College of American Pathologists
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Identity crisis persists— which D-dimer?

January 2003
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Key Terms

Karen Titus

Talk all you want about the nuances of D-dimer testing—variance in antibodies, calibrators, and instrument technology; overreliance on published data to determine cutoff values; possible interference from oral anticoagulant therapy; the hazy understanding of the test’s negative predictive value. Certainly no worthwhile discussion of D-dimer can occur without a firm nod toward these and other issues.

The real problem with D-dimer tests, however, is simple: They desperately need a Madison Avenue makeover.

Clinicians and laboratorians alike understand D-dimer tests can help evaluate patients for deep venous thrombosis and pulmonary embolism, a point reinforced by the literature in recent years. Most acknowledge the longstanding role for D-dimer in looking at patients with disseminated intravascular coagulation. Moreover, there’s growing awareness that D-dimer may eventually help predict risk of recurring venous thromboembolism in patients who discontinue oral anticoagulant therapy, as well as serve as yet another marker of cardiovascular disease.

But which D-dimer test? The traditional latex agglutinin tests? Or the newer, highly sensitive assays?

The difference between the two should be clear—but often it isn’t.

“A lot of physicians don’t know the difference,” says emergency physician Paul Kivela, MD, attending physician at Queen of the Valley Hospital, Napa, Calif. “I’ve even had lab managers not realize which test they have in their own lab. They knew they had a D-dimer, but they didn’t know if they had a latex agglutinin or an ELISA.”

Fact is, as the role of D-dimer has evolved, laboratories and clinicians have been dealt two different tests with two different uses—“but with exactly the same name,” says John D. Olson, MD, PhD, chair of the CAP Coagulation Resource Committee.

“I think that’s probably the source of the problem,” he continues. “Even though we’ve come up with a new test, we haven’t come up with a spiffy name for it, to make it very clear that we’re talking about a different test.”

Dr. Olson laughs—but only slightly—when he says this. Two tests, two purposes, one name. It’s a challenge any marketing genius would love. So far, however, the distinction remains a muddle. Efforts to tag the two as different have fallen as flat as the campaign, years ago, to launch the new Coke. Or was it Classic Coke?

A similar problem plagues C-reactive protein, Dr. Olson notes. Early on, CRP’s primary use was to look at inflammatory states. “Then a new generation of assays was developed that allowed the test to be used in a different clinical environment,” Dr. Olson says. “In the case of C-reactive protein, we now have sensitive CRP, and modestly elevated levels with a sensitive test have predictive value in cardiovascular disease. In the case of D-dimer, the sensitive test allows us to exclude venous thromboembolism in the right setting.”

In the right setting. Perhaps that could be the D-dimer’s tag line. It’s a phrase that hovers over every D-dimer discussion.

The traditional latex agglutinin D-dimer test, available for some two decades, is used to evaluate patients with DIC. But not all labs stop there.

“I just had a call—this morning, actually—from a laboratory in our region that wanted to discuss which were the more sensitive of the ‘standard’ (meaning older, visual endpoint) latex bead agglutination assays,” says Edwin G. Bovill, MD, chairman and professor of pathology at the University of Vermont College of Medicine. While such tests may not be as widely used as they once were, “they’re still out there,” Dr. Bovill says.

As further evidence, Dr. Olson trots out CAP proficiency testing data from the most recent mailing to small laboratories, the segment that makes up the largest proportion of labs surveyed. Of those reporting D-dimer results, just over 625 used a quantitative assay (though not necessarily one sensitive enough for evaluating PE/DVT). For the qualitative or semiquantitative methods, the number was approximately 1,500.

“The biggest problem, I think, is that there are still places where macro latex agglutination tests are being used in trying to exclude venous thromboembolism,” says Dr. Olson. “And the tests are clearly not sensitive enough to do that. But we still haven’t been able to make that clear to clinicians and laboratories.”

Until his own institution switched to an assay capable of measuring D-dimer at the very sensitive end of the spectrum as well as high concentrations, Dr. Olson had intimate knowledge of this double-edged sword. “There was a time when we had two dimers available. We were using a latex agglutinin test for our patients with DIC, and a turbidimetric method for sensitive dimers for excluding venous thromboembolism,” says Dr. Olson, who is professor and director of clinical laboratories, Department of Pathology, University of Texas Health Science Center, San Antonio.

“It was extremely confusing for everyone. It was hopeless, actually,” he says. “This was an area where I finally decided education doesn’t work, and rules do. So we just stopped providing one of them. I couldn’t find a solution that would suffice for both settings.”

Dorothy M. Adcock, MD, medical director of Esoterix Coagulation, has seen that confusion plenty of times as she travels the country visiting sites and giving talks on the topic. “At some institutions, physicians order the D-dimer assay and get the results, but they don’t know which assay the laboratory is using. And in some instances, the laboratory may actually be using the insensitive, semiquantitative assay.”

The matter is also a common theme in her lectures. Invariably, the lightbulb will go on over at least one audience member’s head, who will “come up to me and say, ‘You know, that’s exactly what we’re doing.’”

Quite simply, the latex agglutinin tests are not sensitive enough to exclude venous thromboembolism. “They can actually be quite misleading if they’re used to exclude venous thromboembolism,” says Dr. Bovill. “Remember, using D-dimer in this setting means you may literally send someone out of the emergency room without necessarily pursuing them further diagnostically.”

Despite the high stakes, however, the point is still lost on physicians. It’s even a problem at McMaster University, Hamilton, Ontario, which is surprising, given that the institution has been the source for many of the recent management studies on D-dimer. “We find that people will get a negative D-dimer result and assume the case is closed and disease has been excluded—and that’s not necessarily the case, depending on the assay that you’re using,” says Shannon Bates, MD, an assistant professor in the Department of Medicine at McMaster.

Which leads back, once again, to the question: Which test?

D-dimer demographics are a messy business. It’s not merely a matter of picking the sensitive method, then getting down to the business of ruling out PE/DVT. There may be as many as three dozen D-dimers on the market at any one time. “They come, they go, and the companies develop new generations of them. And there are more coming onstream all the time,” says Dr. Bates.

Not all manufacturers are eager to celebrate this diversity. While some are careful to provide only sober, well-supported data for their tests—think of them as D-dimer’s designated drivers—others, well, not so much. There are assays that have been evaluated in management studies, and those that haven’t—and then there are those that try to piggyback their way onto claims made by other assays. “It’s all very confusing,” Dr. Bates says. “Some manufacturers have been less responsible in the claims they make for their D-dimer. They may have a study and come up with a cutpoint, but that’s it. Yet they’re going around telling people their D-dimer can be used to exclude venous thromboembolism. Well, as far as I’m concerned, until you have the management studies showing that that’s safe, you shouldn’t be making that claim.”

Less insidious, but no less a problem, is that even the best D-dimers are prickly individuals, hard to compare because they have different strengths and weaknesses. No one quantitative method is emerging as an undisputed leader. Even comparing results from the same assay is problematic. Indeed, an International Society on Thrombosis and Haemostasis subcommittee trying to standardize D-dimer assays has been at it for 10 years, without success. “That’s a job that comes with retirement benefits,” jokes one observer. “They’ve had a frustrating time with it.”

The sensitive assays use different monoclonal antibodies, which makes direct comparison between tests difficult. Furthermore, D-dimer is not a unique analyte—in other words, not all D-dimer is the same.

“When we say D-dimer, we’re talking about a very heterogeneous population of molecules,” says John T. Brandt, MD, medical advisor at Eli Lilly and a member of the CAP Coagulation Resource Committee. Assays don’t measure a basic, minimal D-dimer unit, he explains; rather, what’s being measured consists of various components of polymerized fibrin. One patient’s sample, for example, may have relatively large pieces of fibrin that contain the D-dimer unit, while another patient’s sample may contain broken-down pieces of fibrin. Measured by the same assay, the specimens nonetheless may produce vastly different results based solely on the fibrin characteristics.

“Those kinds of problems have made it very difficult to standardize the tests. What do you use as your standard material?” Dr. Brandt asks. “There is no pure substance that reflects the biologic material that we try to measure.”

Some assays use more or less purified standards, while others use digested clots. “You simply look at fibrinogen equivalent units based on the amount of fibrinogen in a tube of blood previous to clotting it,” explains Dr. Bovill. But even similar types of standards vary from test to test.

How do laboratories accommodate this fact? “I think they get a number from their assay and report it,” says Dr. Brandt. “Because I don’t know that there’s a way to figure out what components you have in there.” Researchers have tried, but their efforts have been less than effective. “It’s extremely tedious and not always reproducible,” Dr. Brandt reports.

Cutoff values create another headache for labs. “There’s a real temptation for people to use published data for a cutoff,” says Dr. Olson. The most common published figures are for ELISA assays, with cutoff levels of approximately 400 to 500 ng/mL. “I’m quite sure that those numbers are going to be difficult to transport from one institution to another. It’s important for laboratories to determine that cutoff for themselves.” Indeed, Dr. Kivela reports that at least one major institution in his state uses the same D-dimer assay used at Queen of the Valley, but employs a different, higher, cutoff point. “I’ve had lots of people in that intermediate range who have had pulmonary emboli or DVTs,” he says.

Until labs have collected the necessary data, Dr. Olson suggests, for the safety of the patient, that they use levels within the test’s reference interval. That will translate into a large number of false-positive tests temporarily, he cautions, because this threshold for the majority of assays will be above the upper limits of the reference interval. Obtaining a more exact figure requires within-institution comparisons of the D-dimer assay with a series of patients in whom imaging studies have been done, and either excluded or confirmed the presence of a thrombus.

Given these variations among the tests, laboratorians need to gauge the comfort of the clinicians who will be using the test. Do they want the most sensitive test available, or one that strikes a balance between specificity and sensitivity? Dr. Adcock points to one study done by Kaiser Permanente that compared two assay systems, in which the less sensitive test missed only one DVT. “And we’re not even certain that that wasn’t a false-positive result from radiology,” she says, “that it wasn’t an old clot.”

Picking the right test and becoming familiar with it is only the start. Some trigger-happy clinicians are ordering the test when they shouldn’t.

Not all physicians understand the subtleties of D-dimer’s use; the concept of negative predictive value is simply less familiar to them. “We don’t use tests all that frequently for that reason,” says Dr. Bovill.

“They have difficulty understanding that a positive D-dimer doesn’t provide much information,” agrees Dr. Bates.

Dr. Adcock recalls talking to an emergency room physician who was evaluating a 50-year-old patient who had chest pain. “He mentioned, ‘Well, I’m going to order that D-dimer assay to see if I should rule out pulmonary embolism as the cause of this patient’s pain.’ I told him, ‘That’s really the wrong way to use this test. The test should not be used for its positive predictive value.’ ”

That’s because D-dimer is easily influenced by any number of underlying factors; it’s like a weak-minded board member, easily pushed around by others. “Many conditions will elevate a D-dimer level,” Dr. Adcock says, including underlying atherosclerotic vascular disease. Acute coronary syndrome can also boost levels. “So physicians who think they can use a positive D-dimer assay to help in their differential diagnosis of chest pain are mistaken,” she says.

Laboratories aren’t necessarily absolved of this mistake, she adds. “Many, but not all, laboratories understand that this test is used for its negative predictive value. I don’t know that they necessarily understand what can cause increased levels.” They also need to realize that in patients on oral anticoagulant therapy, D-dimer levels can be falsely negative—it simply doesn’t elevate to the proper level in these patients. That’s no small consideration in a test that’s used for its negative predictive value.

As Dr. Bates points out, it’s not unusual for patients to be treated empirically with heparin until diagnostic tests are performed—which may be a relatively lengthy wait at institutions without a 24-hour laboratory service, or where D-dimer is not routinely available. Heparin can, of course, lower D-dimer levels. “What’s the point where there’s a clinically important drop in sensitivity?” she asks. “We don’t know. Some people say 24 hours; some people say 48 hours.”

Likewise, says Dr. Adcock, “There are so many different entities physiologically that will increase a D-dimer level other than venous thromboembolism disease.” D-dimer levels are used to determine if a patient with ulcerative colitis has active disease; they also correlate with tumor stage in patients with visceral disease. And they elevate with age, during pregnancy, and in postsurgical patients.

Little is known about the effects of ongoing anticoagulant therapy on D-dimer levels, which is another source of concern and confusion. Does long-term warfarin therapy or its equivalent preclude use of a D-dimer assay in evaluating venous thromboembolism? The worry is that such therapy would artificially lower D-dimer levels. “Some studies suggest using D-dimer assays in that setting would be dangerous, whereas our own in-house data with one of our assays suggest that the sensitivity isn’t impaired at all,” says Dr. Bates.

On the flip side of the coin are the clinicians who don’t order a D-dimer test when they should. “Emergency physicians don’t realize how often they miss pulmonary emboli,” says Dr. Kivela. “They [PEs] are far more frequent than we would like to believe. It’s probably frequently missed in the emergency room, because a lot of our time and energy are spent looking for the myocardial infarction.”

The sensitive D-dimer test has proved to be invaluable at Queen of the Valley Hospital, he says—but only after a bit of a struggle.

Echoing Dr. Olson, Dr. Kivela notes that offering two versions of the test made it difficult for the lab and clinicians alike. A simple name change on the computerized ordering form helped—the latex agglutinin test is referred to as D-dimer, while the sensitive, ELISA method for PE/DVT is called DDE. “Until we did that, no one understood there were two different tests,” he said. The emergency department also sent letters to the medical staff, explaining the different tests and their uses.

They may have plenty more to explain in the not-too-distant future, as D-dimer is called to perform in other venues.

One new potential use for D-dimer is assessing the risk of recurrence in patients who’ve had venous thrombosis. No one is ready to put D-dimer to use in this area just yet, but at least one recent study (Palareti G, et al. Thomb Haemost. 2002;87:7–12) has people talking.

The dilemma for these patients is deciding how long to continue oral anticoagulation therapy, or, in some cases, whether patients should continue OAT indefinitely. Other tests, such as ultrasound, are not always effective in such settings because of the high likelihood of false-positives from residual disease. In some patients, D-dimer levels increase after they stop OAT, which may indicate higher risk. As with the primary PE/DVT setting, D-dimer’s strength would lie in its negative predictive value. Its weaknesses, however, also mirror those of using D-dimer to exclude first-time venous thromboembolism. Approximately half of all patients with suspected recurrent DVT or PE are on long-term anticoagulant therapy. Can D-dimer be used in these patients? At this point, no one knows.

Also drawing interest is the possible use of D-dimer as a marker in patients at risk for cardiovascular disease, which would also require a sensitive, quantitative assay.

“What’s surprising is how good the data look so far,” says Dr. Brandt. “For a number of years there’s been a recognition that coagulation and platelet activation play a role in the complications of cardiovascular disease, and probably also in the underlying pathophysiology. So things that would indicate increased activation of the coagulation system might be useful markers.”

As is so often the case with D-dimer assays, specificity is a problem. “But this is a story for people to keep an eye on,” he says.

Dr. Bates echoes him, noting that D-dimer “is a field with a lot of interesting new developments worth watching.” But she quickly returns to the fundamental message, arguing that many clinicians and not a few labs have yet to master the ins and outs of using D-dimer to rule out PE/DVT. This task alone “can be a bit overwhelming,” she concedes. “We need to make the message clear, that no D-dimer test is the same.”

D-dimers: Vive la difference. Madison Avenue, are you listening?

Karen Titus is CAP TODAY contributing editor and co-managing editor.