Identifying high-risk individuals for cardiovascular disease: similarities between venous and arterial thrombosis in perspective. A 2011 update
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- 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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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.
KeywordsAtherosclerosisArterial thrombosisVenous thrombosisHigh-risk individuals for cardiovascular disease
Conditions associated with a raised risk of arterial and venous thrombotic events
Factor V Leiden and/or G20210A prothrombin variant
Antiphospholipid antibody syndrome
Cancer, particularly myeloproliferative disorders
Infection (Chlamydia pneumoniae)
Paroxysmal nocturnal hemoglobinuria
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.  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 ; LMWH are not only effective in preventing and treating venous thrombosis , 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 , 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 [20–22]. Finally, rosuvastatin, a statin known to play a dominant role in the prevention of arterial events, prevents, in a time-dependent fashion, VTE . Furthermore, fish, fruit, and vegetable intakes are related to a lower incidence of arterial events as much as they are with respect to VTE ; regular sports activities decreases the risk of arterial, as much as of venous thrombosis ; and moderate alcohol consumption reduces the risk of arterial events , as much as venous events . 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
Cardiovascular risk factors and venous thromboembolism. A meta-analysis
OR or WMD*
Diagnostic criteria for the metabolic syndrome—NCEP 2001
Abdominal obesity (waist circumference)
>130 and/or >85 mmHg
>100 mg/dL (from 2005)
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.  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. , 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. , 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.  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.  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.  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 . 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 . 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.  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.