Arterial and Venous Thrombosis: Clinical Evidence for Mechanistic Overlap
Authors: Ageno Walter 
Published: October 2019

Abstract
Venous and arterial thromboembolic disorders are usually considered as two separate pathophysiological entities. Over the last years, some clinical evidence challenged this common view. First of all, a number of studies have reported an increased risk of subsequent symptomatic atherothrombosis in patients with venous thromboembolism (VTE), in particular after unprovoked events. In a substudy of the Warfarin optimal duration Italian pulmonary embolism (WODIT PE) trial, the incidence of arterial cardiovascular events in patients affected by unprovoked pulmonary embolism (PE) was significantly higher than in patients with PE secondary to transient risk factors such as surgery, trauma or immobilization. This finding was subsequently confirmed by the results of a large prospective cohort study comparing the incidence of symptomatic atherosclerotic disease in patients with unprovoked VTE and patients with secondary VTE. In a subsequent population-based cohort study from Denmark, the relative risk of cardiovascular events in the first year after deep vein thrombosis (DVT) and after PE was significantly higher than in a control population and remained increased during the subsequent 20 years of follow-up. The results of these and other studies were summarized in a meta-analysis of the literature that confirmed a significantly higher incidence rate ratio of arterial cardiovascular events in patients with unprovoked VTE than in patients with provoked VTE and in controls. A possible explanation for such association between unprovoked VTE and arterial thrombosis could be represented by shared risk factors between these disease entities. Among traditional cardiovascular risk factors, obesity and age have consistently been demonstrated to be independent risk factors also for VTE. Of interest, obesity was also shown to be associated with a significantly increased risk of recurrent VTE. Obesity, and in particular visceral adiposity (abdominal obesity), predisposes to inflammatory and hypercoagulable states thus resulting in a prothrombotic condition that may cause both venous and arterial thrombotic events. A study from Norway found abdominal obesity defined by the measurement of waist circumference to be a better predictor of the risk of VTE than obesity defined by the body mass index. In addition, abdominal obesity is commonly associated with the presence of arterial hypertension, diabetes mellitus, and dyslipidemia. In a meta-analysis of studies on the association between cardiovascular risk factors and VTE, we found all these major arterial risk factors to be significantly associated with venous thrombosis. In addition, we and others found an association between the metabolic syndrome, which is a cluster of cardiovascular risk factors, and VTE. Finally, a large-population based case-control study reported an increased risk of venous thrombosis in both current and ex-smokers compared to those who had never smoked. Although these associations were not fully confirmed by the results of prospective cohort studies, and although the strength of the association was not comparable to that reported for major traditional risk factors for venous thrombosis, these findings may be clinically relevant because cardiovascular risk factors are common, they frequently co-exist, and their co-existence may result in an additive effect. Moreover, most cardiovascular risk factors are modifiable. These observations also raised the question of whether drugs that are effective in preventing arterial thrombosis, such as aspirin and statins, may be also effective for the prevention of venous thrombosis. Two recent randomized controlled trials compared aspirin with placebo for the secondary prevention of VTE after an initial course of anticoagulant therapy. When the results of these two studies were pooled together, there was a statistically significant 32% reduction in the rate of VTE recurrence with no increased risk of major bleeding. In a meta-analysis, we found that statins reduce the risk of a first VTE event by 20%. Other studies have suggested that statins may also play a role in the secondary prevention of VTE, but no randomized controlled trials are available to support this hypothesis. In conclusion, the presence of cardiovascular risk factors should be carefully assessed in patients with unprovoked VTE and their management may concomitantly prevent subsequent atherothrombotic events and reduce the risk of recurrent VTE. Future studies should assess whether the combination of aspirin and statins may result in a substantial reduction of the risk of recurrent VTE.

Disclosures
Ageno: Bayer Healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; STAGO: Honoraria. Off Label Use: I will discuss evidences on the role of aspirin and statins for the prevention of venous thromboembolism.