Transcripts are auto-generated and may contain errors. 

Dr. Craig Jenne: [00:00:00] Once platelet counts start crashing, it’s a strong indicator that we’re seeing these massive leukocyte platelet pathogen aggregates within the microvasculature. And again, that could be the liver. We, we know what happens in the lung as well, and in some models in the brain. 

Nicole Kupchik: This is the sepsis spectrum, a podcast about antimicrobial resistance.

Sepsis and how to expect the unexpected in your practice.

[sponsor acknowledgement]: Sepsis alliance gratefully acknowledges the monetary support provided by Vantive for this podcast series. 

Philip Cotton: My name is Philip Cotton and I’m a sepsis survivor. Eight years ago, I woke up with severe chills, with uncontrollable shaking by the time I got to the emergency room. The shaking had stopped around three 30 in the morning.

I became aware of a nurse in the room. My blood pressure had fallen precipitously, [00:01:00] and a code team rushed to my room. I was in excruciating pain as my organs were shutting down. They administered numerous IVs with tubes down my nose and inserted a port in my neck. My wife was advised to prepare herself as I was not expected to survive the night.

The CT scan showed an abscess on my liver, which was the proximate cause of my sepsis. I spent 10 days in the hospital, five of them in intensive care, where my wife says I was mostly unresponsive and unaware of my surroundings. Prior to the sepsis episode, I was very physically fit, regular at the gym and a hiker.

Because of my good physical condition, I was told I should recover fully, but there was a strong [00:02:00] emotional toll to overcome as I realized how close I had come to death.

Nicole Kupchik: Hi everyone, and welcome to the sepsis spectrum. I’m Nicole Kupchik, critical care nurse, clinical nurse specialist, and your guide through the wide, unpredictable world of sepsis, or as we like to call this season, sepsis and multiorgan dysfunction syndrome. On today’s episode, we’re gonna examine the relationship between sepsis and the liver, specifically, how they can quickly become unwilling dance partners.

When an infection turns the body’s chief detox organ into both the victim and the accomplice. The clip you heard at the beginning of today’s episode was from Philip Cotton, a sepsis survivor whose infection began with a liver abscess that then led to multi-organ failure and a near death experience.

And you know, listening to his [00:03:00] story was just very heart wrenching for me. ’cause we know these patients go through so much and Philip’s story really drives home health. Fast sepsis can turn a localized infection into an absolute full body crisis. To help us unpack what’s happening at the cellular and systemic level when sepsis occurs.

I’m joined by Dr. Craig Jenne, professor of microbiology, immunology, and infectious diseases at the University of Calgary. Dr. Jenne is an internationally recognized researcher whose work uses cutting edge imaging to reveal how infection and inflammation collide inside the body. I can’t wait for you to hear this.

Fascinating discussion. We’ll be right back with Dr. Craig Jenne,

I am so excited to be here today with Dr. Craig Jenne, [00:04:00] who’s doing some really amazing and super interesting work up in Calgary, Canada, in Alberta, so welcome to the show, Dr. Jenne. Hi Nicole. So I wanna open this up. Can you, because you don’t have a typical job, you’ve got a really interesting job where you do some pretty amazing things and so can you let the audience know what it is you’re up to?

Dr. Craig Jenne: Yeah, sure. We, we. We are a basic science lab that that’s located in a hospital, so lots of clinical friends, lots of translational work, and we use a technique known as intravital microscopy to look right inside living animals, look inside their blood vessels, and watch what their immune cells are doing in models of infection with, you know, big focus on sepsis, blood clotting, immuno thrombosis, and, and those other nasty things that happen in our microcirculation.

Nicole Kupchik: Which all of those things go together, as we all know clinically in a patient who’s got sepsis, they’ve got a massive inflammatory response [00:05:00] and their coagulation chains are activated. And so, alright, so tell me, how does this go? So you’ve got an animal that’s septic, 

Dr. Craig Jenne: right? 

Nicole Kupchik: And I’m assuming, are you studying bacterial, viral, fungal, all of the above.

Dr. Craig Jenne: Yeah, sort of all of the above. I mean, we, we, we have a lar large focus on both bacterial and viral sepsis. So bacterial looking at bacteremia and, and soft, soft tissue infections. Viral, a little bit more respiratory. So looking at SARS-CoV-2 influenza. We’re really interested in that innate immune response.

So what happens when those bugs first encounter our innate immune system? And I think the early stages are very much as we anticipate in the textbook, lots of neutrophils, lots of inflammation. And then after that, things get a little bit weirder with, with some of these infections when we start activating platelets and, and we start seeing blood clotting in the microcirculation.

Nicole Kupchik: And when you are [00:06:00] evaluating these types of things, how quickly are you seeing activation of clotting factors? 

Dr. Craig Jenne: So it sort of depends on the model. If we’re looking at bacteria, we are seeing really good evidence of thrombin activation within the first hour or two of a bacteremic model, uh, viral a little longer.

We, we do have to wait for the virus to get in and start replicating really for the body to know it’s there. But the, these acute models of, of intravenous bacterial administration or intraperitoneal within an hour, we can clearly see thrombin activation in organs such as the liver. 

Nicole Kupchik: That’s actually pretty fascinating because I think one of the challenges, um, we have clinically is evaluating this cellular activity that’s happening in, in humans.

So have, do you know, has there been a correlation from the work you are doing into humans and like, is there a time correlation that you’re seeing in humans? 

Dr. Craig Jenne: Yeah, the di difficult part in [00:07:00] humans is, you know, by the time you’re presented an emergency department or, or worse, an intensive care unit, we’re really guessing at the number of hours you may have been experiencing a, a, a given pathogen.

There. There may have been a, a subacute response for quite a while. What we do know is, is obviously in severe sepsis, we do see markers of thrombosis. Uh, you know, we, we do see evidence of DIC in, in human patients, and. I think there’s been a bit of a mystery as to why we still see general, you know, hemostatic parameters for, for most patients, even though there’s evidence of plotting.

What we find by looking in the live animal is we can see most of these reactions are, are limited to the capillary beds or the microcirculation and the macrocirculation stays well perfused through things such as the liver or, or lungs. 

Nicole Kupchik: Ha. ’cause I mean, it’s, it’s so fascinating. Years ago, ’cause I’ve been doing this a long time.

We had like a, these probes that were mostly used in research, but they looked at the sublingual circulation mm-hmm. In humans. Right. In humans. And, [00:08:00] and what we were seeing is that basically in the capillary bed, there was almost like a traffic jam of basically micro thrombosis in the capillaries. Do you know what I’m talking about?

Have you, have you seen this? Yeah, absolutely. 

Dr. Craig Jenne: This, this is what we’re seeing throughout the lungs, throughout the liver, uh, in the kidney. Even in some models, we see it in the brain microcirculation, that, that we’ve seen adherent neutrophils, we see platelets piling up behind them. And although we see strong thrombin activation, the the really.

Fascinating part from our point of view is that does not always translate to fibrotic clock generation. So, so we’re not always seeing fibrin deposition, although we can measure fibrinogen and fibrin in the microcirculation. Some of these vessels remain patent, even though there’s, there’s strong thrombin activation and, and it’s really starting to highlight that that emerging.

Of, of, there’s obviously immuno thrombosis, but there’s also thrombo inflammation where thrombo is driving activation of the innate immune system, activation of, of endothelial biology, independent of the actual plot formation. 

Nicole Kupchik: [00:09:00] And when you’re seeing these open capillary beds, has the model received treatment?

Like, have they gotten fluids or antibiotics, or is this just like you’re kind of letting nature run its course? 

Dr. Craig Jenne: No, we’ve actually been trying to target the, the th the thrombotic side of it as opposed to supportive therapy. So, you know, administration of thrombin inhibitors is highly protective in these models.

For example, if we were to give an animal a, a, a bacterial infection, staph aureus, re coli, and we measure liver damage with a given challenge, if that animal was to receive an anticoagulant at the same time as infection, we can completely inhibit liver damage despite the fact they’re experiencing the same number of bacteria, the same bacterial toxins.

So it seems to be the actual thrombotic events that are causing the organ damage and not necessarily the pathogen. 

Nicole Kupchik: And what, just as an just don’t. ’cause I’m curious, what, what are you giving the animals? What drugs are you giving them? It’s like argatroban or something like that. Yeah, 

Dr. Craig Jenne: argatroban is our [00:10:00] go-to.

Uh, but you know, we’ve done studies of animals on low dose a SA as well. So this concept of a daily, uh, antithrombotic agent and, and, and does that protective. Um, but our focus has really been on what drives this thrombosis and, and is this different than hemostasis? And one of the principle driving factors behind this are actually the neutrophils and the fact that neutrophils can release neutrophil extracellular traps or nets.

Those net structures directly activate thrombin. So if we target the net, so for example, treating a mouse with intravenous Ds to break down nets, we completely inhibit the thrombin signal despite the fact we haven’t touched the coagulation system. 

Nicole Kupchik: That’s actually pretty fascinating. So we, you know, there’ve been so many studies done in humans and I have, I know I give presentations on this and I’ve got a, I call it the, uh, research graveyard.

Right. And I have tombstones of everything that’s been studied. Yeah. And just a lot of things just haven’t panned out clinically. [00:11:00] And so, you know, I wonder, you know, do you know, are there any human studies that are. It’s gonna target maybe things like argatroban and things that we have access to. 

Dr. Craig Jenne: Yeah. So, so there have been a number of studies.

Uh, one of the larger ones was actually led a number of years ago out of, out of Winnipeg here in Canada. They called the Halo study and that was a high dose, uh, low molecular weight heparin in septic patients. And the interim results of that, were showing reasonable protection with, with an acceptable bleeding risk.

So we do still have to be careful, obviously, dosing people with anticoagulants, particularly individuals who may be experiencing DIC, given that it’s partly consumptive is problematic. But overall, if done right, we, we can see improved outcomes in sepsis. Again, fascinating. 

Nicole Kupchik: Now, years ago, now I’m totally dating myself.

Uh, we for, I think it’s a little over a decade, or actually about a decade and a half, we [00:12:00] were using activated protein C. 

Dr. Craig Jenne: Yeah. 

Nicole Kupchik: And then, as we all know, that got pulled off the market. Um, any thoughts on that? 

Dr. Craig Jenne: Yeah, that, that, that is a great question. I’d love to dive back into that. I, I, I think the early results from that were showing there might have been a clear signal in subsets of patients.

When applied across the board, and, and I think that’s something that these animal models are showing us, that if I were to put up pictures of a mouse, who it, it has been challenged with a gram-positive, a gram-negative, or a virus. Most people can’t tell the difference in the phenotype of the pictures, despite the fact the mechanism driving that may be different.

So when we look at a patient, we see that there’s coagulation, but the actual mechanism that led to that, that clotting problem is likely different depending on the agent. And applying the therapy specifically to, to a given infection model might prove more beneficial than a blanket. I mean, you have sepsis, you have a a, a marker of coagulation.

Let’s hit you with an anticoagulant. [00:13:00] 

Nicole Kupchik: Well, and I, and I think the, the tough, that’s the human factor part of all of this is that, like you, I think you made a great point earlier, is that so many humans present late and you know, I mean, let’s be honest, you know, you, you’re, most people are probably at home sick for days on end before they come to the hospital and, you know, and you wonder like, what we’re finding now is so many things that we do are time dependent.

Dr. Craig Jenne: Absolutely time dependent, situation dependent, organ dependent. And I, I mean, that’s where we, we’ve really been trying to dive into what is driving this, this concept of immuno thrombosis, pathogen, independent time, independent, if you have inflammation, what are, what are the downstream effects and can we intervene, can we uncouple the two?

And, and that, that’s something the lab has really been tasked with, is that the concept of trying to uncouple immuno thrombosis. From hemostasis, can we preserve the protective mechanisms while toning down or, or per perhaps even eliminating some of these [00:14:00] pathological aspects of the same pathways? 

Nicole Kupchik: Yeah, well, you know, going back to activated protein C, you know, I have no interest financially or anything, you know, in activated protein C, but I’ll tell you, I did see it work clinically in patients.

Yes. And what I wondered about with some of the follow-up studies that were done is, was the drug given to the right patient population? You know, ’cause the early studies they. Calculated Apache scores and they were giving it to much sicker patients. 

Dr. Craig Jenne: That’s right. Yes. And then 

Nicole Kupchik: follow-up studies, the patients weren’t as sick and they didn’t do as well with the activated protein c.

Dr. Craig Jenne: I, I think that’s exactly it, and I mean, I, I do think there’s a lot of area that we can still be working on, on these concepts of biomarkers or, or more importantly, broader bio fingerprints. I think when we, you know, try to hedge our bets on our two or three favorite markers, they tend to let us down. And, you know, we’ve known about IL six now for.

20, 30 years and, and blocking IL six is not protective, although it can still [00:15:00] be a biomarker. I think getting a better sense of what are the other 90 blood proteins that are shifting at the same time will give us a much better picture of what’s happening in the patient. Or perhaps more critically identify which patients may benefit from drugs such as activated protein c.

Nicole Kupchik: Yeah. Well, okay, so lemme ask you this question. What are you seeing as maybe perhaps in the literature, a promising biomarker for humans? 

Dr. Craig Jenne: Oh, that’s a great question. We’ve actually tried to avoid put, putting our, our eggs in one basket. I mean, there was a lot of work. There’s not, obviously on procalcitonin and, and other markers.

We’ve taken a step back and we, we’ve actually, some of our clinical partnerships. We’ve been trying to measure as many biomarkers as possible, so using these multi arrays of 100 to 300 markers, uh, and coupling that with things such as metabolomics as well. And then we’re, you know, using that large dataset for machine learning.

So, so take the investigator out of it and take my biases out of it, of, of what I [00:16:00] want to see, and instead ask a computer within this, this field of data. Several hundred patients, several hundred biomarkers are patterns emerging, and we, we’ve now been trying to apply that to, to a couple more focused diseases.

And, and I’ve got a fantastic collaboration here in Calgary. Not quite as, as severe as ICU sepsis, although some of the patients end up there is appendicitis and, and we’ve picked up multiple biomarkers, particularly in pediatric cases where the patient is nonverbal and, and really difficult to assess what’s going on.

We’re starting to, to pick up bio patterns that we can. Tell from a blood test whether a person should be prioritized for surgery or whether we can sit and wait on that patient. 

Nicole Kupchik: Yeah, because, and there’s been so much controversy over that in the last 10 years, especially about appendicitis. 

Dr. Craig Jenne: Yeah. 

Nicole Kupchik: You know, do these patients need to go to surgery right away or can we wait?

Dr. Craig Jenne: Especially with the little kids, right? I, I mean, here we’re, we’re pretty fortunate in Calgary. We’ve got a good track record and still, you know, there are a percentage [00:17:00] of patients that we go in and the appendix is per perfectly healthy. Likewise, there’s a few patients that, you know, we think are okay, and, and, and we we’re, we’re observing and we end up with a perforation.

So, um, those ones, you know, tragically end up, uh, as septic patients in, in many cases. So this is a, a great opportunity of trying to understand that, that inflammatory landscape as a whole, and not just, you know, picking our favorite molecule and say, can we use the, the, the body’s, uh, information as a whole to predict who we, we need to address right away.

Nicole Kupchik: Okay, so I wanna talk a little bit about the liver. 

Dr. Craig Jenne: Hmm. 

Nicole Kupchik: You’ve done a lot of work with the liver. That’s right. You like the liver? 

Dr. Craig Jenne: I like the liver, yes. 

Nicole Kupchik: Yeah. And you know, it’s fascinating. One of the things I know I always get, I get on these like little kicks and uh, you know, it’s just so many patients who have septic shock.

Now I’m talking humans who have septic shock, uh, have shocky liver and they have elevated liver enzymes and we’re not like routinely checking them. So [00:18:00] let’s kind of flip the tables a little bit. Let me ask like, what are your thoughts and then what are you seeing in the lab? On just the liver’s involvement or maybe the liver taking a hit in the setting of sepsis and septic shock.

Dr. Craig Jenne: Yeah. I mean, so, so liver, we could, we could have, you know, a, a podcast for multiple days on the liver. Uh, you know, the, the, the liver’s, one of those, those organs that, that I, I like to, you know, cause a little controversy. I, I get invited to some hepatology meetings and, and I, I always try to argue that the liver is actually a primary immune organ that just does some metabolism on the side.

Okay. Um, it, it is truly our barrier. Right? Our, our liver has got more macrophages. Per unit weight than any other tissue in the body. Those macrophages live directly in the bloodstream. They capture pathogens that come in from our gut, you know, everything we had for lunch, whatever’s getting across that barrier our liver deals with, and it, it does a remarkable job of determining [00:19:00] should we react or should we ignore it or immunosuppress.

It’s, it’s this wonderful immune environment. And because of that, because it is, it, it really is that interface of blood and, and interstitial tissues, all pathogens in the blood interact with the liver and, and, and the liver becomes that, that frontline of the fight between the immune system and the pathogen.

We’ve been quite fortunate that, that our intra vial microscopy can dive deep into the liver. We see cou for cells, grab pathogens, eat them, recruit neutrophils, platelets adhere. The whole process plays out right in front of our eyes in real time in the liver sinusoid. And the liver’s really been that, that classroom that we’ve learned a lot about immuno thrombosis, uh uh, and, and the interaction of platelets nets and ssis.

Nicole Kupchik: Okay. That, that is like wild that you’re able to see that on a cellular level. So let’s, let’s hold that thought, because I wanna come back and talk about this. Actually, [00:20:00] I wanna dive in a little deeper because this is, I’m like totally nerding out right now. I’m so excited. So we’re gonna go to, we’re gonna take a break.

Perfect. Just a super quick break and we come back, we are gonna dive a little bit deeper into the liver and talk about these cells that are like doing really cool things. And you know, it’s fascinating. I never thought of the liver as being a big immune. 

Dr. Craig Jenne: Oh yeah, it, it’s just a really meaty spleen. 

Nicole Kupchik: Okay.

All right. Well, let’s go on break and when we come back, let’s chat about it.

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And now back to the show.[00:21:00] 

All right. Welcome back to the show. So, Dr. Jenne and I are gonna type a little deeper. I’m, I’m like loving this topic right now. Okay. So let’s go back to the liver because we know the liver is a massive filter. It’s a massive metabolizer. It produces proteins and or synthesizes proteins. Um, it plays a huge role in coagulation.

Okay, so let’s. Talk about what you’ve seen clinically in these models, these animal models. So I honestly did not think of the liver as being a big, I just playing a huge role in our immune response. Mm-hmm. So let’s just talk a little more. When are you seeing the liver more on overdrive? Is it with bacterial, viral, fungal infections, or It doesn’t seem really, seem to matter.

Dr. Craig Jenne: Doesn’t seem to matter. Like as soon as something is in the blood. It finds the liver and, and the liver, for example, with bacteria are capturing them within seconds. So first pass through the liver, [00:22:00] the coup for cells, the, the resident macrophages are grabbing pathogens. So we could inject, uh, you know, uh, five times 10 to the seven, five times 10 to the eight bacteria.

And within a matter of a couple minutes, there’s none left circulating. And it’s all been, been caught and sequestered by, by the immune cells in the liver. 

Nicole Kupchik: And like, I don’t mean to sound dumb, but like what do these cer cells do with the bacteria? 

Dr. Craig Jenne: Oh, I, yeah, I mean, th this is, this is the, the fascinating part is, is they are really the, this, this decision making infrastructure where they, they filter the, the pathogen outta the blood.

They can go ahead and then internalize phagocytose and kill it, but it, it’s a cooper cell that seems to be the master regulator are of, are we gonna engage adaptive immunity? Are we going to. Build a response or are we gonna. Be tolerant to this. Ha have we cleared the threat? And, and we can tone down the inflammation.

And it seems in, in the [00:23:00] septic models that that things rapidly escalate. That once the Cooper cells have, have caught and captured bacteria within that first hour, we start to see neutrophil infiltration into the liver. Um, adherent neutrophils become these, these landing pads that we see massive platelet aggregation.

Different than a clot, but, but these loose aggregates of platelets and, and those then communicate with the neutrophil and, and platelets binding to the neutrophil trigger other functions such as net release. And it’s this really interwoven network of Cooper cells, neutrophils, and platelets that drive inflammation in the liver.

Wow. 

Nicole Kupchik: Now, one of the things we see clinically in humans is we see low platelet counts. 

[music]: Mm-hmm. Especially 

Nicole Kupchik: in ours. Sicker septic patients. Mm-hmm. And we often look at that as basically a marker of severity, uh, or even of like organ dysfunction when, uh, platelet counts drop. And we know that there’s phagocytosis of platelets, but how do we make that tie?

Like, why are we seeing [00:24:00] such low platelet counts and really sick patient. 

Dr. Craig Jenne: Yeah, there, there will be some platelet phagocytosis, some platelet death, but much of it, at least within, within our animal models is sequestration. So we could measure animals becoming thrombocytopenic within, you know, three to four hours, uh, uh, of an IV bacter remic model.

And if we look in the lungs and we look in the liver, they are packed full of adherent platelets. So the, the, these circulating cells. Have actually started participating in that immune response. And in the liver they could do things such as forming aggregates and shells around the bacteria to try and wall them off.

They communicate with the neutrophils, they drive net formation, uh, and, and, and directly contribute to the pathogen clearance. 

Nicole Kupchik: Wow. I mean, it’s just so fascinating. So what, I mean, is there a tie between low platelet count? I know you’re looking at animal models, but I’m, I’m trying to kind of be the conduit back to humans.

Is it true or is this, [00:25:00] would this statement be true? That when patients drop their platelet counts and septic shock, that is a marker of the severity of their illness? 

Dr. Craig Jenne: In our animal models, it absolutely is. Once platelet counts start crashing it, it’s a strong indicator that we’re seeing these massive leukocyte platelet pathogen aggregates within the micro vasculature.

And again, that can be the liver. We, we know what happens in the lung as well and in some models in the brain. Um, but, but it is more than just this passive platelet aggregation or thrombotic, uh, or pre thrombotic kind of events. Depending on the pathogen. So, so we’ve, we’ve published data showing that some bacterial models, if the platelets are absent, when those cooper cells capture them, the mice will die.

And, and the platelets are critical at a, actually forming a bit of a protective shell and walling off the pathogens. Um, in the absence we see endothelial cell death, we see vascular leakage. We see a rise in hematocrit suggesting, again, fluid loss through the vasculature and, and the mice don’t [00:26:00] do well.

Nicole Kupchik: Oh, fascinating. Okay. This is, I’m, this is like all mind blowing to me because, you know, again, clinically I think we’ve been, you know, I’ve been doing this for three decades and we’ve been searching for the holy grail in sepsis, and I think, you know, it’s just, it’s not one thing, it’s, 

Dr. Craig Jenne: no, 

Nicole Kupchik: it’s everything working in concert.

No, like, one 

Dr. Craig Jenne: of the dilemmas we, we, we try and ask in the lab is, is that question about once. Person, animal becomes thrombocytopenic. Is there value in bringing platelet count back up and, and you know, we, we know platelets are protective. We, we obviously have to maintain hemostasis, but if the platelets are also driving inflammation, if the platelets are, are driving immuno thrombosis.

You know, do, do we, do, we essentially add more fuel to the fire by, by bringing platelet counts back up. And, and I think the question really is gonna depend on, on that, that hemostatic risk. If the, if the individual’s not bleeding, perhaps they tolerate lower platelets for, for a short term. Yeah. Um, but if they’re bleeding, you know, we [00:27:00] obviously have to deal with the acute problem first.

Nicole Kupchik: Yeah. Well, and I think the other thing that is, so. Extremely complex is you’ve got this liver that’s acting as an immune machine, and then on top of it that liver is often hypoperfused. 

Dr. Craig Jenne: Yeah, so, so our, our imaging and, and data is, has been very clear that these, these platelet neutrophil net, uh, aggregates drive local thrombosis.

We do see clots, we do see fibrin, uh, containing clots within the microvasculature, and we can measure areas of the liver that are no longer perfused. So these are areas where if we put a, uh, a contrast agent in, we do not see perfusion through these islands in the liver and can actually track hepatocyte death in those areas.

And those, those islands correspond directly to rises. For example, in a LT if we intervene, if we block that clotting, so whether it be argatroban or we added DNAs, that that actually completely short [00:28:00] circuits the immuno thrombosis, the, the liver doesn’t seem to, to demonstrate that damage nor do the kidneys.

And despite the, the, the animals still fighting the same pathogen load, still has the same neutrophil recruitment, eliminating those ischemic patches seems to be highly protective in preventing liver damage, liver death. 

Nicole Kupchik: I’m just sitting here, just totally dumbfounded. This is so fascinating. Okay, so making that clinical connection do, do you foresee studies that are going to maybe in a randomized control trial in the right patient population, evaluate drugs like our ban.

Dr. Craig Jenne: I mean, we’d like to see that we, we are still learning, right? Yeah. And we are, you know, the, the, the problem is for every good idea, there’s, there’s eight or nine critical ex exceptions to the rule, and we’ve been dealing with some respiratory viruses and, and molecules that interrupt, uh, coagulation and severe viral infection, for example, are highly protective.

But that exact same virus given [00:29:00] at a lower inoculum, a lower challenge, so a mild infection. Those, uh, tho, those, those molecules that interfere with the coagulation cascade actually convert our mild infection to a lethal infection with, with, with mild viruses, so, oh, okay. Yeah. It’s one of those ones that, you know, we, we joke around or I, I joke around that it’s a great tool eventually if we can get these into clinic because.

If a, uh, if, if my kids complain that they’re too sick to go to school today, I can tell them I’ve got a drug that’ll cure you if you’re really sick. But if you’re lying, look out, 

Nicole Kupchik: you’re gonna get in a lot of trouble. That’s right. Oh man, it’s so fascinating. Okay, so let me ask you this one. Are, so you’re still working in the lab?

Dr. Craig Jenne: Mm-hmm. 

Nicole Kupchik: What are you excited about coming down the pike, let’s say like in the next decade? Because let’s be honest, research takes a while, right? 

Dr. Craig Jenne: We’ve seen some really wonderful advances in in, in areas such as [00:30:00] nanomedicine, where we could take some conventional, you know, uh, therapies, argatroban, for example, and we can re.

Formulate that in a context where it is, uh, targetable. So, so we could iv administer a, a broad acting drug, uh, a thrombin inhibitor, but the way it’s packaged, it only gets released at specific sites in the body. So we might be able to functionally uncouple again, hemostasis, where we’re getting sort of extrinsic thrombin activation.

From immuno thrombosis where there would be neutrophils and nets and, and a different context. So we, we we’re, we’re quite excited about the, the concept of being able to develop context dependent drugs that only become activated within a specific environment and not globally. We’re also quite excited about.

We’ve often approached things such as immuno thrombosis, as just, these are procoagulant events, so, so thrombin activation, platelet participation. We tend to ignore the other side that the, [00:31:00] the, the actual fibrinolysis, and we’re slowly learning a lot more about how things such as plasmin are regulated during inflammation and how structures such as neutrophil traps might again, modulate that.

Clinically what we’re seeing may not be just a prothrombotic event. It may actually be a combination of, of we generate a little bit of thrombin and then we don’t clear the, the, the, the small plots or, or small thrombin that are made and, and things snowball from there. So looking at both that, that, that, uh, lytic side, but also critically, these context dependent drugs, I think are, are very exciting and, and offer a great deal of potential in the future.

Nicole Kupchik: Yeah, I, I’m excited. Just understand like what you find in the future. I know, I know all this is gonna take time and to really drill down, but, um, you know, I just feel like I, like I said, I’ve been doing this three decades and I feel like we’ve made some headway in treatment of patients who have sepsis, but I feel like there’s just so much [00:32:00] more to learn.

Dr. Craig Jenne: Yeah. 

Nicole Kupchik: And I, and I think that just speaks to the high complexity of the disease. 

Dr. Craig Jenne: Yeah, I, I mean, I, I know it’s so simple to say and, and so, so, you know, off the cuff, but, but this concept of precision or personalized medicine re really has to be embraced in, in that, you know, we’ve known, as you said, for decades now, not all septic patients are the same.

It seems to be a lot of therapies are simply based on, on symptom support or, or end product support, and not diving into the unique mechanisms that, that each patient may be experiencing in the past. That that concept of personalized medicine may, may have very, very much alluded us because of cost and time and, and, but today, I mean, we can, we can generate more data than we could possibly analyze in a matter of minutes to hours.

And being able to embrace these large data sets, machine learning and, and, and the idea of, of looking at the pictures a whole and not one molecule or one [00:33:00] cell, I think is gonna open an awful lot of doors for, for tailoring even therapies we have today, but tailoring it to the right patient at the right time for for better outcomes.

Nicole Kupchik: Yeah. All right. Well, I’m excited to see, uh, see what the future holds. Well, I just wanna thank you for joining me today. Um, I’m just, I’m really excited that there are people like you in this world who like to do this type of research. ’cause I, it is so important and, you know, we’ve gotta start somewhere and you’re, you’re definitely at the foundation of just building the science that we need to advance, we’re doing clinically.

It’s absolute a pleasure to 

Dr. Craig Jenne: chat with you today. I mean, yeah, this is. It, it’s fun that after 20 plus years it’s still exciting every day. 

Nicole Kupchik: That’s, that’s amazing. That is awesome. So, alright, well just thanks again Dr. Jenne for being here today.

I had so much fun talking with Dr. Jenne about the work that he’s doing in the lab and specifically [00:34:00] looking at the liver and the immune response that the liver plays a role, which I’ll be honest, I had no idea that the liver did so much when we’re infected. I had no idea, and I think it was just fascinating to talk.

Through like exactly what the liver is doing in the cup for cells and platelets, basically attacking the bacteria that is invading the body. So, just fascinating work and you know, and I, the question we always ask is, you know, how is this gonna drive future research that would help patients at the bedside?

So super exciting stuff. Thanks for joining me on today’s episode of the Sepsis Spectrum. If you have a story you want me to read on the air. Visit www.humancontent.com/sepsis. And if you’re enjoying the sepsis spectrum, we wanna hear about it. Please leave a review wherever you’re enjoying this podcast.

It helps a ton. You can also reach me in our awesome [00:35:00] team@infoatsepsis.org or visit sepsis podcast.org to share any stories of your own. Questions, concerns, or episode ideas? To learn more about Sepsis Alliance, visit sepsis.org. The sepsis spectrum is brought to you by Sepsis Alliance. I’m your host, Nicole Kupchik.

Our executive producers are Alice Strickland, Hannah Sass. Claudia Orth and Alex Colvin. Our producers are Aron Korney, Rob Goldman, s Shahnti Brook, and me Nicole Kupchik. Our post-production producer is Sundus Hassan Nooli. Our editor and engineer is Jason Portizo, and our music is by Omer Ben-Zvi to learn about.

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