December 2011: Volume 37, Number 12
The Challenge of Diagnosing Pulmonary Embolism
What’s the Best Role for D-dimer?
By Genna Rollins
Pulmonary embolism (PE) is a diagnostically challenging condition that carries a high cost if not recognized and treated promptly. Of the estimated 650,000–900,000 individuals with PE in the U.S. each year, as many as 200,000 die from the condition. Even though physicians have a number of tools available to assess patients’ risk of PE, accurate diagnosis remains a problem. Among those tools is the D-dimer test, which often is misused and misunderstood as an early rule-out test, leading to further risky, costly, and unnecessary testing and treatments.
“The consequences are very high in both directions. If you fail to diagnose pulmonary embolism, your patient can die. But if you over-diagnose it, then you’re committing that individual to a lifetime of thinking they may have had a potentially fatal disease, and putting them on fairly dangerous medications,” explained Jeffrey Kline, MD, interim chair of emergency medicine at Carolinas Medical Center in Charlotte, N.C. “When patients are not ruled out early, it usually requires radiation and contrast, both of which can injure the body. But emergency medicine doctors generally underestimate the value of the D-dimer test. They either don’t use it or use it in a way that’s not going to help them rule-out the case that’s right before them.”
Making the PE Diagnosis
One of the main challenges in diagnosing PE is that it presents like many other medical problems. Chest pain, dyspnea, syncope, weakness, and hypotension can be present in PE as well as a great many other conditions. Yet emergency physicians hear the diagnosis clock ticking loudly: the majority of PE-related deaths occur within the first hour, so they want to discern PE from non-PE patients with all due haste.
Various clinical prediction rules have been developed to help physicians risk-stratify patients with suspected PE, including the Geneva Score, revised Geneva Score, Wells Score, and Pisa Model. In general, these schemas assign points to predisposing factors, symptoms, and clinical signs to yield low-, intermediate-, and high-risk probabilities of PE. Depending on where a patient falls in these risk groups, clinical guidelines recommend a range of further diagnostic tests and interventions.
The gold standard PE diagnostic is contrast CT scan of the chest, which has its own downsides and incentivizes physicians to rule-out patients before ordering the test, according to Wesley Self, MD, MPH, assistant professor of emergency medicine at Vanderbilt University School of Medicine in Nashville. “Contrast CT is expensive and involves exposure to radiation and iodine, which can cause renal failure or allergic reactions, so it’s not completely benign,” he explained. “And we’re talking about tens of thousands of people across the country who may be taking these scans, so you’re going to have some complications.”
While some physicians and hospitals adhere strictly to algorithms using one of the risk models, others take a more informal approach that relies on the physician’s judgment. Recently updated American College of Emergency Physicians (ACEP) guidelines found either objective criteria or gestalt clinical assessment appropriate in evaluating suspected PE. The guideline found insufficient evidence to support use of one method over the other (See Figure, p. 7, for a suggested algorithm).
An Algorithm for Investigating Suspected Pulmonary Embolism
Numerous algorithms have been proposed for assessing the clinical probability of pulmonary embolism (PE) and using D-dimer results to rule-out PE or pursue further diagnostic work-up. This example for venous thromboembolism (VTE), which encompasses both PE and deep venous thromboembolism, was proposed by Armando Tripodi, PhD.
Source: Clin Chem 2011;57:1256-62. Reprinted with permission.
What’s the Pre-test Probability?
Whether one employs formal or informal risk assessment, use of D-dimer hinges on the physician’s determination of a patient’s pre-test probability of having PE. The ACEP guidelines and others, including the American College of Physicians (ACP)/American Academy of Family Physicians (AAFP) and the European Society of Cardiology (ESC), all recommend that a negative D-dimer result in patients with a low pre-test probability of the disease can be used to exclude patients from further PE work-up (See Box, below).
The guidelines diverge somewhat in their recommendations surrounding patients deemed to be at intermediate pre-test probability. ACEP specified that a negative quantitative D-dimer assay may be used to exclude PE, but did not find strong evidence for this approach. The ESC guideline qualified its endorsement of D-dimer testing in intermediate risk patients to be performed only when using a highly, as opposed to moderately, sensitive assay. The ACP/AAFP extended its D-dimer recommendations only to low-risk patients.
Pulmonary Embolism Guidelines
Several professional organizations have issued guidelines for diagnosing and managing pulmonary embolism (PE), including the American College of Emergency Physicians (ACEP), the American College of Physicians (ACP)/American Academy of Family Physicians (AAFP) and the European Society of Cardiology (ESC).
In patients with a low pretest probability for PE, a negative quantitative D-dimer assay result can be used to exclude PE.
In patients with an intermediate pretest probability for PE, a negative quantitative D-dimer assay result may be used to exclude PE.
Fesmire FM, Brown MD, Espinosa JA, Shih RD, et al. Critical Issues in the Evaluation and Management of Adult Patients Presenting to the Emergency Department with Suspected Pulmonary Embolism. Ann Emerg Med 2011;57:628–52.
In appropriately selected patients with low pretest probability of deep venous thromboembolism or PE, obtaining a high-sensitivity D-dimer is a reasonable option, and if negative indicates a low likelihood of venous thromboembolism.
Qaseem A, Snow V, Barry P, Hornbake ER, et al. Current Diagnosis of Venous Thromboembolism in Primary Care: A Clinical Practice Guideline from the American Academy of Family Physicians and the American College of Physicians.
Ann Intern Med 2007;146:454–58.
A negative D-dimer result in a highly sensitive assay safely excludes PE in patients with a low or moderate clinical probability, while a moderately sensitive assay excludes PE only in patients with a low clinical probability. When using a recently introduced two-level clinical probability assessment scheme, a negative D-dimer result excludes PE safely in PE-unlikely patients either by a highly sensitive or moderately sensitive assay.
Torbicki A, Perrier A, Konstantinides S, Agnelli G, et al. Guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2008;29:2276–2315.
What Does a Positive Result Mean?
Given D-dimer’s crucial place in excluding low- and intermediate-risk patients, physicians’ understanding of the test is paramount, but unfortunately problematic. D-dimer is a product of the degradation of fibrin clots caused by the action of three enzymes, thrombin, activated factor XIII, and plasmin. D-dimer levels rise in the presence of an active clot, so a negative or normal test suggests that either PE or its venous thromboembolism cousin, deep vein thrombosis (DVT), are unlikely. This means the D-dimer test has a high negative-predictive value for ruling-out a clot. However, since D-dimer is very specific for fibrin, it can be elevated in quite a number of conditions besides PE or DVT, including cancer, stroke, infection, liver or renal disease, and aortic dissection, to name a few. This gives the test a poor positive-predictive value, and therein lies the interpretation challenge for physicians.
“People always think that a positive test result means disease is present, but that’s not the case with D-dimer and pulmonary embolism,” said Jeff Ginsberg, MD, FRCPC, professor of medicine in the department of hematology and thromboembolism at McMaster University in Hamilton, Ontario, Canada. “A positive result has no meaning in this situation. It doesn’t make a diagnosis of pulmonary embolism. That’s where people sometimes get confused.”
Because of its specificity for fibrin, none of the guidelines recommend using D-dimer in patients with a high pre-test probability of PE. “The reason we don’t order it in high risk patients is because the test is positive in three-quarters to 80 percent of them. It’s just a waste of time, and in emergency medicine, time is everything,” said Kline.
How to Use D-dimer
Some physicians also tend to view the test as having a dynamic range so that higher concentrations suggest greater risk. Although D-dimer levels have been associated with the severity of PE, most studies have used a 500 ng/L cutoff, with values above that level considered positive. Therefore, most, but apparently not all, clinicians use even quantitative enzyme-linked immunosorbent assays (ELISA) and latex-based automated assays with immunoturbidimetric readings as if they were qualitative tests. “My impression is that some doctors think that the higher the D-dimer is, the more likely the patient has PE, without realizing all the studies are just dichotomous—either positive or negative,” explained Francis Fesmire, MD, medical director of the Chest Pain Center at Erlanger Medical Center and professor and clinical research director of the department of emergency medicine at the University of Tennessee College of Medicine in Chattanooga. “I’ve seen doctors order the test and let’s say the result is 510 ng/L, and they’ll say, ‘Oh, it’s minimally elevated, so I’ll ignore it. But that’s not how you utilize the test. It’s either positive or negative.”
To quell this kind of misunderstanding, and in recognition of the analytical characteristics of the D-dimer test, Massachusetts General Hospital (MGH) in Boston has implemented a third category of test results, according to Kent Lewandrowski, MD, associate chief of pathology and director of laboratory medicine at MGH and associate professor of pathology at Harvard Medical School. “If the cutoff is 500 ng/L, you can get a 490 on one measurement and call it negative, but the next measurement can be 510, and it would be called positive. That’s just due to imprecision of the assay around the cutpoint. So to get rid of that problem, we created a borderline category which spans the cutoff on both sides.”
Physicians also go astray by ordering D-dimer in situations where it is not needed, or worse, likely to muddle rather than clarify their clinical decision-making. “Probably the biggest problem I see is indiscriminate ordering of D-dimer,” said Fesmire. “It’s pretty routine that in smaller hospitals that transfer patients to us, they will have D-dimer on their cardiac profiles, but that’s doing a disservice to the patient. It’s going to lead to so many false positives in patients who shouldn’t have had the test to begin with.” He suggested that labs that currently include D-dimer in their cardiac panels consider removing the test so that it will have to be ordered separately.
Fesmire applies a Golden Rule for ordering D-dimer tests in suspected PE: “I try to take a step back and ask myself, if I didn’t have this assay would I be ordering a CT scan? If the answer is no, then I don’t order the test,” he explained. While Lewandrowski lauded that attitude, he cautioned that it is unlikely to be widely adopted. “It takes a very mature physician to be able to take that approach. It reflects a lot of experience and introspection; however, I think given the high stakes involved in diagnosing pulmonary embolism and the level of risk aversion of doctors, not many will do that,” he predicted.
Kline actually would like to see more D-dimer tests performed in the work-up of PE, in a bid to reduce the number of low-risk patients sent for CT scan. “A normal D-dimer is stronger evidence of the absence of PE than a normal CT scan. If you compare patients with negative CT scans against those who have quantitative D-dimer results less than 500 ng/L and follow them for three months, fewer of the people with low D-dimer levels will manifest certain PE than people with negative CT scan,” he said. Kline also has proposed a model, the Pulmonary Embolism Rule Out Criteria (PERC), to help deal with low-risk patients. Unlike the aforementioned clinical prediction rules that help doctors risk-stratify patients, PERC, which does not involve D-dimer testing, is aimed at ruling out risk of PE in patients who’ve already been categorized as low-risk. The ACEP guidelines recommended that physicians consider using PERC in patients with a low pretest probability of PE to exclude diagnosis based on history and physical examination alone.
Overcoming Testing Challenges
Kline suggested that a few bad experiences using D-dimer will sour physicians on the test. “That’s because they over-estimate the false-positive rate, and they sort of have this non-scientific, non-quantitative approach that it’s positive enough times in patients whom they don’t want it to be positive in, that they quit ordering it.” He outlined a worst-case scenario that he says has played out in too many emergency departments. The physician orders a D-dimer test in a patient being worked up for PE whom he suspects would not do well in a CT scan. The first blood sample is lost, so he has to reorder the test. “Now, 210 minutes after you ordered the first test and at the end of your shift, the D-dimer comes back above the threshold. So you have to look your partner in the eye and say, yes, we’ve had this guy here four hours waiting around for the D-dimer, but since it came back positive, you’re going to have to follow him through the CT scan.”
Both Kline and Lewandrowski suggested that laboratorians could help physicians avoid this type of problem by reminding them that in the majority of emergency patients, D-dimer results will be negative. Lewandrowski also recommended setting up an emergency department-laboratory working group that meets routinely to hash-out issues. “Oftentimes people in healthcare will get furious with another department, but they don’t say anything. They’ll just say, I’m never ordering that test again,” he said. “Left to themselves, they’re going to hate you, and the only way you can cure that problem is to form an ongoing collaborative relationship.”
Lewandrowski also encouraged laboratorians to work with the emergency department in tightening turnaround times as much as possible. With the exception of Kline, who uses a point-of-care (POC) assay, the other clinicians who spoke with CLN rely on lab-based D-dimer tests, and none are thrilled with the turnaround time, generally reported at 1-1½ hours. However, they also emphasized that if they are suspicious enough of PE or believe a patient’s pre-test probability of PE is on the high end of intermediate, they will not wait on the D-dimer results, but proceed to other diagnostic tests or treatments.
A couple of years ago MGH converted to a POC D-dimer assay and found that it cut turnaround time dramatically, to 25 minutes from about 2 hours (Am J Clin Pathol 2009;132:326–331). The entire hospital has since implemented this assay. “One doesn’t like to have two different methods used for the same problem in the same hospital,” Lewandrowski observed.
If turnaround time is a serious concern of clinicians, labs might want to look again at the type of assay they’re using, Lewandrowski suggested. “If you use a quantitative, whole-blood method, you don’t have to spin the sample down and make plasma and you can have the result in 15 to 20 minutes. Whereas, if you have to make plasma, it will take 45 minutes as a minimum turnaround time,” he said. Other considerations include the cutoff determined by clinical studies, high sensitivity, and acceptable specificity (See Box, below).
Considerations for Choosing a D-dimer Test
- Cutoff determined by clinical studies
- High diagnostic sensitivity (high negative-predictive value)
- Acceptable diagnostic specificity
- Easily performed with rapid availability of results (within 30 min)
- Good reproducibility around cutoff
- Quantitative results
Source: Clin Chem 2011;57:1256–62. Reprinted with permission.
Lewandrowski also suggested that labs collaborate with emergency departments on pre-analytical bottlenecks. Sometimes delays attributed to the lab actually occur in the emergency department. Given the hectic and highly variable workflow there, drawing blood or dispatching tubes to the lab may not always take priority. “Nurses are multitasking and have multiple patients. If a nurse is drawing blood for a D-dimer and the patient next door starts crashing, he’s not going to say, I’ve got to get this sample to the lab. He’s going to drop that for the moment and deal with the problem,” he observed.
Ginsburg advised that clear interpretive comments would remind physicians to put D-dimer results in the context of patients’ clinical presentation. “Even if the test result is off-the-map sky-high, then a comment should be made that this can be seen not only in pulmonary embolism but also a variety of other non-thrombotic conditions, so in-and-of-itself does not make a diagnosis of pulmonary embolism.” He also recommended that labs inform clinicians of the type of D-dimer assays they’re using as well as how sensitive the assay is, and keep the medical staff apprised of any changes in methods.
Kline also encouraged labs to evaluate D-dimer thresholds in several specific populations, including pregnant women, patients with cancer, and those older than age 70 or who have a low pre-test probability of PE. “The threshold really needs to be examined. In fact, I think it could be doubled in all those populations,” he said. In a 2005 study published in Clinical Chemistry, he demonstrated a progressive increase in circulating D-dimer levels during normal pregnancy, and called for a large management study to establish new thresholds during each trimester (Clin Chem 2005;51:825-829). For now, the ACEP, ACP/AAFP, and ESC guidelines all note the rising D-dimer levels or decreased specificity of the test in these populations, but none call for revised thresholds.
Kline and others urged laboratorians to collaborate with clinicians to make the best use of D-dimer testing. “They need to be part of the conversation, because we as emergency doctors have an obligation not to subject our patients to the toxicity of CT scanning when we don’t need to. Working together we can accomplish that.”
For Further Information
Agnelli G, Becattini C. Acute Pulmonary Embolism.
N Engl J Med 2010;363:266–74.
Tripodi A. D-Dimer Testing in Laboratory Practice.
Clin Chem 2011;57:1256–62.
Lee-Lewandrowski E, Nichols J, Van Cott E, Grisson R, et al.
Implementation of a Rapid Whole Blood D-dimer Test in the Emergency Department of an Urban Academic Medical Center.
Am J Clin Pathol 2009;132:326–331.
Kline JA, Williams GW, Hernandez-Nino, J. D-dimer Concentrations in Normal Pregnancy: New Diagnostic Thresholds are Needed.
Clin Chem 2005;51:825–29.