Q&A: ‘Primary prevention’ the biggest challenge in managing antiphospholipid syndrome
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Reducing the risk for thrombotic events in patients with antiphospholipid syndrome means striking the proper balance of monitoring and anticoagulation therapy, according to Richard A. Furie, MD, of Northwell Health in New York.
In recognition of June being APS Awareness Month, Healio spoke with Futie about the dangers of thrombotic events associated with APS. Furie discussed the challenges of managing APS, the question of primary prevention and potential future avenues for therapies.
Healio: What are some of the biggest challenges when managing APS?
Furie: I think the big challenge with APS is actually with primary prevention. There are probably a lot of people running around who do have these antibodies, and they are at an increased risk for having a blood clot. We typically will identify them by prolongation of clotting times. Some will do it when a patient is admitted into the hospital, just to have it as part of a routine, but it more often gets drawn when patients are going for a surgical procedure. In daily practice, we don’t typically check clotting times.
Even if you identify someone with these antibodies, what do you do about it? You know they are at an increased risk for a blood clot, and it is a small risk, so you might put someone on a baby aspirin, but the question there is whether you’re treating the patient or the doctor, because there have been some studies showing that a baby aspirin is not protective.
We would surmise that full-blown anticoagulation with warfarin would be protective, but it is a big leap to put someone who has no problems at all, just these antibodies, on full-blown anticoagulation, because that is associated with potential complications. Ideally, what we really need, is to be able to risk stratify someone. For someone who is asymptomatic, most of us avoid full-blown anticoagulation. To try to find out who is enough of a risk that we would do anticoagulation prophylactically, or we need to come up with a better preventive medicine.
Healio: What does clotting time say about the presence of antibodies?
Furie: One of the types of antibodies prolongs the clotting time, specifically the partial thromboplastin time (PTT). If someone has a prolonged PPT, it needs to be evaluated in order determine whether they were born with a clotting factor deficiency, or whether the person acquired an inhibitor.
One can fairly easily distinguish between the two. One of the most common types of circulating inhibitors of clotting is a lupus anticoagulant. We don’t know why certain people develop antibodies against phospholipids. Certain infections can trigger the production. Most recently, COVID-19 infection can trigger the production of these antibodies.
Healio: What is the risk for developing a thrombotic event?
Furie: The risk goes up with how many antibodies someone has, and probably also the degree of elevation of these antibodies. If one is a so-called “triple-positive,” meaning all three that I just mentioned are positive, the annual risk is said to be around 5% per year of having a blood clot. And although that may seem fairly low, over time the cumulative risk increases. There is less of a risk if you are double-positive, and even smaller a risk if you are single positive.
Healio: What are some of the biggest reasons one would avoid full-blown anticoagulation with warfarin if patients have antibodies, but have not had a thrombotic event?
Furie: If someone is asymptotic, meaning they have never had a complication from antiphospholipid antibodies, the problem with using warfarin is the bleeding complications. Warfarin is kind of a pain in the neck. Everybody requires a different amount. The endpoint for establishing the dose is the degree of anticoagulation, which requires a blood test. I have some patients who are rock-stable — I keep them on the same dose — and other patients who are all over the place because the response to warfarin can be very dependent on food intake and other factors. Even if you are rock-stable, it will likely change day-to-day. It is often hard to gauge how to get patients to have stable, reasonably safe results.
There are direct oral anticoagulants (DOACs), which do not require blood tests, but case studies and trials have shown these are not good for patients with APS. Clinical research in this area is very difficult. Essentially, it is difficult because the event rate is so low. If you want to test a new therapy against placebo, you have at best a 5% annual rate of thrombosis. You will need a lot of patients to show a difference between an experimental drug and placebo.
Healio: Are there any upcoming experimental drugs you have your eye on for this?
Furie: There has been a lot of activity in lupus, and lupus and APS share some commonalities, meaning the production of autoantibodies. There are ways to reduce autoantibodies in lupus, but the autoantibodies in APS are more difficult to tackle because they are most likely made by cell types where our drugs don’t get to, such as plasma cells.
Healio: Is there anything rheumatologists should be looking out for, or goals of treatment, other than anticoagulants?
Furie: Once someone has had their first clot, they will typically get treated with heparin and then they will be transitioned to warfarin. Then, it is just a matter of monitoring them and making sure they are not over- or under-coagulated. There are some unusual non-criteria complications of APS. For example, there could be problems with the heart valve, there could be low platelet counts, there could be some unusual forms of vascular disease.
You can’t just anticoagulate and leave the patient alone. You need to follow them and make sure they are not evolving, say, lupus for example. They require the same kind of surveillance we might offer to some of our other patients, like with lupus. Blood tests, urine tests, etc. Maybe every 3 months or so, they will need to come in for a visit. Despite adequate anticoagulation, patients can still have blood clots. It doesn’t occur very often, but it does occur, and that is a very difficult situation. There is no standardized algorithm for patients who are refractory to adequate anticoagulation with warfarin.
Healio: Do you have anything else to add?
Furie: There is a complication that is pretty rare, but life-threatening, called catastrophic APS. Luckily, we do not see to many of these each year, but these are very sick patients with multiorgan thrombotic events that are often microvascular. These patients are very sick with a very high mortality.
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