Clarity on clotting tests in the DOAC

More than 8 million Americans regularly take anticoagulant medications, also known as blood thinners, to prevent a host of complications that could arise from blood clotting. These include stroke, deep vein thrombosis, and pulmonary embolism. Until relatively recently, warfarin was the main oral anticoagulant available for outpatients at risk of forming clots.

Although highly effective, warfarin has a narrow therapeutic window, partially because of the drug’s interactions with food and other medications. That means that people taking it must undergo regular testing to ensure they achieve the correct degree of blood thinning. Experts recommend that patients taking warfarin undergo coagulation testing — which measures the blood's ability to clot — at least once a month.

Because repeated testing carries its own burdens, including more healthcare costs, increased difficulty of patient adherence, and patient inconvenience, patients have gravitated towards a class of drugs known as direct oral anticoagulants (DOACs), which have much more predictable pharmacokinetic properties. The first DOACs were approved by the U.S. Food and Drug Administration in the early 2010s.

Whereas warfarin inhibits an enzyme responsible for activating vitamin K, which in turn lowers the production of clotting factors, DOACs block clotting factors directly. Accordingly, most patients taking them receive a fixed dose and do not require regular monitoring.

That said, there are scenarios in which patients on DOACs might need coagulation testing. In these instances, selecting the right approach often is tricky, because DOACs directly interact with the same clotting factors at play in certain coagulation tests. Although there are coagulation tests that don’t rely on clotting, it’s not always obvious when to use them, which introduces further complications for clinicians and laboratorians seeking to order and interpret tests for patients on DOACs.

To help health professionals navigate these nuances, the Association for Diagnostics & Laboratory Medicine (ADLM, formerly AACC) has released an expert-authored guidance document that synthesizes a large body of publications and medical reports on this topic. This article summarizes key points from that guidance.

TESTING SCENARIOS AND POSSIBLE INTERFERENCES

The document, titled “Coagulation testing in patients using direct oral anticoagulants (DOACs),” is intended to organize and simplify previously published research on the subject, said Lindsay Bazydlo, PhD, an associate clinical professor of pathology at the University of Virginia School of Medicine and chair of the project.

“The idea was to collate all this information that’s in multiple reports throughout the literature,” she said.

A major focus of the document is to outline which coagulation tests might be affected by the presence of a DOAC in a blood sample. Some scenarios in which patients taking DOACs might need to undergo these tests include heavy bleeding, when they’re being tested for a possible clotting disorder — for example, to assess the etiology of a deep vein thrombosis — or before an urgent or elective surgery to ensure bleeding is controlled.

Among the most common coagulation tests are those that measure how long it takes blood to clot, such as the prothrombin time (PT) test, which involves activating the clotting pathway in a blood sample. Under normal circumstances, a prolonged PT could mean that a person has a clotting-factor deficiency. DOACs, however, interfere with this pathway, potentially skewing the results of this testing. The DOAC dabigatran directly inhibits the clotting factor thrombin, while the other three approved DOACs — rivaroxaban, apixaban, and edoxaban — inhibit factor Xa.

“DOACs interfere with clot-based testing because they inhibit the activity of specific clotting factors,” said Louise Man, MD, a hematologist at the University of Virginia Comprehensive Cancer Center and co-author of the guidance document. This type of testing should therefore be avoided for patients on DOACs. "Some non-clot-based testing could be interfered with as well, depending on the specific testing methodology," she added, but there are some methodologies that are free from this interference.

The document details the tests that are not susceptible to interference from DOACs, including polymerase chain reaction (PCR)-based tests, which detect the presence of mutations in DNA that affect clotting ability, and certain immunoassays, which rely on antibodies that bind to and measure specific molecules. Because these tests don’t rely on the activity of clotting factors, they are unaffected by DOACs.

It’s a little more complicated for chromogenic assays, a type of immunoassay in which the enzyme of interest cleaves a substrate that produces a color change, the intensity of which is proportional to the amount of enzyme in the sample. One way to test for thrombophilia, the condition where blood has an increased tendency to clot, is to perform a chromogenic assay for protein C activity, which is instrumental for clotting. Although this particular test is not affected by DOACs because the drugs don’t target this protein, another type of chromogenic assay — antithrombin — is subject to interference, according to the guidance document. Assays for antithrombin, which can be used to test for hypercoagulability, are affected by DOACs that interact with factor Xa, since those tests rely on factor Xa to produce the color signal.

MITIGATION STRATEGIES

Because it may not always be possible to use a different testing methodology on samples from patients taking DOACs, the guidance document explores several strategies for mitigating the drugs’ impact on results.

For example, labs can treat a blood sample before testing with agents that neutralize the effect of DOACs. There are a range of products that can absorb, remove, or filter out DOACs with minimal impact on the clotting proteins at work in clot-based coagulation tests. The coagulation lab at the University of Virginia uses some of these products to remove DOACs, she said.

Although this can be a convenient work-around, the reagents are costly, and the workflow can be time-consuming and labor-intensive, in part because each lab needs to validate each product.

“You have to confirm that the product is doing exactly what the manufacturer claims,” said Olajumoke Oladipo, MD, an associate professor of pathology and laboratory medicine at Penn State College of Medicine and co-author of the guidance document. “Every lab has to validate this in their local environment,” she added, because there’s no universal methodology.

“It’s not currently in widespread use for a multitude of reasons,” Man said of this approach.

Another possibility is to temporarily discontinue DOAC treatment before a coagulation test. “I tend to do this when people are stopping a blood thinner for another occasion,” Man said. This can include operations such as a colonoscopy, biopsy, or surgery. “That is the time when I swoop in to ask to set up lab testing.”

Finally, in some cases where temporary discontinuation of a DOAC might not be feasible, Oladipo noted that another option is a brief switch to a low molecular weight heparin, an anticoagulant that prevents clotting by enhancing the activity of a protein called antithrombin III.

COMMUNICATING WELL

As the guidance document emphasizes, the strategies for performing coagulation testing for patients on DOACs work only if clinicians and lab professionals communicate effectively. Although laboratorians are the experts on potential testing interferences from DOACs on the tests they run, clinicians are the ones who best understand their patients’ medication status and testing needs. Both perspectives are needed to ensure patients get the appropriate tests.

“Communication needs to be bidirectional,” Bazydlo said. “The lab needs to put out information to the providers on issues with testing in this patient population, [and] it’s helpful if the providers can identify for the lab which patients are on these drugs.”

A very good rapport must exist between the two sides, Oladipo said. “In my hospital, we can do DOAC removal [after initial testing], but it is so much easier if we know beforehand that the patient is on a DOAC.” That way, the laboratory staff can do the DOAC removal the first time around, instead of having to do additional testing after receiving questionable test results because of to DOAC interference.

In some systems, when doctors order coagulation tests, they can be prompted to convey whether their patient is on a DOAC, and if so, which one. Oladipo is working on updating the laboratory information system at her hospital to include a similar functionality.

It’s one thing for a doctor in a large medical center to let the in-house laboratory know about their patient’s DOAC, but it can be harder for those in community practices to pass along the information to an outside lab they’re using.

“It seems like it would be a very good idea for big commercial labs to consider having a way to indicate on an electronic order what blood thinner the person is taking,” said Man. However, there may be variations between patient samples that would influence how the interference is mitigated, she notes — including when the patient last took the DOAC and when the sample was drawn.

The stakes of DOAC interference with coagulation testing can be high. “On one hand, if we order testing and there’s interference with a blood thinner, you might miss a diagnosis of a clotting disorder,” Man said. “On the other hand, you might diagnose someone with a clotting disorder [because of DOAC interference] who does not have one. Neither scenario is good.”

The ADLM guidance document can help clinicians and laboratories navigate these tricky scenarios. “What we tried to do,” Oladipo said, “was have a one-stop-shop for people to say, ‘My patient is on a DOAC: What coagulation assays can I, or can I not, order?’”

Yaakov Zinberg is a writer based in the Boston area. +Email: [email protected]

Read the full November-December issue of CLN here.