Hi, my name is Phil Spinella, I'm the co-director of the Trauma and Transfusion Medicine Research Center at the University of Pittsburgh, and I'm going to speak to you today about the use of whole blood for severe traumatic bleeding. Why take blood apart and put it back together again? Here's my disclosure slide. None of these potential COIs are directly related to this presentation. Now damage control resuscitation is a bundle of care intended to reduce death from hemorrhagic shock. The central tenant of damage control resuscitation is hemostatic resuscitation, and that is basically a whole blood based resuscitation, whether it be whole blood itself or components in a one-to-one-to-one unit ratio. Now hemostatic resuscitation is basically pushing blood forward in the resuscitation to push the limits on survivable bleeding. This is a casualty I treated in Baghdad in 04, and with the use of whole blood and tourniquets we were able to save his life. But here again the concept is getting blood earlier to patients to limit survivable bleeding. Now it's very important to start to treat patients with hemorrhagic shock in the pre-hospital phase of resuscitation, and that's because that's where the vast majority of all hemorrhagic deaths occur. While this is military data that I'm showing here, where the vast majority of deaths occur pre-hospital, the same dynamic occurs in civilian settings as well. So when it comes to hemostatic resuscitation, which provides a balanced treatment of shock endothelial, hemostatic, and immune dysfunction, you basically have two options. Either you use whole blood itself or red cells plasma platelets in a one-to-one-to-one unit ratio. And the feasibility of hemostatic resuscitation in the pre-hospital phase is clearly much different than it is in hospital, where obviously in the pre-hospital setting it would be incredibly difficult to get red cells plasma and platelets all available at one time, making whole blood a much more attractive option for pre-hospital resuscitation. So before we start to talk about whole blood, we need to go through some definitions or some differences. Whole blood can either be warm and fresh, and it's typically transfused within eight hours. And most of the military data initially published out of the wars from Afghanistan and Iraq were with warm, fresh whole blood. The majority of civilian data, more recently published, is with cold stored whole blood. This is whole blood that's refrigerated and can be stored all the way out potentially to 35 days, although most institutions are storing it for a maximum of 14 to 21. Whole blood can be ABO-specific in the beginning of the wars, again, with the military data with warm, fresh whole blood. It was typically ABO-specific, but now most of the civilian data being published is with low titer, Group O whole blood. Low titer is defined as an anti-A and B less than 256, although the Red Cross uses less than 200. Now while whole blood has been used for over 100 years, it wasn't until this publication of ours in 2009 from our database in Baghdad that showed an independent association for improved survival with the use of whole blood. And did whole blood itself kind of come back into public consciousness, I guess you would say. It pretty much stopped after the Vietnam War, there was a little bit of use of cold stored whole blood at a few pediatric hospitals along the way, a report of its use in Mogadishu during the Black Hawk Down event, but really pretty much disappeared until early 2004, 2005 when we started to use it again because patients were bleeding to death at a high rate and we were trying to find a better way forward. Now when it comes to the risks and benefits of low titer Group O whole blood compared to components because warm fresh whole blood cannot be used in civilian hospitals due to the fact that warm fresh whole blood doesn't have formal transfusion transmitted disease testing done because it has to be collected and used rapidly. So in the civilian world, low titer Group O whole blood is the most feasible product to use. Now when you consider the advantages versus the potential risks, you can see that whole blood is a more potent product, I'll show you that on the next slide. Whole blood has cold stored platelets within it and we've known since 1973 a cold store platelet has improved hemostasis. Whole blood compared to component therapy has a platelet containing product that will allow for increased storage duration, allowing it to be used in places that cannot afford to keep an inventory of a product that only has a five day shelf life. So if you think about it, if you can now store whole blood up to let's say even 14, 21 days, it can now be put outside of tertiary care centers that currently do not have an inventory of platelets because of the five day shelf life of a room temperature stored platelet. This will allow access of a platelet containing product to more patients with severe bleeding as a result. Since low titer Group O whole blood has Group O red cells in it only, there's a much less risk of ABO and compatible transfusion reactions compared to component therapy because as you know, when component therapy is started for massive transfusions, we eventually try to go to ABO compatible products and just did a human error alone, there's a much higher risk of a fatal hemolytic reaction. Less bacterial contamination risk again for the stored cold. There are logistic advantages of using a Group O whole blood product. Again, it's one giving one product compared to four. And as I'll show you, there's now a few reports showing an independent association of improved survival and less blood products used when Group O whole blood is used compared to components. When it comes to the potential risks of whole blood, well, when you give Group O whole blood to a non-O recipient, there's a potential risk of immune complex formation due to the incompatible plasma. But there hasn't been any data published demonstrating this risk. And then there's the potential for waste. With the inventory needs of stocking Group O whole blood and the variable use, even with the storage duration of typically 14 to 21 days, there may be some waste, but we'll talk about ways to mitigate that at the end of the talk. Now here's a slide to show that when you compare component therapy, when you combine red cells as well as plasma platelets, and cryo even, together, compared to the unit of whole blood that it would come from, it is a much more concentrated, whole blood is a much more concentrated product. And that's because of the increased additives that are in each component compared to a whole blood unit. So if you took the equivalent of six red cells, six plasma, one apheresis platelet units, and compare that to six whole blood units, there's three times the volume of dilutional additive solutions or 700 mLs in just a one transfusion pack, so to speak, or six units of each product. That's a tremendous amount of dilutional additive solution to a patient who's in traumatic hemorrhagic shock. Now again, I've told you since 1973, we've known that a cold-throated platelet has improved hemostatic function. This is a study with cold-throated platelet units, but you can see improved agonometry with the cold-throated platelets compared to room temperature, and in this RCT of adults that had either aspirin, were on aspirin, or had low platelets due to cancer therapy, a much better correction in bleeding time with a cold-throated platelet compared to a room temperature-throated platelet. Then we have this randomized controlled trial in children requiring cardiac surgery, when the children that received cold threshold blood compared to components in a one-to-one-to-one unit ratio had a significant reduction in chest tube output, or blood loss, and that was also associated with improved platelet function on platelet aggregation in the cold-throated group. Now, this whole blood here in this trial was ABO-specific. It wasn't Group O whole blood, but it is an RCT comparing cold-throated whole blood compared to individual components. Now fast-forwarding all the way to 2018, and this was the first study evaluating whole blood versus components out of Pittsburgh, since it was the first, it was when most in the community were using very small amounts of whole blood as they started to use it, and the max here was only two units of whole blood, so even when only two units of whole blood were used in this study of 270 patients, the time to normalization of lactate was significant, was almost half, and statistically significant in the Group O whole blood group compared to the components. The next study published was out of Houston, now 350 patients, and here you can see that the group that received whole blood compared to components not only utilized half the amount of whole blood for their resuscitation, there was a two-fold increase in 28-day survival. Now in this prospective observational study that we published out of St. Louis, a small cohort, 86 patients, with a high amount of penetrating injury, you can see here though that the patients receiving whole blood compared to components had an adjusted survival rate that was improved at both 24 hours and 28 days compared to the component therapy group, a quite significant amount. Interestingly, the MCF on Rhotem was also predictive of survival, so we did a stratified analysis according to an MCF of 60, and whether patients received components or whole blood, and you can see that the whole blood was pretty much only associated with improved survival when the platelet function or the MCF was low, supporting that Group O whole blood is potentially beneficial for patients with low platelet function that are bleeding. In this same study, it was interesting that not only was the total blood use lower in the group that received whole blood, similar to the Houston group, although not statistically significant, there was also no difference in maximum 72-hour mod scores between the two groups. So, independent association with improved survival, reduced blood product utilization, and no difference in organ failure. Now what about children? Again, the group out of Pittsburgh, Christine Leeper et al. have published the majority of the literature in children, and here you can see children receiving Group O whole blood had a faster time to resolution of shock according to the base deficits, and a more efficient reduction in INR with whole blood compared to components, so not only does whole blood in children appear to resolve shock and coagulopathy better than components, in their follow-up study with more patients, they demonstrated that Group O whole blood is independently associated with improved survival at both 72 hours and 28 days, and you can see that there on the Kaplan-Meier curve on the right. In addition, there have been no published increased risks with Group O whole blood compared to components when it comes to the risk of hemolysis or transfusion reactions, and up until a few years ago, Group O whole blood was not a product that was part of the standards within the AABB, which is the American Association of Blood Banks, but in 2018, the Thor Network lobbied AABB and were able to have this changed, and now Group O whole blood is not only licensed by the FDA, it's always been, it is now a standard product. And this has led to a dramatic increase in utilization throughout the country, using whole blood predominantly in trauma centers, and not only at over 40 adult trauma centers, there's at least now 7 pediatric hospitals utilizing whole blood as well. And then that was being used outside of trauma too. This is a small report of roughly 30 patients with placenta accreta, showing that when whole blood is used for these women with placenta accreta, that there's reduced blood products utilized in this patient population too. Now the only, the main difficulty with implementing Group O whole blood programs is what to do with the issue of RH isoimmunization and women of childbearing age. Since RH donors are infrequent, in the 5-10% range, it's much difficult to have RH negative whole blood available. So many centers are using RH positive whole blood. But there's a concern if the woman winds up being RH negative due to the risk of fetal demise from hemolytic disease of the fetus newborn. When the risk has been calculated by this group of transfusion medicine experts here, the risk though is 0.4%. That's in all adult women. But when this group took a closer look and used the age of the woman, going all the way down to the age of zero, including girls and adult women, you can see here the risk of hemolytic disease of the fetus newborn. Now not only including fetal demise, but now also including intrauterine transfusions as a sign of severity of illness. You can see here it ranges up to about 6%. So there were still many programs that were not giving RH positive whole blood to women of childbearing age because of this potential risk. But as you've seen, there's a potential mortality benefit of using whole blood compared to components specifically in the pre-hospital phase where all the deaths are occurring and you can't get all three components. So we did a survey in St. Louis of roughly 400 women and asked them, based upon different potential risks, risk reduction in mortality with using RH positive whole blood, would you be willing to accept it with the potential 4% risk of future hemolytic disease of the fetus newborn? And you can see here, women clearly prefer reducing their risk of mortality and accepting that risk of a future pregnancy complication. I mean, even when the potential risk reduction is 4%, more than 90% of women would want that RH positive whole blood. But even look at the data in another way. If the mortality reduction with whole blood was only 1%, you still have two-thirds of women saying they would rather get the whole blood and worry about the future risk of pregnancy later. So when it comes to implementing Group O whole blood programs, it's probably best to implement it for all patients with life-threatening bleeding, as we are doing here in Pittsburgh. If you're only utilizing patients with trauma, that leads to increased waste because of variable utilization. And it's very likely that non-trauma patients would benefit as well from whole blood too, as we're starting to see in case reports that are being published. It definitely would be much more efficient to also use it in the pre-hospital phase. And if you did within a hospital system, you could rotate it between the pre-hospital and in-hospital system to further reduce waste. And it's my opinion that every program using it should have a maximum of at least eight units because that's where the data shows there's mortality benefits. If you have the maximum amount lower than that, you're going to wind up using a lot more components and basically diluting the potential benefit of Group O whole blood. Where's the future lie? Where is the future lie with whole blood? There is now a DARPA-funded program to make a dried whole blood product. And this is from freeze-dried plasma, freeze-dried platelet-type surrogates, as well as a freeze-dried synthetic red blood cell that's in development too. So in conclusion, it's very important to initiate hemostatic resuscitation in the pre-hospital phase because that's where the most of the deaths from hemorrhagic shock occur. Group O whole blood has potential advantages over components. There's data indicating potential improved survival with less blood utilization and no increased risk of organ failure, hemolysis, or transfusion reactions. And while this is being implemented clinically, there are multiple RCTs that have been funded in adults that will be starting soon and one that has been submitted for funding in children. So with that, I would like to thank you for your attention and we'll be available for questions. Thank you.

whole blood

severe traumatic bleeding

damage control resuscitation

hemorrhagic shock

hemostatic resuscitation

pre-hospital phase