**DIAGNOSIS OF VENOUS THROMBOEMBOLISM**

Jeffrey I. Weitz

Departments of Medicine and Biochemistry, McMaster University

and Henderson Research Centre, Hamilton, Ontario, Canada

[Address Correspondence to]{.underline}:

Dr. Jeffrey Weitz

Henderson Research Centre

711 Concession Street

Hamilton, Ontario

L8V 1C3

(905)574-8550

FAX (905)575-2646

E-mail:

**[INTRODUCTION]{.underline}**:

Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT)
and pulmonary embolism (PE), occurs with an annual incidence of about
0.1% in Caucasian populations (1). Up to one-third of patients with VTE
have symptomatic PE, which, if untreated, is associated with a fatality
rate of 20 to 25% (1, 2). In patients with DVT, the risk of thrombus
extension, and subsequent PE, is increased if anticoagulant treatment is
inadequate (3). With appropriate anticoagulant treatment, however, the
risk of fatal PE in patients who present with DVT or PE is reduced to
about 0.4 and 1.5%, respectively (4). Although anticoagulation therapy
is extremely effective, it is associated with an increased risk of
bleeding, which can be fatal (5, 6). To minimize morbidity and mortality
caused by either a missed diagnosis or by inappropriate anticoagulation
therapy, diagnostic strategies must not only accurately diagnose VTE
when present, but also must reliably exclude it when absent.

The diagnosis of both DVT and PE is complicated because the signs and
symptoms are not unique to these disorders. Thus, many patients
presenting with leg pain and swelling or with chest pain and shortness
of breath who are investigated for DVT or PE, respectively, prove not to
have VTE. Although structured clinical prediction models help categorize
patients in terms of their probability of VTE, objective testing is
needed to confirm or refute the diagnosis. While venography (x-ray of
the veins) and pulmonary angiography (x-ray of the lung arteries) remain
the gold standards for diagnosis of DVT and PE, respectively, these
tests have been supplanted by less invasive and less costly procedures.
These non-invasive tests are often incorporated into diagnostic
algorithms that are designed to limit the need for more invasive
procedures and, in many patients, to enable such a low probability of
VTE after testing so as to justify withholding anticoagulant therapy.

The tests for diagnosis of DVT and PE will be discussed separately.
Incorporation of these tests into diagnostic algorithms is then
reviewed. Diagnostic strategies for PE often overlap with those for DVT,
reflecting, at least in part, the sequential course of VTE with
extension of calf DVT into the more proximal veins and subsequent
embolization of proximal thrombus to produce PE. Therefore, the
identification of asymptomatic DVT in a patient with suspected PE can
indirectly establish the diagnosis of PE; a helpful scenario in patients
whose initial tests for PE are inconclusive. Likewise, if proximal DVT
is excluded at presentation in a suspected PE patient with nondiagnostic
tests, the short-term risk of PE is low and the risk remains low if
proximal DVT does not develop over the subsequent 2 week period.

**[Test for ]{.underline}[Diagnosis of DVT]{.underline}**:

*[Clinical prediction rules]{.underline}*: Structured clinical
assessment can stratify patients according to their pretest probability
of DVT. When incorporated into diagnostic algorithms, this
stratification helps guide the use of other tests (7). The Wells rule,
the most widely used and validated method, uses nine variables to assign
a low, intermediate or high pretest probability of DVT (8,9). The
variables incorporated into the rule include the presence of risk
factors for VTE and typical signs of DVT, and whether there is an
alternative diagnosis to explain the symptoms and signs.

*[D-dimer testing]{.underline}*: A soluble degradation product of
cross-linked fibrin, the major protein component of clots, D-dimer can
be measured in plasma (10). Levels are usually elevated in patients with
acute VTE making D-dimer a sensitive test for this condition. However,
elevated D-dimer levels can be found with many other conditions,
including sepsis, pregnancy, recent surgery and malignancy. Therefore,
although the test is very sensitive, it is not specific for VTE (i.e.,
false positive tests are not uncommon). Because of this non-specificity,
the role of the D-dimer assay is limited to helping exclude the
diagnosis of VTE when D-dimer levels are normal. Thus, the test has a
high negative predictive value, in that a negative test excludes the
diagnosis with over 95% certainty (10).

Many different D-dimer assays are commercially available. The test has
not been standardized and different assays vary in their operating
characteristics. Consequently, only D-dimer assays that have been
validated for VTE diagnosis should be used. These include high
sensitivity plasma-based enzyme immunoassays, some of which can be done
fairly rapidly, as well as whole blood tests that can be done at the
bedside.

*[Compression ultrasonography]{.underline}*: Venous compression
ultrasonography (CUS) is the most widely used noninvasive test for DVT
diagnosis (11). Using the criterion of lack of full compressibility of a
venous segment on application of gentle pressure on the skin with the
ultrasound probe, CUS has a sensitivity of 97% and a specificity of 98%
for proximal DVT (i.e., DVT involving the veins behind the knee or
higher). The sensitivity and specificity of CUS for the diagnosis of
calf DVT are lower. Based on this information and the uncertainty
regarding the need to treat isolated calf DVT, some centers do not
perform routine ultrasonography of the calf veins. Instead, repeat CUS
of the proximal veins is performed 1 week after an initial negative
examination to exclude the 20% of patients whose calf clots extend into
the proximal veins. In the interim, anticoagulant therapy is withheld
(11,12). This approach, which is known as serial testing, has been shown
to be safe; for example, in one study (13), the 3-month rate of
symptomatic VTE after negative serial CUS was 0.7% (95% confidence
intervals \[CI\] 0.3-1.2%). However, repeat testing is inconvenient
because only 1 to 2% of patients will have a new proximal DVT on the
second CUS.

Complete or comprehensive CUS has been introduced to circumvent the need
for serial testing. In this procedure the deep veins in the thigh,
popliteal (behind the knee) and calf are examined at 2-cm intervals
(14). This test is more time-consuming than 3-point compression
protocols that only examine the veins in the groin, thigh and popliteal
regions. A single negative complete CUS in patients with suspected DVT
appears to reliably exclude DVT making it safe to withhold anticoagulant
therapy in such patients. Thus, in the trial by Stevens et al. (15), the
incidence of symptomatic VTE 3-months after a negative complete CUS was
0.7% (95% CI 0.2-2.3%), a rate similar to that reported with serial CUS
(13).

Although a negative complete CUS appears to reliably exclude DVT, this
approach may lead to over treatment. Thus, a large proportion (at least
30%) of DVT detected by complete CUS are isolated calf DVT, a condition
for which the need for anticoagulant therapy is uncertain (16,17).
Furthermore, the specificity of CUS for isolated calf DVT has been
reported to be as low as 42% when compared with venography, the gold
standard (12). It is possible, therefore, that many of the isolated calf
DVT detected by complete CUS are false positives. Using more
contemporary ultrasound equipment, the specificity of complete CUS for
diagnosis of asymptomatic calf DVT was 88% compared with venography in a
recent study (18). Therefore, the rate of false positive diagnosis of
calf DVT is likely declining. Nonetheless, additional studies on the
need to treat isolated calf DVT are necessary to better define the role
of complete CUS in the diagnosis of DVT.

*[Diagnosis of recurrent DVT]{.underline}*: All of the current imaging
modalities used for the diagnosis of initial DVT have limitations for
the diagnosis of recurrent disease. Residual abnormalities on CUS render
the diagnosis of recurrence problematic, particularly if a prior
examination is unavailable for comparison purposes. Even venography is
often non-diagnostic in patients with suspected recurrence.

A new non-compressible venous segment on CUS, an increase in thrombus
length of 9 cm or more (19), or evidence of DVT in the previously
unaffected limb establish a diagnosis of recurrent DVT. A D-dimer assay
may be useful in patients whose CUS is non-diagnostic. A negative
D-dimer test helps to exclude a diagnosis of recurrent DVT. This concept
is supported by the results of a management study that demonstrated the
safety of withholding anticoagulant therapy in patients with suspected
recurrent DVT who had a negative D-dimer result (20). Although this
approach appears promising, additional studies in larger numbers of
patients are needed.

**[Tests for ]{.underline}[Diagnosis of PE]{.underline}**

*** ****[Clinical prediction rules]{.underline}*: The two most widely
used and best validated clinical prediction rules are the Wells
simplified score and the Geneva score (21). Like the Wells score for
DVT, the PE scoring system assesses the presence of risk factors for VTE
and typical symptoms, as well as whether an alternative diagnosis
explains the symptoms and signs. Identification of an alternative
diagnosis can be complicated; a factor that likely contributes to only
moderate interobserver agreement when applying the score (22,23). The
Geneva score is even more complicated, however, because it also requires
arterial blood gas sampling and a chest x-ray (21). Both scoring systems
help stratify patients according to their pretest probability of PE. The
prevalence of PE in those with low, intermediate and high pretest
probability categories is expected to be less than 10%, 25% and 60% or
more, respectively.

*[D-dimer testing]{.underline}*: The negative predictive value of
validated D-dimer assays is sufficiently high to safely withhold
anticoagulation therapy in a patient with suspected PE whose pretest
probability is low and whose D-dimer test is negative (24,25). Although
one study suggested that a single negative D-dimer test can, on its own,
safely exclude the diagnosis of PE, most experts recommend further
diagnostic testing, at least for those patients whose pretest
probability is intermediate or high (24,25). D-dimer assays are less
useful in hospitalized patients with suspected PE than they are in
outpatients because inpatients often have concomitant conditions, such
as sepsis or malignancy, which can be associated with a positive test.

*[Computed]{.underline}[ tomography]{.underline}*: Computed tomography
pulmonary angiography (CTPA) is the procedure of choice for the
diagnosis of PE (11). Not only can this test make a diagnosis of PE, but
it also provides an alternative diagnosis in many patients with
suspected PE (26). CTPA is an evolving technology with multiple-slice
detectors now replacing earlier single-slice models. More advanced
detectors are better able to visualize subsegmental pulmonary arteries,
thereby increasing the sensitivity and specificity of CTPA relative to
pulmonary angiography, the gold standard for PE diagnosis (27). It is
important to visualize emboli in the subsegmenental arteries because
studies using pulmonary angiography reveal that 20% of symptomatic PE
are limited to these smaller arteries and these small emboli can be
harbingers of recurrent VTE (25). While CTPA can stand alone for
diagnosis of central PE or PE in segmental pulmonary arteries,
additional testing is needed to confirm or refute a diagnosis of VTE in
patients whose defects are confined to a subsegmental artery. For this
reason, CTPA is usually incorporated into diagnostic algorithms that
include clinical assessment, D-dimer testing and bilateral CUS.

*[Ventilation-perfusion lung scanning]{.underline}*: Limitations of this
test have reduced its usage. Although a normal perfusion excludes the
diagnosis of PE, only 25% of patients with suspected PE have a normal
scan. Likewise, a high-probability scan establishes the diagnosis of PE,
but is found in only 10% of tested patients. Therefore, about 65% of
patients with suspected PE have a non-high probability scan, which
necessitates additional testing (25). This limitation, and rapid
advances in CTPA, have reduced the usage of lung scanning for PE
diagnosis. However, the test is useful for suspected PE patients whose
renal impairment precludes administration of CT contrast dye.

*[Magnetic resonance (MR) imaging]{.underline}*: Contrast-enhanced MR
angiography is a relatively new addition to the armamentarium of tests
for PE diagnosis. This test has a sensitivity and specificity of 77% and
98%, respectively (28), although sensitivity is likely to improve as the
technology advances. An advantage of MR angiography is that it uses
gadolinium for contrast, an agent that does not produce renal toxicity.
Direct thrombus imaging also is possible with MR by exploiting the fact
that blood undergoes oxidative denaturation after clotting to generate
methemoglobin, which can then be detected. The utility of this technique
has yet to be established. Likewise, management strategies incorporating
contrast-enhanced MR angiography are lacking, reflecting, at least in
part, the limited accessibility to rapid MR scanning. Although MR
remains a powerful tool, more information is needed before it can be
incorporated into routine diagnostic algorithms for PE.

*[Pulmonary angiography]{.underline}*: Although pulmonary angiography
remains the gold standard for PE diagnosis, this expensive invasive test
is associated with serious side effects, is technically demanding to
perform, and can be difficult to interpret (25). Pulmonary angiography
is contraindicated in patients with renal impairment and is difficult to
perform in those who are clinically unstable. For these reasons, the
test is rarely used.

*[CUS]{.underline}*: Detection of asymptomatic DVT is an indirect method
of PE diagnosis. In patients with documented PE, DVT is detectable by
bilateral venography in 75% (29), whereas proximal DVT is found by
bilateral CUS in about 50% (30). Asymptomatic DVT is more likely to be
found in patients with more extensive PE. Therefore, when bilateral CUS
is done in patients with non-diagnostic CTPA or perfusion lung scan
findings, asymptomatic DVT is only found in about 5%. Although normal
bilateral CUS or venogaphy does not exclude the diagnosis of PE, it
reduces its probability.

*[Other tests]{.underline}*: Transthoracic echocardiography can reveal
changes in the right ventricle and pulmonary artery that indirectly
suggest PE (31). These include right ventricular dilatation, tricuspid
regurgitation and increased pulmonary artery pressure. Transesophageal
echocardiography also can visualize thrombus in the central pulmonary
arteries, but the test is invasive. Neither of transthoracic nor
transesophageal echocardiography is suitable for PE diagnosis because
they lack specificity. However, transthoracic echocardiography is useful
to identify patients with massive or submassive PE who may benefit from
thrombolytic therapy (31).

**[Diagnostic algorithms for DVT and PE]{.underline}**

*[Diagnosis of DVT]{.underline}*: An approach to the diagnosis of DVT is
illustrated in Slide 10. Patients with a low pretest probability of DVT
should undergo D-dimer testing. If the D-dimer is negative, the risk of
DVT is sufficiently low that further diagnostic testing is unnecessary.
If the D-dimer is positive, CUS should be performed. A positive CUS
establishes the diagnosis of DVT, whereas a negative test makes the
diagnosis unlikely.

Those with a moderate or high pretest probability, where the prevalence
of DVT is 33% and 85%, respectively, should proceed directly to CUS
because a negative D-dimer cannot reliably exclude the diagnosis. A
negative CUS in these patients does not exclude the possibility of calf
DVT and a D-dimer test is helpful. A negative D-dimer makes calf DVT
unlikely, whereas a positive test warrants repeat CUS in one week or
sooner if symptoms progress.

*[Diagnosis of PE]{.underline}*: An algorithm for diagnosis of PE is
illustrated in Slide 15. Patients with a low pretest probability of PE
should undergo D-dimer testing. A negative D-dimer excludes the
diagnosis, whereas a positive test should prompt CTPA.
Ventilation-perfusion lung scanning or MR angiography can be used in
place of CTPA in patients with impaired renal function.

Patients with a moderate or high pretest probability should proceed
directly to CTPA. A positive test establishes the diagnosis. Those with
a negative or indeterminate test should undergo bilateral CUS and
D-dimer testing. A positive CUS establishes a diagnosis of VTE. If CUS
and D-dimer are both negative, the diagnosis is excluded. If CUS is
negative, but the D-dimer test is positive, CUS should be repeated in
one week.

*[Diagnosis of VTE in pregnancy]{.underline}*: VTE is a major cause of
morbidity and mortality during pregnancy and is second only to
hemorrhage as the most common cause of maternal death (32). Therefore,
accurate diagnosis of VTE in pregnancy is critical. However, diagnosis
of VTE in pregnancy poses special problems. For example, leg swelling is
common in pregnancy, making this sign less useful for DVT diagnosis.
Likewise, D-dimer levels are often elevated in the third trimester of
normal pregnancy, which reduces the negative predictive value of this
test. Furthermore, isolated iliac vein thrombosis, which is difficult to
diagnose with CUS, can occur in pregnancy. Most DVT in pregnancy occurs
in the left leg, possibly reflecting increased compression of the left
iliac vein by the crossing right iliac artery as the uterus enlarges.
Finally, clinicians are reluctant to investigate pregnant women for
suspected VTE because of concerns about radiation exposure to the fetus.

CUS remains the primary diagnostic test for DVT. Ultrasound evidence of
dilation of the proximal veins and reduced blood flow should raise the
suspicion of isolated iliac vein thrombosis. If the initial CUS is
negative, the test should be repeated in 1 week to exclude calf DVT with
interval extension.

CTPA offers advantages over lung scanning in pregnant women with
suspected PE, although its role in pregnancy has yet to be well defined.
The radiation doses to the fetus with single- and multi-detector CTPA
are estimated at 0.06 and 0.03 mSv, respectively, although more recent
estimates are even lower. These values are lower than estimated fetal
radiation dose of 0.1 to 0.2 mSv reported with perfusion lung scanning
(33). All of these values, however, are based on estimated uterine doses
of radiation; estimates that may underestimate fetal radiation exposure.
Although contrast-enhanced MR angiography may be useful, its safety in
pregnancy has yet to be defined. Gadolinium-based contrast agents cross
the placenta and their potential fetal toxicity is uncertain. Although
direct thrombus imaging provides an alternative MR method for PE
diagnosis, this technique has not been validated. Until more information
is available, therefore, MR should likely be avoided in pregnancy.

**[CONCLUSIONS]{.underline}**

Diagnostic tests for DVT and PE have advanced in recent years such that
non-invasive tests have largely replaced invasive ones. The use of
structured clinical assessment rules and D-dimer testing in conjunction
with objective tests has further streamlined the diagnosis. It is
important to follow these diagnostic algorithms so as to use the tests
appropriately and to target expensive tests to those who need them most.

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