Home >> ALL ISSUES >> 2019 Issues >> Navigating the quandaries of coagulation testing

Navigating the quandaries of coagulation testing

image_pdfCreate PDF

Anne Paxton

January 2019—Naming the things about coagulation testing that most perplex clinicians isn’t easy for Michael Laposata, MD, PhD. But there’s a good reason for that: He finds confusion to be pervasive. New drugs with untoward effects on traditional coagulation tests, revamped clinical guidelines, and assays that can be difficult to interpret have been among the more recent contributors to clinicians’ bewilderment. Dr. Laposata, however, sees a more basic problem: “All of coagulation testing is confusing for the average physician in all specialties.”

It’s been that way for some time, says Dr. Laposata, chairman of the pathology department at the University of Texas Medical Branch at Galveston—and he should know. He’s been a faculty member at different institutions since 1985, but even earlier, on his first encounter with clinicians as a resident, he saw there was a knowledge gap. “I realized that the doctors on the floor didn’t know how to interpret even the simplest coag test result—even the brightest doctors. To me, that was a shock.” He found they needed to know not only which test to order but also what the results meant and what the recommended next steps would be.

Coagulation analyzers interactive product guide

But saying “Here is what I recommend for the next step” was stepping out of bounds for pathology, he says. “Historically, what we did [in clinical pathology] was generate results and give them back to doctors and hope they knew what to do.”

Coagulation testing could use an interpretive approach, he thought at the time, similar to that used by anatomic pathologists for breast biopsies, for example. When he tried it at his first faculty job, the results were not what he expected. “We would provide a patient-specific, expert-driven interpretation of the lab data. We did this for several months and it was so well received that I was told to stop it. They told me we were giving the doctors the diagnosis too quickly and it meant fewer consults and less revenue.”

The reaction at Massachusetts General Hospital, where he became the first division chief of clinical pathology, was different. “I said we were going to interpret every single coag test panel that is more than the simplest test and say what it means and what you’re going to do next. We started doing that in 1995, and it was a big hit.”

From then until 2008, Dr. Laposata gave more than 100 talks about providing advice for coagulation test results, a process that evolved into what is known as a diagnostic management team, or DMT. His colleagues over time and at more than one institution expanded the teams to other areas. All are modeled on the original DMT in coagulation; that was the “primordial cell,” Dr. Laposata says.

The purpose of the coagulation DMT is “ending the problem of ordering 20 tests when you need five, or ordering just one when you need the other four,” he says. “As coag specialists, we help doctors get the right tests. Our requisitions say things like ‘Evaluate my prolonged PTT’—they don’t have to pick any tests, we pick them—or ‘Evaluate my patient with a blood clot.’” By doing this in coagulation, “We can stop the process whereby doctors are given bits of information and cannot explain it to their patients, through no fault of their own,” he emphasizes. “It’s not because they don’t study or were poor students. It’s just because those small bits of information about coagulation have multiplied by the hundreds.”

For example, “Back in 2013 we didn’t have as many blood thinners, and they were a source of serious medical errors that could cost you your life. Now we have a half-dozen anticoagulants that are in common use, and at least as many that affect platelets.” But choosing the right drug is crucial to preventing adverse outcomes.

Dr. Laposata

His diagnostic management team for coagulation provides recommendations on how to avoid such outcomes for specific patients. With support from the Centers for Disease Control and Prevention, Dr. Laposata spent two years with Marisa Marques, MD, of the University of Alabama at Birmingham, writing a software application called “Anticoagulation Manager” that steers users through the pertinent questions (for example, What does your patient have? Is your patient over 18? Is urinary function impaired?), gives options for drugs, and then provides the exact dose to be prescribed. “We built dozens of algorithms for use of anticoagulants in different settings to create the app,” he says, noting it has been downloaded by several thousand users. (The Anticoagulation Manager is available free for IOS mobile download from Apple’s App Store.)

“The application is constantly changing because now we have new drugs appearing that are either blood thinners or reversal agents of blood thinners, and the reversal agents are very expensive. For example, the most recent reversal agent of the drugs Eliquis or Xarelto usually costs $10,000 or more for a single dose. So if someone doesn’t know what they’re doing, you’ve wasted $10,000.”

One source of clinicians’ confusion in coagulation are the American College of Physicians’ clinical guidelines for ruling out pulmonary embolism with D-dimer testing. The guidelines set new age-adjusted D-dimer cutoffs, but they are not widely known.

“I came back from a flight from Paris to Houston with a swollen right leg and normal left leg, and I was worried I had a blood clot. When the doctor looked at my D-dimer test, she said the result was elevated, and I said no, it’s not, because I am 66 years old. She asked, ‘Does that matter?’ I said yes and showed her the calculation. She said, ‘I had no idea. Therefore, we have people in here who are 80 and they have a much different range.’” That was one indication to him that as of yet, the age-adjusted cutoffs are not commonly understood, he says.

But perhaps the most vivid example of how confusing coagulation can be is heparin-induced thrombocytopenia, or HIT, an adverse drug reaction that can occur with heparin. “With this allergy, your platelet count decreases,” Dr. Laposata explains. “You would expect, since you need platelets to form blood clots, that you would have a bleeding problem. But in HIT, as platelets decrease in number, they get more activated. So you have to give the patient a blood thinner even though the platelet count is low. It is counterintuitive.”

Deciding whether the low platelet count is because of an allergy to heparin is difficult, he notes. “There are at least four or five other reasonable diagnoses for many patients about why their platelet count is low. And the first consequence of calling it HIT and treating it is that we take away heparin because you’re allergic to it, and we give you a drug that costs $1,000 a bottle and we have to give that drug every six hours.”

Unfortunately, administering that drug makes it easier to develop a bleeding complication. ELISA testing to detect who has HIT has improved, Dr. Laposata says. “But it still is not definitive enough. The confirmatory test, serotonin release assay, is much better but is performed at only a limited number of labs. So you have to send it off and wait up to three days for an answer. If you are spending all this money thinking it is an allergy to heparin, you’re giving this drug that could cause much more bleeding, and then three days later you find out the confirmatory test was negative and the ELISA was a false-positive—then you say, gosh, I don’t want to do that again.”

Direct oral anticoagulants have swiftly become a linchpin of anticoagulant therapy. They are being used more often because they have fewer associated side effects than warfarin and are easier to use, says Dorothy M. Adcock, MD, chief medical officer of LabCorp Diagnostics. “More than 40 percent of all anticoagulant prescriptions in the U.S. are DOACs, and that is a pretty significant increase over the past five years,” she points out. In fact, since DOACs reduce a common danger of warfarin—the risk of serious bleeding and particularly intracranial bleeding—“individuals who previously were not put on anticoagulants are being anticoagulated because of these new drugs.”

An important benefit of DOACs is that they eliminate the need for routine laboratory monitoring, Dr. Adcock notes. This probably means there will be a decrease over time in prothrombin time testing because fewer patients will be prescribed warfarin, though to date LabCorp has not seen a significant impact on traditional PT/INR testing.

But DOACs pose a potential patient safety issue because in their presence, APTT and PT assays are often not reliable indicators of a patient’s level of anticoagulation. DOACs can also interfere with special coagulation testing, for example with lupus anticoagulant testing, where DOACs can cause false-positive results, and some thrombophilia testing, which can be falsely negative.

Dr. Adcock

“When a patient is on warfarin, you can order a PT/INR and that correlates with the level of anticoagulation, plus the patient has been getting PT/INRs typically on a regular basis,” Dr. Adcock says. “Furthermore, a patient on a DOAC can be fully anticoagulated and have a normal APTT and PT result, which can be confusing to clinicians. If a patient is unconscious and you don’t know their drug history, you can’t just run these coagulation tests at the point of care or in the lab and let a normal PT/INR and APTT assure you that these drugs are not present.”

LabCorp is proactive in addressing the potential confusion regarding DOAC impact when providing results of special coagulation assays. For example, in the interpretation it provides with lupus anticoagulation results, “When we suspect a DOAC is present and the result is positive, we state that the positive result could be DOAC interference. A false-positive lupus anticoagulation result may result in a patient mistakenly receiving long-term anticoagulant therapy.”
The most common question Dr. Adcock receives is: How can the laboratory determine if a DOAC is present in an emergency situation such as when a patient requires a surgical intervention or thrombolytic surgery due to a stroke, or if a specific reversal agent is being considered to reverse the effect of the DOAC in a situation of bleeding? “Hospitals that serve as stroke centers have reached out to me about what they should do in cases like these, realizing that you can’t rely on a PT and an APTT to determine if the patient is anticoagulated nor their level of anticoagulation.”

Clinicians in these hospitals have questions about what to do in an emergency situation because they can’t rely on what they have been accustomed to for many years, Dr. Adcock says. “We do have a test, the thrombin time test, although not all labs have it up, that is a very sensitive assay for the presence of dabigatran and would determine its presence, but dabigatran is not used very often anymore.”

CAP TODAY
X