SCCM Resource Library-Managing Anticoagulants and Antiplatelet Agents in the ICU

Video Transcription

All right, we're going to get started with the next session. Nice piggyback onto the last session. This is going to be a great session. I've heard all these speakers talk before.  You truly have the experts here discussing various aspects of managing anticoagulation. The first speaker is Toby Trujillo who is a clinical pharmacy specialist  at the University of Colorado.  All right, thank you. It's a pleasure to be here. So I was given the enviable task of trying to provide a update on antiplatelet and anticoagulant medications in about 15 minutes.  So I'm going to do my best to maybe potentially pick out some things that have happened in the last year or so, highlight them, especially as they might relate  to critical care patients and the patients you might be seeing in your different ICUs. So I'm a clinical specialist in cardiology and anticoagulation.  I direct our inpatient anticoagulation service at University of Colorado and I co-chair our anticoag subcommittee. I apologize, I did not put my disclosures up on the slide  but I will disclose them verbally now. I have served as an advisory capacity to Portola and I receive research funding from CSL Bering.  So in terms of thinking about what I wanted to talk to you guys about in terms of updates in antiplatelet therapy, there have been some interesting developments  over the last year, especially as it relates to the ACS setting. And for some of these, I'm just going to sort of walk through real briefly.  Certainly there continues to be investigation and interesting information coming out about the management of patients who meet criteria for both anticoagulation  and dual antiplatelet therapy. And really the biggest patient population that this sort of that we see is patients who have concomitant atrial fibrillation  and undergo percutaneous coronary intervention, either for ACS or in an elective fashion. And within the last year, we've had the Augustus PCI and the Entrust PCI.  For those of you that are familiar with these, this is the apixaban and the adoxaban versions of these types of studies looking really to see what is the optimal approach  for antithrombotic therapy for meeting these two different indications. So of course, we know historically atrial fibrillation is best treated with anticoagulation  to prevent stroke. But our mindset for atherosclerotic vascular disease, especially PCI and stents, has been dual antiplatelet therapy.  But triple therapy obviously increases the risk of breeding significantly. So these two studies confirmed what we knew from earlier studies, the PIONEER study, the WUSS study,  and that for a great majority of these patients, we can actually go back down to an anticoagulant plus single antiplatelet approach. And that antiplatelet approach generally  is clopidogrel, not aspirin. And a great majority of these patients maintain our efficacy at reducing ischemic events, either stroke or stent thrombosis,  as well as significantly reduce the risk of bleeding. So I would encourage you guys to take a look at those studies if you've not seen those.  My guess is that you're probably seeing patients in the ICUs that have these concomitant indications all the time. Also, there's been some additional information,  continued investigations into the duration of DAPT. How long do we really need to treat people with dual antiplatelet therapy? The most recent interesting trial was a TWILIGHT study  which really looked at three months of DAPT and then, let me back up. So as you guys all probably are aware and remember, 12 months of DAPT is standard of care.  It's guideline recommended to reduce ischemic events post-ACS. So TWILIGHT looked at a three-month duration of DAPT and then the removal of aspirin and continuation  of ticagrelor for the remainder of nine months. Now, these were all comers for PCI, but 2 3rds of them were ACS patients. And the findings were that there was  no difference in ischemic events, but a reduced risk of bleeding when you remove the aspirin. So I think we'll eventually move to a point  where guidelines are probably going to recommend shorter durations of DAPT with the newer generation stents. But this is information that sort of lends itself to that  as we continue to evolve in this area. One thing that I keep seeing a lot is periprocedural bridging with cangrelor or GP2B3 receptor antagonists.  So more and more, we get sick patients into our institution who have had a recent stent placed and are going to need some type of surgical intervention  and are on days and days and days of periprocedural bridging. So there was a nice review published on that that I highlighted there for you.  And the last one I'm going to talk a little bit more detail on is P2Y21 receptor antagonist choice in ACS. And I'm going to talk specifically about the ISAR REACT-5 trial.  And so available P2Y12 antagonists include clopidogrel, prosegryl, and ticagrelor. Current ACS guidelines, whether it's the US or the European  side, would recommend prosegryl or ticagrelor over clopidogrel based on phase 3 clinical trials showing these drugs to be more effective,  likely due to pharmacokinetic pharmacodynamic issues. And there is no data, though, on the relative merits of ticagrelor versus prosegryl.  But we've sort of evolved to this sort of standard that most patients were getting ticagrelor, or most people were comfortable with using ticagrelor here  because of some additional stipulations of the prosegryl that you have to think about in order to make sure it's used appropriately.  So no history of stroke or TIA, maybe dose reduction in patients who are of low body weight. And so this was an investigator-initiated trial. This was not industry-sponsored.  It was a randomized, multi-center, open-label trial patients presenting with acute coronary syndromes and for whom invasive evaluation was planned.  And the primary endpoint was the composite of death, myocardial infarction, or stroke. And secondary endpoint was bleeding. But essentially, patients were randomized  to either prosegryl or ticagrelor, in addition to aspirin, on top of standard of care. And the results were actually surprising to everyone  because this study was designed with the assumption that ticagrelor would be superior to prosegryl. And the results actually showed the opposite.  So you can see here, in terms of the primary endpoint, it occurred in 9.3% of patients with the ticagrelor group, 6.9% of patients with the prosegryl group.  Now, interestingly, that did not result in a statistically significant increase in the risk of major bleeding. So that's your first sort of step back and say, wait a minute.  There might be something funky going on with this trial. Because across any trials with all antithrombotic therapy, you don't get increased efficacy without some sort  of concomitant increase in the risk of bleeding. That just doesn't happen. So there are some limitations here that I would sort of point out. One, it was open-label.  And so if you're taking a BID drug versus a once-daily drug, that could potentially have some bias against ticagrelor. At 12 months, only 2 thirds of the patients in either arm  were on assigned therapy. The safety analysis actually excluded significantly more patients in the prosegryl arm than in the ticagrelor arm, for some reason.  And in general, this also tested two different treatment strategies, not necessarily two different antiplatelet agents. So following what is considered standard of care,  most patients who received ticagrelor were preloaded prior to PCI, whereas patients who received prosegryl did not get the drug until they were actually in the cath lab.  And it was determined that PCI was going to happen. So there's about a 60-minute time difference in terms of when the two drugs were administered.  So in short, these results were interesting. They were unexpected. At minimum, they probably give comfort to clinicians who want to use prosegryl  that it's probably at least as good as ticagrelor. But there probably needs to be more investigation into this area to really determine  if there's a true difference between these two different drugs, again, highlighting some of the methodologic issues with the trial that  might have or may not have led to the results that we saw. Now, I just want to talk briefly about some recent advances in anticoagulant therapy.  I'm going to talk about VTE prevention and treatment in patients with cancer. Can we use DOACs for heparin-induced thrombocytopenia?  And then I hesitate, if you were in here in the last session, to talk about reversal of oral factor XA agents, relatively charged area.  So just briefly, if you remember CHESS guidelines in 2016, still recommended low molecular weight heparins as your standard of care to treat patients  with cancer-associated malignancy. And this is a summary of all the literature to that particular time frame. The CLOT trial is probably the trial that is most familiar to everyone  that showed that low molecular weight heparins were superior to oral vitamin K antagonists for preventing recurrent VTE events in patients with cancer-associated malignancy.  But with the advent of DOACs, the question is, well, are DOACs as good as? Are they inferior to low molecular weight heparins? Where do we stand with that?  And so many of you are probably familiar with the results, at least, of some of these trials. So this is the HOKUS-I VTE trial, which essentially randomized patients  to either Adoxaban or Daltaparin head-to-head for cancer-associated thrombosis. And you can see, in terms of VTE recurrence or major bleed,  there was no difference between the two agents. VTE recurrence was actually lower with Adoxaban compared to Daltaparin. But major bleeding was higher with Adoxaban  compared to Daltaparin. And most importantly, if you actually drill down into the major bleeding data, what you saw was that patients with GI cancers  tend to bleed much more with Adoxaban compared to low molecular weight heparin. And if you took out those patients with GI cancers, the risk of major bleeding was no different.  The SELECT-D trial was essentially the Rivaroxaban version of this particular approach, randomizing patients to Rivaroxaban or Daltaparin and cancer-associated thrombosis.  And again, you saw very similar results. VTE recurrence lower with the DOAC compared to low molecular weight heparin, but major bleeding higher, and especially  in those patients with GI-related cancers. And again, if you take out those GI-related cancers, the risk of major bleeding is not terribly different.  Then lastly, Apixaban's version, the ADAM-VTE trial, which was published within this last year, showed, again, relatively similar results,  randomizing patients with cancer-associated malignancy with Apixaban versus Daltaparin. And you can see that the risk, the rate of recurrent thromboembolism was significantly lower  with Apixaban versus Daltaparin. And so a number of societies have now updated their guidelines. This is the ISTH version. And this was prior to ADAM-VTE being published.  But you can see that for ISTH and also some of the cancer-associated societies like ASCO or NCCN, DOACs are now considered a first-line option  to consider for patients who have DVT or PE in the setting of malignancy. And so this is a nice option. Obviously, patients would probably much prefer to take an oral agent versus  a subcutaneous injection. The one nuance, of course, is that those patients with GI-related cancers are probably not the best candidates for DOACs, where in that particular setting,  a lone-molecule heparin still might be a better option for those particular patients. I want to just talk real briefly about prevention of VTE in cancer, because my suspicion is  that these patients might start to filter into ICUs here and there. And there has been a lot of interest in this over the number of years about identifying patients  who are at high risk for VTE development in cancer and then giving them prophylactic doses of anticoagulants in order to try and prevent VTE from occurring in the first place.  And there were two trials that were published within the last year or so that sort of really addressed this with the DOACs, AVERT with apixaban and CASSINI  with rivaroxaban, using prophylaxis doses of these DOACs. And both of them showed that you can reduce the risk of VTE in patients who are starting chemotherapy with a corona  score greater than 2, which are high-risk patients. And you can reduce that risk by about 50%. So there is the potential to see some of these patients coming  into the ICU for other unrelated issues who might be on these low doses of DOACs. And there is data to support their use in this particular area. And for those of you that are not  familiar with the corona score, it's up here on the slide for you. High-risk cancers like stomach and pancreas are two points. And that gets you a moderate risk all by itself.  And there's some other points scoring. The other parts of the point scoring system are there on the slide for you. What about DOACs for the management of HIT?  Just one slide on this real briefly. The American Society of Hematology released guidelines in 2018 that incorporated DOACs as being a reasonable option  to consider in patients with heparin-induced thrombocytopenia. And this is based on a pretty small observational studies. The most common DOAC that has been used is rivaroxaban.  We're talking less than 100 patients, though. But I think they come up with some pretty reasonable recommendations here in terms of who  to think about would be a reasonable candidate for a DOAC versus using an IV direct thrombin inhibitor. And most of those patients are probably not going to be in the ICU.  So I think more critically ill patients or patients where you suspect there's more life or limb threatening situations, an IV or a parenteral agent  is still probably what is recommended. All right. Lastly, in two minutes or so, reversal of oral factor XA inhibitors. So in one corner, Kcentra. In the other, and Dexanet, right?  So for those of you who don't know, that is Tyson Fury and Deontay Wilder, who are two heavyweight boxers who are actually going to fight about a week from now.  I actually was thinking about putting some more charged pictures up there, maybe some political candidates. But maybe not two. But what I wanted to really highlight  was the uber emotionally charged nature of this discussion. And I probably don't need, if you were in the session before this, you actually saw it.  And my reason for actually talking about this was that maybe try to have us pull back from our emotional charged nature of discussing this.  I feel like I talk to people about this debate all the time. And I feel like folks are coming at it from an emotional state versus just sort of thinking about this  from a scientific state. What I wanted to highlight was some data that was presented at ISTH and American Society of Hematology about an in vitro study that is funded by Portola,  full disclosure, but that I think had some very interesting results that I hopefully would urge you guys just to walk away and think about. Because I think we have a long way  to go before we actually figure out how to appropriately manage patients who are bleeding on oral factor 10A inhibitors. And the purpose of the study, I apologize for the formatting  here. The purpose was to compare three different reversal strategies using a tissue factor initiated thrombin generation. So this is in vitro.  Tissue factor initiated thrombin generation. And looking at really indexonet as well as PCC on their ability to restore thrombin production. So turning on the coagulation cascade.  And what I found really interesting was is that PCCs do not restore endogenous thrombin potential unless you are at plasma concentrations of DOACs that are below trough.  So if you look up here on the slide, you can see that roughly around 75, maybe you argue 50 is trough, 75. That if you look at a restoration  of endogenous thrombin potential for a Rivaroxaban or a Pixaban, it is not brought back to baseline or normal by a PCC. Once the trough levels are below that,  you actually start to see thrombin production. So maybe what this is arguing for is we need a better way to identify rapidly  if patients have therapeutic plasma concentrations of DOACs on board to figure out what reversal agent to actually use. But I wanted to leave you guys with that.  If you guys hadn't seen this information, my understanding is it will appear in a peer-reviewed publication at some point in the next few months.  But I thought this was very interesting data. So with that, I thank you. And I'll move off and go on to our next speaker. All right, that's wonderful.  I love the synergy between pharmacy and surgery. Many of you know I come from a family of pharmacists, my brother, my father, my sister, my niece.  I wasn't smart enough, so they made me a surgeon. That doesn't hold for our next speaker. Dr. Cohn is clearly the world's expert in the topic.  He's about to talk to us about new on the horizon and precision medicine and trauma-induced coagulopathy. He's the chair of surgery at Denver Health in Colorado. Mitch?  Thank you very much. I'm honored to be here.  I definitely resemble that last comment, the one about being the ignorant surgeon. I spent a lot of time looking at my pharmacy colleagues  in the ICU and saying, so what should we do here? Yeah, let's do that. So I'm going to spend 20 minutes, 15, 20 minutes talking about what's on the horizon and really talk  about precision medicine and resuscitation of trauma patients. I'm a trauma surgeon and intensivist in Denver and a basic science and translational investigator.  But for those of you who don't take care of trauma patients, who take care of septic patients, or take care of cancer patients, this stuff is very much appropriate and apropos.  So the big question for us is, what problem are we trying to solve when we resuscitate? So clearly, we want to stop the bleeding as trauma surgeons or trauma practitioners.  And we want to treat coagulopathy. And many of us have made a lot of hay on defining what is acute traumatic coagulopathy or trauma-induced coagulopathy.  But we very much also want to treat this dysregulated immune and inflammatory system. A lot of us are trying to use this word endotheliopathy to describe this sort of amorphous idea  of endothelial dysfunction, immune and inflammatory dysfunction, multiple organ failure. And very much what we are doing is trying to treat that endotheliopathy  and prevent that endotheliopathy. Yes, we want to fix the clot. Yes, we want to stop the bleeding. But we also want to resuscitate the entire patient.  And I'll remind you, in this era of precision medicine, this sort of one-size-fits-all, oh, the tags fixed, we're done. Or, oh, we gave this amount of product, we're done,  is, I think, naive and 20 years ago. And it is not the same in every patient minute to minute and not the same in that individual patient minute to minute.  Coagulation cascade, sequential protease activation, you get clot at the bottom, it's wrong. Looks a lot more like that. It's a very complex system.  This is a network topological representation that Karen Brohi and I put together. And I put it up here because it's a cool picture. But I really put it up here because it  belies the complexity that underlies all of this very complex system. And interestingly, the math and topology of coagulation  is similar to the yeast genome, is similar to the internet, is similar to social science networks. Very complex and very interconnected.  We're only a few steps from every other person on Earth. That's sort of six degrees of separation, which is actually probably two. Same thing in this very complex system.  So what we perturb at one side of it in a well-meaning way sends a huge perturbation and a huge effect throughout that entire cascade and affects the whole patient.  Coagulopathy after trauma, this is hours of talk for another time. But I will give you a few slides here. And it's come a long way from this hand-drawn conception  back in the early 80s out of the Denver Group long before I was part of it. To an understanding in the early 2000s, Karen Brohi's paper showing that patients  arrived to the hospital coagulopathic nearly immediately after injury. If you were coagulopathic, your mortality rate was close to 50%.  If you were not coagulopathic, despite a similar level of injury, your mortality rate was only 10%. Jenna McLeod, who often gets overlooked, published a contemporaneous paper  showing that this endogenous biologic reaction, again, not iatrogenic. It wasn't that we were pumping them full of cold saline  and diluting them and making them cold, all the reasons we thought these patients were bleeding. But instead, there was some endogenous biologic mechanism happening.  Not very long ago, 2003, these papers were contemporaneously published. I'll sum it up in just a few slides. About a third of patients that are severely injured and shocked  are coagulopathic, and it doesn't matter how you measure it. Conventional coagulation tests, PT, INR, PTT, or TEG, or other coagulation tests, these numbers  are remarkably consistent. Single center data, multiple center data, North American, European, the rest of the world, military, civilian, over and over again,  we see these same numbers. If you're coagulopathic and you don't resuscitate it, your mortality rate is very, very high. And there are multiple mechanisms, and I'll show you here.  And I'll tell you that these multiple mechanisms go from a hypocoagulable state, bleeding at 3 in the morning and when we're in the operating room trying to stop it,  very quickly transitioning to a hypercoagulable state. Probably anti-inflammatory early or cytoprotective is maybe a better word. And then they lose that cytoprotectivity.  They end up in the ICU six hours later or six days later. They have multiple organ failure. And the prothrombotic problems that we all treat in our ICUs on a daily basis,  while less sexy to the funding agencies than patients bleeding to death, are frankly a much larger problem in trauma. A couple of mechanisms I'm going to go through really quickly.  These trauma-induced coagulopathy, they include a paired thrombin production, platelet dysfunction, fibrinogen problems, dysregulated fibrinolysis.  And then we've spent a lot of time talking about, well, how do we resuscitate those patients? I know Marty Schreiber is going to talk after me  about goal-directed therapy and viscoelastic. I'm going to tease that just a little bit in this talk. But we've come a long way. In the 1970s, it was all about thrombin,  different active forms. Were we making enough? That became then cell-mediated hemostasis. This idea that it wasn't just about making thrombin.  And in truth, thrombin is not the big problem in trauma, but rather the sort of whole cell-mediated clot. Then tissue factor, really nice work  from a number of investigators, John Griffin and Wilfram Roof at Scripps and others, showing that there are tissue-specific activation of coagulations.  Your coagulation is very different in the mesenteric vessels than it is in the liver, than it is in the kidney, than it is in the brain. We're fond of protein C activation.  Protein C, as we all remember, is a wonderful cytoprotective anti-inflammatory stabilizing protease. When it's activated, however, it cleaves factors 5 and 8,  so it's profoundly anticoagulant. Our group and a number of others have shown that a lot of this is activated immediately after trauma, probably the body trying to keep itself  alive through the acute phase of something that was not meant to be survivable, namely getting shot, stabbed, or run over. And then the sequelae of too much of a good thing  is this profound anticoagulation. The endothelial glycocalyx, Rosemary Kosar and others have worked really beautifully on what happens at the endothelium, that this gets shed.  You end up with endothelial dysfunction, and you also end up with this anticoagulant milieu.  And then platelet function, it's a whole separate talk for a different time. But we now understand that half of our patients that come in immediately after trauma  have platelet dysfunction, half, 50%. They have normal platelets. We look at the CBC. We see 200, 300, 400, 500,000 platelets. We don't bat an eye.  It doesn't register that it's a problem, but they don't work. They do not aggregate. And a number of groups, including the Denver group that I joined a couple of years ago,  Scott Diamond at Penn and others, are working beautifully in these areas.  So that's about clot, right? So we know that clot doesn't form. We resuscitate, and I'll talk about that in a second to try to make that clot better, to fix that tag,  to fix the biochemistry of that clot. But it's not about that only. It's also about this balanced response to inflammation and coagulation. And we know that if we have too little,  we get this immune dysfunction and coagulopathy. If we get too much, we get inflammation and thrombosis and multiple organ failure.  And we've spent so much time in the trauma world trying to fix the clot and resuscitate the patient and fix the tag that I think that oftentimes we've forgotten  that we also really need to resuscitate the patient. And indeed, in the plasma-based resuscitation stuff that I'm going to talk about here, the data that I'm going to talk about  from a number of different trials and frankly what we've just done in trauma empirically,  probably more of the bang for the buck  in treating these patients and the mortality benefits that we've seen is something in that special sauce that is stabilizing the endothelium, stabilizing the inflammatory process,  and not as much about fixing the biochemistry of that clot.  Just a little segue here to remind you that we spent a lot of time geeking out in the basic science lab over the biochemistry of this  and showing these cool network topological problems. But we worked there and there.  The patient actually did well there. You can imagine the bleeding and inflammatory diathesis that that represents. Brain injury where it's not the volume of blood,  but a little bit of coagulopathy and a little bit of neuroinflammation is the difference between a functionally recoverable outcome and a devastating outcome.  And then big triage problems. Before I left San Francisco, we took care of this mass casualty, this Asiana 777 that shorted the runway at SFO and broke up.  And we had about 200 patients that came to San Francisco General Hospital, many massive transfusions straight to the OR, many patients who died,  patients who spent weeks in our ICUs.  But we also had a guy that I rounded on the next day as sort of the walking wounded. And he had his roller bag. I noticed that his roller bag was in the room.  And I said, God, they found your luggage? Like, how is that possible? And he said, oh, no, the plane crashed. And I like went in the overhead and I got my bag out.  And then I jumped down the slide. And there were pictures in the Chronicle of people pulling their roller bags through the fire retardant foam that the San Francisco Fire Department  was spraying all over this field,  which is, like, horrifying. You should probably just leave your stuff and get out of Dodge. But it belies a huge triage problem. That guy was in an ambulance  with all of the really severely injured patients in the back of the plane where that tail broke off. And trying to figure out really quickly who's sick,  who's not, who's off to the races, who can we deal with the next day, is a really interesting big data and biomarker problem.  So we've come a long way from this empiric versus laboratory-guided resuscitation. So many people will remember that for a long time,  we resuscitated with liter after liter of crystalloid and red blood cells, because we knew from the old shock research that our patients needed flow and oxygen carrying capacity.  And so what did we have? We had crystalloid on the shelf,  red blood cells in the blood bank. We forgot that all of those seminal papers from Carrico and Shires and others were done in the era of whole blood.  Whole blood was gone because of HIV, AIDS, hepatitis, and blood-branking practices that gave us components.  And we had to rediscover this. So in the Iraq conflict, Matt Borgman's paper showing that injured warfighters that got closer to this balanced resuscitation,  one-to-one for every unit of red cells they got, they also got a unit of plasma. They did better. That's pretty compelling evidence. Some question about survivor bias.  Did they survive because they got the therapy or they survived long enough to get the therapy? A little unclear, but we'll get there.  And lots and lots of civilian papers, this one from a number of centers showing that if you balance that resuscitation better, patients did better.  To the point where there was almost no equipoise to study this, a paper out of Pittsburgh looking at some of the glue grant data and just looking at what happened over this period  and showing essentially that everyone jumped on the bandwagon. Everyone was minimizing crystalloid, giving some sort of balanced resuscitation, and their patients were doing better.  Marty and I and others were involved in a number of these studies. This PROMPT study was a DOD-funded prospective observational collection of data.  We had 24-7 research staff with iPads following us around getting really good real-time data on what we gave.  I'll cut to the chase and say we didn't legislate one-to-one versus one-to-two, but the more balanced that resuscitation was, really about one-to-one-and-a-half  or one-to-two, patients did much better.  And then we were involved in PROPR, this prospective NIH-funded randomized trial studying one-to-one versus one-to-two.  Six hundred and eighty patients, a pragmatic phase three multisite randomized trial. The primary absolute outcomes were 24-hour and 30-day mortality, probably not optimal,  but what the FDA and NIH pushed us toward. And then a whole bunch of secondary outcomes and secondary papers.  And the bottom line was that there was no difference in the two groups. One-to-one seemed to be equivalent to one-to-two. There was a little bit of a separation  early at three hours, and that went away over time.  Interestingly, what was very cool is that we found out that we could do this big randomized blood bank trial in six hundred and eighty patients  in sort of the most difficult circumstances imaginable, right? These are enrolling a randomized controlled trial at three in the morning on a Saturday  that also happens to be Christmas, with very few protocol deviations and a very high complication rate. These patients were the sickest of the sick.  It showed that we could get blood out of our blood banks quickly. It showed we could get lab sampling and functional tests done quickly, which is really important in this era  of personalized medicine. We'll talk about it in a second. Unfortunately, it tested two very similar ratios with very poor separation.  When you added in what they got before the trial, we weren't really getting good separation in the group, and I think that was unfortunately the fatal flaw of the study.  Ultimately, there was no difference in the predefined outcome, but what it did show was that this plasma-based resuscitation, no matter what you believe,  and we're probably asking the wrong question, one to one versus one to two is probably not the thing, but a balanced resuscitation with minimized crystalloid,  those patients did well. Now, we've come a long way, and I know Marty's going to talk about this, but goal-directed resuscitation, because that proper trial was sort of  the thousand-pound gorilla in the room or elephant in the room,  went to the side for a little while. Senator Rizzoli in Canada had done a really beautiful preliminary trial looking at one to one versus a laboratory result-guided trial.  I don't have the data here, but I will tell you that they showed that that laboratory-guided, those viscoelastic tests made the patients do better. That got put aside.  He participated in proper, and it wasn't until the Denver group before I joined them, Gene Moore and others, actually did a prospective trial of this  and did a viscoelastic-guided resuscitation versus an empiric one to two at the time, and you can show a 20% versus 36% mortality,  and even better if you look at what they actually got, 20% versus 40%, fairly impressive results. There's the Kaplan-Meier curve and the hazard ratio and confidence intervals,  and so decreased mortality from 36% to 20%. Patients did better. More plasmid platelets were used early, but overall they got less product,  and the patients who survived did better in the ICU, all the other non-mortality outcomes. Single center study, but pretty compelling data, and to this day, this is what we use.  We are no longer the Denver Health Trauma Center. We are now the Ernestine Moore Shock Trauma Center after the beautiful work that Gene Moore has done defining our field over years,  but we are very, very TEG-protocoled, and this is what we look like. We spend a lot of time getting viscoelastic tests and guiding resuscitation.  To a fault, if I'm gonna be self-critical, and I'm happy to provide these to anyone who's interested, my email's at the end of this talk. You can take a picture or write it down,  and I'm happy to give all of these slides and our protocols and any help, that sometimes we are so about fixing the clot that our residents and our trainees think,  oh, well, the TEG's fixed, we're done. No, you gotta resuscitate the patient, and again, I personally very much think there is something in that special sauce  of a plasmid-based resuscitation that's keeping that endothelium happy, keeping the inflammatory and immune systems functioning well. I'm just gonna end here real quickly  with the idea of precision medicine. Again, this is dynamic. These patients transition really quickly, and that one-size-fits-all, if you wait until the next morning in the ICU  and you're not continuously monitoring them, those patients become really hypercoagulable. They become pro-inflammatory, for lack of a better word.  And it's 2020, and precision medicine does not mean cancer omics. It means, where is your patient now? Where are they gonna be in the next two minutes, two hours, or two days?  And I think that that's really the future. Tim Buckman, former president of this organization, wrote this editorial where he thinks  that patients don't move linearly through state space, but they move from these conditions in these quantum leaps, and it's up to us to figure out, what are those clinically?  Where is that patient in that physiologic or biologic state now? And where are they gonna be in, again, two minutes, two hours, two days?  And how can we, as they're treating physicians, nurses, and other practitioners, push them toward that healthy state and away from sickness? We spend a lot of time saying,  you know what, in machine learning world, we think like we're in DBNs, meaning we treat the patients like this, right? We think, where are they now? What are we gonna do?  We're gonna perturb them. We're gonna give them medication. We're gonna do some intervention. We're gonna see, did it work or not? That's gonna inform the prior.  We're gonna take one step forward, and we're gonna be smarter about the next thing we do to the patient. And so I'll just end with a few,  I'm just gonna skip through this stuff here, to where I think we really are. I was really lucky to work with a really talented control systems engineer named Amor Menendez,  who's now a young faculty at the University of Florida. And we think you can take this coagulation cascade and you can actually code this up.  So you can take that, you can reduce it.  And you can take thrombin generation curves, which we measure constantly in patients. You can actually do this now with TEG as well, but this is thrombin generation curves,  normal on the left, trauma on the right. And you can fit a mathematical model to it.  And you can do some impenetrable math, which again, we don't have time to discuss, but I'm happy to talk about later. And you can solve for this. And essentially what you can do  is have a black box model with thrombin, with a tissue factor in and thrombin out. And you can code this up as a model, and you can ultimately solve what those are,  2A, 10A, and 5A, and the tissue factor 7A complex. And then you can use the model very quickly with just a few things that you measure at the point of care.  You can say, what does the model predict that I either need to inhibit to bring hypercoagulability down to normal or add to bring a hypocoagulable patient  up to a normal coagulation state. And you can imagine, and so it turns out we have really good performance across all kinds of different trauma patients.  And what I think I did in a high impact journal is we then took these predictions back into trauma plasma. We spiked the trauma plasma, and we showed that the model output  could actually put that patient in the coagulation sweet spot that we defined as clinicians. And I think that's where we're going. We're not going to give,  I hope a few years from now, we're going to say, oh my God, can you believe we used to give these huge volumes of resuscitation products.  Now we can measure exactly where that patient is in the coagulation or inflammation state space. We can put it in a little model. We can run that computer on our phone  or on a little bedside monitor. It can tell us what to give, and we can make those patients better. And why now? Because we capture all of this beautiful data,  and we capture it in real time. Your phone knows more about you than you know about you. And we should be able to do this sort of thing in the ICU.  I'm going to skip past these last couple of slides and get to this, that I'm incredibly proud to walk the halls of what I consider one of the iconic trauma hospitals in the country,  formerly Denver General, then Denver Health, now the Ernestine Moorishock Trauma Center. If you get up on the ambulance and take a picture,  the security people get really twitchy, by the way. And I get to work with those people, and there's my email. So please contact me, and I'm happy to take questions  later during the panel. Thanks.  That's terrific, Mitch. Thank you very much. It gives me great pleasure to present our last speaker, Dr. Marty Schreiber, who is the Chief of Trauma and Acute Care  Surgery at the Oregon Health Sciences Center. And Marty's going to talk to us about, give us an update in visioelastic tests. Marty? Good morning, everyone.  You have here three trauma surgeons and a pharmacist. I think it sounds like a TV show. So I've been assigned talking about thrombolastometry this morning.  And you've heard some of what I'm going to talk to you about, but I'm going to talk about it in a little bit of a different way. I'm a consultant for humanetics, but for the purpose  of this talk, Teg and Rotem are going to be essentially equivalent. So I'm going to talk about the weakness of standard testing, INRPTT, standard coagulation testing.  I'm going to talk about Teg and Rotem versus conventional parameters and what data exists. And I'm going to talk about utility of thrombolastometry  and then summarize the current data that's available. Mitch showed you a version of this. This is the version that one of my residents created.  You heard that severe injury in tissue hypoperfusion creates acute traumatic coagulopathy,  which is exacerbated by resuscitation, particularly with things like crystalloid and packed red blood cells, which then causes a series of events  about some of which you've heard about. But hyperfibroanalysis, dysfibrogenemia, platelet dysfunction, all of these things can be measured more or less with thrombolastometry.  A single test that allows you to look at all aspects of both ATC and TIC with a single blood draw.  So what are some of the problems with INR and PTT? So for INR and PTT, blood's drawn, it's put in a citrated blue top tube. It then is spun for two minutes,  which removes the cellular elements. The red cells are removed. The thing that makes the clot gets removed. So how can you study clot formation  if you take the thing out that makes the clot? INR, you add some stuff. PTT, you also add some stuff. Then you warm it up to 37 degrees,  so you lose the effect of temperature on coagulation as a measurement. Then you put all this in a tube with a little magnet that bounces back and forth against two magnets.  And when that magnet slows down, that's when it's clotted. So this is really problematic because you're studying clot when you take out the red cell,  which makes up the majority of the clot. You can't look at the contribution of temperature. There's an artificial separation of pathways. It takes a long time.  It takes usually at least half an hour from the time you draw the blood till you get any result at all. And another real problem is that if it's really abnormal,  you have to repeat it. So then in the ones that you want the most, it takes even longer because you're repeating it. All of this is based on this.  As you saw from Mitch, it's much more complicated than that. All of the pathways are intermixed. So the concepts of INR and PTT, intrinsic  and extrinsic pathways, actually don't make sense from a physiologic standpoint because all the parts of coagulation are mixed.  And so what you need is tests that look at it in that manner. And really that's what you're getting with Teg and Rotem. So here's the clot. Notice almost all of its red cells.  And you've removed the red cells when you do the tests. So you're gonna lose your accuracy. You can see there's a little bit of fibrin in here and some platelets.  And you're measuring fibrinogen, you're measuring platelets, but you've taken out the red cells. So what about the measurements of platelet and fibrinogen?  These are numerical alone. You get a platelet count. You get a fibrinogen number. Tells you absolutely nothing about the function. What are those platelets doing?  Is the patient on antiplatelet agents? And are those platelets functional? Same thing with the fibrinogen. Is the fibrinogen functional?  So Teg and Rotem are functional tests that allow you to see exactly what these things are doing. And all of these things are affected by common medications  that our elderly populations are taking. So you can't just rely on the tests. So what's the difference between Teg and Rotem? Teg has been around forever.  It was first utilized in 1948. There's a beautiful textbook for all kinds of Tegs in it from the Vietnam War written by General Hardaway. We've been using it for a long time.  How does it work? A pin hangs from a torsion wire, sits in fresh blood, and the cup spins. And what you're measuring is the movement of the pin.  Okay, you're measuring the movement of the pin. What's going on with Rotem? Now, Rotem is a newer test. It's a fancier box. It does some auto QCing, a little bit more modern.  But the main difference now is that you're measuring the resistance to the rotation of the pin. So in this case, the pin is moving, and it's hooked  up to a system that measures resistance. So even if you have a pin moving versus a cup, it doesn't matter. What you're measuring is the development of the clot  and the resistance that the clot is producing to the pin movement. Okay, so you're doing exactly the same thing. Now, the other part of this is they've come up  with different names from things. So you're measuring either test time between the start of the test and the start of clot formation, that's the reaction time,  or R value in Teg, but the coagulation time in Rotem. You're looking at the time to start of clot formation to a certain amplitude, that's the K value in Teg,  the clot formation time in Rotem. You're looking at the slope of the curve, that's the rapidity with which fibrin is cross-linking, alpha angle in both tests.  You're looking at the strength of the clot or the maximum amplitude, which is the maximum amplitude in the Teg, and the maximal clot firmness in the Rotem.  And then you're looking at measures of lysis. So the two things are doing essentially exactly the same thing. Either way, you get a curve that looks like that.  Initially, there's no resistance to movement of the pin or the pin isn't moving. Then the pin starts to move as clot forms. You can measure how rapidly the fibrin is cross-linking.  You reach a maximum amplitude or a strength of the clot, and then you see lysis. So both tests are doing the same things. If you take the same blood and do a Teg  and a Rotem simultaneously, you get essentially the exact same results with respect to clot time, alpha angle, maximum clot firmness. If you measure overall strength or g-parameter,  essentially the two tests give you the exact same numbers. Okay. So based on the name of this section of the conference, does thrombolastometry give you  an accurate measurement of the coagulation status of an anticoagulated patient? Okay? So this is a very early concept that people are looking at, but it does not appear  that thrombolastography gives you a good pre-injury anticoagulation status in acute trauma patients who are on anticoagulation.  I'm going to talk a little bit more about this later with some of the work that we did that I think you'll find interesting. But if you do Tegs and look at patients  who are not anticoagulated versus anticoagulated, you see that there's very little detection of coagulopathy in those anticoagulated patients. Eleven percent versus 15 percent,  these are not coagulated. These are anticoagulated patients. Very little difference in the Tegs and no difference statistically.  But if you do the conventional tests, you do see differences in coagulation tests in anticoagulated patients. And this looked at both patients who were on Coumadin  and patients who were on DOACs. So one of two things is going on here. Either the conventional tests are too sensitive or Teg is not sensitive enough  or there's a combination somewhere in the middle. And this is an unanswered question that I think is really fascinating. And I'll show you some of our data earlier  that we've done earlier. So how can these tests be used functionally? Well, one major use for these tests is to give a more personalized transfusion rate, as Mitch talked about.  And this has primarily largely been done in cardiac patients. And this is an example of one such study, the study by Ak et al., who looked at patients undergoing cardiac surgery.  And they compared patients who underwent transfusion of components based on conventional tests versus those that underwent transfusion based on Teg values  with standardized parameters for when transfusion occurs. And you can see if you look at this intraoperatively for plasma, if you go by the Teg, you give less product.  The use of the Teg to guide transfusion results in the use of less product both intraop and postop and overall. Same thing if you look at this for platelets based on the MA.  You see a reduction in platelet transfusions both intraop and overall when Teg is utilized to guide the transfusion of platelets. So reduction overall in blood product use  in a personalized manner. This was shown to you by Mitch, so I won't go over this extensively. But the same thing that's being done  in cardiac surgery is now being done in trauma surgery. So the idea is you do Tegs or Rotems, and then you base your resuscitation on the result  of those Tegs with guidelines and parameters. You see here the ACT for a rapid Teg, angle, MA, LY30, guide the use of FFP, cryo, platelets, and TXA.  So when you think about this, people have talked about should you just do a balanced resuscitation of 1 to 1 to 1 or some ratio versus should you do this based  on thromboelastometry. In my mind, the correct answer is that you do both. In an exsanguinating patient getting a massive transfusion,  we are giving whole blood to resuscitate the patient, and every 30 minutes we do a Teg, and based on the results of the Teg, we give adjunctive component therapy.  It's not one versus the other. It's both. Okay? So these are results. Mitch showed you this. There's a reduction in mortality if you use thromboelastometry to guide the use  of transfusion in trauma patients. And you can see this overall difference in survival. There has been a Cochran review of prospective randomized trials looking  at thromboelastometry to guide transfusion use. This Cochran review is almost all cardiac studies. There's one transplant study, and there's one burn study.  Okay? Two of the studies are in children. 1,493 participants, 15 prospective randomized trials, shows that with thromboelastometry,  you can reduce mortality, blood usage, and dialysis, meaning a reduction in renal failure rate. So I think this is very, very interesting.  Now, as I mentioned, what about the whole blood era? So our institution, probably somewhere around 30 to 50 institutions around the country are using whole blood now  for the primary resuscitation of trauma patients. These are all bags of whole blood, 44 units. You can see a few units of platelets and some plasma.  And one single unit of crystalloid. I can't quite get rid of that one single unit of crystalloid. I'm really working hard on it. But this is an example of one of the patients  that I recently took care of. It's a typical Oregon patient. It's a cirrhotic motorcyclist, three-week status post MI, who of course is on Plavix after stent placement,  riding his motorcycle. Okay, he comes in, he gets in a bad trauma. He's got a splenic injury. He's bleeding from everything. He's bleeding from his IVs.  We're in the operating room, and we make an incision. It's bleeding heavily. We start the Teg, and using Teg Manager, we start to see this Teg.  The Teg gets to about there, which takes about 10 minutes, and immediately we order fibrinogen and platelets. And based on our protocol, we repeat the Teg in 30 minutes,  and it becomes nice and normal. The bleeding stops. We take out the spleen, and the guy lives to ride his motorcycle once again. So this is another example here.  This is some really good data. The Austrians are really into getting away from the use of components for the resuscitation of trauma patients.  And instead of components, they're using concentrates. And the two concentrates studied in this study were fibrinogen concentrate and PCC.  And the concept here was that upon admission of a trauma patient, you would do a Rotem, and based on the results of the Rotem, you now specifically replace  with either fibrinogen concentrate or PCC. And many of the patients in this study were actually anticoagulated. The majority of them in 2010 were anticoagulated with Coumadin.  So what they found was when they did this, and they used a Rotem-based resuscitation guide, they gave essentially fibrinogen concentrate to essentially all of the patients.  A large amount of patients, about two-thirds of them received prothrombin complex concentrate. And look at this. Only 12 patients, less than 10% actually got FFP,  and maybe 20% got platelets. Essentially replacing component replacement with concentrate replacement guided by the Rotem. And I think that, you know, I see this as the development  of where we're headed in the future. One word of caution, a process that's been identified also from Denver General is this concept of fibrinolysis shutdown.  So what does it mean if you do a Teg on a patient and there's no lysis, or the lysis is less than 0.8%? Well, it turns out that if there is lysis, mortality is actually higher  than when lysis is physiologic, meaning a little bit more lysis. But the highest mortality occurs when there's hyperfibroanalysis. So people are arguing, should we be giving TXA,  which actually shuts down lysis, and a patient already has lysis? So this is an interesting concept that has not been formally worked out.  Now I want to tell you about a study that we finished and published in 2013. And what we looked at was plasma use in our institution.  Plasma use occurs in a lot of patients, for instance, if they're undergoing surgery, they're going to have an epidural place or undergo an IR procedure.  And typically what was being done is that the INR was being measured. And if the INR was elevated, the patients were getting plasma.  Okay? So this is 106 patients, mean age of 60, pretty sick, Apache of 8, 60% males. They received a total of 262 units of plasma. Okay? So if you look at their pre-FFP INR,  the mean was 1.87, which really isn't that abnormal. The post didn't change very much. It changed to 1.53, not much difference in PTT, fibrinogen, D-dimer, or platelets.  Now, if you look at that same patient population, same blood draw, and you do tags on them, their tags are absolutely normal. Just in the center, in the center of the normal range,  all of these values for tag are normal, and minimal change occurs as you give the FFP. So in very few of these 102 patients were the tags  abnormal, and basically we're now guiding our use of the plasma in these patients on the tag, and we're giving much less plasma product. We also measured factors in these pages.  What we found was that the factor levels were decreased by about 30%, which gave those INR values of 1.8. But overall coagulation with that reduction  in factors actually remains normal. So very, very interesting work. But just quickly in summary, thrombolastometry provides compelling data, which I think is very important.  It tells you about the full spectrum of coagulation. The utility in anti-coagulated patients is unknown and needs to be studied further. It's a functional test.  It's rapidly available, and you can see it as it is occurring. And that's all I have. Hopefully we have a little bit of time for questions.  Yeah, we have, I don't believe we have a direct follow-up in this room, so we're more than happy to take some questions. If you'd like to come up to the microphone  and ask a few things.  Everybody's hungry. Time for lunch. Yeah. The front microphone. Hi. Megan Payton, intensivist for HCA. With the last comment using the TEG to guide plasma  for pre-procedural INR, is there any concern you had mentioned earlier that there was some question over whether the TEG wasn't sensitive enough  and the conventional tests were too sensitive? Any concern there with that pre-procedural discrepancy as well? So I think that is the real question  that hasn't been truly worked out. But I think that the area that gives me comfort in using the TEG is when you look at the actual factor levels, as I mentioned,  the degree of reduction of the factor levels is not to a degree that you would expect to cause coagulopathy. And I think what's happening is  that the INR is just extremely sensitive to any decreases in the vitamin K-dependent factors. And so I actually think it's too sensitive.  And the TEG is giving you a more balanced view as to what's really happening in coagulation. Since we've moved to this practice, we're not seeing an increased complication rate.  But that is not, we haven't formally studied that and proven that in any type of randomized trial. I have to be a little of the contrarian,  fully admitting that I don't actually know the answer. We see a discrepancy in trauma patients, in patients that come in an anticoagulation where they have a perturbed TEG,  but a normal INR or vice versa or both. And we've published on this. And the INR, the patients who have a perturbed INR or PTT can bench something  in the conventional coagulation test. I don't think it should be thrown out. There is some biomarker there, which is predictive of additional bleeding risk, worse outcome.  So whether that is some sort of, it's really functioning as a biomarker of worse injury and worse outcome or really a bleeding diathesis,  I don't know, but I still remain, I don't know the answer. I still remain a little uncomfortable when the TEG is stone cold normal and the INR is perturbed  about not resuscitating them or not fixing that in some way. I think those patients bleed. I think they behave differently. Again, in this era of precision medicine,  I think that's the beauty is that these are complimentary tests that help us phenotype our patients. So I think there's a lot more work to be done there,  but we know those patients are not normal. So, you know, and I agree with everything Mitch has said, but I think the real question with the INR is at what point  in a stable non-bleeding patient is going to go an epidural or an ICP monitor placement? At what point does the INR indicate that you should correct it?  And I think that our, if you're using something like a 1.5 or 1.8, I think that's probably a little bit too conservative. If the INR is 5 or 3, you need to correct it,  but in general you're going to see an abnormal TEG with those degrees of abnormalities. I think that's true, but the question is what's the cut point for a TEG?  If you're just going to put, you know, if you're begging your anesthesiologist to put in an epidural or you're going to do some small procedure  with low bleeding risk, maybe they don't need to be corrected at all. I don't think we know the answer, but I agree. I'm Harry Wilkins, former trauma surgeon.  Now I'm an acute care surgeon at a community hospital, and this all confuses me greatly. Last week. Us too. Okay. So I'd like to, because Dr. Cohen,  you mentioned something that troubles me quite a bit. You said, to be honest, you had your residents that now say the TEG is normal, we're done, and that concerns me quite a bit.  So last week I had a 68-year-old woman who wasn't riding her motorcycle, but she had a stent placed two weeks ago, so she's on Berlenta, an aspirin.  She's hypersplenic, so she has a platelet count of 18,000. Then she got pneumonia. She's COPD, so she's on the ventilator, and my intensivist wants me to do a trach  on her at the bedside. She's day nine. She's on 80% oxygen, 10 a peep. Cardiologist is telling me I can't stop the platelet, can't stop the Berlenta.  She's also, by the way, in renal failure, so she's on CRT with citrate because the platelets are too low, and now I have to do my trach.  I looked at her, and none of her IV sites are bleeding. Respiratory just did an arterial stick. It's not bleeding.  She's got 18,000 platelets. I told the intensivist I'm gonna go ahead and do it, and I did her trach absolutely no problem with 18 platelets on Berlenta.  How do you reconcile clinical versus TAG versus pharmacists? Where do we go from this?  Yeah, it's a good question. So I think there are sort of two separate thoughts there. In the acutely injured trauma patient who is in the middle of resuscitation,  you are not done when the TAG is normal, or if the TAG is normal at the beginning. There are plenty of patients. They need resuscitation.  That's fixing the endothelial side of things. In this patient you're discussing, God, we see those all the time, right? I mean, that's what we do, unfortunately.  There are lots and lots of patients that are purposely anticoagulated walking around, and they don't bleed, just like this one, who every number is horrifying.  And so I think without clinical bleeding, yeah, your sphincter tone's a little higher, and you're a little more careful, and you use better surgical technique  and really good hemostasis, but we go forward. And just because the numbers are perturbed, I think we don't resuscitate patients who aren't bleeding.  So if you can get through the procedure in this trach, and I think Marty's gonna say don't do the trach, but if you can get through this procedure at a relatively low risk,  being a little more careful, then you do so, and you don't need to fix it in the advance. On the other hand, she needed a big laparotomy  or a craniotomy by our neurosurgical partners. That's a whole different ball of wax because the bleeding diathesis or the risk is much higher.  Thank you.  Front microphone.  Thank you. Great talks, everyone, by the way. Galit Berman from MGH and MIT. I'm not gonna ask a question about TEG, but actually from the very first lecture,  just a comment on choosing anticoagulants for patients in different indications.  You know, I've read a lot of the papers and gone to a lot of these talks, and what no one ever brings up is the pharmacology mechanism of action,  and I'm not talking about thrombin versus 10A inhibition versus vitamin cantagonist, but more the metabolism of these drugs and choosing them for the right patient.  So I'm not surprised at all that a lot of the 10A inhibitors cause more GI bleeding because they are already in active form and you're administering them to the GI, right?  They're primarily excreted through the urinary tract system, I think in active form also, so genitourinary bleeding, right? Versus something like a vitamin K antagonist  which has to go through metabolism, right? First, liver metabolism. And correct me if I'm wrong, but I think also Pradaxa needs to go through metabolism to get into an active form.  So that's an area that a lot of these papers go into when we think about picking different medications for our patients. It's not just about what the specific drug is doing,  but think about how the drug is metabolized in that patient. If your patient has a history of GI ulcers, you probably don't wanna give something that's already active.  It's gonna be more concentrated and completely stop bleeding in that area versus something like Warfarin, right? Where you have to get to a certain level  and it's not primarily active in the GI, it's systemic. So just something that I would love to hear more about in papers or discussed when results are brought up.  Yeah, so great comment. I would just say what you're describing is kind of what I do. So I mentioned I direct our inpatient antithrombosis service.  And we prospectively surveil everybody in the hospital that comes in that's on Warfarin, DOACs and whatnot. But part of what we do is really patient selection.  And so obviously I didn't really touch on any in my 15 minutes to talk about updates in therapy. But you bring up excellent points. We've got all these phase three trials  that show that DOACs are a great addition to our options to manage patients with thromboembolic disorders. But, and everybody, I think when they first came out,  my fear was like everybody would think,  you know, Warfarin's gone, it's extinct. It gets around all the drawbacks of Warfarin, which it does some, but it also comes with their own drawbacks, right?  So I think one area that just to highlight that's underappreciated is that all of the DOACs still have drug-drug interactions, significant ones that you have to try and manage.  And it's not like Warfarin where you can measure an INR and adjust, it's either a precaution or a contraindication, even though it's not technically called a contraindication  in the prescribing labeling. So, yeah, so I think all your points are excellent in that, yes, okay, now I've got this AFib patient,  but I need to evaluate renal function, hepatic function, drug-drug interactions, other past medical history like a GI bleed, which might push you back towards Warfarin,  or maybe I'm gonna use a PIXIVAN, which appears to have less GI bleeding compared to Warfarin.  So, yes, I agree with you 100%. That's the clinical application of the trial data that we have.  Right here. Good afternoon, my name is Sonia. I'm a critical care pharmacist out of a small community hospital in Northwest Indiana. And I have two quick questions for you.  So we're trying to get TAG in our system, our hospital. First of all, how long did it take you guys to get it approved and all that good stuff?  And then secondly, who's your champion? Who is responsible for reading the curves and calling out the decisions? Because I'm getting a lot of, no, no, no, no, no,  that, no, I can't, I'm not here all the time, or, you know, so I'm getting a lot of finger pointing. So our situation is very special, and what happened was I was the bulldog  that advocated for it. I bothered them enough over about a five-year period that they finally said, just do it yourself. We had accrued a bunch of machines,  some very generously given to us, some we purchased, and we have in-house coordinators 24-7 in-house.  So my coordinators, my research coordinators do all the TAGs and the trauma surgeons read them. That's gonna be a local event. It's gonna be a little bit different in all places.  In some places, the lab takes it on, and it's in a central lab. I think there's advantages and disadvantages of having a central lab. I like having it as a POC,  especially with the new machine, the TAG-6S, that's a mobile machine that's a little bit easier to use, but that's how it happened for us, and it requires an advocate, which was me,  and I got a lot of gray hair and lost some hair over it, and finally we got it, but it was, in the end, it was us that did it. It was our research coordinators  and the trauma surgeons that read it. Yeah, we grew up with it, too, obviously researching on it, which puts us in kind of a different stead, but I think now in 2020,  there's data out there to show that it reduced costs, and I say it, TAG or Rotem, there's data to show and protocols out there like ours that we put up here to say  this is how you can use it, so you don't need to be some investigator like Marty or have someone around. You can actually really protocolize based on it,  and what we've found is in areas where we don't protocolize, but we have bleeding patients, patients that come in anticoagulated, GI bleeders, obstetric hemorrhage,  other non-trauma things,  our practitioners, and I say practitioners, nurses, docs, APPs that just do it become really facile with it and sort of write their own protocols,  and maybe they steal some of those from the literature or their colleagues, but it is just another test, and they say, oh, yeah, this is perturbed,  and I know the clinical situation, so I'm gonna give X, Y, or Z, and we've found that it works. I will tell you, we have a whole research lab of a gajillion of these things,  but we do it through the central lab, and anyone can order it through the electronic medical record. We have trauma surgeons in-house 24-7  that know it if somebody needs a little help, but people don't call that often because they can figure it out pretty readily.  Middle. Conor Miller from Penn State working the heart and vascular ICU there. I think for those who are just getting into Teg,  it's probably worth pointing out that there are a lot of reports of Teg not being very good at picking up platelet inhibition of aspirin or Plavix,  and so clopidogrel, I've certainly seen that where a patient was loaded with Plavix just before getting their stent, and then their Teg was stone cold normal an hour later,  and I wonder if that might overlap somewhat with what you're describing where these trauma patients seem to have platelet dysfunction, and yet their Teg is normal  due to the activation of the platelets in the Teg itself. So I think your last sentence is the problem. So when you're looking at platelet activity  in trauma patients or cardiac patients or major surgical patients, these patients have had a major injury and their platelets are activated, and the platelet mapping is measuring  the response of the platelets to an agonist, right? So you're giving an agonist to the platelets and then measuring their response. If the platelet is already maximally activated,  it will not respond to an agonist, and that's being interpreted as an inhibited platelet, but what it really is is a fully functional platelet that's actually been fully activated  and can't respond to the agonist. So the technology is problematic in certain settings when the platelets are activated. We're working on that exact problem  because independent of whether it's Teg platelet mapping or it's some sort of impedance agrogometry or you're flowing these platelets over collagen, all of which we've done,  again, it's this chicken and egg problem, right? You have ex vivo platelets, which you then re-agonize with some sort of agonist and you wanna see whether they stimulate.  So as Marty said, if they're already fully activated, maybe they're not gonna respond. If they're not activated, so it's this chicken and egg question.  Are they doing what they're supposed to do in the body? And this is a problem for all of us who deal with, and maybe our pharmacy colleagues have better insight on this,  that are putting patients on antiplatelet medications. We have no idea how well, in general, these are working. And it's not a lack of the technology,  it's a lack of this sort of pre-activation, post-activation problem. And we're trying to figure out if there's better ways to look at platelet activation in that regard.  So I think, the way I look at this in general, I think the test tells you what the test tells you, but it has to be interpreted in the specific scenario of the patient.  And this is an example of such a scenario where if the platelets are activated, they're not going to respond to the agonist. So you have to have that knowledge.  And so I think the test is acting appropriately, but you have to interpret it in the setting of which it's done.  Last question. Thanks. It's a pleasure to ask a question to such a distinguished panel of friends of mine. My name is Eric Barquist and I live here in Orlando.  You touched a little bit on a question that I think is really important. One, I can't remember who the speaker was, but you mentioned the prolonged thrombocytopenia  that we see in some of these patients. And it's very perplexing. So recently I had a patient who came in crushed by a car,  multiple, multiple arrests, got better. Day 10, we're still dealing with a platelet count of somewhere between 14 and 20, although we're not having clinical bleeding.  We know we've got a severe endotheliopathy. The patient is sucking up platelets like crazy.  And we go ahead, we know that they're hypercoagulable. We start a low dose heparin, which drives everybody else other than the trauma surgeons crazy,  even though we don't have clinical bleeding. Actually, this patient had a small right ventricular thrombus from having been in an arrest state so many times.  How do you treat that endotheliopathy? One of you sort of said, you didn't say it out loud, but you sort of implied that you just ignore it,  that you live with a platelet count of 20.  And you wait 10, 16, 20, 25 days for that to get better. We don't have any drugs. We lost activated protein C, which is really the only drug we had for endothelial dysfunction.  Do you ignore it? Do you transfuse it? Do you give the heparin and let all the other surgeons in the hospital go crazy? What do you do with that prolonged,  consumptive thrombocytopenic state? So, Eric, you're asking sort of two questions, right? So, endotheliopathy, we have excellent data that shows that both plasma and platelets,  which of course contains, platelets are suspended in plasma in the United States. Plasma is a potent corrector of the endotheliopathy,  but also rebuilds the glycocalyx. That data from Shabani Patti and Rosemary is very, very clear. So I think on that side, that's one issue. The second issue you raised  was the prolonged thrombocytopenic issue, which I think is part of the spectrum of endotheliopathy. And that's a multifactorial problem,  which comes from initially consumption, right? So these are massively bleeding patients. There's a consumptive process. We do not have a good source of platelet replacement  because our stored platelets, which are five days old, stored at room temperature are essentially non-functional. If you use leukodepleted whole blood,  that has a decreased platelet count and decreased platelet function. So we don't have a good replacement. But the other element of this is now that your platelet count has dropped  from consumption and poor replacement, you now have a bone marrow suppression in a severe trauma patient and platelet production is reduced. So as opposed to the other components,  red cells, I think our transfusion is very effective. Plasma, I think it's very effective, whether you're using whole blood or components. But platelets, we do not have a good way  to replace platelets. And then on top of that, you've got this bone marrow suppression, which can last for a very long period of time and you can't replace the platelets.  I'll just add real quickly to that. I think it's easy to say, but you resuscitate the heck out of them early because it establishes that trajectory  to have that bone marrow suppression in that problem. Platelets also in particular, we are learning. So even when the number is good, they're dysfunctional.  They're probably dysfunctional because there's something floating around in that soup, some damp that is inhibiting them. And a number of people are starting to talk  about these things, calling them zombie platelets or ghost platelets. The platelets are there, they're not degranulated, they're just not functional.  Scott Diamond at Penn is doing really beautiful work on that. Lucy Kornbluth at UCSF is doing really nice work on that. And probably something about that dysfunction  also then causes them to be cleared. So you're not making enough and you're actually clearing them. So I think without an answer, that is frankly the next frontier.  I think platelets are very under-recognized in their importance for both endothelial resuscitation and clotting and how to give them because traditionally we've given them,  but there's something floating around that makes them dysfunctional even when we give them and they're not so hot what we give as Marty suggests. I think that's the next big topic.  So I'm hearing you would let them be thrombocytopenia because transfusion isn't helping. And if you need systemic heparin, go for it.  Yeah, if they're not bleeding, then don't fix it. I think your question is, we had the earlier question about the trach. In the end, it's clinical judgment, right?  You get all the information and you put it together and you look at the patient. If they're not bleeding and they seem to be doing fine, you make a clinical judgment.  And it's really hard to get the platelet counts up in these patients when they're not making platelets from bone marrow suppression and the products you're using are not effective.  All right.  I got you, Ben. In HIT. So that, you know, in general, when the patient has heparin-induced thrombocytopenia, that's the only time that we're using our gator band.  Not in general, yeah. All right, I'd like to thank the speakers and enjoy the rest of your conference.

Video Summary

The video discusses updates in antiplatelet and anticoagulant medications, specifically in critical care patients. It covers studies on managing patients with concomitant atrial fibrillation and percutaneous coronary intervention, as well as the duration of dual antiplatelet therapy. The video also explores the use of periprocedural bridging with anticoagulants during surgical interventions and the choice of P2Y12 receptor antagonists in acute coronary syndromes. It highlights recent advances in anticoagulant therapy, including the use of direct oral anticoagulants in preventing and treating venous thromboembolism in cancer patients, and their potential use in heparin-induced thrombocytopenia. The video also discusses the need for more research in anticoagulation and the potential of precision medicine in trauma-induced coagulopathy. <br /><br />Additionally, the video transcript focuses on the use of thromboelastometry (TEG) and rotational thromboelastometry (ROTEM) tests in measuring coagulation. It explains that these tests provide a more comprehensive view of coagulation compared to standard tests and can guide personalized transfusion therapy, leading to reduced blood product usage and improved outcomes. However, the challenges of using TEG and ROTEM in patients on anticoagulation therapy are also mentioned. The video emphasizes the importance of considering factors such as metabolism and patient history when choosing anticoagulants for specific indications. It also addresses the challenges in managing prolonged thrombocytopenia in patients, particularly after trauma, due to platelet dysfunction and reduced platelet production. The speakers stress the value of TEG and ROTEM in assessing coagulation and guiding transfusion therapy, while acknowledging the need for further research and clinical judgment in individual patient management.

Asset Subtitle

Pharmacology, Hematology, 2020

Asset Caption

The Society of Critical Care Medicine's Critical Care Congress features internationally renowned faculty and content sessions highlighting the most up-to-date, evidence-based developments in critical care medicine. This is a presentation from the 2020 Critical Care Congress held February 16-19, 2020, in Orlando, Florida, USA.

Learning Objectives

Differentiate between the latest anticoagulant and antiplatelet agents our patients may be taking and these agents' varied effects on outcome
Adopt the latest practice management guidelines on the balanced resuscitation of trauma-induced coagulopathy
Compare and contrast the advantages and disadvantages of viscoelastic tests (eg, thromboelastography) in the assessment and treatment of coagulopathy and platelet dysfunction

Update in Antiplatelet and Anticoagulant Medications

Toby C. Trujillo

What's New on the Horizon: Precision Medicine, Acute Traumatic Coagulopathy and Endotheliopathy

Mitchell Jay Cohen

Thrombelastometry: An Essential Tool to Assess Coagulopathy

Martin A. Schreiber

Meta Tag

Content Type Presentation

Knowledge Area Pharmacology

Knowledge Area Hematology

Knowledge Level Intermediate

Membership Level Select

Membership Level Professional

Membership Level Associate

Tag Anticoagulation

Tag Transfusion

Tag Coagulation

Year 2020

Keywords

antiplatelet medications

anticoagulant medications

critical care patients

atrial fibrillation

percutaneous coronary intervention

dual antiplatelet therapy

thromboelastometry

rotational thromboelastometry

coagulation tests

personalized transfusion therapy

clinical judgment

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