When a working dog is seriously injured far from veterinary care, getting plasma to the patient can be a problem of logistics as much as medicine. Fresh frozen plasma can help control bleeding, but it must be kept frozen and thawed before it can be administered.
Canine freeze-dried plasma (cFDP) takes a different approach. The plasma is freeze-dried and can be stored without a cold chain, then reconstituted when needed. The technology, developed by Mantel Technologies, based in Fort Collins, Colorado, was developed with working dogs and austere environments in mind, but its potential uses extend beyond the battlefield.
In this Q&A:
- How clinicians should interpret the hypersensitivity reactions seen in cFDP safety studies
- Which dogs were not included in the cFDP safety and efficacy studies
- What changing the plasma's reconstitution volume could mean for traumatic brain injury and low-volume resuscitation
- How military working dogs receive medical care from the point of injury through evacuation and definitive treatment
- Where cFDP could fit in civilian veterinary care, including pre-hospital and emergency settings
- What Mann sees as the next steps toward shelf-stable blood products for dogs
The product is one of the latest projects to come to life for Kelly Mann, DVM, MS, MSS, DACVR, a veterinary radiologist at Colorado State University and retired US Army Veterinary Corps officer who now serves as vice president of veterinary solutions at Mantel. Mann, whose research centers on working dogs, spoke with dvm360 earlier this year about the research behind cFDP, the hypersensitivity reactions observed in safety studies, and what the product could mean for veterinary trauma care.
Editor's note: This dvm360 Q&A has been lightly edited from a verbal interview.
dvm360: Can you introduce yourself and your background?
Mann: I'm Dr Kelly Mann. I'm a veterinary radiologist. I had a career in the US Army Veterinary Corps, where I was a veterinary specialist and clinical radiologist, and then after I retired from the Army, I returned to where I had done my residency, which is Colorado State University. So I live outside of and work in Fort Collins, Colorado. My goal there was to explore being involved in working-dog-related research, but as a clinician, I didn't really know what that meant. I was given an opportunity by some of my previous mentors here at Colorado State and over the last 12 years, I've developed a research portfolio centered mostly around working-dog-related projects. What we're going to talk about today is the latest one that has come to fruition: canine freeze-dried plasma.
dvm360: What is canine freeze-dried plasma, and how does it relate to fresh frozen plasma?
Mann: What canine freeze-dried plasma really is, is FFP [fresh frozen plasma] that you can reconstitute at will. Our experimentation was based on establishing the bioequivalence of canine freeze-dried plasma to the source fresh frozen plasma, and also the safety and efficacy of that product in that it provides the same efficacy as giving FFP. As it is today, the cFDP product is reconstituted with sterile water for injection, and that's 250 mLs. So basically, when you reconstitute that, you have a unit of plasma of 250 mLs.
dvm360: In cFDP safety studies, hypersensitivity reactions occurred in roughly half of dogs. How should clinicians interpret that in context, and what protocols or premedications are recommended?
Mann: As with the administration of any blood product, you can have transfusion reactions. The types of reactions reported in our safety and efficacy data are type I hypersensitivity reactions—hives, some facial swelling, some nausea, occasional vomiting.
I can tell you what I know and what I don't know. Our safety and efficacy studies were not set up to track in depth the immunological response. We were physiologically monitoring the entire time, but our additional laboratory data focused on some histamine testing, which was limited, and C-reactive protein was our primary marker of inflammation.
The reason I say it's what I know and what I don't know is because we were focused on C-reactive protein, which is a really good marker of inflammation, but it's a slightly delayed elevation, whereas histamine is a very acute elevation. Looking back at my data, I can't tease out a lot of information on histamine because it's such an acute inflammatory response with the histamine response. My serial blood collection—designed to support each of our hypersensitivity, coagulopathy, and hypovolemia studies—was not frequent enough to provide the best information on histamine. It provides great information on what was going on with C-reactive protein in the dogs.
Our dogs were also tracked for 24 hours after administration of plasma, so we know we didn't have delayed transfusion reactions. But for what was going on with the mild hypersensitivity reactions we saw with transfusion, I don't have a perfect answer for that.
What I will say is that I lean very heavily on the AVHTM [Association of Veterinary Hematology and Transfusion Medicine] transfusion guidelines. When you read through those, you'll realize I don't believe anybody has the perfect answer for what's going on with our transfusion reactions. But the good thing about the AVHTM is that in their publications that came out in 2021, they summarize the evidence for and against the use of antihistamines, glucocorticoids, and epinephrine, and they provide a really in-depth review of many important considerations for patient monitoring. As always in research, they argue for the use of shared definitions that'll help guide our categorization and research of transfusion reactions in the future.
The reason I started out by saying I don't know that I have the perfect answer for exactly what was going on in my small population of patients is because we were able to characterize our freeze-dried product in vitro and compare it directly to the fresh frozen plasma it's derived from. In these in vitro studies—which included both flow cytometry and proteomics—there were no differences between the source fresh frozen plasma and the reconstituted freeze-dried plasma made from that source plasma.
So, the product itself doesn't seem to be causing the reaction. To me, it is a hypersensitivity immunologic response in the patient, of which my data collection wasn't perfect for tracking the immunology of that response, but we did rule out the major transfusion reactions you could see, which we saw none of that in our patients.
dvm360: Are there specific patient populations in which cFDP should be used with extra caution?
Mann: If your patient requires the administration of plasma, then in some ways cFDP, when reconstituted, is FFP. But all veterinary professionals also know that no blood products are given entirely without risk. Under our FDA [risk review] for cFDP, we did not test our product in dogs that were less than 2 years of age, were in breeding programs, or were pregnant or lactating. In our safety and efficacy studies, the majority of our dogs were spayed females, adults, things like that. So on the one hand, you wouldn't deny plasma to any of those patients if they were presented to you, but we did not specifically evaluate those patient populations.
The other contraindications, warnings, or precautions you'd take into account with cFDP are the same as for all blood products. If your patient has a history of hypersensitivity to the administration of other plasma or plasma-derived products, they would be at higher risk. Blood products must always be administered through a filter. These are the same precautions. And then they're not exactly the same because plasma is acellular, so there are some types of reactions that should not be part of the risk for a patient receiving plasma versus a patient receiving a cellular product. Other than that, during administration, vigilant monitoring for any type of transfusion reaction [is important].
One thing I'd like to mention again is that I considered this question in light of the AVHTM guidelines and consensus statement published in 2021. Throughout each of parts 1, 2, and 3 of the TRACS [Transfusion Reaction Small Animal Consensus Statement] guidelines, they do mention specific patient considerations that came up in their evidence-based review. I believe those guidelines are well worth a reread by clinicians because it reiterated in my mind what the standard of care is when we're using blood products in general.
dvm360: You'll be presenting at the International Veterinary Emergency and Critical Care Symposium in September. Your session notes mention a possible therapeutic effect of cFDP on elevated intracranial pressure in patients with traumatic brain injury and polytrauma. Can you speak more about that?
Mann: I want to start by saying that my comments about the use of hyperosmotic plasma [are] research only. I need to make sure our viewers are aware that currently the only [FDA risk-reviewed] indication for cFDP is for its use in the treatment of hypovolemia and the control of hemorrhage in dogs, and cFDP is supposed to be reconstituted as directed, which is with sterile water for injection. I don't want to appear to tell people to do things off-label.
What I am advocating for though, is the following: prior to cFDP's availability, you could not give hyperosmotic plasma.
What I'm going to share—both in a peer-reviewed manuscript that's in draft form right now, and at the presentation at IVECCS in September—is our in vitro findings that show the properties of the freeze-dried plasma product when you vary either the concentration or the reconstitution fluid being used.
As it is today, cFDP is reconstituted with 250 mLs of sterile water for injection. So when you reconstitute that, you have a unit of plasma of 250 mLs. But if we think about what would happen if you reconstituted with half that amount—125 mLs—then you have doubled the concentration of the plasma proteins in that cFDP.
So, we studied in vitro what happens to your major plasma proteins like fibrinogen, factor V, and factor VIII, and also what the osmolality of that is.
That leads back to your original question. Hyperosmotic solutions are often used in the treatment of elevated intracranial pressure in TBI [traumatic brain injury] or other traumatized victims.
This opens up, in my mind, a whole new world where clinicians would now have the possibility of having a hyperosmotic natural colloid, and that becomes very important in several special patient populations.
One, you already brought up, which is TBI, specifically in the treatment of elevated intracranial pressure.
The other would be low-volume resuscitation protocols.
If you think about at-risk patients that could very easily be volume overloaded, then the ability to decrease the amount of volume you need to give in order to get the same amount of plasma proteins into your patient opens up some exciting possibilities.
dvm360: You spent two decades in the Army Veterinary Corps and directed a major military working dog hospital. What does medical care for a military working dog look like in deployed environments—who is responsible, and what resources are available?
Mann: If you think about the military approach to military working dog medical care, it actually starts with the handler. For many years, the handler has been considered the first responder who's going to be there at the point of injury with the dog. Depending on the working dog program the handler was associated with, different levels of medical response were taught to that handler, initially in their training and also throughout their career. It builds on itself, like any profession.
From the point of injury, the next medical professional that dog-handler team may come in contact with is more than likely going to be a human care provider—if you think about medics at the platoon level.
As you try to take your traumatized military working dog, stabilize them, and move them into higher roles of care for definitive treatment, you're going to go through first medical evacuation to a role 1 or role 2 level facility.
The US military does deploy medical detachments focused on veterinary service support, so we do provide veterinary medical care on the battlefield. However, you can't be everywhere.
If you think about a hub-and-spoke system, the people on the farthest reaches feed back to larger and larger operating bases, and our hospital capabilities, as well as the human hospital capabilities, are going to be located on those bases. Ultimately you'd be moved out of that theater of operations to a fixed facility—depending on where you're located, Germany, Japan, or back in the United States in Texas, or another major military veterinary facility.
So the handler is taught initial care of the canine injury, then they seek medical care. That medical care is going to put them into the medevac lanes that eventually get them to the veterinary medical detachment, but along the way they may see other human care providers. There are military working dog clinical practice guidelines used in the military that help define the scope of practice for human care providers who come in contact with military working dogs in this scenario.
The ultimate goal is to get that dog into the veterinary medical detachment to receive definitive veterinary care, and either be returned to duty in that theater or be strategically evacuated to our larger fixed facilities in order to receive their final definitive care and get back to their home station.
dvm360: One advantage of cFDP is its lower weight and easier storage compared with traditional liquid plasma. How important are those factors in field treatment decisions?
Mann: I believe cFDP and other products like it are vital to the provision of care in far-forward locations or under austere conditions. Our research and development objectives were driven by the need to create a species-specific freeze-dried plasma product that would retain the coagulation proteins, did not require cold-chain storage, was ready for immediate use, was shelf stable, and could not be stored in glass. When you think about transport, weight and cube are huge. When you start meeting those objectives, it allows you to have that [closer-to-injury care]. Pre-hospital care on the civilian side, and point-of-injury care on the military side, becomes a real consideration.
It's a dangerous environment in the military working dog world, and hemorrhage was involved in more than 80% of the non-survivors in one review of military working dog trauma.
So the need for not only canine freeze-dried plasma but other blood products in these far-forward, austere areas closer to the point of injury is very real for dogs in these operational environments.
I would extend that to law enforcement and search-and-rescue canines. When you think about the dangerousness and the types of injury, as well as the austere conditions where search-and-rescue dogs really work, both of those combine to make the ability to deploy blood products without a cold chain, closer to the patient that requires them, very important.
dvm360: How does that continuum of care translate to the civilian side?
Mann: When you talk about the provision of far-forward care and austere-environment care, my research was funded by the military, but I wanted to be able to say that the cFDP product actually allows the administration of fresh frozen plasma on demand to initiate care at the point of injury, but in the civilian world, that's also called pre-hospital care.
You're seeing that more and more in the human medical approach to trauma care, and now it's coming to fruition, in my view, in veterinary medical systems as well.
So not only is it useful very close to the point of injury in pre-hospital care, but on the military side during prolonged field care while you have delayed access to medevac, and it can be used when you're receiving definitive in-hospital care.
These use-case scenarios fit not only the military operational environment but also the provision of veterinary care here in the US.
A couple of examples: you have a small clinic or a satellite hospital that has reduced staffing or reduced ability to operate its own blood bank. And even in level 1 veterinary trauma centers, cFDP may be able to be used as the first unit of plasma administered while you're coordinating for additional plasma or other blood products and therapeutic interventions for that patient. So those are a broader-spectrum view of not just focusing on the austere environment, but more of a continuum of care all the way through definitive care.
dvm360: There's a long history of freeze-dried plasma in human trauma medicine. What practices have carried over into veterinary use, and where are the strongest overlaps between human and veterinary trauma care today?
Mann: That's a great question, and this is an exciting time because there's a broad range of research going on in this area. The pursuit of a shelf-stable whole blood analog is really where things are going. That's exciting because canine freeze-dried plasma is just a portion—it's only one piece of the puzzle of what you'd consider a shelf-stable whole blood analog for canines.
What's exciting to me is the new patient therapeutic options that are going to emerge because of new form factors like lyophilization of plasma, or the novel products in the pursuit of this whole blood analog are going to spin off into synthetic cell production, or even molecular mimetics of different blood components.
Translational research efforts very definitely work to the benefit of both human and veterinary patient populations in this pursuit.
In my work, I seek to support rodent, porcine, and canine trauma research protocols, and that's because each of those informs and advances human patient care, as well as affords us specific veterinary product development and availability for our patient populations.
That's how these puzzle pieces fit together. I'm also excited that along the route of that research and development, there are multiple opportunities for the development of new veterinary blood products available to our community.
dvm360: What would successful adoption of cFDP look like 5 to 10 years from now?
Mann: Currently, in the absence of a whole blood analog or the accessibility of whole blood for your patient today, I think cFDP is the point-of-injury or pre-hospital standard of care for professional working dog organizations, especially those that deploy in dangerous or austere environments. Military, law enforcement, and search and rescue are at the top of my list.
That's what I would see as success, is those working dog organizations would see not only freeze-dried plasma, but other products that are going to emerge in the next couple of years, as the standard of care for their dogs.
Then, I believe the veterinary profession should support continued research and development of therapeutic protocols that lead with the administration of natural colloids, specific component therapy, or—when available—a whole blood analog, based on the pathophysiology of the traumatic injury and other disease processes.
We've seen a shift over the years between the initial use of crystalloids and now a heavy emphasis on the administration of, especially, whole blood when available, or component therapies. And what we're learning through all this research and development is that there are specific pathophysiological reasons why you might want to choose plasma for certain patients. My best example is the effect that sepsis, trauma, and other things have on the endothelial glycocalyx, which seems to be better supported through the administration of plasma versus other potential resuscitation fluids. I'm excited that as more research is done in this area, we can more specifically attack the root cause of what's leading to the potential death or morbidity of our patients.
Mann on the people behind the research
