0
Articles |

Thrombin, Inflammation, and Cardiovascular Disease*: An Epidemiologic Perspective FREE TO VIEW

Russell P. Tracy, PhD
Author and Funding Information

*From the Laboratory for Clinical Biochemistry Research, College of Medicine, University of Vermont, Colchester, VT.

Correspondence to: Russell P. Tracy, PhD, Director, Laboratory for Clinical Biochemistry Research, University of Vermont, 208 South Park Dr, Suite 2, Colchester, VT 05446; e-mail: russell.tracy@uvm.edu



Chest. 2003;124(3_suppl):49S-57S. doi:10.1378/chest.124.3_suppl.49S
Text Size: A A A
Published online

The exploration of coagulation led to identifying inflammation as a major factor in arterial disease throughout life. “Integrative molecular physiology” reflects our emerging understanding of how coagulation and inflammation integrate with one another, in both normal physiology and in pathophysiology. Our own responses to environmental challenge provide much of the damage that cumulatively results in chronic cardiovascular disease. Only by intervening in exquisitely precise ways can we hope to effectively and safely modify the course of lifelong chronic diseases, such as atherosclerosis.

Figures in this Article

Atherosclerosis and resulting clinical cardiovascular disease (CVD) are complex pathophysiologic processes involving a large number of genes and gene products in complicated interactions with a variety of environmental influences. An enormous body of research over the last 20 years has helped us understand that many of the biochemical processes involved in CVD are the same as those involved in ongoing defense against a hostile world, including blood coagulation, inflammation, and immune response. From this same body of research, we are beginning to understand that these processes are intricately linked and, in fact, are interdependent.1While in its infancy, this understanding (which can be termed integrative molecular physiology) has already yielded major health advances, such as the use of activated protein C (APC), an anticoagulant, in the clinical setting of sepsis, an hyperinflammatory infectious condition.2Table 1 lists some of the ways in which population studies, clinical trials, and more basic investigations have supported the interplay between coagulation, fibrinolysis, and inflammation.

Within this framework, the generation of thrombin is a key event, with many ramifications. This article will attempt to review the possible roles for thrombin in CVD; discuss whether a preexisting hypercoagulable state predisposes a patient to CVD; highlight some of the known and hypothesized relationships of coagulation and fibrinolysis, and coagulation and inflammation; and review the known associations of coagulation and inflammation factors with CVD.

CVD is the major cause of death for Americans,14and incidence rates around the world are reaching epidemic proportions.15A major form of CVD is myocardial infarction (MI); in the early 1970s, it became evident, through the work of DeWood and colleagues1617 and others, that the proximal event in MI is commonly an occlusive blood clot in a coronary artery. The term vulnerable plaque has been used to describe a form of atherosclerosis characterized by rapid, focal lipid accumulation, with the development of a large pool of subendothelial fat covered by a thin, mechanically fragile cap.20 There is often little intrusion into the lumen of the vessel, with considerable remodeling into the vessel wall to accommodate the lipid build-up. As the cap ruptures, the cells and soluble factors of the coagulant system are exposed to this large pool of presumably procoagulant lipid, along with many subendothelial components deep into the arterial wall, which results in platelet activation and aggregation, thrombin generation, and the development of a large often occlusive thrombus. If not cleared quickly, significant myocardial damage ensues.

Arterial clots are often so-called “white clots” (ie, platelet-rich), suggesting less of a role for fibrin formation; however, the direct role of thrombin as the ultimate clotting enzyme in this setting is obvious. As others in this supplement will illustrate in detail, thrombin is not only responsible for the cleavage of fibrinogen resulting in fibrin formation, but is also the most powerful platelet agonist, and is believed to play a critical role in the growth of platelet aggregates.

CVD encompasses more than MI. Other coronary syndromes, such as sudden coronary death, may not have a thrombotic component to the same degree or extent. For example, autopsy studies21have revealed that sudden coronary death is associated with coronary thrombosis in > 70% of the cases in younger adults (when the precipitating cause is most frequently incident MI), but that this prevalence decreases to less than a third in older adults. The precipitating cause is less apparent in these cases, and one may speculate that transient platelet aggregation at the site of lesion fracture or erosion, which may be tolerated if occurring in younger hearts, may prove fatal in older, weaker hearts. The atherosclerotic burden associated with events later in life is much greater than that associated with events in younger people, where the actual plaque burden may be limited.2223

This raises the question of whether thrombin might participate in atherosclerotic heart disease in ways that do not directly involve thrombus formation. The answer is that thrombin generation has numerous possible nonthrombotic associations with atherosclerosis and heart disease, and more pathways are certain to be identified.24Many of these pathways are discussed in more detail in other sections of this article. Some center on the role of thrombin as a signaling molecule, through thrombin receptors (protease-activated receptors [PARs]). As discussed by Dr. Brass elsewhere in this supplement and by Patterson et al25 in a review article, these signaling events concern virtually all aspects of vascular biology, including vessel tone, cellular differential, migration and proliferation (especially smooth-muscle cells), angiogenesis and vascular development, and vascular pathology such as atherosclerosis. At least three PARs are expressed by human cells, with attendant G protein-coupled signaling cascades and physiologic effects. Thrombin plays a central role in the activation of all three PARs. Moreover, these signaling events can coordinate with other receptor-based intracellular signaling to modify the resulting effect. In total, then, the possible effects of thrombin in vascular wall biology are large in number and key to both normal and pathologic vascular physiology.

Thrombin is also responsible for the activation of a newly discovered major thrombosis regulator, thrombin-activated fibrinolysis inhibitor,26also discussed in more detail by Dr. Nesheim elsewhere in this supplement. Thrombin-activated fibrinolysis inhibitor appears to play a major role in down-regulating fibrinolysis, which may have important implications in heart disease, as has been proposed.27

Interestingly, along with being the key final enzyme in fibrin formation, and the most powerful known platelet activator, thrombin is also a major anticoagulant in its role as the thrombomodulin-associated activator of protein C28 (see the accompanying article by Dr. Esmon in this supplement). APC is a powerful anticoagulant that has recently been established as a critical new therapeutic weapon in the setting of sepsis.2 It is unlikely that in this role thrombin has a major effect on atherosclerosis and clinical heart disease, however, since low protein C levels are not CVD risk factors.29This theory is supported by the fact that genotypes associated with low protein C levels (or with cofactors that are refractive to APC activity, eg, Factor V Leiden) have not been linked to CVD risk.30 We hypothesize that this lack of association may be due to two factors: the heavy dependence of arterial thrombosis on atherosclerotic plaque rupture and/or erosion, and the high flow rates of blood around areas of stenosis, making it likely that available thrombomodulin may reside downstream of the forming thrombus. However, the anticoagulant role of thrombin may be important in arterial disease once an occlusive thrombus has formed with its attendant stasis, just as it is important in venous thrombosis, which is also predominantly stasis dependent. This hypothesis remains to be tested in a clinical setting.

Meade and colleagues31at the Northwick Park Heart Study produced pioneering research into the molecular epidemiology of coagulation and fibrinolysis, which suggested that a preexisting hypercoagulable state might be present in those most at risk for MI and CVD death. While the research that followed their work has provided little support for this as a general condition—for example, it does not appear that elevations in factor VIIc levels are a major risk factor,3234 as they originally proposed—their results for fibrinogen and factor VIIIc have held up in many other studies. We now interpret these results for fibrinogen and factor VIII as probably best supportive of inflammation rather than hypercoagulability.3234

The plasma level of the fibrin degradation product d-dimer is an integrated marker of coagulant and subsequent fibrinolytic activity. As the population under study becomes older and has greater atherosclerotic burden, d-dimer does predict events. In studies of older middle-aged men with mixed health status and in a study of men with peripheral vascular disease, d-dimer levels were predictive of CVD events.3536 In addition, in the elderly cohort of the Cardiovascular Health Study, where most individuals had moderate-to-extensive vascular disease, d-dimer and the marker of plasmin activation, plasmin-antiplasmin complex, were strongly predictive of events.37In contrast, studies of d-dimer as a CVD risk factor in younger, healthier populations have been negative. In preliminary findings, d-dimer levels did not predict early calcification in younger people.38Also, levels were not associated with incident events in a healthy middle-aged population, such as the Physician’s Health Study.39 Overall, a meta-analysis35 demonstrated moderate risk prediction for d-dimer. The most likely interpretation of these data are that the degree of atherosclerosis and vascular damage causes changes in coagulation status, not vice versa; ie, it does not appear that a preexisting hypercoagulable state is in the causal pathway of atherosclerotic disease and CVD events. This position is supported by the findings such as those of Lowe et al,,40 in which future ischemic events were predicted by d-dimer levels but not by other markers of procoagulant activity, such as prothrombin fragment F1 + 2 and thrombin-antithrombin complex (measures of thrombin generation), or by factor VII coagulant activity (factor VIIc, which at least partly reflects factor VII activation).

Genetic studies also provide some information regarding the possible role of hypercoagulability in precipitating CVD events. For example, there are unambiguous and compelling associations between genetic protein C deficiency (lack of an anticoagulant), factor V Leiden genotype (a procoagulant resistant to inactivation), and prothrombin 20210A genotype (increased procoagulant zymogen levels), and the prevalence and incidence of venous thrombotic disease.4142 The general statement is that the presence of genetic factors that result in either reduced anticoagulation or increased procoagulation are directly in the causal pathway for venous thrombosis. However, key to our interpretation of hypercoagulability, in general none of these factors are risk factors for arterial disease.30 There are rare exceptions, such as atypical arterial thrombosis occurring in otherwise healthy younger women.43 Overall, the preponderance of data indicates a lack of a compelling argument supporting the importance of a preexisting hypercoagulable state as a major risk factor for atherothrombotic disease.

Atherosclerotic coronary heart disease commonly manifests itself clinically via a thrombotic event: so-called “atherothrombosis,” especially in younger men. As mentioned above, this has been clearly understood only since the early 1970s.16 As an overview, the process of blood clotting is comprised of coagulation, limited and controlled by anticoagulation; and the counterbalancing process of fibrinolysis, limited and controlled by antifibrinolysis.

It has been known for a long time that increases or decreases in specific factor levels are associated with risk of venous clotting or bleeding. For example, the lack of factor VIII or factor IX leads to hemophilia A or B, and deficiency of the anticoagulant factor protein C leads to a propensity to form clots, such as occurs in deep vein thrombosis. Because of this knowledge, and the knowledge that blood clots are important in the risk of MI, researchers in the early 1980s pursued the importance of specific factor levels in atherothrombotic risk. Meade and colleagues44pioneered this work in the Northwick Park Heart Study, and demonstrated the clear importance of fibrinogen as a CVD risk factor. This research was quickly confirmed and extended by others,4547 and it became clear that fibrinogen, factor VIII, and several other proteins found in abundance in plasma were risk factors, at least in part, because they reflected chronic, low-level inflammation. Said another way, the specific factors that were elevated in the presence of clinical CVD, and whose levels in otherwise healthy people predicted the occurrence of future CVD, were in general known as acute-phase reactants, ie, proteins known to respond to inflammatory stimulation via the effects of proinflammatory cytokines, such as interleukin (IL)-6.

To support this position, studies of the plasma levels of prothrombin (a key procoagulant protein, but not an inflammation-sensitive protein) and/or the prothrombin G20210A genotype associated with plasma levels, generally have been null for CVD risk in most cases48while consistently positive for venous thrombosis.49 Also, several studies have examined the anticoagulant proteins and their relationship to CVD. As an ancillary study29 to the Thrombolysis in Myocardial Infarction Phase II trial of thrombolytic therapy, we demonstrated that in those entering the health system with MIs, anticoagulant proteins, such as protein C and antithrombin, were elevated, not decreased. We have also demonstrated that in otherwise healthy adults tissue factor pathway inhibitor levels were higher, not lower, in those with increased measures of subclinical disease based on ankle-brachial BP index and carotid ultrasonography.50 Also, Folsom and colleagues34 showed in the Atherosclerosis Risk in Communities study that protein C was weakly, but positively, associated with CVD, even though protein C is not a strong acute phase reactant. This is counter to expectations based on the hypercoagulable hypothesis (ie, lower levels, not higher levels, of anticoagulants would be found in those either with, or at risk for, CVD), but rather supports the inflammatory hypothesis: inflammation, rather than the process of clotting, is more related to CVD risk.

Having suggested that the principal mechanism for association of some coagulation factors with CVD is through their nature as inflammation-related factors, it remains possible that these factors may also reflect risk because, once they are elevated, higher levels increase the likelihood of blood clot formation. Using fibrinogen as an example, possible mechanisms by which higher levels of fibrinogen might be related to increased likelihood of blood clotting include increased platelet crosslinking, increased fibrin clot formation, and increased blood viscosity, among others.51 While it remains unproven whether any of these mechanisms are actually at play in situ, given all the available data it seems likely that higher fibrinogen may well not only reflect the low-grade inflammation caused by the atherothrombosis, but also participate in that process, allowing it to proceed at a faster rate. This “positive feedback” is illustrated in Figure 1 .

Along with their work in clotting, Meade and colleagues31 were also the first to propose that deficiencies in fibrinolysis might also be associated with CVD and that levels of these factors might predict future CVD events. In this same vein, others have demonstrated that levels of the major plasma antifibrinolysis protein, plasminogen activator inhibitor-1 (PAI-1), are elevated in those with existing clinical CVD and did offer some risk prediction for future secondary CVD events.5556 However, this finding, like those in the coagulation system, was not always confirmed in future studies.57It has been suggested that the degree of predictive power may be a function of the adjustment done for other variables,58since PAI-1 levels are associated with inflammation,59 plasma lipid levels, and, most strongly, with adiposity and insulin levels.4 These factors are all CVD risk factors in their own right, and it remains uncertain whether the concept of fibrinolytic capacity is valid and in fact a predisposing risk factor for arterial disease. Sobel60invoked a possible role for PAI-1 in the arterial wall, where it may play more of a role than in blood. Plaques particularly prone to rupture and that precipitate relatively large thrombus formation are characterized by minimal cellularity, among other factors. Migration of cells into the plaque region is likely to require collagenase activity, which is in turn provided by plasmin-mediated activation of collagenase zymogens. PAI-1 in the wall may inhibit plasmin formation and contribute to a lack of cellularity and resultant instability.61

PAI-1 levels are associated with insulin, suggesting that the role of PAI-1 may be particularly important in people with the metabolic syndrome or type 2 diabetes. The regulation of PAI-1 levels—at least in blood—is in part mediated by regulators of glycemic control and inflammation: insulin and proinsulin can stimulate endothelial cells and hepatocytes to produce PAI-1,6263 and PAI-1 is believed to be a weak acute-phase reactant.59 In addition, adipocytes can directly synthesize and secrete PAI-1, helping to explain the known association of PAI-1 levels with body mass index.64

All of these factors associated with PAI-1 levels are also correlated with each other; this high degree of covariance makes it difficult to establish independent associations. To help make these connections, we performed a factor analysis as part of the data analysis of the Cardiovascular Health Study. Factor analysis is a statistical approach that computes a set of hypothetical uncorrelated “factors” from a set of covariate variables. This method has been used to analyze the components of the metabolic syndrome; in several studies,6567 it has consistently yielded four factors: BP, body mass, insulin/glucose, and lipids. We entered these variables, as well as variables related to inflammation and hemostasis; this analysis yielded the established four factors, plus three new factors, which we termed inflammation, vitamin K-dependent coagulation factors, and procoagulant activity.,4 PAI-1 was associated with the insulin/glucose factor and the body mass factor, and not with the others, supporting the notion that PAI-1 reflects both insulin level and adiposity, but only weakly, if at all, inflammation or ongoing coagulant activity.

Research done over the last 10 years has played an important role in identifying inflammation as a key process in atherosclerosis and CVD. We should note that “inflammation” as the term is used here does not mean the full form of the condition (warmth, redness, swelling, and pain), but rather implies a “micro-inflammation.” A person with this condition is characterized by being in the upper part of the “normal” distribution for inflammation status, without the signs and symptoms of overt, clinical inflammation. Molecular epidemiology has played a key role in identifying the role of inflammation in CVD, and recently it has become clear that inflammation is connected to the metabolic syndrome in a complex and important manner.

Acute-phase proteins are a class of secreted proteins, primarily from the liver, that either rise or fall in concentration in response to inflammatory stimuli, such as tissue damage and infection. This change in most cases represents no more than a doubling or tripling in concentration (eg, fibrinogen) or a 30 to 50% decrease (eg, albumin). A few of the known proteins, such as C-reactive protein (CRP), may increase in concentration > 1,000-fold.68 Virtually all of the proteins that have been studied have been shown to be associated with CVD (Table 2 ). Most of the known acute-phase proteins are produced in the liver in response to IL-6. Although these markers have many different functions, they all are moderately to strongly associated with the presence of CVD (in all cases clinical CVD; in some cases subclinical CVD as defined by such techniques as carotid artery ultrasonography); in almost every case, an argument can be made—at least hypothetically—that the protein in question is not only a marker of the process but might also participate in the process.

In population studies or clinical research, inflammation is usually estimated by the measurement of a plasma acute-phase protein, such as CRP or fibrinogen. However, a wide variety of activities, such as innate immunity, coagulation, and others, fall under the term inflammation. Each of these activities plays an important role in our response to trauma and/or environmental challenge: coagulation and fibrinolysis in restricting blood loss and in wound repair69; complement activation and T-cell differentiation as part of innate and adaptive immunity7071; endothelial cell, neutrophil, and monocyte activation in immunity and wound repair72; antioxidation in response to oxidative challenge73; and others. In addition, variances in the genes responsible for the overall regulation of this system may play important roles in disease susceptibility; eg, IL-6 and tumor necrosis factor (TNF)-α genes.75 Finally, other environmental factors (eg, diet, smoking, etc),3,76 and the volume of inflammation-mediating tissue (eg, visceral fat),52 also appear to be important. It is clear, therefore, that the relationship of inflammation to atherosclerosis is complex and much additional research will be needed before we can truly understand these processes and their relationships to health and disease.

A number of inflammatory markers have been shown to predict future CVD events, all with a certain degree of similarity. For example, ceruloplasmin—the major copper-transporting protein in plasma—had similar risk prediction to CRP in the Monitoring Trends and Determinants in Cardiovascular Disease-Augsburg cohort.77 In the Cardiovascular Health Study, fibrinogen, factor VIII, and CRP each independently predicted future CVD events32 with similar relative risks. Also, in the Iowa 65+ Rural Health Study, both CRP and IL-6 predicted future fatal CVD events, again with similar risk prediction.78These similarities, however, do not necessarily mean that one marker can be directly substituted for another. In some cases, there are significant differences in the strengths of association. Also, each marker may participate in the CVD process in a different way. In a side-by-side comparison,79CRP had the strongest risk prediction, but a meta-analysis80 observed no real difference between CRP and fibrinogen in risk prediction.

It has been observed that markers of inflammation are associated with the components of the metabolic syndrome4; this finding is in addition to the known association of inflammation markers, as well as markers of coagulant activity, with diabetes status.8182 For example, CRP values increase with the number of components of the metabolic syndrome present,83 and fibrinogen levels are correlated with albumin excretion, even in those patients without demonstrable impaired glucose tolerance (N. Jenny, PhD; unpublished data). Despite these strong relationships, as mentioned before, factor analysis indicates that inflammation represents a distinct underlying pathophysiologic pathway.4

To help better understand the metabolic pathways associated with inflammation, we and others34,76,8384 have studied the correlates of CRP. The major correlates are adiposity and insulin sensitivity status. CRP is also associated with coagulation activity status, as estimated by markers such as d-dimer (a fibrin degradation product [FDP] that reflects first the formation of fibrin and then fibrinolysis) and plasmin-antiplasmin complex (a marker reflecting plasmin formation rate, itself depending on the stimulation of fibrin formation, as well as the levels of tissue plasminogen activator and PAI-1).34,85Increases in coagulation status in the metabolic syndrome and diabetes have been well documented.8687 The exact mechanism for the association of CRP with coagulation status is not clear; however the work of Ritchie and colleagues10 suggests a possible pathway. Monocytes appear capable of binding FDPs and subsequently producing IL-6, which goes to the liver and affects the wide range of proteins known to be in the acute-phase response. This has been proposed to be the mechanism by which fibrinogen consumption is replaced, and may be an important mechanism connecting coagulation and inflammation. This theory may have far-reaching implications both in the general biology we have been discussing and in such areas as drug development, where the coagulation-inflammation connection in sepsis, as described by Esmon et al,69 has been recently exploited.5

Adipose tissue is a key producer of inflammatory cytokines (so-called “adipokines”), among which IL-6 is a major pathophysiologic mediator of diabetes and the metabolic syndrome, as well as acute-phase proteins, such as CRP.88 In this way, the metabolic syndrome may be a contributor to inflammatory response through the visceral obesity component: increased visceral fat may lead to increased proinflammatory response to a variety of stimulants, resulting in a chronic up-regulation of IL-6 production. Chronic up-regulation of IL-6 may predispose a patient to atherosclerosis in a number of ways. We have demonstrated in murine atherosclerosis that chronic injections of small amounts of IL-6 (yielding a minor chronic acute-phase response) resulted in a twofold to fivefold increase in lesion size.53 In humans, IL-6 activities range from acute-phase response to tissue factor expression by monocytes, and many others.8

The association of CRP with insulin level is at least partially independent of adiposity, and is strongly related to insulin sensitivity.4 This statistical association may be mediated by the key proinflammatory cytokine (also an adipokine) TNF-α, which is a so-called first-wave cytokine influencing IL-6 production,89as well as many other cellular functions. TNF-α receptor (TNFR) I signals programmed cell death, while TNFR II may signal survival or proliferation through cytoplasmic TNFR-associated proteins, which can both negatively regulate apoptosis and positively promote survival.90Although the role (if any) of circulating TNF-α in humans remains uncertain, TNF-α induces insulin resistance in tissue culture and in animal models.9192 Plasma levels are also elevated in the metabolic syndrome, and are associated with insulin resistance in humans.93

We now know that thrombin generation is critical in atherosclerotic heart disease in at least two ways: as the ultimate clotting and platelet-activating enzyme, and as an important cell-signaling effector molecule. While thrombosis remains a major contributor to the morbidity and mortality of atherosclerotic disease, the other roles of thrombin in vascular biology may prove to be the more critical in the overall scheme. We also now know that coagulation, fibrinolysis, and inflammation are critically interconnected, and markers related to all of these activities are associated cross-sectionally with both subclinical and clinical heart disease, and epidemiologically are predictors of future clinical events. These new insights highlight the need to engage in integrative molecular physiology, with the goal of understanding in detail not just the individual pathways, but the ways they intersect and interact. In particular, we will need to understand how to interrupt “pathologic” activities (eg, thrombosis or foam cell proliferation) without interrupting homologous “physiologic” activities (eg, hemostasis or wound repair), which often involve the same mediators and effectors. It is likely that in the future important therapeutic and preventive advances will have to be made with such integrated knowledge in mind.

Funding was provided in part by grants from the National Institutes of Health (HL46696, HL58329) and from AstraZeneca LP.

Abbreviations: APC = activated protein C; CRP = C-reactive protein; CVD = cardiovascular disease; FDP = fibrin degradation product; IL = interleukin; MI = myocardial infarction; PAI-1 = plasminogen activator inhibitor-1; PAR = protease-activated receptor; TNF = tissue necrosis factor; TNFR = tissue necrosis factor-α receptor

Table Graphic Jump Location
Table 1. Findings Supporting the Interplay Between Coagulation, Fibrinolysis, and Inflammation
Figure Jump LinkFigure 1. The complex interplay of atherothrombotic disease with inflammation and clotting. Inflammation and the proinflammatory cytokines, eg, IL-6, are increased by a variety of mechanisms in atherothrombosis. In addition, there is activation of the coagulation system, with subsequent activation of fibrinolysis, leading to a complex interplay. An example concerns the feedback control of fibrinogen levels. The use of fibrinogen in clotting, including the increased clotting of atherosclerotic progression, results in the production of FDPs. FDPs are bound by monocytes, which in turn increase production of IL-6. This IL-6 acts via the endocrine system to increase the hepatic synthesis of fibrinogen.10 As discussed in the text, increased plasma fibrinogen may feedback in a positive manner, increasing the likelihood of atheroprogression. In addition, other causes of inflammation feed into this system, such as chronic infections and diabetes. Also, the elaboration of proinflammatory cytokines is affected by an individual’s capacity for inflammatory response, such as the extent of visceral adiposity.52 A wide variety of genetic influences are easily conceived, and as we have recently observed, increased IL-6 itself may accelerate the atherothrombotic process,53 possibly acting as a potent cell growth regulator, an activator of monocytes and/or other cells, an amplifier of the innate immune response exacerbating uptake of lipid particles by macrophage, or by other potential mechanisms. The plasma proteins affected by IL-6, such as CRP, fibrinogen, and others, may also directly participate in the atherothrombotic process to make it worse. Adapted with permission.54 ICAM = intracellular adhesion molecule; HDL = high-density lipoprotein.Grahic Jump Location
Table Graphic Jump Location
Table 2. Acute-Phase Reactants Associated With CVD
Tracy, R (1997) Atherosclerosis, thrombosis and inflammation: a question of linkage.Fibrinolysis Proteolysis11(suppl 1),137-142
 
Bernard, GR, Vincent, JL, Laterre, PF, et al Efficacy and safety of recombinant human activated protein C for severe sepsis.N Engl J Med2001;344,699-709
 
Tracy, RP, Psaty, BM, Macy, E, et al Lifetime smoking exposure affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in healthy elderly subjects.Arterioscler Thromb Vasc Biol1997;17,2167-2176
 
Sakkinen, PA, Wahl, P, Cushman, M, et al Clustering of procoagulation, inflammation, and fibrinolysis variables with metabolic factors in insulin resistance syndrome.Am J Epidemiol2000;152,897-907
 
Ely, EW, Bernard, GR, Vincent, JL Activated protein C for severe sepsis.N Engl J Med2002;347,1035-1036
 
Ridker, PM, Cushman, M, Stampfer, MJ, et al Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men.N Engl J Med1997;336,973-979
 
Ridker, PM, Rifai, N, Pfeffer, MA, et al Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators.Circulation1998;98,839-844
 
Neumann, FJ, Ott, I, Marx, N, et al Effect of human recombinant interleukin-6 and interleukin-8 on monocyte procoagulant activity.Arterioscler Thromb Vasc Biol1997;17,3399-3405
 
Cermak, J, Key, NS, Bach, RR, et al C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor.Blood1993;82,513-520
 
Ritchie, DG, Levy, BA, Adams, MA, et al Regulation of fibrinogen synthesis by plasmin-derived fragments of fibrinogen and fibrin: an indirect feedback pathway.Proc Natl Acad Sci U S A1982;79,1530-1534
 
Tokunou, T, Ichiki, T, Takeda, K, et al Thrombin induces interleukin-6 expression through the cAMP response element in vascular smooth muscle cells.Arterioscler Thromb Vasc Biol2001;21,1759-1763
 
Bhat, GJ, Raghu, G, Gunaje, JJ, et al Alpha-thrombin inhibits interleukin-6-induced Stat3 signaling and gp130 gene expression in primary cultures of human lung fibroblasts.Biochem Biophys Res Commun1999;256,626-630
 
Eto, M, Kozai, T, Cosentino, F, et al Statin prevents tissue factor expression in human endothelial cells: role of Rho/Rho-kinase and Akt pathways.Circulation2002;105,1756-1759
 
American Heart Association.. Heart disease and stroke statistics–2003 update. 2002; American Heart Association. Dallas, TX:.
 
Sans, S, Kesteloot, H, Kromhout, D The burden of cardiovascular diseases mortality in Europe: Task Force of the European Society of Cardiology on Cardiovascular Mortality and Morbidity Statistics in Europe.Eur Heart J1997;18,1231-1248
 
DeWood, MA, Spores, J, Notske, R, et al Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction.N Engl J Med1980;303,897-902
 
DeWood, M, Spores, J, Notske, R, et al Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction.N Engl J Med1980;303,897-902
 
Kullo, IJ, Edwards, WD, Schwartz, RS Vulnerable plaque: pathobiology and clinical implications.Ann Intern Med1998;129,1050-1060
 
Fuster, V, Badimon, JJ, Chesebro, JH Atherothrombosis: mechanisms and clinical therapeutic approaches.Vasc Med1998;3,231-239
 
Libby, P Current concepts of the pathogenesis of the acute coronary syndromes.Circulation2001;104,365-372
 
Burke, AP, Farb, A, Pestaner, J, et al Traditional risk factors and the incidence of sudden coronary death with and without coronary thrombosis in blacks.Circulation2002;105,419-424
 
Fuster, V, Badimon, L, Badimon, JJ, et al The pathogenesis of coronary artery disease and the acute coronary syndromes (1).N Engl J Med1992;326,242-250
 
Fuster, V, Badimon, L, Badimon, JJ, et al The pathogenesis of coronary artery disease and the acute coronary syndromes (2).N Engl J Med1992;326,310-318
 
Harker, LA, Hanson, SR, Runge, MS Thrombin hypothesis of thrombus generation and vascular lesion formation.Am J Cardiol1995;75,12B-17B
 
Patterson, C, Stouffer, GA, Madamanchi, N, et al New tricks for old dogs: nonthrombotic effects of thrombin in vessel wall biology.Circ Res2001;88,987-997
 
Bajzar, L, Manuel, R, Nesheim, ME Purification and characterization of TAFI, a thrombin-activable fibrinolysis inhibitor.J Biol Chem1995;270,14477-14484
 
Juhan-Vague, I, Morange, PE, Aubert, H, et al Plasma thrombin-activatable fibrinolysis inhibitor antigen concentration and genotype in relation to myocardial infarction in the north and south of Europe.Arterioscler Thromb Vasc Biol2002;22,867-873
 
Esmon, CT The protein C anticoagulant pathway.Arterioscler Thromb Vasc Biol1992;12,135-145
 
Callas, PW, Tracy, RP, Bovill, EG, et al The association of anticoagulant protein concentrations with acute myocardial infarction in the Thrombolysis in Myocardial Infarction Phase II (TIMI II) Trial.J Thromb Thrombolysis1998;5,53-60
 
Juul, K, Tybjaerg-Hansen, A, Steffensen, R, et al Factor V Leiden: the Copenhagen City Heart Study and 2 meta-analyses.Blood2002;100,3-10
 
Meade, TW, Mellows, S, Brozovic, M, et al Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study.Lancet1986;2,533-537
 
Tracy, RP, Arnold, AM, Ettinger, W, et al The relationship of fibrinogen and factors VII and VIII to incident cardiovascular disease and death in the elderly: results from the cardiovascular health study.Arterioscler Thromb Vasc Biol1999;19,1776-1783
 
Tracy R, Psaty B, Bovill E, et al. Fibrinogen and factor VIII, but not factor VII, are positively associated with prevalent cardiovascular disease in older adults: analyses from the Cardiovascular Heart Study [abstract P31]. Paper presented at the 32nd Annual Conference on Cardiovascular Disease Epidemiology, March 19–21, 1992; Memphis, TN.
 
Folsom, AR, Wu, KK, Rosamond, WD, et al Prospective study of hemostatic factors and incidence of coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study.Circulation1997;96,1102-1108
 
Danesh, J, Whincup, P, Walker, M, et al Fibrin D-dimer and coronary heart disease: prospective study and meta-analysis.Circulation2001;103,2323-2327
 
Folsom, AR, Aleksic, N, Park, E, et al Prospective study of fibrinolytic factors and incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study.Arterioscler Thromb Vasc Biol2001;21,611-617
 
Cushman, M, Lemaitre, RN, Kuller, LH, et al Fibrinolytic activation markers predict myocardial infarction in the elderly: The Cardiovascular Health Study.Arterioscler Thromb Vasc Biol1999;19,493-498
 
Jacobs, J, Tracy, R, Gross, M, et al Reactive protein and vitamin C are associated with coronary calcification in young adults: The Cardia Study [abstract].Circulation2000;101,720
 
Ridker, PM, Hennekens, CH, Cerskus, A, et al Plasma concentration of cross-linked fibrin degradation product (D-dimer) and the risk of future myocardial infarction among apparently healthy men.Circulation1994;90,2236-2240
 
Lowe, GD, Rumley, A, Sweetnam, PM, et al Fibrin D-dimer, markers of coagulation activation and the risk of major ischaemic heart disease in the caerphilly study.Thromb Haemost2001;86,822-827
 
Bertina, RM, Rosendaal, FR Venous thrombosis: the interaction of genes and environment.N Engl J Med1998;338,1840-1841
 
Folsom, AR, Cushman, M, Tsai, MY, et al A prospective study of venous thromboembolism in relation to factor V Leiden and related factors.Blood2002;99,2720-2725
 
Rosendaal, FR, Siscovick, DS, Schwartz, SM, et al Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women.Blood1997;89,2817-2821
 
Meade, TW, North, WR, Chakrabarti, R, et al Haemostatic function and cardiovascular death: early results of a prospective study.Lancet1980;1,1050-1054
 
Wilhelmsen, L, Svardsudd, K, Korsan-Bengtsen, K, et al Fibrinogen as a risk factor for stroke and myocardial infarction.N Engl J Med1984;311,501-505
 
Stone, MC, Thorp, JM Plasma fibrinogen: a major coronary risk factor.J R Coll Gen Pract1985;35,565-569
 
Kannel, WB, Wolf, PA, Castelli, WP, et al Fibrinogen and risk of cardiovascular disease: The Framingham Study.JAMA1987;258,1183-1186
 
Smiles, AM, Jenny, NS, Tang, Z, et al No association of plasma prothrombin concentration or the G20210A mutation with incident cardiovascular disease: results from the Cardiovascular Health Study.Thromb Haemost2002;87,614-621
 
Bertina, RM The prothrombin 20210 G to A variation and thrombosis.Curr Opin Hematol1998;5,339-342
 
Sakkinen, PA, Cushman, M, Psaty, BM, et al Correlates of antithrombin, protein C, protein S, and TFPI in a healthy elderly cohort.Thromb Haemost1998;80,134-139
 
Tracy, R, Bovill, E Hemostasis and risk of ischemic disease: epidemiologic evidence with emphasis on the elderly. Califf, R Mark, D Wagner, G eds.Acute coronary care in the thrombolytic era. 2nd ed.1995,27-43 Mosby Year Book. St. Louis, MO:
 
Tracy, RP Is visceral adiposity the “enemy within”?Arterioscler Thromb Vasc Biol2001;21,881-883
 
Huber, SA, Sakkinen, P, Conze, D, et al Interleukin-6 exacerbates early atherosclerosis in mice.Arterioscler Thromb Vasc Biol1999;19,2364-2367
 
Tracy, RP Epidemiological evidence for inflammation in cardiovascular disease.Thromb Haemost1999;82,826-831
 
Hamsten, A, Wiman, B, de Faire, U, et al Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction.N Engl J Med1985;313,1557-1563
 
Hamsten, A, de Faire, U, Walldius, G, et al Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction.Lancet1987;2,3-9
 
Iacoviello, L, Burzotta, F, Di Castelnuovo, A, et al The 4G/5G polymorphism of PAI-1 promoter gene and the risk of myocardial infarction: a meta-analysis.Thromb Haemost1998;80,1029-1030
 
Juhan-Vague, I, Alessi, M, Morange, P PAI-1, obesity, and insulin resistance. Reaven, G Laws, A eds.Insulin resistance: the metabolic syndrome X.1999,317-332 Humana Press. Totowa, NJ:
 
Kluft, C, Verheijen, JH, Jie, AF, et al The postoperative fibrinolytic shutdown: a rapidly reverting acute phase pattern for the fast-acting inhibitor of tissue-type plasminogen activator after trauma.Scand J Clin Lab Invest1985;45,605-610
 
Sobel, BE Coronary artery disease and fibrinolysis: from the blood to the vessel wall.Thromb Haemost1999;82(suppl 1),8-13
 
Sobel, BE Increased plasminogen activator inhibitor-1 and vasculopathy: a reconcilable paradox.Circulation1999;99,2496-2498
 
Alessi, MC, Juhan-Vague, I, Kooistra, T, et al Insulin stimulates the synthesis of plasminogen activator inhibitor 1 by the human hepatocellular cell line Hep G2.Thromb Haemost1988;60,491-494
 
Schneider, DJ, Absher, PM, Ricci, MA Dependence of augmentation of arterial endothelial cell expression of plasminogen activator inhibitor type 1 by insulin on soluble factors released from vascular smooth muscle cells.Circulation1997;96,2868-2876
 
Loskutoff, DJ, Samad, F The adipocyte and hemostatic balance in obesity: studies of PAI-1.Arterioscler Thromb Vasc Biol1998;18,1-6
 
Hanley, AJ, Karter, AJ, Festa, A, et al Factor analysis of metabolic syndrome using directly measured insulin sensitivity: The Insulin Resistance Atherosclerosis Study.Diabetes2002;51,2642-2647
 
Meigs, JB Invited commentary: insulin resistance syndrome? Syndrome X? Multiple metabolic syndrome? A syndrome at all? Factor analysis reveals patterns in the fabric of correlated metabolic risk factors.Am J Epidemiol2000;152,908-911
 
Edwards, KL, Austin, MA, Newman, B, et al Multivariate analysis of the insulin resistance syndrome in women.Arterioscler Thromb Vasc Biol1994;14,1940-1945
 
Kushner, I C-reactive protein and the acute-phase response.Hosp Pract (Off Ed)1990;25,3-16,21–28
 
Esmon, CT, Taylor, FB, Jr, Snow, TR Inflammation and coagulation: linked processes potentially regulated through a common pathway mediated by protein C.Thromb Haemost1991;66,160-165
 
Lagrand, WK, Visser, CA, Hermens, WT, et al C-reactive protein as a cardiovascular risk factor: more than an epiphenomenon?Circulation1999;100,96-102
 
Hansson, GK Immune mechanisms in atherosclerosis.Arterioscler Thromb Vasc Biol2001;21,1876-1890
 
Ross, R Inflammation, growth regulatory molecules and atherosclerosis.J Cell Biochem1992;48(suppl 16A),1-30
 
Berliner, JA, Navab, M, Fogelman, AM, et al Atherosclerosis: basic mechanisms; oxidation, inflammation, and genetics.Circulation1995;91,2488-2496
 
Fishman, D, Faulds, G, Jeffery, R, et al The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis.J Clin Invest1998;102,1369-1376
 
Jenny, NS, Tracy, RP, Ogg, MS, et al In the elderly, interleukin-6 plasma levels and the − 174G>C polymorphism are associated with the development of cardiovascular disease.Arterioscler Thromb Vasc Biol2002;22,2066-2071
 
Mendall, MA, Patel, P, Ballam, L, et al C reactive protein and its relation to cardiovascular risk factors: a population based cross sectional study.BMJ1996;312,1061-1065
 
Koenig, W, Sund, M, Frohlich, M, et al C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992.Circulation1999;99,237-242
 
Harris, TB, Ferrucci, L, Tracy, RP, et al Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly.Am J Med1999;106,506-512
 
Ridker, PM, Stampfer, MJ, Rifai, N Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease.JAMA2001;285,2481-2485
 
Danesh, J, Collins, R, Appleby, P, et al Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies.JAMA1998;279,1477-1482
 
Schmidt, MI, Duncan, BB, Sharrett, AR, et al Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study.Lancet1999;353,1649-1652
 
Juhan-Vague, I, Alessi, MC, Vague, P Thrombogenic and fibrinolytic factors and cardiovascular risk in non-insulin-dependent diabetes mellitus.Ann Med1996;28,371-380
 
Festa, A, D’Agostino, R, Jr, Howard, G, et al Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS).Circulation2000;102,42-47
 
Yudkin, JS, Stehouwer, CD, Emeis, JJ, et al C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue?Arterioscler Thromb Vasc Biol1999;19,972-978
 
Sakkinen, PA, Cushman, M, Psaty, BM, et al Relationship of plasmin generation to cardiovascular disease risk factors in elderly men and women.Arterioscler Thromb Vasc Biol1999;19,499-504
 
Fuller, JH, Keen, H, Jarrett, RJ, et al Haemostatic variables associated with diabetes and its complications.BMJ1979;2,964-966
 
Yudkin, JS Abnormalities of coagulation and fibrinolysis in insulin resistance: evidence for a common antecedent?Diabetes Care1999;22(suppl 3),C25-C30
 
Yudkin, JS, Kumari, M, Humphries, SE, et al Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link?Atherosclerosis2000;148,209-214
 
Aggarwal, B, Puri, R. Human cytokines: their role in disease and therapy. 1995; Blackwell Science. Cambridge, MA:.
 
Arch, RH, Gedrich, RW, Thompson, CB Tumor necrosis factor receptor-associated factors (TRAFs): a family of adapter proteins that regulates life and death.Genes Dev1998;12,2821-2830
 
Qi, C, Pekala, PH Tumor necrosis factor-α-induced insulin resistance in adipocytes.Proc Soc Exp Biol Med2000;223,128-135
 
Hotamisligil, GS The role of TNF-α and TNF receptors in obesity and insulin resistance.J Intern Med1999;245,621-625
 
Nilsson, J, Jovinge, S, Niemann, A, et al Relation between plasma tumor necrosis factor-α and insulin sensitivity in elderly men with non-insulin-dependent diabetes mellitus.Arterioscler Thromb Vasc Biol1998;18,1199-1202
 

Figures

Figure Jump LinkFigure 1. The complex interplay of atherothrombotic disease with inflammation and clotting. Inflammation and the proinflammatory cytokines, eg, IL-6, are increased by a variety of mechanisms in atherothrombosis. In addition, there is activation of the coagulation system, with subsequent activation of fibrinolysis, leading to a complex interplay. An example concerns the feedback control of fibrinogen levels. The use of fibrinogen in clotting, including the increased clotting of atherosclerotic progression, results in the production of FDPs. FDPs are bound by monocytes, which in turn increase production of IL-6. This IL-6 acts via the endocrine system to increase the hepatic synthesis of fibrinogen.10 As discussed in the text, increased plasma fibrinogen may feedback in a positive manner, increasing the likelihood of atheroprogression. In addition, other causes of inflammation feed into this system, such as chronic infections and diabetes. Also, the elaboration of proinflammatory cytokines is affected by an individual’s capacity for inflammatory response, such as the extent of visceral adiposity.52 A wide variety of genetic influences are easily conceived, and as we have recently observed, increased IL-6 itself may accelerate the atherothrombotic process,53 possibly acting as a potent cell growth regulator, an activator of monocytes and/or other cells, an amplifier of the innate immune response exacerbating uptake of lipid particles by macrophage, or by other potential mechanisms. The plasma proteins affected by IL-6, such as CRP, fibrinogen, and others, may also directly participate in the atherothrombotic process to make it worse. Adapted with permission.54 ICAM = intracellular adhesion molecule; HDL = high-density lipoprotein.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Findings Supporting the Interplay Between Coagulation, Fibrinolysis, and Inflammation
Table Graphic Jump Location
Table 2. Acute-Phase Reactants Associated With CVD

References

Tracy, R (1997) Atherosclerosis, thrombosis and inflammation: a question of linkage.Fibrinolysis Proteolysis11(suppl 1),137-142
 
Bernard, GR, Vincent, JL, Laterre, PF, et al Efficacy and safety of recombinant human activated protein C for severe sepsis.N Engl J Med2001;344,699-709
 
Tracy, RP, Psaty, BM, Macy, E, et al Lifetime smoking exposure affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in healthy elderly subjects.Arterioscler Thromb Vasc Biol1997;17,2167-2176
 
Sakkinen, PA, Wahl, P, Cushman, M, et al Clustering of procoagulation, inflammation, and fibrinolysis variables with metabolic factors in insulin resistance syndrome.Am J Epidemiol2000;152,897-907
 
Ely, EW, Bernard, GR, Vincent, JL Activated protein C for severe sepsis.N Engl J Med2002;347,1035-1036
 
Ridker, PM, Cushman, M, Stampfer, MJ, et al Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men.N Engl J Med1997;336,973-979
 
Ridker, PM, Rifai, N, Pfeffer, MA, et al Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators.Circulation1998;98,839-844
 
Neumann, FJ, Ott, I, Marx, N, et al Effect of human recombinant interleukin-6 and interleukin-8 on monocyte procoagulant activity.Arterioscler Thromb Vasc Biol1997;17,3399-3405
 
Cermak, J, Key, NS, Bach, RR, et al C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor.Blood1993;82,513-520
 
Ritchie, DG, Levy, BA, Adams, MA, et al Regulation of fibrinogen synthesis by plasmin-derived fragments of fibrinogen and fibrin: an indirect feedback pathway.Proc Natl Acad Sci U S A1982;79,1530-1534
 
Tokunou, T, Ichiki, T, Takeda, K, et al Thrombin induces interleukin-6 expression through the cAMP response element in vascular smooth muscle cells.Arterioscler Thromb Vasc Biol2001;21,1759-1763
 
Bhat, GJ, Raghu, G, Gunaje, JJ, et al Alpha-thrombin inhibits interleukin-6-induced Stat3 signaling and gp130 gene expression in primary cultures of human lung fibroblasts.Biochem Biophys Res Commun1999;256,626-630
 
Eto, M, Kozai, T, Cosentino, F, et al Statin prevents tissue factor expression in human endothelial cells: role of Rho/Rho-kinase and Akt pathways.Circulation2002;105,1756-1759
 
American Heart Association.. Heart disease and stroke statistics–2003 update. 2002; American Heart Association. Dallas, TX:.
 
Sans, S, Kesteloot, H, Kromhout, D The burden of cardiovascular diseases mortality in Europe: Task Force of the European Society of Cardiology on Cardiovascular Mortality and Morbidity Statistics in Europe.Eur Heart J1997;18,1231-1248
 
DeWood, MA, Spores, J, Notske, R, et al Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction.N Engl J Med1980;303,897-902
 
DeWood, M, Spores, J, Notske, R, et al Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction.N Engl J Med1980;303,897-902
 
Kullo, IJ, Edwards, WD, Schwartz, RS Vulnerable plaque: pathobiology and clinical implications.Ann Intern Med1998;129,1050-1060
 
Fuster, V, Badimon, JJ, Chesebro, JH Atherothrombosis: mechanisms and clinical therapeutic approaches.Vasc Med1998;3,231-239
 
Libby, P Current concepts of the pathogenesis of the acute coronary syndromes.Circulation2001;104,365-372
 
Burke, AP, Farb, A, Pestaner, J, et al Traditional risk factors and the incidence of sudden coronary death with and without coronary thrombosis in blacks.Circulation2002;105,419-424
 
Fuster, V, Badimon, L, Badimon, JJ, et al The pathogenesis of coronary artery disease and the acute coronary syndromes (1).N Engl J Med1992;326,242-250
 
Fuster, V, Badimon, L, Badimon, JJ, et al The pathogenesis of coronary artery disease and the acute coronary syndromes (2).N Engl J Med1992;326,310-318
 
Harker, LA, Hanson, SR, Runge, MS Thrombin hypothesis of thrombus generation and vascular lesion formation.Am J Cardiol1995;75,12B-17B
 
Patterson, C, Stouffer, GA, Madamanchi, N, et al New tricks for old dogs: nonthrombotic effects of thrombin in vessel wall biology.Circ Res2001;88,987-997
 
Bajzar, L, Manuel, R, Nesheim, ME Purification and characterization of TAFI, a thrombin-activable fibrinolysis inhibitor.J Biol Chem1995;270,14477-14484
 
Juhan-Vague, I, Morange, PE, Aubert, H, et al Plasma thrombin-activatable fibrinolysis inhibitor antigen concentration and genotype in relation to myocardial infarction in the north and south of Europe.Arterioscler Thromb Vasc Biol2002;22,867-873
 
Esmon, CT The protein C anticoagulant pathway.Arterioscler Thromb Vasc Biol1992;12,135-145
 
Callas, PW, Tracy, RP, Bovill, EG, et al The association of anticoagulant protein concentrations with acute myocardial infarction in the Thrombolysis in Myocardial Infarction Phase II (TIMI II) Trial.J Thromb Thrombolysis1998;5,53-60
 
Juul, K, Tybjaerg-Hansen, A, Steffensen, R, et al Factor V Leiden: the Copenhagen City Heart Study and 2 meta-analyses.Blood2002;100,3-10
 
Meade, TW, Mellows, S, Brozovic, M, et al Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study.Lancet1986;2,533-537
 
Tracy, RP, Arnold, AM, Ettinger, W, et al The relationship of fibrinogen and factors VII and VIII to incident cardiovascular disease and death in the elderly: results from the cardiovascular health study.Arterioscler Thromb Vasc Biol1999;19,1776-1783
 
Tracy R, Psaty B, Bovill E, et al. Fibrinogen and factor VIII, but not factor VII, are positively associated with prevalent cardiovascular disease in older adults: analyses from the Cardiovascular Heart Study [abstract P31]. Paper presented at the 32nd Annual Conference on Cardiovascular Disease Epidemiology, March 19–21, 1992; Memphis, TN.
 
Folsom, AR, Wu, KK, Rosamond, WD, et al Prospective study of hemostatic factors and incidence of coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study.Circulation1997;96,1102-1108
 
Danesh, J, Whincup, P, Walker, M, et al Fibrin D-dimer and coronary heart disease: prospective study and meta-analysis.Circulation2001;103,2323-2327
 
Folsom, AR, Aleksic, N, Park, E, et al Prospective study of fibrinolytic factors and incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study.Arterioscler Thromb Vasc Biol2001;21,611-617
 
Cushman, M, Lemaitre, RN, Kuller, LH, et al Fibrinolytic activation markers predict myocardial infarction in the elderly: The Cardiovascular Health Study.Arterioscler Thromb Vasc Biol1999;19,493-498
 
Jacobs, J, Tracy, R, Gross, M, et al Reactive protein and vitamin C are associated with coronary calcification in young adults: The Cardia Study [abstract].Circulation2000;101,720
 
Ridker, PM, Hennekens, CH, Cerskus, A, et al Plasma concentration of cross-linked fibrin degradation product (D-dimer) and the risk of future myocardial infarction among apparently healthy men.Circulation1994;90,2236-2240
 
Lowe, GD, Rumley, A, Sweetnam, PM, et al Fibrin D-dimer, markers of coagulation activation and the risk of major ischaemic heart disease in the caerphilly study.Thromb Haemost2001;86,822-827
 
Bertina, RM, Rosendaal, FR Venous thrombosis: the interaction of genes and environment.N Engl J Med1998;338,1840-1841
 
Folsom, AR, Cushman, M, Tsai, MY, et al A prospective study of venous thromboembolism in relation to factor V Leiden and related factors.Blood2002;99,2720-2725
 
Rosendaal, FR, Siscovick, DS, Schwartz, SM, et al Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women.Blood1997;89,2817-2821
 
Meade, TW, North, WR, Chakrabarti, R, et al Haemostatic function and cardiovascular death: early results of a prospective study.Lancet1980;1,1050-1054
 
Wilhelmsen, L, Svardsudd, K, Korsan-Bengtsen, K, et al Fibrinogen as a risk factor for stroke and myocardial infarction.N Engl J Med1984;311,501-505
 
Stone, MC, Thorp, JM Plasma fibrinogen: a major coronary risk factor.J R Coll Gen Pract1985;35,565-569
 
Kannel, WB, Wolf, PA, Castelli, WP, et al Fibrinogen and risk of cardiovascular disease: The Framingham Study.JAMA1987;258,1183-1186
 
Smiles, AM, Jenny, NS, Tang, Z, et al No association of plasma prothrombin concentration or the G20210A mutation with incident cardiovascular disease: results from the Cardiovascular Health Study.Thromb Haemost2002;87,614-621
 
Bertina, RM The prothrombin 20210 G to A variation and thrombosis.Curr Opin Hematol1998;5,339-342
 
Sakkinen, PA, Cushman, M, Psaty, BM, et al Correlates of antithrombin, protein C, protein S, and TFPI in a healthy elderly cohort.Thromb Haemost1998;80,134-139
 
Tracy, R, Bovill, E Hemostasis and risk of ischemic disease: epidemiologic evidence with emphasis on the elderly. Califf, R Mark, D Wagner, G eds.Acute coronary care in the thrombolytic era. 2nd ed.1995,27-43 Mosby Year Book. St. Louis, MO:
 
Tracy, RP Is visceral adiposity the “enemy within”?Arterioscler Thromb Vasc Biol2001;21,881-883
 
Huber, SA, Sakkinen, P, Conze, D, et al Interleukin-6 exacerbates early atherosclerosis in mice.Arterioscler Thromb Vasc Biol1999;19,2364-2367
 
Tracy, RP Epidemiological evidence for inflammation in cardiovascular disease.Thromb Haemost1999;82,826-831
 
Hamsten, A, Wiman, B, de Faire, U, et al Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction.N Engl J Med1985;313,1557-1563
 
Hamsten, A, de Faire, U, Walldius, G, et al Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction.Lancet1987;2,3-9
 
Iacoviello, L, Burzotta, F, Di Castelnuovo, A, et al The 4G/5G polymorphism of PAI-1 promoter gene and the risk of myocardial infarction: a meta-analysis.Thromb Haemost1998;80,1029-1030
 
Juhan-Vague, I, Alessi, M, Morange, P PAI-1, obesity, and insulin resistance. Reaven, G Laws, A eds.Insulin resistance: the metabolic syndrome X.1999,317-332 Humana Press. Totowa, NJ:
 
Kluft, C, Verheijen, JH, Jie, AF, et al The postoperative fibrinolytic shutdown: a rapidly reverting acute phase pattern for the fast-acting inhibitor of tissue-type plasminogen activator after trauma.Scand J Clin Lab Invest1985;45,605-610
 
Sobel, BE Coronary artery disease and fibrinolysis: from the blood to the vessel wall.Thromb Haemost1999;82(suppl 1),8-13
 
Sobel, BE Increased plasminogen activator inhibitor-1 and vasculopathy: a reconcilable paradox.Circulation1999;99,2496-2498
 
Alessi, MC, Juhan-Vague, I, Kooistra, T, et al Insulin stimulates the synthesis of plasminogen activator inhibitor 1 by the human hepatocellular cell line Hep G2.Thromb Haemost1988;60,491-494
 
Schneider, DJ, Absher, PM, Ricci, MA Dependence of augmentation of arterial endothelial cell expression of plasminogen activator inhibitor type 1 by insulin on soluble factors released from vascular smooth muscle cells.Circulation1997;96,2868-2876
 
Loskutoff, DJ, Samad, F The adipocyte and hemostatic balance in obesity: studies of PAI-1.Arterioscler Thromb Vasc Biol1998;18,1-6
 
Hanley, AJ, Karter, AJ, Festa, A, et al Factor analysis of metabolic syndrome using directly measured insulin sensitivity: The Insulin Resistance Atherosclerosis Study.Diabetes2002;51,2642-2647
 
Meigs, JB Invited commentary: insulin resistance syndrome? Syndrome X? Multiple metabolic syndrome? A syndrome at all? Factor analysis reveals patterns in the fabric of correlated metabolic risk factors.Am J Epidemiol2000;152,908-911
 
Edwards, KL, Austin, MA, Newman, B, et al Multivariate analysis of the insulin resistance syndrome in women.Arterioscler Thromb Vasc Biol1994;14,1940-1945
 
Kushner, I C-reactive protein and the acute-phase response.Hosp Pract (Off Ed)1990;25,3-16,21–28
 
Esmon, CT, Taylor, FB, Jr, Snow, TR Inflammation and coagulation: linked processes potentially regulated through a common pathway mediated by protein C.Thromb Haemost1991;66,160-165
 
Lagrand, WK, Visser, CA, Hermens, WT, et al C-reactive protein as a cardiovascular risk factor: more than an epiphenomenon?Circulation1999;100,96-102
 
Hansson, GK Immune mechanisms in atherosclerosis.Arterioscler Thromb Vasc Biol2001;21,1876-1890
 
Ross, R Inflammation, growth regulatory molecules and atherosclerosis.J Cell Biochem1992;48(suppl 16A),1-30
 
Berliner, JA, Navab, M, Fogelman, AM, et al Atherosclerosis: basic mechanisms; oxidation, inflammation, and genetics.Circulation1995;91,2488-2496
 
Fishman, D, Faulds, G, Jeffery, R, et al The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis.J Clin Invest1998;102,1369-1376
 
Jenny, NS, Tracy, RP, Ogg, MS, et al In the elderly, interleukin-6 plasma levels and the − 174G>C polymorphism are associated with the development of cardiovascular disease.Arterioscler Thromb Vasc Biol2002;22,2066-2071
 
Mendall, MA, Patel, P, Ballam, L, et al C reactive protein and its relation to cardiovascular risk factors: a population based cross sectional study.BMJ1996;312,1061-1065
 
Koenig, W, Sund, M, Frohlich, M, et al C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992.Circulation1999;99,237-242
 
Harris, TB, Ferrucci, L, Tracy, RP, et al Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly.Am J Med1999;106,506-512
 
Ridker, PM, Stampfer, MJ, Rifai, N Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease.JAMA2001;285,2481-2485
 
Danesh, J, Collins, R, Appleby, P, et al Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies.JAMA1998;279,1477-1482
 
Schmidt, MI, Duncan, BB, Sharrett, AR, et al Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study.Lancet1999;353,1649-1652
 
Juhan-Vague, I, Alessi, MC, Vague, P Thrombogenic and fibrinolytic factors and cardiovascular risk in non-insulin-dependent diabetes mellitus.Ann Med1996;28,371-380
 
Festa, A, D’Agostino, R, Jr, Howard, G, et al Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS).Circulation2000;102,42-47
 
Yudkin, JS, Stehouwer, CD, Emeis, JJ, et al C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue?Arterioscler Thromb Vasc Biol1999;19,972-978
 
Sakkinen, PA, Cushman, M, Psaty, BM, et al Relationship of plasmin generation to cardiovascular disease risk factors in elderly men and women.Arterioscler Thromb Vasc Biol1999;19,499-504
 
Fuller, JH, Keen, H, Jarrett, RJ, et al Haemostatic variables associated with diabetes and its complications.BMJ1979;2,964-966
 
Yudkin, JS Abnormalities of coagulation and fibrinolysis in insulin resistance: evidence for a common antecedent?Diabetes Care1999;22(suppl 3),C25-C30
 
Yudkin, JS, Kumari, M, Humphries, SE, et al Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link?Atherosclerosis2000;148,209-214
 
Aggarwal, B, Puri, R. Human cytokines: their role in disease and therapy. 1995; Blackwell Science. Cambridge, MA:.
 
Arch, RH, Gedrich, RW, Thompson, CB Tumor necrosis factor receptor-associated factors (TRAFs): a family of adapter proteins that regulates life and death.Genes Dev1998;12,2821-2830
 
Qi, C, Pekala, PH Tumor necrosis factor-α-induced insulin resistance in adipocytes.Proc Soc Exp Biol Med2000;223,128-135
 
Hotamisligil, GS The role of TNF-α and TNF receptors in obesity and insulin resistance.J Intern Med1999;245,621-625
 
Nilsson, J, Jovinge, S, Niemann, A, et al Relation between plasma tumor necrosis factor-α and insulin sensitivity in elderly men with non-insulin-dependent diabetes mellitus.Arterioscler Thromb Vasc Biol1998;18,1199-1202
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543