Gerald Maloney, DO, CPPS, CHCQM, FACEP
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Hi, my name is Jerry Maloney and I'm here to talk to you today about management of bleeding in the anti coagulated patient. Okay, hi two o'clock. I'm the Associate Medical Director for the year the Cleveland VA and I'm also Associate Professor emergency medicine at Case Western. I am also a lieutenant currently Army Reserve and an oaf veteran. I have no disclosures to make. So our objectives for this topic, were listed different anticoagulant drugs and their indications review the lab testing and tech regulated patient. Define what constitutes major bleeding anticoagulant patient discuss reversal agents use and their supporting evidence. So we're going to start things off with a case presentation. 63 year old male with a history of AFib anok hobbies presents for dissident Jaws swelling for the past few days. So five milligrams of Warfarin a day is a sign our check a month ago was 1.8. He's not any new medications, no history of trauma, the sun desert board they held miss some dose and devil up to catch up on his warfarin. So this is the one I walk in the room. What do I see picture. And in this case, what I saw was something that made me very, very nervous right off the bat. In terms of file size is a furrowed brow slightly tachycardic and hypertensive to kip Nick and satting. And kind of borderline low 92% of the Roman era. He's alert looks a little bit anxious, you can open the show a couple of finger breaths. As for the picture, you can see there's pretty much nothing but tongue in there. The floor, his mouth, his hard tongues elevated. His submandibular areas fall in firm, and he actually has a little bit of ecchymosis that mandibular area. As long as he's slightly diminished bilaterally is tacky and irregular isn't a fib on the telemetry monitor. He's not having any mob justice or coughing up any blood right now. So for labs, he's got a normal white blood cell count. His hemoglobin is a little bit lower than baseline baseline is around 14.3. Today is platelet counts normal to 40, his BMP and LFTs are grossly normal, is INR comes back greater than 10. So management, what's the best reversal agent given his elevated INR? And are there any other therapies we should give. And similar vein to our other case presentation this gentleman is somebody who had a recent biopsy of a soft palate mass. It's not a pixel band for a fib had the pixel man held the day before the procedure had the procedure at the Pixabay and restarted that night and was fine and for a day or so and then post op day. Number two, he came in coughing up large clots of blood. So in terms of classes of commonly used anticoagulants, when I was a resident, we really had three vitamin K antagonists, heparin and platelet inhibitors. Now we also add in direct thrombin inhibitors and factor 10 A inhibitors. The vitamin K antagonist category, there's really only one that you set beautifully, which is warfarin. Direct thrombin inhibitors are kind of the first of the what used to call noacs novel oral anticoagulants and doacs Direct oral anticoagulation agents. The bigger trend was the first in that class. The have had some intravenous ones that have Allah Rudan and our gastro ban. The next class of oral anticoagulants under the doac slash noec category was the factor 10 inhibitors and river rocks a ban was the first category followed by pixel ban adoxa ban and kind of the newest kid on the block is vetrix have and they've had injectable factor 10 inhibitors and logging they've had oral ones find a paradox, which for a while is used at our place for cancer related thrombosis heparins unfractionated Heparin, which we don't see uses commonly anymore. The out of hospital raises we're looking most of these medications that people are on at home and come into the Edie with low molecular weight heparin enoxaparin. The most commonly used one is really what we see used for this category. And then platelet inhibitors, the most common which are aspirin and clopidogrel. So since we're talking about anticoagulants, we do need to go into the coagulation cascade briefly. Warfarin causes the most widespread effects of this calculation cascade it knocks out what they call the vitamin K dependent clotting factors choose seven nine and 10. The end result of all this is that it prevents the activation of 10 A which is the common link in both the intrinsic and extrinsic pathways. 10 A is the factor that converts prothrombin to thrombin and activate thrombin necessary to convert fibrinogen into fibrin. Without conversion of fibrinogen into fibrin, we can't form that plug to create the clot. The 10 inhibitors don't affect the rest of the Cascade the way Warfarin does, but they do hit right at 10. A itself. heparin also prints the actuation 10 A and also blocks thrombin to prevent it from activating fibrinogen into fibrin, so do the direct thrombin inhibitors. So we really get down to it. There's really two points where all these anticoagulants seem to work 10 A or thrombin. Since we do strapped people on anticoagulation from the Ed does help to quickly review the indications for these things. Vitamin K antagonists have the broadest indications, mainly because we're using the longest right so a fair both alveolar nerve alveolar fib DVT or PE, both cancer and non cancer related primary clotting disorders. Things like factor five light and protein CNS deficiencies, and also they've been used as prophylaxis, after things like joint replacements. The direct thrombin inhibitors have indication for DVT and PE treatment cancer associated in a fib nonvalvular. The 10 A inhibitors pretty similar they haven't added indication for DVT prophylaxis. The other thing that the 10 inhibitors are used for CBT and PE it can be used in certain cancer related ones as well. Because of increased bleeding rates with GI Gu cancers, they do not recommend using them for those particular indications. heparin obviously is the preferred one particularly low molecular weight heparin for cancer related thrombosis, and for prophylaxis as well. And platelet inhibitors used primarily in stroke and ACS PCI, although they've been used for other things like DVT prophylaxis may be used in patients with afib, who are considered higher risk of being on the stronger anticoagulants. They don't have a primary indication for anticoagulation for any of these other indications per se. So just to go a little bit more into the cancer related indications. They compare two pics Amanda docs better for Oxman Alta Dalta paren, which is another one walkaway heparin for cancer associated venous thromboembolism. And interestingly, although they were rated at a superior or non inferior to Delta parent in terms of treatment of cancer associated VT II, they had higher bleed rates, especially the GI cancers. They are preparing comparing them to the vitamin K antagonists these indications as well. Currently the recommended is no GI or Gu malignancy. I bring that up because for those of you working in the VA, like me, obviously I get probably a couple of patients a week that I sent down from CT because they had their staging CT down and they found multiple asymptomatic PE. So they had some other study down and found that they had a DVT. So they got filtered to the ER so starting them on anticoagulation is something we frequently have to do. I'm a medical toxicologist by training as well. So I do like to talk about things like kinetics. I'm not going to go into this in great detail, but looking at the bigger trends and the most commonly used 10 inhibitors. Looking at the tannic IP plasma concentration is pretty similar with all the right summarize. And the minimum one hour and usually about three hours. There half lives are relatively similar to redox events somewhat shorter half life, but the rest of them, I summarized at least nine and assigned to bigger trans cases 17 hours and the frequency with most use once or twice daily. Some of this depends on renal function. And they are all renally excreted to a significant degree, particularly the biggest fan which is majority renally excreted. They have antidotes which we'll go into a little bit later, but there's n DEXA and Daris ism AB, or prac spined and they all take at least 48 hours after the last dose for complete cessation of all pharmacologic activities. So although they like to say you can hold it for a day, if you really want to complete washout of all their anti Quagga activity, you really got to give it 48 hours. So in terms of laboratory testing, so the INR is primarily for vitamin K antagonists and typically we're looking at a range between two and three occasion up to 3.5 for prosthetic valves on occasion There will be people who are on higher Target INR hours based on something that they've worked out with a hematologist. But rarely is an INR greater than 3.5. So consider the therapeutic range. So in terms of INR with doac, typically the INR is all very the direct but it's not linear relation, it's not like Warframe, where you can kind of determine if they're therapeutically anticoagulated. Based on what their INR is. Frequently it is elevated, not always. So you can also have patient who is taking a doac who has a normal INR but will still have therapeutic anticoagulation activity. So bottom line is that the INR is somewhat helpful if it's elevated, at least confirm the patient's taking a doac. A normal INR does not exclude that the taking of doac and there's no real correlation between the INR level and level of anticoagulation. This has come up because I've occasionally people say, Well, you know, if we get somebody who comes in and their stroke syndrome, and they're not really response, we don't have medical history on them, we can check a quick INR and if it's normal, that unfortunately doesn't exclude a doe x, so it makes it a lot harder to conclusively exclude their anticoagulant in that case. The anti 10 is best for the oxidants low molecular weight heparin but again, short of some facilities that do a lot of research protocols and stuff. With the 10 inhibitors, it's really hard to get a rapid turn around 10 A, the PTT is good for a fraction heparin. It can also be elevated with a direct thrombin inhibitors, but again, similar to INR and the doacs. It's the elevation that you get in PTT with a direct thrombin inhibitor is not correlative of the degree of anticoagulation, same wages for infraction, heparin. So how do we define major bleeding? This is going to be critical site right in the airway, intracranial pulmonary pericardial active GI bleeding not and I had a little bit of melon, but I seem to be having severe like medic ease yeah hematemesis or an uncontrolled extremity bleed. If they hemodynamically unstable if they've lost more than two grams of hemoglobin from their baseline, or if they've been transfused at least treants have packed red blood cells through the bleeding. So if you're looking for the soundbite side of this presentation, this is it. The journal sets major bleeding Control Stop resuscitate reverse, so you want to strap your anticoagulant agent, resuscitate the patient fluids blood, etc and reverse the anticoagulant. This is a module we get to employ frequently at my shop we have on a given month about 10,000 patients through our facility that are on some type of anticoagulation, typically either vitamin K antagonists or doac. There's if there's a handful heparins and find a paradox is thrown in there. These patients have a higher ed use rate than the rest of the population typically. And it's not uncommon at all to see one that come in some type of leading complication. So going on to the agent specific management. Um, each class seems to have a specific reversal agent or therapy. This journal therapies we look at I'll talk about those briefly. Things like FFP tranexamic acid DDAVP, estrogen and platelet transfusion. But the crux is is going to be looking at what specific reversal agents we use for this specific type of anticoagulant. So I'm a toxicologist as I mentioned earlier, so I love antidotes. So looking at our anticoagulants, several of them do have antidotes. The bigger Tran has a darest ism AB or the slightly less tongue twisting prac spined river rocks of n and Pixabay is index alpha or and DEXA. Warfarin the actual antidote for it is actually vitamin K. And heparin uses Protamine some other journal verse legends we talked about again FFP for factor PCC. So vitamin K antagonists, right? So they inhibit vitamin K dependent clotting factors, which are 279 and 10. And they were playing him in st called V K O RC, which activates vitamin K vitamin K isn't activated, then it cannot help with the formulation of the vitamin K dependent clotting factors. And the vitamin K that we give intravenously for phytanic die own is actually UK wide or activated vitamin K. So bypass is a blockade of warfarin. Warfarin interestingly enough came from moldy hay. It was described in cows first who dying from hemorrhage And it was the Wisconsin area Research Foundation that discover this industry thought it was a heparin oId type of thing. Hence the Aeron. So that's where the wharf in the warfarin came from. They also use it for rat poison and they have short and long acting Coumarins. The long acting ones are not used ever for human treatment. Although, as a fellow we certainly followed many people who overdosed and rat poison. I remember one case of a John declining acting coumarin and was still anticoagulants. So detectable levels in his blood. 45 days after it's overdoses, some of these long acting ones really stick around for a while. The advantages to warfarin, we've been using it forever, we know how to monitor it, we have a test that very accurately reflects level anticoagulation with the INR. And because we've used so much for everything, it's something everybody's familiar with his vast experience with their management, disadvantages got higher rate of bleeding than pretty much all the other anticoagulants there's a ton of drug food and drug drug interactions is also widely variable metabolism. So you know, one patient may get therapeutic with a milligram of warfarin, somebody else may take 10 milligrams, so there's a lot of kind of trial and error with Warfarin dose and get somebody therapeutic with their INR. Now for treatment, again, there is an antidote for iron antagonists, and the antidote is vitamin K. The guy says get super therapeutic INR, but they're not bleeding, it's less than five, just hold it no give anything between five and 10 can hold it and give us a small dose of vitamin K, usually, anywhere from one to two and a half milligrams pure IV, it's greater than 10, the checkout holding it and then giving a dose of vitamin K again, depending on situations two and a half to five milligrams, they do not recommend subcutaneous vitamin K, because it's poorly absorbed oral is preferred IV if the patient can't take oral there's a small risk of anaphylaxis with IV vitamin K, the ever major bleeding issue then they recommend kind of hitting them hard 10 milligrams of vitamin K IV and then either FFP or four factor a PCC. So FFP this has been kind of long standing treatment for this, you need to get to at least him about 10% of clotting factors restored to be able to reverse anti coagulation. So if you look at FFP, each unit gives you about 2.5% of clotting factors. Since diagnosis, always four units. And the higher the INR, the more you may need to use a universal donor plasma ab. And typically, if you give a full dose of FFP, for their INR, typically about the best you can graduate to is 1.6. And that gives you about 30 to 50% clotting factor activity that INR. So typically Tiger would give you at least a leader of a hypertonic solution, if not more than that. So the issue has always been a lot of people who are on warfarin and cardiomyopathy or a fib they've got poor UFC can't tolerate a lot of fluids. So there's been concerns about limitations with FFP. And you can't exactly pressure bag this stuff in so it takes hours to go in. So you're also not talking about rapidly reversing somebody how you doing over several hours if you need to reverse them more quickly than that FFP doesn't provide a great option. So now we're looking at four factor PCC this is kind of new on the block, they came up with a three factor prothrombin complex concentrate. The three factor has been used for hemophilia, but the three factor because it's missing factor seven doesn't seem to be as good for reversing warfarin. Same with the four factor case Sentra. The four factors indication is for warfarin reversal. Although it's been used with other bleeding issues, it's only real FDA approved indications for warfarin reversal. It contains factor 279 and 10. It also contains protein CNS, and it contains some heparin in it as well. The dose is based on the weight in the INR it's capped at a weight of 100 kilograms. And to give you kind of a conversion, one vial a PCC equals about two units of FFP. With the case Sentra, you can reverse the INR as low as 1.3 within 30 minutes and usually get about 24 hours of human stasis. What that means is your bleeding should be completely stopped by four hours and no further reversal agents needed in the next 24 hours after giving case, Sandra. Although it seems to be somewhat helpful and small stays with doacs were particularly before they had other antidotal agents where they kind of gave it seemed to help some. It doesn't necessarily make sense that it would be a great reversal agent for doacs with Jo xe issues inhibition of 10 a deficiency of 10 a. So replacing factor 10 isn't necessarily going to be particularly helpful because you still have blackk to the activation that factor 10 Because it's got heparin is contra indicated people with heparin induced thrombocytopenia. And in terms of causing clotting issues similar to FFP. So although there's been concern at our place, we actually have a restriction where I have to talk to a hematologist. If I want to use this. Hematology, his big concern has been that they think there's gonna be higher rates of venous thromboembolism because it's more rapid reversal. But looking at the literature, there does not seem to be that risk compared to giving FFP alone. jacket with a bigger trend a bit. Again, it was the first doac highly renally excreted, which has been an issue limiting its use in people with advanced CKD. The dosing is 150 milligrams once or twice daily. If the GFR is greater than 3075 milligrams, it's 15 to 30 minutes below 15. They don't recommend it. They may place it ceiling dialyze double doac because before they came out with an actual antidote for it, their argument was well if you're having severe bleeding can dialyze it and remove it, which is possible but again to dialyze patients frequently have to use heparin as well. I mean, you can do a saline. Okay, anticoagulation as well for the dialysis but science effective. So dialysis is not a great response when somebody who's acutely bleeding out, which pressured them to come up with an antidote. syndications again, nonvalvular a fib DVT PE. The thing with this one though, is compared to looking at the other doacs It was studied for DVT PE after they had five days apparently oral anticoagulation so basically I'd have them on a heparin drip for five days or Lovenox, or five days and then you could switch them over with does have DVT prophylaxis and occasion for one thing, which is post hip surgery. So now on to the antidote, right? So a Darris ism AB, or prac spine, it's a monoclonal antibody and some AB and binds both free and thrombin bound to bigger trans when you give it it doesn't just find the stuff that's floating around loose, it actually pulls it off thrombin as well. It is renally excreted somewhere to the bigger fan itself, and the halfway is about 10.8 hours. So practice by itself is also dialyze of all that's part of the reason why. Again, for people who are having severe bleeding things, they still recommend dialyze them to point you can remove the prac spine with dialysis, the dose is five grams, which is to 2.5 gram vials when I talked to the rep a few years ago. each vial was $2,500 roughly. So it's about a buck a milligram so that makes it fairly expensive. Again, it's a monoclonal antibodies, it's not surprising. The prac spined does not seem to have an aging thing to it, it doesn't eventually unbind after a while, like some things we worried about, like digibytes. So the practice by and seems to form kind of an irreversible ionic bond with the bigger Tran so you don't have to worry about the practice behind eventually unbinding the patient becoming re anticoagulated. As with all of these things, there is a risk of rebound thrombosis after you use it because these patients obviously had indication behind it in the first place. So now we're taking the rest of doacs Call the Oxy bands. So there was river rocks van Kai the first one picks a ban, which is the other most widely used oxy ban edocs a ban and Bitrex have an ID. So all of these are activated 10 A inhibitors. So they bind to activate 10 A and prevent it from activating thrombin engine into thrombin. So it makes it impossible for you to then activate fibrin inform that clot. Their arrival is really kind of changed the face of anticoagulation single dose and they started the anticoagulant activity right away. There's no ramping up and waiting a few days, like you have with Warfarin They've been shown to be as effective as Warfarin for most indications, and their overall bleeding or seems to be lower than Warfarin as well. So they've absolutely changed the world of managing thrombotic disorders. I've because of the availability of the Oxy bands, the VA, I've rarely had to admit people with uncomplicate DVTs anymore. It's a next step, talking about the Oxy bands. As I said they're all anti tennies river rocks a ban in a pixel ban have indications a lot of the edocs a ban for DVT PE management except for patient gi Gu cancers for non valve a for prophylaxis and rivaroxaban and PIXMA. Also for DVT prophylaxis in hospital Bitrix abandoned Tristan has a DVT prophylaxis indication but that's focused not just in hospital but up to 42 days post discharge. So they're really the only one that looked at doing DVT prophylaxis in the outpatient setting. Additionally, although this is not anything they've gotten an FDA indication for some facilities of like to to use river ox ban or pics of and for VT e prophylaxis in people with severe COVID infections that people are hospitalized for while severe level of disease elevated D dimers. And they've been usually using four to six weeks of either river oxidant or a PIXIV and post discharge. Now it was in some places I my facility is actually using Lovenox. But there are several that are using a doac. Again, this is an off label indication. So bleeding issues with oxymorons, right? Gi is the most common CNS is rare and a lot of these other abnormal bleeding sites like retroperitoneal hemorrhage airway, hemorrhage haemoptysis, are also very rare with the Oxy bands. And we actually reviewed all the serious bleeding issues in our anticoagulated population over a year. And it came out to be you know, probably about 60 to 70% of the bleeds that we saw with the Oxy bands were GI bleeding. More from was kind of all over the place. It was mostly GI bleed or some CNS bleeds that seem to happen more commonly with trauma patients. But Trix have an interest of does have a warning for spinal epidural hematoma. That is in the study of people who have had some type of procedure and lumbar puncture, spinal anesthesia, epidural catheter, etc. Looking specifically at trauma patients, at least the largest retrospective analysis and so far, they have a much lower symptomatic intracranial hemorrhage than vitamin K antagonists. Again, looking at isolated head trauma, the vitamin K antagonists are in 17%. And that was going to have 24 hours post injury. The dogs about 5%. And the delay bleeding rate was a little bit lower as well interest if not zero. This protocol kept everybody for 24 hours and did a initial head CT and then repeat head CT 24 hours and then compared it to a non anticoagulated cohort. Looking at the overall bleed rate for the doacs posttraumatic ich into labeling, he actually seems similar to the controls. So if you read it that way it is the doacs not appear to have any significantly increased risk of me immediate or delayed head bleed compared to a control population. That said, there's still ongoing data with this, so I wouldn't hang my hat on that just yet. But it does appear at least like our local trauma centers are not considering doac use alone as an indication for meeting people for 23 hour odds and repeat head imaging. If there's no other indication to admit them, and there otherwise are logically intact. So now one of my favorite subject the antidotes and DEXA alpha or n DEXA is the intro for the Oxy bands. It was designed for picks a band and river rocks a band but certainly a factor for all of them. Because they're all fairly chemically similar. It's a call a decoy 10 A proteins so it's designed to look like 10 A and preferentially bind to the Oxy ban so it will actually pull them off the real 10 A and get them to bind to it. So Kevin, interesting our concept. The dosing is based on the molar concentration of the ox of n. So fortunately, that doesn't require us to sit there and pull off a guidroz number and figure that out for each individual medication out It does depend on the specific medication the dose of the medication the time from the last dose. So it's not as simple to doses say two vials like crack spine. They've had multiple trials, several of them were looking at, you know, does it seemed to reverse anti correlation, healthy volunteers, the biggest one looking at actual people, the bleeding issue was a Nexus four. And that demonstrated efficacy reversal of anti coagulation hemostasis by lab parameters, right. So they looked at different lab parameters, they looked at things like hematoma size. So this was not a patient oriented outcomes rather, but disease oriented outcomes or lab oriented outcomes. They did not value death or morbidity. So they did look to see if this improved clinical outcomes, though, to see if it improved laboratory outcomes. There's about 10% risk for venous thromboembolism in this study, post reversal. And they also did a single arm study this go out criticism because they didn't compare it to something else. And the author's main argument, well, we can't compare it against placebo because you wouldn't treat bleeding patients with nothing. And they said this medication array guide an FDA indication for reversal of anti 10 A inhibitors it did not have any other medications with this specific indications as well. You know, we didn't compare it against a four factor PCC because four factor PCC doesn't have an indication. So this was a single arm trial. So there was no blinding so there was obviously concern that there could be some bias in the results. Alright, so now our next group the heparin so low molecular weight heparin enoxaparin. So it's commonly used one, anti 10 A is the best test again, as we said before, that's not the easiest test to get. Half Life is four and a half to seven hours or 12 hours for anti coagulation effects, which kind of goes on the fact that we usually doses big unless use a higher dose to try and get a longer duration at coagulation effects. The treatment for severe bleeding with this is Protamine Protamine, is fairly well so choosing with unfractionated heparin with low molecular weight heparin, it seems to have some efficacy but not as much. That's largely because interestingly enough, there seem to be a different size of molecular fragments in low molecular weight heparin. As a result of this, the Protamine binds better It seems to larger ones and smaller ones, and you can wind up having issues where some of the inactive parents bowel and some of it isn't compared to unfractionated heparin and where it binds much better to the molecule. And again, as a result, you get variable reversal. So the Protamine is not quite a magic bullet. When you look at the dosing the Protamine, it really depends on time from last heparin dose. And chi breaks down to how many minutes? This is one that you're perfectly honest, I've rarely given back when I was a resident and Lovenox had first became kind of a big thing. We had cardiologists, progestins to open ox, every single person was admitted with chest pain. And then we started finding people getting hypotensive and shocky afterwards on the floor, and we find out that a lot of again retroperitoneal hematomas. So then we had to familiarize ourselves with Protamine dosing, although, again, the Protamine didn't seem quite as effective for this as for regular unfractionated heparin. That said, I've rarely had to reverse Lovenox. Aspirin, clopidogrel, Plavix, aka DAPT, both with platelet adhesion aggregation. This is gonna die quick there is no real strategy beyond supportive care. If you transfuse platelets, you seem to have an increased mortality actually. So despite the fact that you think while the platelets that we have aren't working, let's give working platelets that just doesn't seem to help recommend strategies Yeah, they have mild bleeding issues they actually recommend just not changing anything, keep them under adapt. If they got moderate bleeding, they're kind of holding one agent prefer the aspirin and then try and restart the adapt in three days when some bleeding center control this severe bleeding stock gapped necessitate source control so they got bleeding also go in and try and score a See also etc. And then reevaluate the agents when bleeding is controlled. Now obviously certain indications somebody recently a drug eluting stent place where their risk of incendiary thrombosis is high without particularly Plavix. But there's still times when the bleeding issues are significant enough that you're not going to be able to do that. Occasionally, students still put in bare metal stents and patients who have other bleeding issues, because they know that they're just not going to be able to safely keep them on Plavix. Just some brief words about the other direct thrombin inhibitors bivalirudin is really used anymore. less bleeding and heparin are the glycoprotein embryos but higher rates of thrombosis. That's really Cath Lab drug argatroban soon was kinda cath lab or impatient drug thrombosis associated with hepatitis thrombocytopenia. But it's also got higher mortality rates because when it bleeds is really nothing to give to reverse it. There's no There's no really discreet reversal agent for either of these to get for limited indications find a parent x. Similarly, with the advent of dough accessing that use very rarely, that saucer injectable 10, a inhibitor. The indexer has not been studied and find a paradox. So there's no real reversal agent 40 of the treatment, like with these other ones is supportive care. So just like it's my therapeutics, we use it leading patient right platelet transfusion. Most cases, it's increased mortality. You can get temporary boosts if somebody has thrombocytopenic from severe liver disease or splenic sequestration. But for most everything else, it doesn't really seem to help a whole heck of a lot. DDAVP is helpful they got von Willebrand disease but doesn't seem helpful and medication induced bleeding disorders and conjugated estrogens simulation work well for your remit platelet dysfunction, but they don't really seem to do a whole heck of a lot for medication induced platelet dysfunction. And so the next one is T XA. This is kind of like the magnesium of procoagulant in something that we try to keep using to find indications for it's a synthetic license that amino acid that prevents the conversion of plasminogen to plasmin. It stabilizes clots by preventing the degradation of fibrin. Interestingly, although this isn't the first thing that we think of for it's only FDA approved uses for severe mineralia. It does reduce deaths due to trauma induced coagulopathy particularly if it's given the first three hours. That's why it's been a lot pre hospital protocols utilizing it now. Several years ago, my previous job was I love one trauma said had tone air medical service. And we'd started giving tranexamic acid to select the trauma patients on the helicopter. It's been steady for head injury doesn't seem to improve mortality and isolated head injury. They've looked at it for a bunch of other stuff, dental end bleeding, postpartum bleeding, post surgical, bleeding and multiple areas. And probably the coolest one was nebulized. For haemoptysis, most of these have not been an anticoagulant patients, except for some dentals and epistaxis studies. They did take a big look at for GI bleeding, but it doesn't seem to really help too much. And people with GI bleeding especially here big virus co lead is that can it happen medication is quite low apathy. So not too many studies have actually looked at this. So most the anticoagulants actually prevent clot formation. Remember 10 A thrombin. You can't convert fibrinogen to fibrin, so you can't make that clot. So since TSA can't reverse any of that stuff, its role is primarily in preventing climate breakdown. If you can't find the cloud to begin with and so clots then TX is trying to do a whole heck of a lot. So I'd seen some benefit with dental extractions and anticoagulant patients or select into procedures you know people who have had for example, a tonsillectomy or biopsy done people with severe epistaxis a view looked at using topical TX A for that. And as I said they had that one case that somebody got nebulised TX say for haemoptysis but overall it's used in medication a coagulopathy seems to be very limited. So to go into our case resolutions that facias was given for factor PCC and Vitamin K went to the O R guide tracheostomy evacuation hematoma is discharged on post update for and then he was ultimately switched back to aspirin only as Chad's VAs score was one. His compliance was an issue so they thought he was too high risk to put back on warfarin, he entered alcohol treatment programs which hopefully is going to help a lot of his compliance issues and other medical issues both short and long term. So to summarize the most common anticoagulant type things going into your vitamin K antagonists, 10 A inhibitors and platelet inhibitors. We do see direct thrombin inhibitors a long walk away heparins used less frequently on the outpatient now, for factor PCC produces more rapid reverse of vitamin K antagonists. dependent coagulopathy you've seen vitamin K though because four factor PCC action is relatively short lived activity, it seems to clear out within a few hours. So if you don't get the vitamin K, there's a chance that they will become re anticoagulated. And x is a trigger for the Oxy bands is methodologic issues with trials and they've looked primarily at lab parameters, clinical parameters, but that said right now it's the only FDA approved game in town for these medications. And if you're looking at trying to start an anti Cragun Joe oxymorphone, comparable effectiveness for most indications, any questions or comments, please feel free to contact me firstname.lastname@example.org Thank you very much.