Laboratory Tests and Ancillaries
DVT
Baseline blood tests when initiating anticoagulation
treatment include a complete blood count (CBC), renal and hepatic function
assessment, prothrombin time (PT), and activated partial thromboplastin time
(aPTT).
D-dimer
Level by Enzyme-linked Immunosorbent Assay (ELISA)
D-dimer level by ELISA assay is a highly sensitive but non-specific screening
test for the presence of VTE. Elevated D-dimer levels
are non-diagnostic of DVT as they may also be elevated in patients with advanced age, MI, disseminated intravascular
coagulation, cancer, inflammation, infection, necrosis, recent trauma or
surgery, kidney or liver disease, pregnancy, etc. Therefore, a high
concentration of D-dimer has a poor positive predictive value for DVT and cannot be used to rule in the disease.
Normal
D-dimer level by ELISA assay (<500 ng/mL) has a high negative predictive
value and is useful to rule out VTE (including recurrent DVT); thus, reducing the need for imaging when used in
conjunction with clinical probability, plethysmography, or ultrasound (US).
Patients with a low clinical pretest probability of DVT and a negative D-dimer assay are considered to have no DVT or have a very low risk of subsequent DVT and can be followed up clinically without further testing
unless new or progressive symptoms develop.
This is most useful in emergency department
patients, in ambulatory care settings, and in patients with recent onset of
symptoms who are not currently taking anticoagulants. It can be used after a
negative duplex ultrasound to determine the need for further radiologic
evaluation. In elderly or inpatients, the D-dimer retains a high negative
predictive value but is normal in <10% of patients and therefore is not
useful in these patients.
Recommended Diagnostic Tests Based
on Clinical Pretest Probability Result
For patients with low pretest probability (5% thrombosis), the
recommended diagnostic tests include D-dimer, duplex venous ultrasonography with
compression, venography, and whole-leg ultrasound.
For patients with moderate pretest probability (25% thrombosis), the
recommended diagnostic tests include D-dimer, proximal duplex venous
ultrasonography with compression, venography, and whole-leg ultrasound.
For patients with high pretest probability (60% thrombosis), the
recommended diagnostic tests include proximal duplex venous ultrasonography with
compression, whole-leg ultrasound, and venography.
Pulmonary
Embolism
D-Dimer
D-dimer is a highly sensitive
but non-specific screening test for the presence of pulmonary embolism.
Sensitivity may be decreased if the duration of VTE manifestations is >2 to
3 days prior to testing and/or if the patient is on Heparin. It is best used
for the evaluation of outpatients in the emergency department.
D-dimer measurement should not
be performed in those with high clinical probability of pulmonary embolism;
proceed directly to imaging. A negative D-dimer test via any D-dimer method
(SimpliRED, Vidas, or MDA) reliably excludes pulmonary embolism in patients
with low clinical probability; such patients do not require imaging for VTE. A
negative result using ELISA (Vidas) or MDA methods reliably excludes pulmonary
embolism in patients with intermediate probability. In adults being assessed
for pulmonary embolism who have a low or intermediate clinical probability of
pulmonary embolism (<50%), an age-adjusted D-dimer level below the
diagnostic threshold, calculated as age × 10 μg/L for fibrinogen equivalent
unit assays, effectively rules out pulmonary embolism and eliminates the need
for imaging. Consider using an age-adjusted cut-off or adapting to clinical
probability as an alternative to the fixed cut-off D-dimer test level.
The
YEARS algorithm can be used to identify which patients suspected of pulmonary
embolism do not need imaging to rule out pulmonary embolism.
A
D-dimer threshold of 500 ng/mL is used in patients who have ≥1 of the
following:
- Clinical signs of DVT
- Hemoptysis and/or
- Pulmonary embolism as the most likely diagnosis
A
D-dimer threshold of 1,000 ng/mL is used for patients who have no YEARS
criteria.
A
positive D-dimer for low or intermediate clinical probability requires further
radiological evaluation to exclude pulmonary embolism adequately. However,
raised levels of D-dimer do not confirm the presence of VTE because such levels
are found in hospitalized patients, obstetrics including the postpartum period,
peripheral vascular disease, cancer, infection, trauma, and many inflammatory
diseases, as well as with increasing age. D-dimer testing is inappropriate for
suspected VTE with recent surgery or trauma, and patients should proceed
directly to radiologic studies (eg duplex US or CTPA).
Diagnostic Tests
First-line diagnostic
tests (eg electrocardiography (ECG), chest X-ray, and arterial blood gases) are
indicated to assess the clinical probability of pulmonary embolism and general
condition of the patient. Laboratory results can be normal, but some abnormal
findings increase the suspicion for pulmonary embolism. Baseline blood tests
when initiating anticoagulation treatment include a CBC, renal and hepatic
function assessment, PT, and aPTT.
Arterial Blood Gas
Arterial blood gas can show hypoxemia, hypocapnia,
and widened (A-a) oxygen (O2) difference.
Electrocardiography (ECG)
ECG can show right axis deviation, supraventricular
arrhythmia, S1Q3T3 pattern or P-pulmonale, sinus tachycardia, or normal tracing.
For acute pulmonary embolism with overt
cardiopulmonary failure, an ECG may show a new right bundle branch block or other
evidence of RV strain (eg inverted T waves in leads V1 to V4).
Biomarkers: B-type Natriuretic
Peptide (BNP) and Cardiac Troponin I/T
BNP and cardiac troponin I/T
should be considered in a patient with substantial clot burden,
abnormal echocardiogram, or clinical findings suggestive of pulmonary embolism.
Elevated BNP and troponin are associated with RV strain and increased mortality
even in the absence of hemodynamic instability. An
elevated troponin level without ECG findings of ischemia may suggest myocardial
injury in the setting of acute pulmonary embolism with elevated risk/incipient
cardiopulmonary failure or with overt cardiopulmonary failure. Measurement of
at least one cardiac biomarker is recommended in patients with acute pulmonary
embolism Category C to identify patients at risk of short-term complications
and/or mortality. Lactate, measured from either arterial or venous blood,
should also be assessed whenever cardiac biomarkers are being used for risk
stratification in patients with acute pulmonary embolism Categories C to E.
Imaging
DVT
Duplex Venous Ultrasonography
(DUS)
Duplex venous ultrasonography is
the primary radiologic device for the evaluation of proximal DVT. It may be in B-mode,
imaging (eg 2D), and pulse-wave Doppler interrogation. It is the most often
used non-invasive test to diagnose DVT in patients with moderate or high clinical pretest
probability. It has a very high sensitivity and specificity for diagnosing
proximal DVT in symptomatic patients, but
less favorable results for calf vein and asymptomatic DVT. The primary diagnostic criteria to establish the presence
of DVT by ultrasound is incomplete vein
compressibility. Proximal and distal compression ultrasound (CUS) for DVT has a 90.3% sensitivity and 97.8% specificity. CUS may be
used as a two-point compression technique for evaluation of the proximal veins
in the groin and popliteal fossa, and as a whole-leg ultrasound scan for
evaluating both the distal and proximal veins.
The combined
use of clinical pretest probability and duplex ultrasound (with compression) is
effective in confirming or excluding the diagnosis of DVT. In patients with clinical suspicion of DVT, positive D-dimer, and negative ultrasound, consider repeat
ultrasound for suspected calf thrombosis or venography for suspected proximal
thrombosis in 3-7 days. Recurrent DVT may be diagnosed by
non-compressibility of a previously unaffected ipsilateral femoral or popliteal
vein segment or an increase of the thrombus diameter in a previously affected
vein segment of at least 4 mm on serial CUS with D-dimer measurement.
In patients with negative computed tomographic
pulmonary angiography (CTPA) results and positive D-dimer and a pulmonary
embolism likely clinical probability, further evaluation with duplex venous
ultrasound should be used to improve the clinical likelihood of diagnosing
disease and avoid more invasive testing. A positive result confirms the
diagnosis of DVT and requires treatment regardless of the
presence or absence of pulmonary embolism. For a negative result, the incorporation
of clinical pretest probability can improve diagnostic accuracy and potentially
avoid unnecessary pulmonary angiography.
CT Venography (CTV)
CTV is an effective method for the diagnosis of
proximal DVT in patients with
suspected DVT and pulmonary embolism.
It has the advantage over ultrasound in the evaluation of pelvic veins or
inferior vena cava and in the detection of concurrent medical conditions
causing pain and swelling. It facilitates vessel measurement and case planning
when intervention is needed due to its high-quality spatial resolution. It may
be considered in patients with suspected proximal DVT with inconclusive ultrasound
assessment or when ultrasound is not feasible. Its disadvantages include cost,
use of iodine contrast, and radiation exposure.
Contrast Venography
Contrast venography is historically considered the gold standard for
establishing the diagnosis of DVT. It offers precise details of
the venous anatomy in multiple recurrent DVT and the ability to reliably
exclude thrombosis in the calf. It can also help distinguish between old and
new clots.
It is excellent for calf veins, but it is an
invasive procedure, not always technically possible, and carries a small risk
of an allergic reaction or venous thrombosis. Other disadvantages include cost,
patient discomfort, significant resource use, availability, the requirement for
foot vein cannulation, intravenous contrast use, radiation exposure, and the possibility of
secondary thrombi.
In some countries, its use has been supplanted by
venous ultrasound. It is generally reserved for difficult diagnostic cases. It
may be considered in patients with suspected proximal DVT with
inconclusive ultrasound assessment or when ultrasound is not feasible.
Magnetic Resonance Imaging (MRI)
MRI provides morphological and functional
information about lung perfusion and right heart function but compared to CT
scan MRI needs improvement in the image quality. It is useful in patients with
suspected thrombosis of the superior and inferior vena cava or pelvic veins; but
should be deferred in patients with suspected first lower extremity DVT.
MRI helps distinguish an acute recurrent thrombus
from a persisting thrombus in the same location and is useful in follow-up
after DVT. It may be considered
in patients with suspected proximal DVT
with inconclusive ultrasound assessment or when ultrasound is not feasible. It
has a similar diagnostic accuracy to that of ultrasound for assessing proximal DVT.
Plethysmography
Computerized strain gauge plethysmography is rapid and
easy to perform. It has shown a sensitivity of 90% for proximal DVT (popliteal, femoral, or iliac vein) and 66% for distal (calf vein) DVT.
Impedance plethysmography (IPG) is another type of
plethysmography. A normal finding with serial IPG is associated with a low risk
of clinically important pulmonary embolism (<1%) or recurrent venous
thrombosis (2%). Serial testing with IPG for 10 to 14 days appears to be
effective for identifying patients with extending calf DVT.
Spiral CT (sCT)
Spiral CT scan has shown promise for the diagnosis of DVT and other soft tissue diseases in patients with leg swelling. It visualizes
proximal obstructions and common, and superficial and deep femoral veins.
Pulmonary
Embolism
Imaging is recommended for
patients who are deemed high probability (>50% probability of pulmonary
embolism) by a validated clinic risk prediction score or an elevated D-dimer
level in order to confirm or exclude pulmonary embolism.
Computed Tomographic Pulmonary
Angiography (CTPA)
CTPA is recommended as the initial lung imaging modality for patients with
suspected pulmonary embolism, as it is the gold standard for the diagnosis of pulmonary embolism. It is increasingly used as
an adjunct or alternative to other imaging modalities and is superior in
specificity to ventilation-perfusion isotope scanning.
Multidetector CT angiography (CTA) has 83% sensitivity and 96% specificity. A
positive CTPA, with intermediate or high clinical pretest probability, is
confirmed positive for pulmonary embolism and no further diagnostic testing is
needed. A normal CTPA, with low or intermediate clinical pretest probability,
is confirmed negative for pulmonary embolism and no further diagnostic testing
is needed.
It enables
direct visualization of the pulmonary emboli and may provide information about
parenchymal abnormalities that might help to establish an alternative diagnosis.
It is more useful for patients with underlying cardiac disease, chronic
obstructive pulmonary disease (COPD), or asthma. It has a high specificity and
sensitivity for central clots and for the diagnosis of lobar and segmental
pulmonary embolism. Patients with good
quality negative CTPA do not require further investigation or treatment for
pulmonary embolism. The main disadvantage of CTPA to that of conventional
pulmonary angiography is that subsegmental clot is less likely to be seen. For
patients who cannot undergo CTPA or for whom CTPA is suboptimal, ventilation-perfusion
lung (V/Q) scanning is an appropriate alternative, with excellent diagnostic
yield, particularly when combined with single-photon emission computed
tomography (SPECT).
Ventilation-Perfusion
Lung Scanning (V/Q Scan)
Normal or near-normal lung
scan with normal chest X-ray is sufficient to exclude pulmonary embolism,
regardless of pretest probability. Low probability scans in combination with a
low pretest probability make the probability of pulmonary embolism low.
High-probability scans provide the predictive power to establish diagnosis in
the context of reasonable suspicion of pulmonary embolism. A V/Q SPECT may also
be considered for the diagnosis of pulmonary embolism. The rate of
non-diagnostic tests is low at <3% compared with planar V/Q scan.
Diagnostic Tests
Chest X-ray
A chest X-ray may demonstrate atelectasis,
pleural-based infiltrates or effusions, or rarely, an engorged central
pulmonary artery associated with a paucity of peripheral vessels. It may also
assess conditions that have similar presentation (eg pneumonia, pulmonary
edema, pneumothorax). Near-normal radiographic results with severe respiratory
compromise are highly suggestive of acute pulmonary embolism. Westermark sign
(focal oligemia) may indicate massive central embolic occlusion. Hampton hump,
a peripheral wedge-shaped density above the diaphragm, usually signifies
pulmonary infarction.
Echocardiography
Echocardiography is the most
useful initial test which typically shows indirect signs of acute pulmonary
hypertension and RV overload if acute pulmonary embolism is the cause of the
hemodynamic changes. It may suggest or reinforce clinical suspicion of
pulmonary embolism with the findings of RV overload and dysfunction in the
presence of Doppler signs of increased pulmonary arterial pressure. It may also
definitively confirm the diagnosis of pulmonary embolism by visualization of
proximal pulmonary arterial thrombi.
It is useful for rapid triage in acutely ill patients with
suspected pulmonary embolism and overt
cardiopulmonary failure. It is usually reliable to differentiate between
illnesses that have radically different treatments compared to pulmonary
embolism (eg acute MI, pericardial tamponade, infective endocarditis, aortic
dissection, etc). If the patient is unstable,
thrombolytic treatment or surgery can be performed based only on compatible
echocardiography findings. If the patient has been stabilized, a definitive
diagnosis should be pursued. Lung scan, spiral CT, and bedside transesophageal
echocardiography (TEE) are usually able to confirm the diagnosis. A normal lung
scan or spiral CT angiogram suggests that another cause of shock should be
found. In patients with acute pulmonary embolism and an elevated clinical
severity score but without evidence of shock, RV imaging is recommended for
short-term risk stratification. It has not been confirmed that echocardiography
can identify patients who would benefit from thrombolytic therapy if they
present without shock or hypotension.
Alternative
Imaging Modalities
Spiral CT Scan
Higher-resolution multidetector-row CT imaging may
be used as an initial imaging procedure for the diagnosis of pulmonary
embolism. It has excellent sensitivity and specificity and
can identify subsegmental embolus.
Venous Ultrasonography (US)
Most pulmonary emboli arise
from the deep veins of the legs; thus, it is rational to search for a residual
DVT in suspected pulmonary embolism patients. It is used to improve the
estimation of the clinical probability of pulmonary embolism and avoid more
invasive testing in patients with a negative lung imaging study (eg CTPA). Selective
venous duplex ultrasonography of the legs may be useful in patients with
clinical findings suggestive of DVT or when confirmation of DVT will influence
management. A CUS demonstrating a proximal DVT in a patient suspicious for pulmonary
embolism confirms the diagnosis of VTE (and pulmonary embolism). If pulmonary
embolism was confirmed using a positive proximal CUS, consider risk assessment
to guide the patient’s management.
A normal ultrasound
examination of the leg veins does not rule out pulmonary embolism, hence, close
monitoring is advised. Ultrasound studies may have false-positive results or
may detect residual abnormalities from past VTE. Only definite positive studies
under certain clinical circumstances (eg patient without a history of VTE but
has a high clinical probability of pulmonary embolism) should serve as a basis
for the start of therapy.
Magnetic
Resonance Angiography (MRA)
MRA may be used as an alternative to CTPA in
patients with iodinated contrast allergy or when other modalities are
contraindicated. It avoids ionizing radiation but has poor sensitivity for
subsegmental clots and limited access is likely to continue for several years.
Conventional
Pulmonary Angiography
Conventional pulmonary angiography is historically
considered the gold standard for the diagnosis of pulmonary embolism. It is now rarely performed and has been replaced by CTPA. Limitations
include the requirement of expertise in performance and interpretation, it is
invasive and there are associated risks; if with subsegmental clot, there can
be inter-observer disagreement in up to ⅓ of cases.
Angiography should be reserved for patients in whom
non-invasive tests remain inconclusive or are not available. The use of
pulmonary angiography may also depend on the patient’s clinical status and the necessity
to obtain an absolute diagnosis.