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Laboratory Tests and Ancillaries
Deep
Vein Thrombosis
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 nonspecific screening test for the presence of venous thromboembolism.
D-dimer levels may also be elevated in patients with myocardial infarction,
sepsis, cancer, inflammation, infection, necrosis, trauma, pregnancy, etc. Therefore,
a high concentration of D-dimer has a poor positive predictive value for deep
vein thrombosis 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 venous
thromboembolism; 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 deep vein thrombosis and a negative D-dimer
assay are considered to have no deep vein thrombosis or have a very low risk of
subsequent deep vein thrombosis 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, the
recommended diagnostic tests include D-dimer, duplex venous ultrasonography with
compression, venography, and whole-leg ultrasound.
For patients with moderate pretest probability, the
recommended diagnostic tests include D-dimer, proximal duplex venous
ultrasonography with compression, venography, and whole-leg ultrasound.
For patients with high pretest probability, the
recommended diagnostic tests include proximal duplex venous ultrasonography with
compression, whole-leg ultrasound, and venography.
Pulmonary
Embolism
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) O2 difference.
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. Near-normal
radiographic results with severe respiratory compromise are highly suggestive
of massive pulmonary embolism. Westermark sign (focal oligemia) may indicate
massive central embolic occlusion. Hampton lump, a peripheral wedge-shaped
density above the diaphragm, usually signifies pulmonary infarction.
Electrocardiography (ECG)
ECG can show right axis deviation, supraventricular
arrhythmia, S1Q3T3 pattern or P-pulmonale, sinus tachycardia, or normal tracing.
For massive pulmonary embolism, an ECG may show a new right bundle branch block
or other evidence of right ventricular strain (eg inverted T waves in leads V1
to V4).
B-type Natriuretic Peptide (BNP)
and Troponin
BNP and troponin are considered in a patient with
substantial clot burden, abnormal echocardiogram, or clinical findings
suggestive of pulmonary embolism. Elevated BNP and troponin are associated with
right ventricular strain and increased mortality even in the absence of
hemodynamic instability.
D-Dimer
D-dimer is a highly sensitive but nonspecific
screening test for the presence of pulmonary embolism. Sensitivity may be
decreased if the duration of venous thromboembolism 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.
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 venous
thromboembolism. A negative result using ELISA (Vidas) or MDA methods reliably
excludes pulmonary embolism in patients with intermediate probability.
A positive D-dimer requires further radiological
evaluation to exclude pulmonary embolism adequately. However, raised levels of
D-dimer do not confirm the presence of venous thromboembolism because such
levels are found in hospitalized patients, obstetrics including postpartum
period, peripheral vascular disease, cancer, infection, trauma, and many
inflammatory diseases as well as increasing age.
Consider using an age-adjusted cut-off or adapting to clinical
probability as an alternative to the fixed cut-off D-dimer test level. D-dimer
measurement should not be performed in those with a high clinical probability
of pulmonary embolism. Inappropriate for suspected venous thromboembolism with
recent surgery or trauma and should proceed directly to radiologic studies (eg
duplex ultrasound or CTPA).
Imaging
Deep
Vein Thrombosis
Duplex Venous Ultrasonography
(DUS)
Duplex venous ultrasonography is the primary
radiologic device for the evaluation of proximal deep vein thrombosis. 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 deep vein thrombosis in patients with moderate
or high clinical pretest probability. It has a very high sensitivity and
specificity for diagnosing proximal deep vein thrombosis in symptomatic
patients, but less favorable results for calf vein and asymptomatic deep vein
thrombosis. The primary diagnostic criteria to establish the presence of deep
vein thrombosis by ultrasound is incomplete vein compressibility. Proximal and
distal compression ultrasound (CUS) for deep vein thrombosis has a 90.3%
sensitivity and 97.8% specificity.
The combined use of clinical pretest probability and
duplex ultrasound (with compression) is effective in confirming or excluding
the diagnosis of deep vein thrombosis. In patients with clinical suspicion of deep
vein thrombosis, positive D-dimer, and negative ultrasound, consider repeat ultrasound
for suspected calf thrombosis or venography for suspected proximal thrombosis
in 3 to 7 days.
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 deep vein thrombosis 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.
Computed Tomography Venography (CTV)
CTV is an effective method for the diagnosis of
proximal deep vein thrombosis in patients with suspected deep vein thrombosis 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 deep vein
thrombosis 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 the gold standard for
establishing the diagnosis of deep vein thrombosis. It offers precise details
of the venous anatomy 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, 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 deep vein thrombosis 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 deep vein
thrombosis.
MRI helps distinguish an acute recurrent thrombus
from a persisting thrombus in the same location and is useful in follow-up
after deep vein thrombosis. It has a similar diagnostic accuracy to that of ultrasound
for assessing proximal deep vein thrombosis. It may be considered in patients with
suspected proximal deep vein thrombosis with inconclusive ultrasound assessment
or when ultrasound is not feasible.
Plethysmography
Computerized Strain Gauge Plethysmography is rapid and
easy to perform. It has shown a sensitivity of 90% for proximal deep vein
thrombosis (popliteal, femoral, or iliac vein) and 66% for distal (calf vein) deep
vein thrombosis.
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 deep vein thrombosis.
Spiral Computed Tomography (sCT)
sCT has shown promise for the diagnosis of deep vein
thrombosis and other soft tissue diseases in patients with leg swelling. It visualizes
proximal obstructions and common, and superficial and deep femoral veins.
Pulmonary
Embolism
Computed Tomographic Pulmonary
Angiography (CTPA)
CTPA is recommended as the initial lung imaging
modality for patients with suspected 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 computed
tomographic 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. The main disadvantage of CTPA to that of
conventional pulmonary angiography is that subsegmental clot is less likely to
be seen. Patients with a good quality negative CTPA do not require further
investigation or treatment for pulmonary embolism.
Echocardiography
Echocardiography is the most useful initial test
which typically shows indirect signs of acute pulmonary hypertension and right
ventricular overload if acute pulmonary embolism is the cause of the
hemodynamic changes. If the patient is unstable, thrombolytic treatment or
surgery can be done based only on compatible echocardiography findings. If the patient
has been stabilized, a definitive diagnosis should be pursued. Lung scan, sCT,
and bedside transesophageal echocardiography (TEE) are usually able to confirm
diagnosis. Normal lung scan or sCT angiogram suggests that another cause of
shock should be found.
It is useful for rapid triage in acutely ill
patients with suspected massive pulmonary embolism. It is usually reliable to
differentiate between illnesses that have radically different treatments
compared to pulmonary embolism (eg acute myocardial infarction, pericardial
tamponade, infective endocarditis, aortic dissection, etc). It may suggest or reinforce
clinical suspicion of pulmonary embolism with the findings of right ventricular
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 has not been confirmed that echocardiography can
identify patients who will benefit from thrombolytic therapy if they present
without shock or hypotension.
Conventional
Pulmonary Angiography
Conventional pulmonary angiography is historically
considered the gold standard for the diagnosis of pulmonary embolism. 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 â…“ 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.
Ventilation-Perfusion
Lung Scanning (V/Q scan)
Normal or near-normal lung scans are 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 VQ
single-photon emission computed tomography (SPECT) may also be considered for
the diagnosis of pulmonary embolism. The rate of non-diagnostic tests is low at
<3%.
Venous
Ultrasonography (US)
Most pulmonary emboli arise from the deep veins of
the legs thus it is rational to search for a residual deep vein thrombosis in
suspected pulmonary embolism patients. A normal ultrasound examination of the
leg veins does not rule out pulmonary embolism. Ultrasound studies may have
false positives or may detect residual abnormalities from past venous
thromboembolism. Only definite positive studies under certain clinical
circumstances (eg patient without a history of venous thromboembolism but has a
high clinical probability of pulmonary embolism) should serve as a basis for
the start of therapy.
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. A distal compression ultrasound demonstrating a
proximal deep vein thrombosis in a patient suspicious of pulmonary embolism
confirms the diagnosis of venous thromboembolism (and pulmonary embolism). If pulmonary
embolism was confirmed using a positive proximal compression ultrasound,
consider risk assessment to guide the patient’s management.
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. MRA appears to
be promising in human and animal models. It avoids ionizing radiation but has
poor sensitivity for subsegmental clots and limited access is likely to
continue for several years.