Testing and Acute Venous Thromboembolism
Cortese Hassett, Ph.D.
Director, Coagulation Laboratory
thromboembolism (VTE) is a common disorder associated with significant
morbidity and mortality. In addition to clinical judgment, the accurate
diagnosis of acute VTE requires objective testing (1).
Physical examination is inadequate for establishing the diagnosis of
For the diagnosis of deep vein thrombosis (DVT), a careful clinical
assessment combined with the results of venous ultrasonography is accurate
in most cases. Ventilation-perfusion lung scans are commonly used to
diagnose pulmonary embolism (PE) although approximately 70% are
nondiagnostic. In most cases, further testing is required to determine
whether anticoagulant therapy is appropriate.
Therefore, to reduce testing and improve diagnostic accuracy,
laboratory tests have been evaluated for use as adjuncts to noninvasive
testing. Measurement of D-dimer is potentially one of the most useful tests.
normal clot formation, a fibrin clot is the result of thrombin-catalyzed
cleavage of soluble fibrinogen to form fibrin monomers.
The resultant thrombus is a network of highly crosslinked fibrin
Plasmin is the major clot lysing enzyme capable of cleaving both
fibrinogen and fibrin to yield various degradation products.
Plasmin lysis of cross-linked fibrin generates the D-dimer fragment
D-dimer levels are found in many clinical conditions including DVT and PE
Therefore, the specificity for VTE is low for all D-dimer assays.
D-dimer can be used to rule out acute VTE.
is due to the high sensitivity and corresponding negative predictive value.
There are commonly used methods for detecting D-dimer levels, all of
which rely on monoclonal antibodies that recognize epitopes on the D-dimer
fragment: enzyme-linked immunosorbent assay (ELISA), latex agglutination
(LA) and whole blood agglutination (WBA).
is considered the reference standard determination of D-dimer concentration.
An antibody with a high affinity to D-dimer is coated onto a membrane
or microtiter well and binds protein in the plasma.
A second tagged antibody is then added and the amount of labeled
substance bound is in direct proportion to the amount of D-dimer present.
The conventional ELISA is not practical in the diagnosis of VTE in
individual patients because it is labor intensive, results may not be
available the same day, expensive and not available in most centers.
agglutination (LA) assays rely on the use of monoclonal antibodies to D-dimer
that are coated onto latex particles.
Macroscopic agglutinates are seen when elevated D-dimer are present
in the plasma sample tested.
Advantages to this method are that it is inexpensive, results are
quickly available, and it can be done in most settings. Unfortunately,
latex agglutination lacks the sensitivity to be used as a screening assay
for VTE (4).
Recent modifications of this method that involve quantification of
the D-dimer using an automated analyzer have been evaluated and appear to be
comparable to the conventional ELISA (98-100%).
Testing in a greater number of patients is needed before this method
can be recommended.
most frequently studied whole blood assay is the SimpliRED assay. This
method relies on a bispecific antibody that causes visible agglutination of
red cells in the presence of D-dimer.
It requires one drop of whole
and the results are available in 2 minutes.
Several reports indicate sensitivities that are similar to
conventional ELISA and are being widely used in many clinical settings
including the emergency room (5).
of elevated levels of cross-linked products has been demonstrated to be a
marker of an incipient or ongoing thrombotic process.
The D-dimer test therefore provides a measure of fibrinolytic
activity in the blood.
Abnormal levels are found in patients with deep venous thrombosis (DVT),
disseminated intravascular coagulation (DIC), arterial thromboembolism (AT),
and pulmonary embolism (PE) as well as in bleeding and post-operative
In addition, it has also been useful in the monitoring of
thrombolytic therapy, cancer therapy and complicated myocardial infarction.
ELISA method of D-dimer determination has a sensitivity for DVT of 90% or
greater as well as a negative predictive value of 90% or greater by most
This suggests that a negative D-dimer level in a symptomatic patient
with clinically suspected DVT provides exclusion of DVT diagnosis.
D-dimer testing is most appropriate in the assessment of outpatients,
since disease prevalence and comorbid conditions are less frequent than
hospitalized patients increasing the value an exclusion test.
ELISA tests show promise as a practical D-dimer test with sensitivity,
similar to that of conventional ELISA for patients with suspected DVT.
Two studies have recently confirmed that a normal D-dimer result (SimpliRED
or Instant IA rapid ELISA) in combination with a noninvasive test and/or
clinical algorithm can reliably exclude DVT in outpatients. (6,7)
Accuracy studies in suspected PE complement the findings in patients
with suspected DVT (8).
of D-dimer has gained importance as the diagnostic applications of this
assay have been elucidated.
ELISA or WBA can be valuable in the
clinical setting to rule out DVT or PE and ensure proper patient management.
The lack of specificity of the D-dimer assay for VTE in hospitalized
patients warrants interpreting positive assay results with caution.
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P, D-dimer. History of the discovery, characterization and utility of this
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PR. Does a negative D-dimer exclude thrombosis? Fibrinolysis.
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DM, et al. D-dimer testing and acute venous thromboembolism. A shortcut to
accurate diagnosis? Arch Intern Med. 1996; 156:939-946.
PS, et. al. A novel and rapid whole-blood assay for D-dimer in patients with
clinically suspected deep vein thrombosis. Circulation.
1995; 91: 2184-2187.
JS, et al. The use of D-dimer testing and impedance plethysmographic
examination in patients with clinical indications of deep vein thrombosis. Arch
Intern Med. 1997; 157: 1077-1081.
E. D-dimer testing as an adjunct to ultrasonography in patients with
clinically suspected deep vein thrombosis: prospective cohort study. The
Multicenter Italian D-dimer Ultrasound Study Investigators Group. BMJ. 1998; 317: 1037-1040.
PS, et al. SimpliRED D-dimer
can reduce the diagnostic tests in suspected deep vein thrombosis [letter]. Lancet.
1998; 351: 1405-1406.