Saskia Middeldorp, MD, PhD Arielle Langer, MD, MPH
Hereditary and acquired thrombophilia are risk factors for venous thromboembolism (VTE). Experts question whether testing should be used to guide management decisions. Screening for inherited thrombophilic conditions is controversial because studies haven’t consistently shown an increased risk of recurrent VTE in patients with these conditions, even though they are at higher risk for a first episode of thrombosis.
In 2023, the American Society of Hematology (ASH) developed guidelines to help clinicians determine when they should test for thrombophilia.1 The guidelines include various patient populations, recommendations on whether to test, and the level of certainty of the recommendation.
In this installment of “Drawing First Blood,” Saskia Middeldorp, MD, PhD, professor of medicine and head of the Department of Internal Medicine at Radboud University Medical Center in Nijmegen, Netherlands, and an author of the ASH guidelines, and Arielle Langer, MD, MPH, director of the Thalassemia Program and the Women’s Bleeding and Clotting Disorders Program at Brigham and Women’s Hospital in Boston, discuss whom to test for thrombophilia and when.
Who needs to be tested for thrombophilia?
Dr. Middeldorp: The general rule is to test if there would be consequences of knowing the result of the test. It’s very hard to pin down which patients should or should not be tested. The main question is: If a patient tests positive (or negative), what are we going to do? Are we going to change management? Are we going to prescribe thrombosis prophylaxis? Are we going to change anticoagulants?
Dr. Langer: In my mind, it’s sometimes easier to say who doesn’t need to be tested because that list is more concrete. The people with unambiguously provoked clots — for example, somebody who had a knee replacement and was only given aspirin for VTE prophylaxis — don’t need to be tested. The person who is unambiguously indicated for lifelong prophylaxis after a clot doesn’t need to be tested. I’m saying something very similar to what you said, which is, if we already know what to do with the patient, regardless of the testing, we shouldn’t be sending the test.
What are the benefits of testing? The drawbacks?
Dr. Middeldorp: The main drawback is that the tests can be complicated to interpret. Just to name one, the antiphospholipid tests are affected by the acute clot. And because you need two tests anyway, I try to defer everything to the outpatient clinic, unless it’s really strange thrombosis in general. There could be some benefits. For instance, in my practice, some people really want to understand why they clot. For some, it really helps them understand and cope with it. But that could also be a drawback and could also lead to massive family testing.
Dr. Langer: That is the most common reason that I send testing in the end — patients are experiencing a lot of distress, and contextualizing things can help them. But that’s also why I advocate for deferring to the outpatient setting once they’ve had a moment to process what’s going on. Every time I have patients referred to me who found out about their status for one of these thrombophilias through a family member, direct consumer genetic testing, or something like that, they’re often shocked that they haven’t clotted after 15 years on estrogen or oral contraception, even though statistically that’s still our expectation. One of the biggest drawbacks in my mind to testing, other than what I already mentioned, is the perceived likelihood that inherited thrombophilias will cause an event in the absence of other provoking factors. Statistically, most people with these things will have something else that tips them over.
I’ve heard you talk about this before. Oftentimes, first-degree family members are tested and have their care limited in ways that are inappropriate. For example, rather than having a shared decision-based approach to prescribing estrogen-containing contraception to a woman who carries factor V Leiden (FVL), physicians just say, “You can’t have it,” and that’s not appropriate. The risks really aren’t a strict contraindication in that regard, so I worry about people misusing and misunderstanding what the data say.
Does the timing of the test matter?
Dr. Langer: Even though it’s common practice, almost nobody needs to be set tested at the moment they clot. The exception is if we’re worried about antiphospholipid syndrome (APS) because it can have an implication about which anticoagulants we should be favoring. But the rest of the testing for thrombophilias, if it is even relevant to care, isn’t well suited to the acute setting. Testing in this setting can lead to people with a lot less expertise making poor decisions, like thinking someone who had a provoked clot that is positive for FVL needs lifelong anticoagulation, which is not evidence based. Or the reverse can happen, and negative testing may give someone false reassurance after a clearly unprovoked high-risk clot, and clinicians try to take the patient off anticoagulation because the test is negative. My number one piece of advice is to slow down. Unless you’re thinking about APS, there’s no reason to be in a rush about deciding whether to test.
Dr. Middeldorp: It’s important to teach your fellows and trainees that the DNA is not affected by anticoagulants, but for instance, protein C and protein S and lupus anticoagulant, for sure, could be interfering with your assays. It’s important to speak to your lab to see what assays are being used in your hospital. In my hospital, we don’t take patients off their direct oral anticoagulants (DOACs) to test. Instead, we draw blood in the trough — just before the next dose — and then our lab will add DOAC-Remove to the sample. It’s important to know what you’re doing with those coagulation assays and to speak to your lab to know what assays they’re using and if and how they interfere with the anticoagulants.
Dr. Langer: I couldn’t agree more that talking to your lab is critical because the assay in use can change. As a hematologist, having a strong relationship with your special coagulation section is mandatory if you’re going to do a good job.
Which thrombophilias should physicians test for?
Dr. Langer: Routinely, none. That’s my succinct answer. [If you do test,] tests should be tailored based on knowing if something is carried in the patient’s family. If testing for inherited syndromes, I would never send anything outside the five well-validated tests: protein C, protein S, antithrombin, prothrombin gene mutation, and FVL. Some other things that get brought up are not appropriate to make clinical decisions on, so I avoid testing them because inevitably they will cause people to make poor decisions.
Dr. Middeldorp: The tests outside the well-validated panel should be forbidden.
How does provoked versus unprovoked VTE affect the decision whether to test?
Dr. Middeldorp: I think we are probably in a bit of disagreement here. With unprovoked VTE with a normal — not increased — bleeding risk, according to the VTE guidelines and many other guidelines, there’s a recommendation to offer indefinite anticoagulation, so you don’t test. Now for the provoked, I think there are two categories. Clearly, the major surgical provoked VTE — new knee, new hip — I don’t care if a patient had proper low-molecular-weight heparin prophylaxis; if a clot happens, that is clearly provoked. Three months of anticoagulation is enough; the recurrence risk after stopping is really low.
The nuances may be in the intermediate-risk factor category. That includes hormones or minor transient risk factors, such as long-haul travel or being on the couch for three days because of an ankle sprain. If you do the math with all the uncertainties — and that’s what we did in the thrombophilia guideline panel, we used a modeling approach — that’s how we came up with a suggestion to test and continue anticoagulation in the patients with thrombophilia. That has raised a lot of controversy because it was really a shift in dogma. The dogma was to never test.
So, how does that translate to your practice as a doctor? For example, we have a 25-year-old who is on the oral contraceptive pill for years, has had massive pulmonary emboli with well-appreciated cognitions about almost dying, and is really afraid to stop her anticoagulation. There’s no heavy menstrual bleeding. So now we have room for personalized treatment where we can say, “If your preference as a patient is to not discontinue this anticoagulant, then perhaps thrombophilia testing may help to justify continuing.”
Dr. Langer: When I hear you explain the guidelines, I’m not so troubled by them, though I was originally vehemently troubled by that particular section of the ASH guidelines. You add back in all the nuance that is very difficult in the language of guidelines — when there’s an individual patient preference, risk stratification, individual discussion, and limited testing, not by default — and my objections start to slide away.
My primary objection is that a nontrivial number of the studies shows that the risk of recurrence is not segregated by your thrombophilia status, so I am still wary that they should be used to influence that decision.
How does the possibility of a recurrence of VTE affect a decision to test or not test?
Dr. Middeldorp: If a patient’s recurrence risk is very high anyway, then you don’t test because you’re going to prolong anticoagulation. It’s the most important driver of continuing or discontinuing anticoagulation in patients with VTE.
I haven’t mentioned a caveat yet, that, of course, there are other predictors that we don’t account for in regular practice. There are, and have been, attempts to better predict recurrence, like residual clot, D dimers, and more risk scores. A beautiful, randomized trial is ongoing right now where they take clinical risk factors and the most common genetic risk factors — the low-risk ones like factor V — in a buccal swab. In a couple of years, we will see if that strategy works. It would be a much nicer concept than this “yes or no” thrombophilia thinking.
Dr. Langer: I agree with everything you said. I would add that, as everybody with even a superficial understanding of VTE knows, provoked versus unprovoked is the biggest determinant of duration of anticoagulation, but it’s often used as a proxy for the risk of recurrence. I think anything we could do to better stratify people, including capture some people with provoked clots who are probably going to have another potentially life-threatening event, would do a great service to patients.
Dr. Middeldorp: Yes, what we really need is to have a better delineation of recurrence risk based on the type of minor risk factors. So, pregnancy related, oral contraceptive related, hormone replacement therapy related, that ankle sprain, or that medical illness are now put together because there are hardly any data, and that is really horrendous. In many studies, hormone-related clots were put in the unprovoked category, and in others, they were put in the provoked, so we really don’t know enough about that intermediate-recurrence risk group.
If a test comes back positive, what is the next step?
Dr. Langer: I hope that before the test is sent, the clinician has a plan for what is going to be done with the results. The conversation then turns to whether to test first-degree family members. I always like to emphasize the same thing I said about testing for thrombophilias, which is that this isn’t the whole story; most people with inherited thrombophilias don’t clot, so everybody else in the family shouldn’t be mandatorily tested if they have no clinical decision to make for themselves. There are so few scenarios in which primary prophylaxis is relevant. So testing all family members in their entirety does a great disservice.
If you don’t test, what do you watch for?
Dr. Middeldorp: People have to be educated about signs and symptoms, and they need to be educated to advocate for themselves if they have signs or symptoms. Specifically, young people are very often disregarded.
Dr. Langer: Yes, I totally agree. Make sure that patient can be a partner in monitoring, especially if you’re taking someone off any coagulation or if you’re choosing not to test a family member. I think one of the difficult balances is that people who are talking about secondary prophylaxis, who’ve had a VTE, often can be extremely anxious. You have to be considerate of how scary some of this stuff is. People can be hypervigilant about symptoms, so teaching them the difference between a foot that hurts for five minutes and a foot that hurts for 36 hours, for example, is critical.
Both of us have said there are many patients we wouldn’t test and some people we test. At the end of the day, that highlights that the point is to be nuanced. We just can’t make these really simple decision rules that make clinical practice easy but patient care poor.
Reference
- Middeldorp S, Nieuwlaat R, Baumann Kreuziger L, et al. American Society of Hematology 2023 guidelines for management of venous thromboembolism: thrombophilia testing. Blood Adv. 2023;7(22):7101-7138.
Disclaimer: The statements made by the participants may not necessarily reflect the opinions or stance of the American Society of Hematology.
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