitor[J]. J Biol Chem, 1998, 273: 27176-81.
2 Sato T, Miwa T, Akatsu H, et al. Pro-carboxypeptidase R is an acute phase protein in the mouse, whereas carboxypeptidase n is not[J]. J Immunol, 2000, 165: 1053-8.
3 Myles T, Nishimura T, Yun TH, et al. Thrombin activatable fibrinolysis inhibitor, a potential regulator of vascular inflammation[J]. J Biol Chem, 2003, 278: 51059-67.
4 Asai S, Sato T, Tada T, et al. Absence of procarboxypeptidase R induces complement-rnediated Iethal inflammation in lipopolysaccharide-primed mice[J]. J Immunol, 2004, 173: 4669-74.
5 Boffa MB, Hamill JD, Bastajian N, et al. A role for CCAAT/Enhancer-binding protein in hepatic expression of thrombin-aetivable fibrinolysis inhibitor[J]. J Biol Chem, 2002, 277: 25329-36.
6 Boffa MB, Hamill JD, Maret D, et al. Acute phase mediators modulate thrombin-aetivable fibrinolysis inhibitor (TAFI) gene expression in HepG2 cells[J]. J Biol Chem. 2003, 278: 9250-7.
7 Maret D, Boffa MB, Brien DF, et al. Role of mRNA transcript stability in modulation of expression of the gene encoding thrombin activable fibrinolysis inhibitor[J]. J Thromb Haemost, 2004, 2(11): 1969-79.
8 Schneider M, Boffa M, Stewart R, et al. Two naturally occurring variants of TAFI (Thr-325 and Ile-325) differ substantially with respect to thermal stability and antifibrinolytie activity of the enzyme[J]. J Biol Chem, 2002, 277: 1021-30.
9 Silveira A, Sehatteman K, Goossens F, et al. Plasma procarboxypeptidase U in men with symptomatic coronary artery disease[J]. Thromb Haemost, 2000, 84(3): 364-8.
10 Schroeder V, Chatterjee T, Mehta H. et al. Thrombin aetivatable fibrinolysis inhibitor (TAFI) levels in patients with coronary artery disease investigated by angiography[J]. Thromb Haemost, 2002, 88(6): 1020-5.
11 谢爽，王鸿利，王学峰，等．冠心病患者血浆凝血酶激活的纤溶抑制物的检测及临床意义[J]．现代检验医学杂志，2004，19(1)：42-43．
12 Morange PE, Juhan-Vague I, Scarabin PY, et al. Association between TAFI antigen and Ala147Thr polymorphism of the TAFI gene and the angina pectoris incidence. The PRIME Study (Prospective Epidemiological Study of MI)[J]. Thromb Haemost, 2003, 89(3): 554-60.
13 Lau HK, Segev A, Hegele RA, et al. Thrombin-activatable fibrinolysis inhibitor (TAFI): a novel predictor of angiographic coronary restenosis [J]. Thromb Haemost. 2003,90(6): 1187-91.
14 Juhan-Vague I, Morange PE, Aubert H, et al. Plasma thrombin-activatable fibrinolysis inhibitor antigen concentration and genotype in relation to myocardial infarction in the north and south of europe [J]. Arterioscler Thromb Vasc Biol. 2002,22: 867-73.
15 Juhan- Vague I, Morange PE, PRIME Study Group. Very high TAFI antigen levels are associated with a lower risk of hard coronary events: the PRIME Study [J]. J Thromb Haemost. 2003,1(10): 2243-4.
16 Brouwers GJ, Leebeek FW, Tanck MW, et al. Association between thrombin-activatable fibrinolysis inhibitor (TAFI) and clinical outcome in patients with unstable angina pectoris [J]. Thromb Haemost, 2003,90(1): 92-100.
17 Santamaria A, Oliver A, Borrell M, et al. Risk of ischemic stroke associated with functional thrombin-activatable fibrinolysis inhibitor plasma levels [J]. Stroke, 2003,34: 2387-91.
18 Montaner J, Ribo M, Monasterio J, et al. Thrombin-activable fibrinolysis inhibitor levels in the acute phase of ischemic stroke [J]. Stroke, 2003, 34: 1038-40.
19 Segev A, Hegele RA, Lau HK, et al. Thr325Ile polymorphism of the TAFI gene is related to TAFI antigen plasma levels and angiographic restenosis after percutaneous coronary interventions [J]. Thromb Res, 2004,114(2): 137-41.
20 Morange PE, Henry M, Frere C, et al. Thr325Iie polymorphism of the TAFI gene does not influence the risk of myocardial infection [J]. Blood, 2002, 99(5): 1878-9.
21 Akatsu H, Yamagata H, Chen Y, et al. TAFI polymorphisms at amino acids 147 and 325 are not risk factors for cerebral infarction [J]. Br J Haematol, 2004, 127(4): 440-7.
2. Brouwers GJ, Leebeek FW, Tanck MW, et al. Association between thrombin-activatable fibrinolysis inhibitor (TAFI) and clinical outcome in patients with unstable angina pectoris[J]. Thromb Haemost, 2003, 90(1): 92-100.
3. Wallentin. Low molecular weight heparin in unstable coronary artery disease[J]. Expert Opin Investig Drugs, 2000, 9(3): 581-592.
4. Nagashima M, Yin ZF, et al. Thrombin-aetivatable fibrinolysis inhibitor (TAFI) defieient mice[J]. Front Biosci, 2002, 7: d556-68.
5. Kokichi Suzuki, Yuko Muto, et al. enhancement of fibrinolysis by EF6265[(S)-7-Amino-2-[[[(R)-2-methyl-1-(3-phenylpropanoylamino)propyl] hydroxypho sphinoyl] methyl] heptanoie Acid], a specific inhibitor of plasma carboxypeptidase B[J]. J Pharmacol Exp Ther, 2004, 309:607-615.
6. Silveira A, Schatteman K, Goossens F, et al. Plasma procarboxypepfidase U in men with symptomatic coronary artery disease[J]. Thromb Haemost, 2000, 84(3): 364-8.
7．中华医学会心血管病分会，中华心血管病杂志编辑委员会．不稳定性心绞痛诊断治疗建议．中华心血管病杂志，2000，28：409-412．
8. Chalmers J, et al.WHO-ISO hypertension guidelines commitee. 1999 world healthy organization-international society hypertension guidelines for management of hypertension[J]. J Hypertens, 1999, 17: 151-185.
9．中华心血管病杂志编委会血脂异常防治对策专题组．血脂异常防治建议．中华心血管病杂志，1997，25：169-175．
10. Report of the expert commitee on the diagnosis and classification of diabetes mellitus[J]. Diabetes Care, 2002, 25(Suppl 1): S5-20.
11. Herrick JB. Clinical features of sudden obstruction of the coronary arteries[J]. JAMA, 1912, 59: 2015-2020.
12. Constantinides P. Plaque fissures in human coronary thrombosis[J]. J Athero Res, 1966, 6: 1-17.
13. Davies MJ, Thomas AC. Plaque fissuring: the cause of acute myocardial infarction, sudden ischemic death and crescendo angina[J]. Br Heart J, 1985, 53: 363-373.
14. Naghavi M, Libby P, Falk E, et al. From vulnerable plaque to vulnerable patient.A call for new definition and risk assessment strategies: part Ⅰ and part Ⅱ[J]. Circulation, 2003, 108: 1664-1778.
15．胡大一．急性冠状动脉综合征的治疗新对策和新模式[J]．中国介入心脏病学杂志，2002，10(1)：3．
16．杨曙光．不稳定性心绞痛的诊断与治疗进展[J]．中国全科医学杂志，1998，1(3)：190．
17．陈纪林．无NA段抬高的急性冠状动脉综合征[J]．中华心血管病杂志，2000，29(8)：501．
18. Salomaa V, Stinson JD, Kark JD, et al. Association of fibrinolytic parameters with early atheroselerosis: The ARIC Study[J]. Circulation, 1995, 91: 284.
19. Heinrich J, Schulte H, Sehonfeld R, et al. Association of variables of coagulation, fibrinolysis and acute-phase with atheroselerosis in coronary and peripheral arteries and those arteries supplying the brain[J]. Thromb Haemost, 1995, 73(3): 374-9.
20. Hoffmeister HM, Jur M, Wendel HP, et al. Alterations of coagulation and fibrinolytic and kallikrein-kinin systems in the acute and postacute phases in patients with unstable angina pectoris[J]. Circulation, 1995, 91: 2520.
21. Toss H, Lindahl B, Siegbahn A, Wallentin L, and for the FRISC Study Group. Prognostic influence of increased fibrinogen and C-reactive protein levels in unstable coronary artery disease[J]. Circulation, 1997, 96: 4204.
22. Wang W, Boffa MB, Bajzar L, et al. A study of the mechanism of inhibition of fibrinolysis by activated thrombin-activable fibrinolysis inhibitor[J]. J Biol Chem, 1998,273: 27176 - 27181.
23. Klement P, Liao P, Bajzar L. A novel approach to arterial thrombolysis [J]. Blood, 1999,94:2735 - 2743.
24. Hosaka Y, Takahashi Y, Ishii H. Thrombomodulin in human plasma contributes to inhibit fibnnolysis through acceleration of thrombin-dependent activation of plasma procarboxypeptidase B [J]. Thromb Haemost, 1998,79(2): 371-7.
25. Boffa MB, Wang W, Bajzar L, et al. Plasma and recombinant thrombin-activable fibrinolysis inhibitor (TAFI) and activated TAFI compared with respect to glycosylation, thrombin/thrombomodulin-dependent activation, thermal stability, and enzymatic properties [J]. J Biol Chem, 1998,273: 2127 - 2135.
26. Leurs J, Wissing BM, Nerme V, et al. Different mechanisms contribute to the biphasic pattern of carboxypeptidase U (TAFIa) generation during in vitro clot lysis in human plasma [J]. Thromb Haemost, 2003, 89(2): 264-71.
27. Bajzar L, Morser J; Nesheim M. TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex [J]. J Biol Chem, 1996,271:16603 -16608.
28. Marx PF, Hackeng TM, Dawson PE, et al. Inactivation of active thrombin-activable fibrinolysis inhibitor takes place by a process that involves conformational instability rather than proteolytic cleavage [J]. J Biol Chem, 2000, 275:12410 -12415.
29. Marx PF, Dawson PE, Bouma BN, et al. Plasmin-mediated activation and inactivation of thrombin-activatable fibrinolysis inhibitor [J]. Biochemistry, 2002, 41(21): 6688-96.
30. Boffa MB, Bell R, Stevens WK, et al. Roles of Thermal Instability and Proteolytic Cleavage in Regulation of Activated Thrombin-activable Fibrinolysis Inhibitor [J]. J Biol Chem, 2000,275:12868 -12878.
31. Lau HK, Segev A, Hegele RA, et al. Thrombin-activatable fibrinolysis inhibitor (TAFI): a novel predictor of angiographic coronary restenosis [J]. Thromb Haemost. 2003, 90(6): 1187-91.
32. Juhan-Vague I, Morange PE, Aubert H, et al. Plasma thrombin-activatable fibrinolysis inhibitor antigen concentration and genotype in relation to myocardial infarction in the north and south of europe[J]. Arterioscler Thromb Vasc Biol. 2002, 22: 867-73.
33. Juhan-Vague I, Morange PE, PRIME Study Group. Very high TAFI antigen levels are associated with a lower risk of hard coronary events: the PRIME Study[J]. J Thromb Haemost. 2003, 1(10): 2243-4.
34. Fuster V, Fallon JT, Nemerson Y. Coronary thrombosis[J]. Lancet, 1996, 348 Suppl 1: s7-10.
35. Klein W, Buchwald A, Hillis SE, et al. Comparison of low-molecular-weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease: Fragrnin in Unstable Coronary Artery Disease Study (FRIC)[J]. Circulation, 1997, 96: 61—68.
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