Abstract
Pulmonary embolism and deep vein thrombosis both account for many deaths in stable patients with chronic obstructive pulmonary disease (COPD), and the frequency of these events is higher during COPD exacerbations. The morbidity and mortality from deep vein thrombosis and pulmonary embolism in patients with COPD is not surprising given the reduced mobility associated with this disorder, in addition to the presence of coagulation abnormalities in smokers. The potential influence of inflammation on coagulation offers further potential to contribute to thrombogenesis in all smokers. Plasma fibrinogen levels are elevated in smokers and are further elevated during acute COPD exacerbation. Oral contraceptives cause significant increases in fibrinogen levels in smokers and nonsmokers, but only the latter appear to have a compensatory increase in antithrombin III activity. Factor XIII, which stabilizes fibrin clots, is increased in smokers. Quantitative exposure to passive smoke has been positively correlated with blood coagulation activity. Exposure to nicotine may also increase plasminogen activator inhibitor-1 (a major regulator of fibrinolysis), although the extent to which nicotine enhances coagulation is unresolved. Venous thromboembolism is a frequent and potentially fatal complication of patients with COPD. The interrelationship between smoking, COPD, and coagulation is intriguing and awaits further characterization.
The link between smoking and arteriosclerosis is undeniable and, although less evidence implicates smoking directly in the pathogenesis of thrombophilic states in the less platelet-dependent venous side of the circulation, there are strong suggestions of culpability. Similarly, the causal association between smoking and the development of chronic obstructive pulmonary disease (COPD) is without question. Nevertheless, although there are clinical trial data that link both smoking and COPD to venous thromboembolism (VTE), the evidence that abnormal blood coagulation contributes directly to the pathophysiology and mortality of COPD, although intuitively compelling, is relatively scarce. The primary goal of the present review, therefore, is to outline the potential means through which smoking can contribute to a thrombophilic milieu and how the latter may play a role in the pathophysiology of COPD (Table 1)
• Increased fibrinogen levels from: Increased interleukin-6 Increased catecholamine release Free fatty acids | |
|---|---|
| • Increased clotting factor levels including factors II (thrombin), V, VIII, X, and XIII | |
| • Increased tissue factor level | |
| • Reduced tissue factor pathway inhibitor level | |
| • Increased homocysteine level | |
| • Lower antithrombin III activity | |
| • Impaired fibrinolysis Reduced tissue plasminogen activator production Impaired tissue plasminogen activator release Increased plasminogen activator inhibitor production | |
| • Increased platelet activation |
Basic research studies have implicated smoking in various abnormalities of coagulation, and inflammation is likely one such connection. The role of fibrinogen, coagulation factors, and impaired fibrinolysis, possibly involved in the pathogenesis of COPD, will be discussed at some length. Although clearly affected by smoking, platelet function and activation will not be emphasized. The emphasis of many basic and clinical studies involving smoking and various aspects of coagulation and fibrinolysis is on arteriosclerotic disease, but potential analogous implications for VTE, defined as the spectrum of deep venous thrombosis (DVT) and pulmonary embolism (PE), will also be considered.
Death occurs in approximately 8% of patients admitted for an acute exacerbation of COPD and their 1-year mortality after discharge is as high as 23% (1). DVT accounts for more than 250,000 hospitalizations annually in the United States (2), and worldwide morbidity and mortality from VTE is substantial (3). The incidence varies with the population studied, ranging from 56/100,000 to 182/100,000 (2, 4). Risk factors include cancer, advanced age, recent surgery or trauma, inherited or acquired thrombophilic states, previous thromboembolism, and hospitalization for acute medical illness such as congestive heart failure or COPD exacerbation (2, 5–8). The most serious complication of DVT is PE, which occurs in 40% of patients with DVT, and is associated with a 3-month mortality rate of 17% (3). For those who survive VTE, chronic pain and disability may result from the post-thrombotic syndrome (9).
COPD is a common comorbidity or risk factor for VTE. In a 5,451-patient DVT registry, 668 (12.3%) had COPD as a comorbid condition (8). The risk of VTE during acute exacerbations of COPD appears to be significant (10, 11). In 196 patients with COPD admitted to a respiratory intensive care unit, the DVT rate was 10.7%, but this was likely underestimated by the poor sensitivity of ultrasound for asymptomatic DVT (12). This study excluded patients with cancer, heart failure, or previous thromboembolism, suggesting that COPD itself or the resulting reduced mobility play important roles in susceptibility to DVT. Pulmonary embolism accounts for approximately 10% of deaths in stable patients with COPD on chronic oxygen therapy (13). The frequency of PE during acute COPD exacerbation has not been evaluated by large, randomized clinical trials, but it may be as high as 29% (14).
The efficacy of prophylactic therapy for VTE in COPD exacerbations has been studied (15–21). Administration of a low-molecular-weight heparin prompted a 45% reduction in the incidence of DVT in acutely decompensated patients compared with placebo in a large, prospective, randomized trial (21). Other studies have included large numbers of patients with COPD and have confirmed the efficacy of low-molecular-weight heparins in preventing VTE in this population (20). A recent review has characterized the clinical problem of VTE in patients undergoing acute exacerbation of COPD (22).
The morbidity and mortality rate from acute DVT/PE in patients with COPD is not surprising in view of the acutely reduced mobility associated with exacerbations of this disorder, in addition to the chronically reduced mobility associated with advanced disease and right ventricular failure. The presence of coagulation abnormalities associated with smoking may increase the risk further. The influence of inflammation on coagulation offers further potential for both smoking and COPD to more directly contribute to thrombogenesis, which is discussed later.
Although the presence of COPD, particularly in the setting of an exacerbation, clearly contributes to the development of VTE, it would appear that smoking can independently increase the risk of thromboembolism. In a random population sample of 855 men, all age 50 years at baseline, only waist circumference (p = 0.004) and smoking (p = 0.02) predicted a VTE event in multivariate survival analysis (4). For men who smoked 15 cigarettes or more per day, the adjusted relative risk was 2.82 (95% CI, 1.30–6.13; p = 0.009) compared with nonsmokers. Similarly, in the large, prospective Nurses' Health Study, 112,822 women age 30 to 55 years were followed from 1976 to 1992 (23). In multivariate analysis, obesity and cigarette smoking were independent predictors of PE.
Fibrinogen is an acute-phase reactant and its potential role as a risk factor for thrombosis may in part relate to its contribution to blood viscosity and, thus, a negative effect on blood rheology. As a thrombin substrate in the formation of fibrin, fibrinogen is essential for thrombus formation. Thrombin is also an important agonist in platelet aggregation, although the role of the platelet in the pathogenesis of VTE is less important than it is in arteriosclerosis.
Proof that smoking is causally related to VTE by virtue of elevated fibrinogen levels requires evidence that the latter is due to smoking and that such an elevation is of clinical significance. Of the hemostatic parameters, fibrinogen is the most consistently associated with occlusive arterial disease. Large-scale epidemiologic studies have demonstrated that an increased plasma fibrinogen concentration is an independent risk factor for a future cardiovascular event (24–26). More limited data suggest that it can also predict future mortality in survivors of myocardial infarction (27) and stroke (28).
Although fibrinogen has been proposed to have a role in venous thrombosis, the supporting data are limited. In a case–control study, a positive relationship between an plasma fibrinogen level greater than 5 g/L and thrombosis in patients who had a first, objectively confirmed episode of DVT was demonstrated (29). A subsequent study on a similar population found the increased levels of fibrinogen to be independent of an acute-phase response (30). In a third study, high levels of fibrinogen were associated with risk of DVT, but primarily in the elderly (31). Fibrinogen was not statistically significantly associated with VTE in two other studies (32, 33); one of these was in patients with mutation of factor V Leiden, the most common known inherited cause of thrombophilia (33).
Increases in plasma fibrinogen have been reported in COPD exacerbations. Wedzicha and colleagues (34) studied 67 patients with COPD who suffered exacerbations and evaluated their fibrinogen levels. The increase compared with baseline was significant (p = 0.001), and the greater increased levels of fibrinogen were associated with purulent sputum, increased cough, a higher baseline fibrinogen, and age. This correlation is not surprising, but the statistical significance does not verify that the demonstrated increase of 0.36 g/L is clinically significant. Of interest, however, is that plasma levels of fibrinogen increased further with exacerbations in association with raised interleukin (IL)-6 levels (34). In view of the procoagulant effect of IL-6, this association could be an important link to VTE.
Although it seems possible that elevated levels of fibrinogen may contribute to an increased rate of VTE, the nature of the relationship between smoking and elevated fibrinogen levels appears much clearer. Indeed, it would appear that cigarette smoking is the strongest known environmental influence on plasma fibrinogen concentration and has consistently been linked to elevated plasma fibrinogen levels (35–40). A dose–effect relationship between the number of cigarettes smoked per day and plasma fibrinogen concentration has been reported (24, 25). Conversely, cessation from smoking results in a rapid reduction in plasma fibrinogen (41, 42). However, fibrinogen levels in a given individual are influenced by a number of factors, increasing with age (43, 44), cancer (45), stress (46), and oral contraception (47, 48). In a manner similar to other acute-phase reactants, fibrinogen levels may be elevated in response to a variety of disease processes but are not a specific marker of thrombosis.
Most of the data available support the correlation between smoking and elevated fibrinogen levels. Two studies, however, suggested that the relationship between smoking and elevated fibrinogen levels occurs only in men (49, 50); another did not find a relationship, but only studied women (46). In Eliasson's study (50), the difference between female smokers and nonsmokers was not significant, although females who actively smoked did have significantly higher fibrinogen levels than ex-smokers. Fruzzetti and colleagues (48) determined that among women using oral contraceptives containing 20–35 μg ethinyl estradiol, there was a significant increase in levels of fibrinogen and fibrinopeptide A in both smokers and nonsmokers. However, unlike nonsmokers, women who smoke did not have a compensatory increase in antithrombin III activity, leaving the procoagulant effects of the oral contraceptives unopposed.
Although substantial work has focused on the relationship between smoking and fibrinogen, the mechanism by which smoking increases the plasma fibrinogen concentration is not clear. Plasma fibrinogen concentrations are the result of both the rates of synthesis and removal of fibrinogen. Hunter and colleagues (51) used stable isotope methodology to perform investigations on the influence of cigarette smoking on fibrinogen synthesis in vivo in human subjects. These studies suggest a primary role for increased synthesis of fibrinogen producing the elevated levels associated with smoking. Abstention from smoking for a period of only 2 weeks induced a significant decrease in the rate of fibrinogen synthesis by the liver, with a concomitant reduction in the plasma fibrinogen concentration (51). The latter decrease is consistent with previous findings (36, 41, 42). Humphries and associates also attributed the rise in the plasma concentration of fibrinogen during the persisting inflammatory insult imparted by chronic smoking to a stimulation of transcriptional activity (52).
Increased plasma fibrinogen may have a role in increasing the risk of arterial or venous thrombosis by virtue of reflecting a vascular endothelial inflammatory state. There are several possible mediators that may be responsible for the difference in the absolute rate of fibrinogen synthesis of smokers and nonsmokers, and in the reduction in fibrinogen synthesis that occurs with abstention from smoking. It has been suggested that the mild, but sustained, acute-phase response exhibited by chronic smokers is characterized by increased plasma concentrations of positive acute-phase proteins that include fibrinogen but also α1-antitrypsin (53). An inflamed vascular wall may increase the production of cytokines including IL-6, IL-1β, and tumor necrosis factor-α, which play major regulatory roles in the hepatic synthesis of acute phase proteins, including fibrinogen (54). IL-6 appears to be the principal procoagulant cytokine in humans (55) and its plasma concentration is elevated in smokers (54). Thus, it is feasible that IL-6 may, at least in part, be responsible for this enhanced rate of fibrinogen synthesis in smokers. Finally, smoking has also been reported to increase the level of C-reactive protein (56). It not surprising that this acute-phase reactant, which is produced in response to IL-6, is able to increase the expression of tissue factor on monocytes (57). Tissue factor is the key to initiation of coagulation in vivo and, thus, to thrombosis.
Catecholamines may contribute to thrombosis formation. Smoking has been shown to stimulate catecholamine release (58), and epinephrine may increase hepatic fibrinogen synthesis directly (59), possibly by enhancing mRNA synthesis (60). No clear evidence has implicated exogenous catecholamine administration to increased synthesis of fibrinogen, however. Indirect evidence suggests that fatty acids could play a role in increasing fibrinogen synthesis in smokers (61, 62). This activity may be facilitated by thrombin, because injection of thrombin into mice has been shown to result in increased nonesterified fatty acid concentrations, and the effectiveness of saturated free fatty acids in stimulating fibrinogen synthesis has been demonstrated in animal models (63).
Although possible modulating roles of smoking on the activity of several factors important in the coagulation cascade have been explored, such a relationship cannot be characterized clearly. Elwakkad and colleagues (64) examined passive smoking in patients with asthma and reported potentially important effects on blood coagulation, with significant elevations in several plasma factors and increased platelet aggregation and fibrinolysis. This is discussed in more detail under Passive Smoking. Although Dotevall (38) found that plasma fibrinogen levels were significantly higher among smokers, plasma factor VIII:C activity did not differ when compared with nonsmokers. Interestingly, Benowitz and associates (65) found that factor VII coagulant activity was significantly lower during cigarette smoking than during either nicotine or placebo patch conditions.
Tissue factor levels may be affected by cigarette smoke. Sambola's group (66) demonstrated that 2 hours after smoking two cigarettes, tissue factor was increased (217 ± 72 versus 283 ± 106 pmol/L per minute factor Xa [FXa], p = 0.003) suggesting another potential connection between smoking and venous thrombosis. Barua (67) determined that levels of the endogenous anticoagulant, tissue factor pathway inhibitor-1 in a cultured cell supernatant was significantly lower in smokers compared with the nonsmoking group (p < 0.05) with no difference in the tissue factor level between both groups (p = 0.5). Basal tissue factor pathway inhibitor-1 in culture correlated negatively with serum cotinine level (r = −0.6, p = 0.01). A distinct relationship between smoking and tissue factor activity requires more study, but a potential relationship is intriguing and merits further evaluation. Thrombin generation also appears to be induced by smoking (68).
Factor XIII covalently cross-links and stabilizes fibrin clots. The relationship of factor XIII to age, sex, smoking, and hypertension has been investigated. Plasma levels of factor XIII A-subunit antigen, the B-subunit antigen, and factor XIII cross-linking activity were measured in 612 healthy individuals (69). In smokers, factor XIII A-subunit levels were significantly increased (117.0% versus 104.6%, p < 0.0005). In a multiple regression model, the A-subunit was significantly increased by female sex (+6.4%, p < 0.007), smoking (+12.3%, p < 0.0005), and increasing age (+3.7% per 10 years, p < 0.0005). It was concluded that the factor XIII A-subunit level increases significantly with female sex, age, and smoking, whereas the B-subunit and factor XIII activity were associated with factor XIII A-subunit levels and fibrinogen. When 75 nonsmoking and 118 smoking pregnant women were compared, it was determined that the smokers had higher fibrinogen levels (70). Although the factor XIII levels declined during normal gestation, there was a later decline in the women who smoked. These findings suggest indirectly the possibility that smoking may contribute to thrombus formation in the crucial step of cross-linking of the fibrin clot.
Effective fibrinolysis requires rapid release of tissue plasminogen activator (tPA) from the vascular endothelium. It is feasible that endothelial dysfunction and abnormalities in fibrinolysis caused by smoking could lead to ill effects on the venous side. Newby and colleagues (71) demonstrated reduced endothelial release of tPA after inhibition of nitric oxide synthase. These authors hypothesized that smoking might adversely affect endogenous fibrinolysis by impairing the ability of the endothelium to release tPA acutely. A comparison of substance P–induced tPA release from the forearm vascular bed of smokers and age- and sex-matched nonsmokers revealed that, despite higher basal plasma tPA antigen concentrations, cigarette smokers had a markedly impaired capacity of the endothelium to release tPA acutely (72). This suggests an important mechanism whereby cigarette smoking could lead to both arterial and venous thrombosis. Fruzzetti's work in patients on oral contraceptives determined that, although increased tissue plasminogen activity and a nonsignificant decrease in plasminogen activity inhibitor (PAI) were present in nonsmokers, the smokers had a trend toward higher levels of PAI (48).
Meade and colleagues (73) sought to determine the extent to which the hemostatic system is implicated in the onset of clinically manifest ischemic heart disease. Characteristics influencing fibrinolytic activity and plasma fibrinogen concentrations were examined in 1,601 men ages 18–64 and 707 women ages 18–59 in several occupational groups in Northwest London. In summary, fibrinolytic activity was significantly less in smokers than in nonsmokers, though the effect was not large.
Barua and associates (67) also researched fibrinolytic parameters as they relate to smoking. Cells incubated with smokers' serum showed lower basal (p < 0.02) and substance P–stimulated (p = 0.059) tPA production but similar basal and stimulated PAI-1 production (p = 0.9 and p = 0.6) compared with nonsmokers. The basal tPA/PAI-1 molar ratio was significantly reduced in smokers (p < 0.005), again suggesting a potential propensity toward thrombosis. Not all studies have suggested such a relationship, however; Eliasson and coworkers (50) found that despite the correlation between smoking and fibrinogen, there was no relationship between tPA activity, PAI-1 activity, and tobacco use. Different experimental models, doses of cigarette smoke/nicotine, and study timing likely account for differing results.
Because smoking both increases the risk of stroke and appears to reduce the risk of thrombolysis-associated intracerebral hemorrhage, Zidovetzki and coworkers (74) studied the effect of nicotine, an important constituent of cigarette smoke, on PAI-1 production by human brain endothelial cells. Nicotine had no effect on the concentration of tPA, but did increase brain endothelial cell PAI-1 mRNA expression and protein production via a protein kinase C–dependent pathway. Again, although the focus of this research was cerebrovascular disease, the potential implications for VTE cannot be ignored.
Elevated levels of cross-linked products reflect an incipient or ongoing thrombotic process. Plasmin cleaves polymerized fibrin and fibrinogen at multiple sites, releasing fibrin and fibrinogen degradation products including d-dimer, the levels of which, therefore, provide a measure of fibrinolytic activity in the blood. Abnormal d-dimer levels are found in patients with VTE. Lee and associates (75) determined that current cigarette smokers had higher d-dimer levels than ex-smokers, who, in turn, had higher levels than those who had never smoked. On multiple regression analyses with age and plasma fibrinogen as covariates, only lifetime smoking in men and systolic blood pressure in women were independent predictors of fibrin d-dimer levels.
From a database of 4,187 current smokers, 4,791 former smokers, and 8,375 never-smokers 18 years of age or older who participated in the Third National Health and Nutrition Examination Survey conducted between 1988 and 1994, Bazzano and coworkers (76) determined that after adjustment for traditional cardiovascular disease risk factors, cigarette smoking was associated with elevated levels of C-reactive protein, fibrinogen, and homocysteine. Compared with never smoking cigarettes, self-reported current cigarette smoking was associated with elevated homocysteine levels (odds ratio, 2.10 [CI, 1.62–2.74]; p < 0.001). There were positive and significant dose–response relationships between measures of cigarette smoking (cigarettes per day, pack-years, and serum cotinine levels) and elevated levels of novel risk factors.
To examine the effect of passive smoking on plasma fibrinogen, a cross-sectional study (controlling for age, body mass index, ethanol intake, serum total cholesterol, diabetes mellitus, and menopausal status) was conducted between 1990 and 1993 in 1,780 Japanese women ages 45 to 74 years (77). Fibrinogen concentrations were 8.6 (95% confidence interval 1.6–15.6) mg/dl higher in women exposed passively to smoking outside the home (n = 435) and 11.2 (95% confidence interval 3.0–19.3) mg/dl higher in women exposed both in and outside the home (n = 272) than in women unexposed in either location (n = 524). These effects of passive smoking were about 40 to 60% of that of current active smoking. The effect of passive smoking at home only was not statistically significant. This association between fibrinogen and passive smoking was primarily observed in women ages 45 to 59 years but not in those ages 60 to 74 years (77).
As noted earlier, Elwaakad and colleagues (64) have evaluated the effects of passive smoking on plasma factors important in blood coagulation, platelet aggregation, and fibrinolysis (antithrombin III, α1-antitrypsin, α2-macroglobulin) in children with asthma. In this study, 46 asthmatic and nonasthmatic children were divided into groups based on their history of exposure to tobacco smoke (passive smoker, asthmatic; asthmatic; passive smoker, control; and control). Exposure to tobacco smoke was determined quantitatively by the urinary cotinine levels; a positive correlation between passive smoking and blood coagulation, and particularly with increased activity of factor X (r = 0.49, p < 0.05) was reported. The combined effects of asthma and passive smoking induced even more potentially important effects on blood coagulation (factors II, V, and X, p < 0.01; factor VIII, p < 0.001), platelet aggregation (p < 0.001), and fibrinolysis (antithrombin III, p < 0.001 and α1-antitrypsin, p <0.05) compared with the normal subjects. These findings suggest that the risk of clinical thrombosis might also be increased because of passive smoking. Although passive smoking might contribute to elevated fibrinogen levels, evidence does not link passive smoking to venous thrombosis, although it has not been studied in an adequately powered clinical trial. Further investigation is necessary. Quantitative exposure to passive smoke has been correlated positively with blood coagulation activity, particularly factor X activity (78).
Available data indicate that neither oral nor transdermal nicotine increase fibrinogen levels (79, 80). Benowitz and associates (65) conducted a crossover study comparing the effects of cigarette smoking, transdermal nicotine, and placebo transdermal nicotine, each for 5 days, in 12 healthy smokers. They found that although smoking was associated with higher levels of fibrinogen in plasma, nicotine itself did not appear to be responsible for the platelet activation or elevation of plasma fibrinogen seen in smokers. Similarly, the use of smokeless tobacco, such as moist oral snuff, does not appear to affect fibrinogen levels (50). Singh (80) found that nicotine did not alter the clot-forming properties of thrombin on fibrinogen. These data suggest that nicotine, at least alone, is not a cause for the rise in fibrinogen associated with smoking.
Other data suggest a potential role for nicotine. A small study suggested that platelet-dependent thrombin levels were enhanced in smokers, even when not smoking, when compared with nonsmokers, and that the increase occurred immediately after smoking (81). When nicotine or cotinine was added to platelet-rich plasma obtained from nonsmoking volunteers, levels of platelet-dependent thrombin increased significantly (p < 0.002), suggesting that the effect of smoking may be related to the ingestion of nicotine, rather than to other toxic components of cigarette smoke or to certain physiologic responses. It is feasible that increases in plasma nicotine and cotinine levels from smoking may be important in the pathophysiology of increased platelet-dependent thrombin generation.
Both clinical and basic research have linked smoking and COPD to abnormalities of coagulation and fibrinolysis and to VTE. Several potential mechanisms involving inflammation, fibrinogen synthesis, clotting factors, and impaired fibrinolysis are suggested as possible links. The emphasis of research involving smoking and various aspects of coagulation and fibrinolysis has tended to focus on the potential impact on arteriosclerosis and less on VTE. Nonetheless, the parallels to VTE must be taken into consideration. Conflicting data exist with regard to smoking and certain aspects of coagulation. The differences in study results likely depend on research methodology and suggest that additional data should be acquired.
In light of existing basic, clinical, and epidemiologic research regarding the role of tobacco smoking in the pathogenesis of VTE, investigators should incorporate quantitative data on smoking status and exposure of nonsmokers to environmental tobacco smoke in studies of risk factors for VTE. Results of such research may affect the morbidity and mortality of the disease, as well as offering further support for even more extensive antismoking campaigns. VTE is a frequent and potentially fatal complication of patients with COPD. The interrelation between smoking/COPD and coagulation is intriguing and awaits further characterization.
V.F.T. received $2,000 from Aventis for consulting and $5,000 from Advisory Boards in 2004 and received $2,000 from AstraZeneca for consulting and $3,500 from Advisory Boards in 2004 and received $8,000 from Aventis for lecture fees between 2003 and 2004 and $4,000 from AstraZeneca in 2004 and has done research with Aventis and received $10,000 from Aventis for research support between 2003 and 2004.
| 1. | Groenewegen KH, Schols AMWJ, Wouters EFM. Mortality and mortality-related factors after hospitalization for acute exacerbation of COPD. Chest 2003;124:459–467. |
| 2. | Anderson FA Jr, Wheeler HB, Goldberg RJ, Hosmer DW, Patwardhan NA, Jovanovic B, Forcier A, Dalen JE. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991;151:933–938. |
| 3. | Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999;353:1386–1389. |
| 4. | Hansson PO, Eriksson H, Welin L, Svardsudd K, Wilhelmsen L. Smoking and abdominal obesity: risk factors for venous thromboembolism among middle-aged men: the Study of Men Born in 1913. Arch Intern Med 1999;159:1886–1890. |
| 5. | Piccioli A, Prandoni P, Goldhaber SZ. Epidemiologic characteristics, management, and outcome of deep venous thrombosis in a tertiary-care hospital: the Brigham and Women's Hospital DVT registry. Am Heart J 1996;132:1010–1014. |
| 6. | Heit JA, Melton LJ III, Lohse CM, Petterson TM, Silverstein MD, Mohr DN, O'Fallon WM. Incidence of venous thromboembolism in hospitalized patients vs community residents. Mayo Clin Proc 2001;76:1102–1110. |
| 7. | Levitan N, Dowlati A, Remick SC, Tahsildar HI, Sivinski LD, Beyth R, Rimm AA. Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy: risk analysis using Medicare claims data. Medicine (Baltimore) 1999;78:285–291. |
| 8. | Goldhaber SZ, Tapson VF. A prospective registry of 5,451 patients with ultrasound-confirmed deep vein thrombosis. Am J Cardiol 2004;93:259–262. |
| 9. | Kahn SR, Hirsch A, Shrier I. Effect of postthrombotic syndrome on health-related quality of life after deep venous thrombosis. Arch Intern Med 2002;162:1144–1148. |
| 10. | Prescott SM, Richards KL, Tikoff G, Armstrong JD, Shigeoka JW. Venous thromboembolism in decompensated chronic obstructive pulmonary disease: a prospective study. Am Rev Respir Dis 1981;123:32–36. |
| 11. | Winter JH, Buckler PW, Bautista AP, Smith FW, Sharp PF, Bennett B. Frequency of venous thrombosis in patients with an exacerbation of chronic obstructive lung disease. Thorax 1983;38:605–608. |
| 12. | Zielinsky J, MacNee J, Wedzicha J. Causes of death in patients with COPD and chronic respiratory failure. Monaldi Arch Chest Dis 1997;52:43–47. |
| 13. | Mispelaere D, Glerant JC, Audebert M, Remond A, Sevestre-Pietri MA, Jounieaux V. Pulmonary embolism and sibilant types of chronic obstructive pulmonary disease decompensations. Rev Mal Respir 2002;19:415–423. |
| 14. | Schonhofer B, Kohler D. Prevalence of deep-vein thrombosis of the leg in patients with acute exacerbation of chronic obstructive pulmonary disease. Respiration 1998;65:173–177. |
| 15. | Dahan R, Houlbert D, Caulin C, Cuzin E. Prevention of deep vein thrombosis in elderly medical in-patients by a low molecular weight heparin: a randomized double-blind trial. Haemostasis 1986;16:159–164. |
| 16. | Bergmann JF, Caulin C. Heparin prophylaxis in bedridden patients. Lancet 1996;348:205–206. |
| 17. | Gardlund B. Randomised, controlled trial of low-dose heparin for prevention of fatal pulmonary embolism in patients with infectious disease. Lancet 1996;347:1357–1361. |
| 18. | Lechler E, Schramm W, Flosbach CW. The venous thrombotic risk in non-surgical patients: epidemiological data and efficacy/safety profile of a low-molecular-weight heparin (enoxaparin): the Prime Study Group. Haemostasis 1996;26(Suppl 2):49–56. |
| 19. | Harenberg J, Roebruck P, Heene DL. Subcutaneous low-molecular-weight heparin versus standard heparin and the prevention of thromboembolism in medical inpatients. Haemostasis 1996;26:127–139. |
| 20. | Samama MM, Cohen AT, Darmon JY, Desjardins L, Eldor A, Janbon C, Leizorovicz A, Nguyen H, Olsson CG, Turpie AG, et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients: Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med 1999;341:793–800. |
| 21. | Fraisse F, Holzapfel L, Couland JM, Simonneau G, Bedock B, Feissel M, Herbecq P, Pordes R, Poussel JF, Roux L. Nadroparin in the prevention of deep vein thrombosis in acute decompensated COPD. Am J Respir Crit Care Med 2000;161:1109–1114. |
| 22. | Ambrosetti M, Ageno W, Spanovello A, Salerno M, Pedretti RFE. Prevalence and prevention of venous thromboembolism in patients with acute exacerbations of COPD. Thromb Res 2003;112:203–207. |
| 23. | Goldhaber SZ, Grodstein F, Stampfer MJ, Manson JE, Colditz GA, Speizer FE, Willett WC, Hennekens CH. A prospective study of risk factors for pulmonary embolism in women. JAMA 1997;277:642–645. |
| 24. | Heinrich J, Balleisen L, Schulte H, Assmann G, van de Loo J. Fibrinogen and factor VII in the prediction of coronary risk: results of the PROCAM study in healthy men. Arterioscler Thromb 1994;14:54–59. |
| 25. | Stone MC. Thorpe J M. Plasma fibrinogen—a major coronary risk factor. J R Coll Gen Pract 1985;35:565–569. |
| 26. | Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti RR, North WR, Haines AP, Stirling Y, Imeson JD, Thompson SG. Haemostatic function and ischemic heart disease: principal results of the Northwick Park Heart Study. Lancet 1986;328:533–537. |
| 27. | Cooper J, Douglas AS. Fibrinogen level as a predictor of mortality in survivors of myocardial infarction. Fibrinolysis 1991;5:105–108. |
| 28. | Resch KL, Ernst E, Matai A, Paulsen HF. Fibrinogen and viscosity as risk factors for subsequent cardiovascular events in stroke survivors. Ann Intern Med 1992;117:371–375. |
| 29. | Koster T, Rosendaal FR, Reitsma PH, van der Velden PA, Briet E, Vandenbroucke JP. Factor VII and fibrinogen levels as risk factors for venous thrombosis: a case-control study of plasma levels and DNA polymorphisms: the Leiden Thrombophilia Study (LETS). Thromb Haemost 1994;71:719–722. |
| 30. | Kamphuisen PW, Eikenboom JC, Vos HL, Pablo R, Sturk A, Bertina RM, Rosendaal FR. Increased levels of factor VIII and fibrinogen in patients with venous thrombosis are not caused by acute phase reactions. Thromb Haemost 1999;81:680–683. |
| 31. | van Hylckama Vlieg A, Rosendaal FR. High levels of fibrinogen are associated with the risk of deep venous thrombosis mainly in the elderly. J Thromb Haemost 2003;1:2677–2678. |
| 32. | Austin H, Hooper WC, Lally C, Dilley A, Ellingsen D, Wideman C, Wenger NK, Rawlins P, Silva V, Evatt B. Venous thrombosis in relation to fibrinogen and factor VII genes among African-Americans. J Clin Epidemiol 2000;53:997–1001. |
| 33. | Billon S, Escoffre-Barbe M, Mercier B, Abgrall JF, Ferec C. Fibrinogen is not an additional risk factor of thromboembolic disease in factor V Leiden patients. Thromb Haemost 1999;81:659–660. |
| 34. | Wedzicha JA, Seemungal TA, MacCallum PK, Paul EA, Donaldson GC, Bhowmik A, Jeffries DJ, Meade TW. Acute exacerbations of chronic obstructive pulmonary disease are accompanied by elevations of plasma fibrinogen and serum IL-6 levels. Thromb Haemost 2000;84:210–215. |
| 35. | Ernst E. The role of fibrinogen as a cardiovascular risk factor. Atherosclerosis 1993;100:1–12. |
| 36. | Kannel WB, D'Agostino RB, Belanger AJ. Fibrinogen, cigarette smoking, and risk of cardiovascular disease: insights from the Framingham Study. Am Heart J 1987;113:1006–1010. |
| 37. | Ernst E, Matrai A, Schmolzl CH, Magyarosy I. Dose-effect relationship between smoking and blood rheology. Br J Haematol 1987;65:485–487. |
| 38. | Dotevall A, Kutti J, Teger-Nilsson AC, Wadenvik H, Wilhelmsen L. Platelet reactivity, fibrinogen and smoking. Eur J Haematol 1987;38:55–59. |
| 39. | Tuut M, Hense HW. Smoking, other risk factors and fibrinogen levels: evidence of effect modification. Ann Epidemiol 2001;11:232–238. |
| 40. | Cigolini M, Targher G, de Sandre G, Muggeo M, Seidell JC. Plasma fibrinogen in relation to serum insulin, smoking habits and adipose tissue fatty acids in healthy men. Eur J Clin Invest 1994;24:126–130. |
| 41. | Rothwell M, Rampling MW, Cholerton S, Sever PS. Haemorheological changes in the short term after abstention from tobacco by cigarette smokers. Br J Haematol 1991;79:500–503. |
| 42. | Feher MD, Rampling MW, Brown J, Robinson R, Richmond W, Cholerton S, Bain BJ, Sever PS. Acute changes in atherogenic and thrombogenic factors with cessation from smoking. J R Soc Med 1990;83:146–148. |
| 43. | Nascetti S, Elosua R, Pena A, Covas MI, Senti M, Marrugat J. Variables associated with fibrinogen in a population-based study: interaction between smoking and age on fibrinogen concentration. Eur J Epidemiol 2001;17:953–958. |
| 44. | Balleisen L, Bailey J, Epping PH, Schulte H, van de Loo J. Epidemiological study on factor VII, factor VIII and fibrinogen in an industrial population: I. Baseline data on the relation to age, gender, body-weight, smoking, alcohol, pill-using, and menopause. Thromb Haemost 1985;54:475–479. |
| 45. | Blann AD, Gurney D, Wadley M, Bareford D, Stonelake P, Lip GY. Increased soluble P-selectin in patients with haematological and breast cancer: a comparison with fibrinogen, plasminogen activator inhibitor and von Willebrand factor. Blood Coagul Fibrinolysis 2001;12:43–50. |
| 46. | Davis MC. Oral contraceptive use and hemodynamic, lipid, and fibrinogen responses to smoking and stress in women. Health Psychol 1999;18:122–130. |
| 47. | Famodu AA, Ehigiegba AE, Fakoya TA, Adeyi J, Diejomach FM. Effects of oral contraceptive on fibrinogen levels in African women. Haematologia (Budap) 1991;24:135–138. |
| 48. | Fruzzetti F, Ricci C, Fioretti P. Hemostasis profile in smoking and nonsmoking women taking low-dose oral contraceptives. Contraception 1994;49:579–592. |
| 49. | Mennen LI, Balkau B, Charles MA, D'Hour A, le Mauff JM. Gender differences in the relation between fibrinogen, tissue-type plasminogen activator antigen and markers of insulin resistance: effects of smoking: DESIR Study Group. Thromb Haemost 1999;82:1106–1111. |
| 50. | Eliasson M, Asplund K, Evrin PE, Lundblad D. Relationship of cigarette smoking and snuff dipping to plasma fibrinogen, fibrinolytic variables and serum insulin: the Northern Sweden MONICA Study. Atherosclerosis 1995;113:41–53. |
| 51. | Hunter KA, Garlick PJ, Broom I, Anderson SE, McNurlan M. Effects of smoking and abstention from smoking on fibrinogen synthesis in humans. Clin Sci 2001;100:459–465. |
| 52. | Humphries SE, Luong L, Montgomery HE, Day INM, Mohamed-Ali V, Yudkin JS. Gene-environment interaction in the determination of levels of plasma fibrinogen. Thromb Haemost 1999;82:818–825. |
| 53. | Chao FC, Tullis JL, Alper CA, Glynn RJ, Silbert JE. Alteration in plasma proteins and platelet functions with aging and cigarette smoking in healthy men. Thromb Haemost 1982;47:259–264. |
| 54. | Mendall MA, Patel P, Asante MA, Ballam L, Morris J, Strachan DP, Camm AJ, Northfield TC. Relation of serum cytokine concentrations to cardiovascular risk factors and coronary heart disease. Heart 1997;78:273–277. |
| 55. | Stouthard JML, Levi M, Hack CE, Veenhof CHN, Romijn HA, Sauerwein HP. Interleukin-6 stimulates coagulation, not fibrinolysis, in humans. Thromb Haemost 1996;76:738–742. |
| 56. | Das I. Raised C-reactive protein levels in serum from smokers. Clin Chim Acta 1985;153:9–13. |
| 57. | Cermak J, Key NS, Bach RR, Balla J, Jacob HS, Vercellotti GM. C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor. Blood 1993;82:513–520. |
| 58. | Cryer PE, Haymond MW, Santiago JV, Shah SD. Norepinephrine and epinephrine release and adrenergic mediation of smoking-associated hemodynamic and metabolic events. N Engl J Med 1976;295:573–577. |
| 59. | Griffin EE, Miller LL. Effects of hypophysectomy of liver donor on net synthesis of specific plasma proteins by the isolated perfused rat liver. J Biol Chem 1974;249:5062–5069. |
| 60. | Roy AK, Sarker J, Bhadra R, Datta AG. Effect of amines on fibrinogen synthesis. Arch Biochem Biophys 1985;239:364–367. |
| 61. | Pilgeram LO, Pickart LR. Control of fibrinogen biosynthesis: the role of free fatty acid. J Atheroscler Res 1968;8:155–166. |
| 62. | Kershbaum A, Bellet B. Cigarette smoking and blood lipids. JAMA 1964;187:32–36. |
| 63. | Pickart LR, Thaler MM. Free fatty acids and albumin as mediators of thrombin-mediated fibrinogen synthesis. Am J Physiol 1976;230:996–1002. |
| 64. | Elwakkad AS, Abouelsoud NH, Elabaid NM, Shrief LS. Blood coagulation and platelet aggregation in asthmatic children exposed to passive smoking [abstract]. J Allergy Clin Immunol 2001;107:S21. |
| 65. | Benowitz NL, Fitzgerald GA, Wilson M, Zhang Q. Nicotine effects on eicosanoid formation and hemostatic function: comparison of transdermal nicotine and cigarette smoking. J Am Coll Cardiol 1993;22:1159–1167. |
| 66. | Sambola A, Osende J, Hathcock J, Degen M, Nemerson Y, Fuster V, Crandall J, Badimon JJ. Role of risk factors in the modulation of tissue factor activity and blood thrombogenicity. Circulation 2003;107:973–977. |
| 67. | Barua RS, Ambrose JA, Saha DC, Eales-Reynolds L. Smoking is associated with altered endothelial-derived fibrinolytic and antithrombotic factors. Circulation 2002;106:905–908. |
| 68. | Kimura S, Nishinaga M, Ozawa T, Shimada K. Thrombin generation as an acute effect of cigarette smoking. Am Heart J 1994;128:7–11. |
| 69. | Ariens RAS, Kohler HP, Mansfield MW, Grant PJ. Subunit antigen and activity levels of blood coagulation factor XIII in healthy individuals: relation to sex, age, smoking, and hypertension. Arterioscler Thromb Vasc Biol 1999;19:2012–2016. |
| 70. | van Wersch JW, Vooijs ME, Ubachs JM. Coagulation factor XIII in pregnant smokers and non-smokers. Int J Clin Lab Res 1997;27:68–71. |
| 71. | Newby DE, Wright RA, Dawson P, Ludlam CA, Boon NA, Fox KA, Webb DJ. The L-arginine:nitric oxide pathway contributes to the acute release of tissue plasminogen activator in vivo in man. Cardiovasc Res 1998;38:485–492. |
| 72. | Newby DE, Wright RA, Labinjoh DE, Ludlam CA, Fox KA, Boon NA, Webb DJ. Endothelial dysfunction, impaired endogenous fibrinolysis, and cigarette smoking: a mechanism for arterial thrombosis and myocardial infarction. Circulation 1999;99:1411–1415. |
| 73. | Meade TW, Chakrabarti R, Haines AP, North WRS, Stirling Y. Characteristics affecting fibrinolytic activity and plasma fibrinogen concentrations. Br Med J 1979;1:153–156. |
| 74. | Zidovetzki R, Chen P, Fisher M, Hofman FM. Nicotine increases plasminogen activator inhibitor-1 production by human brain endothelial cells via protein kinase C-associated pathway. Stroke 1999;30:651–655. |
| 75. | Lee AJ, Fowkes FGR, Lowe GDO, Rumley A. Determinants of fibrin D-dimer in the Edinburgh Artery Study. Arterioscler Thromb Vasc Biol 1995;15:1094–1097. |
| 76. | Bazzano LA, He J, Muntner P, Vupputuri S, Whelton PK. Relationship between cigarette smoking and novel risk factors for cardiovascular disease in the United States. Ann Intern Med 2003;138:891–897. |
| 77. | Iso H, Shimamoto T, Sato S, Koike K, Iida M, Komachi Y. Passive smoking and plasma fibrinogen concentrations. Am J Epidemiol 1996;144:1151–1154. |
| 78. | Thomas AE, Green FR, Humphries SE. Association of genetic variation at the beta-fibrinogen gene locus and plasma fibrinogen levels; interaction between allele frequency of the G/A-455 polymorphism, age and smoking. Clin Genet 1996;50:184–190. |
| 79. | Blann AD, Steele C, McCollum CN. The influence of smoking and of oral and transdermal nicotine on blood pressure, and haematology and coagulation indices. Thromb Haemost 1997;78:1093–1096. |
| 80. | Singh JM, Singh MD. Alkaloids of tobacco and blood coagulation: effect of nicotine on thrombin and fibrinogen. Clin Toxicol 1975;8:43–52. |
| 81. | Hioki H, Aoki N, Kawano K, Homori M, Hasumura Y, Yasumura T, Maki A, Yoshino H, Yanagisawa A, Ishikawa K. Acute effects of cigarette smoking on platelet-dependent thrombin generation. Eur Heart J 2001;22:56–61. |