Comments, Opinions, and Reviews

Venous Thromboembolism After Acute Stroke

J. Kelly, BSC, MRCP; A. Rudd, FRCP; R. Lewis, MD, FRCP; B.J. Hunt, MD, FRCP, FRCPath

Background—Treatment for venous thromboembolism (VTE) is highly effective in preventing morbidity and mortality,
yet pulmonary embolism (PE) accounts for up to 25% of early deaths after stroke. This is because the current diagnostic
paradigm is reactive rather than proactive: the clinician responds to VTE when it becomes symptomatic, in the
expectation that initiation of treatment will prevent progression to more serious manifestations. This approach is flawed,
because sudden death from PE is frequently unheralded and nonfatal symptomatic pulmonary emboli are often
unrecognized or misdiagnosed.
Summary of Comment—Morbidity and mortality from PE could be reduced either by more effective thromboprophylaxis
or earlier diagnosis and treatment of established VTE. The fact that early use of short-term, low-dose, unfractionated
heparin (UFH) is not associated with sustained, clinically meaningful benefit suggests that a fundamental change in the
diagnostic approach to VTE is needed, one which requires a greater appreciation that clinically apparent events are
merely the tip of the thromboembolism iceberg.
Conclusions—Research into a strategy of screening for subclinical VTE in these patients is needed, with a view to
identifying a subgroup at risk of progression to symptomatic and life-threatening events, in whom outcome might be
improved by anticoagulation. (Stroke. 2001;32:262-267.)
Key Words: cerebral infarction 䡲 deep vein thrombosis

I n this article, an overview of data is presented on the

incidence and natural history of venous thromboembolism
(VTE) after stroke. Strategies of thromboprophylaxis, the
greater in those who are more immobile8: in a study of 150
patients admitted to a stroke rehabilitation unit at, on average,
9 weeks after stroke, bilateral venography revealed DVT in
morbidity and mortality associated with established VTE, and 33%.8
the risks of anticoagulant use in acute ischemic stroke are also
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discussed. It is argued that a strategy of screening for Clinical Significance of Asymptomatic

subclinical deep vein thrombosis (DVT) is required, though a
further trial of thromboprophylactic low-dose, low-
molecular-weight heparin (LMWH) may still be justified.
Incidence of DVT After Stroke
Studies with 125I fibrinogen screening in patients with acute
hemiplegic stroke have shown an incidence of DVT of
approximately 50% within 2 weeks in the absence of heparin
prophylaxis; the majority of these affect the paralyzed leg and
are asymptomatic.1 Approximately two thirds of these are
below-knee DVTs,2 in contrast to unselected (nonstroke)
patients presenting with symptomatic DVT, in whom the
majority are proximal.3 DVTs develop as early as the second
day, with the peak incidence between days 2 and 7.1 The risk
of DVT correlates with the degree of paralysis4 and is greater
in older patients5 as well as those who have atrial fibrillation.6
Predilection for the paralyzed leg is probably explained by a
combination of loss of the calf muscle pump and repeated
minor trauma.7
DVT is also present in a significant proportion of patients
during the rehabilitation phase of stroke, the risk being
Proximal DVT After Stroke
The main clinical significance of asymptomatic proximal
DVT is its potential to cause fatal pulmonary embolism (PE).
Indeed, the majority of symptomatic PEs in unselected
patients are unheralded and arise from previously subclinical
DVT.9
In a study of unselected patients performed before antico-
agulants were in routine use, untreated, clinically apparent
DVT was associated with a mortality from PE of up to 37%.10
The risk of fatal PE associated with untreated subclinical
DVT is lower, though it remains significant. Early studies in
patients with hip fractures found the risk to be around
10%,11,12 but a more recent overview in postoperative patients
has suggested that predominantly subclinical DVT diagnosed
by 125I fibrinogen scanning is associated with a 5% risk of
fatal PE.13,14 Although there are few data on the natural
history of untreated subclinical DVT in stroke patients, in one
study patients with proximal subclinical DVT had a 35% risk
of clinical PE.15
Fatal pulmonary emboli usually arise from proximal
DVT,16 which accounts for one third of all DVTs in surgical

Received June 20, 2000; final revision received August 15, 2000; accepted August 31, 2000.
From the Elderly Care Department, St. Thomas’ Hospital, London, England.
Correspondence to Dr J. Kelly, SpR in Elderly Care/GIM, Elderly Care Dept, C/O Alexandra Ward, 9th Floor North Wing, St. Thomas’ Hospital,
Lambeth Palace Rd, Lambeth, London SE1 7EH, UK.
© 2001 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org

262
 Kelly et al
patients.17 If it is assumed that the 5% of postoperative
patients with untreated subclinical DVT who die from PE
have proximal DVT, then 15% of subclinical proximal DVTs
result in fatal PE. Three percent of stroke patients succumb to
PE within 3 months,18 a mortality confined to the half who
develop DVT.1 Because one third of these DVTs are proxi-
mal2 and most are silent,1 the data suggest that the mortality
associated with untreated proximal subclinical DVT after
stroke is some 15%, which is similar to that in postoperative
patients.
A secondary concern is the potential to cause the post-
thrombotic syndrome, characterized by persistent pain and
swelling, with or without venous ulceration.19 The incidence
of this disorder approaches 90% in patients with untreated
symptomatic DVT.10 Although it is recognized that many
patients who present with this syndrome have no history of
clinical VTE (the entire process having been clinically
silent),20 the incidence after untreated asymptomatic DVT is
unknown. The long-term incidence in patients with symptom-
atic, treated proximal DVT is approximately 30%3; however,
there are conflicting data as to whether it occurs in patients
with adequately treated asymptomatic proximal DVT.21,22
Clinical Significance of Asymptomatic
Below-Knee DVT After Stroke
A major concern in patients who have untreated below-knee
DVT is the 20% risk of proximal extension,23 a subgroup that
cannot accurately be predicted on clinical grounds.24 Clinical
PE can, however, occur even in the absence of propaga-
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tion,16,25 and routine ventilation-perfusion (VQ) scanning
demonstrates silent PE in up to one third of patients who have
isolated below-knee DVT.26,27 Although pulmonary emboli
arising from below-knee DVTs are more likely to be small
and asymptomatic and therefore less likely to be life threat-
ening than those associated with proximal DVT,28,29 the risk
of fatal PE attributable to untreated, nonpropagating below-
knee DVT has not yet been defined. Symptomatic, isolated,
below-knee DVT may cause the postthrombotic syndrome,29
but it is unclear whether this entity is a sequela in asymp-
tomatic cases.
Clinical Significance of Pelvic Vein
Thromboses After Stroke
Pelvic vein thromboses may account for a significant minor-
ity of pulmonary emboli in unselected (nonstroke) patients: in
a series of 353 autopsies of patients in whom pulmonary
emboli were found, the pelvic veins accounted for 11.5% and
the inferior vena cava 5% of the identifiable sources of
emboli.30 However, the incidence and clinical significance of
isolated pelvic and inferior vena cava thromboses after stroke
is unknown, because these have not been detected by 125I
fibrinogen scanning,31 the main screening tool used in early
studies investigating the incidence of DVT after stroke.1
Incidence of PE After Stroke
The incidence of clinical PE reported in the absence of
heparin prophylaxis has varied considerably, depending on
the methodology of the studies. In the International Stroke
Trial (IST), the incidence was 0.8% at 2 weeks.32 Similarly,
Venous Thromboembolism After Acute Stroke 263
in a retrospective study of 607 patients who had acute stroke,
PE was reported in 1% during the period of hospitalization.33
However, prospective studies that focused specifically on
venous thromboembolic complications reported incidences of
clinically apparent PE of 10% to 13% (excluding pulmonary
emboli identified at autopsy that were asymptomatic during
life).15,34 These data strongly suggest underascertainment in
studies reporting much lower incidences of PE.
The risk of PE also extends into the rehabilitation phase. In
a retrospective study of 363 patients who did not receive
heparin prophylaxis and entered a rehabilitation unit 4 weeks
after stroke, 4% developed PE (confirmed by VQ scanning)
on average 11 days after entering the unit.35
Only 1 small study has prospectively screened for PE by
using VQ scintigraphy. Dickmann et al36 studied a group of
23 patients 10 days after hemorrhagic stroke and found
evidence of PE in 39%, though the proportion with symptoms
was not stated. Autopsy studies show that half of the patients
who die in hospital after the first 48 hours poststroke have
evidence of PE,15,37 which suggests that pulmonary emboli
are often subclinical and/or unrecognized after stroke.
Morbidity and Mortality Due to PE After
Acute Stroke
Pulmonary emboli account for 13% to 25% of early deaths
after stroke.38 – 40 Although they may occur as early as day 3,41
fatal emboli are unusual in the first week40 and are most
frequent between the second and fourth weeks, when they are
the most common cause of death.18 Those more severely
disabled are most likely to be affected,42 but PE may also
occur in ambulatory patients.18
The mortality attributed to untreated clinical PE in uns-
elected (nonstroke) hospitalized patients is approximately
30%.43 However, PE in stroke patients may have a higher
mortality than that in other clinical settings15,41,44; in one
series of stroke patients, half of the clinical pulmonary emboli
presented as sudden death.41 The morbidity associated with
nonlethal pulmonary emboli should not be overlooked; this
may manifest primarily as impaired cardiorespiratory reserve
adversely affecting rehabilitation and potentially influencing
functional outcome.45
Difficulties in Diagnosis of Symptomatic PE
After Acute Stroke
The signs and symptoms of PE are notoriously nonspecific,46
and both underdiagnosis and misdiagnosis are well docu-
mented, particularly in the elderly.47,48 A number of factors
make diagnosis even more difficult in poststroke patients, a
group in whom antemortem diagnosis is especially poor.39
Patients may not complain of symptoms because of dyspha-
sia, cognitive impairment, or mental obtundation.49 In addi-
tion, pneumonia, the illness for which PE is most often
mistaken,47 is also a common complication after stroke.18
This can lead to misdiagnosis, particularly as it may be
underappreciated that up to two thirds of patients with PE
develop fever.50 Indeed, pneumonia and PE can commonly
occur together, but the possibility of coexistent PE in a patient
with strong clinical evidence of pneumonia is rarely consid-
ered; in a postmortem series of unselected patients found to
 264 Stroke January 2001
have PE, pneumonia coexisted in 40%, though PE had not
been diagnosed antemortem in any of the patients who had
pneumonia.51 Finally, elderly patients with stroke may not be
extensively investigated, and subtle clinical signs of PE, such
as an asymptomatic mild increase in respiratory rate, are
easily overlooked.
Stroke patients with suspected PE will usually undergo VQ
scanning as the imaging modality of first choice. The impor-
tance of integrating this information with an assessment of
the clinical probability of PE, either derived subjectively or
by using scoring systems, has been stressed.9,52
Subclinical VTE
Clinically manifested disease represents the tip of the throm-
boembolism iceberg.53 Screening studies in both stroke and
postoperative patients,1,13,17 together with the low incidence
of symptomatic DVT in patients with PE,9 demonstrate that
the majority of DVTs are asymptomatic. Screening patients
with symptomatic proximal DVT without clinical evidence of
PE reveals evidence of subclinical PE in up to half.54
Furthermore, VQ scanning in predominantly asymptomatic
postoperative patients reveals pulmonary emboli in 12% to
18%.55–57 Clearly, only a small proportion of pulmonary
emboli produce symptoms.
Treatment of Established VTE
Treatment of symptomatic VTE is highly effective in reduc-
ing morbidity and mortality. In an overview of 25 studies,
recurrent fatal PE during a 3-month period of full anticoag-
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ulation occurred in only 1.5% and 0.4% of patients presenting
with PE and DVT, respectively.58 In a meta-analysis of 13
trials comparing unfractionated heparin (UFH) with LMWH
in the initial treatment of VTE, LMWH was found to be at
least as effective as UFH and was associated with a signifi-
cantly lower mortality.59
Although the need for anticoagulation in patients with
symptomatic PE or proximal DVT is clear, the treatment of
patients with symptomatic below-knee DVT is debated. The
current consensus is that these patients should be either fully
anticoagulated or followed up with serial noninvasive testing
for 14 days,60 an approach shown to be safe in the absence of
proximal extension.61– 63 Optimal management of subclinical
DVT has not been studied, but sensible conclusions can be
drawn from a knowledge of the natural history of untreated
DVT and the risks associated with anticoagulation, as dis-
cussed below.
Risks Associated With Anticoagulation in
Acute Stroke
Analysis of data from the IST allows a comparison of the
effect of medium-dose heparin (12 500 U of UFH twice
daily), initiated within 48 hours of ischemic stroke and
continued for 2 weeks, to no heparin on a number of end
points. Although this dosing regime reduced the risk of PE
and recurrent ischemic stroke, the reduction was more than
offset by an increased risk of hemorrhagic stroke transforma-
tion and extracranial hemorrhage. Overall, there was an
excess risk of death or recurrent stroke and major nonfatal
extracranial bleeds of 0.5% and 1.5%, respectively, during
the treatment period.32 White et al64 studied the risk of
warfarin-related complications in 22 000 unselected patients
diagnosed with DVT over a 3-month period. In the subgroup
of 1312 patients with a history of stroke, the readmission rate
due to bleeding was 1.7%. In a comparison cohort of patients
hospitalized because of pneumonia or cellulitis without DVT,
this figure was 0.7%, which suggests that the excess risk
attributable to warfarin in the stroke subgroup was 1.0%. The
excess risk of intracranial hemorrhage in this subgroup was
not specifically studied, though it was 0.1% in the group as a
whole.
The balance of risks might therefore favor initiation of
anticoagulation in established VTE after stroke, where the
risk of major morbidity or mortality associated with untreated
DVT exceeds about 3%, the combined risk of death, recurrent
stroke, and major bleeding associated with a few days’
treatment with heparin followed by 3 months of warfarin after
acute ischemic stroke. This suggests that patients with sub-
clinical proximal DVT would benefit from treatment. The
balance of risks is less clear for nonpropagating, below-knee
DVT, though this may be affected by factors such as
inadequate cardiorespiratory reserve, because even a small
PE can be fatal in such patients.65
Most clinicians would now initiate treatment with LMWH
rather than UFH. Although LMWH is associated with a lower
risk of hemorrhage in medical patients,66 data comparing
LMWH and UFH in stroke patients are insufficient to draw
conclusions about their relative safety in this context.67 In
addition, most diagnoses of clinical VTE are made several
days after stroke onset,40,41 by which time the risk of
hemorrhagic stroke transformation, greatest in the first 4
days, is likely to be lower.68 This approach might be associ-
ated with a more favorable risk-to-benefit ratio.
Heparin Thromboprophylaxis After Stroke
Prophylactic use of UFH in surgical patients reduces the
incidence of DVT, PE, fatal PE, and total mortality,13 and
LMWH is at least as effective.69 An overview of 10 trials of
prophylactic UFH or LMWH in more than 1000 patients with
ischemic stroke has shown an approximate 80% reduction in
the incidence of DVT as detected by 125I fibrinogen scanning
or venography, though the numbers were too small to draw
firm conclusions about the effect on the incidence of PE and
total mortality.70 In a recent Cochrane review71 of 13 trials of
anticoagulants in acute stroke, fatal and nonfatal PE were
found to be significantly reduced by 39%; however, it should
be noted that these trials were heterogenous and included a
mixture of low- and medium-dose anticoagulant regimes.
In the IST, treatment with low-dose heparin (5000 U of
UFH subcutaneously twice daily) significantly reduced the
combined risk of death and recurrent stroke at 14 days from
12% to 10.8%, an effect attributable predominantly to a
reduced risk of recurrent ischemic stroke, as PE was not
significantly reduced. Increases in the incidence of intracra-
nial hemorrhage and of fatal or transfusion-requiring ex-
tracranial bleeds did not reach significance with this regime
and are illustrated in the Table.32 Nevertheless, no reduction
in overall mortality or disability could be demonstrated at 6
months, and routine use of heparin prophylaxis after stroke
 Kelly et al
Effects of Low-dose UFH (5000 units BD) and Aspirin (300 mg
OD) on End Points at 14 Days in the IST32
Aspirin⫹Low- Aspirin, No Aspirin,
Dose UFH No UFH No UFH
Intracranial hemorrhage 0.8% 0.5%
Transfused or fatal extracranial 0.8% 0.5%
bleeds
Recurrent ischemic stroke 2.1% 3.2%
Pulmonary embolism 0.5% 0.7%
has therefore not been recommended subsequent to this
trial.71 One reason that the short-term benefit of low-dose
UFH was not sustained may be that treatment was given for
only 2 weeks, because most fatal PEs occur between the
second and fourth weeks after stroke.18 In addition, there was
no information given as to how DVTs and PEs were diag-
nosed, so that underascertainment may have occurred. A
further trial of low-dose heparin (preferably LMWH) for an
extended period and with a more systematic reporting of VTE
may therefore be justified.
Other Strategies to Prevent VTE After Stroke
Graded elastic compression stockings are frequently used
after stroke and have been shown to reduce the risk of DVT
in surgical patients by about two thirds, though there are
insufficient data to reach a definite conclusion about their
effect on PE. Data are also lacking on their effectiveness in
the context of stroke, or in combination with prophylactic-
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dose heparin,72 and they may be less acceptable to patients
than subcutaneous heparin.73
Intermittent pneumatic compression is effective in prevent-
ing DVT in general surgical and neurosurgical patients as
well as in patients undergoing elective knee and hip replace-
ment, in whom it probably has an effect comparable in
magnitude to that of LMWH.73 However, there have been no
large studies in medical patients.74
Aspirin reduces the risk of VTE in surgical patients by at
least one third,75,76 though it does not reduce overall mortal-
ity.75 In the International Stroke Trial, the incidence of fatal
and nonfatal PE at 2 weeks was 0.6% in those treated with
aspirin compared with 0.8% in controls, an effect that did not
reach significance.32
The Case for a More Anticipatory Approach
to VTE Diagnosis After Stroke
Many pulmonary emboli that occur after stroke present as
sudden death,41 and the majority of these patients do not have
clinical evidence of DVT, the precursor to PE, before death.9
Because the treatment for VTE is highly effective,58 the
current expectant approach to its diagnosis, particularly in the
absence of heparin prophylaxis, should be questioned. A
strategy of screening for VTE in these patients therefore
warrants evaluation.
Methods of Screening for DVT After Stroke
The choice of screening tool for DVT is problematic, because
it would have to be noninvasive, inexpensive, and highly
sensitive. Doppler ultrasound is a powerful technique for
Venous Thromboembolism After Acute Stroke 265
detecting symptomatic proximal DVT.77 However, combined
data from 11 studies in high-risk postoperative patients
indicate that the sensitivity for the diagnosis of asymptomatic
proximal DVT is only 62% and that for asymptomatic
0.3%
below-knee DVT 48%.78 Although thrombi missed with
ultrasound screening tend to be smaller and nonocclusive,79 it
0.3%
has been suggested that the technique may be unsatisfactory
as a screening tool since many DVTs will not be detect-
4.4%
ed.77– 80 The utility of the technique for the detection of
0.9%
asymptomatic DVT after acute stroke has not specifically
been evaluated.
The 125I fibrinogen test is no longer used because of the risk
of transmission of infection with injected fibrinogen31 and
impedance plethysmography is not useful for the detection of
calf vein thromboses or asymptomatic DVT.77 Contrast
venography remains the gold standard for diagnosing lower
limb DVT, but would not be suitable because it is invasive
and associated with a small risk of complications.77
MRI is noninvasive and allows simultaneous imaging of
the venous system in both lower limbs. In addition, pelvic
vein and inferior vena cava thromboses are accurately iden-
tified, an important advantage over other techniques.81 MR
venography compares favorably with contrast venography for
the diagnosis of symptomatic proximal DVT82 but has not
been evaluated for the diagnosis of asymptomatic DVT. More
recently, MR direct thrombus imaging has shown excellent
sensitivity and specificity for the diagnosis of symptomatic
above- and below-knee DVT.83 This technique allows direct
visualization of thrombi so that equally favorable results
might be expected in asymptomatic patients. Although avail-
ability is currently limited, MR technology is likely to play an
increasingly important role in DVT diagnosis in the future.
D-Dimers as a Screening Tool for DVT
After Stroke
D-dimers are a cross-linked fibrin breakdown product gener-
ated from the degradation of the fibrin matrix of fresh venous
thromboemboli.84 For symptomatic DVT or PE in unselected
patients, ELISA assays have been shown to have an average
diagnostic sensitivity of 97% at a threshold of 500 ng/mL,
though the specificity is only 35% to 45%.85,86
Harvey et al87 investigated the utility of a D-dimer assay as
a screening test for subclinical DVT in 105 patients who
were, on average, 25 days poststroke and found that a
threshold of 1092 ng/mL had a sensitivity of 100% and
specificity of 66% for diagnosing DVT as detected by
Doppler ultrasound. Although this study suggests that
D-dimers may have a useful screening role, allowing the
identification of a subgroup of patients who should undergo
targeted imaging, the results cannot be extrapolated to pa-
tients in the first few days after stroke, because acute
nonlacunar ischemic stroke increases D-dimer levels.88 –92
Decay to baseline occurs over the next 30 days, 88 –92 so the
normal range differs in the acute and rehabilitation settings.91
A D-dimer threshold useful in the rehabilitation phase may
therefore not be discriminatory in the first few days after
stroke, the period during which most DVTs develop.1 It
should also be noted that although several commercial
D-dimer assays are now available, results from studies with
 266 Stroke January 2001
one manufacturer’s test cannot necessarily be extrapolated to
another.93 Further studies are required to examine the utility
of D-dimers as a screening test for DVT in acute stroke.
Conclusions
The morbidity and mortality attributable to VTE after stroke
is unlikely to change with a perpetuation of current practice.
As one of the most eminently treatable of stroke complica-
tions, and in the absence of more effective prophylaxis,
research is needed into the development of noninvasive
strategies of screening for subclinical DVT in these patients.
Examples of future studies might include the assessment of
MR technology, investigation of Doppler ultrasound for the
diagnosis of subclinical proximal DVT, and the evaluation of
D-dimers as a possible discriminator of DVT status in acute
stroke, potentially facilitating targeted imaging in a subgroup
with a high risk of underlying DVT.
Although optimal treatment of subclinical DVT after
stroke is currently unknown, extrapolation of current evi-
dence would suggest that the benefits of anticoagulation
outweigh the risks associated with untreated subclinical
proximal DVT. However, the balance of risks might gener-
ally favor an expectant approach in patients with adequate
cardiorespiratory reserve who have isolated below-knee
DVT, with repeat imaging to identify the subgroup in whom
proximal propagation occurs.
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