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(Chest. 2003;124:49S-57S.)
© 2003 American College of Chest Physicians

Thrombin, Inflammation, and Cardiovascular Disease*

An Epidemiologic Perspective

Russell P. Tracy, PhD

* 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{at}uvm.edu


   Abstract
TOP
 Abstract
Introduction
 Connections of Thrombin to...
 Is There a Hypercoagulable...
 There Is a Complex...
 Inflammation Markers and CVD...
 Inflammation and the Metabolic...
 Conclusions
 References
 
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.

Key Words: cardiovascular disease risk • coagulation • epidemiology • fibrinolysis • inflammation • thrombosis


   Introduction
TOP
 Abstract
 Introduction
Connections of Thrombin to...
 Is There a Hypercoagulable...
 There Is a Complex...
 Inflammation Markers and CVD...
 Inflammation and the Metabolic...
 Conclusions
 References
 
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.1 While 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.2 Table 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.


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  		Table 1.. Findings Supporting 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.


   Connections of Thrombin to Clinical CVD
TOP
 Abstract
 Introduction
 Connections of Thrombin to...
Is There a Hypercoagulable...
 There Is a Complex...
 Inflammation Markers and CVD...
 Inflammation and the Metabolic...
 Conclusions
 References
 
CVD is the major cause of death for Americans,14 and incidence rates around the world are reaching epidemic proportions.15 A major form of CVD is myocardial infarction (MI); in the early 1970s, it became evident, through the work of DeWood and colleagues16 17 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.18 19 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 studies21 have 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.22 23

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.24 Many 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,26 also 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.29 This 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.


   Is There a Hypercoagulable State That Predisposes to CVD?
TOP
 Abstract
 Introduction
 Connections of Thrombin to...
 Is There a Hypercoagulable...
There Is a Complex...
 Inflammation Markers and CVD...
 Inflammation and the Metabolic...
 Conclusions
 References
 
Meade and colleagues31 at 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,32 33 34 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.32 33 34

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.35 36 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.37 In 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.38 Also, 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.41 42 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.


   There Is a Complex Interplay Among Atherosclerosis, Thrombosis, and Inflammation
TOP
 Abstract
 Introduction
 Connections of Thrombin to...
 Is There a Hypercoagulable...
 There Is a Complex...
Inflammation Markers and CVD...
 Inflammation and the Metabolic...
 Conclusions
 References
 
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 colleagues44 pioneered 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,45 46 47 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 cases48 while 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 .



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  		Figure 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.

 
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.55 56 However, this finding, like those in the coagulation system, was not always confirmed in future studies.57 It has been suggested that the degree of predictive power may be a function of the adjustment done for other variables,58 since 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. Sobel60 invoked 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-1,62 63 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,65 66 67 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.


   Inflammation Markers and CVD Risk
TOP
 Abstract
 Introduction
 Connections of Thrombin to...
 Is There a Hypercoagulable...
 There Is a Complex...
 Inflammation Markers and CVD...
Inflammation and the Metabolic...
 Conclusions
 References
 
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.


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  		Table 2.. Acute-Phase Reactants Associated With CVD

 
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 immunity70 71 ; 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)-{alpha} genes.74 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.78 These 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,79 CRP had the strongest risk prediction, but a meta-analysis80 observed no real difference between CRP and fibrinogen in risk prediction.


   Inflammation and the Metabolic Syndrome: an Important Relationship
TOP
 Abstract
 Introduction
 Connections of Thrombin to...
 Is There a Hypercoagulable...
 There Is a Complex...
 Inflammation Markers and CVD...
 Inflammation and the Metabolic...
Conclusions
 References
 
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.81 82 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 others3 4 76 83 84 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).3 4 85 Increases in coagulation status in the metabolic syndrome and diabetes have been well documented.86 87 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-{alpha}, which is a so-called first-wave cytokine influencing IL-6 production,89 as well as many other cellular functions. TNF-{alpha} 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.90 Although the role (if any) of circulating TNF-{alpha} in humans remains uncertain, TNF-{alpha} induces insulin resistance in tissue culture and in animal models.91 92 Plasma levels are also elevated in the metabolic syndrome, and are associated with insulin resistance in humans.93


   Conclusions
TOP
 Abstract
 Introduction
 Connections of Thrombin to...
 Is There a Hypercoagulable...
 There Is a Complex...
 Inflammation Markers and CVD...
 Inflammation and the Metabolic...
 Conclusions
References
 
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.


   Footnotes
 
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-{alpha} receptor


   References
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 Abstract
 Introduction
 Connections of Thrombin to...
 Is There a Hypercoagulable...
 There Is a Complex...
 Inflammation Markers and CVD...
 Inflammation and the Metabolic...
 Conclusions
 References
 

  1. Tracy, R (1997) Atherosclerosis, thrombosis and inflammation: a question of linkage. Fibrinolysis Proteolysis 11(suppl 1),137-142
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