Smoking is a serious health problem and most important avoidable causes of death in the world. Smoking is the major risk factor for cardiovascular system for developing atherosclerosis which is also associated for the development thromboembolism. Smoking is one of six major modifiable risk factors for cardiac vascular disease and is the leading cause of death.1 According to the results of recent studies, venous thromboembolism (VTE) can also result from smoking.2 VTE results from a combination of hereditary and acquired risk factors, or hypercoagulable states associated with smoking. It is a common, lethal disorder that affects hospitalized and non hospitalized patients, recurs frequently, is often overlooked, and results in long-term complications including chronic thromboembolic pulmonary hypertension and the post-thrombotic syndrome. Regular smoking has been associated with VTE in different studies.
VASCULAR DAMAGE CAUSED BY SMOKING
Smoke causes toxic chemicals from tobacco to enter the bloodstream and cause blood vessels to constrict and it stimulates the release of catecholamine forcing blood to travel through a smaller space and results in vessel damage and formation of a clot and development of thrombosis.3 Smoking increases cholesterol levels in the blood while lowering the proportion of HDL “good” cholesterol. High build-up of cholesterol leads to fatty plaque deposition in the vessel wall leading to an increased clot and damage to the vessel wall.2,3 Smoking causes morphological changes in the vessel wall causing increased vascular inflammatory mediators. Smoking causes increased levels of the inflammatory cytokine interleukin-6 (IL-6), produced by macrophages in the bronchial epithelium, and damage to the pulmonary vascular wall and further production of C-reactive protein (CRP) that leads to further damage.4 It is known that cigarette smoke results in oxidative stress, an imbalance between oxidants and antioxidants in favor of oxidants, and that it activates the vascular endothelium resulting in damage of the vessel wall.5 Smoking increases vascular reactive oxygen species and metalloproteinase that lead to further lung parenchyma destruction.6 It eventually stimulates inflammatory cell recruitment into the lung parenchyma, leading to release of electrolytic proteases that destroy lung extracellular matrix and result in ischemia damage to the vessel wall that leads to complications like thromboembolism and commonly to pulmonary embolism. Women who smoke and use oral contraceptives are at a much higher risk of developing heart disease and vessel damage. Smoking increases the risk, and act synergistically with oral contraceptives, to develop VTE.7-10 In a large population-based case-control study,9 the Multiple Environmental and Genetic Assessment (MEGA) study, the relative risk of VTE was 1.42 (95% CI 1.28-1.58) in current smokers and 1.23 (95% CI 1.10-1.37) in past smokers, compared to the risk in individuals who had never smoked.
A review of endothelial function and dysfunction identified several aspects of vascular damage caused by smoking. It decreased coronary blood flow and myocardial oxygen delivery. It has adverse effects on lipids, blood pressure, and insulin resistance and decreased activity of endothelial nitrous oxide (NO) systems.9,11 Endothelial damage can lead to a reduced capacity for dilation and increased vessel contraction, prothrombotic and pro-inflammatory states, and cell proliferation in the arterial wall1,3,12,13 and also damage the vascular wall or pulmonary vascular due to the influence of inflammatory mediators.3-5 Smoking is associated with the appearance of high-risk vulnerable plaques, such as non-calcified plaques (NCPs), in vessels with a preserved lumen and their fracture or rupture can often trigger an acute fatal thrombus. Smoking activates platelets, increasing the risk of thrombus formation and venous embolism and causes damage to the lining of the arteries, facilitating the development of atherosclerosis.13,14 In both active and passive smokers, the production of endothelial NO, which mediates endothelium-dependent vasodilatation in response to hemodynamic changes, is reduced. Passive smoking is associated with dose-related impairment of endothelium-dependent dilatation in healthy young adults, suggesting early arterial damage.15,16 In addition to the role of smoking in cancer initiation and promotion, cigarette smoking accelerates atherogenic cardiovascular disease in both a dose- and a duration-dependent manner through several concurrent pathways. It incites an immunologic response to vascular injury, described as oxidative stress leading to lipid peroxidation, endothelial cell dysfunction, and foam cell proliferation in the tunica media and results in thrombosis. Exposure to passive smoking was studied in a Japanese imaging study12 that used multi-slice computed tomography to detect NCPs in 242 consecutive subjects. NCPs were present in 76 subjects, of whom 78% were male, 75% had hypertension, and 64% were current or past smokers.
Logistic regression analysis showed that the incidence of NCPs was significantly influenced by the presence of hypertension (P=0.03) and smoking habit (P=0.0007), but not age, diabetes mellitus, or hyperlipidemia. Thus, smoking-induced blood vessel injury may increase the risk of NCP in young males and the development of VTE. Smoking cessation and the control of hypertension should take precedence over all other risk factors in order to lower the incidence of NCPs and reduce vascular damage. Juonala et al17 examined parental smoking in childhood is predictive of disrupted endothelial function (endothelium-dependent vasodilation) as assessed using brachial flow-mediated dilatation (FMD) methods more than 20 years, and findings suggest that passive exposure to cigarette smoke among children might cause irreversible impairment in endothelium-dependent vasodilatation.
SMOKING CAUSES COAGULATION ABNORMALITIES AND DEVELOPMENT OF VTE IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)
Smoking is one of the major causes of the development of COPD in China. VTE is a fatal complication in patients with COPD and the frequency of development of deep vein thrombosis and PE is higher with COPD. Due to coagulation abnormalities in smokers, the potential influence of inflammation on coagulation offers further potential to contribute to thrombogenesis. Plasma fibrinogen levels are elevated in smokers and are further elevated during acute COPD exacerbation.18 Oral contraceptives cause significant increases in fibrinogen levels in smokers and non-smokers, as explained earlier, but only the latter appear to have a compensatory increase in antithrombin III activity. Factor XIII, which stabilizes fibrin clots, is also increased in smokers.
The plasma levels of fibrinogen increased further with raised IL-6 levels that also cause bone marrow simulation associated with increased levels of circulating IL-1 and IL-6, due to smoking.19 In view of the procoagulant effects of IL-6, this association could be an important link to VTE. 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 and develop VTE in COPD. DVT is higher in COPD, associated with immobilization exceeding three days, current smoking, and respiratory failure type II and pneumonia.20 COPD is a common comorbidity or risk factor for VTE. In a 5451-patient DVT registry of smokers, 668 (12.3%) had COPD as a comorbid condition.21 The risk of VTE during acute exacerbations of COPD appears to be significant.
MECHANISM OF EMBOLISM CAUSED BY SMOKING
Effective fibrinolysis due to smoking causes release of tissue plasminogen activator (tPA) from the vascular endothelium. tPA affects the venous system and its dysfunction reduces endothelial release of tPA after inhibition of nitric oxide synthase. These factors cause a markedly impaired capacity of the endothelium to acutely release tPA in smokers.22 This suggests an important mechanism whereby cigarette smoking could lead to both arterial and venous thrombosis. 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 and also alpha 1-antitrypsin. An inflamed vascular wall may increase the production of cytokines including IL-6, IL-1B, and tumor necrosis factor-alpha (TNFα), which play major regulatory roles in the hepatic synthesis of acute phase proteins, including fibrinogen. IL-6 appears to be the principal procoagulant cytokine in humans and an important link to VTE.23 IL-6 is able to increase the expression of tissue factor on monocytes which is a key to initiation of coagulation in vivo and formation of thromboembolism in smokers. In a Danish follow up study,2 641 cases of VTE were verified and found to have a positive association between current smoking and VTE, with a hazard ratio of 1.52 (95% CI 1.15-2.00) for smoking women and 1.32 (95% CI 1.00-1.74) for smoking men. It shows that smoking is an independent risk factor for VTE. In the population-based, prospective study,24 heavy smoking was apparently a risk factor for VTE. Heavy smokers (>20 pack-years) was associated with a 1.5-fold increased risk of total VTE and a 1.8-fold increased risk of provoked VTE. In a time-dependent analysis25 with a mean follow-up time of 15.5 years (237 375 person-years), 468 participants had VTE events. Adjusting for demographic variables and body mass index (BMI), current smokers were at greater risk, HR of 1.44 and 95% CI 1.12-1.86, compared to non-smokers. Among the well-established CVD risk factors, only current smoking and obesity were independently associated with VTE risk in a large cohort where risk factors were updated serially during follow-up.
SMOKING, ANTHROPOMETRY, GENETIC SUSCEPTIBILITY AND VTE
Studies show that lifestyles that included smoking and obesity have a substantial impact on the risk of VTE in individuals with F5 G1691A and F2 G20210A mutations. Caucasians have well-established risk factors for VTE in current smokers, one is the Factor V Leiden (G1691A) mutation and the other is the prothrombin (G20210A) mutation.26 The mutation results in imbalance of the coagulation system. Juul et al27 found that the simultaneous presence of smoking, obesity and older age resulted in a 10% absolute 10-year risk of VTE in individuals that were heterozygous for F5 G1691A. Pomp et al9 found in a large case-control study that the joint effects of smoking, F5 G1691A and F2 G20210A were higher than the sum of the separate effects. The F5 G1691A and F2 G20210A mutations are linked to an increase in the incidence rate of VTE, but their effects are highly variable. Among noncarriers of factor V Leiden current smoking resulted in a 1.4-fold increased risk, the joint effect of factor V Leiden and current smoking resulted in a 5.0-fold increased risk compared with never smokers without the mutation. For current smokers with the prothrombin 20210A mutation the risk of venous thrombosis increased 6.0-fold compared with never smokers without the mutation.10 The risk of secondary (particularly cancer-related) VTE was increased in smokers compared with never smokers. Body mass index, waist circumference, waist-hip-ratio height, and diabetes were positively associated with VTE risk in the Iowa Women's Health study.28 Maternal Smoking were associated with increased risk of VTE during pregnancy and the puerperium in a population-based case-control study nested within a Danish cohort.29 Smoking acts synergistically with oral contraceptive use, as explained earlier, and prothrombotic genetic mutations to increase risk is an important link to thrombus formation. Smoking is also a risk for future arterial cardiovascular events in patients with idiopathic venous thromboembolism30. Hypothetically, lifestyle factors may interact with a genetic risk factor and cause a synergistic effect that exceeds the sum of the separate effects. The Copenhagen City Heart Study shows smoking to be important risk factors for VTE 31: smoking HR for ≥25 g tobacco per day versus never smoker =1.52 (95% CI, 1.15-2.01); gender HR for men versus women =1.24 (95% CI, 1.08-1.42).
Recently it is found that the CYP1A1 enzyme metabolizes major procarcinogens in cigarette smoke, and a polymorphism of CYP1A1 is associated with many cancer risks. The Ile462Val polymorphism of CYP1A1 is also associated with VTE, especially in the smoking population. Gene and environment interactions play an important role in the development of VTE. The results of a Chinese study have provided convincing evidence that the CYP1A1 polymorphism is an important modifying factor in determining susceptibility to VTE.32 It shows a significant increase in the risk in the individuals carrying variant genotypes of CYP1A1. The Ile462Val polymorphism in smokers has further provided evidence that gene and environment interactions may play an important role in the development of VTE.
In light of existing basic, clinical, and epidemiologic research regarding the positive role of smoking in the development of VTE, investigators should incorporate quantitative data on smoking status and exposure of non-smokers to environmental smoking in studies with risk factors for VTE. Results of such research may show and effect on the morbidity and mortality of the disease, as well as offering further support for even more extensive antismoking campaigns. The interrelation between smoking and VTE is intriguing and awaits further characterization.
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