Internal and Emergency Medicine

, Volume 7, Issue 1, pp 9–13

Identifying high-risk individuals for cardiovascular disease: similarities between venous and arterial thrombosis in perspective. A 2011 update

Authors

    • Regional Reference Centre for Coagulation Disorders“Federico II” University
  • Antonella Tufano
    • Regional Reference Centre for Coagulation Disorders“Federico II” University
  • Walter Ageno
    • Department of Clinical MedicineUniversity of Insubria
  • Paolo Prandoni
    • Department of Cardiothoracic and Vascular Sciences, Thromboembolism UnitUniversity of Padua
  • Giovanni Di Minno
    • Regional Reference Centre for Coagulation Disorders“Federico II” University
IM - REVIEW

DOI: 10.1007/s11739-011-0582-y

Cite this article as:
Di Minno, M.N.D., Tufano, A., Ageno, W. et al. Intern Emerg Med (2012) 7: 9. doi:10.1007/s11739-011-0582-y
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Abstract

The aim of this narrative review is to assess the potential association between arterial and venous thrombotic events. Several studies have suggested that the major cardiovascular risk factors, alone or in combination (e.g. in the metabolic syndrome), are significantly associated with venous thromboembolism (VTE). Recent evidence also suggests that microalbuminuria and non-alcoholic liver steatosis, both markers of arterial disease, may independently predict the risk for VTE. An association between a history of VTE and the risk of future arterial events is also well documented, inflammation and endothelial dysfunction being thought as the common soil on which further investigation in the area should be pursued. The existence of a common pathophysiologic background is also suggested by the evidence that aspirin, low-molecular weight heparin (LMWH) and warfarin are recommended for the prevention and treatment of both venous and arterial thrombosis. In addition, rosuvastatin recently has been shown to prevent venous thromboembolism (VTE) in a time-dependent fashion. Together, these data argue for patients with a history of VTE as being at intermediate/high cardiovascular risk, a concept that implies that VTE patients should undergo a careful assessment for the presence of cardiovascular risk factors and adequate lifestyle changes. The value of routine screening for asymptomatic atherosclerosis (e.g. 2D echocardiography, microalbuminuria, arterial vessel ultrasonography) in these patients should be confirmed in future studies.

Keywords

AtherosclerosisArterial thrombosisVenous thrombosisHigh-risk individuals for cardiovascular disease

Introduction

Almost 15 years ago, while analyzing the long-term clinical course of patients with acute deep venous thrombosis (DVT), Prandoni et al. [1, 2] first reported an association between atherosclerosis and venous thromboses. In a multivariate analysis on 299 consecutive patients with a history of DVT, free from symptomatic atherosclerosis, and in 150 control subjects, they subsequently report that the odds ratio (OR) for carotid plaques identified by carotid ultrasonography is 2.4-fold higher in subjects with spontaneous DVT versus those with secondary thrombosis, as well as versus controls [3].Common knowledge is that arterial and venous thrombosis are separate disease entities. Platelets are known to play a dominant role in arterial thrombosis, their tendency to aggregate and to form thrombi being maximal following plaque rupture/fissuring under high shear stress conditions. Clots in venous thrombosis tend to form in intact vessels, especially at a low shear rate, and differ from the arterial ones in that they are rich in red cells and fibrin [4]. However, there are conditions where similarities between arterial and venous thrombosis exist: (1) fibrin-rich thrombi occur in the left atrial appendage of patients with atrial fibrillation (AF),and in the coronary artery system of patients with myocardial infarction (MI) [5, 6]; (2) aspirin may have an effect in the prevention of venous thromboembolism (VTE), which implies that platelets inevitably play a role in the formation of thrombi in the venous system [7], and (3) subjects with retinal vein occlusion (RVO) commonly have associated major cardiovascular (CV) risk factors (mainly arterial hypertension) [8]. In accordance with this, Hong et al. [9] report a prevalence of coronary calcium in 89 patients with unprovoked VTE of 51.7% as compared to 28.1% in 89 controls (p = 0.001, OR [multivariate model], 4.3 (1.9–10.1)). On the other hand, the relative risk (RR) of VTE in subjects with any arterial thrombosis is 1.4 (1.3–1.5) [10]; and there are a series of conditions associated with an increased risk of both arterial and venous thrombotic events. More in detail, as depicted in Table 1, some risk factors such as hyperhomocysteinemia [11], antiphospholipid antibody syndrome [12], cancer (mainly myeloproliferative disorders) [13], chemotherapy [14], and hormonal therapy [15] have been found to be associated both with arterial and with venous thrombotic events. Available data to support an association between arterial and venous thrombotic disorders will be summarized in the following paragraphs.
Table 1

Conditions associated with a raised risk of arterial and venous thrombotic events

Hyperhomocysteinemia

Factor V Leiden and/or G20210A prothrombin variant

Antiphospholipid antibody syndrome

Factor VIII:C

Cancer, particularly myeloproliferative disorders

Chemotherapy

Hormonal therapy

Infection (Chlamydia pneumoniae)

Paroxysmal nocturnal hemoglobinuria

HIV infection

HIT, DIC

Inflammatory bowel diseases

Association between arterial and venous thrombotic events: hints from interventional studies

In a recent systematic review on antithrombotic and fibrinolytic drugs for retinal vein occlusion (RVO), Squizzato et al. [16] stress that, in spite of the fact that low-molecular weight heparins (LMWH) appeared to have the best risk–benefit profile, a partial improvement of visual acuity is reported in every study devoted to such patients, regardless of the type of drug employed, either antiplatelet or anticoagulant agents. On the other hand, aspirin, a pivotal drug for the prevention of arterial events, has been documented to be useful to prevent venous thrombosis [17]; LMWH are not only effective in preventing and treating venous thrombosis [18], but also for the treatment of arterial events (e.g. acute coronary syndromes); warfarin is recommended for the prevention and treatment of both venous and arterial thrombosis [19], and also the new orally active anticoagulant drugs such as dabigatran and rivaroxaban appear to be effective against arterial thrombosis, as much as they are against venous events [2022]. Finally, rosuvastatin, a statin known to play a dominant role in the prevention of arterial events, prevents, in a time-dependent fashion, VTE [23]. Furthermore, fish, fruit, and vegetable intakes are related to a lower incidence of arterial events as much as they are with respect to VTE [24]; regular sports activities decreases the risk of arterial, as much as of venous thrombosis [25]; and moderate alcohol consumption reduces the risk of arterial events [26], as much as venous events [27]. All such observations strongly support the likelihood of an underlying pathogenetic link between venous and arterial thrombosis.

Association between arterial and venous thrombotic events: common risk factors

In a meta-analysis, Ageno et al. [28] document that the major CV risk factors are significantly associated with VTE (Table 2). In that report, cigarette smoking is not significantly associated with VTE. This finding is in accordance with the results of the FAST Study [29], but not with the results of two recent reports not yet available when the meta-analysis was performed [30, 31], which suggested that the discrepancy between the reports may be related to daily tobacco doses. Microalbuminuria is an important marker of arterial thrombosis. In a large study (PREVEND) carried out in 85,421 individuals aged between 28 and 75 years in the Netherlands [12, 32] 9 of the 8,574 evaluable subjects had a thromboembolic event after a follow-up period of 8.6 years. There is a direct association between the amounts of urinary albumin and the annual incidence of VTE (p for trend <0.001), with an adjusted hazard ratio (HR) for microalbuminuria of 2.00 (p < 0.001) as compared to normo-albuminuria, suggesting that microalbuminuria may also be an independent marker of the risk for VTE.
Table 2

Cardiovascular risk factors and venous thromboembolism. A meta-analysis

 

Cases

Controls

OR or WMD*

95% CI

Smoking habit

3.760

34.520

1.15

0.92–1.44

Diabetes mellitus

5.990

50.367

1.41

1.12–1.77

Visceral obesity

8.125

23.272

2.32

1.69–3.24

Hypertriglyceridemia

1.478

30.552

17.48*

9.64–25.31

Total cholesterol

1.707

31.429

3.89*

−6.02–13.90

Low HDL-cholesterol

895

9.841

−2.96*

−4.34–1.28

Hypertension

12.813

29.742

1.51

1.23–1.85

From Ageno et al. [28], modified

* WMD Weighted mean difference

The metabolic syndrome is strongly associated with cardiovascular disease and cardiovascular mortality [33]. Table 3 reports the parameters of the metabolic syndrome. In 2006, Ageno et al. [34] first reported an association between the metabolic syndrome and DVT, the risk of DVT being almost twice as high in subjects with the metabolic syndrome as compared to those without. This association is further confirmed by the results of subsequent case–control studies [35, 36], and partially confirmed by the results of two cohort studies [37, 38]. In accordance with this, in a case–control study on 138 subjects with a recent idiopathic VTE, nonalcoholic fatty liver, a clinical condition often found in subjects with the metabolic syndrome [39], significantly and independently predicts the development of idiopathic VTE (OR: 1.9; 95% CI: 1.05–3.8; p < 0.0001) [40]. Taken together, the results of these studies suggest that a number of interesting open issues remain to be addressed. These include whether the metabolic syndrome, and in particular, abdominal obesity (with or without other features of the metabolic syndrome), better predict VTE than obesity defined by the BMI; whether the association between the metabolic syndrome and VTE is age or gender-related, as previously reported by some authors for the association with cardiovascular disease, and as previously suggested by one of the two cohort studies, and which of the several definitions of the metabolic syndrome can better predict VTE. These findings have been challenged. In two recent prospective studies [41, 42] of 4,108 and 13,081 subjects, respectively, during a follow-up (14 and 12 years, respectively), an increased carotid intima-media thickness (IMT) or the presence of carotid plaque is not associated with an increased incidence of VTE. However, considering that, carotid plaques and arterial events show an inverse correlation [41], further studies are needed to address this issue. In view of these, to gain useful information on the correlation between CV risk factors and idiopathic VTE, we are performing an individual patient data meta-analysis in over 1,000 subjects with asymptomatic atherosclerosis.
Table 3

Diagnostic criteria for the metabolic syndrome—NCEP 2001

Risk factors

Numeric values

Abdominal obesity (waist circumference)

 Males

>102 cm

 Females

>88 cm

Triglycerides

>150 mg/dL

HDL-Cholesterol

 Males

<40 mg/dL

 Females

<50 mg/dL

Blood pressure

>130 and/or >85 mmHg

Fasting glucose

>110 mg/dL

>100 mg/dL (from 2005)

The coexistence of three or more of these risk factors is needed for the diagnosis of a metabolic syndrome

Association between arterial and venous thrombotic events: history of venous thrombosis and risk of future arterial events

Some relevant reports address this issue in recent years. The paper by Becattini et al. [43] reports data on 360 patients with a history of pulmonary embolism (PE) who were included in a 38 months follow-up study. Of them, 209 had an unprovoked PE and 151 a secondary PE. The risk of acute MI, death and CV events is significantly higher in patients with unprovoked PE as compared to patients with secondary PE. A retrospective cohort study by Bova et al. [44], compares 151 patients with idiopathic VTE with 151 controls. After 43.1 months there were 16 arterial events in patients with a history of VTE and 6 in controls (HR 2.84, p = 0.03). In the paper by Prandoni et al. [45], 1,919 consecutive patients (1,063 with a history of unprovoked VTE and 856 patients with a history of secondary VTE) were prospectively followed up for 48–51 months. At least one CV episode was found in 15.1% of patients with unprovoked VTE and in 8.5% with secondary VTE. After adjusting for age and other CV risk factors, the HR for symptomatic atherosclerosis is 1.6 and, after excluding patients with documented atherosclerosis, the HR is 1.7. Spencer et al. [46] showed that, when compared to controls, patients 20–39 years old with unprovoked juvenile VTE showed an increased risk of acute MI (HR 3.92). Such difference is no longer present when subjects 40–64 years old are taken into consideration. Klok et al. [47] report cumulative arterial CV event rates in patients with unprovoked PE (n = 95), with provoked PE (n = 259) and in control patients without PE (n = 334). As many as 63 arterial events occurred during the follow-up period (4.2 years, mean).The HR is comparable in subjects with a provoked PE and in controls, and significantly different from that of those with unprovoked PE (HR 2.18 vs. 2.62).

The number of fatal MI and fatal strokes in a 10-year follow-up was evaluated by Schulman et al. [48] in the DURAC Study: the risk is found to be 28% higher in patients with a first VTE than in a general population. The risk of death from vascular causes is found to be fourfold higher in patients with a history of DVT and residual venous thrombosis on follow-up scan, than in patients with full recanalization [49]. In a population-based cohort study using nationwide Danish medical databases, the risk of hospitalization due to MI, stroke and transient ischemic attack (TIA) was estimated among 25,199 patients with DVT, 16,925 patients with PE and 163,566 controls [50]. Compared to controls, during the first year of follow-up the risk of acute MI or stroke is 1.5- to 2-fold increased in the DVT cohort, and 2- to 3-fold increased in the PE cohort. In the following 19 years, this risk is still increased by 1.2- to 1.5-fold, as compared to controls. The maximal risk, during the first year of follow-up, is found in subjects with an unprovoked VTE.

An increased risk of CV events is also reported in patients with RVO. The risk of coronary artery disease and ischemic stroke in 45 patients with an early-onset history of RVO was evaluated by Di Capua et al. [8] in an 8-year follow-up. When compared to 145 age and gender matched individuals, the risk for CV events is increased by threefold, and the risk for cerebrovascular events by 5.5-fold. Cerebrovascular events occur mostly at a young age (<50 years of age) in subjects with a history of RVO, mostly after 64 years of age in controls.

Association between arterial and venous thromboembolic events: perspectives

Although “common mechanisms” underlying arterial and venous thrombosis appear largely unknown, some potential lines of research are suggested by the data presently available. Inflammation and endothelial dysfunction may be the common soil on which further investigation should be pursued. While waiting for this information, the data presented above may suggest that patients with a history of VTE should be considered at intermediate/high CV risk. This implies that also patients with VTE might benefit from a careful assessment of CV risk factors and active changes to their lifestyle. The value of routine screening for asymptomatic atherosclerosis (e.g. 2D echocardiography, microalbuminuria, arterial vessel ultrasonography) after VTE should be assessed in future studies. Whether prevention of VTE recurrence with aspirin will also be an appropriate strategy for primary cardiovascular prevention in this setting remains unclear. Hopefully trying to address this intriguing issue, ongoing studies, such as WARFASA (http://www.clinicaltrials.gov/ct2/show/NCT00222677?term=warfasa&rank=1) and ASPIRE (http://www.ctc.usyd.edu.au/trials/other_trials/aspire.htm), have been designed.

Conflict of interest

GDM and PP declare that they served on advisory boards and received honoraria and grants for research unrelated to this study. The other authors have nothing to declare.

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© SIMI 2011