February 28, 2008
The Role of Inflammation in Venous Thromboembolism and the Link Between Arterial and Venous Thrombosis
By Poredos, P Jezovnik, M K
During the last decade, the role of inflammation in the etiopathogenesis of arterial thrombosis has been elucidated. However, little is known about the relationship between inflammation and venous thrombosis. Recently, inflammation has been accepted as a possible mechanism through which different risk factors trigger thrombus formation in veins. The data indicate that inflammation of the vessel wall initiates thrombus formation in an intact vein and that inflammation and coagulation systems are coupled by a common activation pathway. The first event in thrombus formation is most probably activation of endothelial cells, platelets and leucocytes, with initiation of inflammation and formation of microparticles that trigger the coagulation system through the induction of a tissue factor. Therefore, the key event in the initiation of venous thrombus formation is most probably vein wall inflammation. However, expected relationship between inflammatory markers as indicators of inflammatory process and clinical venous thromboembolism (VTE) has not yet been elucidated. C-reactive protein does not appear to be useful in predicting future venous thrombosis or to be useful in the diagnosis of VTE. Recently, it was demonstrated that probable association between VTE and several other markers of inflammation such as: interleukin (IL)-6, IL-8 and tumor necrosis factor-alpha exists. While these markers of inflammation were studied during or after acute venous thrombosis, further prospective studies are needed to determine the predictive value of inflammatory markers for VTE. The identification and elucidation of inflammatory markers relevant to venous thrombosis could provide targets for future therapy. That inflammation is the basic etiopathogenetic process of VTE is also supported by the relation of some risk factors to both arterial and venous thrombosis: age, increased body mass index, hypercholesterolemia, hypertension, lupus anticoagulant and hyperhomocysteinemia. A relation was also found between preclinical and clinical atherosclerotic disease and VTE. Also in line with these arguments are the preventive effects of aspirin and statins in both arterial and venous disease. [Int Angiol 2007;26:306-11]
Etiopathogenesis of venous thromboembolism
Deep venous thrombosis is a multifactorial disease. Classic risk factors of venous thrombosis include: cancer, surgery, immobilization, fractures, paralysis, pregnancy, childbirth, the use of estrogens and inherited genetic disorders. These conditions not only predispose apparently healthy people to thrombosis, but are also likely to trigger thrombotic episodes in patients with prothrombotic tendencies.1-3 Acquired or inherited risk factors potentially responsible for this disorder are identifiable in most patients; however, the basic pathogenetic mechanism in patients with known or unknown risk factors remains unexplained. The most recognizable pathophysiological mechanisms through which risk factors cause venous thromboembolism (VTE) involve endothelial damage, blood stasis, and hypercoagulability.4 Significant advances have been achieved in the understanding of humoral factors of hypercoagulability. However, the details of the interaction between endothelium and constituents of blood in VTE have been less well studied.
Inflammation and initiation of thrombus formation
Similarly as in the arterial part of the circulatory system, it is expected that also in venous thrombosis damage of the vessel wall is a crucial event in the initiation of thrombus formation. However, in some pathological studies no evidence of vein wall injury has been found.5 Another interesting observation is that most venous thrombi consist of two regions: one composed predominantly of fibrin and erythrocytes (red thrombus), and the other composed mainly of aggregated platelets (white thrombus). The fibrin-rich regions appeared to attach thrombi to the vessel wall, while the platelet- rich regions were found away from the site of the attachment.6 These findings suggest that coagulation precedes platelet activation and aggregation during the formation of venous thrombi and that fibrin formation is a primary event in venous thrombosis.
If there is no evidence of damage the question then arises: how does coagulation initiate in an intact vein wall? Recently inflammation has been accepted as a possible mechanism through which different risk factors trigger thrombus formation in veins and it was shown that inflammation could be involved in the pathogenesis of VTE.7 Some data indicate that inflammation and hemostasis are coupled by common activation pathways and feedback regulation systems. During inflammation, the hemostatic balance may be disturbed, resulting in the increased production of procoagulant factors and in the downregulation of anticoagulant mechanisms. Hence, activation of the coagulation cascades with the formation of thrombin, and fibrin deposition could be a consequence of inflammation. Inflammatory mechanisms also inhibit fibrinolytic activity and inflammatory mediators appear to increase platelet activity. These data indicate close interrelationship between these two systems. However, inflammation leads not only to activation of coagulation, but coagulation also considerably affects inflammatory activity. Thus, thrombus formation promotes inflammatory response, which in turns stimulates a prothrombotic tendency. This thesis is supported also by observations that natural anticoagulants not only prevent thrombosis, but they also dampen the inflammatory activity.8, 9 However, the cross link between inflammation and hemostasis is complex and involves different reactions, endothelial damage and the production of cell-derived microparticles, which are released into the circulation.10
Circulating microparticles in the pathogenesis of venous thromboembolism
Under physiological conditions, the vascular endothelium plays an important antithrombotic role, but upon endothelial activation and damage its protective role is shifted towards a prothrombotic state. During venous thrombosis, marked activation of the endothelium and also of platelets and leucocytes occurs. Endothelial cell activation is associated with the release of microparticles which are considered to be markers of ongoing or recent endothelial cell activation. Endothelial microparticles are small (
Different studies in patients with venous thrombosis have also demonstrated a markedly increased leucocyte activation and increased binding of endothelial microparticles to monocytes with triggering of the inflammatory process.14 Therefore, the key event in the initiation of venous thrombus formation is most probably vein wall inflammation caused by the activation of leucocytes and their adhesive interaction with endothelial cells.
Venous thrombosis and inflammatory markers
Although acquired or inherited risk factors potentially responsible for venous thrombosis are identifiable in most patients, the disease still remains unexplained in up to 30% of patients. Therefore, investigators are searching for new risk factors. As venous thrombosis is more and more accepted as inflammatory disease indicators of inflammation are studied. Recently, several studies have suggested a relationship of inflammatory markers to VTE and their role in the etiology of venous thrombosis.
In different studies multiple inflammatory pathways and markers were followed: C-reactive protein (CRP), inflammatory cytokines such as interleukin (IL)-6, IL-8, monocyte chemotactic protein-1, tumor necrosis factor (TNF)-alpha and others.
Two large prospective studies have examined the predictive value of plasma CRP-level for the development of VTE. In the Physicians Health Study, where 22 071 US-male physicians were followed for up to 14 years, mean CRP plasma levels in subjects who during follow- up developed VTE were not statistically different from subjects who did not develop VTE.16 The lack of statistical significance of these differences might be explained by the small number of participants in the study who developed VTE (n=101). Similarly, the analysis of participants in the Cardiovascular Health Study and in the Atherosclerosis Risk In Communities study also demonstrated that there was no association between baseline CRP levels and the subsequent development of VTE. Furthermore, there were no differences in age-, race- and-sex-adjusted VTE incident rates per 1 000 person-years according to the quartile of CRP levels.17 Taken together, these prospective studies indicate that plasma CRP levels do not appear to predict future VTE events. Similarly, in our retrospective study in patients with idiopathic venous thrombosis CRP and other inflammatory markers were not significantly different from healthy subjects.18 In contrast to its predictive value, CRP may be a diagnostic tool to detect or exclude VTE. Up to now at least 4 studies have evaluated the potential role of CRP in the diagnosis of VTE among patients with clinically suspected VTE. In all these studies, elevated plasma CRP levels were defined as >10 mg/ L. In these studies, elevated CRP levels had a sensitivity of 100% and a specificity of 52% for the diagnosis of DVT. These results suggested that non-elevated CRP levels might be useful in excluding DVT in patients with clinically suspected DVT. However, several larger subsequent studies have refuted the concept that plasma CRP levels are of value in the diagnosis of VTE, since in these studies the pooled weighted sensitivity was only 77% and specificity 66%.19 These results indicate that plasma CRP level, in itself, does not have utility for ruling in or ruling out DVT in patients with clinically suspected DVT.
There is indirect evidence that cytokines and chemokines are involved in the pathogenesis of VTE. It has been shown in one study that levels of IL-8 are increased in patients with recurrent thrombosis and in patients with the first event of venous thrombosis, compared with healthy controls.20
In another study, it was found that TNF-alpha, IL-6 and IL-8 levels are determinants of the risk of venous thrombosis. Overall, individuals that have detectable levels of any of these mediators in their plasma had a two-fold increased risk of VTE. For IL-8 in particular, these risks seemed to increase with the actual level observed.21 In line with these findings is the observation that the risk of VTE tended to decrease in cases with higher levels of the anti-inflammatory cytokine IL-10. However, in all these studies cytokine levels were investigated after the thrombotic events. Therefore, an inflammatory reaction as a consequence rather than the cause of venous thrombosis cannot be ruled out. Taken together, these findings suggest that IL-6 and IL-8 in particular may be involved in the etiopathogenesis of VTE.22 However, prospective studies will be required to elucidate this issue further.
In the past few years, results of structural and functional studies have supported a role of inflammation, not only in arterial, but also in venous thrombosis. These studies have demonstrated an increasingly tight interplay between the inflammatory and coagulation systems. Inflammatory response, regardless of its origin, could lead to hypercoagulability and hence it could increase the risk of venous thrombosis. However, the nature of the relationship between inflammation and clinical VTE has not yet been elucidated. Efforts to associate CRP with VTE have failed to demonstrate that it can either predict future VTE or be useful in the diagnosis of VTE. However, recent research demonstrated a probable association between VTE and several other markers of inflammation, such as IL-6, IL-8, TNF-alpha. Further research, especially prospective studies, will be required to determine the precise relationship between these markers of inflammation and VTE. If inflammation is indeed a cause of venous thrombosis, the identification of individuals with high levels of inflammatory markers relevant to VTE could provide targets for future therapy based on drugs with anti-inflammatory properties.
Inflammation: the link between arterial and venous thrombosis
Traditionally, the pathophysiology of thrombosis has been separated into venous and arterial thrombosis. The formation of arterial and venous thrombi has been explained by two distinct mechanisms, influenced by different risk factors. Venous thrombosis has been traditionally associated with red blood cell and fibrin- rich "red clot" formation, whereas arterial thrombi are platelets rich giving the appearance of "white thrombus".23 Over the last few decades, this thesis of two separate mechanisms of venous and arterial thrombosis has been partially challenged by accumulation of evidence which suggests that patients with atherothrombosis may be at increased risk for venous thrombosis.24,25 Further, basic and pathomorphological studies suggest that in spite of seeming differences the etiopathogenetic mechanisms are similar and that inflammation and platelet activation also participate in venous thrombogenesis.23 Atherosclerosis is associated with activation of both platelets and blood coagulation, as well as increased fibrin turnover, which can lead to thrombotic complications. Similarly, a role of this prothrombotic state in promoting venous thrombosis is plausible, on the basis of the assumption that activated platelets and coagulation factors appear in the low-flowing venous system.26 Hence, the data indicate close interrelationship between atherothrombosis and VTE, whereby inflammation as a basic etiopathogenetic process plays important role.23 It is now widely accepted that activation of coagulation cascades with the formation of thrombin and fibrin deposition as a consequence of inflammation is most probably involved in pathogenesis of arterial and venous thrombosis.
That inflammation is the basic etiopathogenetic process of venous and arterial thrombosis is also supported by the relation of some risk factors (known triggers of inflammatory process) to both arterial and venous thrombosis. Older age, related to increased oxidative stress, and systemic inflammatory response and other well known risk factors of atherosclerosis have also long been identified as an independent risk factors of venous thrombosis.27
In the Nurses Health Study with 16 years of follow-up, the risk factors of pulmonary embolism in women were investigated. It was shown that an elevated risk of pulmonary embolism was associated with an increased body mass index, and to the number of cigarettes smoked. In this study, hypertension was also associated with a greater likelihood of pulmonary embolism.28
Studies have also shown that hyperlipidemia is related to VTE. The study of Vaya et al. has demonstrated that a cholesterol value >5.69 mmol/L is an independent risk factor for idiopathic venous thrombosis.29 Although the mechanism remains unclear, some authors have suggested that hypercholesterolemia may impair regulation of coagulation via tissue-factor pathway inhibitor.30 Another explanation may be a hemorheological profile of hypercholesterolemia, increasing blood viscosity and erythrocyte aggregation.31 In animal studies, hypercholesterolemia generates less activated protein C or impairs protein C activation.
In line with these arguments is also the recognition that some other non-classical risk factors, such as hyperhomocysteinemia, factor V Leiden, and lupus anticoagulant which represent potential risk of both atherosclerosis and venous thrombosis.32
The relationship between arterial and venous thrombosis and their relation to the inflammatory process is also supported by the effects of measures used in prevention of atherosclerotic cardiovascular events on the prevention of venous thrombosis. Statins that are effective in prevention of cardiovascular disease among individuals with normal or elevated levels of cholesterol have antithrombotic properties also.33 In a retrospective subgroup analysis of the Heart and Estrogen Replacement Study (HERS), the use of statins was associated with a 50% risk reduction of VTE.34 This beneficial effect of statins may be due to decreased thrombus formation mediated by their anti-inflammatory activity, suppression of the prothrombotic and endothelial-altering properties of circulating lipids and improvement of the rheological properties of the blood. Statins also seem to alter elements of the coagulation cascade consistent with an antithrombotic effect. In this study, it was also first shown that long-term aspirin therapy decreased the risk of VTE in women with established coronary artery disease.34
A relation was also found between subjects with preclinical or clinical atherosclerotic disease and VTE. Prandoni et al. showed that the prevalence of carotid plaques was significantly higher in patients with unexplained (primary) thrombotic events than in those with secondary ones or in age- and sex-matched subjects without thrombosis.35 This association was still present after adjustment for risk factors of atherosclerosis and thrombophilic conditions. In elderly patients, the association became even stronger. In addition, other indicators of preclinical atherosclerosis (such as intima- media thickness of the carotid arteries, the degree of carotid stenosis and the number of carotid segments involved) were more frequent among subjects with spontaneous venous thrombosis. This study suggests either that atherosclerosis can induce venous thrombosis or that the two conditions are related to the common risk factors.
In one of our own studies, we investigated the relationship between of endothelial function and VTE. Endothelial dysfunction, known as one of the earliest measurable functional disturbance in atherogenesis, was also detected in patients with idiopathic venous thrombosis. Patients with thrombosis had significantly lower endotheliumsedependent vasodilating capability of brachial artery than healthy subjects.18 A relationship was also found between manifested atherosclerotic disease and VTE. In the study of Grady et al., women who had myocardial infarction had a 2.1-fold higher risk of VTE over the entire course of follow-up, but during the first 90 days after infarction, the risk was increased by more than 5- fold.34 Further, in a case-control study, an association between VTE disorders and arterial disease of the lower limbs was found.36 The interrelationship between arterial and venous disease was also confirmed in the recently published paper of Bova et al. They found that patients with VTE of unknown origin have an almost three times higher risk of subsequent arterial events compared to control subjects.37
There is evidence of an association between atherosclerotic disease and venous thrombosis. This thesis is supported by common risk factors for both diseases: older age, hyperlipidemia, hypertension, hyperhomocysteinemia, factor V Leiden, and lupus anticoagulant, by similar or identical pathogenetic mechanisms and by the association of the simultaneous appearance of both conditions.
Received on April 19, 2007; acknowledged on April 21, 2007; accepted for publication on May 22, 2007.
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P. POREDOS, M. K. JEZOVNIK
Department for Vascular Disease, University Medical Centre, Ljubljana, Slovenia
Address reprint requests to: P Poredos, MD, PhD, University Medical Centre, Department for Vascular Diseases, Zaloska c. 7, SI- 1525 Ljubljana, Slovenia.
E-mail: [email protected]
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