How do we manage thrombogenicity and thrombosis in the Fontan? New Horizons...

But I think, uh, in order to understand really that balance, we need Doctor Palambo's insight, um, uh, on the thrombogenicity, uh, and, uh, thrombosis in the content. And Joe and I have worked, um, uh, over a period of time trying to wrestle with many of these issues. And, uh, Joe's view about the heart, I'm sad to say, is that it only exists. To support the coagulation cascade and coagulation system. Joe, uh, you are very misguided, but I'd love to hear what you've got to say on the subject. Thanks. Well, well, thank you, Grushed. I, I think, uh, so I, I have just a, uh, a few disclosures. Uh, I have received basic science, uh, research funding from Nova Nordisk in the past, but it is unrelated to this talk. I am currently serving as the institutional PI for a phase 3 trial of rivaroxaban in pediatric patients. And I am not a cardiologist. I'm a pediatric hematologist, so, so please don't ask me any hard questions. Um, I, I think we need to start off by agreeing on the fact that Fontan's circulation can be a profoundly prothrombotic state. Thrombosis is a major cause of death in patients with Fontan's, and many of the thrombotic events that these patients suffer are subclinical, but just because they're subclinical does not mean that they are clinically insignificant. And, and just to give you a a flavor of that, this is um one paper that strongly suggested that the incidence or the prevalence of silent pulmonary embolism in adults with Fontan circulation may be as high as 1 in 5. And uh this is data from Paul Monagle's study comparing aspirin and warfarin, which I'll talk about in a little bit more detail in a minute, but I just want to point out that this is in newer style fontans. And these patients had an overall cumulative risk of 22% for thrombotic events. So these are common and potentially devastating events in this patient population. And this is a very interesting study by uh by uh Carrie that showed what happens with the major complications surrounding Fontane's circulation over time. And I just want to highlight. The fact that the cumulative hazard risk of thrombotic events goes up over time in these patients, and I also want to point out this, this S-shaped curve in this plateau here. I'm going to come back to this over time. I'm going to come back to this in a minute, but over time, Fontane's circulation becomes essentially a freight train of thrombogenicity. How does it compare to other thrombophilia that I would care for as a hematologist? Well, it, it ranks up there with things like paroxysmal nocturnal hemoglobinuria, which is a horrifically thrombogenic disease carrying a risk of 30 to 40% for thrombotic events over a 5-year period. It compares to antiphospholipid antibody syndrome, which has a very high risk of thrombotic events. And I think it, it also compares in many ways to patients who present with unprovoked venous thromboemboli, who have a recurrence rates in the 20 to 30% range. So just keep this in mind as we move forward. So I, I want to toss a case out there just to be a bit provocative, and you guys can go ahead and launch my, my first set of polling questions around this case. This is a 2021 year old with a fontan, um, who also has mild PLE. He's currently on low dose aspirin and he has a superficial thrombophlebitis of the saphenous vein following what is really pretty minor trauma, and this is his laboratory evaluation. He's got a very high factor 8. He's got a really remarkably elevated D-dimer in spite of what is a pretty small clot, modestly low 7, and a modestly elevated PT that makes sense with that mildly low 7. So what would, what would folks do here, and I'll just let you digest that while we move forward. So why is Fontan's circulation such a thrombophilic state? Well, I thought here that it might be useful to go over in detail the coagulation cascade, and then I thought at least half of our audience is going to take a hammer to their routers, so we won't do that. So, I'm gonna try to break this down more like Virkow's triad. So, of course, unfavorable anatomic functional characteristics related to the heart anatomy matter here, but I'm not gonna talk about this because as I said earlier, I'm not a cardiologist. I wanna talk about these, the two points on the triangle. So. Endothelial pathological endothelial activation, I think, is a very important part of the thrombogenicity in fontans, and this was, this is really multifactorial. Relative hypoxia and loss of pulsatile flow, particularly in the venous system, is very thrombogenic when it comes to endothelial cells. It will result in Um, upregulation of tissue factor expression, which is the primary initiator of the clotting cascade, upregulation of important adhesion molecules that can then activate inflammatory cells, and also increased excretion of factor 8 and von Willebrand's factor. This is going to result in activation of the inflammatory system. PLE, as all of you know, is a serious potential complication of Fontan circulation that is going to result in increased inflammatory system activation, and all of that is going to feed into activation of the hemostatic system, which can then be worsened by liver synthetic dysfunction which can develop over time in these patients, ultimately all of this culminating in a highly increased thrombotic risk. So what constitutes optimal thromboprophylaxiss for patients with Fontan's? This is that age-old question that philosophers have argued over for decades, aspirin versus warfarin. I don't think it's a really simple either or question. So, I, I think the data does overall support that in general, warfarin is a better thromboprophylaxis in this setting than aspirin. I, I'm sure many of you or most of you are familiar with Monogle's paper that initially showed that there was really no difference between aspirin and warfarin, but this data was um a reanalysis of that. And it separated out patients who had well controlled warfarin. The time in therapeutic range was 60% or better versus poorly controlled warfarin. And here warfarin was starting to edge out aspirin over time. And this is retrospective data from Cedric Manliot's group that showed that warfarin was, at least in this retrospective report, clearly better than aspirin. But of course I would point out that both were significantly better than no thromboprophylaxis thromboprophylaxis. So, given that warfarin is probably better overall, maybe one simple answer is to simply commit to that. Oh, I, I wanted to briefly touch on time and therapeutic range. An excellent time and therapeutic range above 80% is possible. Both our hematology group and the cardiology group achieved this. And this is data that Grushin recently published showing that in patients with this excellent time in therapeutic range, they observed only one thrombotic event over 53 patient years. So this sort of excellent time and therapeutic range with warfarin is achievable using what amounts to a very paternalistic approach with aggressive monitoring and aggressive phone follow-up. Having said that though, I want to toss out another potentially provocative case. This is a 10 year old boy who has Fontan's circulation, and he has what is described as excellent heart function. He is on low dose aspirin, and he recently found out that he is heterozygous for the factor 5 Leiden mutation. He ended up being tested because of a maternal aunt who was diagnosed with a DVT following knee arthroplasty. But neither the patient's mother nor grandmother has any history of thrombosis, and both are in good health. And this little guy is very active and participates in many sports. So what really is the best option for him? So I'll let you digest those questions while we move on. So as I alluded to earlier, one simple option here is just simply commit every patient with a fontan to indefinite therapeutic anticoagulation. But this does carry a significant bleeding risk. Even with well managed anticoagulation, the bleeding risk is going to be around 2% per year. As you all know, warfarin is very problematic from a pharmacokinetic standpoint, and poorly managed warfarin may actually increase thrombotic risk. The direct oral anticoagulants, or some of you may know these as the new oral anticoagulants such as rivaroxaban, apixaban. Seem to be superior to warfarin in many ways but are completely unproven in Fontan patients, and I'm gonna touch more on these later. And not every patient is going to readily accept the lifestyle limitations that have to come with therapeutic anticoagulation. So is there another more personalized approach? Well, this is very interesting data that's come out of several papers, including uh Monocle's report in that earlier paper I showed you that the thrombotic risk. In patients with a with Fontan circulation follows a bimodal incidence. There's an initial risk that is post-surgical, but then there's this honeymoon phase that can last a variable amount of time, and then there's an inexorable increase in thrombotic risk. But this honeymoon phase can really vary, and the question is, can we predict when this is coming to an end? And while this needs to be studied in more detail, I think the short answer is that yes, maybe we can. So there are established. Biomarkers of thrombophilic risk that have come from the adult literature and particularly for patients who've had unprovoked venous thromboembolism, and I'm just going to show you some examples of that. So this is data showing that an elevated D-dimer is a really strong marker of increased thrombotic risk. And so is an elevated factor 8, and factor 8 can be elevated because of multiple reasons. This can be genetic, but factor 8 can also, as it's made by endothelial cells, be a marker of endothelial cell activation. It's also an acute phase reactant, so it can be a marker of inflammation, both of which I think are major contributors to the thrombogenicity in the fontan. These factors and other factors like this have been looked at in Fontan patients in limited numbers. Here's a study where they showed that factor 8 activity increases significantly post Fontane, and I would highlight these 4 patients in this study that had the highest level. The patients here with the asterisk are the patients that ultimately went on to develop thrombotic complications during the course of this study. Now this is a rather busy slide, but I just want to highlight that in general in patients post Fontan, the natural anticoagulants that are liver derived, such as antithrombin and protein C, are often lower, and this is consistent with the fact that these patients develop liver synthetic dysfunction over time. Uh, and in this study as well demonstrating that factor 8 tends to be significantly higher. Now, the liver synthetic dysfunction, of course, will result in lower levels of the procoagulants as well. But despite this, these patients actually have elevated prothrombin fragment 1.2, which is a very sensitive and specific marker for prothrombin activation to thrombin. So in spite of the fact that these patients have lower procoagulants, they are not really at bleeding risk. They are, based on this anyway, at risk for thrombosis. So Fontan's circulation, even in the context of liver dysfunction, is shifting the hemostatic balance towards a thrombophilic state. So given that there are potential biomarkers that can predict risk of thrombosis, and I think do so in these patients, maybe what we could do is just check all of these labs and you'll be able to figure it out. Yeah, uh, clearly we, we need a little bit more of a, a limited approach. So I think we need to go back to what I think represents the, the major risk factors, uh, the major extra cardiac risk factors for thrombosis in these patients, the endothelial activation and the inflammatory system activation and the liver dysfunction. So, obviously, all of these patients need a very detailed history, particularly a family history, um, but I think that these particular labs could be helpful in predicting who is at risk over time. Um, and these were alluded to earlier in the talk about pregnancy. I put these up here as well, not in bold, because I think these are also possible markers of increased risk but need to be studied more over time. Uh, and I think that that doing this perhaps on an every 6 month basis can predict when that quote unquote honeymoon period of relatively low thrombotic risk is coming to an end. So having said all that, what would I have done with these patients? So this 21-year-old presented with what in another context would have been a very low risk clot, something that you could probably just treat with warm compresses and ibuprofen. But looking at his laboratory evaluation, I think this is somebody who is becoming very thrombophilic and a discussion. About switching to warfarin is needed here and the key here is discussion because all of this has risks and benefits, and I think we need to bring the patient's goals and desires and, and a frank discussion needs to be had. Now, our little guy who is heterozygous for factor 5 Leiden but seemingly and has a fontan but seemingly has no other risk factors. I think eventually, sure, he is going to end up on anticoagulation and a discussion here about uh having his parents move him towards non-contact sports is probably reasonable, but I think for now, he's probably fine on aspirin. Andruschen had mentioned the aspirin Verify now, we rely on that a lot. Uh, I, we find that to be an extremely reliable and reproducible test that the patient is taking their aspirin and having an antiplatelet response. What platelet resistance units are optimal in the Fontaine is not entirely clear, but at least it tells you that they are having an anti-platelet response. So I think it can be very, very helpful. I think in a patient like this, additional comprehensive thrombophilia testing, as we had discussed, can also be very helpful to look at other acquired risk factors, but I think for somebody like him who's doing so well. He's probably gonna be able to stay on aspirin for a while. And I know people in the audience are going to have questions about the DAX. I think the most important take home message here is that we need data. These need to be studied in the Fontan population before we can really say how good or bad they are. Maybe this is the treatment of choice if all you're worried about is atrial fibrillation, but honestly, in a Fontaine patient, I think it's pretty uncommon that that's really all you're worried about. Um, as has been pointed out, this is a, uh, this results in systemic pathology. One major thing we need to be able to start using these drugs more routinely in the Fontane population is the ability to monitor them reliably. The companies that made these have really hang their hat on the fact that they don't need to be monitored in otherwise, uh, in patients with otherwise normal organ function, which I think is great, but as you all know, organ function can change very rapidly in patients with the Fontane, so we need to be able to monitor these, and not all labs are capable of doing these. Um, These agents are most likely better than poorly controlled warfarin, but as I pointed out, uh, high time and therapeutic range is achievable with warfarin in most patients. So with that, I'm gonna end and I'm gonna leave you with what I think is a very beautiful picture. That's the crystal, that's a model of the crystal structure of fibrinogen, and I'll be happy to take any questions. Thanks very much. Thanks very much, Joe. Um, it's a very stimulating talk.