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Pathophysiology of acute ischemic syndromes: recent progress
Session 5
Fibrinolysis & Proteolysis (1997) 11, Suppl. 1, 105-108 © Pearson ProfessionalLtd 1997
AntithromboticTherapy
P a t h o p h y s i o l o g y of a c u t e i s c h e m i c syndromes: r e c e n t progress S. D. Kristensen, E. Falk Department of Cardiology B, Skejby Hospital, Aarhus University Hospital, 8200 Aarhus N, Denmark.
Atherosclerosis without thrombosis is in general a benign disease. However, acute thrombosis, precipitated by plaque disruption, frequently complicates the course of coronary atherosclerosis. It causes unstable angina, myocardial infarction, and sudden death. The risk of plaque disruption depends more on plaque type (composition) than on plaque size or stenosis severity. Major determinants of a plaque's vulnerability to rupture are: the size and consistency of the lipid-rich atheromatous core, the thickness of the fibrous cap covering the core, and ongoing inflammation within the cap. Both plaque vulnerability (intrinsic disease) and rupture triggers (extrinsic forces) are important for plaque disruption. The former predisposes the plaque to rupture while the latter may precipitate it. The resultant thrombotic response, which is important for the clinical presentation and outcome, is in part determined by the reactivity of the circulating platelets and the coagulation system. The challenge of today is to identify and treat the dangerous vulnerable plaques responsible for infarction and death and to optimize anti-thrombotic treatment. Summary
INTRODUCTION
The development of coronary atherosclerosis starts in childhood, but it takes several decades to form the mature plaques responsible for the chronic ischemic episodes that occur in patients with stable angina pectoris. Unfortunately, this slowly developing relatively benign disease sometimes suddenly changes and severe, lifethreatening acute myocardial ischemia arises. Clinically, this gives rise to the acute coronary ischemic syndromes, unstable angina pectoris, acute myocardial infarction, and sudden coronary death. Studies based on autopsy, angiography, and angioscopy have shown that the formation of a coronary thrombus superimposed on an atherosclerotic plaque, leading to total or subtotal occlusion of the artery, and in some cases peripheral embolization, is the key event that causes the devastating change in symptoms and prognosis. The initial event in coronary thrombus formation is usually disruption or fissuring of the plaque. At the site of plaque rupture, platelets adhere to the artery wall and release vasoconstrictory and aggregatory substances. A platelet-thrombus is formed, the coagulation system is activated, and the end-product is a stable coronary Correspondance to: Erling Falk, Telefax: +45 89496009
thrombus consisting of aggregated platelets and fibrin
(Fig. 1A). Plaque type (composition), rather than plaque size (stenosis severity), has emerged as being the most important determinant for the development of the thrombusmediated acute coronary syndromes; lipid-rich and soft plaques are more dangerous than collagen-rich and hard plaques because they are vulnerable to rupture and highly thrombogenic after disruption. Detailed knowledge on the pathophysiology of coronary thrombus formarion may provide tools for prevention and treatment of the ischemic syndromes. This paper focuses on the cause and role of plaque rupture and on the subsequent thrombus formation. ATHEROGENESlS
The generation and growth of the atherosclerotic plaque are the result of a dynamic interaction between the vessel wall and the flowing blood, involving the following pathological processes: 1,2 Inflammation: increased endothelial permeability, endo-
thelial activation/dysfunction, and monocyte recruitment. Growth: smooth muscle cell (SMC) proliferation, migration and matrix synthesis. 105
106
Fibrinolysis & Proteolysis
ciated rapid plaque growth is usually clinically silent. This disruption is probably the most important mechanism responsible for the unpredictable, sudden, and nonlinear progression of coronary lesions frequently observed angiographically, a,3 However, survival is good as long as thrombotic complications do not occur. It is thrombosis, superimposed on mature plaques, that turns a relatively benign disease into a life-threatening acute coronary syndrome. 2,3 MATURE
Fig. A. As illustrated here, coronary thrombosis is a dynamic process. Most coronary thrombi have a layered structure indicating episodic growth by repeated mural deposits. This occluding thrombus has three layers, and aggregated platelets are clearly identifiable (at higher magnification) as the main component of the most recent part of the thrombus located centrally. B. A mature coronary plaque illustrating the two main plaque components: atheromatous 'gruel' (asterisk) and sclerotic tissue. The atheromatous component is lipid-rich, soft, and dangerous. Atherosis destabilizes a plaque, making it vulnerable to rupture, whereby the highly thrombogenic gruel is exposed to the flowing blood. In contrast, the sclerotic component is collagen-rich, hard, and safe. Sclerosis conveys stability to a plaque, protecting it against disruption.
Degeneration: lipid accumulation. Necrosis: cell death (cytotoxic effect of oxidized lipid?). Calcification: possibly an active process rather than a dystrophic phenomenon. Thrombosis: platelet aggregation and fibrin formation.
Proliferation of SMC, matrix synthesis, and lipid accumulation may gradually narrow the arterial lumen and ultimately lead to myocardial ischemia and anginal pain. Plaque disruption itself is asymptomatic, and the assoFibrinolysis & Proteolysis (1997) 11, SuppL 1, 105-108
PLAQUES: TWO MAIN COMPONENTS
In patients with ischemic heart disease, the coronary arteries are diffusely involved with confluent 'plaquing'. The composition, consistency, vulnerability, and thrombogenicity of individual plaques vary greatly without any obvious relation to risk factors for clinical disease. Most importantly, there is no simple relation between the size of a plaque (or stenosis severity) and its composition or vulnerability to rupture. As the name 'atherosclerosis' implies, mature plaques consist typically of two main components: soft, lipid-rich atheromatous 'gruel', and hard, collagen-rich sclerotic tissue (Fig. 1B). The sclerotic component is usually by far the most voluminous but it is relatively innocuous because collagen secreted by SMC probably stabilizes a plaque against disruption. In contrast, the atheromatous component is by far the most dangerous because it destabilizes a plaque, making it vulnerable and susceptible to rupture and thrombosis. 3 The destabilizing atheromatous component or core lacks supporting collagen, is rich in extracellular lipids (predominantly cholesterol and its esters), is avascular and hypocellular, and is usually soft like gruel. PLAQUE DISRUPTION: TRIGGERS
VULNERABILITY
AND
Disruption of vulnerable plaques occurs frequently. It is followed by variable amounts of luminal thrombosis and/ or hemorrhage into the soft gruel, causing rapid growth of the lesion. Autopsy data indicate that 9% of 'normal' healthy persons are walking around with disrupted plaques (without superimposed thrombosis) in their coronary arteries. The numbers increase to 22% in persons with diabetes or hypertension. 3 One or more disrupted plaques, with or without superimposed thrombosis, are usually present in coronary arteries of patients dying of ischemic heart disease. 3 The risk of plaque disruption depends on both intrinsic properties of individual plaques (their vulnerability) and extrinsic forces acting on plaques (rupture triggers). The former predispose plaques to rupture, while the latter may precipitate disruption if vulnerable plaques are present. © Pearson Professional Ltd 1997
3rd International Fibrinogen Symposium
Vulnerability
Plaque disruption occurs most frequently where the fibrous cap is thinnest, most heavily foam cell infiltrated, and, therefore, weakest. 3 For eccentric plaques, this site is often the junction between the plaque and the adjacent less diseased vessel wall, called the shoulder region of the plaque. There seem to be 3 major determinants of a plaque's vulnerability to rupture: core size, cap thickness, and cap inflammation. Core size
The size and consistency of the atheromatous core are important factors for the stability of a plaque. The bigger the core, the more vulnerable (rupture-prone) is the plaque)
107
blood. 3 Superficial plaque inflammation with intimal erosion but no frank disruption (i.e., no deep injury) are found beneath the remaining fatal thrombi, 3 usually in combination with a severe atherosclerotic stenosis. Determinants of thrombosis
Most disrupted plaques are resealed by a small mural thrombus, and only sometimes does a major luminal thrombus evolve. Therefore, the thrombotic response to plaque disruption/erosion is a key event in the pathophysiology of acute ischemic syndromes. Several factors such as the thrombogenic substrate, local flow disturbances and, last but not least, the systemic thrombotic propensity are important. Thrombogenic substrate
Cap thickness
Rupture of the fibrous cap covering the core occurs most frequently at its junctions with the adjacent more normal intima (the shoulder regions) being where the cap usually is the thinnest and, therefore, weakest. 3
The atheromatous 'gruel' is not only the most vulnerable plaque component, it also appears to be the most thrombogenic component. 5 Recent data indicate that macrophage-derived tissue factor could be responsible for the high thrombogenicity of the gruel, s
Cap inflammation
Local flow disturbances
The shoulder regions are predilection sites for macrophage foam cell infikration, and activated macrophages are usually concentrated at the actual rupture/erosion site beneath coronary thrombi, indicating ongoing inflammation. 3 Of note, culprit lesions from patients with unstable coronary syndromes contain significantly more macrophages than do plaques from stable patients. 4 Macrophages are capable of degrading extracellular matrix by secreting proteolytic enzymes such as plasminogen activators and metalloproteinases, which may weaken the fibrous cap, predisposing it to rupture)
A severe stenosis and surface irregularities may activate platelets. A platelet-rich thrombus may indeed form and grow within a severe stenosis, where the blood velocity and shear forces are highest, probably because of shear-induced platelet activation. 3 Irregularities of the exposed surface do also increase thrombus formation. 5
Rupture triggers
Coronary plaques are constantly stressed by a variety of mechanical and hemodynamic forces that may precipitate or 'trigger' disruption of vulnerable plaques. 3Physical exertion and emotional stress could, for example, trigger plaque disruption via surges in sympathetic activity with an increase in blood pressure, pulse pressure, blood flow (shear forces), heart rate, and coronary tone. PLAQUE THROMBOSIS
About 75% of thrombi responsible for acute coronary syndromes are precipitated by plaque disruption whereby the highly thrombogenic gruel is exposed to the flowing © Pearson Professional Ltd 1997
Systemic thrombotic propensity
The actual thrombotic-thrombolytic equilibrium at the time of plaque disruption does also influence the outcome. The importance of platelets is clearly documented by the protective effect of aspirin in patients with stable and unstable angina pectoris and in patients with acute myocardial infarction. 2'6 There is also evidence that a systemic activation of coagulation and increase in platelet reactivity occurs in the acute phase of a myocardial infarction and in unstable angina pectoris. 6 Patients with acute myocardial infarction have a shorter bleeding time and a higher mean platelet volume than controls admitted with chest pain without signs of infarction. 6 Since large platelets are more active hemostatically than small ones, this points to an increased reactivity of the circulating platelets at the time of the acute event. Also the synthesis of proaggregatory thromboxane A2 is increased in the acute phase of acute myocardial infarction and in unstable angina pectoris. 6 A high mean Fibrinolysis & Proteolysis (1997) 11, SuppL 1, 105-108
108
Fibrinolysis & Proteolysis
platelet v o l u m e 7 a n d i n c r e a s e d s p o n t a n e o u s platelet a g g r e g a t i o n 8 h a v e b e e n s h o w n to b e risk factors for reinfarction a n d d e a t h in p a t i e n t s surviving m y o c a r d i a l infarction. Recently, it h a s b e e n r e p o r t e d t h a t a polym o r p h i s m of t h e g l y c o p r o t e i n IIIa g e n e is p r e v a l e n t w i t h a h i g h f r e q u e n c y in y o u n g patients w i t h a c u t e i s c h a e m i c s y n d r o m e s 9 s u g g e s t i n g t h a t t h e platelet g l y c o p r o t e i n Ilb/IIIa r e c e p t o r m a y b e a l t e r e d on a n i n h e r i t e d basis in s o m e of t h e s e patients. P l a s m a f i b r i n o g e n is a w e l l - k n o w n risk factor for t h e d e v e l o p m e n t of i s c h e m i c h e a r t disease. In t h e ECAT a n g i n a pectoris study, t h e base-line levels of fibrinogen, y o n W i l l e b r a n d factor antigen, a n d t-PA a n t i g e n were f o u n d to be i n d e p e n d e n t p r e d i c t o r s of s u b s e q u e n t a c u t e i s c h e m i c s y n d r o m e s . 1° H i g h p l a s m a f i b r i n o g e n levels m a y b e a m a r k e r of o n g o i n g i n f l a m m a t i o n in t h e v a s c u l a r s y s t e m a n d m a y also c o n t r i b u t e to a p r o t h r o m b o t i c state in t h e s e patients.
CONCLUSION Plaque r u p t u r e is u s u a l l y t h e initial e v e n t in t h e format i o n of c o r o n a r y t h r o m b i r e s p o n s i b l e for t h e a c u t e coron a r y s y n d r o m e s . F u r t h e r insight into t h e cause of p l a q u e r u p t u r e is w a r r a n t e d a n d m a y p r o v i d e i n f o r m a t i o n t h a t m a k e s p r e v e n t i o n of p l a q u e r u p t u r e possible. C o a g u l a tion, fibrinolysis, and, in particular, platelets are i m p o r t a n t for t h r o m b u s f o r m a t i o n a n d are t h e targets of antithrombotic therapy.
Fibrinolysis & Proteolysis (1997) 11, SuppL 1, 105-108
REFERENCES 1. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993; 362: 801-809. 2. Fuster V. Lewis A. Conner Memorial Lecture. Mechanisms leading to myocardial infarction: insights from studies of vascular biology. Circulation 1994, 90:2126-2146. 3. Falk E, Shah P K, Fuster V. Coronary plaque disruption. Circulation 1995; 92: 657-671. 4. Moreno P R, Falk E, Palacios I F, Newell J B, Fuster V, Fallon J T. Macrophage infiltration in acute coronary syndromes: implications for plaque rupture. Circulation 1994; 90: 775-778. 5. Fernandez-Ortiz A, Badimon J J, Falk E, Fuster V, Meyer B, Mailhac .4, Weng D, Shah P K, Badimon L. Characterization of the relative thrombogenicity of atherosclerotic plaque components: Implications for consequences of plaque rupture. J Am Coil Cardiol 1994; 23: 1562-1569. 6. Kristensen S D. The platelet-vessel wall interaction in experimental atherosclerosis and ischaemic heart disease - with special reference to thrombopoiesis. Dan Med Bull 1992; 39:110-127. 7. Martin J F, Bath P M W, Burr M L. Influence of platelet size on outcome after myocardial infarction. Lancet 1991; 338:1409-1411. 8. Trip M D, Cats V M, van Capelle F R L, Vreeken J. Platelet hyperreactivity and prognosis in survivors of myocardial infarction. N EnglJ Med 1990; 322: 1549-1554. 9. Weiss E J, Bray P F, Tayback M, Schulman S P, Kickler T S, Becker L C, Weiss J L, Gerstenblith G, Goldschmidt-Clermont P J. A polymorphism of a glycoprotein receptor as an inherited risk factor for coronary thrombosis. N Engl J Med 1996; 334: 1090-1094. 10. Thompson S G, Kienast J, Pyke S D M, Haverkate F, van de Loo J C W for the European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N EnglJ Med 1995; 332: 635-641.
© Pearson Professional Ltd 1997
Fibrinolysis & Proteolysis (1997) 11, Suppl. 1, 105-108 © Pearson ProfessionalLtd 1997
AntithromboticTherapy
P a t h o p h y s i o l o g y of a c u t e i s c h e m i c syndromes: r e c e n t progress S. D. Kristensen, E. Falk Department of Cardiology B, Skejby Hospital, Aarhus University Hospital, 8200 Aarhus N, Denmark.
Atherosclerosis without thrombosis is in general a benign disease. However, acute thrombosis, precipitated by plaque disruption, frequently complicates the course of coronary atherosclerosis. It causes unstable angina, myocardial infarction, and sudden death. The risk of plaque disruption depends more on plaque type (composition) than on plaque size or stenosis severity. Major determinants of a plaque's vulnerability to rupture are: the size and consistency of the lipid-rich atheromatous core, the thickness of the fibrous cap covering the core, and ongoing inflammation within the cap. Both plaque vulnerability (intrinsic disease) and rupture triggers (extrinsic forces) are important for plaque disruption. The former predisposes the plaque to rupture while the latter may precipitate it. The resultant thrombotic response, which is important for the clinical presentation and outcome, is in part determined by the reactivity of the circulating platelets and the coagulation system. The challenge of today is to identify and treat the dangerous vulnerable plaques responsible for infarction and death and to optimize anti-thrombotic treatment. Summary
INTRODUCTION
The development of coronary atherosclerosis starts in childhood, but it takes several decades to form the mature plaques responsible for the chronic ischemic episodes that occur in patients with stable angina pectoris. Unfortunately, this slowly developing relatively benign disease sometimes suddenly changes and severe, lifethreatening acute myocardial ischemia arises. Clinically, this gives rise to the acute coronary ischemic syndromes, unstable angina pectoris, acute myocardial infarction, and sudden coronary death. Studies based on autopsy, angiography, and angioscopy have shown that the formation of a coronary thrombus superimposed on an atherosclerotic plaque, leading to total or subtotal occlusion of the artery, and in some cases peripheral embolization, is the key event that causes the devastating change in symptoms and prognosis. The initial event in coronary thrombus formation is usually disruption or fissuring of the plaque. At the site of plaque rupture, platelets adhere to the artery wall and release vasoconstrictory and aggregatory substances. A platelet-thrombus is formed, the coagulation system is activated, and the end-product is a stable coronary Correspondance to: Erling Falk, Telefax: +45 89496009
thrombus consisting of aggregated platelets and fibrin
(Fig. 1A). Plaque type (composition), rather than plaque size (stenosis severity), has emerged as being the most important determinant for the development of the thrombusmediated acute coronary syndromes; lipid-rich and soft plaques are more dangerous than collagen-rich and hard plaques because they are vulnerable to rupture and highly thrombogenic after disruption. Detailed knowledge on the pathophysiology of coronary thrombus formarion may provide tools for prevention and treatment of the ischemic syndromes. This paper focuses on the cause and role of plaque rupture and on the subsequent thrombus formation. ATHEROGENESlS
The generation and growth of the atherosclerotic plaque are the result of a dynamic interaction between the vessel wall and the flowing blood, involving the following pathological processes: 1,2 Inflammation: increased endothelial permeability, endo-
thelial activation/dysfunction, and monocyte recruitment. Growth: smooth muscle cell (SMC) proliferation, migration and matrix synthesis. 105
106
Fibrinolysis & Proteolysis
ciated rapid plaque growth is usually clinically silent. This disruption is probably the most important mechanism responsible for the unpredictable, sudden, and nonlinear progression of coronary lesions frequently observed angiographically, a,3 However, survival is good as long as thrombotic complications do not occur. It is thrombosis, superimposed on mature plaques, that turns a relatively benign disease into a life-threatening acute coronary syndrome. 2,3 MATURE
Fig. A. As illustrated here, coronary thrombosis is a dynamic process. Most coronary thrombi have a layered structure indicating episodic growth by repeated mural deposits. This occluding thrombus has three layers, and aggregated platelets are clearly identifiable (at higher magnification) as the main component of the most recent part of the thrombus located centrally. B. A mature coronary plaque illustrating the two main plaque components: atheromatous 'gruel' (asterisk) and sclerotic tissue. The atheromatous component is lipid-rich, soft, and dangerous. Atherosis destabilizes a plaque, making it vulnerable to rupture, whereby the highly thrombogenic gruel is exposed to the flowing blood. In contrast, the sclerotic component is collagen-rich, hard, and safe. Sclerosis conveys stability to a plaque, protecting it against disruption.
Degeneration: lipid accumulation. Necrosis: cell death (cytotoxic effect of oxidized lipid?). Calcification: possibly an active process rather than a dystrophic phenomenon. Thrombosis: platelet aggregation and fibrin formation.
Proliferation of SMC, matrix synthesis, and lipid accumulation may gradually narrow the arterial lumen and ultimately lead to myocardial ischemia and anginal pain. Plaque disruption itself is asymptomatic, and the assoFibrinolysis & Proteolysis (1997) 11, SuppL 1, 105-108
PLAQUES: TWO MAIN COMPONENTS
In patients with ischemic heart disease, the coronary arteries are diffusely involved with confluent 'plaquing'. The composition, consistency, vulnerability, and thrombogenicity of individual plaques vary greatly without any obvious relation to risk factors for clinical disease. Most importantly, there is no simple relation between the size of a plaque (or stenosis severity) and its composition or vulnerability to rupture. As the name 'atherosclerosis' implies, mature plaques consist typically of two main components: soft, lipid-rich atheromatous 'gruel', and hard, collagen-rich sclerotic tissue (Fig. 1B). The sclerotic component is usually by far the most voluminous but it is relatively innocuous because collagen secreted by SMC probably stabilizes a plaque against disruption. In contrast, the atheromatous component is by far the most dangerous because it destabilizes a plaque, making it vulnerable and susceptible to rupture and thrombosis. 3 The destabilizing atheromatous component or core lacks supporting collagen, is rich in extracellular lipids (predominantly cholesterol and its esters), is avascular and hypocellular, and is usually soft like gruel. PLAQUE DISRUPTION: TRIGGERS
VULNERABILITY
AND
Disruption of vulnerable plaques occurs frequently. It is followed by variable amounts of luminal thrombosis and/ or hemorrhage into the soft gruel, causing rapid growth of the lesion. Autopsy data indicate that 9% of 'normal' healthy persons are walking around with disrupted plaques (without superimposed thrombosis) in their coronary arteries. The numbers increase to 22% in persons with diabetes or hypertension. 3 One or more disrupted plaques, with or without superimposed thrombosis, are usually present in coronary arteries of patients dying of ischemic heart disease. 3 The risk of plaque disruption depends on both intrinsic properties of individual plaques (their vulnerability) and extrinsic forces acting on plaques (rupture triggers). The former predispose plaques to rupture, while the latter may precipitate disruption if vulnerable plaques are present. © Pearson Professional Ltd 1997
3rd International Fibrinogen Symposium
Vulnerability
Plaque disruption occurs most frequently where the fibrous cap is thinnest, most heavily foam cell infiltrated, and, therefore, weakest. 3 For eccentric plaques, this site is often the junction between the plaque and the adjacent less diseased vessel wall, called the shoulder region of the plaque. There seem to be 3 major determinants of a plaque's vulnerability to rupture: core size, cap thickness, and cap inflammation. Core size
The size and consistency of the atheromatous core are important factors for the stability of a plaque. The bigger the core, the more vulnerable (rupture-prone) is the plaque)
107
blood. 3 Superficial plaque inflammation with intimal erosion but no frank disruption (i.e., no deep injury) are found beneath the remaining fatal thrombi, 3 usually in combination with a severe atherosclerotic stenosis. Determinants of thrombosis
Most disrupted plaques are resealed by a small mural thrombus, and only sometimes does a major luminal thrombus evolve. Therefore, the thrombotic response to plaque disruption/erosion is a key event in the pathophysiology of acute ischemic syndromes. Several factors such as the thrombogenic substrate, local flow disturbances and, last but not least, the systemic thrombotic propensity are important. Thrombogenic substrate
Cap thickness
Rupture of the fibrous cap covering the core occurs most frequently at its junctions with the adjacent more normal intima (the shoulder regions) being where the cap usually is the thinnest and, therefore, weakest. 3
The atheromatous 'gruel' is not only the most vulnerable plaque component, it also appears to be the most thrombogenic component. 5 Recent data indicate that macrophage-derived tissue factor could be responsible for the high thrombogenicity of the gruel, s
Cap inflammation
Local flow disturbances
The shoulder regions are predilection sites for macrophage foam cell infikration, and activated macrophages are usually concentrated at the actual rupture/erosion site beneath coronary thrombi, indicating ongoing inflammation. 3 Of note, culprit lesions from patients with unstable coronary syndromes contain significantly more macrophages than do plaques from stable patients. 4 Macrophages are capable of degrading extracellular matrix by secreting proteolytic enzymes such as plasminogen activators and metalloproteinases, which may weaken the fibrous cap, predisposing it to rupture)
A severe stenosis and surface irregularities may activate platelets. A platelet-rich thrombus may indeed form and grow within a severe stenosis, where the blood velocity and shear forces are highest, probably because of shear-induced platelet activation. 3 Irregularities of the exposed surface do also increase thrombus formation. 5
Rupture triggers
Coronary plaques are constantly stressed by a variety of mechanical and hemodynamic forces that may precipitate or 'trigger' disruption of vulnerable plaques. 3Physical exertion and emotional stress could, for example, trigger plaque disruption via surges in sympathetic activity with an increase in blood pressure, pulse pressure, blood flow (shear forces), heart rate, and coronary tone. PLAQUE THROMBOSIS
About 75% of thrombi responsible for acute coronary syndromes are precipitated by plaque disruption whereby the highly thrombogenic gruel is exposed to the flowing © Pearson Professional Ltd 1997
Systemic thrombotic propensity
The actual thrombotic-thrombolytic equilibrium at the time of plaque disruption does also influence the outcome. The importance of platelets is clearly documented by the protective effect of aspirin in patients with stable and unstable angina pectoris and in patients with acute myocardial infarction. 2'6 There is also evidence that a systemic activation of coagulation and increase in platelet reactivity occurs in the acute phase of a myocardial infarction and in unstable angina pectoris. 6 Patients with acute myocardial infarction have a shorter bleeding time and a higher mean platelet volume than controls admitted with chest pain without signs of infarction. 6 Since large platelets are more active hemostatically than small ones, this points to an increased reactivity of the circulating platelets at the time of the acute event. Also the synthesis of proaggregatory thromboxane A2 is increased in the acute phase of acute myocardial infarction and in unstable angina pectoris. 6 A high mean Fibrinolysis & Proteolysis (1997) 11, SuppL 1, 105-108
108
Fibrinolysis & Proteolysis
platelet v o l u m e 7 a n d i n c r e a s e d s p o n t a n e o u s platelet a g g r e g a t i o n 8 h a v e b e e n s h o w n to b e risk factors for reinfarction a n d d e a t h in p a t i e n t s surviving m y o c a r d i a l infarction. Recently, it h a s b e e n r e p o r t e d t h a t a polym o r p h i s m of t h e g l y c o p r o t e i n IIIa g e n e is p r e v a l e n t w i t h a h i g h f r e q u e n c y in y o u n g patients w i t h a c u t e i s c h a e m i c s y n d r o m e s 9 s u g g e s t i n g t h a t t h e platelet g l y c o p r o t e i n Ilb/IIIa r e c e p t o r m a y b e a l t e r e d on a n i n h e r i t e d basis in s o m e of t h e s e patients. P l a s m a f i b r i n o g e n is a w e l l - k n o w n risk factor for t h e d e v e l o p m e n t of i s c h e m i c h e a r t disease. In t h e ECAT a n g i n a pectoris study, t h e base-line levels of fibrinogen, y o n W i l l e b r a n d factor antigen, a n d t-PA a n t i g e n were f o u n d to be i n d e p e n d e n t p r e d i c t o r s of s u b s e q u e n t a c u t e i s c h e m i c s y n d r o m e s . 1° H i g h p l a s m a f i b r i n o g e n levels m a y b e a m a r k e r of o n g o i n g i n f l a m m a t i o n in t h e v a s c u l a r s y s t e m a n d m a y also c o n t r i b u t e to a p r o t h r o m b o t i c state in t h e s e patients.
CONCLUSION Plaque r u p t u r e is u s u a l l y t h e initial e v e n t in t h e format i o n of c o r o n a r y t h r o m b i r e s p o n s i b l e for t h e a c u t e coron a r y s y n d r o m e s . F u r t h e r insight into t h e cause of p l a q u e r u p t u r e is w a r r a n t e d a n d m a y p r o v i d e i n f o r m a t i o n t h a t m a k e s p r e v e n t i o n of p l a q u e r u p t u r e possible. C o a g u l a tion, fibrinolysis, and, in particular, platelets are i m p o r t a n t for t h r o m b u s f o r m a t i o n a n d are t h e targets of antithrombotic therapy.
Fibrinolysis & Proteolysis (1997) 11, SuppL 1, 105-108
REFERENCES 1. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993; 362: 801-809. 2. Fuster V. Lewis A. Conner Memorial Lecture. Mechanisms leading to myocardial infarction: insights from studies of vascular biology. Circulation 1994, 90:2126-2146. 3. Falk E, Shah P K, Fuster V. Coronary plaque disruption. Circulation 1995; 92: 657-671. 4. Moreno P R, Falk E, Palacios I F, Newell J B, Fuster V, Fallon J T. Macrophage infiltration in acute coronary syndromes: implications for plaque rupture. Circulation 1994; 90: 775-778. 5. Fernandez-Ortiz A, Badimon J J, Falk E, Fuster V, Meyer B, Mailhac .4, Weng D, Shah P K, Badimon L. Characterization of the relative thrombogenicity of atherosclerotic plaque components: Implications for consequences of plaque rupture. J Am Coil Cardiol 1994; 23: 1562-1569. 6. Kristensen S D. The platelet-vessel wall interaction in experimental atherosclerosis and ischaemic heart disease - with special reference to thrombopoiesis. Dan Med Bull 1992; 39:110-127. 7. Martin J F, Bath P M W, Burr M L. Influence of platelet size on outcome after myocardial infarction. Lancet 1991; 338:1409-1411. 8. Trip M D, Cats V M, van Capelle F R L, Vreeken J. Platelet hyperreactivity and prognosis in survivors of myocardial infarction. N EnglJ Med 1990; 322: 1549-1554. 9. Weiss E J, Bray P F, Tayback M, Schulman S P, Kickler T S, Becker L C, Weiss J L, Gerstenblith G, Goldschmidt-Clermont P J. A polymorphism of a glycoprotein receptor as an inherited risk factor for coronary thrombosis. N Engl J Med 1996; 334: 1090-1094. 10. Thompson S G, Kienast J, Pyke S D M, Haverkate F, van de Loo J C W for the European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N EnglJ Med 1995; 332: 635-641.
© Pearson Professional Ltd 1997