Propagation of Arterial Thrombi
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《动脉硬化血栓血管生物学》
Shinya Goto
From the Department of Medicine, Tokai University School of Medicine, Kanagawa, Japan.
It is a common understanding that the rupture of an atheroma in the coronary arteries is the initial event in the onset of arterial thrombosis resulting in myocardial infarction.1 Ex vivo perfusion experiments using human blood have clearly demonstrated that platelet accumulation occurs immediately when the subendothelial matrix, such as collagen, is exposed to the blood stream.2 However, initiation of platelet thrombus formation after endothelial disruption resulting in exposure of the subendothelial matrix does not directly represent the onset of symptomatic atherothrombotic diseases, such as myocardial infarction, which were caused by thrombotic arterial occlusion. For example, coronary intervention, while causing damage to the endothelium, does not, in most cases, result in any symptomatic myocardial ischemia. Moreover, recent advances in clinical imaging techniques, such as intracoronary ultrasonography, have revealed a much higher incidence of atheroma rupture than of symptomatic atherothrombotic coronary artery diseases, including myocardial infarction and unstable angina pectoris.3,4 These observations suggest the contribution of propagating factors for thrombus growth, besides exposure of the subendothelial matrix due to endothelial disruption, in the onset of symptomatic arterial thrombotic diseases.
See page 2420
In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Yamashita et al have elegantly demonstrated in experimental studies the importance of 2 factors in the formation of arterial occlusive thrombi, namely increased vascular wall thrombogenicity induced by the accumulation of tissue factor and reduction of the total arterial blood flow by increased vascular resistance.5 The former explains the difference between the onset of myocardial infarction induced by the rupture of an inflamed tissue factor–rich atheromatous plaque1 and the asymptomatic limited-size thrombus formation initiated by coronary intervention. Blood flow reduction, induced either by local blood flow disturbance after rupture of an atheroma or by increased microvascular resistance6,7 also plays an important role in the propagation of arterial thrombi. In addition, embolization of microvessels by platelet-rich thrombi,8 as well as the microvessel contraction induced by bioactive substances released from activated platelets9 such as thromboxane A2, may play some roles in the reduction of arterial blood flow.
von Willebrand factor, along with its putative platelet receptor GPIb, plays a crucial role in the initiation of platelet thrombus formation (Figure).10 Then the stimulation of various platelet surface receptors, including integrin IIb?3 (GPIIb/IIIa),11 v?3 (vitronectin receptor),12 and catecholamine receptor,13 as well as ADP receptors (P2Y12 and P2Y1)14–16 and others, were involved in the growth of platelet thrombi. Even with those stimulations, platelet thrombi could not grow large enough to cause arterial occlusion by themselves without contribution of fibrin formation. Tissue factor, which is known to initiate coagulation cascade,1 plays a role in fibrin formation around platelet thrombi to cause so called stable mixed thrombi. These contributing effects of tissue factor have been clearly demonstrated by Falati et al with the use of intravital microscopy.17 There still is the discussion on the origin of tissue factor incorporated in the arterial occlusive thrombi. Those present in the vascular wall may play an important role as demonstrated by Yamashita et al,5 although tissue factor in circulating blood, either in a soluble form or in association with membrane of microparticle, may also be involved.18
Mechanism of thrombus initiation and thrombus propagation. Endothelial damage induced by any cause, such as atheroma rupture, erosion, or vascular interventional treatment, initiates platelet accumulation and thrombus formation; however, most of the thrombi do not grow large enough to cause clinical symptoms. The size of the thrombus is augmented when the blood flow velocity is also reduced because of increased vascular resistance. Distal embolization, along with microvascular contraction caused by bioactive materials released from activated platelets, such as thromboxane A2, may play important roles in increasing the vascular resistance. Accumulation of tissue factor in the vascular wall, mostly originating from the inflammatory cells migrated into the vascular wall, along with the fibrin deposition initiated by it, also enhances the propagation of thrombi. Blood flow reduction by small vessel embolization and increased vascular wall thrombogenicity mediated by tissue factor accumulation are presumed to play crucial roles in the formation of arterial occlusive thrombi causing symptomatic diseases.
Until now, the beneficial effects of antithrombotic therapy were supposed to be mediated only by their inhibitory effects on the initiation and growth of thrombi at the site of occlusive thrombus as formation takes place. The experimental results reported by Yamashita et al may suggest other possible mechanisms of action of antiplatelet drugs in the prevention of occlusive thrombus formation, such as the role of aspirin in reducing the vasoconstriction mediated by the inhibition of thromboxane A2 production,19 the role of anti-GPIIb/IIIa in the prevention of distal embolization,6,20 or the effects of clopidogrel in the prevention of release of vasoactive substances from activated platelets.21 According to the experimental results published by Yamashita et al, it might be reasonable to suppose that the inhibition of the accumulation of thrombogenic substances in the vascular wall, as well as the preservation of microvessel function, may be the new targets for the prevention of symptomatic arterial thrombotic diseases.
Acknowledgments
This work was supported in part by a Grant-in-Aid for Scientific Research in Japan (13670744, 15590771), the Tokai University School of Medicine, Project Research 2004, a grant from the Vehicle Racing Commemorative Foundation, and the Grant for Advanced Medicine Supported by the Ministry of Health, Labor, and Welfare (H15-MP-012).
References
Rauch U, Osende JI, Fuster V, Badimon JJ, Fayad Z, Chesebro JH. Thrombus formation on atherosclerotic plaques: pathogenesis and clinical consequences. Ann Intern Med. 2001; 134: 224–238.
Goto S, Tamura N, Handa S, Arai M, Kodama K, Takayama H. Involvement of glycoprotein VI in platelet thrombus formation on both collagen and von Willebrand factor surfaces under flow conditions. Circulation. 2002; 106: 266–272.
Kotani J, Mintz GS, Castagna MT, Pinnow E, Berzingi CO, Bui AB, Pichard AD, Satler LF, Suddath WO, Waksman R, Laird JR Jr, Kent KM, Weissman NJ. Intravascular ultrasound analysis of infarct-related and non-infarct-related arteries in patients who presented with an acute myocardial infarction. Circulation. 2003; 107: 2889–2893.
Rioufol G, Finet G, Ginon I, Andre-Fouet X, Rossi R, Vialle E, Desjoyaux E, Convert G, Huret JF, Tabib A. Multiple atherosclerotic plaque rupture in acute coronary syndrome: a three-vessel intravascular ultrasound study. Circulation. 2002; 106: 804–808.
Yamashita A, Furukoji E, Marutsuka K, Hatakeyama K, Yamamoto H, Tamura S, Ikeda Y, Sumiyoshi A, Asada Y. Increased vascular wall thrombogenicity combined with reduced blood flow promotes occlusive thrombus formation in rabbit femoral artery. Arterioscler Thromb Vasc Biol. 2004; 24: 2420–2424.
Mak KH, Challapalli R, Eisenberg MJ, Anderson KM, Califf RM, Topol EJ. Effect of platelet glycoprotein IIb/IIIa receptor inhibition on distal embolization during percutaneous revascularization of aortocoronary saphenous vein grafts. EPIC Investigators. Evaluation of IIb/IIIa platelet receptor antagonist 7E3 in preventing ischemic complications. Am J Cardiol. 1997; 80: 985–988.
Topol EJ, Yadav JS. Recognition of the importance of embolization in atherosclerotic vascular disease. Circulation. 2000; 101: 570–580.
Marzilli M, Sambuceti G, Testa R, Fedele S. Platelet glycoprotein IIb/IIIa receptor blockade and coronary resistance in unstable angina. J Am Coll Cardiol. 2002; 40: 2102–2109.
Raymenants E, Yang B, Nicolini F, Behrens P, Lawson D, Mehta JL. Verapamil and aspirin modulate platelet-mediated vasomotion in arterial segments with intact or disrupted endothelium. J Am Coll Cardiol. 1993; 22: 684–689.
Ruggeri ZM. Platelets in atherothrombosis. Nat Med. 2002; 8: 1227–1234.
Coller BS, Folts JD, Smith SR, Scudder LE, Jordan R. Abolition of in vivo platelet thrombus formation in primates with monoclonal antibodies to the platelet GPIIb/IIIa receptor. Correlation with bleeding time, platelet aggregation, and blockade of GPIIb/IIIa receptors. Circulation. 1989; 80: 1766–1774.
Goto S, Tamura N, Li M, Handa M, Ikeda Y, Handa S, Ruggeri ZM. Different effects of various anti-GPIIb-IIIa agents on shear-induced platelet activation and expression of procoagulant activity. J Thromb Haemost. 2003; 1: 2022–2030.
Goto S, Ikeda Y, Murata M, Handa M, Takahashi E, Yoshioka A, Fujimura Y, Fukuyama M, Handa S, Ogawa S. Epinephrine augments von Willebrand factor-dependent shear-induced platelet aggregation. Circulation. 1992; 86: 1859–1863.
Andre P, Delaney SM, LaRocca T, Vincent D, DeGuzman F, Jurek M, Koller B, Phillips DR, Conley PB. P2Y12 regulates platelet adhesion/activation, thrombus growth, and thrombus stability in injured arteries. J Clin Invest. 2003; 112: 398–406.
Dorsam RT, Kunapuli SP. Central role of the P2Y12 receptor in platelet activation. J Clin Invest. 2004; 113: 340–345.
Goto S, Tamura N, Eto K, Ikeda Y, Handa S. Functional significance of adenosine 5'-diphosphate receptor (P2Y(12)) in platelet activation initiated by binding of von Willebrand factor to platelet GP Ib induced by conditions of high shear rate. Circulation. 2002; 105: 2531–2536.
Falati S, Gross P, Merrill-Skoloff G, Furie BC, Furie B. Real-time in vivo imaging of platelets, tissue factor and fibrin during arterial thrombus formation in the mouse. Nat Med. 2002; 8: 1175–1181.
Falati S, Liu Q, Gross P, Merrill-Skoloff G, Chou J, Vandendries E, Celi A, Croce K, Furie BC, Furie B. Accumulation of tissue factor into developing thrombi in vivo is dependent upon microparticle P-selectin glycoprotein ligand 1 and platelet P-selectin. J Exp Med. 2003; 197: 1585–1598.
Schror K. Thromboxane A2 and platelets as mediators of coronary arterial vasoconstriction in myocardial ischaemia. Eur Heart J. 1990; 11 (suppl B): 27–34.
Goto S, Tamura N, Ishida H. Ability of anti-glycoprotein IIb/IIIa agents to dissolve platelet thrombi formed on a collagen surface under blood flow conditions. J Am Coll Cardiol. 2004; 44: 316–323.
Herbert JM. Effects of ADP-receptor antagonism beyond traditional inhibition of platelet aggregation. Expert Opin Investig Drugs. 2004; 13: 457–460.(Local and Remote Contribu)
From the Department of Medicine, Tokai University School of Medicine, Kanagawa, Japan.
It is a common understanding that the rupture of an atheroma in the coronary arteries is the initial event in the onset of arterial thrombosis resulting in myocardial infarction.1 Ex vivo perfusion experiments using human blood have clearly demonstrated that platelet accumulation occurs immediately when the subendothelial matrix, such as collagen, is exposed to the blood stream.2 However, initiation of platelet thrombus formation after endothelial disruption resulting in exposure of the subendothelial matrix does not directly represent the onset of symptomatic atherothrombotic diseases, such as myocardial infarction, which were caused by thrombotic arterial occlusion. For example, coronary intervention, while causing damage to the endothelium, does not, in most cases, result in any symptomatic myocardial ischemia. Moreover, recent advances in clinical imaging techniques, such as intracoronary ultrasonography, have revealed a much higher incidence of atheroma rupture than of symptomatic atherothrombotic coronary artery diseases, including myocardial infarction and unstable angina pectoris.3,4 These observations suggest the contribution of propagating factors for thrombus growth, besides exposure of the subendothelial matrix due to endothelial disruption, in the onset of symptomatic arterial thrombotic diseases.
See page 2420
In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Yamashita et al have elegantly demonstrated in experimental studies the importance of 2 factors in the formation of arterial occlusive thrombi, namely increased vascular wall thrombogenicity induced by the accumulation of tissue factor and reduction of the total arterial blood flow by increased vascular resistance.5 The former explains the difference between the onset of myocardial infarction induced by the rupture of an inflamed tissue factor–rich atheromatous plaque1 and the asymptomatic limited-size thrombus formation initiated by coronary intervention. Blood flow reduction, induced either by local blood flow disturbance after rupture of an atheroma or by increased microvascular resistance6,7 also plays an important role in the propagation of arterial thrombi. In addition, embolization of microvessels by platelet-rich thrombi,8 as well as the microvessel contraction induced by bioactive substances released from activated platelets9 such as thromboxane A2, may play some roles in the reduction of arterial blood flow.
von Willebrand factor, along with its putative platelet receptor GPIb, plays a crucial role in the initiation of platelet thrombus formation (Figure).10 Then the stimulation of various platelet surface receptors, including integrin IIb?3 (GPIIb/IIIa),11 v?3 (vitronectin receptor),12 and catecholamine receptor,13 as well as ADP receptors (P2Y12 and P2Y1)14–16 and others, were involved in the growth of platelet thrombi. Even with those stimulations, platelet thrombi could not grow large enough to cause arterial occlusion by themselves without contribution of fibrin formation. Tissue factor, which is known to initiate coagulation cascade,1 plays a role in fibrin formation around platelet thrombi to cause so called stable mixed thrombi. These contributing effects of tissue factor have been clearly demonstrated by Falati et al with the use of intravital microscopy.17 There still is the discussion on the origin of tissue factor incorporated in the arterial occlusive thrombi. Those present in the vascular wall may play an important role as demonstrated by Yamashita et al,5 although tissue factor in circulating blood, either in a soluble form or in association with membrane of microparticle, may also be involved.18
Mechanism of thrombus initiation and thrombus propagation. Endothelial damage induced by any cause, such as atheroma rupture, erosion, or vascular interventional treatment, initiates platelet accumulation and thrombus formation; however, most of the thrombi do not grow large enough to cause clinical symptoms. The size of the thrombus is augmented when the blood flow velocity is also reduced because of increased vascular resistance. Distal embolization, along with microvascular contraction caused by bioactive materials released from activated platelets, such as thromboxane A2, may play important roles in increasing the vascular resistance. Accumulation of tissue factor in the vascular wall, mostly originating from the inflammatory cells migrated into the vascular wall, along with the fibrin deposition initiated by it, also enhances the propagation of thrombi. Blood flow reduction by small vessel embolization and increased vascular wall thrombogenicity mediated by tissue factor accumulation are presumed to play crucial roles in the formation of arterial occlusive thrombi causing symptomatic diseases.
Until now, the beneficial effects of antithrombotic therapy were supposed to be mediated only by their inhibitory effects on the initiation and growth of thrombi at the site of occlusive thrombus as formation takes place. The experimental results reported by Yamashita et al may suggest other possible mechanisms of action of antiplatelet drugs in the prevention of occlusive thrombus formation, such as the role of aspirin in reducing the vasoconstriction mediated by the inhibition of thromboxane A2 production,19 the role of anti-GPIIb/IIIa in the prevention of distal embolization,6,20 or the effects of clopidogrel in the prevention of release of vasoactive substances from activated platelets.21 According to the experimental results published by Yamashita et al, it might be reasonable to suppose that the inhibition of the accumulation of thrombogenic substances in the vascular wall, as well as the preservation of microvessel function, may be the new targets for the prevention of symptomatic arterial thrombotic diseases.
Acknowledgments
This work was supported in part by a Grant-in-Aid for Scientific Research in Japan (13670744, 15590771), the Tokai University School of Medicine, Project Research 2004, a grant from the Vehicle Racing Commemorative Foundation, and the Grant for Advanced Medicine Supported by the Ministry of Health, Labor, and Welfare (H15-MP-012).
References
Rauch U, Osende JI, Fuster V, Badimon JJ, Fayad Z, Chesebro JH. Thrombus formation on atherosclerotic plaques: pathogenesis and clinical consequences. Ann Intern Med. 2001; 134: 224–238.
Goto S, Tamura N, Handa S, Arai M, Kodama K, Takayama H. Involvement of glycoprotein VI in platelet thrombus formation on both collagen and von Willebrand factor surfaces under flow conditions. Circulation. 2002; 106: 266–272.
Kotani J, Mintz GS, Castagna MT, Pinnow E, Berzingi CO, Bui AB, Pichard AD, Satler LF, Suddath WO, Waksman R, Laird JR Jr, Kent KM, Weissman NJ. Intravascular ultrasound analysis of infarct-related and non-infarct-related arteries in patients who presented with an acute myocardial infarction. Circulation. 2003; 107: 2889–2893.
Rioufol G, Finet G, Ginon I, Andre-Fouet X, Rossi R, Vialle E, Desjoyaux E, Convert G, Huret JF, Tabib A. Multiple atherosclerotic plaque rupture in acute coronary syndrome: a three-vessel intravascular ultrasound study. Circulation. 2002; 106: 804–808.
Yamashita A, Furukoji E, Marutsuka K, Hatakeyama K, Yamamoto H, Tamura S, Ikeda Y, Sumiyoshi A, Asada Y. Increased vascular wall thrombogenicity combined with reduced blood flow promotes occlusive thrombus formation in rabbit femoral artery. Arterioscler Thromb Vasc Biol. 2004; 24: 2420–2424.
Mak KH, Challapalli R, Eisenberg MJ, Anderson KM, Califf RM, Topol EJ. Effect of platelet glycoprotein IIb/IIIa receptor inhibition on distal embolization during percutaneous revascularization of aortocoronary saphenous vein grafts. EPIC Investigators. Evaluation of IIb/IIIa platelet receptor antagonist 7E3 in preventing ischemic complications. Am J Cardiol. 1997; 80: 985–988.
Topol EJ, Yadav JS. Recognition of the importance of embolization in atherosclerotic vascular disease. Circulation. 2000; 101: 570–580.
Marzilli M, Sambuceti G, Testa R, Fedele S. Platelet glycoprotein IIb/IIIa receptor blockade and coronary resistance in unstable angina. J Am Coll Cardiol. 2002; 40: 2102–2109.
Raymenants E, Yang B, Nicolini F, Behrens P, Lawson D, Mehta JL. Verapamil and aspirin modulate platelet-mediated vasomotion in arterial segments with intact or disrupted endothelium. J Am Coll Cardiol. 1993; 22: 684–689.
Ruggeri ZM. Platelets in atherothrombosis. Nat Med. 2002; 8: 1227–1234.
Coller BS, Folts JD, Smith SR, Scudder LE, Jordan R. Abolition of in vivo platelet thrombus formation in primates with monoclonal antibodies to the platelet GPIIb/IIIa receptor. Correlation with bleeding time, platelet aggregation, and blockade of GPIIb/IIIa receptors. Circulation. 1989; 80: 1766–1774.
Goto S, Tamura N, Li M, Handa M, Ikeda Y, Handa S, Ruggeri ZM. Different effects of various anti-GPIIb-IIIa agents on shear-induced platelet activation and expression of procoagulant activity. J Thromb Haemost. 2003; 1: 2022–2030.
Goto S, Ikeda Y, Murata M, Handa M, Takahashi E, Yoshioka A, Fujimura Y, Fukuyama M, Handa S, Ogawa S. Epinephrine augments von Willebrand factor-dependent shear-induced platelet aggregation. Circulation. 1992; 86: 1859–1863.
Andre P, Delaney SM, LaRocca T, Vincent D, DeGuzman F, Jurek M, Koller B, Phillips DR, Conley PB. P2Y12 regulates platelet adhesion/activation, thrombus growth, and thrombus stability in injured arteries. J Clin Invest. 2003; 112: 398–406.
Dorsam RT, Kunapuli SP. Central role of the P2Y12 receptor in platelet activation. J Clin Invest. 2004; 113: 340–345.
Goto S, Tamura N, Eto K, Ikeda Y, Handa S. Functional significance of adenosine 5'-diphosphate receptor (P2Y(12)) in platelet activation initiated by binding of von Willebrand factor to platelet GP Ib induced by conditions of high shear rate. Circulation. 2002; 105: 2531–2536.
Falati S, Gross P, Merrill-Skoloff G, Furie BC, Furie B. Real-time in vivo imaging of platelets, tissue factor and fibrin during arterial thrombus formation in the mouse. Nat Med. 2002; 8: 1175–1181.
Falati S, Liu Q, Gross P, Merrill-Skoloff G, Chou J, Vandendries E, Celi A, Croce K, Furie BC, Furie B. Accumulation of tissue factor into developing thrombi in vivo is dependent upon microparticle P-selectin glycoprotein ligand 1 and platelet P-selectin. J Exp Med. 2003; 197: 1585–1598.
Schror K. Thromboxane A2 and platelets as mediators of coronary arterial vasoconstriction in myocardial ischaemia. Eur Heart J. 1990; 11 (suppl B): 27–34.
Goto S, Tamura N, Ishida H. Ability of anti-glycoprotein IIb/IIIa agents to dissolve platelet thrombi formed on a collagen surface under blood flow conditions. J Am Coll Cardiol. 2004; 44: 316–323.
Herbert JM. Effects of ADP-receptor antagonism beyond traditional inhibition of platelet aggregation. Expert Opin Investig Drugs. 2004; 13: 457–460.(Local and Remote Contribu)