Navigating the quandaries of coagulation testing

The other assay to consider for determining the qualitative presence of a DOAC is a chromogenic anti-factor Xa assay calibrated with heparin or low-molecular-weight heparin, she adds. However, using this assay to determine the presence of an Xa inhibitor DOAC is problematic because it is an off-label use. “When the result of a chromogenic anti-FXa assay calibrated with heparin, low-molecular-weight heparin, or a hybrid of both, is below the assay’s lower limit of detection, this would suggest that an Xa inhibitor DOAC, if present, is at a concentration of less than about 30 ng/mL.” Quantitation of the DOAC would require an FXa assay calibrated with the specific DOAC in question, Dr. Adcock says, and all DOAC calibrators are labeled by the FDA for research use only at this time.

“The FDA has not approved the use of laboratory assays to measure DOAC levels in part because the drugs went through FDA approval without the need for these assays,” she says. “The drugs have wide therapeutic windows and predictable pharmacokinetics, and for the routine patient, therapeutic monitoring is not necessary. And yet we find situations where doctors want to know: Is a DOAC present in the patient’s plasma in a significant concentration?” While clinicians know quantitative assays are not generally readily available, “I don’t think they are always aware of the alternative assays that can be used to determine DOAC presence in the emergent situation.”

Clinicians may not understand that the impact of DOACs on special coagulation assays might be outside their bailiwick. “There is a concern that if you administer an anticoagulant like a DOAC that doesn’t require routine monitoring, then the clinician may think, ‘Oh, it doesn’t impact lab assays. I don’t have to worry about ordering factor activity assays, thrombophilia assays, or lupus anticoagulants.’ But the savvy or experienced doctor may have an inclination and reach out to us. It is the clinician who doesn’t reach out to us that we worry about. That’s why we provide interpretations for many of our special coagulation assays and for all of the lupus anticoagulant profiles.”

A second common source of coagulation-related questions is around the interpretation of testing for von Willebrand disease, the most common hereditary bleeding disorder, which leads to such symptoms as increased menstrual bleeding in women, nose bleeds, easy bruising, and increased bleeding with trauma. “The levels of von Willebrand factor and factor VIII can elevate with stress or in response to estrogen as well as increasing age. Levels can decrease with blood group O and there is a common genetic polymorphism that interferes with the von Willebrand ristocetin cofactor activity assay, leading to a falsely low result,” Dr. Adcock explains.

The assay is ordered frequently, she notes, estimating that LabCorp runs about 10,000 von Willebrand disease tests a month. Not only are there common situations that can alter the von Willebrand assay results but also result interpretation is complex, since von Willebrand disease has three major types and multiple subtypes. Therefore, there is a lot for clinicians to know about making the diagnosis based on laboratory results. For that reason, “we provide an interpretation with our von Willebrand disease panel that is based on complex algorithms.”

When dabigatran came on the market as the first anticoagulant other than warfarin that could be swallowed, “It really opened the floodgates,” Dr. Laposata says. Pharmaceutical companies soon developed an array of other DOACs. “Of course it is a huge patient advantage to not have to come in once a month or more often to be tested if you are on warfarin.”

Putting aside the purchase price of reversal agents for DOACs, he says, “If you look at all the patients on warfarin and look at the worst consequence, bleeding inside the brain, warfarin is much more expensive than all the other DOACs. And that, in my estimation, is the biggest reason to try to use one of the newer DOACs—because the intracerebral bleed has such huge consequences.”

However, $40 a month for a prescription for DOACs like Eliquis (apixaban) or Xarelto (rivaroxaban) can be a deal breaker for some patients, and many stay with warfarin, which costs only about $3 a month, for that reason. “We have a number of patients who are taking warfarin instead of a DOAC because of the money.” But they are not taking other expenses into account,

Dr. Laposata points out. “What they don’t quite realize is they are also stuck getting their blood monitored, their diet may change the impact of warfarin, or they are stuck without a medicine they need because they have a cold and it changes the impact of warfarin.”

At ARUP Laboratories in Salt Lake City, a clear trend has been observed to switch patients from warfarin to the DOAC class of drugs, says Kristi J. Smock, MD, medical director of the hemostasis/thrombosis laboratory and associate professor, Department of Pathology, University of Utah. In the process, clinicians have gone from the high comfort level they had with warfarin to “quite a bit of confusion about this new drug class.”

While many patients have been managed fairly straightforwardly on warfarin and consistently achieve therapeutic INR without a lot of problems, “there is definitely a subset of patients for whom warfarin is a suboptimal therapy because they are hard to keep in the therapeutic range,” she notes.

For these patients, DOACs might be the right answer. “But many people are surprised to learn there can be strong interferences from the drugs in some of the widely used coag tests that can generate an unreliable or erroneous result.” While there is no need for routine laboratory monitoring of those drugs, “there are some circumstances where you would like to measure the presence of the drugs, and there are ways that DOAC measurements can be compared against the drug levels of the clinical trials, despite the lack of true therapeutic ranges. But there are currently not any FDA-approved kits or calibrators for those measurements.”

“That is kind of a sticking point,” Dr. Smock points out, because many labs have anti-factor Xa, for example, available for monitoring heparin, but it is calibrated against heparin. “You can’t just take these new drugs and throw them into that assay and get meaningful quantitative anti-factor Xa results without using a drug-specific calibrator.”

Since a number of new DOACs were approved in relatively short order over the past few years, Dr. Smock says, some physicians may not have encountered all of the drugs. That can cause confusion and potentially delays in care while the doctors investigate what implications a particular drug might have in surgery, for example. She believes the next five years will bring further increases in the number of patients on DOACs. “Luckily, in most centers, pathologists are knowledgeable about the drugs and can be contacted for consultation to help with anticoagulation management and anticoagulation bridging for surgeries.”

As to the age-adjusted D-dimer cutoffs, Dr. Smock believes there are also unsettled questions. “D-dimer levels, even in normal individuals, tend to increase as people get older, so should their cutoff for exclusion of venous thromboembolism be different—in fact, higher—than for younger patient populations?” Some large studies have looked at the question of whether a higher cutoff is feasible and safe, she says. “That’s where all these questions and guidelines are coming from.”

But there are mixed feelings about the new cutoffs on the laboratory side. “Of course we want to assist with excluding the proper patients from VTE appropriately, but there is a lot of controversy, I think, surrounding that question.” Adding to laboratories’ reservations, she says, is that the newer cutoffs and algorithms are not included in the labeling of the D-dimer reagents and package inserts.

“Laboratories are struggling over whether these calculations are valid things to do. Are they applicable across all older ages, even for a patient in their 80s or 90s? Probably a lot of patients at those ages may not have been included in the studies. Is there actually a difference with small incremental age increases for patients? There is some intrinsic imprecision in D-dimer measurements, so are these incremental changes and cutoffs valid when you take the imprecision into account?” The calculation laboratories need to make for these age-adjusted cutoffs also depends on what units are used in their D-dimer reporting, and there is a lot of variability in the units used by different assays, she adds. “So there are a number of questions.”

Laboratories can lessen the confusion about coagulation testing, Dr. Adcock believes. “Pathologists and laboratorians need to make themselves readily available to clinicians, and when possible we should provide interpretations with our more complex assays such as lupus anticoagulant and von Willebrand disease profiles.”

“Coag testing has always been a source of confusion,” Dr. Smock says. “It has been a place where sometimes people have felt they didn’t receive a lot of training or exposure to it.” As new issues such as DOACs and age-related cutoffs for D-dimer testing are showing, “The conversations we have can change over time. But pathologists who practice in the area of coagulation have always been accustomed to having a lot of interaction with our clinical colleagues who order coag testing.”

Anne Paxton is a writer and attorney in Seattle.