The Curbsiders (00:00.406)
You know, Paul, the doctor forgot to document the patient's blood type. Oh, no. Paul, it was a bad typo. That's yeah, that's especially awful. All right, Matt, why are there no fairies in the anticoagulation clinic? I don't know, Paul. Why? Because of a pixie ban. That's courtesy of Reddit.

The Curbsiders (00:32.105)
That's not bad.

The Curbsiders (00:35.854)
Curbsiders podcast is for entertainment, education and information purposes only and the topics discussed should not be used solely to diagnose, treat, cure or prevent any diseases or conditions. For the more the views and statements expressed on this podcast are solely those of those and should not be interpreted to reflect official policy or position of any entity aside from possibly cash like more possible and affiliate outreach programs. If indeed there are any in fact there are not pretty much we are responsible if you screw up you should always do your own homework and let us know when we're

The Curbsiders (00:58.806)
Welcome back to the Curbsiders. I'm Dr. Matthew Watto here with my great friend, Dr. Paul Nelson Williams. Uh, and I should mention that he is America's primary care physician, a title which he demands I use on every episode. It's true. It matches the t-shirt I'm wearing. Uh, our guest tonight is Dr. Ariel Langer. We are talking about antiphospholipid antibody syndrome.

I'm sure you all know it by heart, understand it very well and how to manage it, but we thought this would be a useful episode and boy oh boy did we have a great guest. Before we tell you about our guest and introduce our co-host, Paul, can you remind people what is it that we do on the Curbsiders? Sure, happy to as always, Matt. As a reminder to everyone, we are the Internal Medicine Podcast. We use expert interviews to bring you clinical pearls and practice changing knowledge. And as the great Dr. Watto alluded to, we are joined by.

Another co-host, super producer, medical student extraordinaire, my future boss, Malini Gandhi. Malini, how are you? I'm good. Paul, like we have so many future bosses that work for this, Curbsiders. It's great. So good about the future. Like I, Malini, why don't we have you tell us a little bit about who we talk to and maybe even just a couple of things that we talked about. Sure. So we had a fantastic conversation today with our guest, Dr. Ariel Langer.

Dr. Langer obtained her MD and MPH degrees concurrently from Columbia University College of Physicians and Surgeons and Mailman School of Public Health. She did internal medicine residency in a chief resident year at New York Presbyterian Columbia University Medical Center. She then went on to complete her fellowship in hematology oncology and served as a chief fellow at ICANN School of Medicine at Mount Sinai. Dr. Langer is interested in non-belignant hematologic disorders.

including a clinical focus on thalassemia and on hematologic issues affecting pregnancy. She is an assistant professor of medicine at Harvard Medical School and currently serves as director of the Thalassemia Program for Brigham and Women's Hospital and Dana-Farber Cancer Institute, as well as director of the Women's Bleeding and Clotting Disorders Program and serves as hematology lead for a festively named Blood in Guts, the Harvard Medical School pre-clerkship course that covers hematology along with gastroenterology.

The Curbsiders (03:20.466)
So in this episode, we had a great conversation with Dr. Langer, and she taught us a lot of wonderful pearls about how to decide when to test for antiphospholipid syndrome, how to interpret test results, their approach to management of both thrombotic as well as obstetric forms of antiphospholipid syndrome. So without further ado, let's get to it. And a reminder that this and most episodes are available for CME for all health professionals through VCU Health at curb

The Curbsiders (03:49.19)
Thank you to all the people on Patreon who are supporting the show so that we can continue to bring you all this great content, the mini-series, and the video which we've been expanding into, the Digest newsletter that comes out monthly. Anything you'd like to say about that, Paul? Thank our patrons. Sure. No, I would like to thank our patrons for making our continued work possible and for supporting the show.

Ariel, thank you so much for joining us on the show. The audience has heard your formal bio already, but please tell them a hobby or interest that you have outside of medicine. So one of my favorite things actually in the world outside of medicine is black and white photography in a dark room with chemicals, red light, like that thing that has film in it and nothing digital. It really is a wonderful thing I've been doing since I was about 11 years old. And I don't have a ton of time for it right now because of career and three kids.

but it's always something I go back to at every phase of my life. I kind of wish the background now was just all black and white photography so the audience could see. Is any of that there? That's my print. Wow. That's actually the oldest print I still own of my own. It was from high school where I actually won an award in art fair, which is how it's managed to stay with me for so long. Awesome. Amazing.

All right, so Paul, anything you'd like to ask before we get on to the topic here? Sure, I'll ask the feedback question. So, Beaning, is there a piece of advice or feedback that you've either been given or that you like to give to sort of help out our listeners? I, in the medical education world, primarily work with medical students. And so my feedback is definitely geared to that phase, which is to say that if you ever want a letter of recommendation from someone, ask for it.

right after you work with them rather than when you need it. Because even my most treasured experiences with students will fade from my mind. And you really want people to have that detail in to be able to really make it sound like they know you as you. So ask for that letter if you think you're going to need it as close as possible in time to working with someone. That's tremendous advice. I've

The Curbsiders (06:03.638)
Just to piggyback on that, I will sometimes recommend that students, it's that time of year where you need a letter. It's so helpful to me to hear, I might ask for a letter of recommendation at the end of this rotation. That way it kind of cues me to be like, all right, not like I wouldn't be paying attention already, but that really kind of clues me in that I should know what to look out for. That's terrific. For our attendings listening, any coaching you give them to like, or that the attending, should we ask for a list of the patients they saw, or do you tell them to also provide the attendings with something else to make it even easier for them?

Yeah, I've had some students do that preemptively and it was really helpful in that vein of like, oh, and let me recap some of the things that I found to be the most memorable from rotation or what did I take away from this? It's actually also a great get to know you moment as well. And so I think it just is great for mentorship, not just for the letter to be the best letter, but also for getting to know the student to be able to connect with them more, connect them to resources, interests.

and all that. So I think it's really wonderful if one of the two in the letter writing pair can write down some of that as well in real time. Okay, awesome. Malini, anything that you wanted to ask? You have your professor on the hot seat here. One question that we like to ask is a favorite failure you've had doesn't have to be medicine related. Oh, a favorite failure. So I…

played soccer for the longest time, it was always kind of horrible at it. So one of the best failures I had as I was supposed to be captain of my high school soccer team for senior year, I actually quit to run cross country, something I was actually capable of, unlike soccer, where I was truly not good at it. And I think that was one of the best ways ever. It was one of the hardest changes I made in my life. But it was really a great thing to say, sometimes, even if you've been doing something for a long time, it is time to move on. And that was a really hard lesson. But, you know,

20 something years later, it still stuck with me as an important lesson. The only thing I wish I had done was quit sooner. Well, I think soccer is the best sport, but I also like running a lot. So I, you know, I can't- Soccer is a better sport. I just wasn't better at it. Those are different. Okay, fair enough, fair enough. Well, we should get on to-

The Curbsiders (08:21.854)
Everyone's favorite hospital, Kaczalak Memorial, and Malini, if you would read us a case so we can get onto the topic at hand. Sure. So we have a case of Ms. L. She's a 36-year-old woman, no prior past medical history, and she presented to the hospital with left-sided hand and facial weakness that had been ongoing for about 24 hours and was ultimately found to have an ischemic stroke in the right MCA territory. There was no evidence for carotid or vertebral dissection.

No history of hypertension, CKD, diabetes, or hyperlipidemia. No history of substance use. Her lipids A1C were within normal limits, and a TTE with bubble was performed without abnormalities. The team ordered antiphospholipid syndrome labs, which showed positive lupus anticoagulant, a beta-2 glycoprotein, an IgG of 70, IgM of 80, and an anti-cardiolipin IgG of 50 and IgM of 70.

So to start out with before going into Ms. L's clinical presentation and labs in depth, wanted to start just basically with definitions. So what is antiphospholipid syndrome? What is its typical natural history? And when you're explaining to a patient what antiphospholipid syndrome is, how do you, what's your typical spiel in that setting? So I'm gonna start with what I explained to patients because I think that's actually a great conceptual grounding for how we should all be thinking about it.

which is that in antiphospholipid syndrome, you have a strange autoimmune disorder. And of course, I'm speaking directly to patients, I'd explain what autoimmune means, but for us, knowing that where your body starts to recognize some of your clotting proteins. And then with that, it has a very special property that normally when we have autoimmune disorders and they recognize something in our body, they just destroy them. But antiphospholipid has this auto recognition with a really special property, which is that it...

activates those proteins and then accelerates the clotting process. So it's sort of counterintuitive because if you think about autoimmune against the kidney, it's destroying your glomerulus, right? And autoimmune against your heart while we're killing myocytes. And so with all that, it's a very different property. So with that, we have this process. And because it can be variably aggressive and how much it turns on that clotting cascade, different patients have a spectrum of how hard it is to stop them from clotting.

The Curbsiders (10:43.53)
And so there are certain things that predict that, like how strong that autoimmune process is, and that's something we'll come back to when we think about titers of those antibodies. But we also see a bunch of heterogeneity and how accurate these tests come to, and we'll come back to that a little bit about whether or not we're recognizing testing that just shows that they recognize the protein, or are we really able to prove that the person has that process, that special property where it recognizes and then activates the clotting process?

Yeah, that would explain why, I guess part of why it seems so nebulous to us who don't deal with it very often is that it just has such a spectrum of labs and clinical findings and severity. Can you talk a little bit about the clinical things we should look out for? We just mentioned some of the labs that this patient has, but what do you look for clinically when you're taking a history?

So when I'm taking a history, I don't want to try to capture every single person who's ever clotted. That's going to be way too sensitive and pulling in a lot of patients for whom this special physiology just isn't really relevant. I would look for people with certain properties that show that they're clotting more aggressively. One would be that they're clotting through blood centers. Another would be that they're clotting at funny sites. We're talking about arterial clots when we don't have another exploration like atherosclerosis. We're talking about splenic thrombosis.

And those really cover it. We're really trying to identify patients that are when I think about the clots. The other perspective is to think about the host. That's a term I borrow a lot from the ID folks who are always using a host to think about who's the right person to think about this bug in. I think that really actually applies here as well, because when you find that person who's clearly of an autoimmune flavor, we're kind of seeing that they're the right person to pick out as this is a concern. So...

Most commonly that's someone with a history of lupus, but sometimes that's an autoimmune syndrome that's gonna be diagnosed concurrently with this appearing. So let's dig into this a little bit more. Who's like your classic patient that would, does this patient that we presented to you fit into that? We gave you a 36 year old woman without much past medical history and now she's having a stroke. And from what we told you here, she didn't have a carotid dissection. We rolled some things out, but.

The Curbsiders (13:00.322)
So this is exactly the right person to start thinking about it. You've got a clot that seems well out of proportion. If this were a 76 year old person, we should probably be pausing thinking a little bit more about how we didn't find their atherosclerosis or uncontrolled hypertension or any of those risk factors. We've got a young person with no evidence of atherosclerosis and no other evidence of vascular damage clotting in the arterial bed. That's a rare event. That's an example of that clot that seems like too much.

Because we don't have, when we think back to Virkow's trial, any of that endothelial damage that is the usual nidus for arterial stroke or embolization, which again, we've gone through here pretty carefully in the history and ruled out contributions like AFib, which already would have been surprising in our age, but not thinking about AFib, not thinking about a paradoxical embolus through a PFO, we've now got someone clotting in the arterial bed with no explanation. This is the right host. We were talking off mic beforehand about some of the other...

sort of clinical manifestations that patients with antiphospholipid syndrome might get. It sounds like those aren't usually the initial presenting things or if they are, you don't immediately jump to this diagnosis. But can you talk about those? Yeah. So we've got a few other things that make up all the different ways you can get those for the clotting criteria in your antiphospholipid criteria.

And so we think about people who have unusual site thrombosis that should also be raising a flag. So we think about central venous sinus thrombosis, blank neck thrombosis. But we also have people with some of the rare manifestations. So we think about that in terms of obstetric manifestations, which we'll come back to in a little bit. But we also think about some of the rare microvascular complications. So there are some of the rashes like levito racemosa.

And we think about patients who have unexplained nephropathy. We've got patients who have diffuse alveolar hemorrhage. And we also have the patients who present with, usually not at the very first, later in their course, but sometimes as an initial manifestation if it wasn't recognized earlier for people who have catastrophic antiphospholipids so they can have microvascular thrombosis throughout their body, causing simultaneous evidence of stroke and MI, renal injury.

The Curbsiders (15:11.982)
Adrenal hemorrhage is a common presentation in that context, and that's sort of counterintuitive, but it's actually clotting of the adrenal vein that then leads to hemorrhage in the tissue because of the friable nature of the adrenal glands. So those are all kind of these more rare manifestations, but for most people, they're not going to see those rare manifestations. I see them. But for the average general internal medicine person, what we're really expecting to see is...

plotting in a macrovascular setting. So those are the arterial or venous beds. Can you talk us through a little bit? And I might be jumping in here. Some of the limitations of the testing. I feel like a scenario I see is almost anyone with a stroke. There's an order set that you check, and maybe these labs are ordered. And then one of them goes back lately positive, and you're like, oh, no. Now what? So I guess this is sort of the age-old question. Why not just screen everybody with these tests? Or what do we do with this sort of lately abnormal test? Can you just talk us through the test characteristics when we're looking for antiphospholipid syndrome?

Absolutely. So

The Curbsiders (16:37.078)
only identify these antibodies are able to recognize clotting cascade proteins. That's all the tests have. So lupus anticoagulant, beta and anti-cardiolipin tests being positive, just say there's that antigenic recognition. They do not say that there's an in vivo ability to activate. And that is why these tests are sensitive, but not specific. When you take a step back, if you take blood from blood donors, that's our source for secretly...

from the healthy population a lot in science, right? A lot of just people will have positive antibodies and never go on to clot. And there's a host of studies that based on how they collect the data will give you different estimates because the sicker the population, the more likely it is they'll go on to clot. Basic point is the vast majority of people with these tests floating around positive will never clot in their lives because they don't have that second property. And so that's the concept behind the problem.

The other question then is, what about transient positives? Like what causes transient positives? What are the source of false positives? And annoyingly, the answer is inflammation, especially inflammation related to blood vessels, which basically means all the scenarios where we wanna send it do have that risk. That's why our diagnostic criteria require the positivity to be persistently there after 12 weeks. When we think about the half-life of IgG, which is about three weeks,

it actually starts to make sense that the 12 weeks isn't randomly arbitrary. I mean, there's a little bit of arbitrariness to anything, but if you have acute insult and we want that IgG to just decay away, that's giving it enough time to say that it should just clear. And so with that, it's really helpful to think if there's an acute insult and it's not a sustained autoimmune process, that's gonna just be positive, it's gonna go away. Now, if the inflammation continues, maybe your false positive continues.

So it's not a guarantee that if it persists, you necessarily have a true autoimmune recognition, but that's at least a starter in there. And that's where that 12 weeks comes from. So the biggest issue is, Paul, what you've been alluding to, which is that there are a lot of false positives in the acute setting. So when we send it for people, we have a low pretest probability. A positive test probably shouldn't force us to treat them as though they have something.

The Curbsiders (18:55.126)
versus if you have a patient with a high pre-test probability, like the clinical scenario we started with here, and you have a positive test, you need to treat presumptively till you make it to that 12 week mark. Yeah, you know, along a similar line, when you're reading about this, most of the articles mentioned there's people with antiphospholipid antibodies, and then there's people with antiphospholipid antibody syndrome, meaning they've had some sort of thrombotic event or pregnancy-related event.

And I was just thinking like, why are there so many people why we've identified, if they haven't had the pregnancy complication or thrombotic event, then why are we finding these people? Like, what is the situation this testing is being sent? I'm sure this is like one of the bains of your existence, I'd say. It can be, but not because it stresses me out, but because it stresses out the doctors sending them, and then it really stresses out the patients, which can be upsetting when you're trying to walk back something that's really hard on the patients. And so I think that this comes in a couple of flavors.

One is it's one of the diagnostic criteria for lupus. So there are a lot of patients who are identified and that's why I had my caveat of like the rates of who goes on to clot look really different based on what the study population is because the lupus patients who are just antibody positive don't qualify yet as having the syndrome are much more likely to go on to have that than people get it tested in other settings. Other times that people get it tested.

Sometimes even when people wouldn't have met obstetric criteria, it's done as fertility workups. That's a very common reason that people show up in my clinic. And that can be really sticky to navigate, because if you're already dealing with infertility, and one of the criteria is lose 3 pregnancies, that's pretty tough thing to say, Oh, yeah, you're on in your third round of IVF. Let's wait for this one to go poorly before we label you as having something.

So the fertility conversation is really complex in terms of patient preference and the difficulty of kind of making that diagnosis. Another is people who have really thoroughly explained clots who get it sent. And that's one of those I wish we hadn't sent it because actually, there's newer diagnostic classification released by ACR and EULAR jointly that kind of

The Curbsiders (21:07.218)
susses that out a little bit and says like, oh, if you have a provoked clot of positive antibodies, maybe we should be a little bit wary of how we apply this label. But historically that wasn't part of the diagnostic criteria. And I would just say that this is a basic advertisement for American Society of Hematology or ASH is choosing wisely guidelines that please don't send this testing for provoked clots because it doesn't help your patient and it does get confusing.

in that regard. So I would say clots where I didn't necessarily think it was merited, fertility workups, lupus patients, that covers most of it. Sometimes there are other patients where I really, honestly even talk to the patient, can't figure out the thought process beforehand, but it's there. The test is there. Because it was part of a panel or something like that. Or yeah. So that's fair. So that...

people looking for lupus, you know, and then people with fertility, that seems like that could be a lot of patients there. And then obviously we see a lot of provoked clots. So if people are pulling the trigger on this workup for everyone they see with the clot, then that they're going to get some false positives. Especially if they're sick with inflammation, like you said, inflammation from another reason, maybe even get a transient positive and then they didn't notice and the follow-up testing.

Yeah, I would say that the catch 22 on trying to help guide people with that is that when we do worry about it, having one side of the labs be contemporaneous with the clot is helpful for proving causation. And so if there's one test that I'm the most understanding of all the hyper-cliable tests about people sending, it's actually this one, even though it can make a mess because it is actually one thing that may fluctuate over time and it can help us to have it be contemporaneous. So I would just say that.

The clearly provoked clot is not the person to be worrying about this for. It's the people who are unexplained clots, not just your run of the mill, unprovoked VTE. If it's just, there's a lot of unprovoked P's out there. Everyone doesn't deserve the antiphospholipid testing. That's gonna be an overdiagnosis scenario, but the patients who are clotting unusual site, arterial clots without atherosclerosis, and people are clotting through anticoagulation or.

The Curbsiders (23:24.162)
patients with an autoimmune history. That's my list of who, when we're talking about clots, I really want the testing sent in. Can I ask this? And this might be self-evident, but from a pathophysiology standpoint, is the thinking that ongoing inflammation is a requisite ingredient for antifungal syndrome to declare itself in terms of thrombosis? I'm just thinking through it. You see these positive levels in someone who has inflammation, and you think of autoimmune diseases like lupus as being a chronic inflammatory state. Does that inflammation have to be there

to become clinically manifest or am I overthinking things? I don't think that you have to necessarily have evidence of systemic inflammation, because there are a subset of folks who really have this in isolation. So I've said, worry about it with your autoimmune patients, but there are also lots of people who just have antiphospholipid syndrome, ANA negative, no background, other autoimmune process. And so it's certainly not a requirement to have that as well.

And that's just one of the ways you can go to identify the at-risk patients. And certainly if you have a person with uncontrolled antiphospholipid who's clotting through, I'm going to suspect they're inflamed, but that's a little bit of a chicken or egg situation. Moving towards diagnosing our patient here and talking about the criteria, because as you mentioned, I did get to look through the ACR and the UR, like the 2023 paper on like the new classification.

It's pretty dense for a non-hematologist. It's a lot. You know, there's like six, there's what? Six domains in the clotting criteria. And I don't want to read them all off, but can you talk about like the revised Sapporo criteria, which were the older criteria, I think from like 2006. And then we have these newer ones from 2023 and why they're different. Like what was the thinking, why we needed to change them? So,

I don't really think that the new ACRUR criteria are necessarily appropriate to replace them. They actually, and this is the author's declaration, this is not my imposing my perspective on them, is that they're really meant to help clean up our research. As we've already started to talk about, there's a spectrum of folks, there are a spectrum of patients who have antiphospholipid who actually if it was never caught, maybe they would have been okay, they do fine on any anticoagulant that they have before we even.

The Curbsiders (25:45.302)
I'm sure we'll get to management in a second, but there are certain anticoagulants we know are not as ideal now, but there are patients with antiphospholipid who have been on some of those for a decade. They've done fine. They had a single clotting event. And it's really hard to think that those patients are exactly the same as the patients who are clotting through multiple agents, have had times where they had catastrophic antiphospholid syndrome, or they have some of these rare manifestations. And so with that,

It can be really hard sometimes to do research on a rare condition when we already have such heterogeneity and also have some patients who are a little bit wishy-washy if this is really their physiology. And so these guidelines were specifically designed to help make the research better by really refining the population to capture those people who have this special physiology that is really prothrombotic. And so the authors intentionally made this more specific and less sensitive.

And that is part of why it's so complicated. And it's gonna be a brilliant research tool, but it is not a helpful thing for a person who is on the wards. It is too complicated. And this part is my expert opinion. So we've shifted from what the author said to my perspective. It is too complicated to think that you are gonna whip this out and use it for every patient. And truthfully, the extended criteria that go in there, trying to tease out the contribution of people of concurrent thrombocytopenia, thinking about some of these rare manifestations like valvular vegetations.

All this stuff is what a hematologist is gonna do in their office. And so these are really important things I think about all the time with my patients, but if I want someone to get them to a hematologist, I still want them using the support criteria because they're simpler, they're more sensitive, and that's what you need to screen when you're saying, does this person need to think about antiphospholipid syndrome? Does this person need a hematologist to adjudicate if that's the right label? Because I think that's actually what we really want people to do.

And then the other is really a research tool that will also help and also help teach younger hematologists what some of the more difficult to tease apart aspects are. Thank you, that's really clear. So let's talk about the Sapporo criteria and how might you apply that or how might you just diagnose our patient who we've given you, she has a right MCA stroke, age 36 without any clear atherosclerosis or risk factors for it.

The Curbsiders (28:10.246)
Yeah, so she's almost there in terms of meeting the definition. So she has, there's kind of two buckets. We have our clinical criteria. We need one vascular thrombosis. It can be macro or microvascular, but usually it's macrovascular as we've been talking about. So venous thromboembolism, arterial clots that are not explained by atherosclerosis. Although technically, they don't actually say that explicitly that you can't have atherosclerosis in the criteria. That's how I would apply them myself.

or you have a pregnancy morbidity, and I think we'll come back to pregnancy morbidities and more depth a little bit later on. And you need that in combination with the laboratory criteria. So our patient actually qualifies as being triple positive, meaning a positive lupus anticoagulant and a titer of greater than 40 for both anti-cardiolipin and beta antibodies. And so it's that greater than 40 that we typically use to say a true positive. There's this range at most,

labs, their reference range will mark something as positive or sometimes as intermediate when it's between 20 and 40, which is super confusing for everyone and yields a ton of referrals to hematology. And that's okay. We don't want to err on the side of keeping people safe. Part of the criteria that our patient doesn't yet meet is that those laboratory tests need to stay positive for 12 weeks. I was alluding to that before. And so we need to wait 12 weeks to have the patient officially meet criteria.

However, in a patient with all three tests positive with a really compelling thrombotic event, I would start treating the patient like this now. We can always revise that diagnosis in 12 weeks, but we have to keep her safe by assuming that this is what's going on in between. And just to contrast, if she was, I guess, maybe she had like a really bad fracture in her leg and she had a clot afterwards, her anti-cardiolipin was 30, nothing else was positive.

we would still have to treat her if she had a clot, but we wouldn't have to treat her as if this was antiphospholipid syndrome. Yeah. Yeah, Matt, I get your question completely. So what I would say is that person's gonna be anticoagulated, but that person should be anticoagulated without consideration for antiphospholipid syndrome. And at a titer of 30 with a provoked clot, truthfully, I wouldn't actually even be repeating it 12 weeks, but I can take your scenario and make it a little bit thornier, which is to say,

The Curbsiders (30:29.19)
you have a person with an ambiguous clot, maybe they were on a four hour flight and you're like, oh, that doesn't, that's not that long. Like what to do with that. And they had COVID three months ago. Yeah, exactly. Like they've had that. And then they have a titer of like 42 and you're like, oh, that's not that high, but it is technically above. That's one in which you actually just have to sit down with a patient and say, hey, here's the upside and downside of treating you like you have antiphospholipid. I think.

you know, on the scenario I said to you, I'm not so sure you really have it, but here's the downside of not treating you as such. And that's a patient shared decision-making scenario when you have that person who's like really just on the edge of everything, provoked, unprovoked, their titer's high enough that you can't blow it off, but it's not really through the roof. And I will just talk to my patients and say, hey, here's the upside downside of treating you as such while we wait for your confirmatory testing in 12 weeks. And that's also a scenario in which I sometimes go off book, which

this is

The Curbsiders (31:53.09)
didn't want to take the risk upfront, but are having a hard time with blood thinners like an oxaparin or warfarin that we have to use. Paul, I like this game where we propose a scenario and the guest makes it even harder and then tells us what, this is a good game. I like it. This is my clinic. It was like if one person rolls in, the next person's gonna roll in and be the other scenario. So if there's a trainee with me, well, we've gamed it out. And there have been times where for,

continuity fall or someone else like that. They've been like, oh, this is the thing that we like hypothesized could be the next computation. You remember that nightmare scenario? This is it. No, that's the fun scenario if you're a hematologist cause you just have to understand enough to meet the patients where they are. So I want to just ask the logistics when you're testing so that the cardiolipin and the beta two glycoprotein, I think they're affected by inflammation, but if it's six weeks or 12 weeks out and they're still on warfarin,

you can test with them on the anticoagulant or do you have to stop it? So, beta and cardiolipin antibodies are serologic tests, so they're not affected by being on a blood center. So, they are run for heme and heme path and all of our special coag folks, we know that we ship these over to the serology side. Like, these are not clotting-based assays. These are usually in ELISA, but they're different.

ways to do it, but they're antibody-based tests. And so those may be affected by inflammation, but they're not affected by anticoagulants. So you can do them on or off blood thinners. Very different than a lupus anticoagulant, which unfortunately has both false positives and false negatives on blood thinners. So you have to be very cautious. You sometimes can get a clean test on warfarin because it works by affecting clotting proteins, but you have to be a little bit careful, especially like the-

more super therapeutic someone is, it's just, you should be a little wary. And if you're hanging your hat on that, I would always be happiest getting another test off of anticoagulation altogether. But it's the lupus anticoagulant that is sensitive to blood thinners. Okay, yeah. So I will definitely have a hematologist involved, Paul, if I'm messing around with lupus anticoagulant. It's one of the many tests where if I'm checking it, I am in a lot of trouble already. So yeah, I think that's right. So I think that-

The Curbsiders (34:14.558)
Maybe the most useful thing to think about it is that if you're about to start someone on blood thinners and antiphospholipid syndrome is in the back of your mind, get a specimen for the lupus anticoagulant before starting them on blood thinners so that you have one clean test. If that's negative, the future hematologist will be sending you roses saying, thank you for getting this so that I'm not having a conundrum. Because obviously if you think someone has antiphospholipid syndrome, the idea of pausing their blood thinner to prove that they do or don't have it is a bit nerve wracking.

And we usually try to do anything other than that, because if it turns out they have it, they may also be the window in which they have a complication because you stopped their blood thinner. So practically, that turns out to be things like somebody has to go for a colonoscopy or a surgery where I'm obliged to pause their blood thinners. And I don't think they're so high risk from their history that they can't pause it for that. I will have them get a test right when they're in the.

on their way into the endosuite and use it for something else. But I can't even think of the last time I asked someone to stop just for the purpose of figuring out if they had antiphospholipid syndrome because I really think they do. I'm not happy about pausing it. Okay. All right. This is good stuff. Very helpful. One other question sometimes comes up is relating to risk stratification in terms of positive antiphospholipid tests. So in terms of...

thinking about lupus anticoagulant versus the other tests, IgG versus IgM, triple positive versus double or single positives. I wondered if you might talk to that a bit. Yes, so more tests being positive is a problem. The more tests you have that are positive, the more likely you are to clot. And that's been replicated a fair number of times. The higher your titer is also something for consideration.

I have patients who have titers that are in the 1000, 5000 range. You can see why sometimes when somebody comes in with a 39 that they're like, that's close to 40. Doesn't that almost meet criteria? You'll have a lot of hematologists be like, let's not round up because we really can see patients who are truly high in that regard. And so those all take into account. Historically, studies have shown that a lupus anticoagulant is the most, if you're lupus

The Curbsiders (36:31.998)
Antibodies positive, they haven't yet gone on to clot. That's the strongest predictor of the three tests. The problem is that can cut both ways because as we've already just talked about, it's the most subject to false positives by interference from being done on an anticoagulant. So when it's done cleanly and patients are on nothing, it can be really helpful, but I'm always wary if that's the only positive test, because oftentimes when you look back, it was done on anticoagulation. And so just be with a lot of caution.

But the more tests positive, the more likely they are to clot. And the more likely we are to think that they're going to clot through blood thinners. And there's a bunch of negative things associated with that. So high titers, yes. The other thing to keep in mind is it's pretty well validated that IGG is actually more of a concern than IgM. So IgM's are more likely to not persist, and they're less likely to be associated with thrombosis. And so the scenario in which we're the most concerned is a substantially above 40 IgG.

for both tests that are IGG-based plus the lupus anticoagulant, which is by the way, the patient you gave us and why we'd be very confident from this context that she should be treated as antiphospholipid syndrome, even though we haven't waited those full 12 weeks to make the official diagnosis. All right, we're gonna move on to talking about management. I wanna try a recap, Paul. I'm pretty nervous about recap, trying to recap this one, but I'll try, I'll do my best and I'm probably gonna leave some stuff out because we've already talked about a ton.

So we've learned that this is a strange autoimmune disorder because instead of destroying its target, it activates the clotting factors. And what can make it a little confusing, at least from my perspective, is that it's a broad spectrum of disease. And so some people can have more aggressive clotting than others. We talked about ways to clinically identify like who should be tested. People with arterial thrombosis or just thrombosis that seems out of proportion.

thrombosis in weird spots like cerebral, phoenix thrombosis, splenic thrombosis, people clotting through anticoagulation, that's something that's concerning. You can look at host factors, so people with lupus or another autoimmune disorder might be more likely to have antiphospholipid antibody syndrome. We talked about how some people get identified as having antiphospholipid antibodies, but they may not have yet had a clot. These lab tests we've been talking about

The Curbsiders (38:56.598)
They recognize that a person has these antibodies that can recognize the clotting factors, but they don't tell us whether or not they're going to be activating the clotting cascade and causing thrombosis. And what we just talked about there is lupus anticoagulant is one that if someone hasn't yet had a clot and you know they have that, that might be the strongest predictor that they could have future clotting. So there's more. There's more that we've already talked about. We talked about inflammation.

can cause transient clotting. That's why we have to repeat testing. And usually that's done at least 12 weeks later. But you told us that if somebody is on warfarin and is really not going well, you might test earlier at like six weeks just to see if we can maybe switch them over to an agent that's easier to take at that time, or you said anoxaparin or warfarin. We talked about the Soporo criteria and how basically you need thrombosis, which

macrovascular, microvascular thrombosis, or you can have pregnancy complications, but then you also have to have the labs that go along with it. It's helpful to get the labs, or we really need to get the labs at the time of a clot and then 12 weeks later. And then there's these new, fancy, very specific for research purposes ACR and ULAR criteria, which probably are more useful to the hematologist than to our generalist audience.

the criteria that I just mentioned to make the diagnosis and refer them on to hematology. So anything to correct there, Ariel, if so, that's fine. The audience will learn from my mistake and then we can go on to talk about management. So first of all, that was an incredible recap. I hope you were taking notes along the way because if you did that from memory, I should give you my job. But the one thing I would say is that the false positives don't come from inflammation necessarily causing thrombosis.

though it can, they come from inflammation causing false positives in the antibody testing as well as in the lupus anticoagulant testing through different mechanisms. So it can be involved, but the concern is just those false positives can come in any inflammatory state. Okay. So with our patient here, so she's 36, she is at this stroke, and she has these triple positivity. How would you talk to her about what the diagnosis is and how you're going to treat her?

The Curbsiders (41:21.678)
So because we can always be surprised, I always do mention that we're gonna have to check at 12 weeks that we have diagnostic uncertainty because this really sounds like that's what this is gonna be, but we can be surprised and we wanna make sure that isn't confusing for the patient by being more sure than we actually are when we talk to her. So having said that, I would say, you are a person who we think this clot was driven by this unusual autoimmune disorder and I expect you to be on blood thinners the rest of your life.

I also expect that blood thinner actually has to be warfarin in the long term unless you have a clear contraindication. We have more than one study that has shown that warfarin compared to a 10A inhibitor, more commonly called DOACs, were inferior. One study with rivaroxan versus warfarin took triple positive patients. So our patient absolutely was in that study.

it had to be halted early because the breakthrough thrombosis rates were that much higher in the River Ox-Ban arm than they were in the Warfarin arm. And then the second study that's really relevant was a comparison of a pixaban to Warfarin. That was a little bit more of a heterogeneous population coming back to the point about why those new criteria were developed. Patients could be single, double, or triple positive, and they could have had historically reported labs instead of directly verified labs.

Those patients initially were actually having compared a prophylactic dose of the pixaban to warfarin and then later on the protocol was modified so it was a therapeutic dose. But there was breakthrough thrombosis at both dosage levels in patients who are both single, double and triple positive. The majority of them are all strokes. So stroke is actually the indication circling back to our patient that I'm the most diligent that you really need to be using warfarin because we have the most data.

You know, one of the points made was when that River Ox-Ban trial that was for the triple positive patients came out, all the hematologists were scratching their heads to say, okay, but what about my single positive patient? What about my double positive patient? We think overall they clot less, are they really stuck with warfarin? And then we had the second study with the Pixaban that says, this is a broader population, should we be nervous? You know, the difference in rates wasn't as high as the other study. And so...

The Curbsiders (43:41.138)
I always to all patients I'm diagnosing with antiphospholipid syndrome have to talk to them about warfarin first. That's what's evidence-based. However, I will tell you that from my side, when I have a single positive patient who has had a single thrombotic event that is more classic, so not the stroke, because that's where we've had the worst outcomes, but let's just say this is a person who's had...

a central venous sinus thrombosis, no evidence of lasting brain damage, rapid resolution of their clot or something else like that, where it's, you know, there was a good reason to test, we think their syndrome is there, but they're only single positive. I will walk them through this data as much as they can, assuming their health literacy, and say, you know, our recommendation is for Warfarin, but here's this other blood thinner, here are the things we should talk about if you start to struggle with Warfarin. Sometimes I've also had patients who have a family member who's been on Warfarin, and the second you say it, they're like,

not doing that, can't do that, won't do that. And so I just really try to make sure that they know as much as they can in making that choice. So that was a very long-winded answer, but that is actually what you have to walk through with all the patients with this diagnosis, because more than anything, you wanna motivate them to understand why you're picking everyone's least favorite blood thinner to deal with. So Matt and I, in residency, warfarin' was all we had. That's how long we've actually been doing this, which is kind of a depressing thought. And I feel like I remember at one point,

the dogma was for antiphospholipid syndrome, you actually targeted the higher INR. So you're shooting for sort of a little bit of a higher, like I think 2.5 to 3.5, as opposed to 2 to 3 for say, like H-O-V relation or sort of other less worrisome stuff. Is that, where are we, if we're gonna, if we, you know, Ariel, if we have to use Warfront, like do we have to have moving targets for INR goals too? So antiphospholipid syndrome is rare.

So always with the caveat that the studies that show this are small in number, both the number of patients in the studies and the number of studies. But when an iron R goal of 2.5 to 3.5 has been compared to an iron R goal of 2 to 3, it didn't perform any better. In those studies are actually small, they actually don't document a substantially higher bleeding rate, but I'm incredulous because we know that iron R goal in other contexts has a higher bleeding rate, that wasn't about amount of time tracked and the sample size.

The Curbsiders (45:55.958)
But to date, we don't have any data that a higher intensity INR goal is helpful for intaphospholipid syndrome patients. So I don't use it unless there's something else. I do have patients who have the unlucky situation of intaphospholipid syndrome and a mechanical mitral valve. They have an INR goal of 2.5 to 3.5, but that's their cardiology team, not me dictating it. That's actually one specific patient. I shouldn't say that I have buckets of patients in that unfortunate overlap. The other thing I would say is that we have

data for patients who are getting into a place where they have breakthrough thrombosis or they're looking more aggressively, there are other things that we can be doing to reduce their thrombotic risk. This is one my rheumatology colleagues are partners in crime in terms of managing this. And so there's data about things like adding hydroxychloroquine, if it's a sort of an outpatient slow moving concern about...

where their thrombotic process is. And then of course, in the inpatient setting with their aggressively clotting or in that catastrophic antiphospholipid syndrome scenario, first of all, in that scenario, nobody wants anybody on warfarin because they're too sick. But additionally, we know other things like use of complement inhibition with agents like Echolizumab are alternatives that have better data. So generally speaking, I don't use a higher INR goal for those patients.

What about this patient that we gave you had a stroke, usually I think of for strokes putting people on aspirin. How about the addition of aspirin 81 milligrams or two 81 milligram aspirins I saw in some, it gets thrown in there for a bunch of the different scenarios. So for this specific one, what would you do? So for this patient, I probably would not add that as well. This is one of those things I always make a decision in collaboration with the patient's neurologist.

But generally speaking, there's not a lot of data for adding it for a stroke that's thrombotic in origin to begin with. And so it's not something I do upfront. We do also start to ask, start to stack bleeding risks for those patients. And so we have to be cognizant of it. If there's a person who's had a hint of a breakthrough thrombosis or a frank one, it's one of the other things we can do. For breakthrough thrombosis in the arterial bed, that's probably the optimal go-to move.

The Curbsiders (48:09.558)
We will also say that myself and a lot of other hematologists sometimes do use it for patients with breakthrough thrombosis in the venous bed, whether that's with antiphospholipid syndrome or in other contexts. The data there is really weak. It's not data-driven. It's more that the safety data for that is relatively good, because we have a lot of patients who are on anticoagulant in a single antiplatelet. And so that versus other moves we might be tempted to make, like that higher INR goal, which has essentially been disproven and has a much higher bleeding.

rate comparatively than adding an aspirin. Those are reasons why you might sometimes add us. But for this patient, when she was being discharged from the hospital, just anticoagulation, no antiplatelet, as long as neurology doesn't feel like there was some concern about atherosclerosis that we didn't pick up. Great, thank you, that's good. So you have to think, was it arterial or venous? And they could potentially, hydroxychloroquine might be in the conversation.

aspirin might be in the conversation. Maybe, I think I also saw switching to a different anticoagulant. So that would be if someone's on warfarin, maybe you switch them to anoxaparin. Is that a move that some people do as well? Absolutely. And you can do that either because you're confident that they clotted at a goal INR or because they're clotting because they can't sustain a goal INR. So those are two different reasons. And they're meaningfully different in terms of their risk of continuing to clot when you switch them. But those are two reasons.

The two reasons why we don't just use an oxaparin upfront are one, people don't like injecting themselves. But some people actually do. I have a couple of patients, not for this indication, who are on long-term in oxaparin because they're more annoyed by the INR goal and the diet interference and testing and all that stuff than they are by the daily injections. I don't know if that's what I would prefer, but that's what some of the patients prefer. So injections are one, but the other that often doesn't get.

much attention is the fact that it can be really detrimental to bone density over time. And so that's something that if you have a younger patient and you're actually saying, I'm going to have you on an oxyparin for decades, that is something that can be really negatively impactful. And we all know how poor our treatments are for reversing lost bone density. So it's something to keep in mind. And if you are thinking about doing that for these patients, it's definitely something to make sure that they're getting bone density monitoring early on.

The Curbsiders (50:30.846)
I did not know that side effect of inoxaparin, probably because I am only using it for very short periods of a time, but that's, yeah, that is something we probably should know about, Paul. Yep. Yeah, I don't think in the hospital it's relevant very often. Yeah. But it is in the hematology office. Yeah. Okay. So I think we do want to get a little bit to the obstetric.

you know, antiphospholipid syndrome. So, Malini, can we, why don't we move to the second case and then we can swing back and if we missed anything else in treatment, we can swing back and cover it there. Sounds good. We still have our patient, Ms. L. She's coming back to you in clinic about a year later. She's been on warfarin as we talked about. Standard intensity, hasn't had any recurrent strokes or other thrombotic events, has some residual left-hand weakness and facial droop, but has

And she tells you today that she's hoping to become pregnant. So I wanted to ask you first about what is the risk of a recurrent thrombotic event during pregnancy for patients diagnosed with antiphospholipid syndrome? So to start with, if the patient is on appropriate anticoagulation for all of pregnancy, the risks are relatively low. This patient has not had a clot since she was on anticoagulation. That's the most important data point. Because if she had a peri...

a history of recurrent clots, we would be in a really different place. So recurrent clots, well, then the risk is high because the risk was already high before we stacked a pregnancy risk on top. But single thrombotic event has done well with anticoagulation. Risks are relatively low. They're not nothing. And it's really hard to quantify because there is such heterogeneity with antiphospholipid syndrome that I've never, I don't want to quote statistics.

because every patient is a little bit different in the spectrum just as I started to characterize this one. Where was her clot? How big was her clot? What are her deficits? And all those considerations. What is the age entering pregnancy? Is there gonna be need for anything to help get her pregnant in terms of exogenous estrogen being added into the mix? And so there's a lot of different factors that come into that, but just the pregnancy itself, if she's done well, relatively low risk. Now, I also wanna point out that

The Curbsiders (52:47.786)
Low risk is a really subjective term. Some people have been through a lot, might say any increased risk, they're not willing to take it. And some people might say, as long as you don't think I'm guaranteed to die, I wanna be pregnant and I wanna have a kid. So that's something you also really have to approach when you talk to patients about pregnancy in this context. But the risks come in two super different flavors. And I think that that's actually what usually the conversation centers around. The risks of a recurrent clot are relatively low.

but there is also the concern about pregnancy loss and especially preeclampsia spectrum disorders, which are one of the classic manifestations of antiphospholipid syndrome to begin with, and even with measures, there is an increased rate of those going on. So basically they have to think about not only is there risk of clotting during pregnancy, but they might also be at higher risk for things like preeclampsia or other pregnancy complications. And...

whether or not they've done well after their initial clot tells us a little bit about their risk of clotting during pregnancy, but not necessarily their risk for preeclampsia or something like that. Yeah. And I think one of the things that can make it a little bit complicated is that we talked a little bit before about the antibodies and the special property in terms of testing. But one of the reasons that we think that antiphospholipid syndrome has such a strong

preeclampsia spectrum disorders, is that there is a subset of antiphospholipid antibodies that in addition to interfering with the clotting cascade can recognize placental trophoblasts. I'm sure that was not a phrase that people expected to hear on the podcast today. And I won't paint myself as an MFM or anything. But the idea is that these are the cells that grow the structure of a placenta. And so we know that abnormally structured placenta to...

put it down to an internal medicine level from an OB level, is the underlying issue in the majority of preeclampsia. And so with that, the fact that these antibodies can cross react and inhibit the normal growth and then development of the placenta is what the connection is. That also explains why there's a subset of women who have preeclampsia spectrum disorder issues and never go on to clot because they may, the antibodies, it's like a Venn diagram.

The Curbsiders (55:02.794)
you may have antibodies that recognize both placental trophoblasts and the coagulation cascade or one or the other. And so it's only in the ballpark about a third of women who have had obstetric APLS only, like it's only messed up their pregnancy, they've never clotted in their own bodies, actually go on to ever have clotting in their own bodies. And so it's a different physiology when you have obstetric APLS. Paul, you looked...

You looked like you were going to say something. No, I'm just curious about this. I think I assumed it was a vascular phenomenon. I feel like, why am I just hearing this or knowing this now? So that's incredibly helpful. Yeah, I think it explains the troubling mystery of why women who have only had pregnancy complications aren't anticoagulated after their postpartum period. And it's because we're actually not so sure that they're at risk forever doing so. Otherwise, that seems a pretty cavalier move. But that is the standard of care. If you've only ever had.

obstetric complications and you've never clotted a maternal circulation, there is not an indication for ongoing anticoagulation after the postpartum period. This difference in physiology is the why that's rational to pursue. Right. So for her, what would she be on? This is our patient who has prior stroke. She's on warfarin at baseline. So what would she be taking during pregnancy?

And then for six weeks after pregnancy, which I guess is the postpartum period, it seems like we're still giving treatment. Yeah, so she needs to be switched to an Oxyparin. Basically the ideal is before conception. If it's not before conception, it should be the moment that she knows there's a positive test. Warfarin is a known teratogen. It crosses the placenta. So we know that the higher the number of milligrams the pregnant person is taking.

the more likely also there is to be teratogenicity. And so when we know there's a scenario in which someone is trying to get pregnant, that person needs to be switched preemptively to avoid that. We have many decades, I think we might be cruising in on 60 years of using an oxaparin, but that is older than I am. So someone can in fact check me on the exact number of years. But one of the things we know in addition to the fact that it's not teratogenic is it actually also doesn't cross the placenta.

The Curbsiders (57:16.414)
And so you're not anticoagulating the fetus. So it's not just that we're avoiding tratogenicity compared to some other blood thinners. We're also avoiding anticoagulation and bleeding risks, which is not so important during pregnancy, but is really helpful at delivery. So our patient, we've already committed her to lifelong warfarin, so I imagine we would switch her back after the pregnancy at some point. Are you adding aspirin during the pregnancy as just like a preventive measure?

Yes, we had mentioned through the postpartum period, but really what it is, is that when ready postpartum can switch back to warfarin. Warfarin is actually okay when breastfeeding, so that is an option when switching back to breastfeeding if that's a question you get from the patient. But we would be starting aspirin and that's actually less about maternal circulation and more about preeclampsia prevention. There's an increasing use of that for a host of different indications, including some OBs will buy into using it for most women over 35.

things like having had COVID during pregnancy raises risk. So there's a lot of different reasons we're seeing low dose aspirin being given in pregnancy. And it was something that we would add for preeclampsia prevention during pregnancy. Okay. So I think one of the last scenarios we wanted to ask you about, cause we're, you know, we've been talking for around an hour, wanna be respectful of your time.

this is get we're getting deeper and deeper into like, you know, very specialized stuff that, that we don't see as often. So let's just start with a new patient and talk about like, what would it take for if we had another 36 year old woman, what sort of pregnancy complications would get you concerned that she has antiphospholipid syndrome or obstetric antiphospholipid syndrome?

Right. So backing up, I think we were talking about the spora criteria. We went through kind of what the vascular thrombosis criteria were, but then there's the pregnancy morbidity. And so the pregnancy losses are in three different buckets. Basically, there's a lower threshold if it's a more characteristic timing, which is to say that if you lose one pregnancy, and it looks like it's a complication of preeclampsia spectrum disorder, or

The Curbsiders (59:32.066)
there's things like placental insufficiency all coming back to that shared physiology. Just one time does that have to happen in order for that to be considered sufficient to make the diagnosis. Then there's the kind of the second tier, which it's still just one loss, but it's a morphologically normal pregnancy that's after 10 weeks gestation. And that's the second option on how to get there. That one is something that is got a lot of other explanations. And so it's not quite as much of a

definitive connection, but we can understand why, again, circling back to the idea of like, what do you wanna put your patient through to make the point, why it's difficult to make the criteria more stringent. And then there's the least reliable, in my opinion, criteria in pregnancy, which is three pregnancy losses. One thing that is usually skipped in referring physicians is that they're supposed to be consecutive.

If you have two pregnancy losses, a healthy pregnancy, and then another pregnancy loss, and that interceding pregnancy was not treated as though you have antiphospholipid syndrome, that actually doesn't meet criteria. And I think that that's worth remembering because this is a difficult bucket that has more likely to have other explanations than this one, but they are supposed to be consecutive. So three losses before 10 weeks gestation.

In my opinion though, one thing I do in my practice sometimes is get a little bit careful about the timing when there's a person who's trying to get pregnant and we have chemical only pregnancies. I have a harder time counting those towards the three because if you have just a positive HCG and never see even a gestational sac, I don't understand what the physiology is that would link that back to antiphospholipid. It's not that I discount those because they do definitely meet the official criteria, but if that's the only flavor,

I am more skeptical that interceding and adding in coagulation is going to change the picture. And because that's a really emotional place for patients to be in, I try to be transparent about my degree of confidence in the causality. Yeah. So I still think it's always going to be hard to get that history very clearly. You can just see how it'd be a murky if you're counting, trying to count multiple consecutive losses.

The Curbsiders (01:01:55.318)
Well, as an example, so I had a patient in clinic who was referred for a question of antiphospholipid syndrome. She had five pregnancy losses if memory serves, and that sounds really impressive. She also had nine kids. Um, and so as a percentage of pregnancies, that actually wasn't that high. And she had some of those losses at over 40 years old, which

not to be ageist, we know that is also a risk factor for losses and chromosomal abnormalities and also had not had testing of the tissue and the miscarriages that I was able to actually access and see. And so that would be an example of like why it gets to be very difficult to apply the criteria. So if you had a patient that you were convinced that they did have...

um, more than three consecutive losses or we had placental tissue and we, we thought there was abnormality there consistent with, um, a pregnancy complication for a future attempt at pregnancy, what would they be taking? Let's say they don't have any history of thrombosis. They just have these pregnancy, um, complications. Yeah. So without a history of thrombosis, there is more leeway in the guidelines in terms of what one does. I will tell you that.

everybody would put that person on aspirin, again, preeclampsia prevention, aspirin's super important. Technically, some guidelines will tell you that you can put that person on anticoagulation only postpartum, and some will even include in that whether or not the patient gets a C-section. Other guidelines, and this is what I do, will put that person on prophylactic dose inoxaparin from the start of pregnancy through six weeks postpartum.

The rationale for me erring on the more interventional side of that, which for people who know me, is not generally what I pick. I'm an undertester and an underdoer in general as my default in the cognitive bias that I have to counter actively. But in this context, the rates of bleeding are so low. We're talking low single digit bleed rates. And it's really actually quite easy for an experienced.

The Curbsiders (01:04:10.126)
collaboration between Heme and OB to get patients through epidurals without issue, delivery with no issue, that there's really very little downside other than the injections for the patients. I am transparent and try to make sure they feel empowered about what to do, but most patients who are pregnant and want to keep a pregnancy don't want to do the experiment of seeing if they can get away without something like that.

Preeclampsia is also not just about the pregnancy loss. It can be something that jeopardizes the life of the pregnant person. And so for both reasons, this is a space where I feel pretty comfortable airing on the upper end because it's just not that aggressive. Okay, so we talked about the two scenarios. So if someone's pregnant and they've had a prior clot, then they're gonna be on inoxaparin at a therapeutic dose. And then they'll be getting aspirin for preeclampsia prevention.

And then if somebody has had obstetric or pregnancy complications and we want to treat them, everyone's going to get aspirin again for preeclampsia prevention. Some people would just do anoxaparin postpartum only, but because the risk of bleeding is on the lower side, you could put them on just the preventive dose of anoxaparin throughout the whole pregnancy. And Ariel, it sounds like that's your practice to do that.

We just had a couple of questions we thought of that we missed as we were going through the cases here. One would be like, let's say that first patient who had prior thrombosis and she needed to go for a colonoscopy, she's on warfarin, how do we handle that? Or if she was just going to go for any kind of surgical procedure, what's the best practice there? Yeah. So for any break in any coagulation for someone with antiphospholipid syndrome, you want to make it as short as possible.

How short always is negotiation between whoever is taking on the bleeding risk, which is never me and I always have to have a lot of respect for whether it's the GI doctor or the surgeon taking them in there. I don't have to deal with it and I don't get to see what they're seeing. And so I always want to be collaborative about choosing that window. But step one is always as short as possible. Oftentimes for a colonoscopy, if it's just a screening colonoscopy and not a diagnostic one where we're ahead of time expecting biopsies.

The Curbsiders (01:06:28.502)
we may for a higher risk antifasciolid patient, we actually send them on anticoagulation, work with GI and take them back in a different scenario if there's something that they need to take. Some of our advanced endoscopists are amazing, feel comfortable doing the smaller palpeptomies on anticoagulation and that's one moment of collaboration. But if they have to break for it because that's the safe way to do a procedure we do. In terms of that, this is one of the times where I'm extremely lucky to work with an incredible

credible team of pharmacists who do all of the hard work of actually communicating this to the patient, to the procedural team, making sure it actually happens. But we'll bridge them on and off is the answer. So if you have a patient going for a major surgery where they really need to have no any coagulation in their system during the surgery, they will hold usually in the ballpark of a week in advance the warfarin. When their INR gets low, they'll go on an oxyparin so that can be reliably held right before surgery, minimize that window, and then bridge back on after.

The key part here is meticulous bridging. There's a lot of patients we sort of like half-heartedly bridge on and off of warfarin when we do things. And this is not that patient. If you really think that this is the diagnosis, they need that neurotic bridging to get them through it. Thank you. All right, I'm sure that'll help Paul and I and some of the listeners when we...

Fortunately, I don't come across this too often, but it does come up. It always seems like it comes up, Paul, when you're in the teaching clinic, right? Where the resident's like, I have this patient, antiphospholipid syndrome. What should I do with their anticoagulation? So thank you. Also, it's Friday and the procedure's on a Monday. I will say that the actual thing that you want to do is probably page their hematologists, even if it's Friday at 4.9. Oh, I always do.

I will tell you, I don't know a hematologist who feels happy to find out after the fact that someone's changed the anticoagulation for an antiphospholipid patient, even when they've done it perfectly. It's very anxiety provoking for us to hear that we haven't been involved in that conversation. So I think this is your license to harass any hematologist taking care of an antiphospholipid patient if you think that there's an anticoagulation management decision to be made.

The Curbsiders (01:08:40.034)
Paul, I believe our perioperative chief, Dr. Avitala Glasser gave us that advice, basically. This is one where you want the hematologists involved when you're, because they will be bridging and you should have them involved with it. So we got that. All right, Molly. Thank you, that's really helpful. One other question that might come up in primary care is for patients that have had a positive antiphospholipid.

anybody lab testing but have never had a thrombotic event, what the role for aspirin is in primary prevention. I love your thoughts and what the data is on that. Yeah, so speaking to some of the tests we did before about what are the highest risk properties. So people have persistent positive tests with prior obstetric APLS, or if they have a positive lupus anticoagulant, there's a few different factors. Those are at the top of the list of reasons to put them on aspirin as prevention.

triple positive patients, especially higher titer triple positive patients. The truth is that there's not any randomized data about this. So we don't really have clear cut data that this is the right path. And I would emphasize that this is really about what predicts future clotting and what makes us feel like we're not being passive when there's a risk on board. So I would always take that into consideration in combination with

is this a person who's 65 and also already has hypertension? So maybe those aren't criteria yet to put someone on aspirin, Paul, please help me. But knowing that that's the case, but maybe this tips them over. And I think that there's a lot to be said there about being humble, but I would say that in my personal practice, if I have a triple positive patient, I do put all of those patients on aspirin. And if I have a patient with a prior history of obstetric.

APLS, I will talk to them about whether or not they want to be on aspirin in the long term. And that is something that is really variable people's reaction to. So I don't necessarily try to predict and the thrombotic rates aren't high enough that I feel like we're doing a bad thing by not putting them on aspirin, as well as it's not clear that we're going to prevent their outcome with aspirin in a lot of the situations. Thank you for all this teaching. To leave the audience with a few take home points that you really want them to remember.

The Curbsiders (01:10:59.326)
Now is the time. So what do you want them to know? So I'd say something we've repeated a few times, but picking the right person to test, because we've talked a lot about the problems with the false positives, but we also don't want to miss the patients who really have this and wait for that second thrombotic event that proves that there was something different about them. So the right person is someone with no evidence of atherosclerosis who's clotting in an arterial bed, no other explanation. It's an unusual site thrombosis, like in the brain, splenic.

It's a person who has these pregnancy losses, it's a person who's clotting through anticoagulation, or it's a person who has a strong history of an autoimmune process, or gives you that concurrent presenting history that's there. The second point is, we've talked a lot about the testing and why it's sensitive but not specific, because it only tells us that the patients that has these antibodies that recognize the proteins, but not that they have the special property to force thrombosis.

And that's why we have a lot of patients who don't make the cut in terms of the diagnosis. The next point I'll make is if you do think that you've tested the right person and they have a true positive, manage them on inoxaparin or warfarin or whatever your available low molecular weight heparin are is if you're not in the US until you've proven they don't have it in that regard.

Obstetric APLS, as we keep talking about, has a different physiology, and that's why a lot of the patients don't have to be on lifelong anticoagulation. And finally, something I've hinted at, touched back when we were talking about the colonoscopy procedure, is that there's a lot of thrombotic conditions, classic provoked VTE, not all those patients need a hematologist. Every single antiphospholipid patient should have a hematologist. That is not true of most thrombosis, but it is true of this.

And ideally it would be someone who's focused on classical hematology and sees a high enough volume to know about some of these nuances because it is really heterogeneous in and of itself. So if you only see a couple cases, you may not realize all of the finer points. And so much respect for my colleagues in general hematopoietic practice because you have to know a million things. And I've forgotten everything about breast cancer that I was ever taught in fellowship. You don't have to tell.

The Curbsiders (01:13:16.27)
Paul Williams twice to refer to a specialist if he feels out of his depths. He is, right Paul? That's your move. Standard care maybe. That's what the patient's taking care of. It's never wrong, obviously, to send anybody if you're looking to help your patient. I'm just not troubled when I find after the fact that someone had a DVT 15 years ago and didn't meet a hematologist when it was after a knee surgery and they were on anticoagulation for three months and then.

They were told you'll need extra care after other surgeries in terms of prophylaxis. Like that was a perfectly managed patient. Maybe they don't have to meet me. Happy to see them, but not all of those patients have to meet me, but these patients have to meet me. All right. Thank you again so much. We have to let you go so you can get back to your family, but we really appreciate all your time, all your teaching. Well, thank you so much for having me today.

The Curbsiders (01:14:12.15)
This has been another episode of the Curbsiders bringing you a little knowledge food for your brain hole. Yummy! That was nice! I like that one. Still hungry for more? Join our Patreon and get all of our episodes ad-free plus twice monthly bonus episodes at patreon.com slash curbsiders. You can find our show notes at thecurbsiders.com and sign up for our mailing list to get our weekly show notes in your inbox. This includes our Curbsiders Digest, which recaps the latest practice changing articles, guidelines and news in internal medicine.

And we're committed to high value practice changing knowledge. And to do that, we want your feedback. So please email us at askcurbsiders at gmail.com. We'd also love it if you could subscribe, rate and review the show on YouTube, Spotify, Apple podcasts really does, really does help people find the show. When you do that reminder that this and most episodes are available for CME for all health professionals through VCU health at curb

The Curbsiders (01:15:05.058)
Wanted to give a special thanks to our writer and producer for this episode, Malini Gandhi, and to our whole Curbsiders team. Our technical production is done by the team at PodPace, Elizabeth Proto runs our social media, Krista Chu-Man Chu moderates our disc chord, and Stuart Brigham composed our theme music. So with all that, until next time, I've been Dr. Matthew Frank Wadden. And I've been Malini Gandhi. And as always, I mean, Dr. Paul Nelson-Williams, thank you and goodbye.