Life-Saving Trauma Research with Dr. Christine Leeper

Trauma and Transfusion Medicine Research Center | The University of Pittsburgh

Trauma-induced coagulopathy: The past, present, and future | Journal of Thrombosis and Haemostasis

Advances in the understanding of trauma-induced coagulopathy | blood – American Society of Hematology

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Voiceover: This podcast is for informational and educational purposes only. It is not medical care or advice. Clinicians should rely on their own medical judgements when advising their patients. Patients in need of medical care should consult their personal care provider. Welcome to "That's Pediatrics", where we sit down with physicians, scientists, and experts to discuss the latest discoveries and innovations in pediatric healthcare.

Dr. Arvind Srinath: Welcome to "That's Pediatrics." I'm your co-host, Arvind Srinath.

Dr. Amanda Poholek: And I'm your co-host, Amanda Poholek.

Dr. Srinath: Today, we have Dr. Christine Leeper. She is a trauma and general surgeon and intensivist certified by the American Board of Surgery. She's an assistant professor of surgery and critical care medicine at the University of Pittsburgh School of Medicine. She received her medical degree from the University of Pittsburgh School of Medicine and completed her residency and fellowship here at UPMC. Dr. Leeper's clinical interests include trauma-induced coagulopathy and optimal transfusion practice in adult and pediatric trauma. So Dr. Leeper, thank you for, for joining us today.

Dr. Leeper: Thank you for having me.

Dr. Srinath: Can you give us a background of where you're from and what drew you to Pittsburgh and how you got interested in post-traumatic coagulopathy and whole blood for resuscitation in injured kids?

Dr. Leeper: Sure, so I grew up in the Washington DC area originally, and I did my undergrad at Duke University and then came here for medical school, and I have not left since, so I did my residency after that in general surgery and then a, a critical care fellowship. And I've stayed on as faculty now in the Department of Surgery and Critical Care Medicine. So while my clinical practice is in adults, my research interest is in children.

So as a medical student, I started a research project with Dr. Barb Gaines, in the head of the Benedum Trauma Program here at Children's Hospital at Pittsburgh, and started working closely with her and looking into better understanding the changes that happen in children's physiology after injury. And it was an area that was really fairly poorly researched at the time and still, you know, remains an area that's definitely evolving and growing.

Dr. Srinath: That's fantastic. We're so thankful you stayed on. Can you just give us an overview of what trauma-induced coagulopathy is, how and why this process occurs, and perhaps a brief history of how we came to learn about this process?

Dr. Leeper: Sure, so injury impacts the body in a number of different ways. There's the actual tissue trauma from crushing or cutting, and then there's the way that the body responds to that, and so trauma-induced coagulopathy is part of the body's innate response to injury, and it involves an incredibly complex interplay between the hemostatic, inflammatory, and immune systems.

And it's separate from what we would classically call, like, the lethal triad of response to injury, so coagulopathy, acidosis, and hypothermia. And it is certainly something that we're learning more about but remains relatively poorly understood, particularly in, in children.

Dr. Srinath: Thank you.

Dr. Poholek: So question about that. I guess what are the risk factors for trauma-induced coagulopathy and, and thinking a little bit more about, like, how often does it happen in cases of trauma. Does it, does the severity correlate with the severity of trauma?

Dr. Leeper: Yeah, so we see it most commonly in the most severely injured children. And in terms of the incidence in children who are admitted to the intensive care unit, we see it in about a third of those and that's based on admission laboratory values.

So some of the ways that we would define trauma-induced coagulopathy are based on, say, the INR lab test as well as the thromboelastography which is a functional test of coagulation. And so, based on the abnormalities that we see on those parameters, in addition to potentially clinical coagulopathy, that's how we would diagnose TIC, or trauma-induced coagulopathy.

So injury severity is one of the main risk factors. We also see injury mechanism as a contributing factor. So children with penetrating trauma or children who have been victims of child abuse also tend to be at a higher risk for developing TIC.

Dr. Poholek: And, okay, so are there different kinds of trauma-induced coagulopathy or is it all kind of one big umbrella for a variety of different outcomes?

Dr. Leeper: Yeah, it's a, it's a huge umbrella term, and there are really a lot of different distinct phenotypes underneath that umbrella. And part of the work that we've been doing is trying to better understand the different types of TIC as a means of developing effective therapies and maybe different therapies for children who present with different kinds of coagulopathy.

So in looking at the TEG test, for instance, there are children who have high levels of fibrinolysis. There are children who have abnormally low levels of fibrinolysis, and we think that we could potentially develop different treatments in order to target both of those different abnormalities.

Dr. Srinath: Are there certain types of injury that correlate with each type of phenotype, and how can one protect against this occurring too?

Dr. Leeper: Yeah, that's a great question. There's not a direct correlation between injury mechanism and the TIC phenotype. So we have really a lot more learning to do about sort of an individual's response to trauma and why they would potentially develop one versus the other of those.

Dr. Srinath: Got it, good. And how would you, are there ways you can protect from this happening if you're in the setting of a trauma?

Dr. Leeper: Yeah, so we think that early resuscitation has the potential to mitigate some of these adverse effects of TIC, and by resuscitation, I mean, stopping the bleeding, and then transfusing blood products to address shock or blood loss. And so, that is sort of how we got involved in developing different transfusion strategies, and particularly, whole blood as a means to mitigate TIC.

Dr. Poholek: Mm, so, so what are the challenges in trying to effectively resuscitate, right, 'cause I can imagine there's a lotta scenarios where it's hard to, to do that quickly, and it sounds like you wanna do that quickly to try and mitigate this outcome, this trauma-induced coagulopathy outcome.

So what are the sort of challenges to being able to do that? And I guess, how does the whole blood potentially overcome one of those challenges?

Dr. Leeper: Yeah, so there are a number of potential challenges to effective resuscitation, and that may include limited IV access, particularly in children that can be a challenge. Availability of blood products, which here at Children's we're fortunate to have but not all centers have them as readily available as we do. And even here, you know, obtaining additional blood products beyond packed red cells like plasma or platelets, you know, there's a lag time to get those from the blood bank, and so, we really try to target balanced resuscitation, so a comparable amount of red blood cells and plasma and platelets to sort of reconstitute whole blood.

And so part of the benefit of actual whole blood is that it has all those components in one bag. It can be stored in the emergency department refrigerator, and it can be transfused really efficiently in order to quickly address shock and some of these changes like TIC.

Dr. Poholek: How interesting. So can you dive in a little bit more about your research? How does one research this trauma-induced coagulopathy? What are the mechanisms that you're trying to get at and, and just, yeah, share a little bit about what your research is on.

Dr. Leeper: Yeah, so our research has looked at both the potential mechanisms as well as some of the underlying contributors to TIC. And that's taken the form first of, you know, some retrospective chart reviews in order to better understand how children are presenting as well as some prospective observational studies, collecting blood specimens when children come into the trauma bay and looking at different things like the TEG test, endothelial markers, and different lab values to sort of figure out, you know, what is associated with TIC and what are some of the therapies that we can maybe develop to, to improve outcomes in children who have it?

Dr. Srinath: You know, you, it, it's really fascinating because you have two hats, the adult side and the pediatric side too. How do children and adult differ in this phenomenon?

Dr. Leeper: Yeah, so I am really grateful to be speaking to a pediatric audience because I don't have to spend quite as much time belaboring the point that children are different anatomically and physiologically. And when I'm wearing my adult hat, yeah, it takes a great deal of effort to kind of go through and explain why that might be so, but children's response to injury and the injury mechanisms that they have sustained are, are vastly different.

And most of what we know about trauma that is evidence-based and the care that we provide comes from adult data, which is really inappropriate and unfortunate, and so the need for pediatric-specific data regarding optimal hemostatic resuscitation practice is, is tremendous. And we have been working both here and with other centers and collaborators to try to develop guidelines that are specific to the pediatric trauma patient.

Dr. Srinath: And that was my scaffold into my next question in terms of education. So are, are there educational efforts ongoing for pediatricians and or adults about this phenomenon base? To be honest, when we learned about what you were doing, it, it seemed relatively new and from what we're hearing, it is.

Dr. Leeper: Yeah, it's certainly a, a growing field of research, and both on the adult side and on the pediatric side, there are a lot of folks who are invested in learning more about this and, and disseminating this information.

Dr. Srinath: Fantastic.

Dr. Poholek: So kind of getting back to some of the questions related to research, what do you feel like are, like, sort of the biggest open questions in the field of understanding trauma-induced coagulopathy, and is this the kind of thing that you can develop clinical trials to research or, you know, how does one go about answering those questions?

Dr. Leeper: Yeah, in the pediatric population, it's really difficult because while trauma is the number one cause of morbidity and mortality in children from age one through 19, in general, severe trauma is, fortunately, a relatively rare event. So in order to conduct this kind of research and to understand this in a meaningful way, multicenter trials are really necessary.

And so we have been working on a number of collaborative efforts with different centers currently trying to develop a trial comparing whole blood to component therapy, trying to sort out, you know, which of those is the more effective strategy. And so, that's something that I think in the next couple of years will be certainly an emerging area of research.

Dr. Poholek: So it sounds like something that's still ongoing, no answers yet. Can you share with us a little bit in the time that you have been recent, some of the more surprising things that you have learned from the time that you started, where maybe less was known, to sort of where we are now?

Dr. Leeper: Yeah, I think some of what is surprising, to me, is the great diversity of response to trauma that we see in, in children. To your point earlier, there are different phenotypes, and we don't have a great understanding of, you know, why children respond in one way or another. You know, we have children with the exact same injury mechanism who come in with the same vital signs and the, you know, same sort of treatments and, and they respond very differently to that. So we're really getting to the heart of how children are responding and what is the best way to be, to be treating them.

Dr. Poholek: Mm.

Dr. Srinath: Along those lines, in terms of treatment response, for providers out there who are resuscitating children, what clinical science include them in this process is occurring, and what should they do out of their general practice afterwards? What options do they have?

Dr. Leeper: Right, so children are, are tricky because they have superior compensatory mechanisms as compared to adults. So the typical signs that sometimes adult providers might rely on, like hypotension or low blood pressure, are not really reliable indicators in kids. They can maintain a normal blood pressure up to the point of cardiovascular collapse, essentially.

So we really do need to develop better indicators of, of shock and TIC, but at present, you know, tachycardia and relying on your physical exam and, and clinical judgment are really superior to many of the scoring systems that have been developed.

Dr. Srinath: That's fantastic, thanks.

Dr. Poholek: Mm-hm, yeah, I'm curious if there's any, been any efforts for, like, mouse models or any other kind of non-human models that people could try to actually address mechanism more clearly. Obviously maybe not as easy to then address the heterogeneity that you would see across the human population, but yeah, I'm just curious if there's any sort of research at that level.

Dr. Leeper: Yes, yeah, there's a lot of work happening sort of in parallel on the basic science side in trying to get a better idea of what mechanisms might be contributing. And again, a lot of that is happening as well in the adult trauma patients.

It's a little bit more difficult to correlate all that with children, just because it, again, it's not as common of an occurrence, and we really do need to have these multicenter collaborations, I think, in order to answer that question definitively.

Dr. Poholek: Yeah, I can only imagine how hard that would be 'cause, yeah, you have to wait for the patients to come in and then, like you said, there's these outcomes that are so different. It seems like it would be a real challenge to then dive in deeper.

Have there been any, have, has there any evidence that sort of there's a association with sort of genetic background or family history? That might be a little difficult to address, given this sort of the circumstantial evidence of the injury, right?

Dr. Leeper: Yes, yeah, that's a great question, and I think we just don't know. More, you know, time will tell hopefully.

Dr. Poholek: We need more data.

Dr. Leeper: Yeah.

Dr. Poholek: Always more data, yes.

Dr. Leeper: Yeah.

Dr. Srinath: So in the next five to 10 years, what burning questions do you hope to answer?

Dr. Leeper: Yeah, that's a great question. So the whole blood versus components is sort of at the forefront right now, but there are a, a lot of other unanswered questions regarding optimal hemostatic resuscitation practice.

So the use of hemostatic adjuncts in children is another question. The, one of which is tranexamic acid, which is an anti-fibrinolytic medication whose use is rather ubiquitous in adults, but there are limited sort of safety and outcome data in children.

And then there are other potential blood products, freeze-dried plasma, cryoprecipitate, factor concentrates, lots of different products that have the potential to really change practice, but have no data in, in pediatric cohorts at this point.

Dr. Srinath: Thank you. Well, Dr. Leeper, this has been a fascinating discussion on a really novel area of research, and we really appreciate you taking the time to talk to us and educate us all about what you're doing and what we're doing to help children. Thank you so much.

Dr. Leeper: Thank you, thanks again for having me.

Dr. Poholek: Hopefully we can have you back in a few years once you have all that data.

Dr. Leeper: Absolutely.

Dr. Poholek: You can share your results. We're excited to hear more.

Dr. Leeper: That sounds great.

Dr. Poholek: in the future. Thanks so much.

Dr. Srinath: Thanks.

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