While researchers continue to explore the diagnostic and prognostic
potential of D-dimer testing, more diagnostics firms are staking out their
claims, entering the market with new assays and refining their existing
Biosite Inc. is the latest company to throw its hat in the ring, announcing
in February that its Triage D-dimer test had earned FDA clearance as an
aid in evaluating patients suspected of having thromboembolic events,
including pulmonary embolism and deep vein thrombosis. Several months
before Biosite’s announcement, Roche Diagnostics launched its new point-of-care
assay, the Cardiac D-dimer test, which was cleared for use with the company’s
Cardiac Reader instrument for the quantitative determination of D-dimer
in anticoagulated venous whole blood.
The two new tests provide more options for laboratories that want to
add a D-dimer assay to their test menu, but having more options may add
to the confusion that still exists about how to use D-dimer testing appropriately
to exclude deep vein thrombosis or pulmonary embolism. "Currently, we
don’t use D-dimer to rule out DVT or PE. If a physician is considering
pulmonary embolism, they do a spiral CT, and if they’re considering DVT
in the leg, they do an ultrasound," says Sharon Fong, CLS (ASCP), laboratory
manager at Tulare (Calif.) District Healthcare System, a 115-bed acute
Fong’s laboratory was one of the first to bring Biosite’s new Triage
D-dimer on board. But it is using the test now only for diagnosing disseminated
intravascular coagulation, or DIC, because it has had the new assay for
only four months and doesn’t yet have enough experience with it to use
it as a rule-out test for DVT and PE. Before Triage, the laboratory used
a latex agglutination kit, which provided a qualitative result at a cutoff
of 80 ng/mL. "Unfortunately," Fong says, "when we used that kit, it seemed
like every hospitalized patient was positive for D-dimer because there
are so many clinical conditions that will give you a low but significant
D-dimer level. Therefore, the latex assay was really not useful for DIC."
The Biosite assay, however, measures D-dimer levels up to 5,000 ng/mL
or greater, which is helping Fong’s laboratory confirm DIC in more patients
than did the latex agglutination assay.
Tulare District Healthcare System may consider using the Biosite Triage
D-dimer to exclude PE and DVT in the future, but is taking a wait-and-see
posture for now. "We will probably test it to see how it corresponds with
the results from our medical imaging studies, and will watch the marketplace
and see how everyone else is doing with the Triage compared to the [bioMerieux]
Vidas D-dimer Exclusion test, which has the longest track record for PE
and DVT rule-out," she says.
Meanwhile, other institutions are formulating protocols to fine-tune
the process of using D-dimer to rule out PE and DVT. Michael Brown, MD,
MSc, associate professor of emergency medicine and epidemiology at Michigan
State University, Grand Rapids, and his colleagues recently instituted
an algorithm for D-dimer testing in a hospital setting, using computer
pop-up screens with criteria to help clinicians determine how to use D-dimer
to provide the most accurate negative predictive value. Physicians participating
in the study were first asked to determine the patient’s pretest probability
of having pulmonary embolism, and to send subjects with moderate and high
pretest probability of having PE for imaging studies. If the patient had
a low pretest probability, clinicians were then asked to use seven criteria
to determine whether a D-dimer test should be ordered. The criteria state
that D-dimer testing is not recommended in patients who have unexplained
hypoxia, unilateral leg swelling, or hemoptysis since these patients should
be considered to have at least moderate risk for PE. It also urges clinicians
not to order D-dimer tests for patients who have had surgery within the
last four weeks, are pregnant, or are 70 years or older. In these populations,
conditions other than PE or DVT could elevate D-dimer levels, making the
test much less specific. D-dimer was also discouraged if the duration
of symptoms was four days or more since the sensitivity decreases over
The researchers then examined the protocol’s effect on patient outcome
Emerg Med. 2005;12:20-25). "We have a busy emergency department,
with over 100,000 visits a year, and we wanted to see how the protocol
would affect patient care in a real-world setting. Before we implemented
our clinical pathway, there was a lot of variation in how our clinicians
used our D-dimer assay, and there were varying degrees of understanding
of the proper interpretation of the test," Dr. Brown says. During a four-month
period after the protocol was implemented, 71 cases of venous thromboembolism
were diagnosed in a population of 1,207 people evaluated for suspected
PE. Only one missed case of PE was identified on three-month followup,
giving a negative predictive value of 99.9 percent. In addition, 39 percent
of the patient population suspected of PE was discharged without being
subject to radiologic imaging.
Dr. Brown says these simple criteria could help make D-dimer testing
less complicated and more efficient. "In two previous meta-analyses we
performed, it was obvious that the specificity of D-dimer was poor, although
the sensitivity was good. After reviewing multiple studies, we recognized
that the poor specificity most likely reflected comorbid illness and age.
In subjects over 70 years of age, the specificity decreases significantly,"
Dr. Brown says.
The protocol Dr. Brown put in place at Spectrum Health continues to be
used, and the clinicians are pleased with it. "Most people don’t understand
the limitations of the D-dimer test, and they should use a prediction
rule of some type, but most of them don’t. They know about the Wells criteria
and the Geneva criteria, but no one uses them because they are hard to
remember or too complicated," Dr. Brown says. "Having a simple guideline
or clinical pathway is key to successful implementation in the busy clinical
setting of the ED."
Though studies like the one Dr. Brown and his colleagues conducted are
making D-dimer test protocols easier to use, using D-dimer tests appropriately
is still a challenge for many institutions. "What a number of centers
have found is that as they’ve introduced new D-dimer assays, almost every
year, the volume of D-dimer assays performed has increased, so that in
the end introducing these assays may not have been all that cost-effective
because more imaging studies are being done because of the assays’ low
specificity," says Shannon Bates, MD, an assistant professor in the Department
of Medicine at McMaster University, Hamilton, Ontario. Dr. Bates is involved
now in several studies at McMaster that are examining the use of D-dimer
testing in various populations.
Many institutions, she says, are trying to find a D-dimer test strategy
that will work for them. But in addition to developing algorithms, some
are tweaking diagnostic thresholds to boost their assays’ specificity.
"Some centers are looking at rationalizing D-dimer use by using different
cutpoints in different groups of patients. For example, in a low pretest
probability group of patients, where the prevalence is low, you can have
a slightly lower sensitivity and still maintain a high negative predictive
value." In such an instance, Dr. Bates says, instead of having a cutpoint
of 0.50 mg/L to rule out venous thromboembolism in someone with a low
pretest probability, the institution might have a cutpoint of 1.0 mg/L
as a rule-out. "Even though the sensitivity might be slightly lower, the
specificity is going to be higher," she says. This strategy is being evaluated
now in a multicenter randomized trial.
In an article to be published in the May 2005 issue of Clinical Chemistry,
investigators from the Carolinas Medical Center, Charlotte, NC, make a
plea for a large management study that would establish new thresholds
for D-dimer to rule-out venous thromboembolism in pregnant women. Using
the MDA immunoturbidimetric assay from bioMerieux, the researchers measured
D-dimer concentrations pre-conception and during each trimester of pregnancy
in 50 apparently healthy women. Preconception, 79 percent of the women
had D-dimer levels that were lower than the traditional 0.50 mg/L cutoff.
In all of the women, D-dimer concentrations increased significantly each
trimester, and by the third trimester, none of the 23 women remaining
in the study had D-dimer concentrations lower than the 0.50 mg/L cutoff,
rendering the test useless at that threshold for ruling out PE and DVT
in this population.
But struggling to find the right cutoffs is not a new challenge for labs
with D-dimer tests on their menu. Though most assays seem to hover around
the 0.50 mg/L cutoff, it’s still not set in stone. "It’s been thought
that cutoffs are best determined by ROC curves, and this analysis probably
requires a study population of about 200, and labs can’t do that. I always
recommend looking to the literature to see if ROC analysis using a sufficient
population has been done for the test kit they are using, and that laboratories
always try to verify this recommended cutoff in-house with a much smaller
population," says Dorothy M. Adcock, MD, medical director at Esoterix
Coagulation, Denver. Dr. Adcock herself has contributed to the peer-reviewed
literature for D-dimer, most recently having coauthored a study that examined
the inter-rater agreement and external validity of Wells criteria in determining
pretest probability in patients suspected of having PE (Ann
Emerg Med. 2004;44:503-510).
"Different assays, and perhaps the same assay for different indications,
may have different cutpoints, which is definitely confusing," Dr. Bates
says. "While there are a lot of assays that use a cutoff that’s the equivalent
of 0.50 mg/L, there are other assays that have completely different cutoffs."
She says D-dimer assay manufacturers should come up with cutpoints that
are specific to their assays so that the clinical centers can at least
use those as a guideline. "The clinical centers would then need to have
ongoing evaluation to make sure the recommended cutpoint is working for
them," she says.
As more assays enter the market and more D-dimer assay studies are published,
the lack of a standard unit of measure adds to confusion in clinical laboratories
and in the research community. "D-dimer can be reported as FEUs, which
stands for fibrinogen equivalent units, or as D-dimer units," says Dr.
Adcock, who notes that the literature doesn’t always report what units
of measure were used. In addition, since 2 FEUs are equal to one D-dimer
unit, the numbers aren’t interchangeable. "I think some laboratories may
actually be confused as to how they are reporting out results, and may
not know whether they are reporting in FEUs or D-dimer units, and probably
don’t state on the report which unit of measure they’ve used," Dr. Adcock
In fact, the CAP Coagulation Resource Committee has found "significant
confusion" among laboratories between FEU and D-dimer units, as well as
evidence that many laboratories are using the wrong cutoff for their particular
assay, says committee member Elizabeth Van Cott, MD, of Massachusetts
General Hospital. To help resolve this problem, the committee recommends
that laboratories indicate in the patient report which unit of measure
is being used (FEU or D-dimer units), and verify that they are using the
correct cutoff as recommended by the D-dimer reagent manufacturer. In
addition, the committee recommends that manufacturers clearly indicate
in their packaging which unit of measure their assay is generating and
the recommended cutoff.
Clinicians should know which types of assays are being used because all
D-dimer tests are not created equal. Though there have been few comparative
studies of D-dimer assays as a group, a meta-analysis published last year
compared the performance of ELISAs, quantitative rapid ELISAs, semiquantitative
rapid ELISAs, qualitative rapid ELISAs, quantitative latex assays, semiquantitative
latex assays, and whole-blood tests for D-dimer (Ann
Intern Med. 2004;140:589-602). "The authors came out fairly strongly
in favor of the ELISA assays," says Dr. Bates, who adds that she’s not
sure she agrees entirely with their conclusions. "I think the main issue
is that you really have to divide your D-dimer assays into different categories
and use them according to their different test performance characteristics,"
For example, Dr. Bates notes, the SimpliRed D-dimer test from Agen Biomedical,
Brisbane, Australia, is unique in that it has a moderate sensitivity but
a higher specificity in comparison with other assays. "It’s never going
to be used as a stand-alone test. It’s always going to be used in combination
with a low pretest probability or a negative compression ultrasound in
the case of deep vein thrombosis and with other ancillary testing in the
case of pulmonary embolism," she says. "But it does have its advantages.
It’s fast, inexpensive, and easy-to-use."
Other D-dimer assays have been evaluated as stand-alone tests, however,
and more studies are underway at McMaster University to evaluate at least
one of them—bioMerieux’s MDA D-dimer—as a stand-alone test
to exclude recurrent deep vein thrombosis. "You might be able to use D-dimer
as a stand-alone test in this patient population, which would be important
because all of our other diagnostics, like ultrasound or venogram, have
pretty important limitations in people who have had clots before," Dr.
But without large studies, she says most health care providers would
feel uncomfortable using today’s quantitative D-dimer assays as stand-alone
tests. "The only assay that’s probably been used that way widely is the
Vidas D-dimer, which has been used a great deal by the Swiss group of
Bounameaux and Perrier for the exclusion of pulmonary embolism. I don’t
think any of the other assays have been evaluated in that way, however,
even though they may have suitable characteristics for it," Dr. Bates
Recently, new and revised indications for the use of some D-dimer assays
have sparked debate over whether the assays are an aid in diagnosing PE
and DVT or whether they are indicated for use in excluding PE and DVT,
since their worth is mainly in their negative predictive value. Last fall,
the Food and Drug Administration reviewed new performance data for the
Advanced D-dimer assay from Dade Behring and cleared a new intended use
for it as an aid in the diagnosis of venous thromboembolism, DVT, and
PE. And bioMerieux says the Vidas D-dimer Exclusion assay is the only
test cleared by the FDA with the indication for excluding both PE and
Dr. Brown, for one, says the chief function of D-dimer assays is to rule
out VTE, DVT, and PE. "D-dimer is definitely used to exclude disease.
In fact, ruling out disease is all it should be used for," he says.
In the future, there may be fewer cases of venous thromboembolism, PE,
and DVT to rule out, mainly because D-dimer has made inroads into the
diagnostic algorithms for these conditions. "Over the past 15 to 20 years,"
Dr. Adcock says, "the number of individuals who have pulmonary embolism,
among those who are sent for a diagnostic test for pulmonary embolism,
has decreased dramatically. In a study we performed here in Denver, the
prevalence of PE in those patients who were subjected to imaging studies
to evaluate for PE was around 10 percent, and that’s really quite low."
Thirty years ago, Dr. Bates adds, the prevalence of PE might have been
as high as 30 percent. "Clearly, more and more people are being caught
in the net because we have easier tests like D-dimer," she says.
Looking ahead, D-dimer shows promise as an aid in diagnosing a variety
of diseases. "What’s interesting about D-dimer is its potential for other
indications," Dr. Adcock says. "If you think about it, a D-dimer will
be elevated any time you have a clot, whether it’s an arterial clot or
a venous clot. Obviously, stroke and heart attack are arterial clots,
and therefore those patients can have elevated D-dimers."
Roche, Dade Behring, and Biosite have recognized this, and it’s no coincidence
that they’ve positioned their D-dimer assays alongside their cardiac tests
on their point-of-care instruments. "People have been using D-dimer assays
to predict patients at higher risk of thromboembolism if they have atrial
fibrillation," Dr. Bates says. "Once again, though, we have a number of
clinical factors that help us predict whether someone is at risk of stroke
with atrial fibrillation." These include being over 75 and having a previous
stroke, ischemic heart disease, and diabetes.
Perhaps the most obvious use for D-dimer in the future is in diagnosing
stroke. "There have been a number of studies showing that D-dimer concentrations
might be increased after ischemic stroke or transient ischemic attacks,"
Dr. Bates says. "Some people have suggested that the D-dimer concentrations
might be different in the different types of strokes," she adds, warning
that those studies have important limitations. "At this point, I would
not use D-dimer to make management decisions in patients with suspected
stroke or with stroke because I believe we need to see more studies in
that area," she says.
D-dimer has also been shown to be prognostic in terms of evaluating the
risk for a recurrence of venous thrombosis. Says Dr. Adcock, "It’s been
shown that when patients have a venous thrombosis and are put on standard
therapy, if you evaluate a D-dimer level either during therapy or one
month after therapy has been discontinued, you have an idea whether patients
are at an increased risk for recurrence."
McMaster University is enrolling virtually all of its patients with suspected
PE or DVT in one of five clinical trials it is conducting. Researchers
there are evaluating D-dimer in suspected recurrent deep vein thrombosis,
in suspected first deep vein thrombosis, in suspected pulmonary embolism,
in suspected DVT in pregnancy, and in suspected PE in pregnancy. (MDA
D-dimer is being used in the first three and SimpliRed D-dimer in the
latter two.) It will be another year or two before the trials are completed.
For now, many agree that the biggest challenge facing laboratories in
the area of D-dimer testing is ensuring that assays are used in the most
rational, efficient way to get the best outcome for patients. "We want
our clinicians to have confidence in D-dimer testing," Dr. Brown says,
"and if they begin to notice they are getting lots of false-positive results,
they may lose confidence in the test and stop ordering it." False-negatives
are the main concern, of course, because sending a patient home with a
pulmonary embolism "could be disastrous for the patient," Dr. Van Cott
says. The key, then, is for pathologists and clinicians to collaborate
on strategies that will result in good patient care. "The pathologists
probably have the best understanding of the test’s limitations," Dr. Brown
says, "while the clinicians probably have the best understanding of how
to estimate pretest probability."
Thus the two have to work together because, as he says, "you need both
pieces of the puzzle to deliver good patient care."
Sue Parham is a writer in Edgewater, Md.