Q J Med 2002; 95: 199-210
© 2002 Association of Physicians
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Peripheral vascular disease and Virchow's triad for thrombogenesis
From the Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, UK
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Introduction |
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 Top Introduction Virchow's triad and the...Abnormal blood flowBlood constituentsVessel wallThe hypercoagulable state in...ConclusionReferences |
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Peripheral vascular disease (PVD), with its symptomatic manifestation, intermittent claudication, is associated with significant morbidity and mortality,1–3 and is an important cause of clinic visits and hospitalizations.4 Many patients with PVD sustain cardiovascular complications, such as heart attacks and strokes,5 which represent the main causes of death in this condition, rather than PVD per se.2,6 Further, emergency treatment is commonly required in this condition due to thrombosis of the affected artery. Indeed, the ‘costs’ of peripheral artery occlusion resulting in critical leg ischaemia have been estimated at $500–1000 per million per year, with a mortality of about 20% per year in these patients.7
While it would be convenient to treat PVD as a single entity, this is not the case, as several almost distinct processes can be identified. The development of the atherosclerotic plaque is the obvious initial process, eventually progressing in severity and leading to intermittent claudication. The next is the progression to critical ischaemia, with rest pain and gangrene. The basic underlying pathophysiological processes underlying these major complications of PVD are thrombosis and atherogenesis. However, simply suggesting that these events are solely due to the exposure of the blood to the thrombogenic surface of the ruptured plaque, as is the case in coronary artery disease, may be simplistic. Closer examination suggests that thromboembolism, disease progression and the effect(s) of intervention (or failure of the latter) in PVD can be explained by careful reference to Virchow's triad for thrombogenesis.8
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Virchow's triad and the complications of peripheral vascular disease |
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TopIntroductionVirchow's triad and the...Abnormal blood flowBlood constituentsVessel wallThe hypercoagulable state in...ConclusionReferences |
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Over 150 years ago, Virchow postulated that three features predispose to thrombus formation: abnormalities in blood flow, blood constituents and the vessel wall.8 Although Virchow was referring to venous thrombosis, these concepts can also be applied to arterial thrombosis. An update of Virchow's triad for thrombogenesis for the new millennium can be considered by reference to abnormalities of haemorheology and turbulence at bifurcations and stenotic regions (that is, ‘abnormal blood flow’), abnormalities in platelets as well as the coagulation and fibrinolytic pathways (‘abnormal blood constituents’) and finally, abnormalities in the endothelium (‘abnormal vessel wall’).8 The evidence suggests that each of these components of Virchow's triad are present in PVD, fulfilling the conditions of a prothrombotic or ‘thrombogenic’ state in PVD. Furthermore, the processes of thrombogenesis and atherogenesis are intimately related, and an appreciation of the many interactions leading to a prothrombotic or hypercoagulable state in PVD may bring insights into its pathophysiology, as well as helping to identify potential therapeutic targets.
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Abnormal blood flow |
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TopIntroductionVirchow's triad and the...Abnormal blood flowBlood constituentsVessel wallThe hypercoagulable state in...ConclusionReferences |
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‘Abnormal blood flow’ is evident in patients with PVD by various mechanisms, with examples in the literature summarized in Table 1
. Firstly, blood has several rheological properties that determine its ability to flow through any vessel. Blood is, for the purposes of flow analysis, essentially a fluid (plasma) with particles in suspension (mostly red blood cells). In addition, local flow conditions are made up of the viscosity of the blood and the resistance offered by the vessel, as well as turbulence at vessel bifurcations and stenotic regions.
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The flow of blood is altered in PVD, with decreased flow volumes and different flow characteristics compared with healthy individuals.9 With respect to blood itself, quantification of its flow properties can be made by measurement of haemorheological indices, such as plasma viscosity, whole blood viscosity, haemocrit and haemoglobin.10–14 Importantly, both blood and plasma viscosities can be related to symptomatic and asymptomatic PVD.14 For example, in the Edinburgh Artery Study, whole-blood viscosity was independently related to PVD, whilst plasma viscosity was related to the degree of arterial narrowing in the presence of claudication, after correction for other confounding factors. Elevated levels of haemoglobin and plasma viscosity have also been found in patients with PVD.12 As Koenig et al.12 concluded, ‘blood fluidity is pathologically altered’ in this situation.
The increase in plasma viscosity has been shown to be associated with increased symptoms in PVD,15 and may be correlated with the clinical stage of the disease and its progression.16 Nevertheless, abnormalities of haemorheology, such as whole blood viscosity, are also abnormal in the recognized risk factors for PVD, such as diabetes and hypertension,17,18 which raises the question as to whether the changes simply reflect the underlying disease process. However, large epidemiological studies correcting for the presence of these underlying risk factors have clearly shown an independent relationship of whole-blood viscosity with PVD.14
If these abnormalities are pathophysiologically related to PVD, the possibility arises that improvement of haemorheology may ‘improve’ PVD. For example, if a high haemocrit level is corrected by venesection and haemodilution, the tissue oxygen supply can be significantly improved in severe claudicants,10 suggesting that at least part of the symptoms in severe PVD may be due to abnormal haemorheology. Otherwise, the available data examining the effects of interventions on blood rheology on PVD outcomes remain limited. It should not be forgotten that various constituents of blood also contribute to its haemorheological properties, and indices such as fibrinogen and von Willebrand factor19 can be considered under both ‘blood flow’ and ‘blood constituents’ headings. In healthy subjects, for example, plasma fibrinogen contributes more to plasma viscosity than other plasma proteins, and is thus a very important determinant of the rheological characteristics of blood flow.
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Blood constituents |
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TopIntroductionVirchow's triad and the...Abnormal blood flowBlood constituentsVessel wallThe hypercoagulable state in...ConclusionReferences |
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For a hypercoagulable state to exist, Virchow's triad suggests that there must be an increased level of the relevant blood constituent(s) required to produce thrombosis. Examples in the literature suggesting ‘abnormal blood constituents’ in PVD are summarized in Table 2
. Many abnormal indices of blood constituents have been noted in PVD, but most are related to the coagulation and fibrinolytic systems.
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For example, plasma fibrinogen is an essential component of the blood coagulation system. However, at the ‘usual’ plasma levels of 1.5–4.5 g/l, its concentration far exceeds the minimum concentration of 0.5 g/l necessary for haemostasis. It is therefore postulated that elevated levels of plasma fibrinogen (and other clotting markers) may reflect a hypercoagulable or prothrombotic state. Other indices of interest include fibrin degradation products, such as fibrin D-dimer, which reflect intravascular fibrin turnover and intravascular thrombogenesis. The fibrinolytic system is represented by measurement of plasminogen activator inhibitor (PAI-1) and tissue plasminogen activator (tPA) activities. As tPA antigen is also produced by the endothelium, as is von Willebrand factor (vWf), elevated levels of these indices have been used to represent generalized endothelial damage or dysfunction. The ease of measurement of many of these plasma markers has allowed their use in epidemiological studies, and some markers such as fibrinogen, fibrin D-dimer and vWf (which are described further below) have even been shown to have prognostic value in PVD.
Fibrinogen
Fibrinogen is the plasma precursor of fibrin, the base matrix of any clot. It has been repeatedly shown in the Edinburgh Artery Study, among others, that increased fibrinogen concentration is associated with the presence of PVD compared with controls,20–24 independently of smoking23 or diabetes.25 Increased plasma fibrinogen levels can be related to increasing severity of disease at angiography24,26 as well as ankle brachial pressure index (ABPI).27 The prognostic value of fibrinogen is illustrated by the Edinburgh Artery Study, in which median fibrinogen levels were higher in patients who later went on to develop PVD.28 In patients with intermittent claudication, plasma fibrinogen concentrations are also an independent predictor of death.29,30
The observed relationship between increasing fibrinogen and low ABPI27 is pertinent, as all-cause mortality and cardiovascular events are more common in patients with a low ABPI,31,32 emphasizing the importance of abnormal coagulation. Further, the evidence implies that lowering fibrinogen concentrations in patients with PVD and hyperfibrinogenaemia might be beneficial, but the available data are very disappointing, with lack of long-term outcome data. For example, some efforts to reduce plasma fibrinogen concentrations in patients with PVD by supplementation with niacin have been reported33 and plasma fibrinogen levels did decrease, with some resolution of critical limb ischaemia.34 In addition, in one study where patients with PVD were given long-term ibuprofen or pentoxifylline, their claudication distance increased, but there was no significant effect on their plasma fibrinogen concentration.35
Fibrin degradation products
Raised levels of plasma fibrin D-dimer, an index of intravascular thrombogenesis and fibrin turnover, have been consistently reported in patients with PVD.13,23,36–38 Importantly however, there is an increasing linear trend in fibrin D-dimers with increasing severity of PVD.39,40 Raised fibrin D-dimer levels have also been shown in patients with diabetes mellitus and PVD21 and those who smoke,23 leading to the conclusion that these processes might add to the progression of the disease. Importantly, however, there is a relation between fibrin degradation products (FDPs) and the angiographic extent of PVD, with FDPs being an independent predictor of severity.24,41
Not only are FDPs associated with severity of disease but they are also associated, like fibrinogen, with its progression.42 For example, in 1993, the Edinburgh Artery Study reported an independent relationship between FDPs and cardiovascular events in patients with PVD,42 but the most recent analysis from the same investigators28 no longer found an independent relationship between FDPs and PVD progression. Similarly, Boneu et al.43 found no correlation between fibrin D-dimer levels in non-diabetic patients with chronic leg ischaemia and events. In addition, FDPs are not reduced following successful angioplasty and are not useful in predicting restenosis, unlike plasma fibrinogen levels which are lower in restenosis following percutaneous transluminal angioplasty.44 Resolution of critical limb ischaemia also leaves FDPs unchanged,34 and indeed, they are higher in patients with prosthetic infrainguinal bypass grafts, compared to those in whom autologous vein grafts are used.45
Plasminogen activator inhibitor 1 (PAI-1) and tissue plasminogen activator (tPA)
The process of thrombogenesis is a fine balance between the coagulation and fibrinolytic pathways. The fibrinolytic system is primarily influenced by the interaction between plasminogen activators (such as tissue plasminogen activator (tPA), which promotes fibrinolysis) and inhibitors that modulate this activity (such as plasminogen activator inhibitor 1; PAI-1).
The ratio of active tPA to active PAI is approximately 1:8 in healthy male subjects, but in men with atherothrombotic disease, this ratio is severely disturbed at 1:50.45 The suggestion that impaired fibrinolysis may play an important role in the pathogenesis of PVD needs to be further qualified by whether measurements of tPA and PAI-1 antigens or activities are performed. Both tPA and PAI-1 molecules can be assayed by immunological techniques (ELISA) and by a functional technique. Consequently, the problem of structural vs. functional presence arises, and the possibility of (inactive?) tPA/PAI complexes being quantified. Ridker et al. have even suggested that elevations of tPA antigen are the result rather than a cause of atherosclerotic coronary disease.46 Rather than being a measure of fibrinolysis, tPA antigen levels may thus be simply a surrogate for vascular injury, without taking part in haemostasis. Measurement of tPA antigen could therefore be another measure of endothelial cell damage or dysfunction, although this may be a premature assumption as some plasma levels may, like levels of PAI-1, arise from platelets.47
In general, raised levels of plasminogen activator inhibitor 1 (PAI-1) are associated with an impaired fibrinolytic potential, and would thus contribute to a hypercoagulable state. Thus it is unsurprising that patients with PVD have increased PAI capacity, independent of other cardiovascular risk factors.46,47 Levels of PAI-1 are also higher in symptomatic patients with PVD when compared to controls in most22,24,27,48,49 but not all50 studies. Further, PAI-1 concentrations do not increase with acute exercise in claudicants,51 and levels also do not appear to be associated with disease severity.27,49,52 Raised levels are associated with the risk of developing subsequent PVD,47 but contradictory evidence exists as to the predictive value of PAI activity in percutaneous angioplasty. For example, Price et al.44 did not find PAI to be predictive of restenosis, whereas Roller et al.22 suggested that PAI activity increased at 24 and 48 h post procedure in patients who subsequently developed a late restenosis.
Tissue plasminogen activator (tPA) is involved in the promotion of fibrinolysis, and decreased tPA activity is seen in patients with severe claudication when compared with moderate claudication and controls. Decreased tPA activity has also been associated with higher levels of PAI-1 and a marked imbalance in fibrinolytic potential.47,49 However, there are limited data on the relationship of tPA levels to outcomes in PVD. For example, the Edinburgh Artery Study found no association between tPA and progression of the disease.28 Other medical and surgical interventions that influence tPA (or PAI-1) levels have also been disappointing. Arterial blood taken from the site of successful angioplasty shows an immediate fall in tPA levels but this was associated with an immediate increase in fibrinolysis, making the mechanism somewhat uncertain.53 One study reported that tPA levels in young patients with hyperhomocysteinaemia and PVD were normal at baseline and did not change with treatment to decrease homocysteine concentrations.54
Von Willebrand factor (vWf)
The vascular endothelium is intimately associated with the regulation of vessel tone and permeability, haemostasis, fibrinolyis and synthesis of growth factors. vWf is synthesized by and stored in Weibel-Palade bodies of the endothelial cells, megakaryocytes and platelets, and when released, appears to mediate platelet aggregation and adhesion to the vascular endothelium. As vWf is released when endothelial cells are damaged, this molecule has been used as an indicator of endothelial damage or dysfunction.47
A number of studies have found increased vWf in the plasma of patients suffering from PVD, compared to controls.55 High vWf levels have been independently associated with intermittent claudication13 as well as the severity of PVD in symptomatic patients.55,56 However, in the Edinburgh Artery Study, vWf levels did not predict progression of PVD.28
Homocysteine
It has been known for many years that patients with homocysteinuria have a high incidence of atherosclerotic vascular disease, but it is only relatively recently that mildly raised homocysteine levels in the blood have been implicated in vascular disease. Elevated levels of homocysteine have not only been implicated as a risk factor for PVD,57–59 but also in the progression of PVD60 and as a risk factor for failure of vascular intervention in PVD,61 although some studies have not shown an increased risk with hyperhomocysteinaemia.58,62 Within the context of Virchow's triad, it is perhaps a little difficult to determine whether ‘hyperhomocysteinaemia’ should be presented under ‘blood constituents’ or ‘vessel wall’.
Raised levels of homocysteine cause damage to the endothelium in vivo,63 providing evidence for the involvement of the vessel wall. It also, however, promotes auto-oxidation of low-density lipoprotein cholesterol64 and thrombosis. Homocysteine is an independent risk factor for premature vascular disease, with an odds ratio of >3.2 in one study.65 There is an increased prevalence of moderate hyperhomocysteinaemia in patients with premature arterial occlusive disease compared to controls66 and homocysteine is increased in older people with proven PVD.59 In addition to progression of atherosclerotic vascular disease, increased homocysteine is significantly associated with death from cardiovascular disease in those already symptomatic.67 This effect was exaggerated after an oral methionine load (since methionine is a metabolic precursor of homocysteine).
Increased levels of homocysteine are associated with low levels of folate in these patients.59,68 Further, if moderately homocysteinaemic patients who are otherwise well are given supplementary folic acid, arterial endothelial function (as measured by flow-mediated-dilatation) is improved,69 suggesting a possible mechanism leading to a decreased risk of atherosclerotic disease.
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Vessel wall |
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TopIntroductionVirchow's triad and the...Abnormal blood flowBlood constituentsVessel wallThe hypercoagulable state in...ConclusionReferences |
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It should not be forgotten that ‘abnormal vessel wall’ could be demonstrated by well-documented abnormalities in both flow-mediated and pharmacological arterial vasodilatation (or arterial compliance), as well as abnormalities of levels of specific plasma markers of endothelial damage or dysfunction, such as von Willebrand factor (vWf), which have been described above. Examples in the literature suggesting the presence of an ‘abnormal vessel wall’ in PVD are summarized in Table 3
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Colour duplex assessment of the blood through a peripheral artery stenotic lesion classically shows the turbulent flow that, among other things, allows the lesion to be identified. Wall damage can be divided into several categories in the context of PVD. There is a plaque occupying part of the wall, which in itself could be seen as damage, but tends to be covered in endothelium, albeit dysfunctional.70–72 There is also ‘plaque rupture’, revealing the highly thrombogenic lipid core. Rupture is often due to haemorrhage into the lumen of the vessel, exposing the core, which (not having the anti-thrombotic properties of the endothelium) causes fibrinogen activation and platelet aggregation, often resulting in occlusion of the vessel.
Even in the absence of an established atheromatous lesion, some properties of the blood vessel wall may be abnormal in PVD. For example, the elastic properties of the superficial femoral, common femoral, and popliteal arteries are reduced in patients with proven PVD.73 The arterial waveform is also altered in patients with PVD, suggesting the presence of abnormal structure or tone in the peripheral arteries.74 However, this may not be a global phenomenon, as radial artery compliance does not seem to be altered in patients with PVD.75 That said, it is also apparent that aortic stiffness should not be used as a marker for atherosclerosis elsewhere.76 In non-insulin-dependent diabetes, peripheral artery compliance is significantly reduced in patients with no clinical evidence of PVD.77,78 Furthermore, arterial compliance by analysis of the arterial waveform is also reduced in sedentary smokers with no evidence of PVD.79 It is therefore possible that part of the mechanism of development of PVD in these subjects could still be related to abnormalities in arterial compliance.
Perhaps the abnormalities in the ‘vessel wall’ could be more related to basic morphology. For example, the superficial femoral artery atheroma of patients with hyperhomocysteinaemia appears morphologically similar to that in those with normal levels, but there is a significantly decreased smooth muscle/extracellular matrix ratio of the media in hyperhomocysteinaemic patients when compared to those with normal levels and atherosclerotic disease, as well as healthy controls.80 This lack of smooth muscle could result in decreased vessel compliance, as discussed above. Further, the compliance and distensibility of the common femoral artery and common carotid artery are significantly increased by treating familial hypercholesterolaemic patients with a statin (HMG CoA reductase inhibitor)81 and the elasticity of the common carotid artery can be affected by the serum lipid profile, even in young men.82 This theme continues with the almost inevitable finding that carotid distensibility was lower and Young's modulus of elasticity (a measure of resistance to stretching in one plane) is higher in patients with carotid atherosclerosis compared to controls,83 and this method of measuring stiffness has been shown to be not only useful but highly reproducible.84 This seems to be a long-term effect, as the short-term lowering of cholesterol levels in hypercholesterolaemic patients does not appear to significantly alter the haemodynamic and vessel walls of the brachial, femoral or carotid arteries.85
Further enhancing the potential for wall asymmetry is the effect of shear stress, promoting even greater abnormalities of ‘vessel wall’ and perhaps, blood flow. Atherosclerosis is known to be a geometrically focal disease that has the propensity to invade the outer edges of blood vessel bifurcations.86–88 In these particular places, the blood flow is often slow and changes direction with the cardiac cycle. Places with low shear stress have a much higher disease susceptibility than the faster-flowing inner edges.86–88 Indeed, intimal thickness in the undiseased abdominal aorta correlates significantly with mean, minimum and oscillating wall shear stresses at rest measured in a pulsatile flow model using aortas from macroscopically disease-free necropsy specimens from young adults.86–88 No correlations were found with maximum shear stress parameters. Exercise changes the local wall shear stresses away from the characteristics associated with intimal thickness index, suggesting that the high shear stresses from the hyperdynamic flow of exercise might in some way be protective to the endothelium.89 Even at the microscopic level, examination of endothelial surfaces in human thoracic aortas reveals leukocyte adhesion, accumulation of subendothelial macrophages and lymphocytes, irregular endothelial morphology with denuded regions covered with platelets and dilated intracellular clefts in the outer walls, but not the inner walls or flow dividers of bifurcations.90
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The hypercoagulable state in PVD: cause or effect? |
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TopIntroductionVirchow's triad and the...Abnormal blood flowBlood constituentsVessel wallThe hypercoagulable state in...ConclusionReferences |
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Elevated plasma levels of various indices of the prothrombotic or hypercoagulable state in PVD are consistently associated with various vascular disorders and the risk of vascular events. It has been suggested that these associations may be explained by a reactive or secondary rise in components of the hypercoagulable state in PVD, either as an acute-phase response or as an atherosclerosis-related ‘haematological stress syndrome’.91 Since the processes of thrombogenesis and atherogenesis have certain similarities to inflammatory disease, the elevations in plasma indices of the hypercoagulable state may reflect the severity of vascular disorders as a secondary phenomenon rather than act as a true prognostic factor.
The hereditary determination of some indices of the hypercoagulable state, however, makes it less likely that raised levels are simply a secondary response to cardiovascular disorders. Raised plasma indices of the hypercoagulable state are also known to precede cardiovascular events. This is indicated by the prognostic value of some indices of the prothrombotic state, for example, in predicting reinfarction following myocardial infarction,92 and in patients with PVD.42,45 In patients with inflammatory vascular disease, vWf levels also have prognostic indications, with high levels predicting mortality, disease progression and cardiovascular events.93
There is experimental evidence that some indices of the prothrombotic hypercoagulable state may be increased by glucocorticoids and cytokines such as interleukin-1 and tumour necrosis factor, which are produced by monocytes and macrophages.94,95 The well-established increases in plasma indices of the hypercoagulable state in many cardiovascular disorders (including PVD) and atherosclerosis risk factors are however not always associated with an active acute-phase response. The precise mechanism for the elevated indices of the prothrombotic or hypercoagulable state in PVD remains uncertain, although a cytokine-mediated increase in synthesis may well be the final common pathway.
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Conclusion |
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TopIntroductionVirchow's triad and the...Abnormal blood flowBlood constituentsVessel wallThe hypercoagulable state in...ConclusionReferences |
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A great deal has been learnt about the cellular and molecular biology of various indices of the prothrombotic or hypercoagulable state. In PVD, there is clear evidence that the three components of Virchow's triad are fulfilled, with abnormalities of blood flow, blood constituents and vessel wall that are clearly evident in these patients. These abnormalities may be related to severity of disease as well as prognosis. Revascularization and some interventions may potentially alter these abnormalities, although the evidence here is much more limited. Attention to the prothrombotic or hypercoagulable state in PVD may possibly provide answers to the management and the development of new prevention strategies.
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Acknowledgments |
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We acknowledge the support of the City Hospital NHS Trust Research & Development programme for the Haemostasis Thrombosis and Vascular Biology Unit.
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Notes |
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Address correspondence to Professor G.Y.H. Lip, Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham B18 7QH. e-mail: g.y.h.lip{at}bham.ac.uk
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References |
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TopIntroductionVirchow's triad and the...Abnormal blood flowBlood constituentsVessel wallThe hypercoagulable state in...ConclusionReferences |
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