Well, I think it's time for round two. So, Jean, I'm going to ask you to come on up, and we'll get going and thinking a little bit more about the coagulation cascade, and in particular, what's this whole thrombosis versus hemostasis differentiation? Delighted to be here. Let me start. I'm delighted to discuss this. I was once told, as a fellow, never show the coagulation cascade. You'll put people to sleep, and here we are, I won't say how many years later, delighted to be able to discuss. So I'm going to jump right in, and basically, I have two parts to this presentation over the next 10 minutes. One is to review the coag cascade and the role of 11, and then discuss data from natural history of what happens to factor 11 deficient patients, and why does that hold promise for inhibiting 11 as an anticoagulant strategy. So this is a coagulation cascade, and if you look at the copyright on this slide, it's been there for a long time, and I've used this slide for a long time. The coag factors were identified in the 1960s, 1970s. These are soluble proteins that float around in the plasma in an inert form, and they have to be activated. And so we have what was called the intrinsic pathway and the extrinsic pathway. I thought this was potentially, there we go. So intrinsic, extrinsic, and the common pathway, as Kristen already alluded to, 10, 5 is a cofactor, prothrombin, which is factor 2, and fibrinogen, which is factor 1. Now for many, many years, it was thought that the intrinsic pathway was the end-all, be-all, and that's what drove hemostasis. I'm going to stop for a second and just briefly tell you how we measure in vitro in clinical practice the intrinsic pathway and the extrinsic pathway. Because there are differences that are key to understanding, I think, some of the factor 11 inhibitor trial data and how they may work. So the activated partial thromboplastin time, you know, take the patient's plasma, put it in a test tube, add an activator, and you get clotting in the test tube with, you know, average 24 to 37 seconds. The extrinsic pathway monitored by the prothrombin time, add an activator, a lot faster generation of thrombin, right. What's the difference between the activators? The thromboplastin for the PT, that is actually a combination that used to be way back in the old days, schmoozed up sheep brain. It has tissue factor plus phospholipids. The APTT is phospholipids alone and an inert activator. So keep that in mind when we talk about these different pathways. Now as I alluded to, the intrinsic pathway was thought to be the driving force for hemostasis until about 25, 30 years ago when it became recognized that actually no, tissue factor and the extrinsic pathway were really what drives hemostasis in the setting of vascular trauma. And the reason it wasn't recognized is because tissue factor doesn't circulate in the blood. So when you look at this cartoon again from the New England Journal, you can see that tissue factors in the media and adventitia, you have to break through that wall to expose tissue factor. Whereas in some pathologic conditions, all you need to do is get rid of the vascular endothelium through shear stress, through other similar mechanisms and expose collagen, which binds VWF and platelets. But tissue factor-mediated activation of factor VII is critical for hemostasis in setting of surgery, trauma, childbirth. So this is another New England Journal cartoon that came out January of this year in an editorial accompanying the publication of the Abel Asimov AFib trial data. And all of us, many of us who work in this field have done some sort of similar depiction for a review article or an opinion piece of paper, minds in blood advances, right? But of course, New England Journal artists do it best. And so we have hemostasis on the left side. We have thrombosis on the right. And so we see vessel injury and we see that breach in the vascular wall that exposes tissue factor drives very rapidly and locally activation of tissue factor. Factor VII becomes activated when it binds tissue factor and drives down to cause a hemostatic plug. Whereas, in the end there's a little bit of feedback here. We can talk about that because if we inhibit factor XIA, we don't get this circling cycle of thrombogeneration XI and thrombogeneration again. When we look at pathologic thrombosis, right, so this is physiologic hemostasis, pathologic thrombosis, we can have those atherosclerotic plaques that the cardiology world is familiar with. We can have artificial surfaces of medical devices, inflammatory debris that activate XII and XI and drive this pathway forward and end up with pathologic thrombosis here. So the question that's actively being investigated right now in clinical trials, which is just astounding to someone who was told that they couldn't make a living doing clinical COAG when they were a fellow, is can we truly separate physiologic hemostasis from pathologic thrombosis in vivo? It's a very exciting time for coagulation. And Kristin alluded to this somewhat, but I'm going to show like why would XI be better than our current anticoagulants? So when you look at VKA here, we knock off four factors, right. We inhibit the extrinsic or tissue factor pathway by knocking down activity of 7. We inhibit the intrinsic pathway knocking down 9. And then we get both common pathway factors, 10 and 2. The direct oral anticoagulants have been a great advance where you target either 10A or 2A. And you can see pictorially here that there's much less bleeding when hemostasis is needed with the DOACs compared to VKA. The hope will be that by inhibiting just XI on this side and inhibiting pathologic thrombosis, we can allow this rapid drive of tissue factor, binding 7, generating thrombin at the site of vascular injury, plugging the hole and done with it without pathologic thrombosis. So what do we know about patients who have Factor XI deficiency and inherited or congenital Factor XI deficiency? Well roughly 1 in a million in the general population will have Factor XI deficiency. There are definitely founder mutations in populations that are listed here. And particularly in the Ashkenazi Jewish population, roughly 1 in 10 have been calculated to be heterozygous for Factor XI mutation or deficiency, and 1 in 450 homozygous or compound heterozygous. More than 190 pathogenic mutations have been identified in these various groups. Patients with congenital Factor XI deficiency have no spontaneous bleeding. This is absolutely amazing. Because unlike hemophilia A, which is deficiency of Factor XI, or hemophilia B, which is deficiency of Factor IX, these patients do not have spontaneous bleeds. They don't have spontaneous joint bleeding. They don't have trauma if they sit too hard on a sharp object or bang their leg into the coffee table. And it's also not like Factor XII deficiency, which has no bleeding phenotype whatsoever. You can have patients who have no detectable level of 12, and they would never know, except they have a PTT of like 90 to 120 seconds, they never bleed. Patients with congenital Factor XI deficiency can have some surgical or trauma-related bleeding. So we know that XI is inherently important in maintaining hemostasis to some degree. It's primarily found in those with severe deficiency. I have patients in my clinic who have no detectable Factor XI activity, none. They come to light when it's not expected because of family members that have XI when they have surgery, tonsillectomy, oophorectomy, other types of surgery. They have no bleeding on a day-to-day basis. If you look at this small observational data set from Israel, you can see that in patients who have severe Factor XI deficiency following surgery without any replacement of Factor XI, that it's only the tissues that have high intrinsic fibrinolytic activity that actually have bleeding. And so for non-fibrinolytic sites, the percent of bleeders is extremely low. So if you work in the COAG bleeding world in the hospital, you know, what do you think of when you hear fibrinolysis? You want to use an anti-fibrinolytic agent, right? Tyranexamic acid, epsilon-aminocoproic acid. So the frequency of XI mutations are actually higher than you would expect when you look at population genetics. And so the question is, do low levels confer a survival advantage? And so when we look at this data set from Israel and we look at age-adjusted survival function curves and rate of cardiovascular events on the left and rate of venous thromboembolic events on the right, those that have levels greater than 50%, so in the clinical lab we define normal as 50-150%. So those that have normal levels, even if they're at the lower end of normal, have a higher risk of cardiovascular events and VTE than those with levels less than 50%. And similarly, in another large population study where those with Factor XI were matched 7-1 with the general population, you can see that those with Factor XI deficiency here as defined as less than 50%. I have a patient who had donated a kidney to her mother. She found out on periconception, one of those genetic screening panels for like Tay-Sachs and Gaucher's, that she was a carrier for a bleeding disorder. She had a level of 40%, but she had previously donated a kidney and had no bleeding complications whatsoever. So these patients have a lower risk of cardiovascular events and VTE events as shown here. So in summary, Factor VII mediates hemostasis in areas of external vascular trauma when bound to tissue factor. Then tissue factor converts 7 to 7A with rapid production of thrombin. Factor XI is activated by intravascular mediators independent of vessel trauma in pathologic thrombotic conditions as listed here. There's also that feedback amplification loop that happens when thrombin is generated and it directly activates XI. XI comes down the intrinsic pathway and generates more thrombin. So another potential beneficial effect to targeting XI there. Congenital Factor XI deficiency is associated with no bleeding phenotype and only presents risk with surgery and trauma in some patients. As I showed some data, deficiency is associated with decreased MACE and VTE risk. So inhibiting XIA may result in dissociation of physiologic hemostasis and allow that to happen from pathologic thrombosis, allowing for effective anticoagulation with less bleeding than current approaches. So... »» Yeah, get out those phones again. It's time for the next round. And before you read it, I was informed that the scoring, all the points go to whichever team gets the most correct answers. So make sure you enter in correct and that team is going to get all the points for the round. Go ahead, Jean. »» And if you get this wrong, it means you didn't pay attention to what I said. »» Okay. So which of the following is involved in hemostasis but not pathologic thrombosis? Is it tissue factor, factor XI, factor XII, factor VII, or PAR 1? So let's go ahead and pull that up here and we'll enter in our answers. You got 20 seconds. Again, which is involved in hemostasis but not pathologic thrombosis? We've got lots of answers. More answers for this one. I think we've got a lot of confident people or those phones are really going. Maybe it's people got done with their dessert so now they're ready to enter in. »» 62 responses. There we go. »» There we go. So tissue factor. Let's see which team got the most points though. What's the question? Oh, Muhammad Ali. You guys are really, really doing well. Okay. All the points to the Muhammad Ali team. Great. Jean, you want to walk us through this real quick? »» Yeah. No. So I think you hopefully listened to everything I said which tried to capture this answer that tissue factor exposure on the damaged vessel surface is really what initiates activation of the extrinsic pathway. And that's really why we think we can separate by activating, or inhibiting rather, 11. We can still drive necessary hemostasis by not interfering with that. And as I tried to show you, that's a pretty rapid pathway. And so hopefully we get controlled thrombus formation and not pathological thrombus formation. So thank you very much. »» Great. Thank you. Thank you guys. As you're entering your answers in on that audience response, you can also put in questions and we'll do our best to answer those at the end of the session tonight. Bob, maybe I want to start with you. You know, Jean really highlighted for us this idea of separating out thrombosis and hemostasis. And I have to admit, as a cardiovascular specialist, that's not really something I thought about before a couple years ago. Help me understand, as cardiovascular specialists, how do we need to start thinking about this differentiation between hemostasis and sort of the thing we're trying to avoid, the bleeding, the bruising, versus thrombosis? Where does it start to really play a role for us as cardiovascular specialists? »» I think this is one where it's worth thinking historically. And if you go back, say, to the early days of the glycoprotein 2b3 inhibitors, we accepted a lot of bleeding in exchange for a relatively modest benefit with regard to reduction of ischemic events. And if you look, for example, at the early days of Vaxiximab, we accepted a 15% blood transfusion rate in exchange for some myoclonal infarction prevention. But then there was a lot of research done that said, you know, all this bleeding can't be good. And people began to demonstrate that, in fact, this bleeding wasn't good, it carried longer term implications for a variety of reasons that I think are still being sorted out. And that started people thinking, could you separate, could you get, I think you called it the Holy Grail, of where you could separate thrombosis from hemostasis. So separate the ischemic benefit from the bleeding risk. And there's been some contenders, if you will, using the boxing analogy here. One of the big ones was Vorpaxar, with the thrombo receptor antagonist, where in early clinical studies it looked like you could separate, and guess what? In the clinical trials, you couldn't do it. There was still bleeding associated with Vorpaxar. So now, though, we have something that biologically makes a lot of sense, as Gene and Kristen have both described. So now what we've got to do is do the clinical studies to see if that biologic hypothesis bears itself out in the clinic. So I was going to build on that, and Mark, maybe I'll come to you for this question. You know, Gene showed those slides, which I think are starting to become very familiar to us who are thinking about factor XIs, which is that, you know, the data for folks with congenital factor XI deficiency or absence, and we see this remarkable reduction in both venous and arterial thrombosis. Does that excite you about the potential for using a therapeutic to treat this? Or where maybe do we need to have a little caution about saying, just because somebody's congenitally absent in something, is that going to translate into an agent that we can use to treat thrombosis? Where's the excitement versus caution sort of marker for you personally? Well, you know, I've been convinced by the prior talks, and I do think that the hemophilia C experience in some of the animal models is really exciting for the potential here. But I think we have to be very clear that chasing activated factor XI is very different than a factor XI deficient state. I mean, what we're doing with these drugs is very different. And I also want to caution that what we observe in healthy individuals over a lifetime is very different than what happens to a diseased patient with, you know, for example, advanced vascular disease on top of other agents like antiplatelet therapy. For example, we know from the ACS experience with the DOACs, dose was very important in terms of the safety there. So I think it gives us a lot of hope. But as Bob and others have said, I think we really have to understand, you know, what's the right mechanism at the right dose at the right time for the right patient and their background therapy. And I think that can only be learned in clinical trials. Yeah, I think you said it nicely. All of the justification for why this should work is there. So the excitement level I know personally for me is very high. But we've got to prove that it's really going to have efficacy, especially in that treatment side, as opposed to prevention. I think that's a great point. Kristen, I want to come to you for one last point. We talk about the importance of separating out hemostasis from thrombosis, right? Can we prevent the clot that we don't want without causing bleeding? And certainly focusing on the anticoagulant agent's important. But we know that other therapies often contribute to that. I'm thinking about antiplatelet agents. I'm thinking about other things. Talk to me a little bit about what are some of the strategies we can be doing now, maybe while we're waiting for these new agents to come forward, that help us think about ways we can reduce those bleeding complications if a patient is using an anticoagulant? What are some things that we can be thinking about to sort of start that balance shifting in the right direction? Yeah, I think patient education is fundamental to all of this. They need to understand why they're on these medications and that they are accepting, with currently available agents, that they are accepting some bleeding risk. And that may require a lifestyle modification in things that they do. And just practically going through things that they can do to minimize things. I talk to them about obvious things like if they use heavy equipment or things like that. But also common things like shaving cuts and paper cuts and those types of things that they need to be prepared for just to understand exactly what they're doing. And I always find it's helpful to review that med list with them and talk about the over-the-counter meds, right? Absolutely. Aspirin, NSAIDs, let's make sure that they're not taking them if they don't need them. And then when we're prescribing our anticoagulants, can we get them on the right dose? Absolutely. Can we make sure that they're not being overdosed, underdosed, things like that. I think there's strategies we can use while we're waiting for these trials to come out to sort of move us in that direction. But there's a lot more to do, certainly. Absolutely. Patients respond really well with the drug interactions with over-the-counter meds. If you really explain to them what the risk is and what the mechanism is, you can go through that simplistically to say, if you take ibuprofen, it can tear up your stomach lining. And because you're on a blood thinner, that can go bad quickly. They understand that and they appreciate it better when they're involved in that. Great.

coagulation cascade

Factor XI

anticoagulant strategy

thrombosis

bleeding risk

clinical trials