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Fibrinolytic function and atrial fibrillation
Thrombosis Research 109 (2003) 233 – 240
Review Article
Fibrinolytic function and atrial fibrillation Francisco Marı´n a,b, Vanessa Rolda´n a,c, Gregory Y.H. Lip a,* a
Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham B18 7QH, England, UK b Department of Cardiology, General Hospital of Alicante, Spain c Haematology Unit, Hospital of San Vicente, Alicante, Spain Received 4 February 2003; received in revised form 25 April 2003; accepted 28 April 2003
Abstract Atrial fibrillation (AF) is the commonest sustained cardiac arrhythmia, which is associated with a substantial risk of stroke and thromboembolism. A prothrombotic or hypercoagulable state has been observed in these patients, although previous studies have mainly focused on various clotting factors, endothelial damage or dysfunction markers and platelet activation. However, fibrinolytic function has been less frequently studied, despite the fibrinolytic system playing an important role in preventing intravascular thrombosis. Indeed, increasing evidence suggests that an imbalance between the fibrinolytic function is of great importance in cardiovascular disease. This review will begin by providing a brief approach to fibrinolytic function and examine previous studies about fibrinolytic activity and atrial fibrillation. D 2003 Elsevier Science Ltd. All rights reserved. Keywords: Atrial fibrillation; Tissue-type plasminogen activator; Plasminogen activator inhibitor; Fibrinolytic function
1. Introduction Atrial fibrillation (AF) is the commonest sustained cardiac arrhythmia, which is associated with a substantial risk of stroke and thromboembolism [1]. Many clinical and echocardiographic risk factors have identified patients at high risk of stroke and thromboembolism [2– 6]. Recent randomised trials have also demonstrated the efficacy of oral anticoagulation in reducing this risk, but an appreciation of the mechanisms leading to thrombosis and embolism in AF is essential in understanding the pathophysiology of the condition. As long as 150 years ago, Virchow [7] proposed that three conditions should be present for development of thrombosis (thrombogenesis), which include abnormalities in blood flow and abnormalities of the blood vessel wall and blood constituents. Structural abnormalities (for example, dilated atria or poorly contracting dilated left ventricles), valvular heart disease (for example, mitral stenosis) and congestive heart failure, which are clinical features commonly associated with stroke and thromboembolism in AF, * Corresponding author. Tel.: +44-121-507-5080; fax: +44-121-5544083. E-mail address: [email protected] (G.Y.H. Lip).
contribute to the first two components of Virchow’s Triad (abnormalities of blood flow and vessels) [8,9]. Abnormalities of haemostasis, coagulation, platelets and the endothelium are also present in AF, thus fulfilling the third component (‘‘abnormal blood constituents’’) of Virchow’s Triad [10,11]. The fulfillment of the components of Virchow’s Triad has led to the proposal that AF confers a prothrombotic or hypercoagulable state. These abnormalities of haemostasis and coagulation in AF have been associated with left atrial thrombosis and spontaneous echo contrast [10]. The latter has been related to thromboembolism [12] and may have an important role generating thrombosis or reflecting the existence of atria clots. It is possible that the hypercoagulable state observed in AF may be additive to the presence of other risk factors for thromboembolism, such as heart failure [13], hypertension [14] or valvular heart disease [15]. Previous studies have mainly focused on various endothelial damage or dysfunction markers, prothrombotic factors and plasma markers of platelet activation [10,16 – 18]. However, fibrinolytic function has been less studied. This is despite the fibrinolytic system playing an important role in preventing intravascular thrombosis [19]. The aim of this review is to provide an overview of the current knowledge of fibrinolytic function in AF.
0049-3848/03/$ - see front matter D 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0049-3848(03)00259-7
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2. Search strategy and selection criteria Published data for this review were identified by searches of MEDLINE and reference lists from relevant articles. Searches were concentrated on the following keywords: fibrinolytic function, tissue-type plasminogen activator, tissue-type plasminogen activator inhibitor, plasmin – antiplasmin complexes, D-dimer, lipoprotein (a), hypercholesterolemia, AF, hypertension, diabetes, atherosclerosis, stroke and ischaemic heart disease. Representative studies for various reviews about fibrinolytic function and AF were also included.
3. The fibrinolytic system: a brief overview The fibrinolytic system plays an important role preventing intravascular thrombosis. This system comprises a proenzyme, plasminogen, which can be converted to the active enzyme, plasmin, by different plasminogen activators [19]. Two physiological plasminogen activators have been identified: tissue-type (t-PA) and urokinase-type plasminogen activator (u-PA) [20]. Plasmin is a serine protease that cleaves fibrin into soluble fragments, but shows other important functions, such as increasing the activity of matrix metalloproteinases [21], resulting in enhancement of its proteolytic activity. The fibrinolytic system is also regulated by controlled inhibition, and this may occur either at the level of t-PA, by specific plasminogen activator inhibitors (mainly PAI-1 and PAI-2), or at the level of plasmin, the most important a2-antiplasmin [20] (Fig. 1). Fibrinolysis is initiated by t-PA in the region of the thrombus. t-PA has a weak affinity for plasminogen in the absence of fibrin, but it increases the activation rate in the presence of fibrin. Thus, one important way of regulating fibrinolytic function is at the level of plasminogen activation placed at the fibrin surface [20]. In this way, PAI-1 and t-PA also react rapidly, forming 1:1 stoichiometric stable and inactive t-PA/PAI-1 complexes [22]. As PAI-1 levels rise in blood, the active t-PA decreases [23]. Hence, fibrinolytic function in the vascular bed is dependent upon the rate of secretion of t-PA, the inhibition of t-PA by PAI-
Fig. 1. The fibrinolytic system and its interactions.
1 and other inhibitors and the hepatic clearance of t-PA [24]. Plasmin is also rapidly inactivated by a2-antiplasmin in the blood; however, plasmin molecules generated on the fibrin surface (after t-PA acts on plasminogen), bound to fibrin by their lysine-binding sites, are protected from inactivation [20]. These lysine-binding sites play an important role as they mediate the specific binding of plasminogen to fibrin and the interaction of plasmin with a2antiplasmin [25]. The ratio of active t-PA to active PAI-1 is around 1:8 in healthy controls; in contrast, this ratio could be as high as 1:50 in atherosclerotic patients [26]. Both active t-PA and active PAI-1 show circadian variation, with the lowest t-PA activity in the early morning and level increases during the day [27]—thus, a hypofibrinolytic function is present in the early morning [28], which may contribute to the excess of vascular events at that time. As we have just described, plasmin is rapidly inactivated by a2-antiplasmin. A stable and inactive complex is formed: plasmin – antiplasmin complex (PAP). A significant negative correlation has been found between antigen PAI-1 and PAP levels [27]. It is thought that quantification of PAP in plasma reflects plasmin generation, and it can be used as accurate marker of the fibrinolytic system [29]. 3.1. Antigen or activity? Both t-PA and PAI-1 may be assayed by enzymeimmunological techniques (ELISA) and by functional techniques. However, we have to emphasise the distinction between the measurement of activity and antigen levels of these molecules. It seems to be more likely that the measurement of antigen and activity represents very different things. The total amount of t-PA antigen that has been secreted is approximately equal to active t-PA plus t-PA/PAI-1 complex [26]. Only a few percent of t-PA antigen is functionally active. A decrease in t-PA antigen levels is not observed in patients with high PAI-1 levels, while on the contrary, t-PA antigen levels are higher in these patients compared to healthy controls—the slower clearance of t-PA/PAI-1 complexes than the plasma clearance of active t-PA partly explains this [30,31]. Thus, raised t-PA antigen levels probably reflect an increase in circulating complexes formed by t-PA and its inhibitor [32], and may also reflect the PAI-1 concentration [27]. When there is an increase in plasma PAI-1 concentration, t-PA antigen levels rise and half-life of functional t-PA is clearly decreased, impairing the fibrinolytical function [27,33]. Hence, elevated t-PA antigen levels do not necessary reflect an activation of the fibrinolytic system, as reviewed by De Bono [34]. Indeed, high plasma t-PA antigen concentrations are probably a marker for high PAI-1 concentrations and low intrinsic fibrinolytic activity. However, a relationship between t-PA antigen levels, markers of inflammation and endothelial damage markers
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has also been described [35]. As endothelial cells release tPA and PAI-1, it has also been suggested that they could be related as marker of endothelial cell damage or dysfunction [32,36]. However, some plasma levels of PAI-1 could arise from other cells, like platelets [37]. Rather than being a measure of fibrinolysis, t-PA and PAI-1 antigen levels may therefore be a surrogate for vascular injury. 3.2. Other indices related to the fibrinolytic system 3.2.1. Fibrin D-dimer It has been suggested that measurement of plasma fibrin D-dimer can assess potential fibrinolytic activity. Nevertheless, the fibrin D-dimer assay is based on the production by thrombin of cross-linked fibrin, making it a sensitive marker of fibrin turnover and allows the recognition of activated coagulation [38]. Thus, measurement of fibrin D-dimer seems to be a better marker of intravascular thrombogenesis than simply being a marker of fibrinolysis. 3.2.2. Lipoprotein (a) The role of lipoprotein (a) [Lp(a)] in fibrinolytic function is an interesting one. Lp(a) is formed by an LDL particle covalent linked to a single apolipoprotein (a) [apo(a)] [39]. Certainly, Lp(a) is a risk factor for ischaemic heart disease [40,41], although the association between Lp(a) and stroke is less evident [42,43]. Indeed, Lp(a) has both atherogenic and thrombogenic potentials, and several potential mechanisms have been proposed to explain the role of Lp(a) in cardiovascular disease [44]. In vitro studies have shown that Lp(a) induces chemotatic activity to human monocytes and enhances the expression of intercellular adhesion molecule-1 [45,46]. As Lp(a) interferes with plasminogen activation through a mechanism involving the functional lysine binding sites [47], apo(a) can inhibit the lysis of fibrin clots [48]. Indeed, Soulat et al. [49] report that modifications of Lp(a) in a selected group of nephrotic children were accompanied by inverse changes of plasmin formation. Hence, the antifibrinolytic effect of Lp(a) seems to depend not only on the total plasma level of this molecule, but also on the relative concentration of the small apo(a) isoform [50,51]. Moreover, the apo(a) heterogeneity takes importance in cardiovascular disease risk [52]. For example, in the coronary artery risk development in young adults (CARDIA study), the distribution of apo(a) isoforms varied between blacks and whites [53], but despite higher median Lp(a) levels, blacks had a lower frequency of small apo(a) isoforms—resulting in a similar risk of cardiovascular disease. 3.2.3. The insulin resistance syndrome Other important relationship with the fibrinolytic system is the insulin resistance syndrome or ‘metabolic syndrome’ [54,55]. Hence, raised levels of PAI-1 have been proposed to be included in this syndrome, along
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hyperinsulinemia, hypertriglyceridemia, hypertension and obesity [27]. Arguably, the most important regulator of PAI-1 activity is plasma insulin concentration [54]. In the Framingham Offspring Study [55], fasting hyperinsulinemia was associated with markers of impaired fibrinolysis, after adjustment for potential confounders. Importantly, increased levels of PAI-1 and t-PA antigen, and not the other haemostatic factors, were found in glucose-intolerance subjects. In the European Concerted Action on Thrombosis and Disabilities study (ECAT), a significant correlation was observed between insulin and PAI-1 levels [56], and after lowering insulin levels, plasma PAI-1 activity was also reduced. Moreover, after adjustment with insulin resistance parameters, both PAI-1 activity and antigen were not predictive of coronary events. On other hand, the predictive value of t-PA antigen of subsequent incidence of new coronary events disappeared after adjustment by insulin resistance (body mass index, triglycerides, HDL cholesterol, systolic blood pressure and diagnosed diabetes), inflammation (fibrinogen and C-reactive protein levels) and endothelial damage markers (von Willebrand factor) [57].
4. The fibrinolytic system and cardiovascular disease Increasing evidence suggests that an imbalance between the t-PA and PAI-1 is of huge importance for the cardiovascular system. Raised concentrations of t-PA antigen have been associated with acute coronary syndromes [58 – 61], peripheral vascular disease [62] and stroke [63]. Higher levels of PAI-1 and t-PA antigen [64], without differences in PAP levels [65], have been described in idiopathic cardiomyopathy. Patients with cardiovascular risk factors also demonstrate differences in t-PA and PAI-1 levels [66,67]. For example, reduced activity of fibrinolytic function (lower t-PA activity and higher levels of PAI-1) has been reported in patients with hypertension and hypercholesterolemia [66]. In the Framingham Offspring Study, positive associations between blood pressure and PAI-1 and t-PA antigen levels have been described [67]. Furthermore, Mehta et al. [68] reported a positive relation between plasma PAI-1 antigen and serum triglyceride levels. 4.1. The fibrinolytic system and atrial fibrillation Only a few studies have specifically investigated the fibrinolytic function in AF, as summarised in Table 1. For example, Furui et al. [69] reported lower levels of PAP in lone AF patients compared to controls. Similarly, the study by Mitusch et al. [70] reported increased D-dimer and t-PA antigen levels in non-rheumatic patients; however, the authors concluded that these observations could reflect an increased fibrinolytic function in response to a prothrombotic state.
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Table 1 Studies examining fibrinolytic function in atrial fibrillation Author
Reference Patient population
Feinberg WM, 1999
[73]
Igarashi Y, 1998 Mitusch R, 1996
[85]
Lip GYH, 2000
[86]
[71]
Mondillo S, [75] 2000 Rolda´n V, 1998
[72]
Rolda´n V, 2000
[81]
Furui H, 1987
[70]
Sohara H, 1994 Marı´n F, 1999
[77]
Yamamoto K, 1995
[76]
[80]
Findings
586 AF patients of SPAF III study
Raised PAP levels in aged, recent heart failure, systolic dysfunction and recent onset of AF. No differences with antithrombotic therapy or thrombus in left atrial appendage 150 chronic Lp(a) levels were associated AF patients to left atrial thrombus in TEE 69 chronic Raised levels of D-dimer AF patients and t-PA. After anticoagulation, haemostatic markers decreased 57 AF Lp(a) levels were not correlated patients to D-dimer levels or echocardiographic data 45 lone AF Raised t-PA levels. These patients levels correlated to endothelial markers (vWf and sTM) 36 AF patients Increased levels of PAI-1, (15 rheumatic D-dimer, t-PA/PAI-1 and 21 noncomplexes without differences rheumatic) in PAP levels 21 nonAfter anticoagulation, rheumatic D-dimer, t-PA and PAI-1 AF patients levels decreased 20 lone AF Lower PAP in AF than patients controls as at rest as at each exercise stage 13 paroxysmal No differences were found in AF patients D-dimer and PAP levels 13 rheumatic After anticoagulation, levels AF patients of t-PA, PAI-1 and D-dimer decreased, whereas PAP levels increased 12 rheumatic No differences were found in patients PAP and D-dimer levels (11 in AF)
AF: atrial fibrillation; PAP: plasmin – a2-antiplasmin complexes; t-PA: tissue-type plasminogen activator; PAI-1: tissue-type plasminogen activator inhibitor-1; Lp(a): lipoprotein (a); vWf: von Willebrand factor; sTM: soluble thrombomodulin: TEE: transesophageal echocardiography.
We previously described a hypofibrinolytic state in both rheumatic and non-rheumatic AF, with elevated PAI-1 antigen and t-PA/PAI-1 complex levels, with no increase in PAP concentration [71]. In the Stroke Prevention in Atrial Fibrillation (SPAF) III study, increased PAP levels were independently associated with older patients, recent congestive heart failure, impaired systolic function and recent onset of AF, suggesting the authors that high PAP levels could identify high embolic risk patients [72]. Increased levels of fibrin Ddimer have also been reported in AF, without significant differences in PAI-1 levels [73]. In addition, a recent study in lone AF (that is, without other vascular disease) found raised levels of plasma t-PA antigen and PAI-1 antigen [74]. In contrast, a small study of only 11 patients by Yamamoto et al. [75] did not find significant differences in fibrin D-dimer and PAP levels between rheumatic AF patients and controls.
Although paroxysmal AF has shown a similar stroke risk to permanent AF [2], the cross-sectional study by Lip et al. [76] reported intermediate elevated levels of fibrin D-dimer and fibrinogen in patients with paroxysmal AF, compared to chronic AF and those in sinus rhythm. The study by Sohara et al. did not find raised levels of fibrin D-dimer or PAP in their small group of patients with paroxysmal AF [77], although increased levels of markers of platelet activation and fibrinogen were found during episodes of AF of more than 12 h [78]. It is of note that there is a diurnal variation in fibrinolytic activity, with the lowest activity in the early morning, which could be relevant to time of onset of cardiovascular disease [79]. Indeed, a circadian rhythm of stroke onset has been reported among patients with AF [80], although no significant diurnal variation in plasma prothrombotic markers has been found in chronic AF patients [81]. After exercise, PAP levels are increased but lower than that seen in healthy controls [69]. More recently, Li-Saw-Lee et al. [82] found a reduction in PAI-1 levels in patients with chronic AF after exercise, suggesting a transitory activation of the fibrinolytic function [34]. Elevated serum levels of Lp(a) were strongly associated with left atrial thrombus in transesophageal echocardiography in a study of 150 consecutive patients with chronic AF [83]. However, other studies have been disappointing, without any significant relationship between Lp(a) and fibrin Ddimer levels [84], in keeping with the strong genetic influence of Lp(a) and its prothrombotic effects. To our knowledge, there are no studies on the influence of apo(a) isoforms on prothrombotic markers in AF. Nevertheless, analytical methods for Lp(a) and apo(a) levels are not standardized, making it difficult to allow to make precise comparisons of results from different studies [44]. 4.1.1. Effects of antithrombotic therapy There is an improvement in fibrinolytic markers in rheumatic AF after ‘steady state’ oral anticoagulation [85], although in non-rheumatic patients, a less marked improvement was noted [86], suggesting the possible role of confounding factors, such as cardiovascular risk factors, heart failure or ischaemic heart disease. On the other hand, fibrin D-dimer levels do not modify significantly after treatment with aspirin, whereas conventional warfarin therapy reduced this marker [17]. Indeed, fibrin D-dimer levels only reduce after full anticoagulation with adjusted dose warfarin (INR 2 – 3), with no significant changes in patients treated with fixed low dose of warfarin or aspirin – warfarin combination therapy [73]. In contrast, Feinberg et al. [72] observed no difference in PAP levels between patients with and without oral anticoagulation, and these were not associated to INR levels. However, these results should be considered with some caution, as the authors did not study the patients prior to, and after initiation of, anticoagulation, and it is possible that the anticoagulation time was insufficient in some cases.
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4.1.2. Implications Plasmin is thought to be the most important physiological activator in vivo of the matrix metalloproteinases [21]. For example, the increased activity of fibrinolytic function in recent onset of AF [72] could activate metalloproteinases, participating actively in the remodelling of the atria. However, permanent AF seems to give a greater prothrombotic state [87], with impaired fibrinolytic function [71] and decreasing PAP levels. This theoretical hypofibrinolytic state could reduce the activity of matrix metalloproteinase-1, as described in end-stage dilated cardiomyopathy [88], leading to an increase of interstitial amount of collagen in the wall [89]. This hypothesis would need to be fully established in patients with AF. In this way, we have recently described that patients with AF showed impaired matrix degradation, and there was an independent relationship between the matrix metalloproteinase system and the prothrombotic state [90]. Importantly, there are currently no prospective data about the value of fibrinolytic markers and thromboembolic risk in AF, although in the SPAF III study [72], raised PAP levels were associated with known thromboembolic risk factors. Another question arises as to why AF is associated with increased t-PA antigen and PAI-1 antigen levels. The role of confounders could be important. Indeed, it is possible that subjects with higher or uncontrolled blood pressure, more severe heart failure or ischaemic heart disease develop AF. The coexistence of hypertension and insulin resistance could also lead to an impaired fibrinolytic function. However, studies performed in patients with lone AF suggest that AF by itself modifies fibrinolytic markers [69,74]. The high levels of t-PA and PAI-1 antigen could also represent markers of endothelial cell damage or dysfunction. Thus, although there were no statistical differences in t-PA antigen levels between patients and controls, a significant correlation can be shown between t-PA levels and left atrial diameter, at least in the subgroup of rheumatic AF [71]. In other studies, significant correlations were found between t-PA antigen level and accepted endothelial markers, such as von Willebrand factor and soluble thrombomodulin [62,91]. The finding that inflammation could play an important role in AF [92,93] raises the hypothesis that inflammation could increase plasma PAI-1 levels, impairing fibrinolytic function. Indeed, endotoxin or bacterial inflammatory mediators increase PAI-1 production by human endothelial cells [94]. Certainly, it has been stated that ‘‘inflammation can beget local thrombosis, and thrombosis can amplify inflammation’’ [95]. Different anti-inflammatory therapies can potentially be effective against thrombogenesis [96], although the suggestion has been made that antithrombotic therapy may decrease inflammation [95]. Hence, in a recent preliminary study, introducing oral anticoagulation may have an anti-inflammatory effect in AF by decreasing C-reactive protein levels, but not interleukin-6 levels [97]. These observations could in part explain the improvement in fibrinolytic function with stable anticoagulant therapy [85,86].
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5. Conclusion Raised levels of PAI-1 and fibrin D-dimer, with inconsistent findings in plasmin – a2-antiplasmin concentrations, have been described in AF. Different hypotheses have been proposed about the role of fibrinolytic function in AF, including endothelial damage or dysfunction, inflammation or other confounders, such as hypertension or insulin resistance. New prospective studies are required to characterise the interaction of fibrinolytic function and clinical outcomes in AF.
Acknowledgements VR was supported by a research grant from the Spanish Association of Hematology (AEHH). FM was supported by a research grant from the Spanish Society of Cardiology. We acknowledge the support of the Dowager Countess Eleanor Peel Trust and the City Hospital Research and Development programme for the Haemostasis Thrombosis and Vascular Biology Unit.
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Review Article
Fibrinolytic function and atrial fibrillation Francisco Marı´n a,b, Vanessa Rolda´n a,c, Gregory Y.H. Lip a,* a
Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham B18 7QH, England, UK b Department of Cardiology, General Hospital of Alicante, Spain c Haematology Unit, Hospital of San Vicente, Alicante, Spain Received 4 February 2003; received in revised form 25 April 2003; accepted 28 April 2003
Abstract Atrial fibrillation (AF) is the commonest sustained cardiac arrhythmia, which is associated with a substantial risk of stroke and thromboembolism. A prothrombotic or hypercoagulable state has been observed in these patients, although previous studies have mainly focused on various clotting factors, endothelial damage or dysfunction markers and platelet activation. However, fibrinolytic function has been less frequently studied, despite the fibrinolytic system playing an important role in preventing intravascular thrombosis. Indeed, increasing evidence suggests that an imbalance between the fibrinolytic function is of great importance in cardiovascular disease. This review will begin by providing a brief approach to fibrinolytic function and examine previous studies about fibrinolytic activity and atrial fibrillation. D 2003 Elsevier Science Ltd. All rights reserved. Keywords: Atrial fibrillation; Tissue-type plasminogen activator; Plasminogen activator inhibitor; Fibrinolytic function
1. Introduction Atrial fibrillation (AF) is the commonest sustained cardiac arrhythmia, which is associated with a substantial risk of stroke and thromboembolism [1]. Many clinical and echocardiographic risk factors have identified patients at high risk of stroke and thromboembolism [2– 6]. Recent randomised trials have also demonstrated the efficacy of oral anticoagulation in reducing this risk, but an appreciation of the mechanisms leading to thrombosis and embolism in AF is essential in understanding the pathophysiology of the condition. As long as 150 years ago, Virchow [7] proposed that three conditions should be present for development of thrombosis (thrombogenesis), which include abnormalities in blood flow and abnormalities of the blood vessel wall and blood constituents. Structural abnormalities (for example, dilated atria or poorly contracting dilated left ventricles), valvular heart disease (for example, mitral stenosis) and congestive heart failure, which are clinical features commonly associated with stroke and thromboembolism in AF, * Corresponding author. Tel.: +44-121-507-5080; fax: +44-121-5544083. E-mail address: [email protected] (G.Y.H. Lip).
contribute to the first two components of Virchow’s Triad (abnormalities of blood flow and vessels) [8,9]. Abnormalities of haemostasis, coagulation, platelets and the endothelium are also present in AF, thus fulfilling the third component (‘‘abnormal blood constituents’’) of Virchow’s Triad [10,11]. The fulfillment of the components of Virchow’s Triad has led to the proposal that AF confers a prothrombotic or hypercoagulable state. These abnormalities of haemostasis and coagulation in AF have been associated with left atrial thrombosis and spontaneous echo contrast [10]. The latter has been related to thromboembolism [12] and may have an important role generating thrombosis or reflecting the existence of atria clots. It is possible that the hypercoagulable state observed in AF may be additive to the presence of other risk factors for thromboembolism, such as heart failure [13], hypertension [14] or valvular heart disease [15]. Previous studies have mainly focused on various endothelial damage or dysfunction markers, prothrombotic factors and plasma markers of platelet activation [10,16 – 18]. However, fibrinolytic function has been less studied. This is despite the fibrinolytic system playing an important role in preventing intravascular thrombosis [19]. The aim of this review is to provide an overview of the current knowledge of fibrinolytic function in AF.
0049-3848/03/$ - see front matter D 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0049-3848(03)00259-7
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2. Search strategy and selection criteria Published data for this review were identified by searches of MEDLINE and reference lists from relevant articles. Searches were concentrated on the following keywords: fibrinolytic function, tissue-type plasminogen activator, tissue-type plasminogen activator inhibitor, plasmin – antiplasmin complexes, D-dimer, lipoprotein (a), hypercholesterolemia, AF, hypertension, diabetes, atherosclerosis, stroke and ischaemic heart disease. Representative studies for various reviews about fibrinolytic function and AF were also included.
3. The fibrinolytic system: a brief overview The fibrinolytic system plays an important role preventing intravascular thrombosis. This system comprises a proenzyme, plasminogen, which can be converted to the active enzyme, plasmin, by different plasminogen activators [19]. Two physiological plasminogen activators have been identified: tissue-type (t-PA) and urokinase-type plasminogen activator (u-PA) [20]. Plasmin is a serine protease that cleaves fibrin into soluble fragments, but shows other important functions, such as increasing the activity of matrix metalloproteinases [21], resulting in enhancement of its proteolytic activity. The fibrinolytic system is also regulated by controlled inhibition, and this may occur either at the level of t-PA, by specific plasminogen activator inhibitors (mainly PAI-1 and PAI-2), or at the level of plasmin, the most important a2-antiplasmin [20] (Fig. 1). Fibrinolysis is initiated by t-PA in the region of the thrombus. t-PA has a weak affinity for plasminogen in the absence of fibrin, but it increases the activation rate in the presence of fibrin. Thus, one important way of regulating fibrinolytic function is at the level of plasminogen activation placed at the fibrin surface [20]. In this way, PAI-1 and t-PA also react rapidly, forming 1:1 stoichiometric stable and inactive t-PA/PAI-1 complexes [22]. As PAI-1 levels rise in blood, the active t-PA decreases [23]. Hence, fibrinolytic function in the vascular bed is dependent upon the rate of secretion of t-PA, the inhibition of t-PA by PAI-
Fig. 1. The fibrinolytic system and its interactions.
1 and other inhibitors and the hepatic clearance of t-PA [24]. Plasmin is also rapidly inactivated by a2-antiplasmin in the blood; however, plasmin molecules generated on the fibrin surface (after t-PA acts on plasminogen), bound to fibrin by their lysine-binding sites, are protected from inactivation [20]. These lysine-binding sites play an important role as they mediate the specific binding of plasminogen to fibrin and the interaction of plasmin with a2antiplasmin [25]. The ratio of active t-PA to active PAI-1 is around 1:8 in healthy controls; in contrast, this ratio could be as high as 1:50 in atherosclerotic patients [26]. Both active t-PA and active PAI-1 show circadian variation, with the lowest t-PA activity in the early morning and level increases during the day [27]—thus, a hypofibrinolytic function is present in the early morning [28], which may contribute to the excess of vascular events at that time. As we have just described, plasmin is rapidly inactivated by a2-antiplasmin. A stable and inactive complex is formed: plasmin – antiplasmin complex (PAP). A significant negative correlation has been found between antigen PAI-1 and PAP levels [27]. It is thought that quantification of PAP in plasma reflects plasmin generation, and it can be used as accurate marker of the fibrinolytic system [29]. 3.1. Antigen or activity? Both t-PA and PAI-1 may be assayed by enzymeimmunological techniques (ELISA) and by functional techniques. However, we have to emphasise the distinction between the measurement of activity and antigen levels of these molecules. It seems to be more likely that the measurement of antigen and activity represents very different things. The total amount of t-PA antigen that has been secreted is approximately equal to active t-PA plus t-PA/PAI-1 complex [26]. Only a few percent of t-PA antigen is functionally active. A decrease in t-PA antigen levels is not observed in patients with high PAI-1 levels, while on the contrary, t-PA antigen levels are higher in these patients compared to healthy controls—the slower clearance of t-PA/PAI-1 complexes than the plasma clearance of active t-PA partly explains this [30,31]. Thus, raised t-PA antigen levels probably reflect an increase in circulating complexes formed by t-PA and its inhibitor [32], and may also reflect the PAI-1 concentration [27]. When there is an increase in plasma PAI-1 concentration, t-PA antigen levels rise and half-life of functional t-PA is clearly decreased, impairing the fibrinolytical function [27,33]. Hence, elevated t-PA antigen levels do not necessary reflect an activation of the fibrinolytic system, as reviewed by De Bono [34]. Indeed, high plasma t-PA antigen concentrations are probably a marker for high PAI-1 concentrations and low intrinsic fibrinolytic activity. However, a relationship between t-PA antigen levels, markers of inflammation and endothelial damage markers
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has also been described [35]. As endothelial cells release tPA and PAI-1, it has also been suggested that they could be related as marker of endothelial cell damage or dysfunction [32,36]. However, some plasma levels of PAI-1 could arise from other cells, like platelets [37]. Rather than being a measure of fibrinolysis, t-PA and PAI-1 antigen levels may therefore be a surrogate for vascular injury. 3.2. Other indices related to the fibrinolytic system 3.2.1. Fibrin D-dimer It has been suggested that measurement of plasma fibrin D-dimer can assess potential fibrinolytic activity. Nevertheless, the fibrin D-dimer assay is based on the production by thrombin of cross-linked fibrin, making it a sensitive marker of fibrin turnover and allows the recognition of activated coagulation [38]. Thus, measurement of fibrin D-dimer seems to be a better marker of intravascular thrombogenesis than simply being a marker of fibrinolysis. 3.2.2. Lipoprotein (a) The role of lipoprotein (a) [Lp(a)] in fibrinolytic function is an interesting one. Lp(a) is formed by an LDL particle covalent linked to a single apolipoprotein (a) [apo(a)] [39]. Certainly, Lp(a) is a risk factor for ischaemic heart disease [40,41], although the association between Lp(a) and stroke is less evident [42,43]. Indeed, Lp(a) has both atherogenic and thrombogenic potentials, and several potential mechanisms have been proposed to explain the role of Lp(a) in cardiovascular disease [44]. In vitro studies have shown that Lp(a) induces chemotatic activity to human monocytes and enhances the expression of intercellular adhesion molecule-1 [45,46]. As Lp(a) interferes with plasminogen activation through a mechanism involving the functional lysine binding sites [47], apo(a) can inhibit the lysis of fibrin clots [48]. Indeed, Soulat et al. [49] report that modifications of Lp(a) in a selected group of nephrotic children were accompanied by inverse changes of plasmin formation. Hence, the antifibrinolytic effect of Lp(a) seems to depend not only on the total plasma level of this molecule, but also on the relative concentration of the small apo(a) isoform [50,51]. Moreover, the apo(a) heterogeneity takes importance in cardiovascular disease risk [52]. For example, in the coronary artery risk development in young adults (CARDIA study), the distribution of apo(a) isoforms varied between blacks and whites [53], but despite higher median Lp(a) levels, blacks had a lower frequency of small apo(a) isoforms—resulting in a similar risk of cardiovascular disease. 3.2.3. The insulin resistance syndrome Other important relationship with the fibrinolytic system is the insulin resistance syndrome or ‘metabolic syndrome’ [54,55]. Hence, raised levels of PAI-1 have been proposed to be included in this syndrome, along
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hyperinsulinemia, hypertriglyceridemia, hypertension and obesity [27]. Arguably, the most important regulator of PAI-1 activity is plasma insulin concentration [54]. In the Framingham Offspring Study [55], fasting hyperinsulinemia was associated with markers of impaired fibrinolysis, after adjustment for potential confounders. Importantly, increased levels of PAI-1 and t-PA antigen, and not the other haemostatic factors, were found in glucose-intolerance subjects. In the European Concerted Action on Thrombosis and Disabilities study (ECAT), a significant correlation was observed between insulin and PAI-1 levels [56], and after lowering insulin levels, plasma PAI-1 activity was also reduced. Moreover, after adjustment with insulin resistance parameters, both PAI-1 activity and antigen were not predictive of coronary events. On other hand, the predictive value of t-PA antigen of subsequent incidence of new coronary events disappeared after adjustment by insulin resistance (body mass index, triglycerides, HDL cholesterol, systolic blood pressure and diagnosed diabetes), inflammation (fibrinogen and C-reactive protein levels) and endothelial damage markers (von Willebrand factor) [57].
4. The fibrinolytic system and cardiovascular disease Increasing evidence suggests that an imbalance between the t-PA and PAI-1 is of huge importance for the cardiovascular system. Raised concentrations of t-PA antigen have been associated with acute coronary syndromes [58 – 61], peripheral vascular disease [62] and stroke [63]. Higher levels of PAI-1 and t-PA antigen [64], without differences in PAP levels [65], have been described in idiopathic cardiomyopathy. Patients with cardiovascular risk factors also demonstrate differences in t-PA and PAI-1 levels [66,67]. For example, reduced activity of fibrinolytic function (lower t-PA activity and higher levels of PAI-1) has been reported in patients with hypertension and hypercholesterolemia [66]. In the Framingham Offspring Study, positive associations between blood pressure and PAI-1 and t-PA antigen levels have been described [67]. Furthermore, Mehta et al. [68] reported a positive relation between plasma PAI-1 antigen and serum triglyceride levels. 4.1. The fibrinolytic system and atrial fibrillation Only a few studies have specifically investigated the fibrinolytic function in AF, as summarised in Table 1. For example, Furui et al. [69] reported lower levels of PAP in lone AF patients compared to controls. Similarly, the study by Mitusch et al. [70] reported increased D-dimer and t-PA antigen levels in non-rheumatic patients; however, the authors concluded that these observations could reflect an increased fibrinolytic function in response to a prothrombotic state.
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Table 1 Studies examining fibrinolytic function in atrial fibrillation Author
Reference Patient population
Feinberg WM, 1999
[73]
Igarashi Y, 1998 Mitusch R, 1996
[85]
Lip GYH, 2000
[86]
[71]
Mondillo S, [75] 2000 Rolda´n V, 1998
[72]
Rolda´n V, 2000
[81]
Furui H, 1987
[70]
Sohara H, 1994 Marı´n F, 1999
[77]
Yamamoto K, 1995
[76]
[80]
Findings
586 AF patients of SPAF III study
Raised PAP levels in aged, recent heart failure, systolic dysfunction and recent onset of AF. No differences with antithrombotic therapy or thrombus in left atrial appendage 150 chronic Lp(a) levels were associated AF patients to left atrial thrombus in TEE 69 chronic Raised levels of D-dimer AF patients and t-PA. After anticoagulation, haemostatic markers decreased 57 AF Lp(a) levels were not correlated patients to D-dimer levels or echocardiographic data 45 lone AF Raised t-PA levels. These patients levels correlated to endothelial markers (vWf and sTM) 36 AF patients Increased levels of PAI-1, (15 rheumatic D-dimer, t-PA/PAI-1 and 21 noncomplexes without differences rheumatic) in PAP levels 21 nonAfter anticoagulation, rheumatic D-dimer, t-PA and PAI-1 AF patients levels decreased 20 lone AF Lower PAP in AF than patients controls as at rest as at each exercise stage 13 paroxysmal No differences were found in AF patients D-dimer and PAP levels 13 rheumatic After anticoagulation, levels AF patients of t-PA, PAI-1 and D-dimer decreased, whereas PAP levels increased 12 rheumatic No differences were found in patients PAP and D-dimer levels (11 in AF)
AF: atrial fibrillation; PAP: plasmin – a2-antiplasmin complexes; t-PA: tissue-type plasminogen activator; PAI-1: tissue-type plasminogen activator inhibitor-1; Lp(a): lipoprotein (a); vWf: von Willebrand factor; sTM: soluble thrombomodulin: TEE: transesophageal echocardiography.
We previously described a hypofibrinolytic state in both rheumatic and non-rheumatic AF, with elevated PAI-1 antigen and t-PA/PAI-1 complex levels, with no increase in PAP concentration [71]. In the Stroke Prevention in Atrial Fibrillation (SPAF) III study, increased PAP levels were independently associated with older patients, recent congestive heart failure, impaired systolic function and recent onset of AF, suggesting the authors that high PAP levels could identify high embolic risk patients [72]. Increased levels of fibrin Ddimer have also been reported in AF, without significant differences in PAI-1 levels [73]. In addition, a recent study in lone AF (that is, without other vascular disease) found raised levels of plasma t-PA antigen and PAI-1 antigen [74]. In contrast, a small study of only 11 patients by Yamamoto et al. [75] did not find significant differences in fibrin D-dimer and PAP levels between rheumatic AF patients and controls.
Although paroxysmal AF has shown a similar stroke risk to permanent AF [2], the cross-sectional study by Lip et al. [76] reported intermediate elevated levels of fibrin D-dimer and fibrinogen in patients with paroxysmal AF, compared to chronic AF and those in sinus rhythm. The study by Sohara et al. did not find raised levels of fibrin D-dimer or PAP in their small group of patients with paroxysmal AF [77], although increased levels of markers of platelet activation and fibrinogen were found during episodes of AF of more than 12 h [78]. It is of note that there is a diurnal variation in fibrinolytic activity, with the lowest activity in the early morning, which could be relevant to time of onset of cardiovascular disease [79]. Indeed, a circadian rhythm of stroke onset has been reported among patients with AF [80], although no significant diurnal variation in plasma prothrombotic markers has been found in chronic AF patients [81]. After exercise, PAP levels are increased but lower than that seen in healthy controls [69]. More recently, Li-Saw-Lee et al. [82] found a reduction in PAI-1 levels in patients with chronic AF after exercise, suggesting a transitory activation of the fibrinolytic function [34]. Elevated serum levels of Lp(a) were strongly associated with left atrial thrombus in transesophageal echocardiography in a study of 150 consecutive patients with chronic AF [83]. However, other studies have been disappointing, without any significant relationship between Lp(a) and fibrin Ddimer levels [84], in keeping with the strong genetic influence of Lp(a) and its prothrombotic effects. To our knowledge, there are no studies on the influence of apo(a) isoforms on prothrombotic markers in AF. Nevertheless, analytical methods for Lp(a) and apo(a) levels are not standardized, making it difficult to allow to make precise comparisons of results from different studies [44]. 4.1.1. Effects of antithrombotic therapy There is an improvement in fibrinolytic markers in rheumatic AF after ‘steady state’ oral anticoagulation [85], although in non-rheumatic patients, a less marked improvement was noted [86], suggesting the possible role of confounding factors, such as cardiovascular risk factors, heart failure or ischaemic heart disease. On the other hand, fibrin D-dimer levels do not modify significantly after treatment with aspirin, whereas conventional warfarin therapy reduced this marker [17]. Indeed, fibrin D-dimer levels only reduce after full anticoagulation with adjusted dose warfarin (INR 2 – 3), with no significant changes in patients treated with fixed low dose of warfarin or aspirin – warfarin combination therapy [73]. In contrast, Feinberg et al. [72] observed no difference in PAP levels between patients with and without oral anticoagulation, and these were not associated to INR levels. However, these results should be considered with some caution, as the authors did not study the patients prior to, and after initiation of, anticoagulation, and it is possible that the anticoagulation time was insufficient in some cases.
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4.1.2. Implications Plasmin is thought to be the most important physiological activator in vivo of the matrix metalloproteinases [21]. For example, the increased activity of fibrinolytic function in recent onset of AF [72] could activate metalloproteinases, participating actively in the remodelling of the atria. However, permanent AF seems to give a greater prothrombotic state [87], with impaired fibrinolytic function [71] and decreasing PAP levels. This theoretical hypofibrinolytic state could reduce the activity of matrix metalloproteinase-1, as described in end-stage dilated cardiomyopathy [88], leading to an increase of interstitial amount of collagen in the wall [89]. This hypothesis would need to be fully established in patients with AF. In this way, we have recently described that patients with AF showed impaired matrix degradation, and there was an independent relationship between the matrix metalloproteinase system and the prothrombotic state [90]. Importantly, there are currently no prospective data about the value of fibrinolytic markers and thromboembolic risk in AF, although in the SPAF III study [72], raised PAP levels were associated with known thromboembolic risk factors. Another question arises as to why AF is associated with increased t-PA antigen and PAI-1 antigen levels. The role of confounders could be important. Indeed, it is possible that subjects with higher or uncontrolled blood pressure, more severe heart failure or ischaemic heart disease develop AF. The coexistence of hypertension and insulin resistance could also lead to an impaired fibrinolytic function. However, studies performed in patients with lone AF suggest that AF by itself modifies fibrinolytic markers [69,74]. The high levels of t-PA and PAI-1 antigen could also represent markers of endothelial cell damage or dysfunction. Thus, although there were no statistical differences in t-PA antigen levels between patients and controls, a significant correlation can be shown between t-PA levels and left atrial diameter, at least in the subgroup of rheumatic AF [71]. In other studies, significant correlations were found between t-PA antigen level and accepted endothelial markers, such as von Willebrand factor and soluble thrombomodulin [62,91]. The finding that inflammation could play an important role in AF [92,93] raises the hypothesis that inflammation could increase plasma PAI-1 levels, impairing fibrinolytic function. Indeed, endotoxin or bacterial inflammatory mediators increase PAI-1 production by human endothelial cells [94]. Certainly, it has been stated that ‘‘inflammation can beget local thrombosis, and thrombosis can amplify inflammation’’ [95]. Different anti-inflammatory therapies can potentially be effective against thrombogenesis [96], although the suggestion has been made that antithrombotic therapy may decrease inflammation [95]. Hence, in a recent preliminary study, introducing oral anticoagulation may have an anti-inflammatory effect in AF by decreasing C-reactive protein levels, but not interleukin-6 levels [97]. These observations could in part explain the improvement in fibrinolytic function with stable anticoagulant therapy [85,86].
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5. Conclusion Raised levels of PAI-1 and fibrin D-dimer, with inconsistent findings in plasmin – a2-antiplasmin concentrations, have been described in AF. Different hypotheses have been proposed about the role of fibrinolytic function in AF, including endothelial damage or dysfunction, inflammation or other confounders, such as hypertension or insulin resistance. New prospective studies are required to characterise the interaction of fibrinolytic function and clinical outcomes in AF.
Acknowledgements VR was supported by a research grant from the Spanish Association of Hematology (AEHH). FM was supported by a research grant from the Spanish Society of Cardiology. We acknowledge the support of the Dowager Countess Eleanor Peel Trust and the City Hospital Research and Development programme for the Haemostasis Thrombosis and Vascular Biology Unit.
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