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The Proceedings of the American Thoracic Society 2:34-43 (2005)
© 2005 The American Thoracic Society

Markers of Hemostasis and Systemic Inflammation in Heart Disease and Atherosclerosis in Smokers

Peter K. MacCallum

Barts and The London, Queen Mary's School of Medicine and Dentistry, London, United Kingdom

Correspondence and requests for reprints should be addressed to: Peter K. MacCallum, M.D., F.R.C.P., F.R.C.Path, Wolfson Institute of Preventive Medicine, Queen Mary's School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK. E-mail: p.k.maccallum{at}qmul.ac.uk


   ABSTRACT
TOP
 ABSTRACT
THE HEMOSTATIC SYSTEM
 HEMOSTATIC AND INFLAMMATORY...
 SPECIFIC MARKERS ASSOCIATED WITH...
 SMOKING EXPOSURE AND RISK...
 COPD AND HEMOSTATIC MARKERS
 CONCLUSIONS
 REFERENCES
 
Smoking is a major cause of both chronic obstructive pulmonary disease (COPD) and coronary heart disease, the latter being more common in individuals with COPD. Acute coronary events are usually caused by the development of a platelet-rich thrombus associated with atheromatous plaque rupture or erosion. Levels of systemic biomarkers of inflammation and hemostasis may reflect the presence of atherosclerosis and predisposition to thrombosis, and may allow identification of "vulnerable plaque" and "vulnerable blood" in "vulnerable patients." Hemostasis and inflammation, often viewed as separate processes, are integrated closely, and their response to smoking likely has contributed to the current coronary heart disease epidemic. Coagulation is initiated after exposure of blood to tissue factor present in atheromatous plaques. Fibrinogen and other hemostatic factors important in thrombus formation are influenced by inflammatory stimuli, possibly reflecting both vascular and systemic inflammation. Smokers who develop COPD may have higher basal levels of inflammatory markers, such as fibrinogen, due to lung damage, and respiratory infections to which they are prone may further increase levels, predisposing smokers to coronary events. In summary, smoking predisposes to coronary heart disease and the mechanisms may involve proinflammatory and procoagulant changes. These changes may be more marked in smokers with COPD.

Key Words: chronic obstructive pulmonary disease • coronary heart disease • hemostasis • smoking • systemic inflammation

The increase in mortality rates from coronary heart disease (CHD) during the 20th century in the developed countries (Figure 1) had a number of underlying causes, such as changes in diet, although the increase in cigarette smoking over this period is likely to have been one of the most important factors (1). After a seemingly inexorable rise, age-standardized CHD mortality subsequently has fallen substantially in many developed countries over the past 25 or so years. A recent analysis from England and Wales, where CHD mortality declined by 62% in males and 45% in females between 1980 and 2000, suggests that almost half of this decline was due to the reduction in cigarette smoking (2).



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  		Figure 1. Change in chronic heart disease mortality in England and Wales over the 20th century (men and women, aged 50–59 years). Data from the Office for National Statistics.

 
It was long considered that CHD was simply a consequence of passive lipid infiltration of the coronary artery wall, with thrombosis being the result rather than the cause of acute myocardial infarction (MI). In the 1950s, however, Morris suggested that the CHD epidemic could not be explained entirely by gross morphologic changes in the coronary arteries, and hypothesized that the cause was either increased thrombogenicity of the vessel wall or of the blood (3). Of course, the two are not mutually exclusive, and much of the evidence now supports the view that both are involved in the pathogenesis of CHD events. It is widely believed that acute coronary syndromes arise mainly as a result of rupture of atheromatous plaques or erosion of coronary vascular endothelium with formation of localized occlusive thrombus (4). Atheroma formation itself is an inflammatory process characterized by infiltration of the coronary artery wall by monocytes/macrophages and T lymphocytes, and with vulnerable plaques characterized by active inflammation, a thin cap with a lipid-rich core, endothelial denudation with superficial platelet aggregation, and plaque fissures (4, 5).

The hemostatic and immune systems are linked intricately to the processes of inflammation and host defense (Table 1). In addition to interactions between the immune system and plasma-based clotting factors, platelets participate in the inflammatory process by releasing cytokines and chemokines (13). Thus, changes in the immune system in response to environmental challenges are linked to changes in the hemostatic system, and both contribute to vascular pathology (14). A key site of interaction is at the level of the vascular endothelium that normally functions to inhibit thrombosis. The endothelium is perturbed at all stages of atheroma formation, resulting in presentation to the blood of a prothrombotic surface (5).


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  		TABLE 1. Examples of links between coagulation and inflammation

 
The concept of the "vulnerable patient" has been advanced, comprising "vulnerable blood" and "vulnerable myocardium" in addition to the "vulnerable plaque" noted above (4, 15). "Vulnerable blood" has been categorized into markers that reflect metabolic and immune disorders and those that reflect hypercoagulability (15). In the present review, emphasis is given to the hemostatic system, its response to smoking, and the possible effects of this on CHD risk. The effect of hemostatic changes with smoking on risk of venous thromboembolism is considered separately by Tapson in this issue (pp. 71–77). In addition, because the overriding theme of this issue is the impact of smoking and chronic obstructive pulmonary disease (COPD) on cardiovascular function, topics such as systemic and vascular inflammation, dyslipidemia, and aberrant endothelial function in smokers with and without COPD are reviewed by others in this same issue.


   THE HEMOSTATIC SYSTEM
TOP
 ABSTRACT
 THE HEMOSTATIC SYSTEM
HEMOSTATIC AND INFLAMMATORY...
 SPECIFIC MARKERS ASSOCIATED WITH...
 SMOKING EXPOSURE AND RISK...
 COPD AND HEMOSTATIC MARKERS
 CONCLUSIONS
 REFERENCES
 
The hemostatic system is comprised of two inextricably linked components: cellular (principally platelets) and plasma protein–based (i.e., the coagulation cascade) (16–19).

Coagulation
An outline of the coagulation system is shown in Figure 2. Coagulation is initiated by contact of blood containing activated clotting factor (F) VII (FVIIa) with tissue factor (TF), a transmembrane glycoprotein receptor expressed constitutively like a hemostatic envelope on the surface of extravascular cells, and normally separated from circulating blood (20). Subsequent activation of both FIX and FX by FVIIa leads to the generation of thrombin, the key enzyme product of coagulation system activation (19, 21). The extrinsic or TF pathway is switched off by a specific inhibitor, tissue factor pathway inhibitor, and continuing generation of thrombin is then dependent upon recruitment of the intrinsic pathway through activation of FXI and the cofactors VIII and V by thrombin (21). Thrombin converts fibrinogen to fibrin, and the resulting fibrin polymers are cross-linked, and thereby stabilized, by FXIIIa, a transglutamase activated by thrombin (22). Indeed, thrombin has multiple functions both within the hemostatic and other systems (23–27). Hemostasis is localized by the need for appropriate negatively charged phospholipid surfaces upon which clotting factors are assembled for efficient activation, and a healthy endothelium inhibits thrombosis within the vessel away from the site of vessel wall injury (23). Several endogenous inhibitors of coagulation regulate the clotting process further, and include antithrombin, protein C, and others (23). Fibrin is lysed by plasmin, which is cleaved from its precursor, plasminogen, by the enzyme tissue-type plasminogen activator (tPA). Fibrinolysis is inhibited by (1) plasminogen activator inhibitor type 1 (PAI-1), which inhibits tPA; (2) {alpha}2-antiplasmin, which inhibits free plasmin; and (3) thrombin-activatable fibrinolysis inhibitor, which inhibits binding of plasminogen to fibrin (28, 29) (Figure 2).



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  		Figure 2. Outline of the coagulation system and its regulation. APC = activated protein C; AT = antithrombin; EPCR = endothelial protein C receptor; FDPs = fibrin degradation products (includes D-dimer); PAI-1 = plasminogen activator inhibitor type 1; PC = protein C; PS = protein S; TAFI = thrombin activatable fibrinolysis inhibitor; TF = tissue factor; TFPI = tissue factor pathway inhibitor; t-PA = tissue-type plasminogen activator; vWF = von Willebrand factor; XL-fibrin = cross-linked fibrin. Bold lines represent the main procoagulant reactions (reprinted by permission from Reference 128).

 
Platelets
Exposure of vessel wall subendothelium leads to a series of steps in which platelets initially adhere to underlying subendothelial collagen and von Willebrand factor. Platelets become activated in a process that involves change in shape and inversion of the cell membrane such that negatively charged phospholipids become exposed on the outer surface. Aggregation takes place whereby adjacent platelets link to each other by fibrinogen, von Willebrand factor, or possibly fibronectin bridges, thereby forming the initial hemostatic plug (30–32). These processes are mediated via specific platelet membrane glycoprotein receptors (30, 32). Platelets are activated by a number of agonists, one of the most important being thrombin acting via protease-activated receptors–1 and –4 (30). Platelet activation is accompanied by a series of intracellular reactions, such as generation of thromboxane A2, the release of which leads to further activation. Exposure of negatively charged phospholipids on the platelet exterior provides a surface on which coagulation proteins can assemble. Platelet responses cannot distinguish between traumatic and pathologic vessel damage (32).

Recent models of hemostasis emphasize the integration of the coagulation and cellular components. Exposure of blood to extravascular cells that express TF constitutively, or to TF-rich atheromatous plaques, results in thrombin generation. In order for coagulation to continue, platelet activation is necessary, providing a surface upon which the clotting process can amplify and propagate (17). Recent evidence suggests that circulating TF may be important in continuing the process of thrombin generation (33). Possible sources of circulating TF include monocytes, platelets, or circulating procoagulant microparticles; or TF may circulate in a soluble form lacking the transmembrane domain (34, 35). It has been suggested that the adhesion molecule P-selectin, expressed on activated platelets, binds to its ligand, P-selectin glycoprotein ligand-1, present on hemopoietic cell–derived microparticles. Because P-selectin glycoprotein ligand-1 is linked to TF on these microparticles, it is envisaged that platelet activation, aside from providing a suitable surface for thrombin generation, may also lead to provision of additional TF, which in turn promotes further thrombin generation (35).


   HEMOSTATIC AND INFLAMMATORY VARIABLES AS MARKERS OF CHD RISK
TOP
 ABSTRACT
 THE HEMOSTATIC SYSTEM
 HEMOSTATIC AND INFLAMMATORY...
SPECIFIC MARKERS ASSOCIATED WITH...
 SMOKING EXPOSURE AND RISK...
 COPD AND HEMOSTATIC MARKERS
 CONCLUSIONS
 REFERENCES
 
As a result of large prospective epidemiologic studies, a number of candidate biomarkers of CHD have emerged, and it is hoped that their measurement may improve our ability to predict the likelihood of CHD over traditional risk factors. In addition to being markers of predisposition to coronary events, some markers may be causally involved in the pathogenesis of CHD, based largely on the strength of the epidemiologic evidence and biological plausibility.

Although such causality is often difficult to prove, a suggested approach is through the use of genetic epidemiology, "Mendelian randomization" (36), in which common inherited polymorphisms affect the level of a given intermediate phenotype throughout life (i.e. before the onset of disease). The finding of an association of a relevant polymorphism with clinical outcome strengthens the case for a causal association of the intermediate phenotype with CHD. This approach has been used to support a causal role for homocysteine in the risk of CHD, stroke, and venous thromboembolism (37). Drawbacks to this approach include the tendency for common polymorphisms to account for only a small proportion of the variability in candidate risk factors, requiring large numbers of events to enable the drawing of any conclusions—in the case of homocysteine and CHD, this was about 10,000 cases and a similar number of controls. For fibrinogen it has been suggested that 30,000 cases and a similar number of controls would be necessary to exclude an effect (38). Support from genetic data for a causal role in CHD exists for at least one clotting factor. Men with hemophilia and female carriers of hemophilia, with severe and intermediate reductions in FVIII levels, respectively, appear to be protected against acute MI (39, 40). In a large study, individuals with blood group O, who have lower levels of FVIII than those of group A or B, had a lower risk of CHD (41).

A second approach to the question of causation is to look at reversibility with treatment, as shown for cholesterol by the efficacy of the statins (see review by Hunninghake in this issue, pp. 44–49). The success of aspirin and other antiplatelet agents in CHD prevention points to the importance of platelets in causation (42). Similarly, the benefit of warfarin in preventing CHD (43) supports a role for thrombin generation in the pathophysiology of CHD events.


   SPECIFIC MARKERS ASSOCIATED WITH CHD AND SMOKING
TOP
 ABSTRACT
 THE HEMOSTATIC SYSTEM
 HEMOSTATIC AND INFLAMMATORY...
 SPECIFIC MARKERS ASSOCIATED WITH...
SMOKING EXPOSURE AND RISK...
 COPD AND HEMOSTATIC MARKERS
 CONCLUSIONS
 REFERENCES
 
Fibrinogen
Of the hemostatic variables associated with CHD and with smoking, plasma fibrinogen (serum is clotted, thereby containing no fibrinogen) has been the most widely reported. First studied as a possible risk factor in the Northwick Park Heart Study (44), a more recent metaanalysis of prospective studies suggested that individuals with fibrinogen levels in the top tertile of distribution had a risk of CHD 1.8-fold (95% confidence interval, 1.6–2.0) that of the bottom tertile (45). The potential mechanisms whereby higher fibrinogen could contribute to risk include increased fibrin formation, platelet aggregation, plasma viscosity, and through-binding of leukocytes to endothelial cells (46). A number of inherited polymorphisms and environmental factors, including smoking, influence fibrinogen levels (46). Although studies are inconsistent, polymorphisms of the ß-fibrinogen gene may modify the effect of smoking on plasma fibrinogen (47).

Although there are no specific fibrinogen-lowering drugs suitable for long-term administration, the fibrate class of drugs reduces mean plasma fibrinogen as well as modifying serum lipid levels beneficially. Administration of bezafibrate, which lowered fibrinogen by 13%, was reported recently to have no overall effect on CHD events in a randomized, placebo-controlled trial involving 1,568 men with peripheral arterial disease, although it may have reduced nonfatal events in younger men (48). The reason for the lack of efficacy may have been an accompanying bezafibrate-induced rise in plasma homocysteine negating any benefit from the alterations in fibrinogen and lipids (49).

Links between the effect of smoking on fibrinogen and CHD risk may be complicated by other factors. For example, an interaction between fibrinogen and polymorphisms of FXIII has been suggested on the basis of data from stroke patients (Figure 3) through an influence on fibrin structure and function in which the Leu34 FXIII polymorphism appears to be protective (50). Thus, smoking could interact with polymorphisms of the fibrinogen genes to determine protein levels, and the consequence of altered fibrinogen levels on fibrin structure, and conceivably clinical risk, could be modified by polymorphisms of FXIII. This illustrates the complicated nature of gene–gene and gene–environment interactions.



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  		Figure 3. Overview of complex gene–environment interactions and their impact on clinical outcome. Environmental factors (e.g., smoking) influence fibrinogen levels, the consequence of which involves further interaction with factor XIII polymorphisms (reprinted by permission from Reference 50).

 
Interaction of Smoking and Prothrombotic Genotypes on CHD Risk
The regulation of hemostasis varies in different vascular beds (51). The pathogenesis of arterial thrombosis and venous thromboembolism differs in terms of the importance of contributions from the vessel wall, platelets, and blood flow. It is not surprising, therefore, that risk factors for venous and coronary artery thrombosis should also differ. A number of inherited predispositions to venous thromboembolism are recognized. Some such mutations result in relatively uncommon deficiencies of endogenous anticoagulants, such as antithrombin, protein C, and protein S. However, clear associations of these deficiencies with arterial thrombosis are lacking. Likewise, associations with MI of more common polymorphisms, including V Leiden (the main genetic cause of resistance to activated protein C, and the most common known inherited cause of thrombophilia) and the prothrombin G20210A variant (which increases circulating prothrombin levels), are uncertain and at most minor, in contrast to their predisposing role in venous thromboembolism. The difference may be partly because the thrombotic stimulus resulting from plaque rupture might be so strong, and endothelial damage and the flow rates of blood in areas of coronary stenosis sufficiently great, that physiologic variations in levels of pro- and anticoagulant proteins could be of minor importance in contributing to coronary thrombosis (52–54).

In contrast to their apparent lack of importance in CHD as a whole, some studies have suggested that V Leiden and the prothrombin variant may be associated more strongly with CHD in certain subgroups. For example, in a case–control study of 560 male subjects under 70 years of age with MI and 646 age-matched control subjects, V Leiden and the prothrombin variant were not significant risk factors in nonsmokers (odds ratio, 1.3 [95% CI, 0.7–2.5]). Smoking itself was a risk factor in noncarriers of these mutations (odds ratio, 3.3 [95% CI, 2.5-4.2]), but in carriers who smoked the odds ratio rose to 6.1 (95% CI, 3.0–12.5) (55). Similarly, in a case–control study of 84 women under 45 years of age with MI and 388 age-matched control subjects, V Leiden alone did not appear to be a risk factor (odds ratio, 1.1 [95% CI, 0.1–8.5]). In smokers who were noncarriers of V Leiden, the risk was nine-fold higher than that in nonsmokers. In smokers who were V Leiden carriers, however, the odds ratio increased to 32 (95% CI, 7.7–133) (56).

The relative risk of MI in smokers appears to be greater in females and to decline with age in both sexes (57). The pathogenesis of CHD events may be different in younger patients, smokers, and females—for example, in one autopsy study, arterial thrombosis was present in 70% of individuals under 40 years of age with sudden cardiac death compared to 30% among patients over 60 years of age (58). In men with coronary disease who died suddenly, smoking was an independent risk factor for acute thrombosis detected at autopsy (59). Young women who died of coronary thrombosis were often smokers with plaque erosions rather than rupture (60). It is possible, therefore, that prothrombotic disturbances of the blood may be particularly important in young female smokers with plaque erosions.

D-Dimer
D-dimer, a product of lysis of cross-linked fibrin, is one of the more widely studied hemostatic variables for association with CHD. Increased D-dimer levels indicate increased fibrin turnover. As for fibrinogen, a number of prospective studies have shown associations with incident CHD events (61). Cross-sectional studies show increased levels of D-dimer in smokers compared to nonsmokers (62).

Tissue Factor
As well as being expressed constitutively on cells surrounding the vasculature, TF, the main initiator of coagulation, is also present in atheromatous plaques, and there is a correlation between the TF content and thrombin generation across these lesions (63, 64). Exposure of TF to blood containing FVIIa is thought to produce a strong thrombogenic stimulus that is critical to the development of coronary thrombosis after plaque rupture. In a study of carotid endarterectomy plaques from 28 smokers and 28 age- and sex-matched nonsmokers, the former were reported to have increased TF expression and activity (65).

As discussed above, it has been suggested that circulating TF may have an important role in hemostasis and thrombosis. Elevated levels of circulating TF have been described in patients at risk of thrombotic disorders. In a study comparing 10 smokers and 15 nonsmokers, the former had significantly higher plasma TF activity, and levels rose further 2 hours after smoking. Conceivably, this could contribute to the thrombotic risk of smoking (66).

Platelets and Smoking
Despite their evident importance in MI, it has proven difficult epidemiologically to demonstrate associations between platelet properties and CHD events in prospective studies. This likely reflects problems in handling of platelets ex vivo and uncertainty about relevant markers of platelet function. Increased mean platelet volume and spontaneous platelet aggregation have been suggested to predict risk of recurrent MI (67, 68).

P-selectin expression, a marker of platelet activation, is increased in smokers compared to nonsmokers (69). Baseline platelet-dependent thrombin generation appears to be significantly greater in smokers than in nonsmokers and to rise further immediately after smoking (70). Platelet thrombus size has been shown to increase after smoking, particularly at high shear rates (71).

In a recent cross-sectional study comparing smokers and nonsmokers, the former appeared to have increased CD40 ligand (CD40L) expression on platelets and CD40 expression on monocytes, as well as increased circulating platelet–monocyte aggregates (Figure 4) (72) that may contribute to both atheroma formation and thrombosis (73). In addition, soluble CD40L levels appeared higher in smokers (72). Soluble CD40L has recently been suggested as a potential cardiovascular risk factor in women (74) and to predict future cardiovascular events in patients with acute coronary syndromes (75). Although produced by other cells, such as CD4+ T lymphocytes, it is thought that soluble CD40L is derived largely from platelets (76). CD40L expressed on platelets and on T lymphocytes interacts with its receptor, CD40, expressed on a variety of other cells, including B lymphocytes, endothelial cells, monocytes/macrophages, and smooth muscle. The CD40–CD40L interaction promotes a number of inflammatory processes, including release of cytokines and expression of adhesion molecules, matrix metalloproteinases, and TF (77). Interestingly, soluble CD40L levels appear to correlate positively with plasma F1.2, a marker of thrombin generation in vivo, and inversely with lung function, expressed as FEV1, in patients with cystic fibrosis (78). In summary, upregulation of the CD40/CD40L dyad and increased platelet–monocyte aggregation may contribute to the atherothrombotic consequences of smoking (72).



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  		Figure 4. sCD40L (A), monocyte surface expression of CD40 (B), platelet surface expression of CD40L (C), and platelet-monocyte aggregates (D) in smokers and age- and sex-matched control subjects. PMA = platelet–monocyte aggregates (reprinted by permission from Reference 72).

 
At a molecular level, a number of polymorphisms of genes encoding surface membrane glycoproteins on platelets that are integral to adhesion and aggregation have been described and linked putatively to cardiovascular risk. For example, a common polymorphism of glycoprotein IIb/IIIa, in which a T/C polymorphism at position 1565 on exon 2 of the glycoprotein IIIa gene leads to a substitution of proline for leucine at amino acid 33, has been linked to MI risk in young patients (79). One case–control study of 200 survivors of MI under 45 years of age found a modest increase in risk of about 1.6 with this so-called PlA2 polymorphic allele, which was increased substantially to 13.7 in carriers who smoked (80). It was concluded that almost 50% of premature MI was attributable to an interaction between these two risk factors (80). Nevertheless, the majority of studies to date have not confirmed a link between this or other polymorphisms of platelet surface membrane glycoprotein and risk of MI (52, 54).

Overall, however, the data support upregulated activation by smoking both of platelets and the coagulation system, the latter supported by the finding in smokers of increases in activation peptides throughout the clotting cascade leading to increased thrombin generation (81).

Fibrinolytic Activity
Impairment of plasma fibrinolytic activity has been associated with CHD events in a number of prospective observational studies. Perhaps the most commonly employed marker is tPA antigen, elevated levels of which indicate impaired fibrinolytic activity (rather than enhanced fibrinolytic activity that is determined by the level of its inhibitor, PAI-1, which forms a complex with tPA and is positively associated with tPA antigen levels) (82). Circulating tPA antigen, produced mainly by vascular endothelial cells, is positively associated with CHD risk (83). High plasma PAI-1 levels, resulting in impairment of fibrinolytic activity, are thought to be an important component of the CHD risk that accompanies the metabolic syndrome (84).

Smokers have higher PAI-1 levels than nonsmokers or former smokers (85). Newby and colleagues, by studying coronary artery and coronary sinus fibrinolytic activity after substance P infusion, elegantly showed that coronary tPA release was impaired significantly in smokers compared with nonsmokers (86). It appears then that impaired fibrinolytic activity, caused both by increased circulating PAI-1, which has a number of sites of origin, and impaired endothelial tPA release, could be a factor linking smoking to risk of MI.

Homocysteine
Homocysteine has emerged in recent years as a risk factor for CHD. As noted above, evidence for a causal role for homocysteine in CHD has been strengthened by confirmation of an association of the thermolabile 5,10 methylene tetrahydrofolate reductase polymorphism, a determinant of plasma homocysteine levels, with CHD (37), as the presence of the polymorphism clearly predates development of CHD. So, the resulting increase in homocysteine would predate development of CHD rather than being either a consequence of it or a covariate with other risk factors. This polymorphism has only a relatively minor role in the determination of homocysteine levels, more so in subjects whose intakes of dietary folate are suboptimal. Cross-sectional studies suggest that one environmental determinant of homocysteine levels is smoking (87). The mechanism underlying the effect of hyperhomocysteinemia is uncertain, but it could contribute to the smoking/CHD association by, for example, causing injury to the vascular endothelium or inducing monocyte TF expression (88, 89). As would be expected, administration of folic acid to smokers significantly reduces plasma homocysteine (90), a potentially important intervention.

Inflammatory Markers
The focus of this review is on components of the hemostatic system and only brief reference will be made to markers that are regarded as part of the inflammatory system, as other articles in this issue cover much of this topic (see articles in this issue by MacNee, pp. 50–60, Wouters, pp. 26–33, and Van Eeden and colleagues, pp. 61–67, in particular). However, this is an area of considerable interest at present in light of the emerging epidemiologic data and the potential for discovery of new candidate targets for therapeutic intervention.

Of variables studied in recent years, C-reactive protein (CRP) is currently the subject of greatest interest as a result of the development of highly sensitive assays that distinguish between levels of CRP that are within the normal range in healthy individuals (91). Much evidence has emerged showing associations of CRP with CHD risk in prospective observational studies (91). As well as being simply a possible marker of the extent of atherosclerosis, there are a number of biologically plausible mechanisms whereby CRP might have a causal role in the pathogenesis of CHD. These include properties such as binding to low-density lipoprotein, particularly damaged low-density lipoprotein, and increasing its uptake by macrophages, increasing adhesion molecule expression, activation of complement and codeposition with complement in atheromatous plaques, stimulation of monocyte TF, and increase in the size of MI when infused into experimental animals (11, 92–94). CRP may predict the efficacy of aspirin in prophylaxis against MI (9). Mean levels are lowered by statins in a manner that is independent of the cholesterol-lowering properties of these agents (95) (see article by Hunninghake in this issue, pp. 44–49).

Debate continues as to the utility of CRP as a predictor of events (96) and the clinical benefit of CRP-lowering by drugs. Polymorphisms of the CRP gene are recognized (97), but it is too soon to assess whether these support a causal role for CRP in CHD. Also unclear is whether circulating CRP is important as a marker of degree of local vessel wall inflammation (where it may be playing a causal role), or whether CRP derived from other sites of inflammation (e.g., the lungs) is important in CHD pathogenesis (94, 98). Rheumatoid arthritis, which is characterized by chronic inflammation, appears to be associated with an increased risk of CHD, and it has been suggested that this risk may be reduced by the immunosuppressant drug, methotrexate, possibly through an effect on systemic inflammation and CRP (99). In cross-sectional studies, CRP levels are higher in smokers than in nonsmokers (6, 100–102; see also article by Man and Sin in this issue, pp. 78–82).

CRP is the classical acute phase protein that is produced by the liver in response to stimulation by cytokines, in particular interleukin (IL)-6 (94). Prospective observational studies have suggested associations of IL-6 with CHD (103, 104). Weak associations of systemic markers of endothelial disturbance with CHD have also been described (105). These include serum intercellular adhesion molecule-1 and E-selectin (103, 105–107), adhesion molecules that promote the attachment of leucocytes to endothelium, one of the initial processes in atheroma formation. Again, levels appear to be higher in current smokers than in nonsmokers (106), even in multiple regression models (108). Likewise, plasma levels of matrix metalloproteinase-9, which may contribute to rupture of atheromatous plaques, have been found to be higher in smokers than in nonsmokers (109).

A recent prospective study in 1,489 nonsmokers, 1,685 ex-smokers, and 2,901 current smokers, followed-up for 18 years, suggested that in each smoking category, having two or more inflammatory markers in the top quartile was associated with an increased risk of MI (110). Smokers were more likely to have raised inflammatory markers than nonsmokers. The inflammatory markers measured were orosomucoid, {alpha}1-antitrypsin, haptoglobin, fibrinogen, and ceruloplasmin, suggesting that a heightened inflammatory response was associated with increased CHD risk. In summary, the data support an effect of smoking on both early and late inflammatory processes involved in the development of atheroma.


   SMOKING EXPOSURE AND RISK OF CHD
TOP
 ABSTRACT
 THE HEMOSTATIC SYSTEM
 HEMOSTATIC AND INFLAMMATORY...
 SPECIFIC MARKERS ASSOCIATED WITH...
 SMOKING EXPOSURE AND RISK...
COPD AND HEMOSTATIC MARKERS
 CONCLUSIONS
 REFERENCES
 
Although it remains a matter of debate, the majority of independent analyses of the effects of environmental tobacco smoke support the view that the relationship between the degree of smoking and CHD risk is nonlinear. Law and colleagues (111, 112) argue that the effect of environmental smoking is much greater than would be expected from the amount of smoke inhaled, and that this is consistent with evidence that the risk of CHD in smokers of 20 cigarettes/day is barely double that of smokers of 5 cigarettes/day (as opposed to four-fold greater). This contrasts both with the linear dose effects of smoking on other smoking-related illnesses (e.g., lung cancer), and also the linear associations of levels of other risk factors (e.g., cholesterol) with CHD. Based on data from a number of studies on effects of environmental tobacco smoke and active smoking of 1 or 2 cigarettes on platelet aggregation, and on earlier data from the Caerphilly study, linking platelet aggregation to risk of MI, they suggest that smoking has a maximal effect on platelet aggregation at low dose and that, at higher doses, other mechanisms come into play. Therefore, CHD risk rises quickly on exposure to small amounts of tobacco smoke before rising more slowly as the number of cigarettes per day increases (Figure 5). Law and colleagues' analysis, therefore, supports an important prothrombotic contribution to the CHD risk that accompanies smoking.



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  		Figure 5. Model proposed by Law and Wald to show dose–response relationship between tobacco smoke and ischemic heart disease events compartmentalized into separate associations attributable to confounding, cause and effect maximal at low dose, and cause and effect with linear dosimetry (reprinted by permission from Reference 112).

 
An alternative explanation was suggested by the community-based Bruneck study, in which passive smoking was associated with a 1.3-fold increase in carotid atherosclerosis. Passive smoking was associated with increases in both chronic infections (mainly respiratory) and CRP, but only those with chronic infections appeared to be at risk of early atherosclerosis (113). Another study in Japanese women suggested that passive smoking outside the home was associated with a significant rise in fibrinogen that was about 50% that of active smoking (114). The effect was confined to younger women, however.

In a different group of individuals—smokers who stop smoking—fibrinogen levels begin to fall quickly, but it takes several years before they have returned to the levels found in nonsmokers (115, 116). It has been suggested that this could explain part of the benefit of smoking cessation on CHD risk (115). The mechanism for the fall in fibrinogen is probably a reduction in the increased rate of fibrinogen synthesis that is seen in smokers and that is likely to be cytokine-mediated (117). Levels of D-dimer also fall to levels seen in nonsmokers five or more years after quitting, whereas CRP levels remain elevated for longer (101).


   COPD AND HEMOSTATIC MARKERS
TOP
 ABSTRACT
 THE HEMOSTATIC SYSTEM
 HEMOSTATIC AND INFLAMMATORY...
 SPECIFIC MARKERS ASSOCIATED WITH...
 SMOKING EXPOSURE AND RISK...
 COPD AND HEMOSTATIC MARKERS
CONCLUSIONS
 REFERENCES
 
There has been limited study to date of hemostatic variables in COPD. Elevated plasma fibrinogen levels are associated with reduced FEV1 and increased risk of COPD (118). Fibrinogen appears to be elevated, as do markers of thrombin generation and fibrin turnover (prothrombin fragment F1.2 and D-dimer, respectively) in patients with COPD, even after stratification for smoking status (119, 120). Platelets too appear to be activated (121). The contribution these changes make to the increased CHD risk seen in these patients remains to be explored, as does the effect of quitting smoking.

Evidence has been advanced that respiratory tract infections in the general population may increase the short-term risk of thrombotic events, including CHD and stroke (122–124). Whether a similar phenomenon applies to exacerbation of COPD is unclear, although COPD is associated with CHD independent of smoking (125). The East London COPD study followed 93 patients with COPD for 1 year with daily diary cards (126). Over this time, 67 patients were seen during 120 exacerbations. Their mean baseline fibrinogen concentration was 3.9 g/L, a level higher than that of an age-matched healthy population of 3.1 g/L. Exacerbations were associated with significant increases in both fibrinogen and IL-6, but levels had reverted to baseline levels by 6 weeks (Figure 6). Greater rises in fibrinogen were associated with higher baseline levels, increasing age, purulent sputum, and the presence of upper respiratory tract symptoms. In a subsequent study, baseline fibrinogen was higher in carriers of respiratory syncytial virus and the rise in fibrinogen was higher in viral exacerbations than in nonviral exacerbations (127). There is debate about the importance of viral infections in COPD, but these data suggest that they may stimulate an acute phase response and, conceivably, may contribute to links between COPD and CHD events. Through chronic upregulation of inflammation and increased susceptibility to viral infections stimulating inflammatory and hemostatic responses further, the presence of COPD might amplify effects of smoking on CHD risk. Further study in this area is required.



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  		Figure 6. Plasma fibrinogen and interleukin-6 (IL-6) in patients with stable chronic obstructive pulmonary disease, at exacerbation and at convalescence. Fibrinogen expressed as mean ± SEM and IL-6 as median ± interquartile range (reprinted by permission from Reference 126).

 

   CONCLUSIONS
TOP
 ABSTRACT
 THE HEMOSTATIC SYSTEM
 HEMOSTATIC AND INFLAMMATORY...
 SPECIFIC MARKERS ASSOCIATED WITH...
 SMOKING EXPOSURE AND RISK...
 COPD AND HEMOSTATIC MARKERS
 CONCLUSIONS
REFERENCES
 
The process of atherothrombosis is complicated, with multiple cellular and humoral components interacting to produce an inflammatory and prothrombotic state, both locally and systemically. There are a number of steps in the process that are affected by smoking, perhaps more in certain genetically predisposed individuals than in others, and that potentially increase CHD risk. Study of the relationship between the amount smoked and CHD risk suggests a mechanism that is maximally stimulated at low dose, with separate mechanisms coming into play as the number of cigarettes smoked increases. In patients with COPD, the vast majority of whom have a smoking history, hemostatic and inflammatory variables may contribute to CHD risk. Viral exacerbations may conceivably increase CHD risk further through effects on prothrombotic and proinflammatory mediators, although further studies are necessary for confirmation.


   ACKNOWLEDGMENTS
 
P.K.M. received £1,380 in May 2004 for speaking at the AstraZeneca COPD Conference.

(Received in original form June 15, 2004; accepted in final form August 20, 2004)


   REFERENCES
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 ABSTRACT
 THE HEMOSTATIC SYSTEM
 HEMOSTATIC AND INFLAMMATORY...
 SPECIFIC MARKERS ASSOCIATED WITH...
 SMOKING EXPOSURE AND RISK...
 COPD AND HEMOSTATIC MARKERS
 CONCLUSIONS
 REFERENCES
 

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