Hello, everyone. My name is Javier Lorenzo. I am a clinical associate professor of anesthesiology and critical care medicine at Stanford Hospital. Welcome to our crosstalk lecture this afternoon. Our topic today is titled Balancing Act Between Bleeding and Thrombosis, Difficult Anticoagulation Cases in the ICU. We actually have real cases to discuss, and I am really excited to introduce our two speakers this afternoon. First to my right, or to my left, however we are positioned, is Dr. Gerald Levy, who is a professor of anesthesiology and critical care and a professor of surgery at Duke University. He's also the chair of perioperative and critical care thrombosis and hemostasis committee of the International Society of Thrombosis Hemostasis. I also have Brian Gilbert, who is an emergency medicine pharmacist and a residency program director of critical care pharmacy from Wesley Medical Center in Kansas. Welcome, gentlemen. Thank you for your time this afternoon. First, I want to get a pulse of how things are going in your institution. We can begin a discussion about thrombosis in the ICU without addressing COVID-19 and everything that we've learned so far about his prothrombotic potential. So I like to start asking Dr. Levy, what has been your anecdotal experience in the care of patients with COVID-19 infection? And how has your institution gone around managing and mitigating this risk? Well, in Durham, North Carolina, and in the Triangle, the density of our population is certainly, I don't think, like some of the bigger cities. So I think across the U.S. we've all seen surges, but the reality is that, and actually I just came off service, so the ICU was filled and at one point our cardiac ICU was the only empty bed. What we've done is kind of kept, tried to keep the COVID patients separately and moved our transplant patients into the unit. The cardiothoracic ICU is taking really the, all the transplants, liver transplants used to go to the surgical now coming to us. And so it's been an interesting spin, I think, and certainly a challenging perspective, but I think, you know, it seems, it certainly seems to have started to level off, but I think we now need to wait for the next surge that occurs after an even bigger holiday Christmas. So that being said, and it's good, you know, collaborative efforts among our teams. So, and an interesting time to be an intensivist. Thank you. Yeah, I'll echo those sentiments as well. In terms of our COVID capacity here, we sort of got a little bit of a delayed start. Obviously it's one of those almost tidal wave type situations where you can see it coming, but there's really nothing you can do. Being in Kansas, seeing all of the initial reports out of New York and trying to prepare as much as possible. I think everybody can probably attest that you can have the best made plans, but once it reached us, it was really just trying to mitigate those co-infections and mitigate the spread as much as possible. You know, Wichita, Kansas was up to about a 14% positive rate as of two or three weeks ago. So we really had a surge that we, one, were not really accounting for as we thought that we could potentially mitigate some of the spread. And with us being a rural sort of access hospital for much of Kansas and Oklahoma and some parts of Nebraska, dealing with the surges has just been, you know, obviously priority one. But we're starting to hopefully see some of the numbers go down and hopefully we don't see any larger spikes now that we have the vaccine available. Javier, what's your experience way out West? So here in California, actually it's a kind of a tale of two states, Southern California versus Northern California, but we are experiencing our biggest surge. Initially had been mid-July, but we are now to the point where we've activated two surge teams in our units. And as of this weekend, we had 30 ICU patients and up to 95 patients in the hospital with COVID infection. So we're seeing a real surge. It is putting a stress on our ability to care for the patients. We've canceled elective cases. We've had to move folks around. But, you know, there's a lot of enthusiasm and there's a lot of willingness to adapt and to move forward. And it's an incredible time to be an intensivist. I do want to echo that. I'm really proud of the work that we're doing. On that note, I want to ask a question about ICU management for these patients. And I think it's a point in question just because not too long ago, actually the ACTIV-4 trial put out an announcement that they were changing or pausing enrollment in one of the arms. But Dr. Levy, in your institution, is it just business as usual when it comes to prophylactic doses of anticoagulants in critically ill patients, or do you guys use intermediate dosing and then only systemically anticoagulate when there's evidence of a thromboembolic event? How are you managing things in Duke? So that's a great question. Basically, what we've been doing is similar to what the Brigham and Women's are doing. And I know we published, my gang's published in Thrombosis Research, Brigham and Women's published their experience in chest using a dose adjustment that's based on specific criteria. More than just ICU admission, D-dimers up to perhaps five times upper limits of normal, as well as perhaps a cutoff fibrinogen level, and going to a dose adjustment based on that. Clearly, if you have a thrombotic sequelae, there's a rationale for anticoagulation. But I think in looking at all this data, it's just not being in the ICU, it's qualifying at ICU and having a pretty relatively high D-dimer level or dose adjusted. That's sort of been the track followed by our group and sort of led by our well-known hematologists. So that's sort of been the spin. And to me, that makes a lot of rational sense. And I know the active four with the randomization, but again, once you get into a larger scenario, it may change a little bit of the paradigm. But I think to me, that makes a lot of sense, not just empiricism, but using some sort of objective biomarker or coagulation testing. So I'll stop there. Brian, I know that you probably spent a lot of your clinical time in the ED, but do you know what your ICUs and your institution is doing to address this question? Yeah. I mean, the algorithm that Brigham's put out as well as from UNC has been sort of our basis of what we used and tried to tailor care to individual patients based off of that and some of the data that we have. I think to point out too is just in monitoring and trying to identify those times to dose adjust or to utilize full systemic anticoagulation has been probably the most difficult aspect, utilizing D-dimer, but also other surrogates to try to make that sort of switch to full dose. In addition to wondering when antiplatelet regimens should be administered as well, or are there some institutions that have utilized systemic thrombolysis in lower dosing as well? So we've tried to gather as much information as we can, but that UNC algorithm has been sort of our cornerstone with some of our bigger questions coming as well as how long do we fully anticoagulate some of these patients or do we still give them full anticoagulation once they've left the ICU, knowing that some of these adverse events associated with the COVID-19 infection has been a repeat thrombotic events once they've left the ICU. Yeah. Similarly in Stanford, we do something where we kind of offer an intermediate dose, but I agree with Dr. Levy's that it can't just be all empiric. We really need to look at some of these biomarkers, signs of systemic inflammation, systemic thrombosis, but we have seen, just like the literature has supported an increased risk of thromboembolic event on these patients, I do remember even arterial thrombosis in some of my most notable COVID patients. All right. So thank you for that. I think that's a good way to start a discussion of thrombosis in the ICU. So I like to move on with a case that I think every intensivist has encountered maybe in the last five to 10 years as the use of novel oral anticoagulants has increased. So I like to talk about, to Dr. Levy, this is your area of expertise. I want to ask you a question about when you're managing a patient that comes in and say, my own experience, for example, is somebody that comes in and it's altered because of intracranial bleed. He's taking a NOAC, but it's not really able to tell me a story, not really able to tell me the last time that he took his medication. How do you manage, what's your approach to a patient that's coming in with an emergent acute intracranial head bleed and is taking one of these novel anticoagulants? And I leave it vague because I think you can give me an approach to direct thrombin inhibitors, or you can give me an approach for the other class if it is different. How would you approach this patient that's not able to give you a history, but is definitely bleeding in the head? So great question, and that's been the focus before COVID-19 coagulopathy, that was our focus. So first thing from the ED perspective, you've got to figure out what the patient's receiving. And sometimes I can tell you the coagulation testing can be confusing. Even if you don't have a specific anti-TIN-A assay for apixaban, rivaroxaban, a good screen is to get a anti-TIN-A level or your low molecular weight heparin assay, which is sort of nonspecific for quantitative, but it will give you a qualitative perspective. Get a thrombin time, so everybody should have a thrombin time, and a prothrombin INR. And there from that you can pretty much figure out what's going on, whether it's an anti-TIN-A. The interesting thing is only one to two percent of the population is the bigotrium. I was involved with the reversal, the specific reversal, antidote if you will, Idaricizumab, Praxpine, but I mean almost nobody's on that. But it's going to be generic soon, so get ready for dealing with that. But the point is first you got to figure out what they're on. The problem is if you're, the bigotrium is very sensitive to renal dysfunction. The levels can go super sky high. So if levels of a normal level is, you know, about maybe 150-200 nanograms per milliliter, so the levels start going to 6-700, which they can with renal failure, it'll affect your prothrombin INR. So it's just a little something to think about, and it'll make your thrombin time go quite high. So figure out what they're on. With the bigotrium, it's kind of easy for a reversal strategy because you've got Idaricizumab, Praxpine, which has been extensively studied in trauma, surgery, ICH. It's a little bit different I think on the hospital based on an anti-TIN-A like Apixaban or Rivaroxaban. The head bleed story, if you look at the Annexa IV data, it's basically 60-64% is all intracranial hemorrhage. But if you bled more than 60 mils in your head, you weren't really studied. And the interesting thing is even in Warfarin reversal with prothrombin complex concentrate, even with reversal, whether you change outcomes or not is an interesting paradigm, but the bottom line is that's what we do when we treat and we reverse. So just to sort of summarize, I would use, you know, in that situation, Andexanet makes a lot of sense, and that's the study, and most people get away with just the gram of that. If you're bleeding and exsanguinating, then you have to think about prothrombin complex concentrates and multimodal therapy. But focusing on ICH in a nutshell, that's pretty much the perspective. Thank you, Dr. Levy. How about you, Brian? Any insight on how you manage these in the acute setting in the ED? Yeah, I'll just echo his thoughts. As a community hospital, you know, a lot of times we don't always have access to identify, you know, some of these more agent-specific assays. So we do utilize our low molecular weight heparins and use that as our qualitative, you know, a yes, no, this patient has drug present. In our trauma patient population, it's pretty routine for us to use viscoelastography as well, and we'll utilize that as a measure of a degree of coagulopathy as well. We're an institution, we utilize PCCs in this situation just based off of some of the more retrospective data and a recent study that just came out through the Neurocritical Care Society to fix ICH study having efficacy rates of about 82% in terms of ICH in terms of volume expansions. And it goes back to what Dr. Levy said, whether or not we're actually, by giving sort of these reversal agents, whether or not we're actually preventing death or helping with neurological outcomes really remains to be seen. But that's our current strategy. I'd be curious, Dr. Levy, your thoughts on PCC dosing for DOAC-associated ICH bleed. We're currently an institution that caps. We do 25 units per kilo just based off of some of the data on Bromine generation potential, but I'd be curious to know your thoughts. So pretty much if you look at the totality of the data, it's 1,500 to 2,000 units and 25 per kilo is about 1,500. So you're really right there from what's been reported. The interesting thing is there's a great paper that really says if your level is over 75 nanograms per mil, the PCCs probably don't work. In most patients, even with renal dysfunction, apixaban and rivaroxaban is cleared pretty rapidly. So by the time you get in the hospital, your levels are probably below 75 nanograms per mil or close to that. So therefore, that makes a lot of sense. The issue is that you're trying to restore thrombin generation, and just to remember that it has a much longer half-life than andexanet. When you give andexanet, it only has about a two to three-hour half-life, and then you rapidly return to the placebo patients, probably you've sequestered it, now you're eliminating from the body. So PCCs, efficacy, remember in the INEXA-4 study, patients were re-scanned. So the efficacy is sort of clinical scenarios, and the PCC studies have not been with scanning. So bottom line, interesting scenario, but PCCs, I still think, make a lot of sense, although clearly off-label and not approved in that scenario. And honestly, probably a three-component PCC like profil-9 or bebulin is probably as reasonable because, you know, there's just a difference in factor VII, and for the most part, it doesn't make that much difference. And we've actually studied that in volunteers looking at either, you know, three- or four-factor PCCs. Just one more thing to piggyback off that. I think the other thing to consider with that long half-life of PCC is, for anyone watching this, and it's been more of a focus of, I would say, the general ICH population, but it's getting that VTE prophylaxis back on as quickly as possible in patients who are stable. Yeah, I'm going to stop you there because if you have a head bleed, you're going to be super reluctant, but you're right. You're at now pro-thrombotic risk, but the reality is, you know, and I deal with that in the VAD population, you know, you're anticoagulant, but with the HeartMate 3, it's less of an issue because it's, you know, you can go without anticoagulation, and you have to be careful there. It's different in the trauma patient where you have a massive hemorrhage. If you're bleeding a lot, guess what? You're autoplasmophoresing the drug out. But the point is that, and you need to, even when you give an antidote, whether it's PCCs or Andexanet or Praxpine, you still have to measure platelets, coagulation factors, fibrinogen. Everybody thinks these are not Lazarus drugs. You've taken the anticoagulation out of the picture, but you still have to treat the coagulopathy, and with a major bleed, traumatic or otherwise, surgical, you really have to do the standard multimodal therapy, and we've really preached that quite extensively. Important to think about. It's important too, like you're saying, because these patients are usually on concomitant antiplatelets as well, so getting the ability to measure that antiplatelet function, especially with a lot of surgeon utilization and desmopressin these days, even for, you know, irreversible versus reversible binding, there's been some data with that in the ICH population that's emerged here recently, even within the Society of Critical Rare Medicines. So interestingly enough too, there's some of that, and I'd be curious your thoughts in terms of in vitro data on, you know, the DOACs causing, I'm just, I've got the rock star here, a legend, you've got to get the time when you can, but you've got, you know, DOACs associated with decreased thrombin potential that's downstream having antiplatelet effects as well, so I totally agree with you in terms of that multimodal approach. Yeah, DDAVP, remember, is a V2 agonist that releases von Willebrand factor from the, you know, from the endothelial stores. There is almost no data on DDAVP efficacy. In fact, you're releasing TPA and you're creating fibrinolysis when you give it. If you're in shock and you've been in, you've probably depleted your DDAVP, your von Willebrand factor stores, but I mean realistically, one of the, there's a lot of things we do that are very proactive. DDAVP, whether it's effective or not, what may be effective is things that are augmenting von Willebrand factors, so maybe it does have some efficacy. You know, in vitro and clinical bleeding are really disconnected, so as you all both know, but an interesting paradigm. Again, multimodal therapy, don't forget to measure stuff, and the problem, as you said, you're on antiplatelet and antithrombin stuff, so you reverse the antithrombin, but the P2Y12 inhibitor lasts for days, so interesting spin what to do. So to summarize, kind of find out what they're taking, contextualize the care, multimodal approach to hemostasis, and then figure out, once you know what they're taking, figure out what the reversal agent you're going to give. Are we ever, Dr. Levy, are we ever going to get, you know, a reversal agent to rule them all, one ring to rule them all? Is that ever going to happen, or are we always going to have to? Seroparentag is a really, is that drug, you know, it's like the universal antidote. The reality with seroparentag is that you can't really measure its effect. You have to have the specific coagulometer, and you know, the fact that it sort of sat on the back burner, I was actually at the FDA meeting in 2014, where we talked about all these potential studies and other issues, and it really hasn't gone anywhere, which makes you think there's some interesting issues. I don't know, I think, in the meantime, you know, if you actually look at the data on anti-10A bleeding, rivaroxaban, apixaban, outcomes are much better than with warfarin. The half-life's far, far shorter, and a lot of the other issues that occur. So you're better off with a, in my opinion, with you bleed on a 10A inhibitor, but the reality is that I don't, I think we're a long way out for a universal reversal agent. You know, one of the things that people complain about is the thrombotic effects of the studies, but if you're bleeding, you want thrombosis. You can't have it both ways. It's too thick or too thin, and we as clinicians never get it completely right. I'll stop there. All right, so speaking of coagulopathy, I want to bring forward a second case that I took care of a few months ago, and the reason why I bring it up is because it was an NCH liver disease patient, and we all know the coagulopathy that comes associated with that disease process, but this particular patient ended up having venous sinus thrombosis that cause an intracranial head bleed. And it's always, it's one of those clinical contexts where the medical student looks at you and says, why are we anticoagulating somebody with a head bleed? This is interesting. And why is it that somebody that's walking around with platelets in the thirties and forties and INR of 2.1 developed this clot? And I guess that's a great question. Medical students always have some, some of the most insightful questions. My question to you guys is why is that? Why, why is this patient with low platelets and high INR prone to thromboembolic phenomena and, and, you know, how do you manage that on somebody that comes in with an acute head bleed because of venous sinus thrombosis and you actually need to anticoagulate that patient. So it's the complexity, it's for instance, people have these coagulopathies, you know, it's a consumptive coagulopathy, kind of like it's a DIC scenario, you know, in this infinite DIC literature and a well-known investigator out of Japan named Gando has done a lot of interesting work and they've described as a hemorrhagic version or the thrombotic version. I think, you know, COVID-19 hypercoagulability has a DIC spin to it in the sense that high denimers and hyperfibrinogenemia. The problem is that when you get hemostatic activation, microparticleization, you create an impressively prothrombotic milieu that really increases the hypercoagulability. The liver also makes anticoagulants. It's kind of like the patients who have shock liver. There's two causes of acrocyanosis or symmetrical peripheral gangrene, basically a septic DIC picture or a shock liver or the combination, because you decrease protein C, the anticoagulants, and that's part of the hepatic issues associated with, I think, some of the scenarios that we see. You decrease the anticoagulants, perhaps more than the procoagulants, and you get this prothrombotic milieu that causes issues. And interestingly, it's not an arterial thrombosis because the endothelium is protective. It's a venous or sort of venous thrombosis. Arterial thrombosis tends to be more arterial mediated. So it's an interesting sort of paradigm. Why do you anticoagulate? Well, you anticoagulate because you've got thrombotic sequelae, kind of like the story with, you know, that I know we'll get to, but the idea of heparin-induced thrombocytopenia where an anticoagulant creates prothrombosis because you've microparticulized and activated platelets. It's an interesting spin. And coagulationese is like Japanese or anything. It's a language that I spent lots of years trying to study, and I still don't completely understand it. So I keep working on it. But I think it's that hypercoagulability of, and the liver is, in French, you know, the French word for liver is foie, which also means my faith. So it's very epicenter of, you know, of the coagulation cascade. I'll stop. Yeah, I mean I don't have any foie gras stories, but I definitely can, I can just elaborate a little bit too. So remembering that INR and end-stage liver disease and cirrhotics, it's more of a qualitative evaluation of these patients saying, okay, yes, there is liver dysfunction and there is some intrinsic values that are no longer normal. But INR in these situations, platelets in these situations, don't actually capture that hemostatic risk. You know, also again remembering too in that sequestering, you also have low levels of endotoxin trapped there within that portal vein, which is causing hyperactivation of platelets itself. So it's sort of a paradox of, yes, I have levels that suggest that I should be at higher risk for bleeding, but it's currently, you know, that situation doesn't unfold and that's not clinically what is taking place. So we have to find new measures and ability to, you know, assess and stratify these thrombosis versus bleed risk, which, you know, I think probably the most beneficial in my opinion would be, you know, thromboelastography or viscoelastography depending on the situation or what institution you may be at. The new acute liver guidelines, liver failure guidelines and acute and chronic liver failure guidelines through SCCM are now actually promoting the utilization of viscoelastography. So it's something I think that we're going to start taking something like TEG and Rotem from a more, let's use this as a study type of test into how can we use it in clinical practice. Yeah, I would be a little careful about TEG and Rotem because the hypercoagulability maximal clot firmness or maximal amplitude is very fibrinogen dependent, very fibrinogen dependent. And part of the problem is that a lot of the issues like for is to me about tissue factor and other activation. The other thing is remember the hypercoagulability of cancer, cancer because of all the, you know, things that are happening and it's a pretty impressive scenario. So, you know, people keep going back to TEG and Rotem. It's a great test and it's a whole blood coagulation, but like every test it's a test kind of like you can go to Vegas, you can figure out the test or the game, you can game it. Every coagulation test can be game too. So you have to be a little careful. Like you said, you're still clotting with a high INR. You see that in ventricular assist devices all the time because of all the elements. You have to be super careful about that. And the TEG Rotem is only one piece of the puzzle. You can't put, it's very helpful, but again, like multimodal resuscitation, it's multimodal analysis too. So a little careful there because it's hyperfibrinogenemia makes you look hypercoagulable when there's other aspects too, sorry. And doing the appropriate, you know, testing modalities, appropriate reagents to go along with it, the operational aspects that we don't really tend to think about, but those can actually invalidate your results as well as the interpretation. So absolutely agree with you. It's with caution, so. So speaking from one hypercoagulable state in state-delivered disease to another one, and thank you for bringing the cancer setting as well. I like to discuss the hypercoagulable state of pregnancy, particularly that of pregnancy involved in an infection. I recently took care of a pregnant woman, she was in her third trimester and she came in really sick with COVID pneumonia, developed respiratory failure, developed an acute kidney injury. So we actually scanned her chest and she ended up having really large clot burden with multiple PEs. And we anticoagulated her with heparin because she had a pretty, you know, noticeable kidney injury and she developed heparin-induced thrombocytopenia. So if you're faced this question of managing somebody with a QPE, hypoxic, infected with COVID-19, needs anticoagulation, now develops heparin-induced thrombocytopenia, she's pregnant, she's also at risk of potentially delivering at any time if she goes into preterm labor because she is very close to her due dates. How would you manage that patient, Dr. Levy? And what learning lessons can you share with us about this particular hypercoagulable state? So pregnancy at baseline is a hypercoagulable state. With the scenario that actually looks almost like the COVID coagulopathy, remember a normal fibrinogen level is 200 to 400 milligrams per deciliter, plus or minus. In pregnancy, it goes up almost 100%, 500 to 600 milligrams per deciliter. The D-dimer is pretty much doubled. The upper limit of normal is 500 nanograms per mL. In pregnancy, it's a bit higher. So you already have the milieu of hypercoagulability. Postpartum hemorrhage, still a major cause of mortality worldwide, unfortunately. Furthermore, and to add one more thing, one of the things that's not always talked about is the von Willebrand factor story. They have doubling of the baseline von Willebrand factors, which is also, again, an endothelial injury, COVID coagulopathy, and once they get COVID, they have an endothelialopathy, which further drives the complexity of this hypercoagulability milieu, which will push them to preeclampsia or eclampsia, like the scenario you described. So they're at greater risk compared to the children who have totally normal endothelium, lower coagulation levels, 20 to 40%, depending upon the age, that are less of an issue. So that's really complex. Regarding drugs to avoid in pregnancy, with renal failure, argatroban is going to be your really drug of choice in a patient like this, and honestly, what goes across the placenta or not, bivalarin is about a 4,000 molecular weight peptide, but eliminated by the kidney, longer half-life. Argatroban is, to me, a better anticoagulant. You know, I had a lot, I'm in Dukie now, but I had a lot of it in Emory many years. We did thrombogeneration sequences on all these drugs. Argatroban's a great drug, but for the HIT story, you're obliged to a direct thrombin inhibitor, either one. I think you have to figure out, argatroban, I'm not sure about. It's a 500 molecular weight inorganic molecule that basically is a great anticoagulant. What did you use? You could use one or the other, just understanding bival has a longer half-life. Is argatroban contraindicated in pregnancy? It's not, and we ended up using argatroban because we could turn it off whenever we needed to. It was easier to monitor, and I had more practice and more experience with that infusion, and it's what all the other services associated with our care also wanted to use, so that's what we ended up using. Brian, I think bival is used a lot because it was used a lot in the cath lab, but argatroban, for a lot of the reasons like you described, renal dysfunction, titratability, a little bit longer half-life, I think is the better agent, and it has a more interesting thrombin generation inhibitory effect, and this is a woman with massive thrombosis. What do you think, Brian? I would agree. I'd 100% would have done argatroban in this situation. I'm curious as to what APTT goal you used in that situation. You know, that's a good question. I think I ... You can tell me if I'm mistaken about this, but this was a couple of months ago. I want to say that our protocol actually is INR-driven. Will you actually ... No, you probably ... I think you probably ... Well, see, this is the goofy thing, is that it interferes with INR when you transition. It does interfere with INR prothrombin time, and that's the reason when you transition patients to warfarin, you follow chromogenic factor 10 levels basically to transition, because an INR of 2 is a level of about 40, 45%, and INR of 3 is about 20, 25%. The thing about it, there's actually some bigger hospitals can actually do argatroban levels that can help you. It's confusing, and just so you all know, an INR ... I mean, a partial thromboplastin time of 40 to 50, which is a great starting point. When you use argatroban, or about 1.5 to 2 times baseline is probably where you want to go at least initially, but a PTT on bival, heparin, and argatroban probably has a different antithrombotic effect, but again, this is the test we used in 2020, a thought. Brian, what do you think? Yeah, actually, just to add to that, it was a transition point from argatroban to Coumadin was INR driven, but I think for the infusion it was PTT. Yeah, he's exactly right. That INR, it's fool's gold initially when you get a lot of young clinicians that get excited about it. The other thing to consider in that situation too is earlier, and this is maybe a nerdy pharmacy thing too, is dose reductions and liver failure. That's always a kinetic variable that can sometimes get missed, especially in a patient with COVID-19 that may be displaying a quote unquote shock liver in that situation as well. The other thing that always comes up is whether or not ... and he's dropping molecular weights on me, so 526 Daltons, I had to look it up, argatroban, while we were doing it. We're essentially looking at any molecular weight less than 500, it's probably going to freely cross or at least have some variability there, so argatroban has been described in the literature pretty safely. Bivalis, a little less. Fondoparanox would be obviously a great choice in this situation if there wasn't any renal failure. The question being whether or not you're going to monitor TIN-A levels at that situation and how accurate they would be, especially with, and correct me if I'm wrong, there's been some antithrombin 3 deficiency associated with COVID-19, correct? Dr. Levy? No, antithrombin 3 is more with a classic DIC sepsis. The problem is that when you look at this crazy data is that there's no timestamp on the report of the coagulopathy. If you're in the ICU long enough, 50% of people are going to have a ventilator-associated pneumonia, the secondary DIC, and a more consumptive effect. And then antithrombin starts taking a hit. For the most part, antithrombin is pretty reasonable. The reason I threw out the molecular weight is because of antigenicity, hypersensitivity, and other issues. Small drugs like argatroban don't have that hypersensitivity, which is not inconsequential in a patient who already got hit positive in IgG antibodies. Well, gentlemen, normally these Crosstalk sessions will actually draw a big audience and we'll have audience participate. Unfortunately, we can't do this with this format, but I hope that we will have a big audience. And as such, I want to give you both each an opportunity to maybe share with the audience what you might consider to be a big pet peeve when it comes to anticoagulation or thrombosis. If you have, let's say you have 50 people listening to us right now, you have their undivided attention, what would you want them to stop doing? Like, please don't do this or don't order this this way. What's one thing that really irritates you when somebody does it in a way that you don't think they should be doing it? Here's your chance to at least set the audience a little bit better. I think the thing, where do we start? One of the things that, in the COVID world, everybody talks about heparin resistance. Remember all the things that affect heparin resistance. One is hyperfibroendogenemia because the PTT test is a clot-based assay. When you're confused or something, you need to think about following anti-TIN-A assays and some hospitals have switched over because it's a better test. Brian, I'm going to let you perhaps later talk about, if you don't mind, an anti-TIN-A. But everybody forgets that there's the weight-based consideration of the big person, then you may need more heparin. Second thing, the other thing that may do it is thrombocytosis, high platelet counts. Platelets when they activate and release PF4, PF4 is a basic molecule that neutralizes heparin. And then they get, platelets get somewhat activated. So there are a lot of things that cause heparin resistance. The classic story of heparin resistance was defined 25 years ago or more, where they, in heart surgery, where it was like more than 400 units, 500 units of heparin to get an ACT to a therapeutic level of 4, 480 seconds. I think heparin resistance is over-discussed. A lot of things certainly may cause it. I think that's one of the big things. The second thing is, you know, when you're having trouble anticoagulating with heparin, people switch to BiVal. BiVal, as I said, there's a growing use of this thrombogeneration assay, basically that looks at peak area under the curve endogenous thrombin potential and latency or onset. So it's a lot more complex. But I would caution people switching to BiVal when they're having trouble anticoagulating. And think about argatrabin. A direct thrombin inhibitor makes a lot of sense. You don't need antithrombin. Antithrombin costs about $3.50 a unit, and you've got to give a lot of it to work. So one, antithrombin, a direct thrombin inhibitor makes a lot of sense. And then again, whether it's BiVal or argatrabin, it's probably moot. But the bottom line is careful. Don't switch back. If you do, a direct thrombin inhibitor is not a bad idea. And the antithrombin story, still a quarter of a century working with this is still being figured out. So I'll stop there. Brian, your thoughts? I think my biggest thing and takeaway, and I alluded to it earlier, is that these patients are typically on anticoagulants for a reason. And so when we go, and going back into the reversal, once we've reversed those, getting on prophylaxis as soon as possible in those situations, you're already at a pro-thrombotic state. That's why these patients are taking it. And then by creating thrombin, you're just putting them at a higher risk. So VTE prophylaxis as soon as it's possible. Javier, one other thing that I think that we do a lousy job, as intensivists, maybe as the ED, is that when they go home, extended venous thromboembolic prophylaxis is totally something that we need to get our colleagues to work on. With the oral anticoagulants, several of the active studies are going to look at that long-term prophylaxis in the hospital. They make you walk and get up. And you go home, you feel terrible. You know, the post-infectious state causes some pretty dramatic lethargy, long-term effects. I had the privilege of being an ICU fellow at Mass General, many years ago, with Richard Hotchkiss, who's shown long-term immunoconsequences in recurrent infections. So extended prophylaxis is something that we really need to do a better job of. And not that we discharge people from home to home, but something to think about. Brian, your thoughts? No, those are great. Absolutely agree. Absolutely agree. You've got a whole team around you that's driving you, pushing you, and then, you know, like you said, you go home, and you feel crappy, and then you're just sitting there on the couch. And how many of these patients end up coming with either repeat infections or repeat VTEs in that situation? So, couldn't agree more. I feel that way after a week of working in the ICU. Come home, feel crappy, just like you described, but I don't VTE prophylaxis. Well, gentlemen, we have about two minutes left, so I want to ask you one last question. This was a really, a very difficult year. So I want to know, how did you manage to stay well this year? What did you do to revisit your wellness, and what are you looking forward in 2021? Dr. Levy, maybe you can start. Yeah, good question. You know, part of it, my hobby is food and wine. So I come home at the end of the day, eat some really tasty treats, and have a neat bottle of wine, and try to unload, and not let my wife tell me problematic issues. Only happy things. Only happy thoughts. Sounds good. And you, Javier, what do you do? I do the same thing. I mean, I really enjoy a good glass of wine after a very long, long day in the ICU. I like to stay, you know, go outside and hike. Luckily, in California, we have the ability, you know, our geography and weather can help us do that. In fact, you might see some of my favorite National Park posters behind me. But I just got a puppy. I've had a puppy for a few days, and that's going to keep me busy for a few years. So I'm looking forward to that. How about you, Brian? How did you manage? I bought a great hiking in Kansas, and it's pretty flat here. You know, so I think one of the things that I've been, obviously, food, wine, and I'm planning a wedding, so that's been really fun and exciting and not at all stressful with COVID, 100%. But I think that one of the things I've realized this past year is that I've gotten back to basics. You know, taking care of patients bedside, teaching residents, and then, you know, being able to sort of disregard some of the fluff of what we do has been really sort of satisfying and getting back to those roots. Thank you, Brian. Thank you, Dr. Levy. Thank you very much for your time, and thank you for all the work that you both have put in during this really, really difficult and challenging year. With that, I will conclude our discussion on the difficult thrombosis cases in the ICU. And again, I want to thank our two speakers, Dr. Gerald Levy and Brian Gilburn. Thanks guys. Thank you all. ♪♪♪

thrombosis cases

intensive care unit

COVID-19

coagulation

management

novel oral anticoagulants

thrombosis in pregnancy

anticoagulant