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Acute coronary syndromes: Thrombosis versus fibrinolysis
Fibrinolysis (1993) 7, Suppl 1 : 44-49 8 1993 Lnngmn Group UK Lid
Thrombolytic Therapy: Clinical Experience
Acute Coronary Syndromes: Versus Fibrinolysis
injury and thrombus size is much more variable than in animals, suggesting that the thrombogenic stimuli andfor the haemostatic response are not directly proportional to the anatomic damage. K&gel3 observed at necroscopy that a thrombus was associated with plaque rupture in 53% of cases in acute coronary syndromes. Arbustini4 reported that, at necroscopy, in 50% of cases of death occurring from non-cardiac causes, there was a significant coronary stenosis, and in 5% there was a coronary thrombus. Occasionally, fissured plaques without thrombi, and thrombi without plaque fissure, may be observed. These observations suggest that factors other than vascular injury play a role in determining thrombus formation and coronary ischemia.
Thrombosis
Luigi M Biasucci and Attilio Maseri Universitd Cattolica, L.urgo A. Gemelli 8,00168 Roma, Italy
Intracoronary thrombi are a common feature of unstable angina and acute myocardial infarction as assessed by angiographic angioscopic and pathologic studies. Although coronary thrombosis is the ultimate, common cause of these acute coronary syndromes, its occurrence is very rare even in patients with extensive atberosclerosis and is often unheralded. Several angiographic studies have shown that there is no difference in the number of diseased vessels found in stable and unstable angina and post-mortem studies showed that coronary atherosclerosis is extensive also in many patients dying of non-cardiac causes. These observations are in keeping with recent data showing that, in most of the cases of myocardial infarction, the culprit lesion is not significantly stenotic after thrombolysis’ or was not seen in a previous angiogram and seem to indicate that the extent of the atherosclerosis cannot be the only determinant of acute coronary syndromes.
Thrombogenic stimuli and thrombus growth: the lesson of the animal studies If the severity of the vessel lesion is not the only determinant of acute coronary syndromes, the possibility of either strong, local thrombogenic stimuli, unrelated to the anatomic vessel wall damage, or of thrombus growth, out of proportion to the local thrombogenic stimulus, caused by an enhanced thrombotic response or by a defective fibrinolytic response should be considered. The physiological response to thrombogenic stimuli of different intensity can be inferred from animal studies. The type of thrombi that develop in the coronary arteries of otherwise healthy dogs (who are supposed to exhibit normal hemostasis) depends on the intensity of the local thrombogenic stimulus. In dogs the insertion of a 3 mm copper coil into the main left coronary artery is followed within about five minutes by complete coronary occlusion caused by a red thrombus.5 This experiment demonstrates that (a) even in previously healthy animals an occlusive thrombus can develop very rapidly in response to a strong, persisting thrombogenic stimulus, and (b) rapidly developing occlusive arterial thrombi are predominantly composed of red cells and fibrin. Conversely the application of an anodal current to the coronary lumen via a stainless steel electrode causes a local occlusive white thrombus.> The rate at which the thrombus develops depends on the intensity of the electrical current and is of the order of about one hour. When a low intensity current is applied, the formation of thrombi may take hours and may be inhibited by antiplatelet agents.6
Role of the vessel injury In healthy animals the severity of the injury to the vessel wall is an important determinant of the size of the thrombus. On the basis of these findings, Fuste? proposed a pathophysiologic classification of vascular injury that divides it into three types: (1) functional endothelial changes without morphologic alteration, (2) endothelial denudation and intimal lesion leading to platelet deposition, and (3) rupture of a lipid rich plaque with very deep injury and thrombus formation. A proportional relation between the severity of intimal injury and thrombus size is to be expected in previously normal arteries of otherwise healthy animals, as the repair process (thrombus formation) is proportional to the intensity of the mechanical damage. However, in patients with acute coronary syndromes, the relation between anatomical vessel wall 44
Fibrinolysis
Are platelets responsible for a disproportional thrombus growth? In humans a disproportional large thrombus relative to the thrombogenic stimulus may develop either because of enhanced platelet adhesion and aggregation, increased generation of thrombin and defective fibrinolysis. The predominant platelet composition of arterial thrombi, suggests they form gradually in response to rather weak thrombogenic stimuli. Markers of platelet activation have been described in acute coronary syndromes. The formation of platelet rich (white) thrombi occurs in three steps: platelet adhesion, activation and release. Platelets may also provide a necessary membrane support for the initiation of coagulation, and modulate fibrinolysis as they carry both plasminogen activators (tPA and u-PA) and inhibitors (PAI-1). The large variation in ex-vivo platelet responses to aggregating agents in normals, and the possibility that the enhanced platelet response in ischemic patients represents a physiological rather than a pathological response to acute and chronic vessel damage, prevent fii conclusions about the possible role of the platelet in growing thrombi out of proportion.
45
question arises whether a continuous activation of the system exists during ischemia, or a chronic prethrombotic state is present in these patients. A prethrombotic state has been proposed however: it is possible that the prethrombotic state might be present only a few days or even hours before the event, and/or may have a significant pathogenic role in some patients, but not in others. Recently the possibility that an inflammatory state could increase procoagulant activit in unyo stable angina has been also reported. Falk in a post-mortem study demonstrated that unstable angina is often characterized by a mural multilayered thrombus; these findings are consistent with the clinical presentation of the syndrome, with anginal attacks alternating with asymptomatic periods and suggest the occurrence of episodes of weak thrombogenic stimuli.
Conclusions In patients the thrombogenic stimuli and the mechanisms of thrombosis in unstable angina and infarction, therefore, are more complex than those responsible for the thrombus that forms in a previously healthy animal as an acute repair mechanism, which is necessarily proportional to the severity of the received injury.
Evidence of a possible imbalance of the hemostaticfibrinolytic system The stability of the platelet thrombus, and its growth, lie on the amount of thrombin generation by the hemostatic system, leading to fibrin deposition, and, on the other hand, on the activity of the fibrinolytic system. Normally a physiological balance exists between thrombosis and fibrinolysis; it has been supposed that an imbalance between hemostasis and fibrinolysis, due either to increased thrombotic or to reduced fibrinolytic activity, could lead to acute myocardial ischemia. Several authors have reported an increase of thrombin generation or activity in the acute coronary syndromes, measuring the thrombin-antithrombin III complexes (TAT), or the fibrinopeptide A (FPA), which is cleaved from fibrinogen by thrombin during the generation of fibrin. Epidemiological studies have also reported a hypercoagulable state in ischemic heart disease (IHD): in the Northwick Heart Park Study7 an association was found between FVII, fibrinogen, and IHD. Increased levels of fibrinogen were also associated with IHD in the Framingham* and in the Caerphillyg studies. Reduced fibrinolytic activity as a consequence of an increase in PAI- has been reported in survivors of myocardial infarction. Since PA.I-1 and fibrinogen are acute phase reactant, these relations could be spurious ones. Moreover most of these studies have been accomplished on the basis of one single blood sample: it is questionable whether conclusions on the long term behaviour and meaning of substances with such a large variability such as PAI-1, or with a half life as short as 5 minutes, such as TAT and FPA, might be drawn on the basis of one single measurement, and the
References 1. Hackett D, Davies G, Maseri A. Pm-existing coronary stenoses in patients with first myocardial infarction are not necessarily severe. Eur Heart J 1988; 9: 1317-1323. 2. Fuster V, Badimon L, Badimon JJ, Chesebm JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992; 326; 242-250. 3. Kmgel AH, Gertz SD, Roberts WC. Morphologic comparison of frequency and types of acute lesions in the major coronary epicardial arteries in unstable angina pectoris, sudden comnary death and acute myocardial infarction. J Am Co11 Cardioll991; 18; 801-808. 4. Arbustini E, Grasso M, Diegoli M, et al. Coronary atherosclerotic plaques with and without thrombus in ischemic heart syndromes. Am J Cardiol 1991; 68; 36B-50B. 5. Sahuar AE. Experimental myocardial infarction, induction of coronary thrombosis in the intact closed-chest dog. Circ Res 1961; 9: 1351. 6. Kodenat RK, Kezdi P, Stanles EL. A new catheter technique for producing experimental coronary thrombosis and selective coronary visualization. Am Heart J 1972; 83: 360. 7. Meade TW, Mellows S, Brozovic M. Haemostatic function and ischemic heart disease: principal results of the Northwich Park Heart Study. Lancet 2; 233-237; 1986. 8. Kannel WB, Wolf PA, Castelli WP, D’Agostino RB. Fibrinogen and risk of cardiovascular disease. JAMA 1987; 258; 1183-l 186. 9. Yamell JWG, Baker LA. Sweetnam PM. Fibrinogen,viscosity, and white blood cell count are major risk factors for ischemic heart disease. Circulation 1991; 83; 836-844. 10. Falk E. Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death. Circulation 1985; 4; 699-708.
Thrombolytic Therapy: Clinical Experience
Acute Coronary Syndromes: Versus Fibrinolysis
injury and thrombus size is much more variable than in animals, suggesting that the thrombogenic stimuli andfor the haemostatic response are not directly proportional to the anatomic damage. K&gel3 observed at necroscopy that a thrombus was associated with plaque rupture in 53% of cases in acute coronary syndromes. Arbustini4 reported that, at necroscopy, in 50% of cases of death occurring from non-cardiac causes, there was a significant coronary stenosis, and in 5% there was a coronary thrombus. Occasionally, fissured plaques without thrombi, and thrombi without plaque fissure, may be observed. These observations suggest that factors other than vascular injury play a role in determining thrombus formation and coronary ischemia.
Thrombosis
Luigi M Biasucci and Attilio Maseri Universitd Cattolica, L.urgo A. Gemelli 8,00168 Roma, Italy
Intracoronary thrombi are a common feature of unstable angina and acute myocardial infarction as assessed by angiographic angioscopic and pathologic studies. Although coronary thrombosis is the ultimate, common cause of these acute coronary syndromes, its occurrence is very rare even in patients with extensive atberosclerosis and is often unheralded. Several angiographic studies have shown that there is no difference in the number of diseased vessels found in stable and unstable angina and post-mortem studies showed that coronary atherosclerosis is extensive also in many patients dying of non-cardiac causes. These observations are in keeping with recent data showing that, in most of the cases of myocardial infarction, the culprit lesion is not significantly stenotic after thrombolysis’ or was not seen in a previous angiogram and seem to indicate that the extent of the atherosclerosis cannot be the only determinant of acute coronary syndromes.
Thrombogenic stimuli and thrombus growth: the lesson of the animal studies If the severity of the vessel lesion is not the only determinant of acute coronary syndromes, the possibility of either strong, local thrombogenic stimuli, unrelated to the anatomic vessel wall damage, or of thrombus growth, out of proportion to the local thrombogenic stimulus, caused by an enhanced thrombotic response or by a defective fibrinolytic response should be considered. The physiological response to thrombogenic stimuli of different intensity can be inferred from animal studies. The type of thrombi that develop in the coronary arteries of otherwise healthy dogs (who are supposed to exhibit normal hemostasis) depends on the intensity of the local thrombogenic stimulus. In dogs the insertion of a 3 mm copper coil into the main left coronary artery is followed within about five minutes by complete coronary occlusion caused by a red thrombus.5 This experiment demonstrates that (a) even in previously healthy animals an occlusive thrombus can develop very rapidly in response to a strong, persisting thrombogenic stimulus, and (b) rapidly developing occlusive arterial thrombi are predominantly composed of red cells and fibrin. Conversely the application of an anodal current to the coronary lumen via a stainless steel electrode causes a local occlusive white thrombus.> The rate at which the thrombus develops depends on the intensity of the electrical current and is of the order of about one hour. When a low intensity current is applied, the formation of thrombi may take hours and may be inhibited by antiplatelet agents.6
Role of the vessel injury In healthy animals the severity of the injury to the vessel wall is an important determinant of the size of the thrombus. On the basis of these findings, Fuste? proposed a pathophysiologic classification of vascular injury that divides it into three types: (1) functional endothelial changes without morphologic alteration, (2) endothelial denudation and intimal lesion leading to platelet deposition, and (3) rupture of a lipid rich plaque with very deep injury and thrombus formation. A proportional relation between the severity of intimal injury and thrombus size is to be expected in previously normal arteries of otherwise healthy animals, as the repair process (thrombus formation) is proportional to the intensity of the mechanical damage. However, in patients with acute coronary syndromes, the relation between anatomical vessel wall 44
Fibrinolysis
Are platelets responsible for a disproportional thrombus growth? In humans a disproportional large thrombus relative to the thrombogenic stimulus may develop either because of enhanced platelet adhesion and aggregation, increased generation of thrombin and defective fibrinolysis. The predominant platelet composition of arterial thrombi, suggests they form gradually in response to rather weak thrombogenic stimuli. Markers of platelet activation have been described in acute coronary syndromes. The formation of platelet rich (white) thrombi occurs in three steps: platelet adhesion, activation and release. Platelets may also provide a necessary membrane support for the initiation of coagulation, and modulate fibrinolysis as they carry both plasminogen activators (tPA and u-PA) and inhibitors (PAI-1). The large variation in ex-vivo platelet responses to aggregating agents in normals, and the possibility that the enhanced platelet response in ischemic patients represents a physiological rather than a pathological response to acute and chronic vessel damage, prevent fii conclusions about the possible role of the platelet in growing thrombi out of proportion.
45
question arises whether a continuous activation of the system exists during ischemia, or a chronic prethrombotic state is present in these patients. A prethrombotic state has been proposed however: it is possible that the prethrombotic state might be present only a few days or even hours before the event, and/or may have a significant pathogenic role in some patients, but not in others. Recently the possibility that an inflammatory state could increase procoagulant activit in unyo stable angina has been also reported. Falk in a post-mortem study demonstrated that unstable angina is often characterized by a mural multilayered thrombus; these findings are consistent with the clinical presentation of the syndrome, with anginal attacks alternating with asymptomatic periods and suggest the occurrence of episodes of weak thrombogenic stimuli.
Conclusions In patients the thrombogenic stimuli and the mechanisms of thrombosis in unstable angina and infarction, therefore, are more complex than those responsible for the thrombus that forms in a previously healthy animal as an acute repair mechanism, which is necessarily proportional to the severity of the received injury.
Evidence of a possible imbalance of the hemostaticfibrinolytic system The stability of the platelet thrombus, and its growth, lie on the amount of thrombin generation by the hemostatic system, leading to fibrin deposition, and, on the other hand, on the activity of the fibrinolytic system. Normally a physiological balance exists between thrombosis and fibrinolysis; it has been supposed that an imbalance between hemostasis and fibrinolysis, due either to increased thrombotic or to reduced fibrinolytic activity, could lead to acute myocardial ischemia. Several authors have reported an increase of thrombin generation or activity in the acute coronary syndromes, measuring the thrombin-antithrombin III complexes (TAT), or the fibrinopeptide A (FPA), which is cleaved from fibrinogen by thrombin during the generation of fibrin. Epidemiological studies have also reported a hypercoagulable state in ischemic heart disease (IHD): in the Northwick Heart Park Study7 an association was found between FVII, fibrinogen, and IHD. Increased levels of fibrinogen were also associated with IHD in the Framingham* and in the Caerphillyg studies. Reduced fibrinolytic activity as a consequence of an increase in PAI- has been reported in survivors of myocardial infarction. Since PA.I-1 and fibrinogen are acute phase reactant, these relations could be spurious ones. Moreover most of these studies have been accomplished on the basis of one single blood sample: it is questionable whether conclusions on the long term behaviour and meaning of substances with such a large variability such as PAI-1, or with a half life as short as 5 minutes, such as TAT and FPA, might be drawn on the basis of one single measurement, and the
References 1. Hackett D, Davies G, Maseri A. Pm-existing coronary stenoses in patients with first myocardial infarction are not necessarily severe. Eur Heart J 1988; 9: 1317-1323. 2. Fuster V, Badimon L, Badimon JJ, Chesebm JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992; 326; 242-250. 3. Kmgel AH, Gertz SD, Roberts WC. Morphologic comparison of frequency and types of acute lesions in the major coronary epicardial arteries in unstable angina pectoris, sudden comnary death and acute myocardial infarction. J Am Co11 Cardioll991; 18; 801-808. 4. Arbustini E, Grasso M, Diegoli M, et al. Coronary atherosclerotic plaques with and without thrombus in ischemic heart syndromes. Am J Cardiol 1991; 68; 36B-50B. 5. Sahuar AE. Experimental myocardial infarction, induction of coronary thrombosis in the intact closed-chest dog. Circ Res 1961; 9: 1351. 6. Kodenat RK, Kezdi P, Stanles EL. A new catheter technique for producing experimental coronary thrombosis and selective coronary visualization. Am Heart J 1972; 83: 360. 7. Meade TW, Mellows S, Brozovic M. Haemostatic function and ischemic heart disease: principal results of the Northwich Park Heart Study. Lancet 2; 233-237; 1986. 8. Kannel WB, Wolf PA, Castelli WP, D’Agostino RB. Fibrinogen and risk of cardiovascular disease. JAMA 1987; 258; 1183-l 186. 9. Yamell JWG, Baker LA. Sweetnam PM. Fibrinogen,viscosity, and white blood cell count are major risk factors for ischemic heart disease. Circulation 1991; 83; 836-844. 10. Falk E. Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death. Circulation 1985; 4; 699-708.