Relationship between Venous and Arterial Causal Perspective

Transcription

Relationship between Venous and Arterial
Thrombosis: A Review of the Literature from a
Causal Perspective
Downloaded by: Universitaetsbibliothek - Med. Universitaet Wien. Copyrighted material.
Willem M. Lijfering, M.D., Ph.D.,1 Linda E. Flinterman, M.Sc.,1
Jan P. Vandenbroucke, M.D., Ph.D.,1 Frits R. Rosendaal, M.D., Ph.D.,1,2
and Suzanne C. Cannegieter, M.D., Ph.D.1
ABSTRACT
Venous thrombosis and arterial thrombosis are traditionally regarded as two
different diseases with respect to pathophysiology, epidemiology, and treatment strategies.
Research findings of the past few years suggest that this categorical distinction may be too
strict. However, whether the described relationship between venous and arterial thrombosis is real or a result of other factors such as confounding, chance, or bias is still unclear.
In this review, we discuss the current literature while using causal diagrams to better
understand possible causal relations between cardiovascular risk factors, atherosclerosis,
arterial thrombosis, and venous thrombosis. Furthermore, we propose study designs to
investigate the causal link between venous and arterial thrombosis. In addition, we
comment on the effect of statin use on the occurrence of both arterial and venous
thrombosis. The possible clinical implications of these findings are discussed.
KEYWORDS: Venous thrombosis, arterial thrombosis, atherosclerosis, vascular
diseases, epidemiology
V
enous thrombosis and arterial thrombosis are
traditionally regarded as two different diseases with
respect to pathophysiology, epidemiology, and treatment strategies.1 According to textbooks, arterial
thrombi tend to occur at places where plaques are
formed and where shear stress is high, which results
in platelet-rich ‘‘white thrombi.’’ In contrast, in venous
thrombotic disease, thrombi tend to occur at sites
where the vein wall is undamaged, but where blood
flow and shear stress are low, resulting in red cell-rich
‘‘red thrombi.’’ Therefore, antiplatelet therapy is considered the favorite choice in preventing arterial throm-
bosis, while anticoagulant therapy (vitamin K
antagonists, heparinoids, or direct factor X inhibitors)
is the recommended therapy in venous thrombosis. If
venous thrombosis and arterial thrombosis were completely separate entities, then cardiovascular drugs
should be specific, that is, antiplatelet agents and statins
should only affect arterial disease; classical arterial risk
factors should not increase the risk of venous thrombosis; and conversely, risk factors for venous thrombosis, such as elevated levels of coagulation factor VIII, or
impaired fibrinolysis should not increase the risk of
arterial thrombosis.
1
M.A.I.M.S., F.F.Sc. (RCPA), Massimo Franchini, M.D., and
Giuseppe Lippi, M.D.
Semin Thromb Hemost 2011;37:885–896. Copyright # 2011 by
Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY
10001, USA. Tel: +1(212) 584-4662.
DOI: http://dx.doi.org/10.1055/s-0031-1297367.
ISSN 0094-6176.
Department of Clinical Epidemiology; 2Department of Thrombosis
and Hemostasis, Leiden University Medical Center, The Netherlands.
Address for correspondence and reprint requests: Willem M.
Lijfering, M.D., Ph.D., Department of Clinical Epidemiology, Leiden
University Medical Centre, P.O. Box 9600, 2300 RC Leiden, The
Netherlands (e-mail: [email protected]).
Coagulopathies and Thrombosis: Usual and Unusual Causes and
Associations. Part V; Guest Editors, Emmanuel J. Favaloro, Ph.D.,
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SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 37, NUMBER 8
2011
Table 1 Risk Estimates for Venous Thrombosis and Arterial Thrombosis
Venous Thrombosis
Relative Risk*
Venous thrombosis
Arterial thrombosis
NA
1.0–4.5
Arterial Thrombosis
Discussed in
This Article
Reference
Relative Risk*
Reference
NA
1.2–3
NA
5,6
97
Yes
4
NA
Yes
Yes
Atherosclerosis
0.8–2.3
8–10
1.5–2.5
Surgery, trauma, immobilization
5–50
71
Unknown to us
Pregnancy and puerperium
3–5
72
3–4
98
No
Oral contraceptives
4–7
73,74
2–4
99,100
Yes
Overweight and obesity
2–3
28,38
1.5–2.0
101
Yes
Hypertension
0.7–1.3
37,38
1.5–2.0
101
Yes
Diabetes mellitus
Male sex
0.7–2.0
0.8–1.3
37,39
2–3
1.5–2.0
101
Yes
No
Smoking
1.2–1.4
38,49
2.5–3.5
47,103
Yes
Dyslipidemia
0.8–1.5
38,46
2–3
104
Yes
Increasing age
1-1
35
1-1
105
Yes
Malignancy
7–20
75
Unknown to us
Lupus anticoagulant
3–10
76
5–50
106
No
Rheumatoid arthritis
2–2.5
77
1.5–2.5
107
No
Systemic lupus erythematosus
Inflammatory bowel disease
3–8
3–4
78
3–8
1.0–2.0
108
No
No
Hyperthyroid disease
1.5–3
80
1.0–1.7
110
No
HIV infection
3–10
81
2–5
81
No
Nephrotic syndrome
3–10
82
3–10
82
No
Chronic kidney disease
1.3–1.7
83,84
1.2–1.7
111
No
Microalbuminuria
1.5–2.5
36
1.5–2.0
112
No
Air travel
1.5–3
85
Unknown to us
Transient infectious disease
Antithrombin deficiency
1.0–3.0
15–20
86
3–5
1.0–1.5
113
No
Yes
15–20
87
1.0–4.5
55
Yes
Protein S type I deficiency
15–20
87
1.3–7
55
Yes
Factor V Leiden
5–7
88
1.1–1.3
54
Yes
Prothrombin G20210A
2–3
89
1.1–1.5
54
Yes
Non-O blood group
1.5–1.8
90
1.2–1.8
114
No
Low free protein S levels
5–10
91
1.5–2.5
51
No
High factor VIII
Hyperhomocysteinemia
3–5
1.5–2.5
30,92
1.5–3
1.5–2.5
30,51,115
No
No
Hypofibrinolysis
1.5–2.5
94,119
1.5–2.5
118,119
No
High platelet reactivity
Unknown to us
2–3
120
No
High CRP
1.3–2.0
1.3–1.7
121
Yes
Protein C deficiency
35,38
79
87
93
95,96
Yes
102
No
109
No
55
116,117
*As compared with the normal population.
Nevertheless, recent research has shown 40 to
50% risk reductions for venous thrombosis occurrence
in patients taking statin, and also a 1.5- to 3-fold
increased venous thrombosis risk in individuals who
were exposed to traditional arterial risk factors
(Table 1).2,3 Furthermore, it appears from the literature
that patients with arterial thrombosis have a 1.2- to more
than 4-fold increased risk of developing subsequent
venous thrombosis,4 that venous thrombosis is a predictor of subsequent arterial thrombosis risk,5–7 and that
patients with atherosclerosis have a twofold increased
risk of venous thrombosis,8 although the latter finding
has been refuted by others.9,10 A drawback of these
studies is that it is not immediately obvious how these
associations can be explained from a causal perspective.
A BRIEF NOTE ON CAUSALITY
Causal factors are those antecedents that are the producer of an effect, result, or consequence, which can
graphically be summarized as ‘‘cause ! effect.’’ In
medicine, causal factors are often called risk factors,
and it is believed that if a risk factor can be taken
away, it will no longer produce disease.11 Causes can
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Figure 1 Directed acyclic graphs that illustrate four hypotheses of how venous and arterial thromboses may be associated.
AS, atherosclerosis; AT, arterial thrombosis; RF, risk factors; VT, venous thrombosis.
lead to an effect either directly or indirectly. Noncausal
relationships are associations that are due to other
factors, such as chance, bias, or confounding. Chance
is the unknown and unpredictable element in happenings that seems to have no assignable cause, which is
most often a result of small numbered studies. Bias is a
misrepresentation of data in a study that arises from
the way that subjects or data are collected. Confounding is a mixing or blurring of effects that arises when a
confounding variable is associated with the exposure
and affects the outcome, yet is not an intermediate
link in the chain of causation between exposure and
outcome.11
For a better understanding of possible causal
relations for the associations between cardiovascular
risk factors, atherosclerosis, arterial thrombosis, and
venous thrombosis, we propose four different hypotheses, illustrated by directed acyclic graphs (DAGs)
(Fig. 1),11 to be discussed in this review. In short,
they consist of either a direct or indirect causal effect
of one disease on the other, or occurrence of both
diseases due to the presence of common confounding
variables.
ARTERIAL THROMBOSIS AND
SUBSEQUENT RISK OF VENOUS
THROMBOSIS
Patients hospitalized with acute myocardial infarction
are at high risk of subsequent venous thrombosis. In a
meta-analysis published in 1996, reviewing placebocontrolled studies of antithrombotic drugs, it was shown
that 4% of patients with myocardial infarction (MI) had
symptomatic pulmonary embolism within 2 weeks
after hospitalization.12 Patients with acute ischemic
stroke are also at a high risk of venous thrombosis. In
one study, the incidence of symptomatic deep vein
thrombosis or pulmonary embolism was 3 and 5%,
respectively, after 21 days of hospitalization.13 One
direct causal explanation is the temporary inflammatory
or procoagulant response due to sudden tissue damage or
necrosis after the arterial thrombotic event onset. This
tissue damage may consequently result in temporary or
long-term increased venous thrombosis risk. However,
all these patients were, obviously, subjected to hospitalization which is generally accompanied by periods of
immobilization that offers an alternative (indirect causal)
explanation of venous thrombosis due to stasis. Therefore, one cannot conclude from these studies that the
arterial event itself has been the causative factor and thus
a risk factor for venous thrombosis.
A way to distinguish between hospitalization or
to the event itself as an explanation is to use a study
design in which a longer period between arterial and
venous event is studied. This was done in a recent large
population based case–control study.4 Cases (n ¼ 5824)
were individuals with a venous thrombosis, and they
were compared with age- and sex-matched controls
(n ¼ 58,240). An arterial thrombotic event was associated with a large increase in venous thrombotic risk in
the subsequent 3 months: relative risk 4.2 (95% confidence interval [CI], 2.3–7.6) after MI, and 4.4 (95%
CI, 2.9–6.7) after stroke. However, this increased risk
did not extend beyond that of accompanying hospitalization in patients with MI. Stroke patients, however,
seemed to have a long-term 1.2-fold increased risk of
venous thrombosis. As ischemic stroke may lead to longterm impaired mobility, this may explain the extended
excess risk of venous thrombosis.
As alternative explanations for a direct effect of
arterial thrombotic disease on venous thrombosis, as
postulated in Fig. 1A-1, we propose the following
mechanisms: Fig. 1A-2 summarizes the explanations
given above: the arterial event leads to a certain situation
(immobilization, necrosis) which in its turn increases the
risk of venous thrombosis. Second, there is a possibility
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RELATIONSHIP BETWEEN VENOUS AND ARTERIAL THROMBOSIS/LIJFERING ET AL
that the presence of atherosclerosis is a common cause of
both arterial and venous thromboses (Fig. 1B-2) (see
below). Third, risk factors that are associated with both
venous and arterial thromboses, such as obesity, could
explain the association (Fig. 1D-1) (see below). Adjustment for immobilization, common risk factors, or atherosclerosis should help distinguish between a true direct
effect and any of the other three explanations: in the first
case the association will remain, while it will disappear
when one of the other mechanisms is present.
ATHEROSCLEROSIS AND THE RISK OF
VENOUS THROMBOSIS
In 2003, Prandoni et al reported that atherosclerosis
(measured by carotid intima media thickness [IMT])
was twice as prevalent in patients with unprovoked
venous thrombosis as in age- and sex-matched controls.8
As in this study IMT was performed after venous
thrombosis occurred, its temporal relation and causality
were not entirely clear.14 Currently, there is little evidence available, apart from the study by Prandoni et al,8
that venous thrombosis and atherosclerosis are causally
associated. However, there is some biological evidence
that may give credence to the causality of this association, as hemostatic and inflammatory markers are elevated in individuals who have atherosclerosis.15–17 Two
options are theoretically possible in the association—(1)
that the presence of atherosclerosis directly increases the
risk of venous thrombosis (Fig. 1B-1) or (2) that venous
thrombosis leads to an acceleration of the atherosclerotic
process (Fig. 1C-2, 3). For the latter, it could be
hypothesized that an inflammatory process, activated
by venous thrombosis, leads to acceleration of growth
of atherosclerotic plaques in individuals with previous
venous thrombosis. Adjustment for hemostatic or inflammatory risk markers (e.g., C-reactive protein or
factor VIII) should then lead to an attenuation of effect.
The former explanation, (Fig. 1B-1), that the presence
of atherosclerosis may (e.g., through elevation in hemostatic markers) lead to venous thrombosis, has as far as
we know not been studied yet.
Alternatively, the relation can be explained by the
presence of risk factors for both atherosclerosis and
venous thrombosis (Figs. 1B-2 and D-1). This was the
case in two large prospective population-based studies
where the relation disappeared after adjustment for
various potential confounders.9,10 For example, in the
Atherosclerosis Risk in Communities (ARIC) study
(n > 13,000) a graded positive effect (dose response
relation) was found between IMT thickness and venous
thrombosis risk; relative risks of venous thrombosis
across quartiles of baseline IMT were 1.0, 1.2, 1.6, and
1.5.10 However, this association disappeared after adjustment for various cardiovascular risk factors. A presentation of such a finding is depicted in Fig. 1D-1.
2011
VENOUS THROMBOSIS AND
SUBSEQUENT RISK OF ARTERIAL
THROMBOSIS
Recent studies have shown that the incidence rate of
arterial thrombotic events after a first venous thrombosis
may be as high as 2 to 5% per year.6,7 In a retrospective
age- and sex-matched case–control study from Sørensen
et al, containing more than 40,000 patients with venous
thrombosis and 160,000 controls, a two- to three-fold
increased risk of MI or ischemic stroke after a first
episode of venous thrombosis was shown, most predominantly in the first year following the initial event.5
According to a meta-analysis of published studies on
this issue, detection bias (by which we mean that patients
with venous thrombosis are closely monitored and therefore sooner diagnosed with ‘‘soft’’ arterial thrombotic
endpoints such as angina pectoris or transient ischemic
attacks) cannot explain the association. The meta-analysis included only ischemic stroke and MI as clinical
endpoint, leading to a 1.9-fold (95% CI, 1.2–2.9)
increased risk of arterial thrombosis after venous thrombosis.18
Several other (unbiased) explanations for the
relationship between venous thrombosis and subsequent
arterial thrombosis exist. Because atherosclerosis enhances inflammation,19 and coagulation,20 it can be speculated that arterial thrombosis and venous thrombosis are
associated diseases through atherosclerosis (Fig. 1B-2).
Studies on this issue, as far as we know, have not been
performed yet. The link between venous and arterial
thrombosis may also be causal (Fig. 1C-1–3). One causal
explanation is that the inflammatory process instigated
by the thrombus,21 leads to arterial thrombosis. This
hypothesis may also clarify why the risk of arterial
thrombosis is highest in the first few months after the
venous event takes place, as inflammation is most pronounced shortly after venous thrombosis is diagnosed,
and diminishes slowly afterward.22 A second causal
explanation is that treatment with vitamin K antagonists
(at present one of the mainstays of venous thrombotic
disease treatment) may lead to increased arterial calcification,23,24 thereby increasing arterial thrombotic risk
(Fig. 1C-3). Nevertheless, as the results of these investigations are based on animal studies,23 or are small
numbered,24 this explanation should be interpreted
with caution. Other causal explanations are that other
unknown or not well-studied mechanisms (for example,
paradoxical emboli in patients with deep vein thrombosis),25 explain the link between venous and arterial
thrombosis.
If we assume that the association is not causal
(Figs. 1B-2 and D-1), then adjustment for risk factors
(e.g., smoking and obesity) would lead to a diminishment of the relative risk. In the one study that reported
on this issue (n ¼ 302) the authors could adjust the
findings for classical arterial risk factors (such as
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hypertension, overweight/obesity, or smoking) but
found no attenuation of the effect.26
venous thrombosis before adjustment for age, which
disappeared after adjustment for age.36–38
COMMON RISK FACTORS FOR VENOUS
AND ARTERIAL THROMBOTIC DISEASE
(CONFOUNDING)
All relationships between atherosclerosis, arterial and
venous thromboses described above could be explained
by the presence of common risk factors (Figs. 1B-2 and
D-1). Below we will discuss some well-known risk
factors for arterial disease and their relation with venous
thrombotic disease. Moreover, we will discuss the effect
of statin use on the occurrence of both arterial thrombosis and venous thrombosis.
Diabetes Mellitus
Diabetes mellitus, like hypertension, is an age-related
disease, but in contrast to hypertension, studies on
diabetes have shown an age-adjusted 1.5- to 2-fold
increased risk of venous thrombosis.37,39,40 However,
after controlling for hospitalization, major surgery or
medical illness, and nursing home confinement, diabetes
was no longer associated with venous thrombosis in a
large population-based case–control study (n ¼ 4037).39
A similar result was found in the Copenhagen City
Heart Study.38 Therefore, diabetes mellitus does not
seem to be causally related to venous thrombotic disease.
Overweight/Obesity
Of all classical arterial cardiovascular risk factors (including overweight/obesity, hypertension, diabetes
mellitus, metabolic syndrome, smoking), obesity has
most consistently been reported as a risk factor for
venous thrombosis.3,27,28 It is, however, not completely
understood why obesity predisposes to venous thrombosis. People with overweight or obesity tend to be
more immobile, which may lead to clot formation
through stasis. It is also possible that these individuals
acquire a prothrombotic state. Indeed, there are studies
available that have shown a correlation between increase in body mass index and factor VIII,29 which is a
risk factor for venous thrombosis and arterial thrombosis.30 Adipose tissue may contribute to enhanced
coagulation by direct tissue factor production, but
hypercoagulability could also be due to direct effects
of adipose tissue on the hepatic synthesis of coagulation
factors.31,32 Another explanation is that estrogen levels
are higher in obese males and females due to an
increased conversion from androgen to estrogen in
adipose tissue.33 As estrogens and progestagens increase factor VIII levels,34 this may also be a possible
pathway. A third explanation may be that obesity is
considered a chronic low-grade inflammatory state that
may result in increase of clotting factors leading to
venous thrombosis.32
Hypertension
A recent meta-analysis reported that hypertension was
associated with a 1.5-fold increased risk (95% CI, 1.2–
1.9) of venous thrombosis compared with normotensive
individuals. However, in this analysis it was not possible to adjust for age,3 which would have been necessary,
because hypertension is strongly associated with increasing age, as is the occurrence of venous thrombosis.35 Indeed, original studies on venous thrombotic risk
in hypertensive individuals showed increased risks for
Metabolic Syndrome
The metabolic syndrome has also been associated with
venous thrombosis.41,42 As the metabolic syndrome is a
cluster of abdominal obesity, hypertension, high triglycerides, reduced levels of high-density lipoprotein
(HDL) cholesterol, and elevated fasting plasma glucose,
an interesting question is whether this increased risk is a
result of one or more of the individual components or of
the total interplay between these cardiovascular risk
factors. Two recent studies showed that the clustering
of components of the metabolic syndrome was predictive
of venous thrombosis only in the presence of abdominal
obesity.43,44 Particularly, total/HDL/low-density lipoprotein (LDL) cholesterol levels and triglycerides levels
do not increase venous thrombotic risk.36,38,45,46 Therefore, the metabolic syndrome nor its other components
(apart from obesity) seem to be important in venous
thrombosis etiology.
Smoking
Smoking, a well-known risk factor for arterial thrombosis,47 did not increase the risk of venous thrombosis
in some studies.36,46 This could have been a result of
chance, as these studies were small numbered, and
because biological evidence of smoking (which results
in systemic activation of coagulation and inflammation),48 on venous thrombotic risk suggests otherwise.
In the Multiple Environmental and Genetic Assessment (MEGA) study of risk factors for venous thrombosis, a large population-based, case–control study,
3989 patients with venous thrombosis were compared
for smoking habit with 4900 controls.49 Relative risk of
venous thrombosis was 1.4 (95% CI, 1.3–1.6) in current
smokers and 1.2 (95% CI, 1.1–1.4) in ex-smokers
compared with those who had never smoked. Those
who smoked heaviest or longest had the highest relative
risk of 4.3 (95% CI, 3.0–7.1). So, this study showed a
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clear dose-dependent and reversible association of
smoking habit on risk of venous thrombosis.49 This
result has recently been confirmed in two large followup studies.38,50
Thrombophilia
Although elevated levels of factors VIII, IX, XI, and
fibrinogen have been associated with 1.5- to 3-fold
increased risks of arterial thrombosis,51–53 and the inherited thrombophilias with 1.2- to 2.5-fold increased
risks,54,55 the effects are up to 10 times weaker than in
venous thrombosis (Table 1). This difference in relative
risk is probably explained by the role of atherosclerosis in
arterial thrombosis. It is plausible that there must be a
local thrombotic focus (plaque rupture) for occlusion to
occur because of exposure of tissue factor to circulating
blood and platelets.56 This may be so strong in promoting local clot formation that it matters only minimally
whether the coagulation system is competent or overcompetent, as in factor V Leiden or prothrombin
G20210A carriers. While further studies are required,
one study suggested that the lower risk estimates found
for the genetic (in this case natural anticoagulant deficient) thrombophilias on arterial thrombotic risk could
also be due to the influence of competing classical arterial
risk factors.55 These individuals had an overall risk of
arterial thrombosis that was 2.3-fold increased compared
with individuals without a deficiency. However, this risk
was 5.5-fold increased for subjects aged <55 years and
only 1.3-fold increased for age 55 years. Apparently,
classical arterial risk factors were more important in
predicting arterial thrombotic risk after the age of
55 years than natural anticoagulant deficiencies in that
study.
Results from studies on incompetent clotting,
however, have yielded consistent results arguing for a
role for coagulation in arterial thrombotic disease. Patients with hemophilia have a strongly reduced risk of
MI (80% reduction).57,58 Female carriers of hemophilia,
who have an intermediate reduction of factors VIII or
IX, have an intermediate 25% reduced risk of MI.59
Furthermore, treatment with oral anticoagulants, reducing factors II, VII, IX, and X has a substantial effect on
risk of recurrent MI.60
Statins
Statins, a class of medications first introduced in the
1980s,61 reduce blood levels of LDL and boost levels of
HDL. That statins are able to reduce mortality and
morbidity in patients with arterial thrombosis is ascribed to antidyslipidemic and anti-inflammatory properties.62 The results of recent observational and
experimental studies that showed 40 to 50% risk reductions for first venous thrombosis occurrence when
2011
using a statin,2,63,64 are somewhat surprising, particularly because the mechanism behind this effect is unclear.65 Dyslipidemia may be the most plausible culprit
to be considered. However, as dyslipidemia is not
related to an increased risk of venous thrombosis,38,46,64
or to hypercoagulability,45 and because nonstatin lipidlowering drugs (i.e., fibrates) do not reduce venous
thrombosis risk,2,63 it is unlikely that statins decrease
venous thrombosis risk by lipid-lowering activities.
Based on reports showing that statins can reduce
thrombin generation,66,67 one would suspect that their
use protects, to some extent, against venous thrombosis
by downsizing coagulation activation. However, these
findings should be interpreted with caution as not all
studies consistently reported a favorable outcome of
statin treatment on coagulation factor levels. For example, in a small randomized study of Dangas et al
(n ¼ 93), an increase in fibrinogen level was observed
when individuals were exposed to pravastatin compared
with placebo.68 For arterial thrombosis, statins may,
next to their ability to influence lipid levels, have an
anti-inflammatory component. However, the impact of
such a component on arterial risk is hard to assess as the
reduction of inflammatory response in statin users is
accompanied by similar reductions of dyslipidemia.69
Because dyslipidemia is not associated with increased
venous thrombosis risk,38,84 it is possible that reduction
of inflammation is the driving force behind the reduced
venous thrombosis risk that has been observed in statin
users. It should be noted that the latter statement is
hypothetical and it is presently not known whether
these results can be explained by a reduction in inflammation or coagulation activation in individuals who use
a statin.
THE LINK BETWEEN VENOUS AND
ARTERIAL THROMBOSIS EXPLAINED?
Which of the four putative pathways in Fig. 1 may be
considered most likely to explain the link between
venous and arterial thrombosis is in our opinion presently an unanswerable question as the necessary study
material on this issue is absent. Therefore, we will not try
to answer this question but propose study designs that
are needed to sufficiently study these hypotheses. First of
all, a population-based study is essential as selection of
subjects could give rise to bias. Second, the best design
would be a follow-up study for two reasons: (1) we
unequivocally need to know the temporal relation between venous and arterial thrombosis and (2) in a case–
control study several potential confounders or factors in
the causal pathway (laboratory or radiological) will have
been measured after the thrombosis, and the event may
have changed these variables (post-hoc phenomenon).
Third, such a follow-up study should not end its followup after the first arterial or venous thrombotic event is
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documented because then the temporal relationship
between the two diseases cannot be obtained.
Next, the studies must have recorded data of
variables that have been associated with both venous
and arterial thrombosis, and most preferably data on
atherosclerosis at different time points (as for example
was done in the ARIC and Cardiovascular Health
Study). This is important for answering the study question whether the relationship between venous and arterial thrombosis is causal (Fig. 1A, C) or mediated
through atherosclerosis or through common risk factors
(Fig. 1B, D). Although the list of potential confounders
is long (as shown in Table 1), one should keep in mind
that many of these confounding variables occur rarely in
the general population (such as human immunodeficiency virus [HIV] infection or nephrotic syndrome) and
are therefore unlikely to fully elucidate the (in this case
confounded) relationship between venous and arterial
thrombosis. For other more common exposures, such as
factor V Leiden, the relative risk increases for arterial
thrombosis are too low to fully explain the relationship
(20% of patients with venous thrombosis have factor V
Leiden, but the relative risk for arterial thrombosis in
factor V Leiden carriers is less than 1.2).54 Therefore,
probably the main contributors to a supposed confounded relationship of venous to arterial thrombosis,
and vice versa, could be variables such as age, sex, oral
contraceptive use, smoking, and overweight/obesity.
Because some of these variables may change over time,
it is also important to have data available that record
these differences over time. Otherwise, it will be difficult, or even impossible, to make a distinction between
Fig. 1B, 1 (in Fig. 1B-2 the risk factor, e.g., atherosclerosis confounds the association between venous and
arterial thrombosis, while in Fig. 1C-3 the risk factor,
atherosclerosis, is a result of venous thrombosis that
finally causes arterial thrombosis).
Although it is possible to record data on several
variables in a population cohort study at different time
moments, this will be time-consuming and expensive,
given the large number of individuals that need to be
tested and retested. However, retesting during followup will be necessary to distinguish between several
causal pathways, but can be restricted to a subgroup.
We will elucidate this with a hypothetical example on
atherosclerosis and venous thrombotic disease, graphically illustrated in Fig. 2A–C. If we assume that
atherosclerosis is not independently associated with
future venous thrombotic risk, then progression of
atherosclerosis should be similar for individuals who
will or will not develop venous thrombotic disease.
Venous thrombosis cases will develop during followup period. When they are compared with an appropriate control group in whom IMT measurements were
performed at time of enrollment (similar to the cases)
and at the end of follow-up (similar to cases), then one
can calculate whether atherosclerosis progressed more
in cases after they had venous thrombosis than in
controls or not. Such a finding is graphically illustrated
in Fig. 2A. In another scenario, it could be that
atherosclerosis is an independent risk factor for venous
thrombosis. One could still analyze if venous thrombosis itself accelerated atherosclerosis even more after
the event occurred using the same nested case–control
design. If atherosclerosis progression at the second
measurement is more than at the first measurement,
venous thrombosis may have lead to this increased
atherosclerosis progression. Such a finding is illustrated
in Fig. 2B. When one conducts a study in which at
baseline everyone has the same extent of atherosclerosis
progression (but cases with venous thrombosis develop
atherosclerosis faster than others during follow-up,
independent of venous thrombosis occurrence
[Fig. 2C]), it will appear to the researcher that venous
thrombosis accelerated atherosclerosis progression,
while in fact it was not dependent on venous thrombosis disease, but on other underlying (unknown)
factors. To distinguish these scenarios, one need at
Figure 2 Hypothetical example of a nested case–control study to determine if venous thrombosis leads to atherosclerosis
progression. Solid line indicates a person who develops venous thrombosis at follow-up, dashed line indicates a control subject
without venous thrombosis who was enrolled and followed similar as the individual who developed venous thrombosis. Of
note, this example assumes that atherosclerosis is somehow associated with venous thrombosis which may not be true.
*Atherosclerosis progression can be measured, for example, by carotid intima media thickness. VT, venous thrombosis.
least three atherosclerosis measurements as well as
information on which individual in the cohort develops
venous thrombosis at a certain time point (for example,
by direct access of the researcher to chart reviews in
electronic medical records). The first measurement
should take place at time of enrollment in all individuals. When someone develops a venous thrombosis,
this participant’s IMT should be remeasured as soon as
possible, together with that of a (matched) control
person(s). A third measurement should be taken at
the end of follow-up period in both the case and
control(s). Although theoretically possible, one will
need a scrupulous system that regularly screens individuals, on possible venous thrombosis occurrence,
which may practically be unachievable.
CLINICAL RELEVANCE OF THE SUPPOSED
ASSOCIATION BETWEEN VENOUS AND
ARTERIAL THROMBOSIS
In terms of clinical policy, it is pivotal to meticulously
investigate the proposed hypotheses for the association
between venous and arterial thrombosis. If, on the one
hand, the association between venous and arterial
thrombosis is causal, then all patients with venous
thrombotic disease should not only be treated with
anticoagulants, but also with arterial thrombosis prevention strategies to avoid subsequent arterial thrombosis. If, on the other hand, the association between
venous and arterial thrombosis is not caused by venous
thrombotic disease, but if arterial thrombotic risk is
increased via common etiological risk factors such as
smoking or obesity, then targeting venous thrombosis
patients with arterial thrombosis prevention strategies
is not rational. Still, individuals with cardiovascular risk
factors have an increased venous thrombotic (and arterial thrombotic) risk in this scenario. Therefore, they
should receive arterial thrombotic risk prevention strategies from a clinician who is specialized in both venous
and arterial thrombotic disease, and has access to
laboratories that are specialized in both diseases. This
is probably the most beneficial scenario for the individual patient.70
CONCLUSIONS
Venous thrombosis and arterial thrombosis seem to
share many pathogenic mechanisms. Inflammation,
elevated levels of coagulation factors, and inherited
thrombophilia are characteristics of both disorders. In
addition, older age, obesity, smoking, and possibly
atherosclerosis are not only related to arterial thrombotic disease but also to venous thrombosis. Venous
thrombosis increases the risk of subsequent arterial
thrombosis. Although the mechanism that can explain
this association is currently unknown, it may be causal.
2011
Conversely, arterial thrombosis does not seem to increase venous thrombotic risk after the effect of hospitalization has diminished. Of agents that are
specifically targeted to prevention of arterial thrombotic disease, statin use seems promising to reduce
venous thrombotic risk; an approach that should be
evaluated by appropriately designed observational
studies or clinical trials.
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Relationship between Venous and Arterial Causal Perspective

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