Hey everyone, welcome back to another episode of Behind the Knife's Journal Review Series. We are the Miami Trauma Team, back with another episode from Jackson Memorial Hospital's Reiter Trauma Center. In this episode, we're going to be talking about venous thromboembolism prophylaxis. I know it's not the sexiest topic in trauma surgery, but it's incredibly important nonetheless. What exactly is there to talk about? Don't we just give people Lominox twice daily if we're able to and call it a day? That's exactly why we need to be talking more about this topic. Even with standard chemoprophylaxis, VTE rates in high risk trauma patients can approach 30 percent. Today we're going to focus on two recent papers that describe somewhat novel approaches to VTE chemoprophylaxis and attempt to move the needle on this shockingly high VTE rate. The first paper discusses the addition of aspirin to VTE chemoprophylaxis regimen, and the second offers some new insight into the monitoring of factor Xa levels by examining the association of changes in antithrombin activity over time with responsiveness to enoxaparin prophylaxis and risk of trauma related

VTE. So, hopefully this will be helpful for all levels of our listeners, as these are topics I have heard a lot about recently, but I personally don't have a good understanding of how it should be applied to clinical practice. Fortunately, we have the privilege of being joined today by Dr. Brian Cotton, who co authored one of these papers to help guide our discussion. As always, we'd like to start with some introductions. I'm Mike Kobler Lichter, PGY 4 in General Surgery, in my second of two years of dedicated research with our trauma faculty here in Miami. And I am a graduate of the general surgery program in Miami, and shortly I'll be on my way to my first year of vascular surgery fellowship at the University of Pennsylvania. I'm Eugenia Kwan, a newly minted trauma and surgical critical care attending at Loma Linda University, having just graduated from fellowship at the Ryder Trauma Center. Hey, my name is Brandon Parker. Thanks so much for having me on today. I'm originally trained in emergency medicine and surgical critical care and now an assistant professor of surgery at the University of Miami and the medical director for the trauma ECMO program

here at Rider. I'm Brian Cotton. I'm in Houston at the University of Texas Health Science Center in Houston and at the Red Duke Trauma Institute at Memorial Hermann Hospital. Active research in trauma surgery problems such as bleeding too much and not bleeding enough, clotting too much and not clotting enough. So I think that's why I'm invited here today. All right. So as mentioned, today is all about VTE prophylaxis. Should we be dosing Lovenox differently? What about adding aspirin? We're going to be talking about all this stuff and more. And the links to both of those papers will be in our show notes. So let's get into it and first talk about the aspirin paper. So to give a bit of background, though current chemoprophylaxis regimens largely target the inhibition of thrombin, ongoing platelet activation through alternative pathways is thought to play a critical role in post injury VTE development as well. Aspirin has demonstrated efficacy in VTE prevention within both medical and orthopedic literature and has even been shown to be non inferior to Lobanostra VTE prophylaxis in isolated orthopedic trauma

patients. This paper we're going to be talking about then tried to determine if a similar effect would be seen in polytrauma patients with the addition of aspirin. So Eva, how is this study designed? Yes, so this was a retrospective observational study of prospectively collected data from all adult patients admitted to a single American College of Surgeons Level 1 trauma center from January 2012 to June 2015. All patients 16 years of age or older who sustained a traumatic injury admitted to the trauma service were included. Exclusion criteria included presence of VTE on admission, discharge or death prior to starting chemoprophylaxis, or a present diagnosis or being presently treated for venous thromboembolism prior to admission. Patients who had charge codes for both aspirin and lovinox or infractionated heparin were made part of the standard chemoprophylaxis plus aspirin group. While those with charge codes of only lovinox or infractionated heparin were made part of the standard chemoprophylaxis only group. The standard prophylaxis group dosing paradigm was lovinox 30mg Q12 for patients weighing less than 150 kilos, or 40mg Q12 hours for patients that were

over 150 kilos. Imaging was only ordered if there was suspicion of VTE, so there was no screening duplexes or screening chest CTs in patients, and patients were risk stratified based on the Trauma Embolic Scoring System, or the TESS score. Primary outcome was symptomatic VTE diagnosed during hospitalization. and secondary outcomes were bleeding complications. So I want to talk a bit about this risk stratification before we get too far into this paper. So at our institution, all of our trauma ICU admits are risk stratified with a RAP score. And we actually do order screening duplex ultrasounds on high risk patients with RAPs greater than 10. Dr. Cotton, I'm curious if your institution does anything similar in terms of risk stratification and if this is common at other institutions, because you know, back in med school, I don't remember this happening in our trauma center there. Yeah, so this is that's a great question. It was actually something we talked about when we were designing a current trial. We're doing was the diversity in people identifying a risk stratifying is incredible. The amount of

differences in the way that we practice pretty eye opening and a lot of centers do use a rap score. We do not. We pretty much assume any trauma patients high risk. Then we take it to the next level based on weight and we weight adjust. And then we also use a 10 a adjustment for our patients, but we don't actually risk stratify the patient. based on traditional RAP scores or these other clotting high risk factor scores. We probably should. It's probably not a bad idea. But what we've at least identified at our center, which is a pretty aggressive center when it comes to TB, starting it after TBI, starting after solid organ injury, not that every patient is the same, but really treating kind of out of the gate as the same based on their weight. And we really have it Pulled in a rap score or stratification. Otherwise, the only addition that we do is if they have a significantly elevated. M. A. Or maximal amplitude on their tag, adding aspirin to some of these patients because we

identified those at high risk of getting a V. T. E. Event above and beyond what our normal trauma population gets. And with that M. A. Knowing that it's majority, not completely majority platelet driven added aspirin to our protocol for that. Yes, as Mike mentioned, you know, here at rider, we've started using the risk assessment profile and a cut off of 10. I think there is a huge variety of, you know, what centers are doing and it's ultimately in a center decision on what you want to do. I completely agree that all trauma patients are high risk when you identify that group. That is a little bit more high risk. You have to decide what you're going to do with it. So we've decided to do lower extremity duplexes. There's some data that we have here that, you know, treating those patients early will prevent progression to pulmonary embolism, but that's going to be the ultimate decision is if you do find this sub. set of population that is higher risk. You know, what are you going to do with that population? Yeah, I think that's a good point about what you're going to do with it. And again, I think that's probably part and it's not defending why that we don't use it because we probably should use that or a

similar system. But I think because we are so aggressive and have a historical aggressiveness about our PE side. That we, again we feel like we're picking up quite a bit. We're probably missing some DBTs 'cause we're not, we looked at the data, it doesn't seem cost effective to do screening ultrasounds outside of study populations. But if you cough in the ICU on a trauma patient on day two, you're getting a CT chest. So, because we're so aggressive about that, I think that's maybe why we've justified inside of our own heads here in Houston to not use a stratification score. But I still advocate for 'em. I think they're incredibly useful. To get back to the paper, what did they find, Eugenia? So, briefly going over demographics, out of 13, 221 adult trauma patients over the study period, about 2, 600 were excluded for lack of chemoprophylaxis administration, leaving 8, 646 in the standard chemoprophylaxis group and 1, 886 in the aspirin and chemoprophylaxis

group. The aspirin group tend to be older, more often obese, and more severely injured, and had higher test scores, though there were no differences in terms of TEC values. This group additionally had more known risk factors for VTE, including operations longer than two hours, more central lines, more venous injuries requiring repair, higher rates of blood transfusions of more than four units, more spine fractures, and spinal cord injuries. Higher rates of cardiovascular disease and COPD as well as smoking. Yeah, so given that this is not a randomized trial, that makes sense, right? So people that are taking aspirin at baseline probably have more medical problems. They may be more frail older set of population, etc. We also see that patients that start taking aspirin once they're in the ICU or in the trauma center, Separate of places that are using MA to add aspirin are likely patients that have a more significant injury, whether that be a peripheral vascular injury or even a blunt cerebral vascular injury. So although most of these variables aren't massively different in the groups that were

studied here, the combination of all these small differences likely did add up to a substantially different cohort in aggregate. So what did the actual outcomes of interest show, Eva? Well, as you'd expect with the differences that you were just discussing, the Aspen group did have more VTEs. It was 5. 8 percent compared to the other group at 2. 8 percent. The Aspen group also tended to be diagnosed with VTEs later on day six versus day five. However, After using a Cox proportional hazard model to adjust for the dose of chemoprophylaxis, major venous repair, their TESS score, receiving aspirin of any dose was associated with a decreased risk of VTE with a hazard ratio of 0. 57 and an absolute risk reduction of 1. 8 percent and a number needed to treat being 55 at 60 days. However, the authors were unable to demonstrate a difference in VTE risk based on aspirin dose and did not demonstrate a decrease in PE, only the overall rate of VTEs. In regards to secondary outcomes, after controlling for blood transfusions of at least four units, central venous lines,

OR time over two hours, and cardiovascular disease, there were actually no differences between bleeding complications in the two groups. Okay. Very interesting. Any major issues or limitations you see with this study? Yes, definitely. There were several limitations. So the first thing that we've already just discussed is the fact that the aspirin group was a group of patients that either happened to be taking aspirin prior to their trauma, or they had some sort of clinical indication based off of their injuries to be starting aspirin in the hospital, like their vascular injuries, which the non aspirin group did not have. So these populations are very, very different. And even though some of these statistical methods do control for some of this confounding, not all differences in these populations were controlled for or could have been controlled for, something that the authors did point out in their discussion. Additionally, on average, these patients were not severely injured and the majority were not in the high risk VTE group. So these results may not be applicable to those high risk patients where VTE rates can approach 30 percent, and these are the patients that these types of interventions would make the biggest difference in. So, the authors do note that

these results should be hypothesis generating because of all the affirmation limitations. I know that orthopedic literature has been very interested in this question of aspirin as chemoprophylaxis recently. What do you think the role of aspirin in chemoprophylaxis currently is, Drs. Parker and Cotton? And where do you think future directions of study should go to address this question? Yeah, I think that's a great question. And to answer that, I'd like to briefly discuss constipation. And bear with me for a second. So this is actually something I got from Jonathan Mazzosa. So I'm not sure where he got it from. It actually may have been you, Dr. Cotton. So I'm not sure. But let's think about constipation. We have patients in our ICU. We're trying to prevent constipation or treat it. They're on Senna, Colace, Miralax, maybe getting suppository. You're hitting that constipation pathway with multiple mechanisms of action. And then you go to something as important as and we're trying to rely on a single mechanism of action in a single class of drug. And when you look at something like the M. A. that Dr. Cotton already mentioned, the reason why the clot strength is attributed to the platelets is because 80 percent of that clot strength is coming from the platelets.

So. If you're not giving an antiplatelet drug, then you're missing a significant portion of what is potentially causing a VTE. So, the exact question of dose, timing, patient population, I think all that's yet to be figured out. I think going by MA is a reasonable starting point. But the fact that we need another mechanism of action, another class of drug, I think is a no brainer at this point. Yeah, before I dive into whether we should be using aspirin or not, which again, I'm definitely an advocate of it because again, I do think you need to attack it like you're talking about constipation pathway. Some of the things about that study are some of the problems that a lot of other Non randomized trials of this have found difficult is that aspirin is so complex, not only are a lot of patients coming in on it, then we stop it, maybe does that make them hypercoagulable, there are other ones that are on, put on aspirin for like, I think you kind of mentioned part of it, or they put on after you've done a bypass, you know, vascular repair, or they put

on it, Now at least at our center, it would be almost impossible. We had a study that was done a few years back showing a benefit of aspirin, but now it would be almost impossible because we have so many people on aspirin now for BCBI management that it's hard to detect it. So that's why, again, one of the reasons we're doing a randomized trial now, not with aspirin, but with Noxpirin adjustments is because the aspirin signal is so, Overwhelming in, in, in our sickest population. Again, all those in the ICU and things like that that have BCVI or vascular trauma, that so many are on it, that it would be hard to kind of tease out the impact. And again, in the highest risk population, which are gonna be those ones that show up in an ICU or a step down setting. And then if you want to pivot to adding it to it again, we started adding it after our MA study way back when, and then again, Danny Lammers did our data. We had a big study that we had done before, and it kind of died on the process of just all those papers looking for a journal that all of

us ended up doing. having over the years. And it was resurrected by Daniel Ambrose and Holcomb at UAB, but it's all Houston data. And they found it and showed, again, what we found at the time, which was adding aspirin to it. And again, this was before we went full throated into, one, screening for BCBI, and two, finding it and then starting aspirin on them. And we actually found an impact and a benefit for that adventure. Additional adjunct of doing aspirin plus enoxaparin and not just straight enoxaparin. So it's the data's out there Again at our center today would be hard to do but this was data from way back you know in like 2012 2015 time frame and we were able to show a difference But now again, it'd be hard to tease out, but it makes absolute biological plausibility sense whenever you're talking about terminology you want to use to have a combination therapy and not just a single one. There's other stuff now that people are looking at like adding a statin to get that endothelial lining, you know, stabilized or resurrected and repaired and whether or not that'll help. So

there's so many different components that you can add and just to think that one drug fits all and one drug is going to take care of all your clotting is kind of, kind of silly and kind of oversimplistic. Yeah. And something we haven't mentioned directly, but obviously we all know and appreciate is that the other side of the coin here is we're, you know, talking about potential risk for bleeding, but I think given the use of aspirin in the BCBI population, the bypass population, we're becoming more and more comfortable with that. And also in, you know, the trauma ICUs we're a little bit used to patients bleeding. We're okay with a little bit of bleeding. We're okay with transfusion as long as you know, they're not dying of a massive pulmonary embolism. Okay. All awesome points. Moving on to our next study. Association of changes in antithrombotic activity over time with responsiveness to anoxic parent prophylaxis and risk of trauma related venous thromboembolism. So, since you're one of the authors on this paper here, Dr. Cotton, what was the inspiration behind this study? Yeah, so it's an interesting question. So this came from a beautiful marriage, if you will, between basic scientist and a

clinician, a dumb, dumb trauma surgeon, myself and a brilliant basic scientist, Jessica Cardenas similar to again, successful careers over the decades with Angela Sao and Jean Moore or John Holcomb and Charlie Wade. I was able to work with her until recently and still working now remotely from her. Cause she's moved on to Colorado, but we, she was a fresh graduate from, you know, being a postdoc and finished up and was working with us on it. She took some calls with me and we saw some, some cases where. Profound hemorrhagic shock patients, severely injured patients were resurrected at least at the macro level and taken to the I. C. U. And we're watching them and they're having to go back the next day for a take back or two days later, and we're finding knocked off bowel. We're finding bowel that's become ischemic. And, and there's been some concern that on my side that there's something at the

endothelial level that's disturbed. It's making these microvascular hits and these clots go off. And these patients are ended up, a lot of them dying from, you know, sepsis and multi organ failure. And in kind of looking at kind of some autopsies and or looking at some of the literature out there knowing that there is absolutely some microvascular clotting seen in some of these severely injured patients with shock. And that when I, was rounding with her talking about some of the reasons for it and antithrombin deficiency came up as one of those possibilities. And so I remember sending some antithrombin levels on some of these patients during their extremis and seeing them in the teens where, you know, normally they should be, you know, well in the like hundred range or close to it. And seeing them so low, Again, true, true and unrelated or related and related was something that we were interested in. So we started looking at that. I started also talking about back in the day when we were given heparin drips for

PEs back when I was in training. And if we couldn't get them therapeutic my, my mentor, Mike Metzler would suggest giving a couple of units of plasma, which sounds absolutely, you know, to the unexperienced insane. But what you're doing is you're giving back antithrombin in a cheaper form and giving you a plasma and all of a sudden their PTT would correct. And we've done that throughout the last, you know, several decades. And I told her about that and she started working on the mechanistic stuff in the lab. And that's really where it came out of. There are multiple studies at the bench side that predate this. study that were really a labor of love between her and myself of kind of seeing if antithrombin is not only, we know it's a problem with getting therapeutic and anticoagulation, is it a problem with getting prophylactically therapeutic and anticoagulation to prevent these clots? And she's really blown it up and really led the charge on this, which led us to this observational study, which was the, you know, the predecessor to what we're getting ready, you know,

we've recently started, which is a randomized trial looking at antithrombin supplementation. One thing I wanted to touch on before we get into the meat of this paper, the background cites an interesting statistic that trauma patients demonstrated low responsiveness to Lovenox with 50 to 70 percent of patients failing to achieve the recommended peak anti Factor Xa range of 0. 2 to 0. 4. Drs. Parker and Clanton, what are the current thoughts surrounding the utility of routine monitoring of Factor Xa levels? I've heard a lot about it in some recent work and it's not always used at Jackson. Yeah, I think it's great to look at that. And I think just as Dr. Cotton mentioned, you know, we've got a lot of the macro down in terms of, you know, what's the right blood pressure, what's the right transfusion, you know, rate, but the micro is where the frontier is and why these patients are dying of, you know, multisystem organ failure a few days later. And the 10A level and its interaction with antithrombin is a more direct representation of how your low molecular weight heparin or heparin is actually working. So, we know that

PTT can either be not affected or falsely lower, depending on your factor 8, depending on your fibrinogen or on your antithrombin. So, you know, going directly to the source and monitoring that 10A level seems to be a little bit more beneficial. Yes, and the one last thing before I get into the 10A. And this is something a lot of people don't realize. They're like, oh, I'm giving heparin. Oh, I'm giving anoxaparin. You're giving the thing that helps antithrombin work. I'm not giving antithrombin to help anoxaparin and heparin work. It's what works in your body. It's actually what's breaking down the clot and attacking things. It is The actual thing working. It's heparin and enoxaparin are what we're being, what we're giving our patients to kind of help it work. So antithrombin is a huge deal in part of this. And obviously we can measure antithrombin levels. It's a little bit more time sensitive in what have you, but the anti 10 A has become that. Now, as it translates to

that, it's become kind of our hospital based, at least for us at Houston, a quick turnaround and something we can arrange. Because again, we know one size doesn't fit all, but we also want somebody to tell us, like when we're giving warfarin, we know what we want an R& R to be. We have no idea when we're in peperin, we got a PTT. What the hell are we going to do with anoxaparin? And we actually have those ranges. Now we have a 0. 2 to 0. 4 for prophylaxis, a 0. 4 to 0. 7, maybe a little bit higher for you know, for full on anticoagulation. And I do think that TEN A does correlate pretty darn well with being therapeutic on other, you know, Kind of lab lab based not clinically based testing and they do correlate pretty well So we've adopted 10a because of that and have utilized that as our go to to get to that right Right patient dosing for our cohort. It's all very interesting. And in the paper you did talk about dr Cotton in your paper you talked about your team and how you've used the supplementation of this ex

vivo antithrombin in patients because of the fact That they have this acquired deficiency and this is also something we're not doing here so I was just curious, like, what's the current climate and using this exogenous antithrombin and like how you've used it and how you think it's going to sort of progress in other centers? Sure. So if you look at it on kind of, again, the paper we're getting into where we add it, and it's making, again, you're getting into ranges of Tene being therapeutic and being able to anticoagulate and work it makes sense. It makes sense from historically from, you know, a lot of centers and including ours as well as where I trained in Missouri, where we're giving plasma back as a, again, a non concentrated version of the antithrombin and all of a sudden, ta da, our heparin drip is now therapeutic. All those layers, I think are starting to, people starting to appreciate that it really is antithrombin that is the drug that's working. It's not heparin those are just facilitating antithrombin doing its job. This paper, a lot of this

paper, was really focused on trying to spread the awareness that antithrombin tanks right after injury, and it tanks differently the more severely injured you are, the more severely injured, the more profound shock like endothelial other endothelial things, like we test for syndicane 1 and other glycocalyx disturbances, which are all part of that inflammation coagulation cascade, and whether it's homeostatic or pathologic, It's one of those in that mix that absolutely gets disturbed, gets dysfunctional after those multiple insults, and it does recover, but it takes a while to get back to what you and I are walking around with right now. That's why you and I are walking around right now, not clotting random crap off. We're actually able to you know, not form clots, at least pathologically as opposed to someone that's got a acquired deficiency after a big hit, a big insult and is sitting in an ICU where they are at an incredible risk, even though we're pounding what we think is the standard of

care at them, whether that's again, weight based or non weight based an ox apparent. And then we're shocked when they don't. When they end up with a P. E. or a D. V. T. We seem surprised and befuddled because they didn't miss a dose. The nurse gave it on time. We didn't hold it for a head bleed or a solid organ injury. We did all the right things by teak whip and all these other judges of best practice, and they still got a clock. What? What is the problem? And it's it. At the end of the day, it's not as complex as we think, especially if we view it the way that, again, that it's antithrombin and these other things are helping antithrombin not the other way around. Thank you, Dr. Cotton. It's always good to hear how other senders do things differently than we do now onto the paper. Mike, do you want to tell us a little bit about the design of this trial? Absolutely. So this was a single center prospective cohort study at UT Houston and Memorial Hermann Hospital. And the goal was to examine time dependent changes in antithrombin activity,

responsiveness to Lovenox as measured by factor Xa levels. and incidence of VTE after severe trauma, and then to assess the association of ex vivo thrombin supplementation with patient sensitivity to lobenox prophylaxis. As mentioned, the prior work of Dr. Cotton's group has been limited by using only samples collected on hospital admission. For this, all patients between the ages of 18 and 70 who were admitted to the trauma service and started receiving prophylactic doses of anticoagulants between January 2019 and February 2020 were included. Exclusion criteria consisted of pregnancy, incarceration, death or discharge from the ED, immediate initiation of therapeutic doses of levonoxirheparin, pre existing anticoagulant use, known hematologic or immunologic disorders, or had what was called an ineligible injury pattern. And just to take a step back, Dr. Kahn, what is the standard of care VT prophylaxis at your institution? Sure. So we currently, we have gotten rid of delays with the exception

of an acute spine with a, with an epidural or a head bleed. Other than that, even our solid organ injuries are supposed to start day one, getting either an ox apparent 30 Q12. If they're standard weight, once you hit 90, we go up to 40. Once you hit 120, we go up to 50. Otherwise, we have the same for heparin. If it's based off of creatinine clearance, if you're under a certain threshold, you're going to get heparin instead of oxaparin. You get 5, 000 Q8 for standard weight dosing. And once you go above 90, we transition to 7, 500 Q8. As far as holding it, we will hold it for 24 hours based on a spine epidural to go into the OR, or 24 hours post stable head CT on an intracranial bleed. Those are the only times they're not getting it right outta the gate. And then again using 10 a based therapy regardless of whether we start at 30, 40, or 50 based on weight, thawing up on a 10, a

four hours after their third dose of an oxy parin. Great. And what about blood collection and analysis, Mike? So, whole blood was collected on ED arrival and at least once daily during hospitalization between four to six hours after the first daily dose of Globinox. This continued for eight days after ED arrival or until a patient died, was discharged, developed VTE, or was started on therapeutic anticoagulation. The samples were eventually used to measure antithrombin activity, INR, anti factor Xa levels, fibrinogen levels, neutrophil elastase, thrombin antithrombin complex levels. Thrombin generation and clot formation using kinetic testing. Antithrombin deficiency was defined as antithrombin activity below 80 percent and adequate 10A levels for those on Lovenox was defined as 0. 2 IUs per milliliter or greater. Antithrombin was then supplemented ex vivo to 120 percent, 150 percent, or 180 percent using antithrombin concentrate based on antithrombin values.

And so what did they find Mike? So just to touch on the demographics and patient characteristics briefly, 2150 patients in total were screened of whom 237 met eligibility criteria. After 87 patients either declined or were unable to consent. 150 patients were left for analysis. Patients tended to be young, with median age of 35, were more often male, 75 percent of the cohort, and white, 75 percent of the cohort. The black patients were overrepresented in this cohort at 21 percent of patients. The overall VTE rate in this cohort was 18. 7%. 12 patients developed DVT or PE, and 2 both DVT and PE. Median time to VTE diagnosis was 4 days. There was no significant difference in demographics, admission vitals, or injury characteristics between patients with and without VTE, though the systolic blood pressure and base deficit trended towards being lower in the VTE group, systolic of 109 versus 119 with a p value of 0. 09, and a base deficit of minus 7 versus

minus 5, p of 0. 06. Suggesting that the VTE patients may have been more critically ill. This is further supported by the fact that the VTE group did receive significantly more blood products in the first 24 hours after arrival. A median of 4 units as compared to 0 of red blood cells and 3 units versus 1 of plasma. As well as had higher distributions of whole blood and cryo administration. Additionally, the VTE group had fewer ICU free days, 19 versus 25, and hospital free days at 17 versus 6, though no differences in mortality were observed. And no in hospital deaths were directly attributed to VTE. Okay, all right, so this makes sense. So the more critically ill you were, the more likely you were to develop the VTE, as expected. So let's get a little bit more into the results regarding the blood analysis. Right, so 87 percent of those enrolled were able to actually receive lovinox while the other 13 percent got unfractionated heparin. In addition, 35 percent of patients were also receiving aspirin because of concomitant cerebrovascular

arterial injuries, and there was no difference in VTE incidents, anti 10A levels, or antithrombin activity in those who took aspirin compared to those who didn't. 39 patients received lovinox dose escalations. The time to first VTE prophylaxis dose was similar between the two groups, so 35. 3 hours versus 31. 2, but time to achieve an anti 10A level of 0. 2 or greater was significantly higher in the VTE group, eight days as compared to four. In regards to other coagulation parameters, there was no difference between platelet count, INR, fibrinogen, tag values, or thrombin generation between the VTE groups, both on admission and over time. Interestingly though, although no significant differences were found, the group without VTE exhibited relatively stable peak thrombin, endogenous thrombin potential, and rate of thrombin generation over time, while the VTE group demonstrated time dependent increases in these parameters. Eugenia, how about the results in this study pertaining to the antithrombin? So, similar to prior work by Dr. Cotton's group, 126 patients had

antithrombin values available on admission, and 17. 5 percent of these patients were antithrombin deficient. More importantly, the VT group had significantly lower antithrombin activity levels on admission, a median of 91 percent as compared to 100%, as well as lower antithrombin activity on hospital day 5 through 8. So 90%, 97%, 82%, and 99% as compared to the a hundred fourteen, a hundred twenty three, a hundred twenty three and 123% overall, antithrombin activity declined during the first two days and started to rebound in the group without VT on day three to four, but did not rebound in the VT group. From there, multivariable regression was performed to assess the effect of antithrombin activity over the first three days on the development of VTE. The period of three days was chosen because of increased missing data at later time points and to stay on the earlier side of the median time to VTE diagnosis at four

days. The predictors in the regression were age, sex, obesity, ISS, and antithrombin activity. Thank you. Female sex, obesity, and average antithrombin activity were all independently associated with VTE development, with odds ratios of 3. 1. 52, respectively. For every 10 percent decrease in average antithrombin activity during the first three days, the risk of VTE increased 1. 5 fold. Okay, that's a lot. So, to summarize here, the patients in the VTE group were more likely to have had decreased antithrombin activity, and they took twice as long to get therapeutic anti TEN A levels, which is important for the monitoring that Dr. Cotton was mentioning, and based on logistic regression for each 10 percent reduction in the activity, there was an increased 1. 5 fold risk of VTE, which is a really big impact in this cohort, and it does support the use of follow up TEN A levels. That was what I thought. Just every

little 10 percent drop, bam, 1. 5 fold increase. So that's huge right there. And really supports, you know, not only the use of the antithrombin monitoring, the 10 a monitoring, and then subsequent antithrombin as a therapy as well. So what else did they find like? So, to assess mechanisms of antithrombin deficiency following trauma, they also analyzed correlations between antithrombin activity and some of the other lab values we mentioned earlier on hospital day two, when antithrombin activity was the lowest. There were no correlations between antithrombin and ALT, AST, or albumin, but antithrombin activity was inversely correlated with thrombin antithrombin complex level with a correlation coefficient of negative 0. 22. and neutrophil elastase with a correlation coefficient of negative 0. 47, which the authors concluded pointed towards a combination of antithrombin consumption by thrombin and inhibition by neutrophil elastase. They then went on to examine temporal changes in Lovenox responsiveness in those who received three or more consecutive Lovenox doses, which resulted in

110 patients for analysis. Since patients received the third dose of Lovenox on hospital day two at the earliest, anti 10A was not assessed on admission or day one. Patients without VTE exhibited relatively stable 10A levels around 0. 2 between days two to five before surpassing this target value. But those with VTE exhibited a reduction in TEN A levels between days 2 and 4, and this remained low. On hospital days 7, the VTE group had lower TEN A levels than the group without VTE. Furthermore, the incidence of TEN A levels less than 0. 2 declined over time in the group without VTE, but there was a time dependent increase in subprophylactic TEN A levels in the VTE group, 80 to 100 percent of the patients in the VTE group, depending on day, versus less than 50 percent in the non VTE group. From this data, the authors went on to categorize patients into three phenotypes. Always responders, a 10A of 0. 2 or higher after each course of Lovenox. Transient responders, 10A of 0. 2 or higher at least once after the third dose.

And never responders, never achieving a 10A level of 0. 2 or greater. 16. 4 percent of patients were always responders, 60 percent were transient responders, and 23. 6 percent were never responders. And in the never responder group, the incidence of VTE was 30. 8 percent compared to less than 6 percent in the other groups. Antithrombin activity also varied between these phenotypes, with the always responders having higher levels than the transient responders, who had higher levels than the never responders on multiple days. Man, you guys really packed a lot into this paper. I think the only thing we haven't touched on is the the antithrombin supplementation. So Eugenia, what happened with that? So the authors had 14 never responders with at least three plasma samples over time to work with compared to baseline in this cohort, supplementation of antithrombin to 120%, 150%, and 180% was significantly associated with increased 10 A levels at all time points, with the exception of the 120% group on day five.

The absolute increase in 10A levels did tend to decrease at the later time points with the greater amount of antithrombin necessary to achieve the goal 10A levels of 0. 2. The authors also assess the association of antithrombin supplementation with clot kinetics by supplementing day two samples with 120 percent antithrombin and measuring changes. This resulted in significant prolongation of time to clot formation and reduced clotting rates. Though supplementing antithrombin into antithrombin depleted plasma was associated with attenuated clot connects in a dose dependent manner, there was no difference in fibrin formation, even with supplementation to 150%, and no 10A levels ever surpassed 0. 37 accordingly. So to summarize, overall, only 16 percent of patients consistently achieved the goal 10A level of 0. 2. The time to goal 10A level was greater in the VTE group and 24 percent of patients never achieved the goal 10A level despite dose escalations. Acquired

antithrombin deficiency was associated with this reduced responsiveness to lovonox and was independently associated with VTE. And finally, supplementation of antithrombin seemed to improve lovonox responsiveness. This was a ton of amazing data, so kudos to your team, Dr. Cotton. Before we talk about what this data actually means for clinical practice, I think it's important to talk about any limitations of the paper. So, Mike, is there anything that jumped out to you while you were reading this? So, as the authors mentioned, it is a single center study, and some of the subgroups did end up with relatively low numbers. Additionally, the antithrombin supplementation was performed ex vivo, so the results would need to be extended to real patients as, you know, a next step. One additional thing I noted was that these patients seemed to be pretty sick, with a median ISS of 29 and 27 VTE and non VTE groups, respectively. So as the authors mentioned, these findings may not be applicable to the mildly or moderately injured patients. These ISS's really struck me though as you know, I read through the inclusion criteria and thought it was

all trauma admissions. So Dr. Cotton, I was just wondering, do all your trauma admissions really have a median ISS of 28 or how is this severely injured cohort actually selected for? So I think you nailed something. And again, I mean, there's, this is with this podcast, it's kind of, obvious, but you've, as I tell my trainees, You got to read past the abstract on a lot of these things. You guys have read past the abstract and you nailed that this was a sick ass population. This was incredibly severely injured patients. These were pretty much just ones hit in the ICU. And we did that based off of that's where we had all of our VTE events. But, you know, given exceptions. That's where most of them work again. I think it's the same reason you got to read past the abstract of the New England Journal Aspirin versus an ox apparent study that we were also involved in where the severity is so low in that population. It's overwhelmingly a floor trauma patient, you know, almost isolated single ortho injury patient population and they have a very low VTE event rate and

aspirin may be just okay in those. So again, reading past the abstract thing is incredibly important and seeing what populations you're dealing with. So you've nailed it. These are sick path population patients. I'm about to start my career as a new attending. Drs. Parker and Cotton, what do you think I should take away from this paper? Will this or has this changed your clinical practice at all? And what do you think the next step should be? Yeah, so I do think that practice should change but this is a frustrating and exciting I think it's a really exciting time because exactly how it changes. It's in my mind still unknown. I do not think that VTE is a never event, no matter what any hospital administrator will tell you, but I think the rates that we're experiencing now are still leaving room for improvement and where that improvement is, I think, is really ripe for investigation, which is ongoing right now in terms of whether it's multimodal or variation in dosage or screening, whether that be with lower extremity duplex or with You know, following 10 a levels. But right now, I think the change in practice should be do not accept

the status quo and continue to look in the data that's being put out there by people like Dr cotton or participate in these studies and really figure out what the next steps need to be. Yeah, I think 1 of the things that I already kind of mentioned earlier is I try to tell. Again, my fellows, my trainees read past the abstract. And as a young attending, I would tell you, don't just grab that crappy paper that cotton posts on Twitter and run with it, dive into the actual papers, which is what I try to do. Anytime I post something on Twitter, supporting or not supporting a paper I've read, I try to, you know, Literally read the paper before I whip out a response to it because there's a lot of stuff to unpack in this study and in any studies. Reading past the abstract and figuring it out. Really getting in, diving into the paper to see what you're dealing with. Again, you look at that New England Journal aspirin lovinox study and you go, Oh, we should stop using lovinox. No, no, no, no. These are really uninjured patients. It's a really, really low DVT rate population. These patients are, these are floor.

Guys and girls. These are a different cohort, and aspirin probably is okay on that isolated ortho on the floor. However, on these really sick, like you pointed out, severely injured patients that were in shock, you know, almost like that initial Karen Brody study on on the coagulopathy of trauma, right? It was not just Then injury severity, it was injury severity and shock. Those combos that really sent the whole APC and all the other stuff going crazy in the coagulation cascade. So really looking at this one, then you walk away going, all right, you might need a little bit of something, something extra, some multimodal, like Dr. Parker said. in these higher risk, more severely injured patients. In retrospect, I wish we would have calculated RAP scores just so we could have reported them and had that as a correlation, but we weren't practicing that. So I I couldn't put that in there, but that's again, something to consider in your career is really just trying to Be not only try to work within the confines of your hospitals purchasing, you know, powers and things like that and restrictions, but also

trying to really assess differences in the literature. Because you can have some pretty good groups, pretty robust studies that come out that have conflicting data, but when you dig into it past the abstract, you realize. Why those differences exist and that we really are a lot closer in our practices or beliefs and understanding when we dive down into it like that. Okay. Well, great work team. Thank you so much. I think that was a really excellent discussion of two very interesting papers. Again, thank you so much, Dr. Cotton for joining us and discussing your excellent paper. And so now I think it's time for some quick hits. So First, on adjusted analysis, the standard VTE prophylaxis plus aspirin group had a lower odds ratio of developing a VTE, though limitations of the study highlight need for future prospective work. Number two, trauma patients often suffer from decreased activity of antithrombin 3, which may mediate the relatively higher rates of VTE in this population. Number three, trauma patients who went on to develop VT

were more likely to not achieve satisfactory anti 10A levels with a VT rate of 30 percent in the never responder group, the group for which 10A levels were never higher than 0. 2. And lastly, ex vivo supplementation of antithrombin seemed to improve Lovenox responsiveness. Remember Lovenox and heparin are helping antithrombin 3, not the other way around. Again, I'd just like to give a special thanks to Dr. Cotton for joining the Miami trauma team for this episode. Dr. Cotton, would you do the honor of signing us off? Absolutely. So I want to thank the team for the opportunity to participate in this and highlighting our research. It's fantastic. This is how collaborations and things happen again, starting with getting Miami involved in our upcoming study and getting others involved. This is where these things happen. These things happen at meetings. Meetings are critical to attend both. in the auditorium where the presentations occur and at the bar where a lot of big time decisions are actually made. So to borrow from my mentor

and an absolute legend James Red Duke for the University of Texas Health Science Center in Houston, I'm Brian Cotton. Read past the abstract and dominate the day.