Does provoked VTE warrant thrombophilia testing?

When the American Society of Hematology (ASH) released its 2023 guidelines for thrombophilia testing in the management of venous thromboembolism (VTE), one recommendation stood out as a significant departure from previous suggestions: For patients with VTE provoked by transient, nonsurgical triggers (such as hospitalization, injury, pregnancy, or combined oral contraceptives) who completed primary short-term anticoagulant treatment, the ASH panel suggested testing for thrombophilia to guide treatment duration (Blood Adv 2023; doi: 10.1182/ bloodadvances.2023010177). The panel suggested indefinite anticoagulant treatment for those patients found to have thrombophilia and treatment cessation for those who didn’t.

Because about 15% of the estimated 1 million cases of VTE in the United States are associated with these nonsurgical factors, this guidance could significantly increase test volumes for clinical laboratories by driving testing requests for inherited and acquired thrombophilia, according to Anna Merrill, PhD, DABCC, codirector of clinical chemistry and a clinical associate professor of pathology at the University of Iowa (Clin Chem 2025; doi: 10.1093/clinchem/hvae167).

Whether such a rise in testing has occurred yet remains unclear. Nevertheless, lab leaders should work to optimize appropriate testing and foster relationships with ordering physicians that promote informed, individualized decision-making.

About the guidelines

The thrombophilia-testing guidelines are part of a series of VTE guidelines from ASH, said Saskia Middeldorp, MD, PhD, professor and head of the department of internal medicine at Radboud University Medical Center in Nijmegen, the Netherlands. Although clinical guidelines are ideally based on evidence from randomized, controlled clinical trials, no such studies exist in this case. That’s because standard practice has been not to test for thrombophilia in patients with VTE. “We had to develop an entirely new methodology based on indirect evidence or modeling the effects of testing,” Middeldorp explained. “Much to our surprise, there were some recommendations that actually challenged this dogma of ‘do not test.’”

Although most patients fall into high- or low-risk categories for recurrence of VTE, some of those with major transient provoking factors are at intermediate risk, Middeldorp said. This includes women who take oral contraceptives and those who have had pregnancy-related clots — a group previously lumped in with provoked VTEs from major surgery or trauma, with a recommended anticoagulant treatment duration of 3 months.

Through their modeling exercises, the guideline authors estimated that testing that group of patients and continuing treatment in those found positive for thrombophilia would save enough recurrent thromboses — 21 in 1,000 patients — to conditionally recommend offering testing.

“That was somewhat shocking to us, because we as a panel were also raised with the idea that, with a provoked clot, you stop treatment and don’t test,” Middeldorp said. “This raised quite some discussion, if I say it politely.”

All recommendations in the guidance are conditional because of the methodology, Middeldorp noted. Although critics stated that guidelines frequently are used as “cookbooks or bibles,” she said, “this is a fantastic resource to do personalized medicine. The way I use it in my clinical practice is that now, at least, I can justify the fact that I do thrombophilia testing in some patients — but first we discuss the potential implications.”

What’s changed

Previously, ASH guidelines recommended that most patients with an unprovoked VTE with no determined cause should be treated with anticoagulants in perpetuity because they’re at high risk for recurrence, Merrill said. Those with a provoked VTE for any reason typically underwent a few months of anticoagulant treatment, after which testing for thrombophilia was not advised.

“Those were the two options, and both argued against thrombophilia testing,” she said.

The new recommendation is based on estimates from observational studies that indicate that 38% of patients with VTE provoked by nonsurgical factors will be found to have thrombophilia by laboratory testing, and that continuing anticoagulation therapy indefinitely in these individuals will decrease their VTE recurrence risk from approximately 8% to approximately 1% in the first year, with only a small increase in bleeding risk, Merrill said.

However, the guidance does not look at benefits beyond 1 year, she explained. “We know that the longer you take an anticoagulant, the more likely you are to have a bleeding event, and as you get farther away from the time at which you had a VTE, your chance of recurrence goes down,” she said. Most patients with longer courses will likely be put on direct oral anticoagulants (DOACs), a safer option than warfarin, she added.

Impact yet to be determined

It’s hard to predict whether the guidelines will be implemented widely. “[They] did make a fairly big splash, because they were different than the standard practice before that,” said Stephen Jenkins, MD, associate professor of medicine and medical director of the thrombosis service at the University of Utah Health. However, testing for thrombophilia patterns still may vary widely depending on where physicians practice and train, he said. At his institution, the culture favors the “minimalist” side for such testing. “The question we always ask before testing is, ‘Is this going to change our management?’”

Because most patients fall into high- or low-risk scenarios, there generally isn’t a strong role for thrombophilia testing, Jenkins said.

“Anytime somebody has a clotting event, the main question we ask is ‘What provoked this clot? Was it out of the blue, or did they just have a total hip replacement?’” he said. If it’s provoked by a surgery — a strong risk factor for a blood clot — that patient has a very low risk of getting a future clot if anticoagulation is stopped.

“If the clot happened out of the blue, we know those patients have a very high risk of a recurrent clot if we stop anticoagulation. So testing them for thrombophilia doesn’t help a lot either, because even if they test negative, we'll still recommend that they stay on anticoagulation because they have such a high clotting risk,” Jenkins said.

Jenkins’ institution does test patients for an acquired thrombophilia called antiphospholipid syndrome, because a positive result changes clinical management. In that situation, guidelines recommend using warfarin, he said.

Academic centers likely already performed frequent testing for thrombophilia based on preference and culture, Jenkins said. “I predict that these guidelines probably have increased the amount of thrombophilia testing mostly based on the fact that guidelines give you permission to go forward with it where maybe there wasn’t a super strong rationale for testing before.”

Since the guidelines’ publication, Jenkins said that he has found himself testing more. “I’m more willing to entertain different scenarios and talk more with patients about the conditions where it might be helpful,” he said.

Although she hasn't yet systematically studied the impact, Merrill, too, said that some of the hematologists at her institution “are not super fond of the recommendations, because there’s very low certainty.” But if the guidelines were followed perfectly across the nation, an estimated 150,000 patients would fall into the category of provoked VTE for whom testing is now recommended. “That could have pretty significant consequences,” Merrill said.

Middeldorp, who is based in Europe, isn’t aware of the impact in the U.S. “I do think that it raised controversy amongst experts, and that had to do with the fact … that it’s a modeling exercise,” she said. Thrombophilia testing also was questioned in the national “Choosing Wisely” campaign on judicious use of testing, in which experts recommended not to test in clots provoked by surgery, suggesting "expert advice" instead when VTE occurs in the setting of pregnancy or hormonal therapy.

Testing concerns

Testing for thrombophilia when a patient has an acute clotting event brings potential for false positive results because functional assays detect levels of proteins affected by an acute clot, Jenkins said. For example, if a laboratory tested a patient in the acute setting, results might indicate that they have a protein C or protein S deficiency when they don’t. A patient then could be prescribed an anticoagulant longer than needed. For that reason, he said, it’s recommended to wait at least 3 months after the clot to test.

Additionally, anticoagulants themselves can affect test results, so lab professionals should take this into consideration when running tests. Better yet, request that patients stop the medications before testing, Merrill said.

A game plan for laboratories

Regardless of whether clinical laboratories conduct thrombophilia testing in-house or outsource it, laboratorians should develop good relationships with their hematology providers, explain the laboratory’s capabilities, and decide on their recommended first-line test, Merrill advised. For example, there are several ways to test for protein S deficiency that measure total protein S antigen, free S antigen, and protein S activity. Moreover, certain tests are recommended over others if a patient still takes anticoagulants, she said.

“It’s a good time for labs to understand what they offer for thrombophilia testing and to ensure that the testing they offer is the recommended first-line test,” she said. “That will help prevent diagnostic error.”

Because the strength of evidence is pretty low in these guidelines, Merrill advises against labs promoting that testing must be done in these circumstances. “Deciding whether to follow these guidelines really should be up to the provider and should come from their discussions with their patients.”

Laboratory directors also could ensure that order sets in electronic records direct clinicians to select the appropriate tests at the appropriate time, Jenkins advised.

Laboratory professionals performing thrombophilia testing should review patient charts or conduct screening tests to look for anticoagulant medications that might interfere with results, or conduct screening tests to see what medications are in the samples that get sent out for thrombophilia testing, Merrill added. A higher proportion of samples may be from patients on anticoagulants, she noted.

Don’t assume that all providers who order thrombophilia testing know how anticoagulants might interfere. “As laboratories, we should look for opportunities to take a more active role in providing interpretive guidance,” Merrill said. “That could be comments that are sent along with your results. Make sure they’re valid and digestible, and that they will be meaningful for those reading the results.”

Karen Blum is a freelance medical and science writer in Owings Mills, Maryland. +Email: [email protected]