1 Comment


Williams Hematology



Introduction: Coronary Artery Disease and Thrombosis
Clinical Presentations of Coronary Artery Disease
Pathophysiology of Atherosclerotic Disease

Classification of Atherosclerotic Plaques

Animal Models of Atherosclerosis

Response-to-Injury Model of Atherosclerosis

Thrombosis and Plaque Rupture

Models of Acute Arterial Injury and Thrombus Formation
Molecular Basis of the Atherothrombotic State

Tissue Factor

Tissue Factor Pathway Inhibitor

The Fibrinolytic System: Plasminogen Activators

Plasminogen Activator Inhibitor 1

Plasminogen Activator Inhibitor 2 (PAI-2)

Receptor for UPA

Transgenic Mouse Models and the Fibrinolytic System



Prothrombin Fragments 1 and 2 and Fibrinopeptide A


Treatment of Acute Coronary Syndromes

Unstable Angina

Acute MI

Treatment of the Post-Mi Patient
Chapter References

Atherosclerosis manifested by cardiovascular, cerebrovascular, and peripheral vascular disease is the leading underlying cause of mortality in the United States and other industrialized countries. This disease is characterized by an inflammatory and proliferative response of the arterial wall and the subsequent development of thrombosis, often in association with plaque rupture. Many of the important developments in the treatment of acute coronary syndromes, such as the use of aspirin, thrombolytic drugs, and antiplatelet agents, have targeted the thrombotic component of atherosclerosis.
Tissue factor (TF) is thought to be a key determinant of plaque thrombogenicity and of the hypercoagulable state associated with acute arterial injury. The cellular source of plaque TF is likely to be macrophages and smooth-muscle cells (SMC). However, the location of the TF most important for initiating or propagating arterial thrombosis may be extracellular, arising from cell necrosis, apoptosis, and vesiculation from the cell surface. Circulating TF may also play an important role in determining the extent of arterial thrombosis. The fibrinolytic system is thought to provide the normal arterial wall with an antithrombotic surface. However, the role of plasminogen activators in protecting injured or atherosclerotic vessels against thrombosis remains controversial. Plasmin may also be important in mediating vascular remodeling by its effects on metalloproteinase activation and SMC proliferation and migration.

Acronyms and abbreviations that appear in this chapter include: ADP, adenosine diphosphate; CAD, coronary artery disease; CAPRIE study, Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events study; CARS, Coumadin Aspirin Reinfarction Study; EC, endothelial cells; EGF, epidermal growth factor; FGF, fibroblast growth factor; LPC, lysophosphatidylcholine; LPS, lipopolysaccharide; MCP-1, monocyte chemoattractant protein-1; MI, myocardial infarction; NO, nitric oxide; PAI-1, plasminogen activator inhibitor 1; PAs, plasminogen activators; PDGF, platelet-derived growth factor; PTCA, percutaneous transluminal coronary angioplasty; SK, streptokinase; SMC, smooth-muscle cells; TF, tissue factor; TFPI, tissue factor pathway inhibitor; TGF-b, transforming growth factor beta; tPA, tissue-type plasminogen activator; UA, unstable angina; uPA, urokinase-type plasminogen activator; uPAR, uPA receptor.

Atherosclerosis is the leading underlying cause of mortality in the United States and other industrialized countries.1,2 The major manifestations of atherosclerosis are coronary artery disease (CAD) (myocardial infarction (MI), angina, sudden death), cerebrovascular disease (ischemic stroke), and peripheral vascular disease (intermittent claudication, ischemic limbs). It is estimated that more than 1.5 million MIs occur annually in the United States, with approximately 500,000 resulting in death2. A substantial portion of these deaths (200–300,000) occur before patients reach the hospital, largely due to arrhythmias.2
An additional 200,000 deaths are attributable to stroke and peripheral vascular disease. Among survivors of MI, approximately 200,000 die annually from complications of heart failure; this number is rising as the incidence of death from acute MI falls.
The association of coronary atherosclerosis with thrombosis was first made in 1912 by Herrick,3 who noted thrombotic coronary occlusions in patients presenting with acute MI. Subsequently, the term coronary thrombosis entered the vernacular to describe MI. In an autopsy study of patients dying of MI in 1966, Constantinides4 demonstrated that thrombotic occlusion was associated with fractures of the fibrous lining of atherosclerotic plaques. A series of studies by Davies and colleagues5,6 and 7 further established the importance of plaque rupture as the cause of acute ischemic syndromes—MI, unstable angina (UA), and sudden death.
Studies demonstrating that coronary artery spasm might be an important cause of MI in patients with coronary atherosclerosis8,9 led to a reevaluation in the 1970s of the role of thrombosis as the precipitating event in acute coronary syndromes and raised a question as to whether the thrombus seen at autopsy was deposited subsequent to a vasospastic occlusive event.
In the 1980s, the identification of thrombosis on coronary angiography,10 and studies demonstrating the efficacy of intracoronary11 and intravenous12,13 thrombolysis in opening occluded coronary arteries refocused attention on thrombosis as the main cause of acute MI. The success of aspirin in the treatment of UA and in secondary prevention of MI13,14 further helped to establish thrombosis as a major cause of acute coronary events and also suggested that platelet aggregation played a critical role. The importance of platelet aggregation has been buttressed by the success of new antiplatelet agents in the treatment of acute coronary syndromes.15,16 Although the mechanism of coronary thrombosis remains to be fully elucidated, the inciting event in the majority of patients appears to be rupture of the atherosclerotic plaque.
The Framingham Heart Study was established in 1948 to examine factors associated with risk for CAD.17 To date, approximately 75 percent of the original Framingham Heart Study participants have died, the leading cause of death being CAD. The Framingham Heart Study was instrumental in defining the risk factors for CAD.18 Many other programs have subsequently provided important data to corroborate the Framingham findings and to establish additional risk factors (see Pasternak and colleagues19 and Table 130-1).


Angina pectoris results from reversible myocardial ischemia and is characterized by episodic chest discomfort lasting for up to 20 min. Angina is the most common presentation of CAD, with a prevalence of greater than 20 percent in men ages 65 to 69 years and greater than 13 percent in women of similar age.2 The principal pathologic finding underlying typical angina is stenosis (>70%) of one or more coronary arteries.
UA is an acute coronary syndrome characterized by chest pain of new onset or an abrupt worsening of previously stable angina. Like stable angina, episodes are reversible and not associated with evidence of cardiac muscle damage. The risk of MI and death within a year of an episode of UA is as high as 15 percent.20,21,22 and 23
MI, death of cardiac muscle, is due to irreversible ischemia resulting from prolonged coronary artery occlusion. Sudden death is a frequent concomitant of MI and is due to the development of arrhythmias, usually ventricular fibrillation.
Studies in humans have been largely confined to pathologic examination at a single point in time of vessels taken at autopsy, plaques removed during surgical or percutaneous endarterectomies, and fragments removed during coronary atherectomies. These studies have been instrumental in establishing the progression of coronary atherosclerosis over decades.
The American Heart Association has classified atherosclerotic plaques into five phases (Fig. 130-1), based upon the work of Stary and colleagues.24 Phase 1 (types I–III) is characterized by a small plaque, often present during the first decade of life. Type I lesions are not apparent by gross examination and are characterized by isolated foam cells in the arterial wall. Type II lesions have a more abundant accumulation of foam cells organized to form a fatty streak, the first lesion that is apparent on gross examination. Type III lesions are characterized by a raised fatty streak, comprised of foam cells, increased number of SMC, and small extracellular accumulations of lipid. Phase 2 (types IV and Va) is characterized by nonobstructive “soft” lesions. Type IV lesions are characterized by diffuse extracellular lipid. Type Va lesions also have a high extracellular lipid content; however, the lipid is more localized and surrounded by a thin cap. The type Va lesion is thought to have the highest propensity to rupture.

FIGURE 130-1 Classification of atherosclerotic plaques based upon gross pathologic and clinical findings. Roman numerals and phases indicate histologic types, as classified by the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. (Reproduced with permission from Fuster V: Mechanisms leading to myocardial infarction: insights from studies of vascular biology. Circulation 94:2013, 1994.)

Phase 3 and 4 are characterized by plaque rupture (Fig. 130-1) and thrombosis (phase 3 if mural, phase 4 if occlusive) and the development of a type VI complex lesion. Organization of the thrombus by connective tissue ultimately results in severely stenotic (type Vb) or occlusive (type Vc) fibrotic lesions. In some cases, type Va lesions do not rupture and progress to type Vb and Vc lesions, characterized by thick fibrous caps comprised of SMC and collagen. These lesions become increasingly stenotic over time.
Most animals are resistant to atherosclerosis and do not develop plaques when raised on normal laboratory chow. Virtually all models of atherosclerosis have therefore relied on the use of high-fat, high-cholesterol diets, many of which more closely simulate the diet of individuals in industrialized countries. Normal and Watanabe heritable hyperlipidemic rabbits25,26 primarily develop fatty streaks when kept on atherogenic diets, although prolonged feeding can result in more advanced lesions. Similarly, dietary-induced atherosclerosis in pigs27 leads to early lesions. Hypercholesterolemic diets in nonhuman primates28,29,30 and 31 generate lesions ranging from fatty streaks to more advanced fibrous plaques.
Perhaps the most important advance in the study of atherosclerosis has been the development of transgenic and knockout mouse models (reviewed in Breslow32). Normal mice and rats fail to develop atherosclerotic lesions, even when fed diets rich in cholesterol and fat. Mice deficient in apolipoprotein E (ApoE–/–), the major protein constituent of HDL, have severe hypercholesterolemia and develop all lesion types, including advanced lesions with necrotic cores and fibrous caps.33 Similarly, mice lacking the LDL receptor (LDLR–/–) have extremely high cholesterol levels and develop severe lesions.34 Mice overexpressing apolipoprotein B, the major protein constituent of LDL, have cholesterol levels and profiles similar to those seen in hypercholesterolemic humans but develop less severe lesions.35 The use of these transgenic animal models has allowed investigators to study the molecular events associated with the development of atherosclerosis under conditions in which lesion progression is greatly accelerated. Furthermore, by mating these mice with those deficient in a specific gene hypothesized to be important in atherosclerosis, one can establish the role of that gene in plaque development or progression. For example, an important role for monocyte chemoattractant protein-1 (MCP-1) in plaque development has been established by generating LDLR–/– mice that are also lacking MCP-1,36 or ApoE–/– mice lacking the MCP-1 receptor, CCR2.37 Both mice have a 50 percent reduction in plaque size and macrophage-derived foam cell accumulation within the lesions. An even greater reduction in plaque size and foam cell accumulation has been found when the mice overexpressing apolipoprotein B are mated to the MCP-1–/– mice.38 Despite the power of atherosclerotic mouse models, their lesions remain distinct from those of humans in two critical aspects: They do not rupture spontaneously, and they do not display intramural thrombosis.
Data derived from studies on animal models of atherosclerosis and the examination of pathologic specimens from human disease have led to a widely accepted hypothesis, first advanced by Ross and colleagues, that atherosclerosis develops as a response to injury.39,40 This hypothesis views atherosclerosis as a normal wound-healing process designed to repair an insult to the arterial wall. The first line of defense against atherosclerosis is a normal endothelial layer. The endothelium provides a nonadherent, nonthrombogenic surface, helps in the formation of the basement membrane, and acts as a semipermeable barrier to and from the underlying media. Normal endothelium also promotes vasodilatation by the secretion of nitric oxide (NO) and prostacyclin (see Chap. 114). The atherosclerotic process is thought to begin with damage to this layer, resulting in endothelial dysfunction. Endothelial dysfunction does not require denudation or severe damage. It may occur in response to circulating factors, such as tumor necrosis factor a (TNF-a) and interleukin-1 (reviewed in Pober and Cotran41 and Libby and coworkers42) or mechanical forces, such as shear stress and cyclic stretch.43,44 Many of the established risk factors for CAD (Table 130-1) are thought to act by causing injury to the normal endothelial surface.
Table 130-2 lists some of the properties of dysfunctional endothelium.45,46 Endothelial dysfunction is associated with a decrease in the production of vasorelaxants, such as NO, and an increase in the secretion of vasoconstrictors, such as endothelin-1. Dysfunctional endothelium also provides a more thrombogenic surface, as a result of an increase in platelet adherence, activation of the coagulation cascade, and perhaps down-regulation of fibrinolysis. “Activated” endothelial cells may also up-regulate the synthesis of SMC growth factors and may down-regulate the synthesis of factors that normally inhibit SMC growth and migration.


One of the most important properties of dysfunctional endothelium is enhanced permeability, manifested in part by transport of LDL into the vessel wall.47 These lipids may be modified by the endothelium. The most important modification appears to be oxidation.48 Oxidized LDL is toxic to endothelial cells (EC) and also acts as an activator of SMC and macrophages.49,50 and 51 Oxidized LDL may also stimulate tissue factor synthesis in SMC, EC, and macrophages, thereby promoting a procoagulant state.
Another feature of dysfunctional endothelium is the up-regulation of proinflammatory molecules, including endothelial-leukocyte adhesion molecules and leukocyte chemoattractants.45,52 One of the earliest morphologic events in the development of a plaque is the adherence of circulating leukocytes, particularly monocytes, to the endothelium.27,28 and 29 Adherent monocytes subsequently migrate into the arterial wall, and along with some activated SMC, ingest modified lipids and lipoproteins and become lipid-filled foam cells, ultimately generating a visible type II fatty streak. Monocytes also differentiate into activated macrophages that secrete cytokines, growth factors, metalloproteinases, and procoagulant molecules. Among the cytokines are a variety of chemoattractants, such as MCP-1, that stimulate further leukocyte migration. Among the growth factors are platelet-derived growth factor (PDGF) and fibroblast growth factors (FGFs), which stimulate SMC to proliferate, migrate, and synthesize extracellular matrix, thereby enlarging the fatty streaks and ultimately generating large plaques (type III). More advanced lesions (type IV and Va) are characterized by necrosis of foam cells, leading to the development of a lipid-rich core surrounded by a thin cap comprised of SMC, macrophages, and matrix. The lipid-rich core also contains high levels of tissue factor,53 presumably derived from activated macrophages and SMC.
Thrombosis is often the final event leading to catastrophic arterial occlusion. The steps leading to acute thrombosis are not fully understood. Plaque rupture is thought to play a major role in the majority of cases (Fig. 130-2).54,55 and 56 Plaque rupture often involves “vulnerable” plaques with large lipid cores and thin fibrous caps.57,58 Features of plaque vulnerability include the presence of an inflammatory cell infiltrate, made up of macrophages and T lymphocytes.59,60 These inflammatory cells, along with activated SMC, elaborate cytokines42 and metalloproteinases.61 The metalloproteinases are a family of enzymes (see Libby60 for review) that degrade extracellular matrix and may thus help disrupt the fibrous cap. Mechanical stress may also play an important role in plaque rupture.62,63 In about 25 percent of cases, thrombosis is associated with superficial erosion of the plaque surface rather than rupture.59,64 Erosion-related thrombosis often occurs in the setting of a severely stenotic vessel dominated by a heavily calcified “stable” plaque that is rich in proteoglycan matrix and SMC and lacks a superficial lipid core.59

FIGURE 130-2 Morphologic characteristics of an advanced atherosclerotic plaque. Hematoxylin and eosin stain (original magnification ×25) of a human left main coronary artery, showing a necrotic core (NC) and fibrous cap (FC). Arrows depict site of plaque rupture. A thrombus (T) can be seen in the lumen (L). (Courtesy Dr. John T. Fallon, Mount Sinai School of Medicine, NY.)

Models of acute arterial injury have been used for several decades to examine changes in the vessel wall associated with the development of atherosclerosis, but it is not clear to what extent the molecular events associated with acute injury reflect those occurring during chronic atherosclerosis. The development of percutaneous transluminal coronary angioplasty (PTCA), and more recently coronary artery stenting, to treat CAD has stimulated interest in arterial injury models, because they may reflect events associated with these procedures. In particular, the development of intimal hyperplasia in response to injury is thought to be an important contributor to restenosis after angioplasty and stenting.
Thrombus formation is commonly associated with acute arterial injury induced by PTCA65 and stenting.66 Although acute thrombosis can result in rapid and total occlusion of the vessel lumen, it can largely be prevented by the use of platelet inhibitors and anticoagulants. Thrombosis is also a common feature of many animal models of arterial injury. When the arterial endothelium is denuded, circulating platelets rapidly adhere to the surface, in part through the interaction between von Willebrand factor and glycoprotein (Gp)Ib (reviewed in Shafer67). Collagen and thrombin stimulate platelet activation, causing the release of arachidonic acid and the subsequent formation of thromboxane A2. Adenosine diphosphate (ADP) is secreted by activated platelets and induces further platelet activation. This results in conformational changes in glycoprotein IIb/IIIa and platelet aggregation. Additional thrombin is generated on the platelet surface, leading to fibrin deposition.
The presence and extent of fibrin deposition varies with the degree of injury (superficial or deep), the type of vessel (carotid, femoral, aorta, or coronary), the state of the vessel prior to injury (normal, cholesterol fed, previously injured), and the species. In the pig carotid balloon injury model,68,69 superficial injury, defined as endothelial denudation and no medial injury, is associated with platelet deposition but no fibrin generation. Deeper injury, defined by the presence of a medial tear, results in marked platelet accumulation and fibrin generation.
Balloon injury to normal rodent arteries is associated with platelet deposition without fibrin, even when medial smooth muscle injury is present.70,71,72,73 and 74 Platelet-fibrin microthrombi are found when previously injured arteries are subjected to a second injury.70,71,73,75,76 Treatment of these doubly injured rabbits with intravenous heparin reduces platelet accumulation by approximately 50 percent,71 suggesting that activation of the coagulation cascade may be involved.
A number of molecules have been implicated in the development of the athero-thrombotic state. Some of these will be discussed in detail in the following sections.
TF is a low-molecular-weight transmembrane protein that initiates the extrinsic clotting cascade and is considered the major initiator of coagulation and hemostasis77,78 and 79 (see Chap. 112). TF was first identified as a component of human atherosclerotic plaques in 197280 and currently is considered the major initiator of thrombosis associated with acute coronary syndromes.
Although EC, SMC, macrophages, and fibroblasts synthesize TF, its distribution in the normal arterial wall is not uniform. TF mRNA and antigen are abundant in the adventitia of normal arteries,81,82 but they are minimal in normal intima and media. The constitutive expression of TF in the adventitia allows for rapid hemostasis in the event of external injury to the blood vessel and presumably evolved to prevent hemorrhage. In contrast, the expression of active TF on the luminal surface could be potentially catastrophic by initiating intraarterial thrombosis.
TF antigen has been detected in all cellular elements comprising the atherosclerotic plaque (see Fig. 130-3).53,82,83,84,85 and 86 TF is most abundant in the foam cells, macrophages, and intimal SMC located in the fibrous cap and tissues surrounding the lipid-rich necrotic core. TF antigen is also present in the medial SMC and EC overlying the plaque. TF antigen is also abundant in the extracellular matrix of the intima and within the necrotic core.53,86

FIGURE 130-3 Expression of tissue factor in a human atherosclerotic plaque. Human coronary artery stained with an antibody to tissue factor. Staining is most prominent in the necrotic core (between arrows). Original magnification ×25. (Courtesy Dr. John T. Fallon, Mount Sinai School of Medicine, NY.)

TF activity has been detected in 90 percent of specimens from directional coronary atherectomies84 and may be attenuated by the presence of tissue factor pathway inhibitor (TFPI).87 In studies employing an ex vivo perfusion system, the lipid rich necrotic core, an abundant source of TF, was found to be the most thrombogenic component of the plaque.88,89 Macrophages and intimal SMC are the most likely source of the TF found in the core. This TF may derive from cell debris, may be released during apoptosis,90 or may be shed from the plasma membrane of activated healthy cells.91 Plaque rupture may thus expose active TF to circulating blood, leading to acute thrombosis.
TF mRNA and activity are induced in the media as an early event (1 to 2 h) after arterial balloon injury in animals,92,93,94 and 95 returning to baseline levels after several days. However, TF antigen subsequently accumulates throughout the developing neointima in these animal models.53
Animal models of injury to normal arteries are not often associated with the deposition of fibrin or the generation of thrombi. This suggests that the induction of TF mRNA and protein in the arterial wall is not sufficient to establish arterial thrombosis. The presence of an intact internal elastic lamina separating the media from the lumen, the rapid accumulation of platelets on the luminal surface, and the rapid secretion of matrix by injured SMC may effectively prevent newly synthesized medial TF from coming into contact with circulating blood and initiating coagulation. In addition, the TF antigen and activity identified in the media may be intracellular or encrypted on the cell surface (discussed in detail below) and therefore ineffective in initiating thrombosis. TF exposed on the cell surface may also rapidly associate with TFPI or other inhibitors. Sequential arterial injury is more frequently associated with fibrin deposition and mural thrombosis.70,71,73,75 This may be due in part to the immediate exposure of intimal TF.
A number of animal studies93,96,97,98,99 and 100 have provided evidence that TF also plays a role in intimal hyperplasia. Studies using inhibitors of TF activity have also provided evidence that TF expression is critical to the development of platelet-fibrin thrombi after sequential arterial injury.75,76
TF is present in whole blood and plasma.101,102,103 and 104 Plasma TF levels are elevated in patients with sickle cell disease,103 disseminated intravascular coagulation,101 and acute MI.102 Circulating TF may play a primary role in the initiation or propagation of arterial thrombosis.104 Thrombi that form on normal porcine arterial media and on collagen-coated glass slides perfused for 5 min with native human blood contain TF antigen, and antibodies against TF markedly reduce thrombus formation on both surfaces. TF antigen is most abundant in membrane vesicles that cluster near the surface of platelets. Thus circulating TF may adhere to exposed surfaces and may act alone or in concert with TF located in the injured vessel wall to propagate arterial thrombosis. The source of this circulating TF is unknown, but it is likely that it derives from blood leukocytes or endothelial cells.
In most models of acute arterial injury, the endothelial is denuded, and SMC are the most likely source of TF activity. In models in which injury is produced on a substrate of atherosclerosis, macrophages rapidly accumulate in the intima and media and thus provide a second source of TF. In established atherosclerotic plaques, macrophages appear to be the most abundant source of TF, followed by intimal SMC, and to a much lesser degree medial SMC and regenerating endothelium.
TF is a member of the class of “immediate early” genes, which are expressed at low levels in quiescent cells and rapidly induced by serum and growth factors.105 Under most circumstances, the induction of TF occurs principally at the level of transcription, although increases in TF mRNA stability are also partly responsible (reviewed in Edgington and coworkers77). In addition to its regulation by serum and growth factors, TF is also induced by a variety of cytokines, endotoxin lipopolysaccharide (LPS), antigen-antibody complexes, lymphocyte products, and lipoproteins (see Table 130-3). Many of these agents are found in abundance in atherosclerotic plaques and in the injured arterial wall.


TF is induced in EC and monocytes by modified and oxidized forms of LDL.106,107 This raises the possibility that hypercholesterolemia may directly promote thrombosis, even at an early stage in plaque development. TF is also induced during monocyte-macrophage differentiation in cell culture.108 The differentiation of monocytes to macrophages is an early event in the development of atherosclerotic lesions and occurs concomitantly with migration of monocytes into the arterial wall. The induction of TF by thrombin in SMC and EC109,110 and 111 is also intriguing, because thrombin is an end-product of TF activation. Thus, thrombin may be part of a positive feedback loop, helping to perpetuate a procoagulant state. TF is also induced by laminar shear stress in cultured EC and fibroblasts.112,113
Mammalian TF promoter regions share striking sequence similarities, suggesting that the mechanism of TF gene regulation is highly conserved.114,115,116 and 117 Human TF gene regulation involves several elements, working either cooperatively or singly (reviewed in Mackman118). Basal TF gene expression is regulated by a series of Sp1 sites. Induction of TF by growth factors and cytokines in EC and monocytes is dependent upon two AP-1 sites and an NFkB-site. These sites have been implicated in the regulation of many genes by growth factors, cytokines, and mediators of inflammation. TF transcription thus appears to be part of an extensive genetic program induced by processes such as growth, inflammation, and wound healing.
Under virtually all culture conditions, the induction of TF mRNA is accompanied by the accumulation of TF protein and an increase in procoagulant activity. A critical determinant of whether TF expression in atherosclerotic or injured vessels leads to a procoagulant state is whether the protein is present in an active state and is accessible to the circulation. Studies employing monolayers of SMC, EC, fibroblasts, and macrophages have found that, although TF protein is present on the cell surface, the majority of surface TF is not active.91,111,119,120,121,122,123,124 and 125 This “encrypted” or “latent” TF can be activated by processes that alter the structure or phospholipid composition of the cell membrane or cause cell lysis. It is likely that much of the TF present in cells of the arterial wall or atherosclerotic plaque is similarly encrypted or intracellular. Thus, in addition to inducing de novo TF synthesis, arterial injury and plaque rupture may convert encrypted TF already present in the arterial wall into active TF. Release of intracellular TF as a consequence of cell necrosis or apoptosis may also be important in generating a procoagulant state within the arterial wall.
A substantial amount of TF antigen in the atherosclerotic plaque appears to be located in the extracellular matrix or in the lipid-rich necrotic core. Cultured cells can release TF into the culture medium in microparticles or small vesicles.90,91,126,127 These particles presumably bud from the cell surface as a normal consequence of cellular metabolism, rather than as a consequence of necrosis or apoptosis. TF-containing microparticles may be an important source of procoagulant activity in the arterial wall.
TFPI is an endogenous Kunitz-type proteinase inhibitor that directly inhibits activated factor X and, in a factor Xa-dependent fashion, produces feedback inhibition of the factor VIIa/TF catalytic complex (reviewed in Broze128 and Mann and colleagues129 and Chap. 113). The second Kunitz domain inhibits factor Xa, whereas the first Kunitz domain inhibits factor VIIa in the TF-factor VIIa complex. In addition to attenuating TF activity, TFPI may directly inhibit SMC proliferation.130
TFPI is made predominantly by EC,131,132 although SMC may provide a second source.133 TFPI is highly bound to lipoproteins, particularly LDL, but is rapidly released by heparin and other negatively charged ions. Circulating TFPI, normally found at a concentration of 1 to 2 nM, probably modulates TF activity. Because lysophosphatidylcholine (LPC), a component of oxidized LDL, has been shown to decrease levels of TFPI in EC,134 LPC accumulating in the atherosclerotic vascular wall may suppress TFPI synthesis, attenuating the antithrombotic properties of the endothelium.
Sixty percent of TFPI-deficient (TFPI(K1)–/–) mice die of yolk sac hemorrhage between embryonic days 9.5 and 11.5.135 Animals that progress beyond embryonic day 11.5 develop normally but die in late gestation of hemorrhage, particularly in the central nervous system. These animals exhibit intravascular thrombosis, suggesting that the hemorrhage is a consequence of a consumptive coagulopathy consistent with unregulated TF-factor VIIa activity.
TFPI antigen and mRNA have been detected in the adventitia of normal arteries.136 Low levels of TFPI mRNA have also been detected in medial SMC,136 whereas TFPI antigen has been found in medial SMC and intimal endothelium of normal human coronary arteries.133 In contrast, high levels of TFPI antigen and mRNA have been found in EC, SMC within the fibrous cap, and macrophages within the shoulder region of human carotid endarterectomy specimens and in early fatty streaks of hypercholesterolemic rabbits.87 Areas rich in TFPI also stain prominently for TF antigen.
In animal models, TFPI treatment has been shown to attenuate intimal hyperplasia and stenosis after balloon injury98,100 and to prevent thrombotic arterial reocclusion after tPA-mediated thrombolysis.137 The role of exogenous TFPI in treating human disease remains to be determined.
The fibrinolytic system is thought to play an important role in offsetting the effects of increased TF expression in the arterial wall. This is underscored by the success of activators of fibrinolysis in revascularization in the setting of acute MI (see below). A general scheme of the fibrinolytic system is shown in Chap. 116. Fibrinolysis requires the generation of plasmin from plasminogen, an inactive proenzyme. The active plasmin degrades fibrin, as well as other extracellular matrix proteins.
Plasminogen activators (PAs) convert plasminogen to plasmin. Plasmin cleaves fibrin, thus acting as an endogenous thrombolytic agent. Two types of plasminogen activator have been identified, tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). EC of the normal arterial wall secrete tPA, but little or no uPA.138,139,140,141 and 142 Low levels of tPA mRNA and antigen have also been detected in SMC of normal arteries.142
The secretion of tPA by normal EC is thought to be important in maintaining an antithrombotic surface, but experimental data are conflicting regarding PAs in atherosclerotic lesions.142,143,144,145,146 and 147 PA activity may be modulated by the presence of plasminogen activator inhibitor-1 (PAI-1).
In animal models, after balloon arterial injury, uPA activity in carotid arteries rapidly increases, reaching a maximum between 16 and 24 h, whereas tPA activity appears at 3 days148; uPA and tPA mRNA increase steadily, reaching a maximum at 7 days. The induction of PAs, particularly uPA, may prevent fibrin accumulation. It remains to be determined whether a similar induction of PAs occurs after human coronary angioplasty.
The expression of PAs in atherosclerotic and injured vessels may serve functions other than fibrinolysis. Plasmin has been shown to activate latent cytokines, such as transforming growth factor beta (TGF-b) and basic FGF.149,150 The activation of TGF-b by plasmin has been implicated in the suppression of SMC proliferation151 and migration152 in cell culture. Apo(a) overexpressing mice display decreased plasminogen activation and increased atherosclerosis.153 It is thought that this is in part due to the ability of lipoprotein(a) to inhibit plasmin generation and therefore to inhibit TGF-b.
Plasmin also activates metalloproteinases, such as collagenase and stromelysin,154 which may serve to promote SMC migration and proliferation. In the rat carotid artery injury model, most of the induced tPA is present in the media before the SMC migrated into the intima.148 Tranexamic acid, a synthetic inhibitor of plasmin activity, reduces SMC migration by 73 percent after arterial balloon injury,155 suggesting that in this model the effect of plasmin in promoting migration may be more important than its effect on TGF-b–mediated growth suppression. In contrast, continuous infusion of tPA for 7 days causes an 80 percent decrease in intimal hyperplasia in hypercholesterolemic animals subjected to balloon injury of the common iliac artery.156 The administration of exogenous tPA may therefore have a significantly different effect on the arterial wall than that of endogenously regulated PAs.
Plasminogen activator inhibitor 1 is the major physiologic inhibitor of tPA and uPA.157 PAI-1 is found in the circulation largely in association with platelets and to a lesser extent in plasma.158 Plasma PAI-1 is bound to vitronectin,159 and its level displays a circadian rhythm, with a peak in the morning and a trough in the evening, inverse to that of tPA.160 Higher PAI-1 levels are seen with increases in age,161 blood pressure, triglyceride levels, and body mass162; the levels correlate with insulin resistance.163 PAI-1 binds to fibrin and forms a stable complex with tPA or uPA.164 This inhibits plasmin activation and protects the thrombus from lysis. PAI-1 may also limit the efficacy of exogenous thrombolytic agents.165,166
Increased PAI-1 levels and/or reduced fibrinolysis have been found in patients with coronary artery disease (reviewed in Prisco and colleagues167), angina,168,169 and 170 and MI.171,172 and 173 Increased plasma PAI-1 activity has also been found in patients with stroke174 and carotid atherosclerosis.175 Increased circulating PAI-1 has also been shown to correlate with decreased patency of coronary arteries after thrombolytic therapy for acute MI.173 In contrast, decreased levels of PAI-1 activity after PTCA have been associated with reduced risk of restenosis.176
There is little PAI-1 in normal vessels,157 but significant amounts are present in all three cellular components of atherosclerotic plaques: SMC, EC, and macrophages.157,177 Highest levels are detected in SMC and macrophages around the necrotic core.147,178,179 PAI-1 colocalizes in human atherosclerotic coronary arteries with other components of the plasminogen activator system, including tPA, uPA, and uPA receptor (uPAR). However, levels of PAI-1 appear to be substantially higher.147,180,181 and 182
In addition to its presence in atherosclerotic plaques, PAI-1 has also been identified in extracts of thrombi. Levels of PAI-1 antigen in these thrombi are substantially higher (as much as 2000-fold) than that found in circulating blood and also much higher than that of tPA or the tPA-PAI-1 complex.180,181,183 This is likely due to the accumulation of platelets within the thrombus.
In animal models, PAI-1 mRNA is not detectable in uninjured carotid arteries but is rapidly induced (within 3 h) by balloon arterial injury.184,185 PAI-1 induction is first detected in the adventitia, and within 24 h in the media. PAI-1 antigen and mRNA subsequently accumulate over time in neointimal SMC and EC. The induction of PAI-1 activity follows the same time course. PAI-1 is also increased in animal models of arterial thrombosis.186 PAI-1 mRNA increases in EC and macrophages juxtaposed to the thrombus and in SMC adjacent to the neointima.
PAI-1 is secreted by EC, SMC, fibroblasts, macrophages, and hepatocytes.187,188 and 189 Its synthesis is upregulated in SMC and EC by cytokines (interleukin 1, TNF-a), TGF-b, basic FGF, PDGF, angiotensin II, plasminogen, and a thrombin190,191,192,193,194 and 195 a-thrombin, a potent stimulator of TF, also stimulates synthesis of PAI-1 in cultured SMC.196,197 Therefore, thrombin is part of two positive procoagulant feedback loops, potentiating the synthesis of TF and PAI-1. SMC from atherosclerotic arteries also express higher levels of PAI-1, in association with decreased levels of tPA.198
Lipoprotein(a), a risk factor for coronary artery disease, induces PAI-1 antigen, activity, and steady-state mRNA levels in EC.199 SMC and macrophages may play an important role in regulating the synthesis of PAI-1 by cultured EC.189,200 Quiescent SMC appear to inhibit PAI-1 production by EC, whereas proliferating and atherosclerotic SMC may secrete a soluble factor that stimulates PAI-1 production by EC. Differentiated macrophages also secrete a soluble factor that regulates endothelial cell PAI-1 production.
A second inhibitor of PAs, PAI-2, also has been identified.201 PAI-2 is found largely as an intracellular protein. Therefore, its role in regulating thrombosis is unclear. It is possible that under conditions of cell injury, PAI-2 is released into the extracellular matrix and can contribute to inhibiting fibrinolysis (for review see Bachmann202).
In addition to generating plasmin, PAs may also have direct effects on the arterial wall through interactions with cell surface receptors. The uPAR is a transmembrane glycoprotein, which is thought to be critical for localizing the activity of uPA to the cell surface, accelerating plasminogen activation, delaying PAI-1 inhibition of plasminogen activation,203 and regulating the clearance of uPA.204 uPAR is expressed by cultured EC, macrophages, and SMC.205,206 The induction of uPAR in SMC is common to a number of growth agonists, including epidermal growth factor (EGF), TGFb, basic FGF, PDGF, phorbol esters, and a thrombin.206,207
uPAR expression is also upregulated at the leading edge of migrating SMC,208 EC,209 and monocytes.210 Studies suggest that uPAR may be involved in integrin-mediated cell adhesion and migration through interactions with vitronectin (reviewed in Wei and colleagues211) and the Mac-1 receptor (CD11b/CD18).212,213 Binding of uPA to uPAR has also been implicated in intracellular signaling via tyrosine phosphorylation,214,215 macrophage protease expression,216 growth,217,218 and chemotaxis.214,215 These effects do not require uPA enzymatic activity and can be initiated by enzymatically inactive fragments of uPA.219
uPAR expression is up-regulated in SMC and macrophages of early lesions of cholesterol-fed animals.220 The expression of uPAR is also markedly increased in the intima of human coronary atherosclerotic lesions147,207 and in SMC and macrophages of thickened saphenous vein grafts.207 The significance of increased uPAR in atherosclerosis is unknown.
Studies of transgenic mice lacking one or more of the components of the fibrinolytic system have provided considerable insights into the role of plasminogen activation in mediating arterial thrombosis and intimal hyperplasia (reviewed in Carmeliet and Collen221).
In plasminogen-deficient (Plg–/–) mice, wound healing (i.e., neointima formation and reendothelialization) after vascular injury is significantly impaired.222 In Plg–/– mice, SMC accumulate at the uninjured borders but fail to migrate into the necrotic center. Proliferation of SMC is not affected. Analogous abnormalities in the healing of skin wounds were also noted.223
uPA–/– mice, either alone or in combination with tPA–/–, have less intimal hyperplasia in response to arterial injury.224 SMC accumulate at the uninjured borders but fail to migrate into the necrotic center. Cultured uPA–/– SMC also demonstrated decreased migratory capacity. In contrast, tPA–/– mice do not exhibit altered intimal hyperplasia or SMC migration.
In PAI-1–/– mice subjected to arterial injury, wound healing is significantly enhanced, and there is increased neointima formation.225 Proliferation of SMC is not affected by PAI- 1 deficiency. However, SMC originating from the uninjured borders migrate into the necrotic center of the arterial wound more rapidly than wild-type SMC. There are no differences in reendothelialization of the injured arteries. PAI-1 deficiency in mice is associated with increased thrombolysis.226
uPAR-deficient (uPAR–/–) mice have no abnormalities of fertility, development, or hemostasis,227 and skin wounds heal normally.228 They also have no abnormalities in intimal hyperplasia or SMC migration after vascular injury.229 uPA becomes bound to the cell surface of uPAR+/+ cells, whereas it binds to the pericellular space around uPAR–/–cells. This suggests that binding of uPA to uPAR is not required to provide sufficient uPA-mediated plasmin proteolysis to allow SMC migration into the vascular lesion.
a2-antiplasmin (a2-AP) is the principal inhibitor of plasmin and plays an important role in determining clot lysis.230 a2-AP circulates in the blood at a concentration of approximately 1 µM, over 1000-fold higher than PAI-1. Small amounts have been detected in human platelets.231 a2-AP can be cross-linked to fibrin via factor XIII.232 High concentrations of PAI-1 and a2-AP have been found in extracts prepared from human thrombi.180
Evidence links elevated levels of fibrinogen with coronary atherosclerosis and ischemic vascular events. Fibrinogen is synthesized in the liver and circulates at a concentration of 200 to 400 mg/dl. Increased levels of fibrinogen correlate positively with most risk factors for coronary artery disease, including menopause,233 obesity,233,234 elevated levels of LDL cholesterol and lipoprotein(a),233 hypertension,235 and diabetes mellitus.236 Levels increase in patients who smoke237 and may decrease with smoking cessation.233,238 Levels also decrease with increasing levels of HDL cholesterol.233 Levels of fibrinogen have been shown to be increased in patients with stroke and MI (reviewed in Wilhelmsen239 and Kannel and colleagues240). In the Framingham Study,240 Northwick Park Heart Study,241 and Bezafibrate Infarction Prevention (BIP) Study,242 an elevated fibrinogen level was found to be an independent risk factor for MI. A meta-analysis of six prospective studies found an odds ratios for cardiovascular events for the upper versus the lowest tercile of 2.3 and strengthened the concept that fibrinogen levels are an independent variable for cardiovascular disease.243
Patients with UA and MI appear to have a hypercoagulable state and display increased levels of prothrombin fragments 1 and 2 and fibrinopeptide A.244,245,246 and 247 Fibrinopeptide A levels return quickly to normal, suggesting that activation may occur only during the acute thrombotic event. Levels of prothrombin fragments 1 and 2 may remain elevated for as long as 6 months,247 suggesting that some abnormality may persist after the acute event. This appears to be independent of the extent of coronary artery disease.
Homocysteine is a sulfhydryl-containing amino acid produced by demethylation of methionine. Folate and vitamin B12 are required for remethylation of homocysteine to methionine, and therefore levels of homocysteine are related inversely to levels of folate and B12. Very high levels of homocysteine were initially found in the blood of patients with homocystinuria, an autosomal recessive disease characterized by skeletal abnormalities, ocular lens dislocation, mental retardation, premature atherosclerosis, and a predisposition toward thromboembolic events.248 Most cases of homocystinuria are due to a deficiency in the enzyme, cystathionine b-synthase, which is involved in the catabolic transsulfuration of homocysteine.249,250 More moderate elevations of homocysteine appear to be an independent risk factor for coronary artery disease, peripheral vascular disease, and stroke (reviewed in Welch and Loscalzo251). In some studies, the correlation extends into the “normal” range (5–15 mmol/liter) and does not appear to have a threshold. Homocysteine levels are reduced by treatment with folic acid, alone or in combination with vitamins B6 or B12.252
Homocysteine is toxic to cultured EC and causes endothelial damage and desquamation in animal models.253,254 and 255 The effects of homocysteine may in part be due to its oxidation and the formation of superoxide and hydrogen peroxide.256 Homocysteine has numerous effects on endothelial and platelet function that may promote a prothrombotic state. These include an increase in platelet consumption,257 inactivation of protein C,258 a decrease in prostacyclin synthesis and an increase in the synthesis of thromboxane A2.259,260 Homocysteine also causes alterations in von Willebrand factor secretion,261 increased factor V262 and TF expression,263 inhibition of thrombomodulin264 and heparan sulfate expression,265 and modulation of binding of tPA to EC.266 Homocysteine enhances the binding of lipoprotein(a) to fibrin267 and thus may potentiate the thrombotic properties of lipoprotein(a).268,269 and 270
Lipoprotein(a) consists of an LDL particle complexed with apolipoprotein(a).271 Lipoprotein(a) is synthesized in the liver and circulates in the blood at concentrations ranging from 1 mg/dl to 100 mg/dl, but usually is less than 20 mg/dl. Levels correlate with those of LDL cholesterol.272 Higher levels are present at menopause and in patients with diabetes mellitus and acute MI.272,273 High levels of lipoprotein(a) have been found in patients with familial hypercholesterolemia274 and in siblings and offspring of patients with early coronary artery disease.275 Several large studies have found that lipoprotein(a) is an independent risk factor for serious cardiovascular events, including MI and death.276,277,278 and 279 Other studies, however, have failed to confirm this.280,281 Lipoprotein(a) has also been associated with an increased incidence of coronary artery disease in Asian populations282 but not in American blacks.283
Several mechanisms have been proposed to explain the relationship between lipoprotein(a), atherosclerosis and thrombosis (reviewed in Harpel284 and Hajjar and Nachman285). Lipoprotein(a) has been found in atherosclerotic plaques.286,287 Lipoprotein(a) displaces plasminogen from sites on fibrin and fibrinogen and inhibits plasminogen activation by streptokinase (SK) and tPA.288 Lipoprotein(a) may similarly inhibit endogenous fibrinolytic activity.289 Lipoprotein(a) also increases the release of PAI-1 and down-regulates plasmin generation in EC.199 Lipoprotein(a) may enhance the delivery of LDL cholesterol to the vessel wall290 and thus promotes foam cell development. High levels of lipoprotein(a) may also interfere with activation of latent growth factors, such as TGFb, which may be important in regulating SMC proliferation.
Guidelines for the treatment of stable angina can be found in a document prepared by the task force of the European society of cardiology.291 Treatment of unstable angina includes bed rest, supplemental O2, and pain management. Nitrates remain the choice for the immediate relief of angina.20,292,293 However, tolerance can develop within 24 h.294 It is important to note that “rebound” angina and even MI can occur after abrupt cessation of nitrates.293 Although nitrates are highly effective for pain management, they have not been shown to reduce the incidence of MI or death in UA. b-blockers have also been shown to be effective in relieving symptoms and in reducing the incidence of MI in patients with UA (reviewed in Yusuf and coworkers295). In view of their beneficial effect on secondary prevention of MI and sudden death, b-blockers are usually continued indefinitely.
Although aspirin may have limited effects on anginal pain, several large trials have demonstrated that aspirin prevents MI and death in patients with UA by as much as 50 percent.14,296,297,298 and 299 Aspirin, 325 mg, is thus given immediately to most patients with UA or suspected MI and continued indefinitely at 81 mg/day or more.
Intravenous heparin, most often given as a 5000-unit bolus every 6 h or as a bolus followed by a continuous infusion, is one of the preferred treatment modalities for UA.297,298,300,301 and 302 In some studies, heparin has been shown to be effective in relieving angina.297,302 Heparin has also been shown to reduce death and MI as compared to placebo,300 but it is not clear whether heparin alone is more or less effective than aspirin. Several studies have suggested that the combination of heparin and aspirin is most beneficial.298,303,304 Subcutaneous heparin has also been shown to be effective in reducing angina and ischemia.297
Low-molecular-weight heparins have been proposed as an alternative to standard heparin because they are easier to administer, and there is no need to monitor therapy. Comparisons with standard heparin are conflicting, with some studies demonstrating improved efficacy for low-molecular-weight heparin,304,305 whereas others suggest no difference.306 In these studies, most patients have also been treated with aspirin.
Although oral anticoagulation has little place in the acute treatment of UA, it may reduce the incidence of significant cardiac events in the longer term.299,307 Although the ATACS study suggested a possible benefit of the combination of low-dose warfarin and aspirin at 12 weeks in patients with UA, the much larger Coumadin Aspirin Reinfarction Study (CARS) study, which examined patients after MI, failed to show such benefit.308
Despite its role in the treatment of patients with acute MI, thrombolytic therapy does not appear to benefit patients with UA and may in fact paradoxically increase the incidence of MI.309,310,311,312,313 and 314
Abciximab, a monoclonal antibody fragment to the platelet glycoprotein IIb/IIIa receptor has been evaluated in high-risk patients (e.g., those with UA, recent MI, or high-risk angiographic lesions) undergoing angioplasty with or without stent placement315,316,317 and 318 and was found to produce significant decreases in short- and long-term clinical events. The CAPTURE trial, which focused on patients with UA, also showed a significant benefit in clinical outcomes with abciximab treatment, even before percutaneous coronary intervention.319
Small molecule antagonists of glycoprotein IIb/IIIa (tirofiban, integrilin, lamifiban) have also been studied and been found safe and efficacious in the treatment of UA when combined with heparin.320,321,322,323,324 and 325
Treatment of UA patients with hirudin, an antithrombin isolated from the leech, results in lower rates of death, nonfatal MI, or refractory angina as compared to heparin.326,327 and 328 Hirulog, a synthetic antithrombin peptide has also been shown to control anginal symptoms329 and to reduce the incidence of death and MI330 in patients with UA. Whereas hirudin has been found to be more effective than heparin in reducing serious events after angioplasty in patients with UA,331 hirulog has failed to show a similar benefit.332
In many centers, intervention with PTCA and, when appropriate, stent placement, is the treatment of choice for UA, with an initial success rate of greater than 90 percent. Complication rates of interventions are high, however, and include a greater than 5 percent incidence of MI, a greater than 5 percent incidence of emergency bypass surgery, and a higher restenosis rate.333,334,335 and 336 Also of note is a higher rate of acute closure, often successfully treated with thrombolytic agents.337,338 The timing of angioplasty remains controversial, with some studies supporting the use of heparin or aspirin for 24 to 48 h prior to PTCA,339 and others showing no benefit by waiting.340 Prior to the advent of PTCA, bypass surgery was frequently employed for the treatment of patients with UA refractory to medical treatment.341 Because of the relatively high 1-year mortality in patients with UA (often approaching 20 percent),342,343 bypass surgery was also widely employed after initial medical stabilization. Because of the predilection of many centers for early angiography and PTCA in patients with UA, bypass surgery in the acute setting has been largely relegated to failed PTCA or for patients with left main or triple vessel disease. Bypass surgery after medical stabilization continues to be the procedure of choice in patients with severe disease.
Initial treatment of acute MI includes careful monitoring, supplemental O2, and management of pain with morphine sulfate. Based upon its beneficial effects on mortality in several large trials,13,14,296,297 aspirin, 325 mg per day, is given immediately upon diagnosis and is continued indefinitely at a dose of at least 81 mg/day. Nitrates are effective for the treatment of peri- and post-MI angina. Although early studies of nitrates in acute MI suggested a significant reduction in mortality,344 recent large-scale trials have failed to confirm these benefits.345,346
Thrombolysis is the cornerstone of reperfusion therapy for acute MI and is considered in all patients with ST segment elevation who present within 12 h from the onset of symptoms. Virtually all studies have shown a significant reduction in mortality with pooled data from over 60,000 patients demonstrating an overall reduction of 18 percent.12,13,347,348 There is an inverse relationship between the time to onset of treatment and the survival benefit, with patients treated in the first hour having the highest benefit349 and those treated after 12 h having none.350,351 Absolute contraindications for thrombolytic therapy are active bleeding and recent stroke, trauma, or major surgery. Relative contraindications are severe hypertension (>180/110 mm Hg), previous cerebrovascular history, prior gastrointestinal hemorrhage, active menstruation, pregnancy, prolonged cardiopulmonary resuscitation, recent surgery and recent noncompressible vascular puncture, or ongoing warfarin therapy.
Several large trials have examined the effects of different thrombolytic regimens on mortality. The GISSI-2 trial352 found no significant difference in the 30-day mortality of 20,749 patients randomized to t-PA or SK. The ISIS-3 trial found no difference in mortality among 41,299 patients randomized to t-PA, streptokinase, or anistreplase.353 In contrast, GUSTO-I, which evaluated 41,021 patients,354 found that accelerated alteplase t-PA, administered over 90 min with intravenous heparin, reduced 30-day mortality by 15 percent (1 percent absolute mortality benefit) as compared to streptokinase with intravenous or subcutaneous heparin, or the combination of t-PA and streptokinase with intravenous heparin. The differences correlated with earlier complete infarct vessel patency and were maintained at 1 year of follow-up.354,355 Based upon this study, t-PA is used in more than 75 percent of patients treated in the United States.
In centers that can provide short transit times to the cardiac catheterization laboratory, PTCA has been used as an alternative to thrombolysis. PTCA is also used as a “rescue” for unsuccessful thrombolysis, particularly in patients with large MIs. Rescue PTCA has been associated with a decrease in mortality and improvement in left ventricular function, particularly in patients treated within 2 h of unsuccessful thrombolysis.356,357,358 and 359 In contrast, PTCA performed immediately after successful thrombolysis is associated with a higher mortality, a more frequent need for emergency bypass surgery, and no improvement in left ventricular function.360,361 and 362 The experience with stenting for acute MI has shown a significant reduction in death, reinfarction, or reintervention as compared with balloon dilatation alone.363,364 and 365 Because of the success of thrombolysis, the use of bypass surgery in acute MI is limited.
After the initial treatment of acute MI, attention focuses on “secondary” prevention. This includes aggressive risk factor modification, such as cessation of smoking, decreasing LDL cholesterol (with diet or lipid-lowering agents), weight reduction, and regular physical activity. Several pharmacologic interventions are also routinely employed.
b-blockers remain a cornerstone of post-MI treatment.344,366,367 and 368 Angiotensin converting enzyme inhibitors have been shown to increase survival, reduce the incidence of heart failure, reduce the incidence of reinfarction, and decrease the need for revascularization in patients with acute MI and left ventricular dysfunction.345,346,369,370 and 371
A large number of clinical studies have supported the use of aspirin for secondary prevention after MI.13,372,373 and 374 Although there remains some question as to the dosage necessary to provide a maximal effect on secondary prevention, regimens of 81 to 325 mg/day of aspirin is in widespread use in post-MI patients. A meta-analysis of six randomized trials calculated a 13 percent reduction in cardiovascular mortality, a 31 percent reduction in the rate of nonfatal MI, and a 42 percent reduction in nonfatal strokes with long-term aspirin treatment.375 The CAPRIE study found a similar event rate in patients treated with clopidogrel (75 mg/day) as compared to aspirin (325 mg/day).376
Several studies of warfarin in post-MI patients showed a reduction in risk for death and reinfarction but an increase in serious bleeding episodes.299,307,377 The recent CARS study found no improvement with the combination of full-dose aspirin and low-dose warfarin when compared with aspirin alone and also suggested an increase in bleeding.308 Warfarin has been associated with decreased risk for embolic events in patients with echocardiographic evidence of left ventricular thrombus.378,379 The use of warfarin after MI is limited largely to patients with this complication.

Tunstall-Pedoe H, Kuulasmaa K, Amouyel P, Arveiler D, Rajakangas AM, Pajak A: Myocardial infarction and coronary deaths in the World Health Organization MONICA Project. Registration procedures, event rates, and case-fatality rates in 38 populations from 21 countries in four continents. Circulation 90:583, 1994.

Heart and Stroke Facts: 1997 Statistical Supplement. Dallas, TX: American Heart Association, 1997.

Herrick JB: Clinical features of sudden obstruction of the coronary arteries. JAMA 59:2015, 1912.

Constantinides P: Plaque fissures in human coronary thrombosis. J Atheroscler Res:1, 1966.

Davies MJ, Fulton WF, Robertson WB: The relation of coronary thrombosis to ischaemic myocardial necrosis. J Pathol 127:99, 1979.

Davies MJ, Thomas A: Thrombosis and acute coronary-artery lesions in sudden cardiac ischemic death. N Engl J Med 310:1137, 1984.

Davies MJ, Thomas AC: Plaque fissuring—the cause of acute myocardial infarction, sudden ischaemic death, and crescendo angina. Br Heart J 53:363, 1985.

Maseri A, L’Abbate A, Baroldi G, et al: Coronary vasospasm as a possible cause of myocardial infarction. A conclusion derived from the study of “preinfarction” angina. N Engl J Med 299:1271, 1978.

Bertrand ME, LaBlanche JM, Tilmant PY, et al: Frequency of provoked coronary arterial spasm in 1089 consecutive patients undergoing coronary arteriography. Circulation 65:1299, 1982.

DeWood MA, Spores J, Notske R, et al: Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 303:897, 1980.

Rentrop P, Blanke H, Karsch KR, Kaiser H, Kostering H, Leitz K: Selective intracoronary thrombolysis in acute myocardial infarction and unstable angina pectoris. Circulation 63:307, 1981.

Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico (GISSI). Lancet 1:397, 1986.

Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet 2:349, 1988.

Lewis HD Jr, Davis JW, Archibald DG, et al: Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study. N Engl J Med 309:396, 1983.

Theroux P: Glycoprotein IIb/IIIa inhibitors in unstable angina. Curr Opin Cardiol 12:447, 1997.

Gonzalez ER: Antiplatelet therapy in atherosclerotic cardiovascular disease. Clin Therapeut 20:B18, 1998.

Dawber TR, Meadors GF, Moore FEJ: Epidemiological approaches to heart disease: the Framingham Study. Am J Public Health 41:279, 1951.

Kannel WB, Wilson PW: An update on coronary risk factors. Med Clin North Am 79:951, 1995.

Pasternak RC, Grundy SM, Levy D, Thompson PD: 27th Bethesda Conference: matching the intensity of risk factor management with the hazard for coronary disease events. Task Force 3. Spectrum of risk factors for coronary heart disease. J Am Coll Cardiol 27:978, 1996.

Krauss KR, Hutter AM Jr, DeSanctis RW: Acute coronary insufficiency. Course and follow-up. Circulation 45:I66, 1972.

Heng MK, Norris RM, Singh BM, Partridge JB: Prognosis in unstable angina. Br Heart J 38:921, 1976.

Cairns JA, Singer J, Gent M, et al: One year mortality outcomes of all coronary and intensive care unit patients with acute myocardial infarction, unstable angina or other chest pain in Hamilton, Ontario, a city of 375,000 people. Can J Cardiol 5:239, 1989.

Anderson HV, Cannon CP, Stone PH, et al: One-year results of the Thrombolysis in Myocardial Infarction (TIMI) IIIB clinical trial. A randomized comparison of tissue-type plasminogen activator versus placebo and early invasive versus early conservative strategies in unstable angina and non-Q wave myocardial infarction. J Am Coll Cardiol 26:1643, 1995.

Stary HC, Chandler AB, Dinsmore RE, et al: A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 92:1355, 1995.

Rosenfeld ME, Tsukada T, Chait A, Bierman EL, Gown AM, Ross R: Fatty streak expansion and maturation in Watanabe Heritable Hyperlipemic and comparably hypercholesterolemic fat-fed rabbits. Arteriosclerosis 7:24, 1987.

Rosenfeld ME, Tsukada T, Gown AM, Ross R: Fatty streak initiation in Watanabe Heritable Hyperlipemic and comparably hypercholesterolemic fat-fed rabbits. Arteriosclerosis 7:9, 1987.

Gerrity RG, Naito HK, Richardson M, Schwartz CJ: Dietary induced atherogenesis in swine. Morphology of the intima in prelesion stages. Am J Pathol 95:775, 1979.

Faggiotto A, Ross R: Studies of hypercholesterolemia in the nonhuman primate. II. Fatty streak conversion to fibrous plaque. Arteriosclerosis 4:341, 1984.

Faggiotto A, Ross R, Harker L: Studies of hypercholesterolemia in the nonhuman primate. I. Changes that lead to fatty streak formation. Arteriosclerosis 4:323, 1984.

Masuda J, Ross R: Atherogenesis during low level hypercholesterolemia in the nonhuman primate. II. Fatty streak conversion to fibrous plaque. Arteriosclerosis 10:178, 1990.

Masuda J, Ross R: Atherogenesis during low level hypercholesterolemia in the nonhuman primate. I. Fatty streak formation. Arteriosclerosis 10:164, 1990.

Breslow JL: Mouse models of atherosclerosis. Science 272:685, 1996.

Nakashima Y, Plump AS, Raines EW, Breslow JL, Ross R: ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler Thromb 14:133, 1994.

Ishibashi S, Goldstein JL, Brown MS, Herz J, Burns DK: Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice. J Clin Invest 93:1885, 1994.

Young SG: Using genetically modified mice to study apolipoprotein B. J Atheroscler Thromb 3:62, 1996.

Gu L, Okada Y, Clinton SK, et al: Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell 2:275, 1998.

Boring L, Gosling J, Cleary M, Charo IF: Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 394:894, 1998.

Gosling J, Slaymaker S, Gu L, et al: MCP-1 deficiency reduces susceptibility to atherosclerosis in mice that overexpress human apolipoprotein B. J Clin Invest 103:773, 1999.

Ross R, Glomset JA: Atherosclerosis and the arterial smooth muscle cell: proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis. Science 180:1332, 1973.

Ross R: Cell biology of atherosclerosis. Annu Rev Physiol 57:791, 1995.

Pober JS, Cotran RS: Cytokines and endothelial cell biology. Physiol Rev 70:427, 1990.

Libby P, Sukhova G, Lee RT, Galis ZS: Cytokines regulate vascular functions related to stability of the atherosclerotic plaque. J Cardiovasc Pharmacol 25 suppl 2:S9, 1995.

Davies PF, Tripathi SC: Mechanical stress mechanisms and the cell. An endothelial paradigm. Circ Res 72:239, 1993.

Gimbrone MA Jr, Resnick N, Nagel T, Khachigian LM, Collins T, Topper JN: Hemodynamics, endothelial gene expression, and atherogenesis. Ann N Y Acad Sci 811:1, 1997.

Gimbrone MA Jr: Vascular endothelium: an integrator of pathophysiologic stimuli in atherosclerosis. Am J Cardiol 75:67B, 1995.

Cines DB, Pollak ES, Buck CA, et al: Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 91:3527, 1998.

Simionescu N, Vasile E, Lupu F, Popescu G, Simionescu M: Prelesional events in atherogenesis. Accumulation of extracellular cholesterol-rich liposomes in the arterial intima and cardiac valves of the hyperlipidemic rabbit. Am J Pathol 123:109, 1986.

Henriksen T, Mahoney EM, Steinberg D: Enhanced macrophage degradation of low density lipoprotein previously incubated with cultured endothelial cells: recognition by receptors for acetylated low density lipoproteins. Proc Natl Acad Sci USA 78:6499, 1981.

Cathcart MK, Morel DW, Chisolm GM: Monocytes and neutrophils oxidize low density lipoprotein making it cytotoxic. J Leukoc Biol 38:341, 1985.

Rosenfeld ME, Palinski W, Yla-Herttuala S, Carew TE: Macrophages, endothelial cells, and lipoprotein oxidation in the pathogenesis of atherosclerosis. Toxicol Pathol 18:560, 1990.

Steinberg D: Antioxidants and atherosclerosis. A current assessment. Circulation 84:1420, 1991.

Luscinskas FW, Gimbrone MA Jr: Endothelial-dependent mechanisms in chronic inflammatory leukocyte recruitment. Annu Rev Med 47:413, 1996.

Thiruvikraman SV, Guha A, Roboz J, Taubman MB, Nemerson Y, Fallon JT: In situ localization of tissue factor in human atherosclerotic plaques by binding of digoxigenin-labeled factors VIIa and X. Lab Invest 75:451, 1996.

Fuster V, Badimon L, Badimon JJ, Chesebro JH: The pathogenesis of coronary artery disease and the acute coronary syndromes (1). N Engl J Med 326:242, 1992.

Fuster V, Badimon L, Badimon JJ, Chesebro JH: The pathogenesis of coronary artery disease and the acute coronary syndromes (2). N Engl J Med 326:310, 1992.

Kullo IJ, Edwards WD, Schwartz RS: Vulnerable plaque: pathobiology and clinical implications. Ann Intern Med 129:1050, 1998.

Davies MJ, Richardson PD, Woolf N, Katz DR, Mann J: Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage, and smooth muscle cell content. LA – Eng. Br Heart J 69:377, 1993.

Davies MJ: Stability and instability: two faces of coronary. Paul Dudley White Lecture 1995. Circulation 94:2013, 1996.

Van der Wal AC, Becker AE, van der Loos CM, Das PK: Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 89:36, 1994.

Libby P: Molecular bases of the acute coronary syndromes. Circulation 91:2844, 1995.

Galis ZS, Sukhova GK, Lark MW, Libby P: Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest 94:2493, 1994.

Richardson PD, Davies MJ, Born GV: Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques. Lancet 2:941, 1989.

Cheng GC, Loree HM, Kamm RD, Fishbein MC, Lee RT: Distribution of circumferential stress in ruptured and stable atherosclerotic lesions. A structural analysis with histopathological correlation. Circulation 87:1179, 1993.

Davies MJ: A macro and micro view of coronary vascular insult in ischemic heart disease. Circulation 82: (3 Suppl):1138, 1990.

Losordo DW, Rosenfield K, Pieczek A, Baker K, Harding M, Isner JM: How does angioplasty work? Serial analysis of human iliac arteries using intravascular ultrasound. Circulation 86:1845, 1992.

Nath FC, Muller DW, Ellis SG, et al: Thrombosis of a flexible coil coronary stent: frequency, predictors and clinical outcome. J Am Coll Cardiol 21:622, 1993.

Schafer AI: Antiplatelet therapy. Am J Med 101:199, 1996.

Steele PM, Chesebro JH, Stanson AW, et al: Balloon angioplasty. Natural history of the pathophysiological response to injury in a pig model. Circ Res 57:105, 1985.

Heras M, Chesebro JH, Penny WJ, Bailey KR, Badimon L, Fuster V: Effects of thrombin inhibition on the development of acute platelet-thrombus deposition during angioplasty in pigs. Heparin versus recombinant hirudin, a specific thrombin inhibitor. Circulation 79:657, 1989.

Stemerman BM: Thrombogenesis of the rabbit arterial plaque. Am J Pathol 73:7, 1973.

Groves MH, Rathbone-Kinlough LR, Richardson M, Jorgensen L, Moore S, Mustard FJ: Thrombin generation and fibrin formation following injury to rabbit neointima. Lab Invest 46:605, 1982.

Clowes AW, Reidy MA, Clowes MM: Kinetics of cellular proliferation after arterial injury. I. Smooth muscle growth in the absence of endothelium. Lab Invest 49:327, 1983.

Richardson M, Kinlough-Rathbone LR, Groves HM, Jorgensen L, Mustard JF, Moore S: Ultrastructural changes in re-endothelialized and non-endothelialized rabbit aortic neointima following re-injury with a ballon catheter. Br J Exp Path 65:597, 1984.

Consigny MP, Tulenko NT, Nicosia FR: Immediate and long-term effects of angioplasty-balloon dilation on normal rabbit lliac artery. Arteriosclerosis 6:265, 1986.

Asada Y, Hara S, Tsuneyoshi A, et al: Fibrin-rich and platelet-rich thrombus formation on neointima: recombinant tissue factor pathway inhibitor prevents fibrin formation and neointimal development following repeated balloon injury of rabbit aorta. Thromb Haemost 80:506, 1998.

Courtman DW, Schwartz SM, Hart CE: Sequential injury of the rabbit abdominal aorta induces intramural coagulation and luminal narrowing independent of intimal mass: extrinsic pathway inhibition eliminates luminal narrowing. Circ Res 82:996, 1998.

Edgington TS, Mackman N, Brand K, Ruf W: The structural biology of expression and function of tissue factor. Thromb Haemost 66:67, 1991.

Nemerson Y: Tissue factor: then and now. Thromb Haemost 74:180, 1995.

Rapaport SI, Rao LV: The tissue factor pathway: how it has become a “prima ballerina.” Thromb Haemost 74:7, 1995.

Zeldis SM, Nemerson Y, Pitlick FA, Lentz TL: Tissue factor (thromboplastin): localization to plasma membranes by peroxidase-conjugated antibodies. Science 175:766, 1972.

Drake TA, Morrissey JH, Edgington TS: Selective cellular expression of tissue factor in human tissues. Am J Pathol 134:1087, 1989.

Wilcox JN, Smith KM, Schwartz SM, Gordon D: Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci USA 86:2839, 1989.

Annex BH, Denning SM, Channon KM, et al: Differential expression of tissue factor protein in directional atherectomy specimens from patients with stable and unstable coronary syndromes. Circulation 91:619, 1995.

Marmur JD, Thiruvikraman SV, Fyfe BS, et al: Identification of active tissue factor in human coronary atheroma. Circulation 94:1226, 1996.

Moreno PR, Bernardi VH, Lopez-Cuellar J, et al: Macrophages, smooth muscle cells, and tissue factor in unstable angina. Implications for cell-mediated thrombogenicity in acute coronary syndromes. Circulation 94:3090, 1996.

Hatakeyama K, Asada Y, Marutsuka K, Sato Y, Kamikubo Y, Sumiyoshi A: Localization and activity of tissue factor in human aortic atherosclerotic lesions. Atherosclerosis 133:213, 1997.

Caplice NM, Mueske CS, Kleppe LS, Simari RD: Presence of tissue factor pathway inhibitor in human atherosclerotic plaques is associated with reduced tissue factor activity. Circulation 98:1051, 1998.

Fernandez-Ortiz A, Badimon JJ, Falk E, et al: Characterization of the relative thrombogenicity of atherosclerotic plaque components: implications for consequences of plaque rupture. J Am Coll Cardiol 23:1562, 1994.

Toschi V, Gallo R, Lettino M, et al: Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation 95:594, 1997.

Mallat Z, Hugel B, Ohan J, Leseche G, Freyssinet JM, Tedgui A: Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques : A role for apoptosis in plaque thrombogenicity. Circulation 99:348, 1999.

Maynard JR, Heckman CA, Pitlick FA, Nemerson Y: Association of tissue factor activity with the surface of cultured cells. J Clin Invest 55:814, 1975.

Marmur JD, Rossikhina M, Guha A, et al: Tissue factor is rapidly induced in arterial smooth muscle after balloon injury. J Clin Invest 91:2253, 1993.

Pawashe AB, Golino P, Ambrosio G, et al: A monoclonal antibody against rabbit tissue factor inhibits thrombus formation in stenotic injured rabbit carotid arteries. Circ Res 74:56, 1994.

Speidel CM, Eisenberg PR, Ruf W, Edgington TS, Abendschein DR: Tissue factor mediates prolonged procoagulant activity on the luminal surface of balloon-injured aortas in rabbits. Circulation 92:3323, 1995.

Gertz SD, Fallon JT, Gallo R, et al: Hirudin reduces tissue factor expression in neointima after balloon injury in rabbit femoral and porcine coronary arteries. Circulation 98:580, 1998.

Jang IK, Gold HK, Leinbach RC, Fallon JT, Collen D, Wilcox JN: Antithrombotic effect of a monoclonal antibody against tissue factor in a rabbit model of platelet-mediated arterial thrombosis. Arterioscler Thromb 12:948, 1992.

Golino P, Ragni M, Cirillo P, et al: Antithrombotic effects of recombinant human, active site-blocked factor VIIa in a rabbit model of recurrent arterial thrombosis. Circ Res 82:39, 1998.

Jang Y, Guzman LA, Lincoff AM, et al: Influence of blockade at specific levels of the coagulation cascade on restenosis in a rabbit atherosclerotic femoral artery injury model. Circulation 92:3041, 1995.

Harker LA, Hanson SR, Wilcox JN, Kelly AB: Antithrombotic and antilesion benefits without hemorrhagic risks by inhibiting tissue factor pathway. Haemostasis 26 (suppl 1):76, 1996.

Oltrona L, Speidel CM, Recchia D, Wickline SA, Eisenberg PR, Abendschein DR: Inhibition of tissue factor-mediated coagulation markedly attenuates stenosis after balloon-induced arterial injury inminipigs. Circulation 96:646, 1997.

Fukuda C, Iijima K, Nakamura K: Measuring tissue factor (factor III) activity in plasma. Clin Chem 35:1897, 1989.

Suefuji H, Ogawa H, Yasue H, et al: Increased plasma tissue factor levels in acute myocardial infarction. Am Heart J 134:253, 1997.

Key NS, Slungaard A, Dandelet L, et al: Whole blood tissue factor procoagulant activity is elevated in patients with sickle cell disease. Blood 91:4216, 1998.

Giesen PLA, Rauch U, Bohrmann B, et al: Blood-borne tissue factor: a new view of thrombosis. Proc Natl Acad Sci USA 99:2311, 1999.

Hartzell S, Ryder K, Lanahan A, Lau LF, Nathan D: A growth factor-responsive gene of murine BALB/c 3T3 cells encodes a protein homologous to human tissue factor. Mol Cell Biol 9:2567, 1989.

Drake TA, Hannani K, Fei HH, Lavi S, Berliner JA: Minimally oxidized low-density lipoprotein induces tissue factor expression in cultured human endothelial cells. Am J Pathol 138:601, 1991.

Brand K, Banka CL, Mackman N, Terkeltaub RA, Fan ST, Curtiss LK: Oxidized LDL enhances lipopolysaccharide-induced tissue factor expression in human adherent monocytes. Arterioscler Thromb 14:790, 1994.

van den Eijnden MM, Steenhauer SI, Reitsma PH, Bertina RM: Tissue factor expression during monocyte-macrophage differentiation. Thromb Haemost 77:1129, 1997.

Brox JH, Osterud B, Bjorklid E, Fenton JW: Production and availability of thromboplastin in endothelial cells: the effects of thrombin, endotoxin and platelets. Br J Haematol 57:239, 1984.

Taubman MB, Marmur JD, Rosenfield CL, Guha A, Nichtberger S, Nemerson Y: Agonist-mediated tissue factor expression in cultured vascular smooth muscle cells. Role of Ca2+ mobilization and protein kinase C activation. J Clin Invest 91:547, 1993.

Schecter AD, Giesen PL, Taby O, et al: Tissue factor expression in human arterial smooth muscle cells. TF is present in three cellular pools after growth factor stimulation. J Clin Invest 100:2276, 1997.

Grabowski EF, Zuckerman DB, Nemerson Y: The functional expression of tissue factor by fibroblasts and endothelial cells under flow conditions. Blood 81:3265, 1993.

Lin MC, Almus-Jacobs F, Chen HH, et al: Shear stress induction of the tissue factor gene. J Clin Invest 99:737, 1997.

Mackman N, Morrissey JH, Fowler B, Edgington TS: Complete sequence of the human tissue factor gene, a highly regulated cellular receptor that initiates the coagulation protease cascade. Biochemistry 28:1755, 1989.

Mackman N, Imes S, Maske WH, Taylor B, Lusis AJ, Drake TA: Structure of the murine tissue factor gene. Chromosome location and conservation of regulatory elements in the promoter. Arterioscler Thromb 12:474, 1992.

Moll T, Czyz M, Holzmuller H, et al: Regulation of the tissue factor promoter in endothelial cells. Binding of NF kappa B-, AP-1-, and Sp1-like transcription factors. J Biol Chem 270:3849, 1995.

Taby O, Rosenfield CL, Bogdanov V, Nemerson Y, Taubman MB: Cloning of the rat tissue factor cDNA and promoter: identification of a serum-response region. Thromb Haemost 76:697, 1996.

Mackman N: Regulation of the tissue factor gene. Thromb Haemost 78:747, 1997.

Drake TA, Ruf W, Morrissey JH, Edgington TS: Functional tissue factor is entirely cell surface expressed on lipopolysaccharide-stimulated human blood monocytes and a constitutively tissue factor-producing neoplastic cell line. J Cell Biol 109:389, 1989.

Le DT, Rapaport SI, Rao LV: Relations between factor VIIa binding and expression of factor VIIa/tissue factor catalytic activity on cell surfaces. J Biol Chem 267:15447, 1992.

Carson SD: Manifestation of cryptic fibroblast tissue factor occurs at detergent concentrations which dissolve the plasma membrane. Blood Coagul Fibrinolysis 7:303, 1996.

Greeno EW, Bach RR, Moldow CF: Apoptosis is associated with increased cell surface tissue factor procoagulant activity. Lab Invest 75:281, 1996.

Mulder AB, Smit JW, Bom VJ, et al: Association of smooth muscle cell tissue factor with caveolae. Blood 88:1306, 1996.

Sevinsky RJ, Rao MVL, Ruf W: Ligand-induced protease receptor translocation into caveolae: a mechanism for regulating cell surface proteolsis of the tissue factor-dependent coagulation pathway. J Cell Biol 133:293, 1996.

Bach RR, Moldow CF: Mechanism of tissue factor activation on HL-60 cells. Blood 89:3270, 1997.

Carson SD, Perry GA, Pirruccello SJ: Fibroblast tissue factor: calcium and ionophore induce shape changes, release of membrane vesicles, and redistribution of tissue factor antigen in addition to increased procoagulant activity. Blood 84:526, 1994.

Satta N, Toti F, Feugeas O, et al: Monocyte vesiculation is a possible mechanism for dissemination of membrane-associated procoagulant activities and adhesion molecules after stimulation by lipopolysaccharide. J Immunol 153:3245, 1994.

Broze GJ Jr: Tissue factor pathway inhibitor and the revised theory of coagulation. Annu Rev Med 46:103, 1995.

Mann KG, van’t Veer C, Cawthern K, Butenas S: The role of the tissue factor pathway in initiation of coagulation. Blood Coagul Fibrinolysis 9 (suppl 1):S3, 1998.

Kamikubo Y, Nakahara Y, Takemoto S, Hamuro T, Miyamoto S, Funatsu A: Human recombinant tissue-factor pathway inhibitor prevents the proliferation of cultured human neonatal aortic smooth muscle cells. FEBS Lett 407:116, 1997.

Bajaj MS, Kuppuswamy MN, Saito H, Spitzer SG, Bajaj SP: Cultured normal human hepatocytes do not synthesize lipoprotein-associated coagulation inhibitor: evidence that endothelium is the principal site of its synthesis. Proc Natl Acad Sci USA. 87:8869, 1990.

Werling RW, Zacharski LR, Kisiel W, Bajaj SP, Memoli VA, Rousseau SM: Distribution of tissue factor pathway inhibitor in normal and malignant human tissues. Thromb Haemost 69:366, 1993.

Caplice NM, Mueske CS, Kleppe LS, Peterson TE, Broze GJ, Jr, Simari RD: Expression of tissue factor pathway inhibitor in vascular smooth muscle cells and its regulation by growth factors. Circ Res 83:1264, 1998.

Sato N, Kokame K, Miyata T, Kato H: Lysophosphatidylcholine decreases the synthesis of tissue factor pathway inhibitor in human umbilical vein endothelial cells. Thromb Haemost 79:217, 1998.

Broze GJ Jr: Tissue factor pathway inhibitor gene disruption. Blood Coagul Fibrinolysis 9(suppl 1):S89, 1998.

Drew AF, Davenport P, Apostolopoulos J, Tipping PG: Tissue factor pathway inhibitor expression in atherosclerosis. Lab Invest 77:291, 1997.

Haskel EJ, Torr SR, Day KC, et al: Prevention of arterial reocclusion after thrombolysis with recombinant lipoprotein-associated coagulation inhibitor . Circulation 84:821, 1991.

Gross JL, Moscatelli D, Jaffe EA, Rifkin DB: Plasminogen activator and collagenase production by cultured capillary endothelial cells. J Cell Biol 95:974, 1982.

Levin EG, Loskutoff DJ: Cultured bovine endothelial cells produce both urokinase and tissue-type plasminogen activators. J Cell Biol 94:631, 1982.

Nachman RL, Hajjar KA: Endothelial cell fibrinolytic assembly. Ann N Y Acad Sci 614:240, 1991.

Levin EG, del Zoppo GJ: Localization of tissue plasminogen activator in the endothelium of a limited number of vessels. Am J Pathol 144:855, 1994.

Lupu F, Heim DA, Bachmann F, Hurni M, Kakkar VV, Kruithof EK: Plasminogen activator expression in human atherosclerotic lesions. Arterioscler Thromb Vasc Biol 15:1444, 1995.

Ljungner H, Bergqvist D: Decreased fibrinolytic activity in human atherosclerotic vessels. Atherosclerosis 50:113, 1984.

Bjorkerud S: Impaired fibrinolysis-inducing capacity for postinjury phenotype of cultivated human arterial and human atherosclerotic intimal smooth muscle cells. Circ Res 62:1011, 1988.

Underwood MJ, De Bono DP: Increased fibrinolytic activity in the intima of atheromatous coronary arteries: protection at a price. Cardiovasc Res 27:882, 1993.

Reilly JM, Sicard GA, Lucore CL: Abnormal expression of plasminogen activators in aortic aneurysmal and occlusive disease. J Vasc Surg 19:865, 1994.

Raghunath PN, Tomaszewski JE, Brady ST, Caron RJ, Okada SS, Barnathan ES: Plasminogen activator system in human coronary atherosclerosis. Arterioscler Thromb Vasc Biol 15:1432, 1995.

Clowes AW, Clowes MM, Au YP, Reidy MA, Belin D: Smooth muscle cells express urokinase during mitogenesis and tissue-type plasminogen activator during migration in injured rat carotid artery. Circ Res 67:61, 1990.

Lyons RM, Gentry LE, Purchio AF, Moses HL: Mechanism of activation of latent recombinant transforming growth factor beta 1 by plasmin. J Cell Biol 110:1361, 1990.

Saksela O, Rifkin DB: Release of basic fibroblast growth factor-heparan sulfate complexes from endothelial cells by plasminogen activator-mediated proteolytic activity. J Cell Biol 110:767, 1990.

Grainger DJ, Kirschenlohr HL, Metcalfe JC, Weissberg PL, Wade DP, Lawn RM: Proliferation of human smooth muscle cells promoted by lipoprotein(a). Science 260:1655, 1993.

Kojima S, Harpel PC, Rifkin DB: Lipoprotein(a) inhibits the generation of transforming growth factor beta: an endogenous inhibitor of smooth muscle cell migration. J Cell Biol 113:1439, 1991.

Grainger DJ, Kemp PR, Liu AC, Lawn RM, Metcalfe JC: Activation of transforming growth factor-beta is inhibited in transgenic apolipoprotein(a) mice. Nature 370:460, 1994.

He CS, Wilhelm SM, Pentland AP, et al: Tissue cooperation in a proteolytic cascade activating human interstitial collagenase. Proc Natl Acad Sci USA 86:2632, 1989.

Jackson CL, Reidy MA: The role of plasminogen activation in smooth muscle cell migration after arterial injury. Ann NY Acad Sci 667:141, 1992.

Kanamasa K, Ishida N, Kato H, et al: Recombinant tissue plasminogen activator prevents intimal hyperplasia after balloon angioplasty in hypercholesterolemic rabbits. Jpn Circ J 60:889, 1996.

Loskutoff DJ, Sawdey M, Keeton M, Schneiderman J: Regulation of PAI-1 gene expression in vivo. Thromb Haemost 70:135, 1993.

Booth NA, Simpson AJ, Croll A, Bennett B, MacGregor IR: Plasminogen activator inhibitor (PAI-1) in plasma and platelets. Br J Haematol 70:327, 1988.

Green F, Humphries S: Genetic determinants of arterial thrombosis. Baillieres Clin Haematol 7:675, 1994.

Lijnen HR, Bachmann F, Collen D, et al: Mechanisms of plasminogen activation. J Intern Med 236:415, 1994.

Aillaud MF, Pignol F, Alessi MC, et al: Increase in plasma concentration of plasminogen activator inhibitor, fibrinogen, von Willebrand factor, factor VIII:C and in erythrocyte sedimentation rate with age. Thromb Haemost 55:330, 1986.

Juhan-Vague I, Vague P, Alessi MC, et al: Relationships between plasma insulin triglyceride, body mass index, and plasminogen activator inhibitor 1. Diabete Metab 13:331, 1987.

Juhan-Vague I, Alessi MC, Vague P: Increased plasma plasminogen activator inhibitor 1 levels. A possible link between insulin resistance and atherothrombosis. Diabetologia 34:457, 1991.

Wagner OF, de Vries C, Hohmann C, Veerman H, Pannekoek H: Interaction between plasminogen activator inhibitor type 1 (PAI-1) bound to fibrin and either tissue-type plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA). Binding of t-PA/PAI-1 complexes to fibrin mediated by both the finger and the kringle-2 domain of t-PA. J Clin Invest 84:647, 1989.

Vaughan DE, Declerck PJ, Van Houtte E, De Mol M, Collen D: Reactivated recombinant plasminogen activator inhibitor-1 (rPAI-1) effectively prevents thrombolysis in vivo. Thromb Haemost 68:60, 1992.

Fay WP, Eitzman DT, Shapiro AD, Madison EL, Ginsburg D: Platelets inhibit fibrinolysis in vitro by both plasminogen activator inhibitor-1-dependent and -independent mechanisms. Blood 83:351, 1994.

Prisco D, Chiarantini E, Boddi M, Rostagno C, Colella A, Gensini GF: Predictive value for thrombotic disease of plasminogen activator inhibitor-1 plasma levels. Int J Clin Lab Res 23:78, 1993.

Aznar J, Estelles A, Tormo G, et al: Plasminogen activator inhibitor activity and other fibrinolytic variables in patients with coronary artery disease. Br Heart J 59:535, 1988.

Huber K, Resch I, Stefenelli T, et al: Plasminogen activator inhibitor-1 levels in patients with chronic angina pectoris with or without angiographic evidence of coronary sclerosis. Thromb Haemost 63:336, 1990.

Zalewski A, Shi Y, Nardone D, et al: Evidence for reduced fibrinolytic activity in unstable angina at rest. Clinical, biochemical, and angiographic correlates. Circulation 83:1685, 1991.

Gram J, Kluft C, Jespersen J: Depression of tissue plasminogen activator (t-PA) activity and rise of t-PA inhibition and acute phase reactants in blood of patients with acute myocardial infarction (AMI). Thromb Haemost 58:817, 1987.

Hamsten A, de Faire U, Walldius G, et al: Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 2:3, 1987.

Barbash GI, Hod H, Roth A, et al: Correlation of baseline plasminogen activator inhibitor activity with patency of the infarct artery after thrombolytic therapy in acute myocardial infarction. Am J Cardiol 64:1231, 1989.

Ridker PM, Hennekens CH, Stampfer MJ, Manson JE, Vaughan DE: Prospective study of endogenous tissue plasminogen activator and risk of stroke. Lancet 343:940, 1994.

Salomaa V, Stinson V, Kark JD, Folsom AR, Davis CE, Wu KK: Association of fibrinolytic parameters with early atherosclerosis. The ARIC Study. Atherosclerosis Risk in Communities Study. Circulation 91:284, 1995.

Huber K, Jorg M, Probst P, et al: A decrease in plasminogen activator inhibitor-1 activity after successful percutaneous transluminal coronary angioplasty is associated with a significantly reduced risk for coronary restenosis. Thromb Haemost 67:209, 1992.

Schneiderman J, Sawdey MS, Keeton MR, et al: Increased type 1 plasminogen activator inhibitor gene expression in atherosclerotic human arteries. Proc Natl Acad Sci USA 89:6998, 1992.

Lupu F, Bergonzelli GE, Heim DA, et al: Localization and production of plasminogen activator inhibitor-1 in human healthy and atherosclerotic arteries. Arterioscler Thromb 13:1090, 1993.

Chomiki N, Henry M, Alessi MC, Anfosso F, Juhan-Vague I: Plasminogen activator inhibitor-1 expression in human liver and healthy or atherosclerotic vessel walls. Thromb Haemost 72:44, 1994.

Robbie LA, Bennett B, Croll AM, Brown PA, Booth NA: Proteins of the fibrinolytic system in human thrombi. Thromb Haemost 75:127, 1996.

Robbie LA, Booth NA, Brown AJ, Bennett B: Inhibitors of fibrinolysis are elevated in atherosclerotic plaque. Arterioscler Thromb Vasc Biol 16:539, 1996.

Loskutoff DJ: PAI-1 inhibits neointimal formation after arterial injury in mice: a new target for controlling restenosis? Circulation 96:2772, 1997.

Fay WP, Parker AC, Condrey LR, Shapiro AD: Human plasminogen activator inhibitor-1 (PAI-1) deficiency: characterization of a large kindred with a null mutation in the PAI-1 gene. Blood 90:204, 1997.

Sawa H, Lundgren C, Sobel BE, Fujii S: Increased intramural expression of plasminogen activator inhibitor type 1 after balloon injury: a potential progenitor of restenosis. J Am Coll Cardiol 24:1742, 1994.

Hasenstab D, Forough R, Clowes AW: Plasminogen activator inhibitor type 1 and tissue inhibitor of metalloproteinases-2 increase after arterial injury in rats. Circ Res 80:490, 1997.

Sawa H, Fujii S, Sobel BE: Augmented arterial wall expression of type-1 plasminogen activator inhibitor induced by thrombosis. Arterioscler Thromb 12:1507, 1992.

Loskutoff DJ, van Mourik JA, Erickson LA, Lawrence D: Detection of an unusually stable fibrinolytic inhibitor produced by bovine endothelial cells. Proc Natl Acad Sci USA 80:2956, 1983.

Laug WE: Vascular smooth muscle cells inhibit the plasminogen activators secreted by endothelial cells. Thromb Haemost 53:165, 1985.

Tipping PG, Davenport P, Gallicchio M, Filonzi EL, Apostolopoulos J, Wojta J: Atheromatous plaque macrophages produce plasminogen activator inhibitor type-1 and stimulate its production by endothelial cells and vascular smooth muscle cells. Am J Pathol 143:875, 1993.

Gelehrter TD, Sznycer-Laszuk R: Thrombin induction of plasminogen activator-inhibitor in cultured human endothelial cells. J Clin Invest 77:165, 1986.

Saksela O, Moscatelli D, Rifkin DB: The opposing effects of basic fibroblast growth factor and transforming growth factor beta on the regulation of plasminogen activator activity in capillary endothelial cells. J Cell Biol 105:957, 1987.

Hasselaar P, Loskutoff DJ, Sawdey M, Sage EH: SPARC induces the expression of type 1 plasminogen activator inhibitor in cultured bovine aortic endothelial cells. J Biol Chem 266:13178, 1991.

Reilly CF, McFall RC: Platelet-derived growth factor and transforming growth factor-beta regulate plasminogen activator inhibitor-1 synthesis in vascular smooth muscle cells. J Biol Chem 266:9419, 1991.

Sawdey MS, Loskutoff DJ: Regulation of murine type 1 plasminogen activator inhibitor gene expression in vivo. Tissue specificity and induction by lipopolysaccharide, tumor necrosis factor-alpha, and transforming growth factor-beta. J Clin Invest 88:1346, 1991.

van Leeuwen RT, Kol A, Andreotti F, Kluft C, Maseri A, Sperti G: Angiotensin II increases plasminogen activator inhibitor type 1 and tissue-type plasminogen activator messenger RNA in cultured rat aortic smooth muscle cells. Circulation 90:362, 1994.

Noda-Heiny H, Fujii S, Sobel BE: Induction of vascular smooth muscle cell expression of plasminogen activator inhibitor-1 by thrombin. Circ Res 72:36, 1993.

Wojta J, Gallicchio M, Zoellner H, et al: Thrombin stimulates expression of tissue-type plasminogen activator and plasminogen activator inhibitor type 1 in cultured human vascular smooth muscle cells. Thromb Haemost 70:469, 1993.

Christ G, Hufnagl P, Kaun C, et al: Antifibrinolytic properties of the vascular wall. Dependence on the history of smooth muscle cell doublings in vitro and in vivo. Arterioscler Thromb Vasc Biol 17:723, 1997.

Etingin OR, Hajjar DP, Hajjar KA, Harpel PC, Nachman RL: Lipoprotein (a) regulates plasminogen activator inhibitor-1 expression in endothelial cells. A potential mechanism in thrombogenesis. J Biol Chem 266:2459, 1991.

Christ G, Seiffert D, Hufnagl P, Gessl A, Wojta J, Binder BR: Type 1 plasminogen activator inhibitor synthesis of endothelial cells is downregulated by smooth muscle cells. Blood 81:1277, 1993.

Kruithof EK, Gudinchet A, Bachmann F: Plasminogen activator inhibitor 1 and plasminogen activator inhibitor 2 in various disease states. Thromb Haemost 59:7, 1988.

Bachmann F: The enigma PAI-2. Gene expression, evolutionary and functional aspects. Thromb Haemost 74:172, 1995.

Higazi AA, Mazar A, Wang J, et al: Single-chain urokinase-type plasminogen activator bound to its receptor is relatively resistant to plasminogen activator inhibitor type 1. Blood 87:3545, 1996.

Blasi F: The urokinase receptor and cell migration. Semin Thromb Hemost 22:513, 1996.

Barnathan ES, Kuo A, Kariko K, et al: Characterization of human endothelial cell urokinase-type plasminogen activator receptor protein and messenger RNA. Blood 76:1795, 1990.

Reuning U, Bang NU: Regulation of the urokinase-type plasminogen activator receptor on vascular smooth muscle cells is under the control of thrombin and other mitogens. Arterioscler Thromb 12:1161, 1992.

Okada SS, Golden MA, Raghunath PN, et al: Native atherosclerosis and vein graft arterialization: association with increased urokinase receptor expression in vitro and in vivo. Thromb Haemost 80:140, 1998.

Okada SS, Tomaszewski JE, Barnathan ES: Migrating vascular smooth muscle cells polarize cell surface urokinase receptors after injury in vitro. Exp Cell Res 217:180, 1995.

Pepper MS, Sappino AP, Stocklin R, Montesano R, Orci L, Vassalli JD: Upregulation of urokinase receptor expression on migrating endothelial cells. J Cell Biol 122:673, 1993.

Estreicher A, Muhlhauser J, Carpentier JL, Orci L, Vassalli JD: The receptor for urokinase type plasminogen activator polarizes expression of the protease to the leading edge of migrating monocytes and promotes degradation of enzyme inhibitor complexes. J Cell Biol 111:783, 1990.

Wei Y, Lukashev M, Simon DI, et al: Regulation of integrin function by the urokinase receptor. Science 273:1551, 1996.

Sitrin RG, Todd RF, 3rd, Albrecht E, Gyetko MR: The urokinase receptor (CD87) facilitates CD11b/CD18-mediated adhesion of human monocytes. J Clin Invest 97:1942, 1996.

Wong WS, Simon DI, Rosoff PM, Rao NK, Chapman HA: Mechanisms of pertussis toxin-induced myelomonocytic cell adhesion: role of Mac-1(CD11b/CD18) and urokinase receptor (CD87). Immunology 88:90, 1996.

Anichini E, Fibbi G, Pucci M, Caldini R, Chevanne M, Del Rosso M: Production of second messengers following chemotactic and mitogenic urokinase-receptor interaction in human fibroblasts and mouse fibroblasts transfected with human urokinase receptor. Exp Cell Res 213:438, 1994.

Resnati M, Guttinger M, Valcamonica S, Sidenius N, Blasi F, Fazioli F: Proteolytic cleavage of the urokinase receptor substitutes for the agonist-induced chemotactic effect. Embo J 15:1572, 1996.

Rao NK, Shi GP, Chapman HA: Urokinase receptor is a multifunctional protein: influence of receptor occupancy on macrophage gene expression. J Clin Invest 96:465, 1995.

Rabbani SA, Mazar AP, Bernier SM, et al: Structural requirements for the growth factor activity of the amino- terminal domain of urokinase. J Biol Chem 267:14151, 1992.

De Petro G, Copeta A, Barlati S: Urokinase-type and tissue-type plasminogen activators as growth factors of human fibroblasts. Exp Cell Res 213:286, 1994.

Higazi AA, Upson RH, Cohen RL, et al: Interaction of single-chain urokinase with its receptor induces the appearance and disappearance of binding epitopes within the resultant complex for other cell surface proteins. Blood 88:542, 1996.

Noda-Heiny H, Daugherty A, Sobel BE: Augmented urokinase receptor expression in atheroma. Arterioscler Thromb Vasc Biol 15:37, 1995.

Carmeliet P, Collen D: Molecular genetics of the fibrinolytic and coagulation systems in haemostasis, thrombogenesis, restenosis and atherosclerosis. Curr Opin Lipidol 8:118, 1997.

Carmeliet P, Moons L, Ploplis V, Plow E, Collen D: Impaired arterial neointima formation in mice with disruption of the plasminogen gene. J Clin Invest 99:200, 1997.

Romer J, Bugge TH, Pyke C, et al: Impaired wound healing in mice with a disrupted plasminogen gene. Nat Med 2:287, 1996.

Carmeliet P, Moons L, Herbert JM, et al: Urokinase but not tissue plasminogen activator mediates arterial neointima formation in mice. Circ Res 81:829, 1997.

Carmeliet P, Moons L, Lijnen R, et al: Inhibitory role of plasminogen activator inhibitor-1 in arterial wound healing and neointima formation: a gene targeting and gene transfer study in mice. Circulation 96:3180, 1997.

Farrehi PM, Ozaki CK, Carmeliet P, Fay WP: Regulation of arterial thrombolysis by plasminogen activator inhibitor-1 in mice. Circulation 97:1002, 1998.

Bugge TH, Suh TT, Flick MJ, et al: The receptor for urokinase-type plasminogen activator is not essential for mouse development or fertility. J Biol Chem 270:16886, 1995.

Bugge TH, Flick MJ, Danton MJ, et al: Urokinase-type plasminogen activator is effective in fibrin clearance in the absence of its receptor or tissue-type plasminogen activator. Proc Natl Acad Sci USA 93:5899, 1996.

Carmeliet P, Moons L, Dewerchin M, et al: Receptor-independent role of urokinase-type plasminogen activator in pericellular plasmin and matrix metalloproteinase proteolysis during vascular wound healing in mice. J Cell Biol 140:233, 1998.

Robbie LA, Booth NA, Croll AM, Bennett B: The roles of alpha 2-antiplasmin and plasminogen activator inhibitor 1 (PAI-1) in the inhibition of clot lysis. Thromb Haemost 70:301, 1993.

Plow EF, Collen D: The presence and release of alpha 2-antiplasmin from human platelets. Blood 58:1069, 1981.

Sakata Y, Aoki N: Significance of cross-linking of alpha 2-plasmin inhibitor to fibrin in inhibition of fibrinolysis and in hemostasis. J Clin Invest 69:536, 1982.

Folsom AR: Epidemiology of fibrinogen. Eur Heart J 16 (suppl A):21, 1995.

Thompson WD, Smith EB: Atherosclerosis and the coagulation system. J Pathol 159:97, 1989.

Letcher RL, Chien S, Pickering TG, Sealey JE, Laragh JH: Direct relationship between blood pressure and blood viscosity in normal and hypertensive subjects. Role of fibrinogen and concentration. Am J Med 70:1195, 1981.

Kannel WB, D’Agostino RB, Wilson PW, Belanger AJ, Gagnon DR: Diabetes, fibrinogen, and risk of cardiovascular disease: the Framingham experience. Am Heart J 120:672, 1990.

Ernst E, Matrai A, Schmolzl C, Magyarosy I: Dose-effect relationship between smoking and blood rheology. Br J Haematol 65:485, 1987.

Yarnell JW, Sweetnam PM, Rogers S, et al: Some long term effects of smoking on the haemostatic system: a report from the Caerphilly and Speedwell Collaborative Surveys. J Clin Pathol 40:909, 1987.

Wilhelmsen L, Svardsudd K, Korsan-Bengtsen K, Larsson B, Welin L, Tibblin G: Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med 311:501, 1984.

Kannel WB, Wolf PA, Castelli WP, D’Agostino RB: Fibrinogen and risk of cardiovascular disease. The Framingham Study. JAMA 258:1183, 1987.

Meade TW, Mellows S, Brozovic M, et al: Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet 2:533, 1986.

Barasch E, Benderly M, Graff E, et al: Plasma fibrinogen levels and their correlates in 6457 coronary heart disease patients. The Bezafibrate Infarction Prevention (BIP) Study. J Clin Epidemiol 48:757, 1995.

Ernst E: Fibrinogen as a cardiovascular risk factor—interrelationship with infections and inflammation. Eur Heart J 14 (suppl K):82, 1993.

Eisenberg PR, Sherman LA, Schectman K, Perez J, Sobel BE, Jaffe AS: Fibrinopeptide A: a marker of acute coronary thrombosis. Circulation 71:912, 1985.

Kruskal JB, Commerford PJ, Franks JJ, Kirsch RE: Fibrin and fibrinogen-related antigens in patients with stable and unstable coronary artery disease. N Engl J Med 317:1361, 1987.

Neri Serneri GG, Gensini GF, Carnovali M, et al: Association between time of increased fibrinopeptide A levels in plasma and episodes of spontaneous angina: a controlled prospective study. Am Heart J 113:672, 1987.

Merlini PA, Bauer KA, Oltrona L, et al: Persistent activation of coagulation mechanism in unstable angina and myocardial infarction. Circulation 90:61, 1994.

McCully KS: Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 56:111, 1969.

Finkelstein JD: The metabolism of homocysteine: pathways and regulation. Eur J Pediatr 157 (suppl 2):S40, 1998.

Kraus JP: Biochemistry and molecular genetics of cystathionine beta-synthase deficiency. Eur J Pediatr 157 (suppl 2):S50, 1998.

Welch GN, Loscalzo J: Homocysteine and atherothrombosis. N Engl J Med 338:1042, 1998.

Brattstrom L: Vitamins as homocysteine-lowering agents. J Nutr 126:1276S, 1996.

Harker LA, Ross R, Slichter SJ, Scott CR: Homocystine-induced arteriosclerosis. The role of endothelial cell injury and platelet response in its genesis. J Clin Invest 58:731, 1976.

Dudman NP, Hicks C, Lynch JF, Wilcken DE, Wang J: Homocysteine thiolactone disposal by human arterial endothelial cells and serum in vitro. Arterioscler Thromb 11:663, 1991.

Ueland PM, Refsum H, Brattström L: Plasma homocysteine and cardiovascular disease, in RBJ Francis, editor, Atherosclerotic Cardiovascular Disease, Hemostasis, and Endothelial Function, p 183. Marcel Dekker, New York, 1992.

Loscalzo J: The oxidant stress of hyperhomocyst(e)inemia. J Clin Invest 98:5, 1996.

Harker LA, Slichter SJ, Scott CR, Ross R: Homocystinemia. Vascular injury and arterial thrombosis. N Engl J Med 291:537, 1974.

Rodgers GM, Conn MT: Homocysteine, an atherogenic stimulus, reduces protein C activation by arterial and venous endothelial cells. Blood 75:895, 1990.

Panganamala RV, Karpen CW, Merola AJ: Peroxide mediated effects of homocysteine on arterial prostacyclin synthesis. Prostaglandins Leukot Med 22:349, 1986.

Wang J, Dudman NP, Wilcken DE: Effects of homocysteine and related compounds on prostacyclin production by cultured human vascular endothelial cells. Thromb Haemost 70:1047, 1993.

Lentz SR, Sadler JE: Inhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine. J Clin Invest 88:1906, 1991.

Rodgers GM, Kane WH: Activation of endogenous factor V by a homocysteine-induced vascular endothelial cell activator. J Clin Invest 77:1909, 1986.

Fryer RH, Wilson BD, Gubler DB, Fitzgerald LA, Rodgers GM: Homocysteine, a risk factor for premature vascular disease and thrombosis, induces tissue factor activity in endothelial cells. Arterioscler Thromb 13:1327, 1993.

Hayashi T, Honda G, Suzuki K: An atherogenic stimulus homocysteine inhibits cofactor activity of thrombomodulin and enhances thrombomodulin expression in human umbilical vein endothelial cells. Blood 79:2930, 1992.

Nishinaga M, Ozawa T, Shimada K: Homocysteine, a thrombogenic agent, suppresses anticoagulant heparan sulfate expression in cultured porcine aortic endothelial cells. J Clin Invest 92:1381, 1993.

Hajjar KA: Homocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptor. J Clin Invest 91:2873, 1993.

Harpel PC, Chang VT, Borth W: Homocysteine and other sulfhydryl compounds enhance the binding of lipoprotein(a) to fibrin: a potential biochemical link between thrombosis, atherogenesis, and sulfhydryl compound metabolism. Proc Natl Acad Sci USA 89:10193, 1992.

Alfthan G, Pekkanen J, Jauhiainen M, et al: Relation of serum homocysteine and lipoprotein(a) concentrations to atherosclerotic disease in a prospective Finnish population based study. Atherosclerosis 106:9, 1994.

von Eckardstein A, Malinow MR, Upson B, et al: Effects of age, lipoproteins, and hemostatic parameters on the role of homocyst(e)inemia as a cardiovascular risk factor in men. Arterioscler Thromb 14:460, 1994.

Glueck CJ, Shaw P, Lang JE, Tracy T, Sieve-Smith L, Wang Y: Evidence that homocysteine is an independent risk factor for atherosclerosis in hyperlipidemic patients. Am J Cardiol 75:132, 1995.

Utermann G: The mysteries of lipoprotein(a). Science 246:904, 1989.

Heinrich J, Sandkamp M, Kokott R, Schulte H, Assmann G: Relationship of lipoprotein(a) to variables of coagulation and fibrinolysis in a healthy population. Clin Chem 37:1950, 1991.

Maeda S, Abe A, Seishima M, Makino K, Noma A, Kawade M: Transient changes of serum lipoprotein(a) as an acute phase protein. Atherosclerosis 78:145, 1989.

Seed M, Hoppichler F, Reaveley D, et al: Relation of serum lipoprotein(a) concentration and apolipoprotein(a) phenotype to coronary heart disease in patients with familial hypercholesterolemia. N Engl J Med 322:1494, 1990.

Berg K, Dahlen G, Borresen AL: Lp(a) phenotypes, other lipoprotein parameters, and a family history of coronary heart disease in middle-aged males. Clin Genet 16:347, 1979.

Rosengren A, Wilhelmsen L, Eriksson E, Risberg B, Wedel H: Lipoprotein(a) and coronary heart disease: a prospective case-control study in a general population sample of middle aged men. Br Med J 301:1248, 1990.

Sigurdsson G, Baldursdottir A, Sigvaldason H, Agnarsson U, Thorgeirsson G, Sigfusson N: Predictive value of apolipoproteins in a prospective survey of coronary artery disease in men. Am J Cardiol 69:1251, 1992.

Schaefer EJ, Lamon-Fava S, Jenner JL, et al: Lipoprotein(a) levels and risk of coronary heart disease in men. The Lipid Research Clinics Coronary Primary Prevention Trial. JAMA 271:999, 1994.

Bostom AG, Cupples LA, Jenner JL, et al: Elevated plasma lipoprotein(a) and coronary heart disease in men aged 55 years and younger. A prospective study. JAMA 276:544, 1996.

Jauhiainen M, Koskinen P, Ehnholm C, et al: Lipoprotein (a) and coronary heart disease risk: a nested case-control study of the Helsinki Heart Study participants. Atherosclerosis 89:59, 1991.

Ridker PM, Hennekens CH, Stampfer MJ: A prospective study of lipoprotein(a) and the risk of myocardial infarction. JAMA 270:2195, 1993.

Sandholzer C, Boerwinkle E, Saha N, Tong MC, Utermann G: Apolipoprotein(a) phenotypes, Lp(a) concentration and plasma lipid levels in relation to coronary heart disease in a Chinese population: evidence for the role of the apo(a) gene in coronary heart disease. J Clin Invest 89:1040, 1992.

Moliterno DJ, Jokinen EV, Miserez AR, et al: No association between plasma lipoprotein(a) concentrations and the presence or absence of coronary atherosclerosis in African-Americans. Arterioscler Thromb Vasc Biol 15:850, 1995.

Harpel PC, Hermann A, Zhang X, Ostfeld I, Borth W: Lipoprotein(a), plasmin modulation, and atherogenesis. Thromb Haemost 74:382, 1995.

Hajjar KA, Nachman RL: The role of lipoprotein(a) in atherogenesis and thrombosis. Annu Rev Med 47:423, 1996.

Rath M, Niendorf A, Reblin T, Dietel M, Krebber HJ, Beisiegel U: Detection and quantification of lipoprotein(a) in the arterial wall of 107 coronary bypass patients. Arteriosclerosis 9:579, 1989. Published erratum appears in Arteriosclerosis 10:1147, 1990.

Dangas G, Mehran R, Harpel PC, et al: Lipoprotein(a) and inflammation in human coronary atheroma: association with the severity of clinical presentation. J Am Coll Cardiol 32:2035, 1998.

Loscalzo J, Weinfeld M, Fless GM, Scanu AM: Lipoprotein(a), fibrin binding, and plasminogen activation. Arteriosclerosis 10:240, 1990.

Hervio L, Chapman MJ, Thillet J, Loyau S, Angles-Cano E: Does apolipoprotein(a) heterogeneity influence lipoprotein(a) effects on fibrinolysis? Blood 82:392, 1993.

Bihari-Varga M, Gruber E, Rotheneder M, Zechner R, Kostner GM: Interaction of lipoprotein Lp(a) and low density lipoprotein with glycosaminoglycans from human aorta. Arteriosclerosis 8:851, 1988.

Management of stable angina pectoris. Recommendations of the Task Force of the European Society of Cardiology. Eur Heart J 18:394, 1997.

Mulcahy R, Al Awadhi AH, de Buitleor M, Tobin G, Johnson H, Contoy R: Natural history and prognosis of unstable angina. Am Heart J 109:753, 1985.

Figueras J, Lidon R, Cortadellas J: Rebound myocardial ischaemia following abrupt interruption of intravenous nitroglycerin infusion in patients with unstable angina at rest. Eur Heart J 12:405, 1991.

Jugdutt BI, Warnica JW: Tolerance with low dose intravenous nitroglycerin therapy in acute myocardial infarction. Am J Cardiol 64:581, 1989.

Yusuf S, Wittes J, Friedman L: Overview of results of randomized clinical trials in heart disease. II. Unstable angina, heart failure, primary prevention with aspirin, and risk factor modification. JAMA 260:2259, 1988.

Cairns JA, Gent M, Singer J, et al: Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian multicenter trial. N Engl J Med 313:1369, 1985.

Theroux P, Ouimet H, McCans J, et al: Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med 319:1105, 1988.

Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. The RISC Group. Lancet 336:827, 1990.

Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis (ASPECT) Research Group. Effect of long-term oral anticoagulant treatment on mortality and cardiovascular morbidity after myocardial infarction. Lancet 343:499, 1994.

Telford AM, Wilson C: Trial of heparin versus atenolol in prevention of myocardial infarction in intermediate coronary syndrome. Lancet 1:1225, 1981.

Holdright D, Patel D, Cunningham D, et al: Comparison of the effect of heparin and aspirin versus aspirin alone on transient myocardial ischemia and in-hospital prognosis in patients with unstable angina. J Am Coll Cardiol 24:39, 1994.

Neri Serneri GG, Modesti PA, Gensini GF, et al: Randomised comparison of subcutaneous heparin, intravenous heparin, and aspirin in unstable angina. Studio Epoorine Sottocutanea nell’Angina Instobile (SESAIR) Refrattorie Group. Lancet 345:1201, 1995.

Cohen M, Adams PC, Parry G, et al: Combination antithrombotic therapy in unstable rest angina and non-Q- wave infarction in nonprior aspirin users. Primary end points analysis from the ATACS trial. Antithrombotic Therapy in Acute Coronary Syndromes Research Group. Circulation 89:81, 1994.

Gurfinkel EP, Manos EJ, Mejail RI, et al: Low molecular weight heparin versus regular heparin or aspirin in the treatment of unstable angina and silent ischemia. J Am Coll Cardiol 26:313, 1995.

Theroux P, Waters D, Qiu S, McCans J, de Guise P, Juneau M: Aspirin versus heparin to prevent myocardial infarction during the acute phase of unstable angina. Circulation 88:2045, 1993.

Low-molecular-weight heparin during instability in coronary artery disease, Fragmin during Instability in Coronary Artery Disease (FRISC) study group. Lancet 347:561, 1996.

Smith P, Arnesen H, Holme I: The effect of warfarin on mortality and reinfarction after myocardial infarction. N Engl J Med 323:147, 1990.

Randomised double-blind trial of fixed low-dose warfarin with aspirin after myocardial infarction. Coumadin Aspirin Reinfarction Study (CARS) Investigators. Lancet 350:389, 1997.

Bar FW, Verheugt FW, Col J, et al: Thrombolysis in patients with unstable angina improves the angiographic but not the clinical outcome. Results of UNASEM, a multicenter, randomized, placebo-controlled, clinical trial with anistreplase. Circulation 86:131, 1992.

Karlsson JE, Berglund U, Bjorkholm A, Ohlsson J, Swahn E, Wallentin L: Thrombolysis with recombinant human tissue-type plasminogen activator during instability in coronary artery disease: effect on myocardial ischemia and need for coronary revascularization. TRIC Study Group. Am Heart J 124:1419, 1992.

Schreiber TL, Rizik D, White C, et al: Randomized trial of thrombolysis versus heparin in unstable angina. Circulation 86:1407, 1992.

Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-Q-wave myocardial infarction. Results of the TIMI IIIB Trial. Thrombolysis in Myocardial Ischemia. Circulation 89:1545, 1994.

Ambrose JA, Almeida OD, Sharma SK, et al: Adjunctive thrombolytic therapy during angioplasty for ischemic rest angina. Results of the TAUSA Trial. TAUSA Investigators. Thrombolysis and Angioplasty in Unstable Angina trial. Circulation 90:69, 1994.

White HD, French JK, Norris RM, Williams BF, Hart HH, Cross DB: Effects of streptokinase in patients presenting within 6 hours of prolonged chest pain with ST segment depression. Br Heart J 73:500, 1995.

Abbott RD, Wilson PW, Kannel WB, Castelli WP: High density lipoprotein cholesterol, total cholesterol screening, and myocardial infarction. The Framingham Study. Arteriosclerosis 8:207, 1988.

Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. The EPIC Investigation. N Engl J Med 330:956, 1994.

Topol EJ, Califf RM, Weisman HF, et al: Randomised trial of coronary intervention with antibody against platelet IIb/IIIa integrin for reduction of clinical restenosis: results at six months. The EPIC Investigators. Lancet 343:881, 1994.

Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. The EPILOG Investigators. N Engl J Med 336:1689, 1997.

Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE Study. Lancet 349:1429, 1997.

Theroux P, Kouz S, Roy L, et al: Platelet membrane receptor glycoprotein IIb/IIIa antagonism in unstable angina. The Canadian Lamifiban Study. Circulation 94:899, 1996.

Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. The RESTORE Investigators. Randomized Efficacy Study of Tirofiban for Outcomes and REstenosis. Circulation 96:1445, 1997.

Randomised placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT-II. Integrilin to Minimise Platelet Aggregation and Coronary Thrombosis-II. Lancet 349:1422, 1997.

Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. N Engl J Med 338:1488, 1998.

A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Study Investigators. N Engl J Med 338:1498, 1998.

Alexander JH, Harrington RA: Recent antiplatelet drug trials in the acute coronary syndromes. Clinical interpretation of PRISM, PRISM-PLUS, PARAGON A and PURSUIT. Drugs 56:965, 1998.

A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb investigators. N Engl J Med 335:775, 1996.

Comparison of the effects of two doses of recombinant hirudin compared with heparin in patients with acute myocardial ischemia without ST elevation: a pilot study. Organization to Assess Strategies for Ischemic Syndromes (OASIS) Investigators. Circulation 96:769, 1997.

Effects of recombinant hirudin (lepirudin) compared with heparin on death, myocardial infarction, refractory angina, and revascularisation procedures in patients with acute myocardial ischaemia without ST elevation: a randomised trial. Organisation to Assess Strategies for Ischemic Syndromes (OASIS-2) Investigators. Lancet 353:429, 1999.

Lidon RM, Theroux P, Juneau M, Adelman B, Maraganore J: Initial experience with a direct antithrombin, Hirulog, in unstable angina. Anticoagulant, antithrombotic, and clinical effects. Circulation 88:1495, 1993.

Fuchs J, Cannon CP: Hirulog in the treatment of unstable angina. Results of the Thrombin Inhibition in Myocardial Ischemia (TIMI) 7 trial. Circulation 92:727, 1995.

Serruys PW, Herrman JP, Simon R, et al: A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty. Helvetica Investigators. N Engl J Med 333:757, 1995.

Bittl JA, Strony J, Brinker JA, et al: Treatment with bivalirudin (Hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. Hirulog Angioplasty Study Investigators. N Engl J Med 333:764, 1995.

De Feyter PJ, Suryapranata H, Serruys PW, et al: Coronary angioplasty for unstable angina: immediate and late results in 200 consecutive patients with identification of risk factors for unfavorable early and late outcome. J Am Coll Cardiol 12:324, 1988.

Myler RK, Shaw RE, Stertzer SH, et al: Unstable angina and coronary angioplasty. Circulation 82 (3 Suppl):1188, 1990.

Bentivoglio LG, Detre K, Yeh W, Williams DO, Kelsey SF, Faxon DP: Outcome of percutaneous transluminal coronary angioplasty in subsets of unstable angina pectoris. A report of the 1985-1986 National Heart, Lung, and Blood Institute Percutaneous Transluminal Coronary Angioplasty Registry. J Am Coll Cardiol 24:1195, 1994.

Mehran R, Ambrose JA, Bongu RM, et al: Angioplasty of complex lesions in ischemic rest angina: results of the Thrombolysis and Angioplasty in Unstable Angina (TAUSA) trial. J Am Coll Cardiol 26:961, 1995.

Gulba DC, Daniel WG, Simon R, et al: Role of thrombolysis and thrombin in patients with acute coronary occlusion during percutaneous transluminal coronary angioplasty. J Am Coll Cardiol 16:563, 1990.

Schieman G, Cohen BM, Kozina J, et al: Intracoronary urokinase for intracoronary thrombus accumulation complicating percutaneous transluminal coronary angioplasty in acute ischemic syndromes. Circulation 82:2052, 1990.

Laskey MA, Deutsch E, Barnathan E, Laskey WK: Influence of heparin therapy on percutaneous transluminal coronary angioplasty outcome in unstable angina pectoris. Am J Cardiol 65:1425, 1990.

Antoniucci D, Santoro GM, Bolognese L, et al: Early coronary angioplasty as compared with delayed coronary angioplasty in patients with high-risk unstable angina pectoris. Coron Artery Dis 7:75, 1996.

Kaiser GC, Schaff HV, Killip T: Myocardial revascularization for unstable angina pectoris. Circulation 79:160, 1989.

Bertolasi CA, Tronge JE, Riccitelli MA, Villamayor RM, Zuffardi E: Natural history of unstable angina with medical or surgical therapy. Chest 70:596, 1976.

Scott SM, Deupree RH, Sharma GV, Luchi RJ: VA Study of Unstable Angina. 10-year results show duration of surgical advantage for patients with impaired ejection fraction. Circulation 90:(II):120, 1994.

Yusuf S, Peto R, Lewis J, Collins R, Sleight P: Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 27:335, 1985.

GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Gruppo Italiano per lo Studio della Sopravvivenza nell’infarto Miocardico. Lancet 343:1115, 1994.

ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. Lancet 345: 669, 1995.

Effect of intravenous APSAC on mortality after acute myocardial infarction: preliminary report of a placebo-controlled clinical trial. AIMS Trial Study Group. Lancet 1:545, 1988.

Wilcox RG, von der Lippe G, Olsson CG, Jensen G, Skene AM, Hampton JR: Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction. Anglo-Scandinavian Study of Early Thrombolysis (ASSET). Lancet 2:525, 1988.

Boersma E, Maas AC, Deckers JW, Simoons ML: Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour. Lancet 348:771, 1996.

Late Assessment of Thrombolytic Efficacy (LATE) study with alteplase 6–24 hours after onset of acute myocardial infarction. Lancet 342:759, 1993.

Randomised trial of late thrombolysis in patients with suspected acute myocardial infarction. EMERAS (Estudio Multicentrico Estreptoquinasa Republicas de America del Sur) Collaborative Group. Lancet 342:767, 1993.

GISSI-2: a factorial randomised trial of alteplase versus streptokinase and heparin versus no heparin among 12,490 patients with acute myocardial infarction. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico. Lancet 336:65, 1990.

ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41,299 cases of suspected acute myocardial infarction. ISIS-3 (Third International Study of Infarct Survival) Collaborative Group. Lancet 339:753, 1992.

The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. The GUSTO Angiographic Investigators. N Engl J Med 329:1615, 1993.

Califf RM, White HD, Van de Werf F, et al: One-year results from the Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries (GUSTO-I) trial. GUSTO-I Investigators. Circulation 94:1233, 1996.

Topol EJ: Coronary angioplasty for acute myocardial infarction. Ann Intern Med 109:970, 1988.

Abbottsmith CW, Topol EJ, George BS, et al: Fate of patients with acute myocardial infarction with patency of the infarct-related vessel achieved with successful thrombolysis versus rescue angioplasty. J Am Coll Cardiol 16:770, 1990.

Ellis SG, da Silva ER, Heyndrickx G, et al: Randomized comparison of rescue angioplasty with conservative management of patients with early failure of thrombolysis for acute anterior myocardial infarction. Circulation 90:2280, 1994.

McKendall GR, Forman S, Sopko G, Braunwald E, Williams DO: Value of rescue percutaneous transluminal coronary angioplasty following unsuccessful thrombolytic therapy in patients with acute myocardial infarction. Thrombolysis in Myocardial Infarction Investigators. Am J Cardiol 76:1108, 1995.

Topol EJ, Califf RM, George BS, et al: A randomized trial of immediate versus delayed elective angioplasty after intravenous tissue plasminogen activator in acute myocardial infarction. N Engl J Med 317:581, 1987.

Immediate vs delayed catheterization and angioplasty following thrombolytic therapy for acute myocardial infarction. TIMI II A results. The TIMI Research Group. JAMA 260:2849, 1988.

Simoons ML, Arnold AE, Betriu A, et al: Thrombolysis with tissue plasminogen activator in acute myocardial infarction: no additional benefit from immediate percutaneous coronary angioplasty. Lancet 1:197, 1988.

Schomig A, Neumann FJ, Walter H, et al: Coronary stent placement in patients with acute myocardial infarction: comparison of clinical and angiographic outcome after randomization to antiplatelet or anticoagulant therapy. J Am Coll Cardiol 29:28, 1997.

Antoniucci D, Santoro GM, Bolognese L, Valenti R, Trapani M, Fazzini PF: A clinical trial comparing primary stenting of the infarct-related artery with optimal primary angioplasty for acute myocardial infarction: results from the Florence Randomized Elective Stenting in Acute Coronary Occlusions (FRESCO) trial. J Am Coll Cardiol 31:1234, 1998.

Rodriguez A, Bernardi V, Fernandez M, et al: In-hospital and late results of coronary stents versus conventional balloon angioplasty in acute myocardial infarction (GRAMI trial). Gianturco-Roubin in Acute Myocardial Infarction. Am J Cardiol 81:1286, 1998.

Randomised trial of intravenous atenolol among 16 027 cases of suspected acute myocardial infarction: ISIS-1. First International Study of Infarct Survival Collaborative Group. Lancet 2:57, 1986.

Mechanisms for the early mortality reduction produced by beta-blockade started early in acute myocardial infarction: ISIS-1. ISIS-1 (First International Study of Infarct Survival) Collaborative Group. Lancet 1:921, 1988.

Soumerai SB, McLaughlin TJ, Spiegelman D, Hertzmark E, Thibault G, Goldman L: Adverse outcomes of underuse of beta-blockers in elderly survivors of acute myocardial infarction . JAMA 277:115, 1997.

Ambrosioni E, Borghi C, Magnani B: The effect of the angiotensin-converting-enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction. The Survival of Myocardial Infarction Long-Term Evaluation (SMILE) Study Investigators. N Engl J Med 332:80, 1995.

Kober L, Torp-Pedersen C, Carlsen JE, et al: A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med 333:1670, 1995.

Vantrimpont P, Rouleau JL, Wun CC, et al: Additive beneficial effects of beta-blockers to angiotensin-converting enzyme inhibitors in the Survival and Ventricular Enlargement (SAVE) Study. SAVE Investigators. J Am Coll Cardiol 29:229, 1997.

Elwood PC, Sweetnam PM: Aspirin and secondary mortality after myocardial infarction. Lancet 2:1313, 1979.

The aspirin myocardial infarction study: final results. The Aspirin Myocardial Infarction Study research group. Circulation 62:(V):79, 1980.

Klimt CR, Knatterud GL, Stamler J, Meier P: Persantine-Aspirin Reinfarction Study. Part II. Secondary coronary prevention with persantine and aspirin. J Am Coll Cardiol 7:251, 1986.

Collaborative overview of randomised trials of antiplatelet therapy—I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists’ Collaboration. Br Med J 308:81, 1994.

A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 348:1329, 1996.

Goldstein RE, Andrews M, Hall WJ, Moss AJ: Marked reduction in long-term cardiac deaths with aspirin after a coronary event. Multicenter Myocardial Ischemia Research Group. J Am Coll Cardiol 28:326, 1996.

Weintraub WS, Ba’albaki HA: Decision analysis concerning the application of echocardiography to the diagnosis and treatment of mural thrombi after anterior wall acute myocardial infarction. Am J Cardiol 64:708, 1989.

Kouvaras G, Chronopoulos G, Soufras G, et al: The effects of long-term antithrombotic treatment on left ventricular thrombi in patients after an acute myocardial infarction. Am Heart J 119:73, 1990.
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology


  1. […] are the Skin Benefits of Exercisefloortiles − Off-Label Fillers Help Reposition Aging EyesCHAPTER 130 ATHEROSCLEROSIS, THROMBOSIS, AND CORONARY ARTERY DISEASE var wpmlAjax = […]

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

%d bloggers like this: