Clotting and coagulation disorders in cats

Kelly St Dennis: Welcome everyone. I am Dr Kelly St Dennis, co-editor of The Journal of Feline Medicine and Surgery and JFMS Open Reports. I am here today with Dr Joseph Evans and Ronald Li from North Carolina State University, and we are talking about their recent clinical spotlight article in JFMS. Clotting and coagulation disorders in cats, a clinical review of causes, diagnosis and management. Welcome to both of you. Thank you for joining me. Before we get started, I did wanna say thank you so much for writing this article for us. It is such a nice, practical article that will be really helpful for people in general practice to use, just to read it in general, but also have as a reference article in their practice. We're talking about coagulation disorders. So for all of us out here who don't always think about these things as much as you guys do, I wondered if we could just go through a little refresher on the three phases of haemostats in the traditional models, the primary, secondary, tertiary, maybe Dr Evans, you wanna take this one? Joseph Evans: Yeah. Yeah. So generally when we think about the traditional model, there's three phases. Primary haemostats, secondary haemostats, and then the last part is tertiary haemostats. And it's more of a model that helps us conceptualise how haemostats works rather than like these different chains in the body 'cause they're all happening all at the same time at different speeds. But for things like primary haemostats, I think a, a good way to think of it is just peas, right? So P primary is like platelet plug. So that's where we generally have our platelet formation and aggregation. So that comes in three steps. So you have adhesion of platelets, activation of platelets, and then aggregation of platelets. And we can get like pretty deep into the physiology, like the, the biochemistry of it, but like really what it is that there's a, like you just have some sort of insult, some sort of activation for the platelets which become activated then begin to aggregate. Kelly St Dennis: That includes the Von Willebrand factor (VWF), right? So that's the factor you're talking about that's helping to activate those platelets. Joseph Evans: Yeah, exactly. Then like secondary haemostats, in the traditional sense, it's the like this cascade model. So it's all our clotting factors that work together ultimately to form a form fibrin clot, like helping attach to those platelets that become activated and really the ultimate goal of secondary haemostats is to form fibrin. You have the two pathways, the intrinsic and extrinsic. Both of those have like different activation, like the extrinsic pathway is our factor 7 that then comes in contact with like tissue factor, is just becomes activated and starts off this whole cascade. When we think about the intrinsic pathway, so our like 12, 11 factors to get down to factor 10, that is a, the amplification pathway. So we start to see that like once the intrinsic pathway becomes activated and activate itself again, and that's really where that cascade model comes from, is just factors begin activating factors, begin activating more factors from one single stimulus, just a massive activation of clotting factors very quickly rather than just a slow process. And then, yeah, again, like ultimately the product is fibrin. So that's fibrinogen into fibrin, which is factor 1 into 1A is all down from 12 to 1. However, the last part of the traditional model is fibrinolysis, or the tertiary haemostats. So that's once we start to form clots from the platelet plug and the cascade, clotting factor cascade, we then have to break it down. Otherwise the blood would just become one big clot. So it's really involving plasmin mediated breakdown fibres, so the like, things like tissue plasminogen activator, urokinase, like different molecules in the blood are both breaking down the bonds between fibrin and helping loosen up those clots as well as independently inhibiting different clotting factors when they become activated by the activation of clotting factors. Kelly St Dennis: Good. Thank you. When we talk about coagulation disorders, a lot of us think about bleeding disorders, but of course the article also talks about hypercoagulable disorders. And Dr Lee, this might be an area that you wanna talk about, is how common these are and you mentioned HCM in cats as one of the potentially related issues. Do you wanna just talk a little bit about hypercoagulable disorders in cats and what we're looking at there? Ronald Li: Yeah. This is my area of interest, and I'll try to be brief, but cats are really unique compared to other species. The reason why I love studying platelets in cats is because I think if you think about them being carnivores and subject to injuries, it's an evolutionary advantage for them to have very activated platelets and so in that sense, studying the platelets is really fun because they evolved to have these hyperreactive platelets. Unfortunately, that also translates to thrombotic disorders and how common is it, if we think about HCM, we think about one in seven cats, right? The numbers might make higher in older cats and out of those HCM cats, we're thinking about 11% of them having complications manifested as thromboembolism or clot formation. The most common word is when saddle thrombus, we call it, right? But we now also recognise that thrombosis can also manifest as a stroke-like event. So based on our recent studies, we found that a lot of cats have acute neurologic signs, deterioration, sudden death. We don't always think that they have arrhythmias. But it could be acute CNS thrombosis, like stroke-like symptoms. And apart from HCM, I think another disease that we commonly see that manifests as thrombosis in cats is neoplasia, particularly pulmonary carcinoma. Second most common, arterial thrombus in cats, and then heartworm disease and other types of neoplasia. So arterial thrombosis, I would say by far is the most common in cats, and mainly because of the activated platelets. Compared to humans and dogs, they probably less likely to have venous thrombus. Something like pulmonary thromboembolism is less likely, I would say in cats. Kelly St Dennis: Okay. Thank you. And I know with HCM, and I'm sure you can talk about this a little bit, is we're looking at that two-pronged medical approach to treating those hypercoagulable disorders, platelet inhibition drugs, and clotting factor inhibition. Ronald Li: Mm-hmm. Kelly St Dennis: So do you wanna just touch on that a little bit? Ronald Li: That's a great question. Dr Evans did great job dissecting pretty much what we learned in school, right? Primary, secondary, and tertiary. And we learned it as separate entities. Kelly St Dennis: Yes. Ronald Li: However, during rounds, during CE lectures, I tell veterinarians that this doesn't exist inside the animal, right? Everything happens at the same time, and so the idea of two-pronged approach really is that inhibiting primary haemostats actually indirectly inhibits secondary haemostats and vice versa. And so because the outcome of ATE or saddle thrombus is so bad, right? The mortality rate is really high, we're still looking at 50%, right? 50% mortality in hospital, really high recurrence rate. Our effort really now is to look at what is the best prophylaxis or prevention at the time of diagnosis, right, before saddle thrombus kicks in, right, and the idea of a dual pathway inhibition a two-pronged approach where we're inhibiting primary haemostats, mainly by clopidogrel or aspirin, and then secondary haemostats using either heparin, low micro heparin, and more recently, a lot of research about direct oral anticoagulant and limited evidence that we have right now seems to favour dual pathway inhibition more than single pathway inhibition. And so in our practice, we usually would recommend dual pathway inhibition in cats that we think are at high risk of developing ATEs. So these are cats that have a very enlarged left atrium. When we see smoke or spontaneous cycle contrast and atrial fibrillation as well, although that's not very common, but when that atrial fibrillation, very high risk as well as intracardiac thrombosis. So there's a clot that we can see in the left atrium. Those are really high risk patients, and we would start them on dual therapy. Kelly St Dennis: Dual therapy. Okay. Thank you for addressing that. We're talking about platelets here to some degree, and I always call this elephant in the room, platelet clumping. You mentioned cats have hypercoagulable, or they auto aggregate quite easily and I know this is a problem I see. I'm a consultant on VIN and we often have people that are writing in and saying, this cat is love platelets, but it doesn't have any clinical signs. And we always say, oh, you need to go back and actually really check to see how much aggregation you have. So I just wondered if maybe Dr Evans can talk to why it is that this is happening and what kind of things that we do with our blood samples that predispose to this happening so that we could try to avoid seeing this occur so much in cats. Joseph Evans: Yeah, absolutely. I'd love to. So like Dr Lee was colluding to earlier, because cats, they just tend to have these hyperreactive platelets. Like anything, any sort of stimulus can get them to start activating and aggregating because like they aggregate, they activate with really such little stimulus that there are a lot of things that can cause like an astrogenetically low platelets, right? When we take a blood sample, even if it's run immediately, the cat is upset, it's activated, it's got high epinephrine response. It's freaked out, struggling. So the very first step of clinically normal, but low platelets on an analyser can be that there's just lots of agglutination and the platelet clumps that form just from a hard stick or the cat being stressed out aren't caught by like an automated analyser. Really, I'd say far and away the most common thing that like we see here in our ER here in all of our patients that we've got here, when they're everywhere else too. The other things are the sample. So sample handling, right? So if the blood sits for too long, even in the case where we put it in calcium EDTA, or like appropriately handle it, if the sample sits for too long, those platelets could still become activated, aggregate, and then become falsely low for analyser, as well as the temperature, right? If it's very hot or not put in the fridge or cooled down right away, then all of those cells, red blood cells, platelets especially, can still be metabolically active and still continue to aggregate and be well. So I'd say those are like the very big things for clinically normal. Hey, this is a really scary load platelet count on our analyser. That doesn't make sense. Ronald Li: Yeah. One tip that I commonly would tell practitioners is that, especially when they're doing automated count in their practice is, if their first count is low, place that tube of blood in the warmer, let the platelet rest a little bit for at least 30 minutes and recheck it again. Most of the time, the count will jump back up. It's, I cannot stress, and I know we certainly do it here in our practice, that always verify your platelet count with a blood smear. And so if you see clumps, then definitely your automated account is an underestimate. Kelly St Dennis: Okay, good, thanks. So I guess one of the last things, if you don't mind covering and whoever wants to take this one, just in regards to preparing samples to send them out for those tests in the external lab. I know there's some caveats to how, again, just like with platelets, how we deal with the sample. Do you wanna just talk about what we need to be careful with when we're doing? Ronald Li: Yeah, yeah, for sure. So no matter what, even if it's point of care versus sending it out, always make sure that the blood is filled to the mark that is indicated on the tube because of the 10%, right? It's the 10% citrate. So any alterations in the ratio of blood to citrate will affect your test because how we test these is basically recalcifying our samples, and so if there's too little or too much citrate, it will affect our results, and so really pay attention to those tubes. Even, they could be in the same size, but sometimes there's 3mls versus 1.8 versus 1.4, so really pay attention. A lot of reference laboratories also were very militant about how these are filled, and let's say you can't send the samples right away. What we recommend also is spinning this plasma down and immediately freezing it. And that would help to preserve a lot of the clotting factors for reference laboratory testing. Kelly St Dennis: Okay. Cool. Thank you again to both of you for this article, and I hope everyone checks this out. This, like I said, it's such a good reference article to have. I love having these types of articles in my practice, so if I can't remember something or I need a quick information when things are happening, these are really good. You guys have some amazing tables in here, talking about the different hemostatic disorders and this article really helps with that, so I appreciate it.