Quantitative D-dimer: Ruling out
Andrea Cortese Hassett, Ph.D.
Chief Science Officer, ITxM Diagnostics
As the U.S. population ages, the medical and economic impact of venous
thromboembolism (VTE) is expected to increase. The most common manifestations
of VTE are deep vein thrombosis (DVT) and pulmonary embolism (PE).1,2,3
The initial diagnosis of VTE is often subjective, relying on “clinical
impression,” and is then followed by more objective and expensive testing. The
use of an inexpensive screening test to eliminate the diagnosis of VTE can
result in significant savings in healthcare costs. Quantitative D-dimer is an
inexpensive test now available for exclusion of VTE.
The D-dimer is a specific
fragment of a fibrin clot. Covalent cross-linking of polymerized fibrin
monomers by activated Factor XIII stabilizes the fibrin clot. D-dimers are
generated by plasmin lysis of this cross-linked fibrin.4 Under
normal physiological conditions, the coagulation process is balanced by
activation of fibrinolysis, which leads to dissolution of the clot and release
of soluble fragments, including D-dimers, into the plasma. Therefore, the
presence of D-dimers indicates degradation of fibrin specifically and serves as
an indirect indicator of thrombotic activity.
Rationale for Use
The D-dimer assay is used in
several diagnostic settings as a marker of an incipient or ongoing thrombotic
process. Semi-quantitative assays help confirm ongoing systemic
coagulation seen in disseminated intravascular coagulation (DIC), which is
associated with very elevated D-dimer levels.5 This type of assay
should not be used to differentiate the presence or absence of VTE.
Only quantitative assays can be
used to exclude DVT and
PE. It has been demonstrated that quantitative D-dimer assays have sufficient
specificity and clinical sensitivity to have negative predictive value for VTE.5
If the level of
D-dimer in the blood is
not elevated, then no thrombotic process is ongoing and VTE is not present.
However, if the quantitative D-dimer level is elevated, a clotting process is
occurring, which may be due to VTE, but also may be due to other clinical
conditions (DIC, trauma, post surgery, pregnancy, cancer, etc.).
The ability to use
quantitative D-dimer as a negative predictor is based on the
premise that the formation of a thrombus involves both coagulation and
fibrinolytic activation. Although the presence of D-dimer fragments suggests
that a coagulation-fibrinolytic process is taking place, the test’s lack of
specificity does not allow one to definitively conclude that a thrombus has
Clinical D-dimer Assays
There are many different D-dimer assays currently available on the market. All
of these assays rely on monoclonal antibodies. The original assay is
semi-quantitative and utilizes visual macroscopic latex agglutination (used in
DIC diagnosis).5 The most sensitive quantitative D-dimer assay is
based on the ELISA format, but these are time consuming and require specialized
equipment and training. The most practical quantitative assays are the
latex-enhanced photometric assays that are turbidimetric or colorimetric. These
assays utilize latex particles coated with human monoclonal antibodies to the D-dimer
antigen. They can be performed in the laboratory or at the bedside and still
maintain the needed sensitivity. Turnaround times are rapid, facilitating their
use as an emergency test.6,7
D-dimer Laboratory Guidelines
The most difficult aspect of establishing the D-dimer assay for the exclusion of
VTE is determining the cut-off value. Each laboratory must establish their own
cut-off value and cannot rely on the manufacturers’ recommended value or another
laboratory’s value. The main criteria for establishing the cut-off is that it
must have 100% negative predictive value.8,9 The following steps
need to be taken:
validation, verifying the intra- and inter-assay variability.
Establish normal range using a minimum of 30 normal subjects.
Determine D-dimer levels on at least 20 suspected VTE patients (diagnosis
based on imaging results). Use ROC graph to establish cut-off.
Re-evaluate/adjust cut-off after evaluation of more patients (100 patients
Re-evaluate annually and if the methodology changes.
Establish Clinical Guidelines
Once the quantitative D-dimer has been validated with an established cut-off,
the assay can be used as a negative predictor of VTE. Guidelines for the use of
D-dimer should be developed with input from the clinical staff to develop
criteria to be used as a negative predictor. Two major points should be
incorporated into the procedure for the use of D-dimer assay.9
- Use the
D-dimer with caution on inpatients since numerous disease processes and
invasive procedures can elevate D-dimer levels in the absence of VTE.
- Do not
use the D-dimer assay in patients on anticoagulant therapy (heparin or
coumarin). Anticoagulants can decrease D-dimers and possibly generate a
falsely low value, below the established cut- off.
Since the range of detection
necessary for assays for DIC and exclusion of VTE are significantly different,
it is generally recommended that a facility provide two D-dimer assays.
The determination of quantitative D-dimer levels is both a diagnostic and a
cost-saving tool to rule out VTE. The assay can be used to eliminate those
individuals without VTE, but with low or moderate clinical suspicion. After
appropriate validation, the assay can be 100% sensitive in ruling out DVT or PE,
but will not confirm the presence of VTE as numerous other diseases and
procedures can increase levels.
J, et al. Management of deep vein thrombosis and pulmonary embolism.
Circulation, 1996; 93:2212-2245.
DW and Leeper KV. DVT and pulmonary embolism: Part I. Diagnosis. American
Family Physician 2004; 69: 2829-2836.
DW and Leeper KV. DVT and pulmonary embolism: Part II. Treatment and
Prevention. American Family Physician 2004; 69: 2841-2848.
P, D-dimer. History of the discovery, characterization and utility of this
and other fibrin fragments. Fibrinolysis, 1993; 7: 2-8.
MJ and Rodgers GM. Disseminated intravascular coagulation: clinical and
laboratory aspects. Am. J. Hematol. 1998; 59: 65-73.
PD et al. D-dimer for the exclusion of acute venous thrombosis and pulmonary
embolism. Ann. Int. Med. 2004; 140: 589-602.
Schreiber DH. The role of D-dimer in the diagnosis of venous thromboembolism.
Lab. Med. 2002; 33: 136-141.
SL. Explorations of the D-dimer. Adv. Lab. 2004; July 54-60.
RA. D-dimer: Establishing a laboratory assay for ruling out venous
thrombosis. MLO 2002; Nov. 28-32.
For questions regarding this TMU, please contact: Andrea
Cortese Hassett, PhD at:
or call 412-209-7345.
©2004, Institute For Transfusion
Editor: Donald L. Kelley, M.D., MBA: