Venous and Arterial Thrombosis: Is there a Link?
Paolo
Prandoni, Marta Milan, Valentina Vedovetto, Lucia Sarolo, Angelo Adamo, Franca
Bilora
Paolo Prandoni, Marta Milan, Valentina
Vedovetto, Lucia Sarolo, Angelo Adamo, Franca Bilora, Department of
Cardiothoracic and Vascular Sciences, Vascular Medicine Unit, University
Hospital of Padua, Italy
Correspondence to:
Paolo Prandoni, Department of Cardiothoracic and Vascular Sciences,
University of Padua, Via Giustiniani 2, 35128, Padua, Italy.
Email: paoloprandoni@tin.it
Telephone: +39-049-8212656
Fax:
+39-049-8213781
Received: December 30,
2014
Revised: January 19, 2015
Accepted: January 25, 2015
Published online: July 6, 2015
ABSTRACT
Following the
demonstration that patients with deep venous thrombosis of the lower
extremities have a significant higher prevalence of carotid plaques than
matched control individuals, numerous studies have consistently shown that
patients with venous thromboembolism – especially those with events of unknown
origin – have a remarkably higher risk of developing subsequent arterial
thrombotic events than control subjects. The two vascular disorders share
several risk factors (including age, obesity, smoking habit, diabetes mellitus,
hypertension, hypertriglyceridemia, and metabolic syndrome) and the abnormal
elevation of markers of endothelial dysfunction (such as microalbuminuria and
the plasma levels of soluble P-selectin and von Willebrand factor). These findings
have potential implications for both research and medical practice. Patients
with venous thromboembolism could be examined for asymptomatic atherosclerosis,
in order to modify the risk profile in those with abnormal test results.
Measures could include appropriate counseling about lifestyle changes, control
of risk factors for atherosclerosis and the use of drugs, such as statin and
aspirin, whose effectiveness in reducing the risk not only of arterial but also
of venous thrombotic disorders has recently been shown.
© 2015 ACT. All
rights reserved.
Key words: Venous thromboembolism; Deep vein thrombosis; Pulmonary
embolism; Myocardial infarction; Ischemic stroke; Atherosclerosis
Prandoni P, Milan
M, Vedovetto V, Sarolo L, Adamo A, Bilora F. Venous and Arterial Thrombosis: Is
there a Link? International Journal of Hematology Research 2015; 1(2): 29-34
Available from: URL: http://www.ghrnet.org/index.php/ijhr/article/view/1002
INTRODUCTION
Venous and arterial thrombotic disorders have long been viewed as
separate pathophysiological entities, partly because of the obvious anatomical
differences, as well as their distinct clinical presentations. In particular,
arterial thrombosis has long been held to be largely a phenomenon of platelet
activation, whereas venous thrombosis is largely a matter of activation of the
clotting system. However, there is evidence that this dichotomy is likely to be
an oversimplification. Fibrin-rich thrombi form in the left atrial appendage of
patients with atrial fibrillation and in the coronary artery system of patients
with myocardial infarction. Accordingly, anticoagulant drugs are highly
effective for prevention of arterial embolism related to atrial fibrillation[1],
and for prevention and treatment of coronary artery disease[2].
Likewise, platelets play an inevitable role in the formation of thrombi in the
venous system, and antiplatelet agents have been shown to be effective for
prevention of venous thromboembolic (VTE) disorders, although to a smaller
extent than anticoagulant drugs[3,4]. As another example, subjects
who sustain a retinal vein thrombosis commonly have associated cardiovascular
risk factors[5], and the causes of mortality on follow-up are
usually arterial vascular events[6].
Generation
of the hypothesis
In the second half of the ‘90s, the author’s group published the
results of a prospective cohort study dealing with the long-term follow-up of a
wide cohort of patients after their first episode of both unprovoked and
provoked acute deep vein thrombosis (DVT) of the lower extremities[7].
While the predominant interest of this observation focused on the development
of recurrent VTE and late post-thrombotic sequelae, we were surprised by the
unexpectedly high proportion of patients who died of acute myocardial
infarction, ischemic stroke or experienced a sudden otherwise inexplicable
death. Although there was not a control group without thrombosis, we had the
perception that this proportion would be higher than that expected in matched
individual subjects free from thromboembolic disorders.
Association between VTE and
atherosclerosis
In order to assess whether an association exists between VTE and
atherosclerosis, in 1996, a prospective case-control study was initiated and
its results were published in 2003[8]. Ultrasonography of the
carotid arteries was performed in 299 unselected patients with DVT without
symptomatic atherosclerosis and in 150 control subjects. In a multivariate
analysis taking into account risk factors for atherosclerosis, the odds ratio (OR)
for carotid plaques in patients with unprovoked as compared to provoked DVT
(i.e., DVT associated with active cancer, recent puerperium, trauma or
fracture, prolonged immobilization or estrogens use) and controls was found to
be 2.4 (95% CI, 1.4 to 4.0).
Subsequently,
three studies have provided further evidence in support of the association
between VTE and atherosclerosis. In a case-control study, Hong et al found a
higher prevalence of coronary artery calcium, as assessed by chest CT scan, in
patients with unprovoked VTE than in matched control individuals[9].
In a series of almost 24 000 consecutive autopsies, Eliasson et al found an
increased prevalence of VTE in patients with arterial thrombosis, except for
those with coronary artery thrombosis[10]. Finally, in a recent
case-control study conducted on subjects older than 50 years, we assessed the
prevalence of symptomatic or subclinical atherosclerosis in 100 unselected
patients with unprovoked VTE, and compared it with that of 100 patients with provoked
VTE and of 100 matched control individuals free from VTE disorders [11]. In
patients with unprovoked VTE, the adjusted OR for symptomatic or subclinical
atherosclerosis was 5.1 (95% CI, 2.0 to 13.1) in comparison to patients with
provoked VTE, and 14.5 (95% CI, 5.8 to 36.3) in comparison to controls. The
prevalence of atherosclerosis was higher in patients with provoked VTE than in
controls (OR, 3.1; 95% CI, 1.6 to 6.1).
Risk
factors of atherosclerosis and venous thromboembolism
Ageno et al reviewed the evidence favouring the association of the most
important risk factors for atherosclerosis and VTE[12]. After
reviewing 21 case-control and cohort studies dealing with a total of 63 552
patients meeting the inclusion criteria, factors that were found to be
significantly associated with an increased risk of VTE were obesity, blood
hypertension, diabetes mellitus, and hypertriglyceridemia. According to the
results of subsequent population-based study, abdominal obesity appears to be the
pivotal risk factor among the individual components of the metabolic syndrome[13-15].
While the
review by Ageno et al. failed to identify smoking as an additional potential
risk factor for VTE, the findings from two more recent population-based studies
provided strong evidence that this is the case[16,17]. Interestingly
enough, in a cross-sectional study a few markers of atherosclerosis (namely,
male sex and arterial hypertension) were found to be independently associated
also with an increased risk of recurrent VTE after a period of 3 to 6 months of
vitamin K antagonist therapy for the first VTE event[18].
Nature of the association
Although information coming from the above reported investigations
suggests the existence of an association between VTE and atherosclerosis, it
does not clarify the nature of this association. On the one hand,
atherosclerosis has the potential to promote the development of thrombotic
disorders in the venous system. Atherosclerosis is associated with a detectable
activation of both platelets and blood coagulation as well as an increased
fibrin turnover, which can lead to thrombotic complications[19-28].
The role of this prothrombotic state in favouring venous thrombotic events is
plausible given the assumption that activated platelets and coagulation factors
appear in the slow-flowing venous system.
On the other
hand, the two clinical conditions may share common mechanisms or risk factors.
In addition, there are many examples of conditions accounting for both arterial
and venous thromboembolic disorders, such as hyperhomocysteinemia,
antiphospholipid antibodies, malignancies, paroxysmal nocturnal
haemoglobinuria, infectious states, inflammatory bowel disease, and the use of
hormonal therapy[29].
Interestingly
enough, a few markers of endothelial dysfunction have been found to be
significantly higher in patients with unprovoked DVT than in matched control
individuals[30,31].
Microalbuminuria, a well know marker of endothelial dysfunction and of
arterial cardiovascular events, was found to be independently associated with
an increased risk for VTE as well[32].
Is atherosclerosis predictive
of VTE?
In an attempt to assess whether atherosclerotic disease predisposes to
VTE, the authors of two similar population-based cohort studies carried out in
the USA, the Atherosclerosis Risk in Communities and the Cardiovascular Health
Study, evaluated the rate of VTE development in subjects younger and older than
65, respectively, who had carotid ultrasound and the assessment of other
subclinical parameters of atherosclerosis, and were then followed-up
prospectively for several years[33,34].
In the former
study, 13,081 adults aged 45-64 years underwent carotid ultrasonography to
assess the intima-media thickness and the presence of atherosclerotic plaques[33].
After adjustment for age, sex, ethnicity, body mass index and diabetes, no
association was found between ultrasound parameters of subclinical
atherosclerosis and VTE development after a mean follow-up of 12.5 years
(adjusted hazard ratio (HR) of VTE for presence of carotid plaques, 0.97; 95%
CI, 0.72 to 1.29).
In the latter
study, 4108 individuals aged at least 65 years underwent non-invasive
assessment of subclinical atherosclerosis using carotid ultrasound (intima-media
thickness and presence of plaques), ankle-brachial blood pressure index and
electrocardiogram, and then were followed-up for a median of 11.7 years[34].
Surprisingly enough, the adjusted relative risk (RR) of overall and unprovoked
VTE for presence of any type of subclinical atherosclerosis was 0.60 (95% CI,
0.39 to 0.91) and 0.32 (95% CI, 0.18 to 0.59), respectively. These unexpected
findings were mostly explained by an inverse association of high-risk carotid
plaques and arterial events during follow-up.
While in the
former of the two above reported studies, the occurrence of cardiovascular and
cerebrovascular events was significantly associated with the development of VTE[33],
in the latter the opposite was seen[34].
In an attempt
to determine the impact of cardiovascular risk factors, including family
history of myocardial infarction, on the incidence of VTE, investigators from
Norway extracted data from more than 21 000 subjects, aged 25-96 years, who had
been enrolled in a prospective, population-based study (the Tromsø Study)[35,36].
In multivariable analysis, family history of myocardial infarction was
significantly associated not only with an increased risk of infarction but also
of total VTE (HR, 1.27; 95% CI 1.01-1.60) and unprovoked VTE (HR, 1.46; 95% CI:
1.03-2.07. The risk was found to increase with increasing number of affected
individuals. The association was not explained by modifiable atherosclerotic
risk factors. In another population-based study, having first degree relatives
with myocardial infarction before the age of 60 years was positively associated
with VTE compared to participants not having a positive family history (OR 1.3;
95% CI 1.1-1.6)[37]. Finally, in a more recent population-based
study conducted in Denmark patients with a history of arterial cardiovascular
events had a clearly increased relative risk of VTE events in the first three
months following the index event, then the risk decreased yet remained
statistically significant[38].
Based on these
findings, asymptomatic atherosclerosis is unlikely to constitute a risk factor
of venous thromboembolic disorders. Whether patients developing symptomatic
complications of atherosclerosis such as myocardial infarction or stroke are at
a higher risk of VTE complications is controversial. A logical explanation for
the difference could be that advanced atherosclerosis and complicated atheromas
are frequently associated with arterial thrombosis.
Is VTE
predictive of arterial cardiovascular events?
Another scenario assumes that the same biological trigger is
responsible for activating coagulation and inflammatory pathways in both
arterial and venous thromboembolism, in such a way determining a simultaneous
risk of arterial and venous thrombotic complications. This assumption is
supported by the results of a cohort study. Indeed, in an attempt to evaluate
whether elevated clotting factors, which have been linked to chronic
sub-clinical inflammation and arterial thromboembolic disease, have a high
prevalence in patients with VTE as well, Luxembourg et al measured the
plasma level of fibrinogen, factor VIII, and high-sensitivity C-reactive
protein in a cohort of sex- and age-matched patients with unprovoked VTE,
patients with provoked VTE and controls[39]. They found that these
markers of inflammation were significantly higher in patients with unprovoked
compared to provoked VTE and controls, in such a way providing evidence in
support of the hypothesis that VTE and arterial thromboembolism may share
common risk factors.
If this is
true, subjects with VTE may be at a higher risk of subsequent arterial
cardiovascular events than matched control individuals. This hypothesis was
tested in 11 studies[40-50] (Table 1) and summarized in a
meta-analysis[51]. All together, the results of these studies are in
keeping with the observation of a higher prevalence of carotid atherosclerosis
in patients with unprovoked DVT than in matched control individuals[8,11],
and strongly suggest that patients with VTE have also an increased risk of
subsequent symptomatic arterial cardiovascular events. Of particular relevance
is a population-based cohort study carried out in Denmark. Using nationwide
Danish medical databases, Sorensen et al assessed the risk of hospitalization
due to myocardial infarction, stroke and transient ischemic attack among 25 199
patients with DVT, 16 925 patients with PE and 163 566 population controls
discharged from the Danish hospitals in a 25-year period[45].
Patients with both DVT and PE were found to have a substantially increased risk
of myocardial infarction and stroke during the first year after the thrombotic
event. For patients with DVT, the RRs varied from 1.60 for myocardial
infarction (95% CI 1.35 – 1.91) to 2.19 (95% CI 1.85-2.60) for stroke. For
patients with PE, the RRs were 2.60 (95% CI 2.14-3.14) for myocardial
infarction and 2.93 (95% CI 2.34-3.66) for stroke. The RRs were also elevated,
though less markedly, during the subsequent 20 years of follow-up, with 20 to
40% increases in risk for arterial cardiovascular events. RRs were similar for
those with provoked and unprovoked DVT and PE.
Whether the
risk of subsequent arterial thrombotic disorders applies to all VTE patients or
to the only patients with unprovoked disease is uncertain. According to the
results of a meta-analysis of six studies, the risk appears higher in patients
with unprovoked VTE compared to those with provoked VTE (Incidence Rate Ratio
1.86, 95% CI 1.19-2.89)[51]. Of interest, based on recent findings
the persistence of residual thrombosis, as assessed with ultrasonography three
months after an episode of proximal DVT, predicts the development of arterial
thrombotic disorders both in patients with unprovoked and in those with
provoked DVT[52].
Implications of the
association
We speculate that venous and arterial thrombosis are two aspects of the
same disease (i.e., thrombosis), and that this disease may electively affect
genetically predisposed individuals resulting in clinically manifestations that
are, in turn, depending on a variety of elements including the age of patients,
their lifestyle, and the occurrence of co-morbidities and circumstantial
factors: the venous thrombotic events being more frequent, for example, after
triggering risk factors such as surgery or trauma, and the arterial thrombotic
events being more frequent in subjects who have developed atherosclerosis.
These findings
have several implications for both research and medical practice. Patients with
VTE of unknown origin could be examined for asymptomatic atherosclerosis, in
order to modify aggressively the risk profile in those with abnormal test
results. Measures could include appropriate counselling about lifestyle changes
and control of risk factors for atherosclerosis. Interestingly enough,
lifestyle factors are likely to have a major impact on the risk of VTE. A diet
including greater fish, fruit, and vegetable intakes and less red and processed
meat[53], the Mediterranean diet[54], the supplementation
of vitamin E[55], and alcohol consumption[56,57] have
recently been found to be associated with a lower incidence of venous
thrombosis. Whether regular sport activity decreases this risk as well is
controversial, as there data in favour[58] and against[59]
this association. Consistent with these findings are the results of a
prospective cohort study conducted in Sweden on 40 000 Swedish women who were
followed-up for a mean of 11 years: women non-smokers who were physically
active and who consumed alcohol in moderation were found to have a lower risk
of VTE[60]. Conversely, sedentary life was recently found to
increase the risk of unprovoked PE in women[61].
In addition, a
potential role for prophylaxis of both recurrent VTE and arterial
cardiovascular events with antiplatelet therapy or statins may be explored.
Interest in statins has increased, given recent data that consistently suggest
an unexpected role in lowering the risk of venous thromboembolism[62-67].
As far as the role of aspirin is concerned, according to the results of recent
studies, aspirin in low doses when administered for the long-term management of
patients with unprovoked VTE reduces by approximately 35% the risk of recurrent
VTE while offering a considerable protection against the development of
arterial cardiovascular events[68-70].
In conclusion,
the separate nature of arterial and venous thrombotic disorders has been
challenged. Future studies are needed to clarify the nature of this
association, to assess its extent, and to evaluate its implications for clinical
practice.
CONFLICT OF INTERESTS
The austhor have no conflicts of interest to declare.
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Peer reviewer: Stavros
K. Kakkos, MD, PhD, RVT, Department of Vascular Surgery, University of Patras
Medical School, Patras, 26504, Greece.
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