*, Abdul Aleem
, Mukesh Singh3
, Yuan Z. Li4
, Stacey J Smith4
1Department of Cardiovascular Medicine, Lehigh Valley Health Network, Pennsylvania, USA,2
Medical College, Karnataka, India,
3Department of Cardiology, Chicago Medical School, North Chicago, Illinois,
4Department of Medicine, Lehigh Valley Health Network, Pennsylvania, USA.
Corresponding Author: Dr.Nasir Shariff, MD, Lehigh Valley Hospital and Health Network, Allentown, PA 18103, Ph: 610-402- 8275, Fax: 610-402-1675.
Atrial fibrillation (AF) and venous thromboembolism (VTE) are the two most common medical conditions
managed with anti-coagulation therapy. Not all
the patients with decreased mobility or
similar risk for thromboembolism. The risk factors for venous
thromboembolism and thromboembolism
pathophysiologic basis of clot formation, one
could imply that the risk factors for the
of thrombosis could be similar. The present review focuses on the similarities and differences in the
clinical risk factors of VTE and AF related thromboembolism. We will also be discussing the role of
-VASc scoring system in the risk assessment of VTE.
In the mid eighteenth century, Virchow proposed a
triad for the cause of venous thrombosis. This was
constituted by stasis of blood, changes in the vessel
wall and blood coagulability. Atrial fibrillation
(AF), the most common sustained cardiac arrhythmia
with an increased risk of thromboembolism.
all the changes occur in
is also noted that stroke patients suffering from AF
have a higher incidence of venous thromboembolism
Several factors have been studied and
established as risk factors for developing VTE and
thromboembolism in patients with AF. We will review
An estimated 200,000 people in the United States
are diagnosed with VTE annually.3-7
106,000 patients with deep venous thrombosis
(DVT) and 94,000 with pulmonary embolism (PE).3-7
.the incidence of VTE occuring for the first time in about 100 per 100,000 people.6
to about 300,000 to 600,000 hospitalizations and
100,000 deaths annually. Death occurs in about 6%
of patients with DVT and 12% of PE cases within
a month of diagnosis6.
In the International Cooperative
Pulmonary Embolism Registry
at 3 months, associated
In the Worcester, Massachusetts
metropolitan area study, patients with PE
had mortality rate of 11.1%.9
AF is the commonest sustained cardiac arrhythmia,
which is associated with significant risk of
morbidity and mortality resulting from thromboembolism.10 Approximately 2.2 million Americans
suffer from AF.11-12
.By 2050, an estimated 16
million Americans are predicted to have AF.13
screening of patients with ischemic stroke, AF is
recognized in 6.7% of patients on routine electrocardiogram,
24 hour Holter and 15.6%
7 day event
While the stroke risk is
increased by 5 folds by AF, this risk is not homogeneous
as it is altered by other stroke risk factors.10
Hemostasis is primarily a protective mechanism
of reducing bleeding after vascular injury. In situations
of endothelial dysfunction, stasis or hypercoagulability,
there is increased activation
mechanism resulting in thrombosis. Arterial
distinct entities with different clinical
presentations and management strategies. Arterial
thrombosis generally develops
as a result of
is largely a phenomenon
Unlike arterial thrombosis,
The venous clots are relatively
in size compared to arterial clots
composed predominantly of fibrin enmeshed with
cellular components including red blood cells. Activation
coagulation system is
thrombosis and precedes platelet
Surgery or trauma
may cause direct injury to the vessels resulting in
exposure of the subendothelial tissue factor (TF).
This however, is not common in non-surgical patients
with VTE. Venous
formation by not flushing out the activated
coagulation factors from endothelial dysfunction.
Circulating TF-bearing microparticles are also
suggested to play an important role in VTE. These
particles attach to activated endothelial cells and
transfer TF to them initiating coagulation reactions
and clot formation.17-18
This is different from
thrombus formation in the arterial system. The
TF-bearing micro-particles may also contribute
to the hypercoagulable state associated with disease
an increased risk
In patients with AF, there is abnormal stasis of
blood in the atrium with endothelial dysfunction,
and hypercoagulable states resulting in thrombus
Systemic fibrinogen and fibrin
D-dimer levels are elevated in patients with persistent
and paroxysmal AF
which increases the
Both von Willebrand factor
and TF are also over expressed in the atrial endothelium
of patients with AF
AF seems to fulfill
the Virchow's triad for thrombogenesis, and the
thrombus formed has a 'venous-type clot'. These findings are suggestive of similar pathophysiologic
AF, which may
imply similar risk factor for the occurrence
thrombosis. This could also explain for the
anticoagulants and not antiplatelets in
of VTE and AF
Systematic reviews of epidemiologic cohorts and
clinical trials have identified various risk factors
associated with AF and their impact on stroke.
The risk factors and their adjusted relative risk
(RR) as described by the Stroke in AF Working
Group are: previous stroke/transient ischemic attack
(RR 2.5), age (RR 1.5/decade), hypertension
Congestive heart failure (CHF)
history was not associated with stroke risk in this
study, although moderate systolic dysfunction
was still an independent predictor. In a systemic
review by the National Institute of Health and
Clinical Evidence (NICE), history of stroke or TIA,
advanced age, hypertension and structural heart
disease were predictors of stroke.25
and gender were not significant factors to
predict stroke risk in this review. The CHADS2
score was derived by adding the AF investigators
and Stroke Prevention in AF (SPAF) -1 trials.
factors included were CHF, hypertension, age >
75 years, diabetes mellitus, and prior stroke/TIA.
This scoring was simple and was validated in assessing
of thromboembolic stroke in patients
low risk group from low risk and intermediate
To further refine and define the
risk of stroke in AF patients, the European Society
of Cardiology came up with the CHADS-VASc
score to complement the CHADS2 scheme.
this the major risk factors were age > 75 years and
previous stroke/TIA (with allocated two points);
the non-major risk factors were CHF, hypertension,
female gender (with
point for each)
CHADS-VASc score has also been well validated
and is efficient in identifying patients at high and
moderate risk of thromboembolic events.
VASc score identifies patient who are at very low
risk of thromboembolism or stroke.30
In low risk
patients (CHADS-VASc score = 0), the rate of
thromboembolism per 100 person-years was 1.67
[95% confidence interval (CI) 1.47−1.89].
of any of the minor risk factors significantly
increased the risk of stroke (absolute risk 2.01;
CI 1.70−2.36). The negative predictive value
(i.e. the percent categorized as not being at higher
risk, actually being free from thromboembolism)
for CHADS-VASc was 99.5% suggesting that other
clinical or laboratory factors may not have significant
contribution to thromboembolic risk.
Table 1: Factors and adjusted thromboembolic stroke risks in patients with atrial fibrillation (CHADS-VASc scoring)
Adapted from European Heart Rhythm Association Guide- lines27 and Lip GY, et al.28
is a multifactorial disease with 2 or more
factors being present at the same time.
overview of the risk factors for VTE is provided
in Table 2.32 Genetic risk factors predisposing for
VTE include deficiencies of antithrombin, protein
C, protein S, and the factor V Leiden (FVL) mutation
and prothrombin 20210A gene variant.
factors including variations
protein C, or protein S deficiencies are associated
with approximately 5 to 10 fold, 4 to 6 fold and 1
to 10 fold increased risk of VTE respectively.34-35
Table 2: Risk factors for venous thrombosis and pulmonary embolism
Adapted from Goldhaber SZ, et al.32
Prothrombin G20210A variant and FVL mutation
and 7 fold increased
of VTE respectively.36-37
But for these genetic
risk factors, there are several acquired clinical risk
factors which increase the risk for VTE. The clinical
risk factors include triggering factors
and chronic medical conditions. The
include immobilization, plaster
trauma. The demographic and
age, hormone replacement therapy and
These acquired factors cause either
stasis or hypercoagulability predisposing to VTE.
table2 Hospitalization is a risk factor for VTE considering
that these patients are exposed to more than
one acquired risk factor including immobility,
cancer, surgery, CHF, infections and chronic kidney
Similar to thrombosis in patients with AF, a combination
for VTE episodes. Genetic risk factors (deficiency
of protein C and S, and FVL mutation), and temporary
triggering risk factors (trauma,
that predispose to the development
of VTE have not been studied extensively in patients
with AF. Hence these factors will not be reviewed.
In our discussion we will be describing the studies
factors (i.e. CHADS-VASc
of thromboembolism in patients with
of these factors in
assessing VTE risk.
Levels of prothrombin activation fragment F1.2, an
index of thrombin generation, increase with age in
the general population40-42
suggesting an age-related
prothrombotic diathesis. In patients with AF,
is associated with left atrial (LA) enlargement,
reduced left atrial appendage (LAA) flow
velocity, and spontaneous echo contrast (SEC), all
of which predispose to LA thrombus formation.
The implication of aging on risk of stroke in patients
has been evaluated
in 17 studies.46
Twelve studies found an independent effect of
age on stroke risk while five studies failed to find
such an association.46
In the analysis of pooled data
from five randomized controlled trials, the annual
risk of stroke increased from 15% to 20% in patients
aged <65 years
and >65 years
with no other
In this study
the overall relative risk of stroke associated with
every decade of life was 1.4 (95% CI 1.1-1.8). In the
Framingham study, age 65 years and older was associated
with a 3-fold increase in risk of stroke.48
VTE has an incidence of 1 to 2 cases per 1000 person-years,
in 100000 in children to 1 in 100 in older
VTE rises exponentially from <5
cases per 100000 persons in younger than 15 years
age to about 500 cases (0.5%) per 100000 persons
at age 80 years.
The incidence of VTE increased
significantly with age in a population based study
with the noted incidence of about 100 per 100000 in
people aged 50 years and more than 450 per 100000
in people aged 75 years.52
Thus, advanced age is a
risk factor for thromboembolism associated with
AF as well as for development of VTE.
b. Sex (female gender)
Women face several unique situations during theirlifetime, such as pregnancy, use of oral contraceptives
and hormone replacement
risk of thromboembolism.
female gender has been observed
to be a
risk factor for thromboembolic stroke
in some studies53-57
but not in others.58-62
SPAF trial, 2012 participants given aspirin were
evaluated, female gender was associated with significantly
higher risk of stroke with a RR of 1.6.
Similar to this trial, the Framingham study and the
AnTicoagulation and Risk factors In Atrial fibrillation
(ATRIA) study noted a significantly higher
incidence of stroke in women with AF with the
noted RR of 1.7 and 1.6 respectively.55,63
AFASAK trial, female gender was not associated
with occurrence of stroke. Of note, there was no
association of age or left atrial size with increased
incidence of stroke in this study.59
Similar to this
study, Aronow et al, did not find any association
of gender with risk of thromboembolic stroke in
elderly patients with chronic AF.61
In a Norwegian study, the incidence of first VTE
events was 1.43 per 1000 person-years, with a noted
in women than in men.50
Contradictory to this finding, in a communitybased
study, incidence was
higher for men than
In the Olmsted county
study, the age-adjusted rates of VTE was significantly
higher in males than females (130 vs. 110
In this study it was
noted that the incidence of VTE in women
younger than 55 years, was higher than men. This finding may be related to the differential exposure
to clinical risk factors in this specific population
of women (pregnancy, postpartum state, or oral
contraceptive use). In a meta-analysis of 15 studies
(nine randomized controlled and six prospective
observational), the estimate of the RR of recurrent
VTE for men was significantly higher compared
to women (RR 1.6, 95% CI 1.2-2.0).65
women younger than 55 years age are at a higher
risk of VTE, but with aging the risk of VTE is simi-
lar or higher in men.
Hypertension is a common risk factor for arterial
thrombosis and also AF. Hypertension in patients
with AF is associated with reduced left atrial appendage (LAA) flow velocity, spontaneous echocontrast
(SEC), and thrombus
Ventricular diastolic dysfunction might underlie
the effect of hypertension on left atrial (LA) dynamics,
relationship is still speculative.67-68
Hypertension is an important predictor of stroke
in patients with AF,48,53-54,58,61,69-70
especially in those
with systolic blood pressure greater than 160 mm
During a 2.0 year follow-up of patients
with non-valvular AF, history of hypertension
was associated with significantly higher risk of
stroke with a RR of 2.0.53
In a systematic review
of risk factors for stroke in patients with AF, hypertension
associated with increased
95% CI 1.6-2.5).24
In a study involving the population from the
Atherosclerosis Risk In Communities (ARIC)
and Cardiovascular Health Study (CHS) to assess
the association of established risk factors of
associated with VTE.71
The relative risk for
VTE in patients with history of hypertension was
1.20 (95% CI 0.90-1.60) which was comparable to
patients with normal blood pressures (RR 1.21
(95% CI 0.99-1.47). There was no difference when
groups with systolic blood pressure less than 114
mmHg were compared with patients with systolic
blood pressure between 114 and 130 mmHg and
those with systolic blood pressure of more than
140 mmHg. In another study of patients with antiphospholipid
syndrome, presence of
increased the incidence
of arterial thromboembolism but not VTE72
d. Diabetes Mellitus
Diabetes mellitus has been associated with en-
hanced coagulation and reduced fibrinolytic potential which may contribute to thrombosis.73
the meta-analysis of independent predictors of
stroke in non-anticoagulated patient with nonvalvular
Stroke Risk in AF
was present in 15% of the study cohorts and was
an independent risk factor for stroke. (RR 1.7, 95%
Studies indicate that the reduction in
stroke among warfarin-treated patients with diabetes
In a study of assessing the association of traditional
risk factors on occurrenceof VTE, diabetes and obesity were each associated
with significant increase in events even in age, race
and sex adjusted models.71
In this study the incidence
VTE increased from
in non-diabetics to 2.12 events
among diabetics (RR 1.70, 95%
On adjusting for body mass index
(BMI), diabetes still persisted to be significantly
associated with VTE though the risk for events
was attenuated (HR 1.46, 95% CI 1.03-2.05). Diabetic
as compared to patients with idiopathic VTE
1.62 vs. 1.27 respectively).
e. Congestive Heart Failure
CHF is a prothrombotic state resulting from impaired
This is compounded by
abundance of adhesion molecules
of procoagulants and anticoagulants.76
Patients with CHF have abnormally elevated von
Willebrand factor levels, soluble thrombomodulin
(indexes of endothelial damage/dysfunction)
(an index of endothelial activation).8
It is well established that AF and CHF
are inter-related in a varieties of ways with each
predisposing to the occurrence of other. In regards
to the risk of stroke in patients with
CHF, there are different studies noting variable
association. In the SPAF
trial, recent (within
months) history of CHF was
with a substantial risk for thromboembolism
than 7% per
In contrast to
this study, the Embolism in Left Atrial Thrombi
(ELAT) study did not find an association of CHF
with occurrence of stroke. However, in this study
there was significant relation of CHF with all cause
In the Stroke in AF Working Group as-
sessment, CHF was not significantly associated
with stroke. The presence of moderate systolic left
ventricular dysfunction was still an independent
In the National Institute for Health and
Clinical Evidence (NICE) review, structural heart
disease was independently associated with stroke
Stasis of blood in the lower extremities in patients
with CHF activates coagulation system, leading to
fibrin formation which results in thrombus formation
extremities. The reported incidence
in patients with CHF
ranges from 1% to 59%and that for PE from 1% to 39%.3,78-81
In a review
of the US National Hospital Discharge Survey, the
incidence of PE and DVT were significantly higher
in patients with diagnosis of CHF than those without
CHF. The noted relative
risks of 2.15 and 1.21
In a study addressing the out-patient
risk, CHF was
an independent risk factor for
with an adjusted OR
of 2.6 (95% CI, 1.4-4.7).83
Stroke is a consequence of a prothrombotic state resulting
in occlusion of
cerebral arteries. Stroke
the most feared complication
in turn increases
and hence secondary
of strokes. Several
found a previous
risk factor for secondary stroke.53-55,62,69
AF increases the risk of stroke by five-fold, and the
use of anticoagulation reduces this risk by twothirds
whilst antiplatelet therapy
In a systematic evaluation of risks,
prior stroke/TIA had the higher risk association
for stroke occurrence in patients with AF (RR 2.5,
95% CI: 1.8-3.5).24
Stroke patients are at high risk
for VTE due to immobility caused by stroke.
Patients with stroke have several related risk factors
including immobility, hypertension, diabetes,
increase the incidence
ranges from 10% to 75%, depending
the diagnostic method and timing of evaluation.86
In patients with acute hemiplegic stroke,
of DVT is approximately 50%
in the absence of prophylaxis.87
study, among patients who were not on any prophylactic
to be 53% in the paralyzed leg and 5% in the
In a MRI based direct thrombus
imaging study, of the 102 unselected patients
acute ischemic stroke, the prevalence
and PE after 21 days were
In this study, non-ambulatory
status of patients
time of admission
the hospital was
of VTE. In the International
the incidence of PE in patients with stroke was
0.8% at 2 weeks in patients not receiving heparin
prophylaxis and 0.5% in patients receiving heparin
This relatively lower incidence of PE reported in the IST study could be due to under-reporting
mobilization of patients
described in the study.
g. Vascular disease
Patients with peripheral vascular disease have
other risk factors for the thromboembolism which
include hypertension, diabetes, myocardial infarction
and structural heart disease. These factors have
been associated with VTE and also thromboembolism
arterial disease confers
poor prognosis in patients with AF.
Lin et al.94
in their nationwide cohort
study found that
peripheral artery disease
an independent predictor of stroke among
with odds ratio
1.8 (95% CI, 1.2-2.8). Vascular
also a risk factor
of subsequent stroke in AF patients age <65 years
in the Loire Valley Atrial Fibrillation Project,
peripheral artery disease was an independent predictor
of stroke and death in the Danish Diet, Cancer,
Rasmussen et al found an
incidence rate of stroke at 1-year follow-up of 10.9
per 100 person-years in patients with new-onset
AF and peripheral artery disease, vs. a rate of 4.6
in new-onset AF patients without vascular disease.96
In a Danish nationwide cohort study, the
presence of vascular disease also increased the
risk of thromboembolism significantly at 5 and
10 years of follow-up, with hazard ratios (HRs) of
2.04 and 2.22, respectively.30
In a small observation study of 176 patients, there
was noted significantly higher incidence of DVT
in patients admitted for arteriography, angioplasty
or arterial reconstruction surgeries when
compared to control patients without peripheral
In review of a large US healthcare
claims database of hospitalized medically ill
of age > 40 years
age, a diagnosis of
arterial disease at
index admission was
associated with incidence of venous
thromboembolism within 90 days of hospital admission (HR 1.68, 95% CI 1.28-2.21).98
Of the CHAD-VaSc risk factors, five appear to be
associated with the occurrence of VTE; these include
age, CHF, diabetes, stroke and peripheralvascular disease. Patients aged over 75 years have
a 5 fold increased risk when compared to patients
aged <50 years. CHF also increases the incidence
of VTE. The OR of DVT and PE in patients with
CHF is 2.15 and 1.21 respectively. Diabetes has
been noted to increase the incidence of VTE by 2
fold. Similarly, stroke significantly increases the
risk of VTE. The noted incidence of DVT in patients
with stroke ranges from 10% to 75%. After
index hospital admission for peripheral arterial
disease, higher incidence of
than 55 years
of age are at a higher risk of
after 55 years,
higher in men. Hypertension does not
to the development
AF and VTE are two common medical conditions
associated with significant morbidity and mortality.
They share a similar pathophysiology for the
of thrombus and management with
associated with AF.
and VTE, these factors
a role in risk assessment of VTE. Though
factors including age, CHF, diabetes, stroke
of both conditions; factors
and sex have
with the two conditions. The studies in general
not been exclusively
factors on incidence
VTE and hence further studies
are needed to
specifically delineate these factors and the use of
CHADS-VASc score for risk assessment of VTE..
No disclosures relevant to this article were made
by the authors.
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