Good morning, everybody. Thank you for showing up early in the morning after probably going out last night. So thank you for that. And again, thanks, Rob, for putting together the guideline process. It was a tremendous amount of work and we're all appreciative of it. So as Matt suggested, I'm gonna talk about whole blood and TXA in a little bit more detail and the trial that we have funded and hope to start pretty soon called the MATIC-2 trial. Here's my disclosures. So when it comes to the potential benefits and risks of whole blood compared to components, I've summarized them here on this slide. And I'm gonna get through this fairly quickly because of the time limitation. But when you compare a low-titer group of whole blood to individual components, given in a one-to-one-to-one unit ratio, right? So we combine red cells, plasma, and platelets together, you wind up getting a more potent product with whole blood compared to components because you wind up diluting that resuscitative solution with anticoagulants and additive solutions. With low-titer group of whole blood, it's stored cold. So you get a cold-stored platelet, which we've known since 1973 from randomized trials that are more hemostatically active and better for bleeding patients. With low-titer group of whole blood, you now have a platelet-containing product that can be stored for at least 21 days. Some centers go out to 35. So this increases the availability of a platelet-containing product because of the three to four times increased storage duration, right, compared to room-temperature platelets, which are usually five days, maybe some places seven days. This allows whole blood now to be positioned at non-level one trauma centers or non-tertiary care medical centers, where this is where the most children and adults are dying from bleeding in the first place. So this is real important. The safety of whole blood compared to components is better due to it being a group O product, so there's virtually no chance of a fatal hemolytic reaction or very, very small. And there's also less bacterial contamination risk compared to components because it's, again, stored cold. The logistic advantages can't be overstated. And those of you who transfuse and resuscitate patients with massive bleeding, you know time is of the essence. And when you only have one product to give versus three, it's much easier for the blood bank to get it to you. It's much easier for you to give it rapidly to a patient. And of course, this has tremendous implications in the pre-hospital phase of resuscitation too. And then the data now is starting to really add up that low-titer group O whole blood compared to components is associated with improved outcomes and utilization of less blood products too, and we'll go through some of that data. What are the potential risks of whole blood compared to components? Well, there's this theoretical risk and in the non-group O recipients, the group O blood will lead to ABO complexes and hemolysis, but that's really only theoretical. And in this massively bleeding population, it's not been borne out in the literature at all. And then there's a potential for waste. If you're incorporating whole blood into your blood bank inventory, if you're not utilizing it, it may lead to waste, which is a very big problem. But centers that have also started using whole blood for non-trauma, massive bleeding, and have a regional system where they're sharing blood between pre-hospital and in-hospital have a less than 1% waste. And that's the system down in South Texas. So when it comes to the data, it was easiest for me to just to use this meta-analysis that Christine Leeper and myself and others at Pittsburgh will hopefully get published soon. And this is a meta-analysis of 24 studies that include close to 60,000 patients and over 5,000 of them received low-titer Group O whole blood. And this meta-analysis is different because it only includes cold-stored low-titer Group O whole blood. Previous meta-analyses have included fresh, warm whole blood, which is a different product, and I think really shouldn't be included. The two shouldn't be used together in a meta-analysis. And here you can see from this meta-analysis, both 24-hour survival and 28-day, 30-day, mortality was associated with low-titer Group O whole blood compared to components. No evidence of small study bias, and all studies were graded as moderate level of bias. Here are the forest plots if you're a visual person, and you can see both 24-hour survival and 28-day survival. In all the studies, there was an association with improved survival. And then when you look at the pediatric studies, of which there were three, again, the odds ratio was very similar to what they were in the overall cohort, too. So there's meta-analysis data in children that whole blood may improve both 24-hour and 28-day survival. And then, again, the group in Pittsburgh, who has been leading the way in this field, have also shown that when whole blood is used compared to components, and I should say whole blood used as part of the resuscitation, right? In all of these studies, nobody is getting whole blood exclusively. And that's because most centers don't have all the whole blood they would like to have in their inventory. And some centers will even, or have a maximum amount of whole blood that can be given to a patient, which is interesting, because if you're using it because you think it's going to improve survival, why would you limit the amount you use, especially when all the safety data is showing it's safe? But anyway, it's important to recognize that the amount of whole blood being given is usually in the 30, 40% range of the total resuscitation. And in that previous slide, I'm not going to try to go backwards, the use of whole blood in children had a faster time to shock resolution according to base deficits and better correction of the INR. So there's some mechanistic data showing how or why whole blood may be improving outcomes in children. And then whole blood may be able to be used as a blood management tool, right? There are now plenty of studies showing when whole blood is used, less total blood is used compared to when components are used. And you can see here in these three pediatric studies, two in trauma, one actually in randomized control trial and PCT surgery. This was ABO compatible whole blood to be fair, but still a dramatic reduction in total blood product utilization ranging between 18% reduction to 40%. But in postpartum hemorrhage, women with placenta accreta, a two liter total reduction in blood products used when whole blood was used compared to components. So I like to say with this, this is doing more with less, which is real important. Safety data in children, you can see here, there's been no increased risk of hemolysis, end organ injury, et cetera, both adults and children. All right, now moving on to transaminic acid. TXA as you know, inhibits plasminogen. And the adult data is pretty strong and it's affected improving outcomes. And not only trauma patients, I get obstetric hemorrhage, TBI, et cetera, although it is only licensed in the US for the IV form for menstrual bleeding. So it's used off label and all other indications. Some of the studies have shown that Ebola dosing could even be better than the bolus versus maintenance dosing that was used in some of the initial crash trials. And this has led many of us in practice to go to a bolus only approach and is now the preferred approach for the US military and their guidelines. So again, in adults, it's standard of care, but in children, it isn't. There isn't enough pediatric data to make it standard of care. And there's a very wide variable use of it for its indication. The dosing is all over the map. And again, there's a lack of high quality data. So in the MATIC study that Matt reviewed a little bit, we looked at any antifibrillinic, either TXA or Amicar. And we found after adjusting for confounders that either antifibrillinic was independently associated with improved survival in all children with life-threatening bleeding. And there was a trend for trauma, medical and operative bleeding for either fibrillinic for improving outcomes as well. The numbers got very small when you looked at TXA only in the trauma cohort, but it was suggestive that antifibrillinics may be useful in children with massive bleeding too. So all of this data led us to want to design the MATIC-2 trial, which is a pragmatic Bayesian group sequential combined non-inferiority, superiority, randomized controlled, multi-center phase three platform trial, where we are gonna compare both whole blood to components and also compare TXA to placebo. And in the platform trial structure, we'll be able to make some of these therapies standard of care over time and add in additional therapies over time. The initial funding is for five years, but we have options to go out to 10 years to start to add other therapies over time too. That's the beauty of a platform trial. We're hypothesizing as you might imagine, whole blood is gonna be at least non-inferior, but probably superior to components without increasing adverse events and TXA will be superior to placebo for 24 hour mortality. We're also involving very sophisticated mechanistic studies in this trial using a multi-omics platform in TEG to not only define TIC endotypes in children or determine if there's heterogeneity of treatment effect, as well as determining mechanisms. And then a plasma repository pharmacokinetics of TXA. We're gonna involve at least 20 centers. We may go up to 24,000 subjects, less than 18 years of age. We're using EFIC for the trial, which is obvious why we need that. Crossover cluster design. I'll show you that in the next slide. To help minimize waste by getting whole blood at all 20 sites at once, that's actually minimize need for 24 hour coordinator support. This cluster crossover design allows us to start centers that'll be randomized into one of these four groups into starting with either whole blood versus TXA. After 250 patients, they switch to components versus placebo and so on and so on. This, oh, my time is up. Too bad I'm not done. Can you stop that from beeping? There we go. Primary outcome, 24 hours mortality. And this is based upon, this is when children die from hemorrhagic shock in traumatic injury. Most kids are dying well before 24 hours, but we felt this was a more appropriate primary outcome than 28 day, 30 day survival. We can get to that in the Q&A session if there's time. Secondary outcomes, as you see there. Exploratory endpoints, I'm gonna go faster because as you have heard, my time is up. Safety endpoints, what you'd expect. We are also, so I won't get into that. If you wanna ask me about RH in girls during the question and answer session, you can do that then. We're including children with an MTP activation that also have either two of three, hypotension or tachycardia for age or a mechanism associated with life-threatening bleeding. Exclusion criteria, we're excluding kids with seizure because we're using TXA, but we're excluding children who are enrolled with more than three hours from the time of injury also due to the concerns about TXA. Low titer group of whole blood, max of eight units, components or standard components. Keep going. TXA will be a bolus of 25 mgs per kg with the two max bolus given over one minute. Makes it simple and easy. And this is actually based on pharmacokinetic data that we're about to publish. You can see me and Christine, as well as Steve and Angelo and Wahed are the co-PIs. I mentioned this already. Cryo could be the next product because we have data that cryo, given early, may improve survival in children with life-threatening bleeding too. So we have a lot of things to add into the trial over time, and I am not that late, at least compared to Matt. He was much later than I was, so I'm done. Thank you.

low-titer group O whole blood

massive bleeding treatment

transaminic acid (TXA)

MATIC-2 trial

pediatric survival rates